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IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Contents
Articles
Kidney
Renal function
13
Renal corpuscle
22
Nephron
24
Glomerulus
29
Bowman's capsule
33
Renal physiology
36
41
42
44
45
46
49
51
53
Ammonia
54
Urine
74
Clearance (medicine)
81
Blood pressure
85
Erythropoietin
100
Calcium metabolism
109
Fluid balance
113
Vasopressin
117
Aldosterone
128
Countercurrent multiplication
134
Osmoregulation
135
Loop of Henle
139
Water-electrolyte imbalance
142
Hyponatremia
143
Hypernatremia
149
Acidbase homeostasis
151
Acidosis
154
Alkalosis
157
Glomerulonephritis
159
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Interstitial nephritis
164
Diabetic nephropathy
166
171
176
178
Dialysis
185
Kidney transplantation
190
References
Article Sources and Contributors
199
204
Article Licenses
License
207
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
Kidney
Kidney
System
Artery
Renal artery
Vein
Renal vein
Nerve
Renal plexus
MeSH
Kidney
[1]
The kidneys are organs that serve several essential regulatory roles in vertebrate animals. They are essential in the
urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acidbase
balance, and regulation of blood pressure (via maintaining salt and water balance). They serve the body as a natural
filter of the blood, and remove wastes, which are diverted to the urinary bladder. In producing urine, the kidneys
excrete wastes such as urea and ammonium, and they are also responsible for the reabsorption of water, glucose, and
amino acids. The kidneys also produce hormones including calcitriol, erythropoietin, and the enzyme renin.
Located at the rear of the abdominal cavity in the retroperitoneum, the kidneys receive blood from the paired renal
arteries, and drain into the paired renal veins. Each kidney excretes urine into a ureter, itself a paired structure that
empties into the urinary bladder.
Renal physiology is the study of kidney function, while nephrology is the medical specialty concerned with kidney
diseases. Diseases of the kidney are diverse, but individuals with kidney disease frequently display characteristic
clinical features. Common clinical conditions involving the kidney include the nephritic and nephrotic syndromes,
renal cysts, acute kidney injury, chronic kidney disease, urinary tract infection, nephrolithiasis, and urinary tract
obstruction. Various cancers of the kidney exist; the most common adult renal cancer is renal cell carcinoma.
Cancers, cysts, and some other renal conditions can be managed with removal of the kidney, or nephrectomy. When
renal function, measured by glomerular filtration rate, is persistently poor, dialysis and kidney transplantation may
be treatment options. Although they are not normally harmful, kidney stones can be painful and repeated, chronic
formation of stones can scar the kidneys. The removal of kidney stones involves ultrasound treatment to break up the
stones into smaller pieces, which are then passed through the urinary tract. One common symptom of kidney stones
is a sharp to disabling pain in the medial/lateral segments of the lower back or groin.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
Anatomy
Location
In humans the kidneys are located in
the abdominal cavity, more specifically
in the paravertebral gutter and lie in a
retroperitoneal position at a slightly
oblique angle. There are two kidneys.
One is on each side of the spine. The
asymmetry within the abdominal
cavity caused by the liver typically
results in the right kidney being
slightly lower than the left, and left
kidney being located slightly more
medial than the right. The left kidney
is approximately at the vertebral level
T12 to L3,[3] and the right slightly
lower. The right kidney sits just below
the diaphragm and posterior to the
liver, the left below the diaphragm and
posterior to the spleen. Resting on top
of each kidney is an adrenal gland. The
upper (cranial) parts of the kidneys are
partially protected by the eleventh and
twelfth ribs, and each whole kidney
and adrenal gland are surrounded by
two layers of fat (the perirenal and
pararenal fat) and the renal fascia.
Each adult kidney weighs between 125
and 170grams in males and between
115 and 155grams in females. The left
kidney is usually slightly larger than
the right kidney.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
Structure
The kidney has a bean-shaped structure; each kidney
has a convex and concave surface. The concave
surface, the renal hilum, is the point at which the renal
artery enters the organ, and the renal vein and ureter
leave. The kidney is surrounded by tough fibrous
tissue, the renal capsule, which is itself surrounded by
perinephric fat, renal fascia (of Gerota) and paranephric
fat. The anterior (front) border of these tissues is the
peritoneum, while the posterior (rear) border is the
transversalis fascia.
The superior border of the right kidney is adjacent to
the liver; and the spleen, for the left kidney. Therefore,
both move down on inhalation.
The kidney is approximately 1114cm in length, 6cm
wide and 4cm thick.
1.Renal pyramid 2.Interlobular artery 3.Renal artery 4.Renal
vein 5.Renal hilum 6.Renal pelvis 7.Ureter 8.Minor calyx
9.Renal capsule 10.Inferior renal capsule 11.Superior renal
capsule 12.Interlobular vein 13.Nephron 14.Minor calyx
15.Major calyx 16.Renal papilla 17.Renal column
Blood supply
The kidneys receive blood from the renal arteries, left and right, which
branch directly from the abdominal aorta. Despite their relatively small
size, the kidneys receive approximately 20% of the cardiac output.
Each renal artery branches into segmental arteries, dividing further into
interlobar arteries, which penetrate the renal capsule and extend
through the renal columns between the renal pyramids. The interlobar
arteries then supply blood to the arcuate arteries that run through the
boundary of the cortex and the medulla. Each arcuate artery supplies
several interlobular arteries that feed into the afferent arterioles that
supply the glomeruli.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
The interstitium is the functional space in the kidney beneath the individual filters (glomeruli), which are rich in
blood vessels. The interstitum absorbs fluid recovered from urine. Various conditions can lead to scarring and
congestion of this area, which can cause kidney dysfunction and failure.
After filtration occurs the blood moves through a small network of venules that converge into interlobular veins. As
with the arteriole distribution the veins follow the same pattern, the interlobular provide blood to the arcuate veins
then back to the interlobar veins, which come to form the renal vein exiting the kidney for transfusion for blood.
Histology
Renal histology studies the structure of the kidney as viewed under a
microscope. Various distinct cell types occur in the kidney, including:
The renal artery enters into the kidney at the level of first lumbar
vertebra just below the superior mesenteric artery. As it enters the
kidney it divides into branches: first the segmental artery, which
divides into 2 or 3 lobar arteries, then further divides into interlobar
arteries, which further divide into the arcuate artery, which leads into
the interlobular artery, which form afferent arterioles. The afferent
arterioles form the glomerulus (network of capillaries closed in
Bowman's capsule). From here, efferent arterioles leaves the
glomerulus and divide into peritubular capillaries, which drain into the
Microscopic photograph of the renal cortex
interlobular veins and then into arcuate vein and then into interlobar
vein, which runs into lobar vein, which opens into the segmental vein and which drains into the renal vein, and then
from it blood moves into the inferior vena cava.
Innervation
The kidney and nervous system communicate via the renal plexus, whose fibers course along the renal arteries to
reach each kidney. Input from the sympathetic nervous system triggers vasoconstriction in the kidney, thereby
reducing renal blood flow. The kidney also receives input from the parasympathetic nervous system, by way of the
renal branches of the vagus nerve (cranial nerve X); the function of this is yet unclear. Sensory input from the kidney
travels to the T10-11 levels of the spinal cord and is sensed in the corresponding dermatome. Thus, pain in the flank
region may be referred from corresponding kidney.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
Functions
The kidney participates in whole-body homeostasis, regulating acid-base balance, electrolyte concentrations,
extracellular fluid volume, and regulation of blood pressure. The kidney accomplishes these homeostatic functions
both independently and in concert with other organs, particularly those of the endocrine system. Various endocrine
hormones coordinate these endocrine functions; these include renin, angiotensin II, aldosterone, antidiuretic
hormone, and atrial natriuretic peptide, among others.
Many of the kidney's functions are accomplished by relatively simple mechanisms of filtration, reabsorption, and
secretion, which take place in the nephron. Filtration, which takes place at the renal corpuscle, is the process by
which cells and large proteins are filtered from the blood to make an ultrafiltrate that eventually becomes urine. The
kidney generates 180 liters of filtrate a day, while reabsorbing a large percentage, allowing for the generation of only
approximately 2 liters of urine. Reabsorption is the transport of molecules from this ultrafiltrate and into the blood.
Secretion is the reverse process, in which molecules are transported in the opposite direction, from the blood into the
urine.
Excretion of wastes
The kidneys excrete a variety of waste products produced by metabolism. These include the nitrogenous wastes
called "urea", from protein catabolism, as well as uric acid, from nucleic acid metabolism. Formation of urine is also
the function of the kidney. The concentration of nitrogenous wastes, in the urine of mammals and some birds, is
dependent on an elaborate countercurrent multiplication system. This requires several independent nephron
characteristics to operate: a tight hair pin configuration of the tubules, water and ion permeability in the descending
limb of the loop, water impermeability in the ascending loop and active ion transport out of most of the ascending
loop. In addition, countercurrent exchange by the vessels carrying the blood supply to the nephron is essential for
enabling this function.
Reabsorbed nutrient
Notes
H2O
Collecting tubules
Na+(35%), H2O
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
Pregnancy reduces the reabsorption of glucose and amino acids.
Acid-base homeostasis
Two organ systems, the kidneys and lungs, maintain acid-base homeostasis, which is the maintenance of pH around
a relatively stable value. The lungs contribute to acid-base homeostasis by regulating carbon dioxide (CO2)
concentration. The kidneys have two very important roles in maintaining the acid-base balance: to reabsorb
bicarbonate from urine, and to excrete hydrogen ions into urine
Osmolality regulation
Any significant rise in plasma osmolality is detected by the hypothalamus, which communicates directly with the
posterior pituitary gland. An increase in osmolality causes the gland to secrete antidiuretic hormone (ADH), resulting
in water reabsorption by the kidney and an increase in urine concentration. The two factors work together to return
the plasma osmolality to its normal levels.
ADH binds to principal cells in the collecting duct that translocate aquaporins to the membrane, allowing water to
leave the normally impermeable membrane and be reabsorbed into the body by the vasa recta, thus increasing the
plasma volume of the body.
There are two systems that create a hyperosmotic medulla and thus increase the body plasma volume: Urea recycling
and the 'single effect.'
Urea is usually excreted as a waste product from the kidneys. However, when plasma blood volume is low and ADH
is released the aquaporins that are opened are also permeable to urea. This allows urea to leave the collecting duct
into the medulla creating a hyperosmotic solution that 'attracts' water. Urea can then re-enter the nephron and be
excreted or recycled again depending on whether ADH is still present or not.
The 'Single effect' describes the fact that the ascending thick limb of the loop of Henle is not permeable to water but
is permeable to NaCl. This allows for a countercurrent exchange system whereby the medulla becomes increasingly
concentrated, but at the same time setting up an osmotic gradient for water to follow should the aquaporins of the
collecting duct be opened by ADH.
Hormone secretion
The kidneys secrete a variety of hormones, including erythropoietin, and the enzyme renin. Erythropoietin is
released in response to hypoxia (low levels of oxygen at tissue level) in the renal circulation. It stimulates
erythropoiesis (production of red blood cells) in the bone marrow. Calcitriol, the activated form of vitamin D,
promotes intestinal absorption of calcium and the renal reabsorption of phosphate. Part of the
renin-angiotensin-aldosterone system, renin is an enzyme involved in the regulation of aldosterone levels.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
Development
The mammalian kidney develops from intermediate mesoderm. Kidney development, also called nephrogenesis,
proceeds through a series of three successive phases, each marked by the development of a more advanced pair of
kidneys: the pronephros, mesonephros, and metanephros.
Evolutionary adaptation
Kidneys of various animals show evidence of evolutionary adaptation and have long been studied in ecophysiology
and comparative physiology. Kidney morphology, often indexed as the relative medullary thickness, is associated
with habitat aridity among species of mammals.
Related terms
Medical terms related to the kidneys commonly use terms such as renal and the prefix nephro-. The adjective renal,
meaning related to the kidney, is from the Latin rns, meaning kidneys; the prefix nephro- is from the Ancient
Greek word for kidney, nephros (). For example, surgical removal of the kidney is a nephrectomy, while a
reduction in kidney function is called renal dysfunction.
Autosomal dominant polycystic kidney disease afflicts patients later in life. Approximately one in 1000 people
will develop this condition
Autosomal recessive polycystic kidney disease is far less common, but more severe, than the dominant
condition. It is apparent in utero or at birth.
Renal agenesis. Failure of one kidney to form occurs in approximately one in 750 live births. Failure of both
kidneys to form is invariably fatal.
Renal dysplasia
Unilateral small kidney
Multicystic dysplastic kidney occurs in approximately one in every 2400 live births
Ureteropelvic Junction Obstruction or UPJO; although most cases appear congenital, some appear to be an
acquired condition
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
Acquired
Diabetic nephropathy
Glomerulonephritis
Hydronephrosis is the enlargement of one or both of the kidneys
caused by obstruction of the flow of urine.
Interstitial nephritis
Kidney stones (nephrolithiasis) are a relatively common and
particularly painful disorder.
Kidney tumors
Wilms tumor
Renal cell carcinoma
Lupus nephritis
Minimal change disease
In nephrotic syndrome, the glomerulus has been damaged so that a
large amount of protein in the blood enters the urine. Other frequent
features of the nephrotic syndrome include swelling, low serum
albumin, and high cholesterol.
Pyelonephritis is infection of the kidneys and is frequently caused
by complication of a urinary tract infection.
Renal failure
Acute renal failure
Stage 5 Chronic Kidney Disease
Kidney Failure
Generally, humans can live normally with just one kidney, as one has more functioning renal tissue than is needed to
survive. Only when the amount of functioning kidney tissue is greatly diminished does one develop chronic kidney
disease. Renal replacement therapy, in the form of dialysis or kidney transplantation, is indicated when the
glomerular filtration rate has fallen very low or if the renal dysfunction leads to severe symptoms.
Diagnosis
Clinical
Many renal diseases are diagnosed on the basis of classical clinical findings. A physician (usually a nephrologist)
begins by taking a detailed clinical history and performs a physical examination. In addition to medical history and
presenting symptoms, a physician will ask about medication history, family history recent infections, toxic/chemical
exposures and other historical factors that may indicate an etiology for the patient's renal disease. Often, some
diseases are suggested by clinical history and time course alone. For example, in a formerly healthy child with a
recent upper respiratory tract infection and facial/lower limb swelling, findings of proteinuria on urinalysis, a
diagnosis of minimal change disease is highly suggested. Similarly, a patient with a history of diabetes who presents
with decreased urine output is most likely to be suffering from diabetic nephropathy. Often, such cases do not
require extensive workup (such as with renal biopsy). A presumptive diagnosis can be made on the basis of history,
physical exam and supportive laboratory studies.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
Laboratory
Laboratory studies are an important adjunct to clinical evaluation for assessment of renal function. An initial workup
of a patient may include a complete blood count (CBC); serum electrolytes including sodium, potassium, chloride,
bicarbonate, calcium, and phosphorus; blood urea, nitrogen and creatinine; blood glucose and glycocylated
hemoglobin. Glomerular filtration rate (GFR) can be calculated.[6]
Urine studies may include urine electrolytes, creatinine, protein, fractional excretion of sodium (FENA) and other
studies to assist in evaluation of the etiology of a patient's renal disease.
Urinalysis is used to evaluate urine for its pH, protein, glucose, specific gravity and the presence of
blood/hemoglobin. Microscopic analysis can be helpful in the identification of casts, red blood cells, white blood
cells and crystals.
Imaging studies
Imaging studies are important in the evaluation of structural renal disease caused by urinary tract obstruction, renal
stones, renal cyst, mass lesions, renal vascular disease, and vesicoureteral reflux.
Imaging techniques used most frequently include renal ultrasound and helical CT scan. Patients with suspected
vesicoureteral reflux may undergo voiding cystourethrogram (VCUG).
Renal biopsy
The role of the renal biopsy is to diagnose renal disease in which the etiology is not clear based upon noninvasive
means (clinical history, past medical history, medication history, physical exam, laboratory studies, imaging studies).
A detailed description of renal biopsy interpretation is beyond the scope of this article. In general, a renal pathologist
will perform a detailed morphological evaluation and integrate the morphologic findings with the clinical history and
laboratory data, ultimately arriving at a pathological diagnosis. A renal pathologist is a physician who has undergone
general training in anatomic pathology and additional specially training in the interpretation of renal biopsy
specimens.
Ideally, multiple core sections are obtained and evaluated for adequacy (presence of glomeruli) intraoperatively. A
pathologist/pathology assistant divides the specimen(s) for submission for light microscopy, immunofluorescence
microscopy and electron microscopy.
The pathologist will examine the specimen using light microscopy with multiple staining techniques (hematoxylin
and eosin/H&E, PAS, trichrome, silver stain) on multiple level sections. Multiple immunofluorescence stains are
performed to evaluate for antibody, protein and complement deposition. Finally, ultra-structural examination is
performed with electron microscopy and may reveal the presence of electron-dense deposits or other characteristic
abnormalities that may suggest an etiology for the patient's renal disease.
Calculations
Calculations of kidney performance are an important part of physiology and can be estimated using the calculations
below.
Filtration Fraction
The filtration fraction is the amount of plasma that is actually filtered through the kidney. This can be defined using
the equation:
FF=GFR/RPF
FF is the filtration fraction
GFR is the glomerular filtration rate
RPF is the renal plasma flow
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
10
Renal Clearance
Renal clearance is the volume of plasma from which the substance is completely cleared from the blood per unit
time.
Cx=(Ux)V/Px
More information regarding renal function can be found on the Renal function Wikipedia page.
In other animals
In the majority of vertebrates, the mesonephros persists into the adult,
albeit usually fused with the more advanced metanephros; only in
amniotes is the mesonephros restricted to the embryo. The kidneys of
fish and amphibians are typically narrow, elongated organs, occupying
a significant portion of the trunk. The collecting ducts from each
cluster of nephrons usually drain into an archinephric duct, which is
homologous with the vas deferens of amniotes. However, the situation
is not always so simple; in cartilaginous fish and some amphibians,
there is also a shorter duct, similar to the amniote ureter, which drains
A pig's kidney opened.
the posterior (metanephric) parts of the kidney, and joins with the
archinephric duct at the bladder or cloaca. Indeed, in many
cartilaginous fish, the anterior portion of the kidney may degenerate or cease to function altogether in the adult.
In the most primitive vertebrates, the hagfish and lampreys, the kidney is unusually simple: it consists of a row of
nephrons, each emptying directly into the archinephric duct. Invertebrates may possess excretory organs that are
sometimes referred to as "kidneys", but, even in Amphioxus, these are never homologous with the kidneys of
vertebrates, and are more accurately referred to by other names, such as nephridia.
The kidneys of reptiles consist of a number of lobules arranged in a broadly linear pattern. Each lobule contains a
single branch of the ureter in its centre, into which the collecting ducts empty. Reptiles have relatively few nephrons
compared with other amniotes of a similar size, possibly because of their lower metabolic rate.
Birds have relatively large, elongated kidneys, each of which is divided into three or more distinct lobes. The lobes
consists of several small, irregularly arranged, lobules, each centred on a branch of the ureter. Birds have small
glomeruli, but about twice as many nephrons as similarly sized mammals.
The human kidney is fairly typical of that of mammals. Distinctive features of the mammalian kidney, in comparison
with that of other vertebrates, include the presence of the renal pelvis and renal pyramids, and of a clearly
distinguishable cortex and medulla. The latter feature is due to the presence of elongated loops of Henle; these are
much shorter in birds, and not truly present in other vertebrates (although the nephron often has a short intermediate
segment between the convoluted tubules). It is only in mammals that the kidney takes on its classical "kidney" shape,
although there are some exceptions, such as the multilobed reniculate kidneys of cetaceans.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
11
History
The Latin term renes is related to the English word "reins", a synonym for the kidneys in Shakespearean English
(e.g. Merry Wives of Windsor 3.5), which was also the time the King James Version was translated. Kidneys were
once popularly regarded as the seat of the conscience and reflection,[7][8] and a number of verses in the Bible (e.g.
Ps. 7:9, Rev. 2:23) state that God searches out and inspects the kidneys, or "reins", of humans. Similarly, the Talmud
(Berakhoth 61.a) states that one of the two kidneys counsels what is good, and the other evil.
Kidneys as food
The kidneys can be cooked and eaten (along with other offal).
Kidneys are usually grilled or sauted, but in more complex dishes
they are stewed with a sauce that will improve their flavor. In many
preparations, kidneys are combined with pieces of meat or liver, as in
mixed grill or meurav Yerushalmi. Dishes include the British steak and
kidney pie, the Swedish hkarpanna (pork and kidney stew), the
French rognons de veau sauce moutarde (veal kidneys in mustard
sauce) and the Spanish riones al Jerez (kidneys stewed in sherry
sauce) .[9]
Additional Images
Dissection images
Right Kidney
Kidney
Right Kidney
Right kidney
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney
12
Left kidney
Kidneys
Left kidney
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Kidney
[2] http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ five/ 000056330. htm
[3] Blens ytanatomy (Superficial anatomy of the trunk). Anca Dragomir, Mats Hjortberg and Godfried M. Romans. Section for human anatomy
at the Department of medical biology, Uppsala university, Sweden.
[4] Clapp, WL. "Renal Anatomy". In: Zhou XJ, Laszik Z, Nadasdy T, D'Agati VD, Silva FG, eds. Silva's Diagnostic Renal Pathology. New
York: Cambridge University Press; 2009.
[5] Le, Tao. First Aid for the USMLE Step 1 2013. New York: McGraw-Hill Medical, 2013. Print.
[6] Post TW, Rose BD, auths and Curhan GC, Sheridan AM, eds. Diagnostic Approach to the Patient With Acute Kidney Injury (Acute Renal
Failure) or Chronic Kidney Disease. UpToDate.com, Dec. 2012. http:/ / www. uptodate. com. ezproxy2. library. arizona. edu/ contents/
diagnostic-approach-to-the-patient-with-acute-kidney-injury-acute-renal-failure-or-chronic-kidney-disease?source=preview& anchor=H12&
selectedTitle=1~150#H12
[7] The Patient as Person: Explorations in Medical Ethics p. 60 by Paul Ramsey, Margaret Farley, Albert Jonsen, William F. May (2002)
[8] History of Nephrology 2 p. 235 by International Association for the History of Nephrology Congress, Garabed Eknoyan, Spyros G. Marketos,
Natale G. De Santo, 1997; Reprint of American Journal of Nephrology; v. 14, no. 46, 1994.
[9] Rognons dans les recettes (http:/ / cuisine. notrefamille. com/ recettes-cuisine/ rognons-recette. html)
External links
The NephCure Foundation offers educational materials on the kidney diseases/conditions Nephrotic Syndrome
and FSGS (http://www.nephcure.org)
The Kidney Foundation of Canada (http://www.kidney.ca)
electron microscopic images of the kidney (Dr. Jastrow's EM-Atlas) (http://www.uni-mainz.de/FB/Medizin/
Anatomie/workshop/EM/EMNiereE.html)
European Renal Genome project kidney function tutorial (http://www.euregene.org/euregene/pages/
kidney_tut_e.html)
Kidney Foundation of Canada kidney disease information (http://www.kidneyquebec.ca/ang/kidney_disease/
index.htm)
Renal Fellow Network: Structure & Function of Other Animals' Kidneys (http://renalfellow.blogspot.com/
2009/06/structure-function-of-other-animals.html)
Kidney Stones (http://symptomsofakidneystone.com)
Kidney Diseases (http://www.kidney-stone.us)
Kidney Information (http://www.redurine.com/urinary_tract/kidney_facts.html)
Animated Presentatin on Kidney Function (http://www.davita.com/kidney_animation/)
CAT Scans of various kidney diseases and conditions (http://www.ctcases.net/ct-cases-database/4 Abdomen
And Pelvis/6 Kidneys/) - CT Cases
Kidney Stones; Information and Treatments (http://www.mountsinai.org/patient-care/service-areas/
urological-conditions-and-surgery/areas-of-care/kidney-disease-program)
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal function
Renal function
Renal function, in nephrology, is an
indication of the state of the kidney and its
role in renal physiology. Glomerular
filtration rate (GFR) describes the flow
rate of filtered fluid through the kidney.
Creatinine clearance rate (CCr or CrCl) is
the volume of blood plasma that is cleared
of creatinine per unit time and is a useful
measure for approximating the GFR.
Creatinine clearance exceeds GFR due to
creatinine secretion, which can be blocked
by cimetidine. In alternative fashion,
overestimation by older serum creatinine
methods resulted in an underestimation of
creatinine clearance, which provided a less
biased estimate of GFR. Both GFR and CCr
may
be
accurately
calculated
by
comparative measurements of substances in
the blood and urine, or estimated by
formulas using just a blood test result
(eGFR and eCCr).
Diagram showing the basic physiologic mechanisms of the kidney
The results of these tests are important in
assessing the excretory function of the
kidneys. For example, grading of chronic renal insufficiency and dosage of drugs that are excreted primarily via
urine are based on GFR (or creatinine clearance).
It is commonly believed to be the amount of liquid filtered out of the blood that gets processed by the kidneys. In
physiological terms, these quantities (volumetric blood flow and mass removal) are related only loosely.
Indirect markers
Most doctors use the plasma concentrations of the waste substances of creatinine and urea (U), as well as electrolytes
(E), to determine renal function. These measures are adequate to determine whether a patient is suffering from
kidney disease.
However, blood urea nitrogen (BUN) and creatinine will not be raised above the normal range until 60% of total
kidney function is lost. Hence, the more accurate Glomerular filtration rate or its approximation of the creatinine
clearance is measured whenever renal disease is suspected or careful dosing of nephrotoxic drugs is required.
Another prognostic marker for kidney disease is an elevated level of protein in the urine. The most sensitive marker
of proteinuria is elevated urine albumin. Persistent presence of more than 30mg albumin per gram creatinine in the
urine is diagnostic of chronic kidney disease (microalbuminuria is a level of 30299mg/L urine or 30-299 mg/24
hrs; a concentration of albumin in the urine that is not detected by usual urine dipstick methods).
13
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal function
There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). The
above formula only applies for GFR calculation when it is equal to the Clearance Rate.
Pressure definition
More precisely, GFR is the fluid flow rate between the glomerular capillaries and the Bowman's capsule:
Where:
is the GFR.
is called the filtration constant and is defined as the product of the hydraulic conductivity and the surface
14
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal function
15
Kf
Because this constant is a measurement of hydraulic conductivity multiplied by the capillary surface area, it is almost
impossible to measure physically. However, it can be determined experimentally. Methods of determining the GFR
are listed in the above and below sections and it is clear from our equation that
can be found by dividing the
experimental GFR by the net filtration pressure:
PG
The hydrostatic pressure within the glomerular capillaries is determined by the pressure difference between the fluid
entering immediately from the afferent arteriole and leaving through the efferent arteriole. The pressure difference is
approximated by the product of the total resistance of the respective arteriole and the flux of blood through it:
Where:
Where:
And,
G
Blood plasma has a good many proteins in it and they exert an inward directed force called the colloid osmotic
pressure on the water in hypotonic solutions across a membrane, i.e., in the Bowman's capsule. Because plasma
proteins are virtually incapable of escaping the glomerular capillaries, this oncotic pressure is defined, simply, by the
ideal gas law:
Where:
R is the universal gas constant
T is the temperature.
And, c is concentration in mol/L of plasma proteins (remember the solutes can freely diffuse through the
glomerular capsule).
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal function
B
This value is almost always taken to be equal to zero because, in a healthy nephron, there should be no proteins in
the Bowman's Capsule.
Example: A person has a plasma creatinine concentration of 0.01mg/ml and in 1 hour produces 60ml of urine with a
creatinine concentration of 1.25mg/mL.
The common procedure involves undertaking a 24-hour urine collection, from empty-bladder one morning to the
contents of the bladder the following morning, with a comparative blood test then taken. The urinary flow rate is still
calculated per minute, hence:
16
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Renal function
To allow comparison of results between people of different sizes, the CCr is often corrected for the body surface area
(BSA) and expressed compared to the average sized man as mL/min/1.73 m2. While most adults have a BSA that
approaches 1.7 (1.6-1.9), extremely obese or slim patients should have their CCr corrected for their actual BSA.
Estimated values
A number of formulae have been devised to estimate GFR or Ccr values on the basis of serum creatinine levels.
This formula expects weight to be measured in kilograms and creatinine to be measured in mg/dL, as is
standard in the USA. The resulting value is multiplied by a constant of 0.85 if the patient is female. This
formula is useful because the calculations are simple and can often be performed without the aid of a
calculator.
When serum creatinine is measured in mol/L:
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Estimated GFR (eGFR) using Modification of Diet in Renal Disease (MDRD) formula
The most recently advocated formula for calculating the GFR is the one that was developed by the Modification of
Diet in Renal Disease Study Group. Most laboratories in Australia, and The United Kingdom now calculate and
report the MDRD estimated GFR along with creatinine measurements and this forms the basis of chronic kidney
disease. The adoption of the automatic reporting of MDRD-eGFR has been widely criticised.
The most commonly used formula is the "4-variable MDRD," which estimates GFR using four variables: serum
creatinine, age, ethnicity, and gender. The original MDRD used six variables with the additional variables being the
blood urea nitrogen and albumin levels. The equations have been validated in patients with chronic kidney disease;
however both versions underestimate the GFR in healthy patients with GFRs over 60 mL/min. The equations have
not been validated in acute renal failure.
For creatinine in mol/L:
Creatinine levels in mol/L can be converted to mg/dL by dividing them by 88.4. The 32788 number above is
equal to 18688.41.154.
A more elaborate version of the MDRD equation also includes serum albumin and blood urea nitrogen (BUN) levels:
Where the creatinine and blood urea nitrogen concentrations are both in mg/dL. The albumin concentration is
in g/dL.
These MDRD equations are to be used only if the laboratory has NOT calibrated its serum creatinine measurements
to isotope dilution mass spectrometry (IDMS). When IDMS-calibrated serum creatinine is used (which is about 6%
lower), the above equations should be multiplied by 175/186 or by 0.94086.
Since these formulae do not adjust for body mass, they (relative to the Cockcroft-Gault formula) underestimate
eGFR for heavy people and overestimate it for underweight people. (see Cockcroft-Gault formula above).
where SCr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is -0.329 for females and -0.411 for
males, min indicates the minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 1.
A clearer version may be as follows: For creatinine (IDMS calibrated) in mg/dL:
Black Female
18
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19
Black male
If serum creatinine (Scr) <= 0.9
Where k is a constant that depends on muscle mass, which itself varies with a child's age:
In first year of life, for pre-term babies K=0.33 and for full-term infants K=0.45
For infants and children of age 1 to 12 years, K=0.55.
The method of selection of the K-constant value has been questioned as being dependent upon the gold-standard of
renal function used (i.e., creatinine clearance, inulin clearance, etc.) and also may be dependent upon the urinary
flow rate at the time of measurement.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal function
In 2009, the formula was updated to use standardized serum creatinine (recommend k=0.413) and additional
formulas that allow improved precision were derived if serum cystatin measured in addition to serum creatinine.
Importance of calibration of the serum creatinine level and the IDMS standardization
effort
One problem with any creatinine-based equation for GFR is that the methods used to assay creatinine in the blood
differ widely in their susceptibility to non-specific chromogens, which cause the creatinine value to be
overestimated. In particular, the MDRD equation was derived using serum creatinine measurements that had this
problem. The NKDEP program in the United States has attempted to solve this problem by trying to get all
laboratories to calibrate their measures of creatinine to a "gold standard", which in this case is isotope dilution mass
spectrometry (IDMS). In late 2009 not all labs in the U.S. had changed over to the new system. There are two forms
of the MDRD equation that are available, depending on whether or not creatinine was measured by an
IDMS-calibrated assay. The CKD-EPI equation is designed to be used with IDMS-calibrated serum creatinine values
only.
Cystatin C
Problems with creatinine (varying muscle mass, recent meat ingestion, etc.) have led to evaluation of alternative
agents for estimation of GFR. One of these is cystatin C, a ubiquitous protein secreted by most cells in the body (it is
an inhibitor of cysteine protease).
Cystatin C is freely filtered at the glomerulus. After filtration, Cystatin C is reabsorbed and catabolized by the
tubular epithelial cells, with only small amounts excreted in the urine. Cystatin C levels are therefore measured not
in the urine, but in the bloodstream.
Equations have been developed linking estimated GFR to serum cystatin C levels. Most recently, some proposed
equations have combined (sex, age and race) adjusted cystatin C and creatinine. The most accurate is (sex, age and
race) adjusted cystatin C, followed by (sex, age and race) adjusted creatinine and then cystatine C alone in slightly
different with adjusted creatinine.
Normal ranges
The normal range of GFR, adjusted for body surface area, is 100-130 ml/min/1.73m2 in men and women. In children,
GFR measured by inulin clearance is 110 ml/min/1.73m2 until 2 years of age in both sexes, and then it progressively
decreases. After age 40, GFR decreases progressively with age, by about 0.4 - 1.2 mL/min per year.[citation needed]
20
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21
90
Stage 2
60 89
Stage 3
30 59
Stage 4
15 29
Stage 5
< 15
The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the
MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g.,
proteinuria):
0) Normal kidney function GFR above 90mL/min/1.73m2 and no proteinuria
1) CKD1 GFR above 90mL/min/1.73m2 with evidence of kidney damage
2) CKD2 (mild) GFR of 60 to 89 mL/min/1.73m2 with evidence of kidney damage
3) CKD3 (moderate) GFR of 30 to 59 mL/min/1.73m2
4) CKD4 (severe) GFR of 15 to 29 mL/min/1.73m2
5) CKD5 kidney failure - GFR less than 15 mL/min/1.73m2 Some people add CKD5D for those stage 5
patients requiring dialysis; many patients in CKD5 are not yet on dialysis.
Note: others add a "T" to patients who have had a transplant regardless of stage.
Not all clinicians agree with the above classification, suggesting that it may mislabel patients with mildly reduced
kidney function, especially the elderly, as having a disease. A conference was held in 2009 regarding these
controversies by Kidney Disease: Improving Global Outcomes (KDIGO) on CKD: Definition, Classification and
Prognosis, gathering data on CKD prognosis to refine the definition and staging of CKD.
References
[1] - "Glomerular Filtration Rate"
[2] GFR (Cockcroft & MDRD) calculator at medical-calculator.nl (http:/ / www. medical-calculator. nl/ calculator/ GFR/ ) - Cockcroft and
MDRD calculator and details about inulin clearance
[3] GFR Calculator at cato.at - Cockcroft-Gault (http:/ / www. cato. at/ webservice/ servlet/ location?goto=SERVICE_CALC& lang=EN&
URL="calc/ cato_GFR_CG. htm") - GFR calculation (Cockcroft-Gault formula)
31. Creatinine clearance calculator (Cockcroft-Gault Equation)- by MDCalc (http:/ / www. mdcalc. com/
creatinine-clearance-cockcroft-gault-equation/)
External links
Online GFR calculators
Online GFR Calculator (http://nkdep.nih.gov/lab-evaluation/gfr-calculators.shtml)
Schwartz formula (http://www-users.med.cornell.edu/~spon/picu/calc/crclschw.htm) for estimating
pediatric renal function
Reference links
National Kidney Disease Education Program website. (http://www.nkdep.nih.gov/professionals/index.htm)
Includes professional references and GFR calculators
eGFR at Lab Tests Online (http://labtestsonline.org/understanding/analytes/gfr/tab/test)
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal corpuscle
22
Renal corpuscle
Renal corpuscle of Malpighi
The structure on the left in blue and pink is the renal corpuscle. The structure on the right is the renal tubule. The blue structure (A) is
the Bowman's capsule (2 and 3). The pink structure is the glomerulus with its capillaries. At the left, blood flows from the afferent
areteriole (9), through the capillaries (10), and out the efferent arteriole (11). The mesangium is the pink structure inside the
glomerulus between the capillaries (5a) and extending outside the glomerulus (5b).
The renal corpuscle in the cortex (outer layer) of the kidney. At the top, the renal corpuscle containing the glomerulus. The filtered
blood exits into the renal tubule, at right. At left, blood flows from the afferent arteriole (red), enters into the renal corpuscle and feeds
the glomerulus; blood flows out of the efferent arteriole (blue).
Latin
corpusculum renis
Gray's
[1]
In the kidney, a renal corpuscle is the initial blood-filtering component of a nephron. It consists of two structures: a
glomerulus and a Bowman's capsule.
The glomerulus is a small tuft of capillaries containing two cell types. Endothelial cells, which have large fenestrae,
are not covered by diaphragms. Mesangial cells are modified smooth muscle cells that lie between the capillaries.
They regulate blood flow by their contractile activity and secrete extracellular matrix, prostaglandins, and cytokines.
Mesangial cells also have phagocytic activity, removing proteins and other molecules trapped in the glomerular
basement membrane or filtration barrier.
The Bowman's capsule has an outer parietal layer composed of simple squamous epithelium. The visceral layer,
composed of modified simple squamous epithelium, is lined by podocytes. Podocytes have foot processes, pedicels,
that wrap around glomerular capillaries. These pedicels interdigitate with pedicels of adjacent podocytes forming
filtration slits.
The renal corpuscle filtration barrier is composed of: the fenestrated endothelium of glomerular capillaries, the fused
basal lamina of endothelial cells and podocytes, and the filtration slits of the podocytes. This barrier permits passage
of water, ions, and small molecules from the bloodstream into Bowman's space (the space between the visceral and
parietal layers). Large and/or negatively charged proteins are prevented from passing into Bowman's space, thus
retaining these proteins in the circulation. The basal lamina is composed of 3 layers: lamina rara externa, lamina
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal corpuscle
23
densa, and lamina rara interna. The lamina rara externa is adjacent to the podocyte processes. The lamina densa is the
central layer consisting of type IV collagen and laminin. This layer acts as a selective macromolecular filter,
preventing the passage of large protein molecules into Bowman's space. The lamina rara interna is adjacent to
endothelial cells. This layer contains heparan sulfate, a negatively charged glycosaminoglycan that contributes to the
electrostatic barrier of the glomerular filter.
There are two poles in the renal corpuscle, a vascular pole, and a urinary pole. The vascular pole is where the
afferent and efferent arterioles communicate with the glomerulus. The urinary pole is where the corpuscle opens into
the lumen of the proximal convoluted tubule.
Fluid from blood in the glomerulus is collected in the Bowman's capsule to form "glomerular filtrate", which is then
further processed along the nephron to form urine. The three types of filtration carried out in the Bowman's capsule
are: 1) Basement Filtration 2) Visceral Filtration 3) Endothermic Filtration
Eponym
A renal corpuscle is also known as a Malpighian corpuscle, named after Marcello Malpighi (16281694), an Italian
physician and biologist. This name is not used widely anymore, probably to avoid confusion with a Malpighian
corpuscle in the spleen.
Additional images
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Renal corpuscle
24
External links
Renal+corpuscle [2] at eMedicine Dictionary
BU Histology Learning System: 16003loa [3]
References
[1] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=253#p1221
[2] http:/ / www. emedicinehealth. com/ script/ main/ srchcont_dict. asp?src=Renal+ corpuscle
[3] http:/ / www. bu. edu/ histology/ p/ 16003loa. htm
Nephron
Nephron
Nephron of the kidney. The labelled parts are 1. Glomerulus, 2. Efferent arteriole, 3. Bowman's capsule, 4. Proximal convoluted
tubule, 5. Cortical collecting duct, 6. Distal convoluted tubule, 7. Loop of Henle, 8. Duct of Bellini, 9. Peritubular capillaries, 10.
Arcuate vein, 11. Arcuate artery, 12. Afferent arteriole, 13. Juxtaglomerular apparatus.
Latin
Nephroneum
Gray's
System
Urinary system
Precursor
MeSH
Nephrons
[1]
[1]
Nephron (from Greek - nephros, meaning "kidney") is the basic structural and functional unit of the kidney.
Its chief function is to regulate the concentration of water and soluble substances like sodium salts by filtering the
blood, reabsorbing what is needed and excreting the rest as urine. A nephron eliminates wastes from the body,
regulates blood volume and blood pressure, controls levels of electrolytes and metabolites, and regulates blood pH.
Its functions are vital to life and are regulated by the endocrine system by hormones such as antidiuretic hormone,
aldosterone, and parathyroid hormone. In humans, a normal kidney contains 800,000 to 1.5 million nephrons.
Types of nephrons
Two general classes of nephrons are cortical nephrons and juxtamedullary nephrons, both of which are classified
according to the length of their associated Loop of Henle and location of their renal corpuscle. All nephrons have
their renal corpuscles in the cortex. Cortical nephrons have their Loop of Henle in the renal medulla near its junction
with the renal cortex, while the Loop of Henle of juxtamedullary nephrons is located deep in the renal medulla; they
are called juxtamedullary because their renal corpuscle is located near the medulla (but still in the cortex). The
nomenclature for cortical nephrons varies, with some sources distinguishing between superficial cortical nephrons
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Nephron
and midcortical nephrons, depending on where their corpuscle is located within the cortex.
The majority of nephrons are cortical. Cortical nephrons have a shorter loop of Henle compared to juxtamedullary
nephrons. The longer loop of Henle in juxtamedullary nephrons create a hyperosmolar gradient that allows for the
creation of concentrated urine.
Anatomy
Each nephron is composed of an initial filtering component (the "renal
corpuscle") and a tubule specialized for reabsorption and secretion (the
"renal tubule"). The renal corpuscle filters out solutes from the blood,
delivering water and small solutes to the renal tubule for
modification.[citation needed]
Renal corpuscle
Composed of a glomerulus and the Bowman's capsule, the renal
corpuscle (or Malphigian corpuscle) is the beginning of the nephron. It
is the nephron's initial filtering component.[citation needed]
The glomerulus is a capillary tuft that receives its blood supply from an
afferent arteriole of the renal circulation. The glomerular blood
pressure provides the driving force for water and solutes to be filtered
out of the blood and into the space made by Bowman's capsule. The
remainder of the blood (only approximately 1/5 of all plasma passing
through the kidney is filtered through the glomerular wall into the
Bowman's capsule) passes into the efferent arteriole.The diameter of
Kidney nephron drawing with labels of the
efferent arteriole is comparatively less than that of afferent arteriole,
following: the Bowman's capsule, proximal
increasing the hydrostatic pressure in the glomerulus. It then moves
convoluted tubule, loop of Henle, descending
into the vasa recta, which are only found in juxtamedullary nephrons
limb of loop of Henle, ascending limb of loop of
Henle, distal convoluted tubule, and collecting
and not cortical nephrons. The vasa recta are collecting capillaries
duct.
intertwined with the convoluted tubules through the interstitial space,
in which the reabsorbed substances will also enter. This then combines
with efferent venules from other nephrons into the renal vein, and rejoins the main bloodstream.[citation needed]
The Bowman's capsule, also called the glomerular capsule, surrounds the glomerulus. It is composed of a visceral
inner layer formed by specialized cells called podocytes, and a parietal outer layer composed of simple squamous
epithelium. Fluids from blood in the glomerulus are filtered through the visceral layer of podocytes, and the resulting
glomerular filtrate is further processed along the nephron to form urine.[citation needed]
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Renal tubule
Renal tubule
Latin
tubulus renalis
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the
glomerulus.[3]Wikipedia:Link rot After passing through the renal tubule, the filtrate continues to the collecting duct
system, which is not part of the nephron.[citation needed]
The components of the renal tubule are:
Proximal convoluted tubule (lies in cortex and lined by simple cuboidal epithelium with brushed borders which
help to increase the area of absorption greatly.)
Loop of Henle (hair-pin like i.e. U-shaped and lies in medulla)
Descending limb of loop of Henle
Ascending limb of loop of Henle
The ascending limb of loop of Henle is divided into 2 segments: Lower end of ascending limb is very thin
and is lined by simple squamous epithelium. The distal portion of ascending limb is thick and is lined by
simple cuboidal epithelium.
Thin ascending limb of loop of Henle
Thick ascending limb of loop of Henle (enters cortex and becomes DCT-distal convoluted tubule.)
Distal convoluted tubule
Functions
The nephron carries out nearly all of the kidney's functions. Most of these functions concern the reabsorption and
secretion of various solutes such as ions (e.g., sodium), carbohydrates (e.g., glucose), and amino acids (e.g.,
glutamate). Properties of the cells that line the nephron change dramatically along its length; consequently, each
segment of the nephron has highly specialized functions.[citation needed]
The proximal tubule as a part of the nephron can be divided into an initial convoluted portion and a following
straight (descending) portion. Fluid in the filtrate entering the proximal convoluted tubule is reabsorbed into the
peritubular capillaries, including approximately two-thirds of the filtered salt and water and all filtered organic
solutes (primarily glucose and amino acids).[citation needed]
The loop of Henle, also called the nephron loop or the loop of Hundley, is a U-shaped tube that extends from the
proximal tubule. It consists of a descending limb and ascending limb. It begins in the cortex, receiving filtrate from
the proximal convoluted tubule, extends into the medulla as the descending limb, and then returns to the cortex as the
ascending limb to empty into the distal convoluted tubule. The primary role of the loop of Henle is to concentrate the
salt in the interstitium, the tissue surrounding the loop.[citation needed]
Considerable differences aid in distinguishing the descending and ascending limbs of the loop of Henle. The
descending limb is permeable to water and noticeably less impermeable to salt, and thus only indirectly contributes
to the concentration of the interstitium. As the filtrate descends deeper into the hypertonic interstitium of the renal
medulla, water flows freely out of the descending limb by osmosis until the tonicity of the filtrate and interstitium
equilibrate. Longer descending limbs allow more time for water to flow out of the filtrate, so longer limbs make the
filtrate more hypertonic than shorter limbs.[citation needed]
Unlike the descending limb, the Thin ascending limb of loop of Henle is impermeable to water, a critical feature of
the countercurrent exchange mechanism employed by the loop. The ascending limb actively pumps sodium out of
the filtrate, generating the hypertonic interstitium that drives countercurrent exchange. In passing through the
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Nephron
ascending limb, the filtrate grows hypotonic since it has lost much of its sodium content. This hypotonic filtrate is
passed to the distal convoluted tubule in the renal cortex.[citation needed]
The distal convoluted tubule has a different structure and function to that of the proximal convoluted tubule. Cells
lining the tubule have numerous mitochondria to produce enough energy (ATP) for active transport to take place.
Much of the ion transport taking place in the distal convoluted tubule is regulated by the endocrine system. In the
presence of parathyroid hormone, the distal convoluted tubule reabsorbs more calcium and secretes more phosphate.
When aldosterone is present, more sodium is reabsorbed and more potassium secreted. Atrial natriuretic peptide
causes the distal convoluted tubule to secrete more sodium. In addition, the tubule also secretes hydrogen and
ammonium to regulate pH.[citation needed]
Juxtaglomerular apparatus
The juxtaglomerular apparatus is a specialized region of the nephron responsible for production and secretion of the
enzyme renin, involved in the renin-angiotensin system. This apparatus occurs near the site of contact between the
thick ascending limb and the afferent arteriole. It contains three components: the macula densa, juxtaglomerular
cells, and extraglomerular mesangial cells.[citation needed]
Clinical relevance
Because of its importance in body fluid regulation, the nephron is a common target of drugs that treat high blood
pressure and edema. These drugs, called diuretics, inhibit the ability of the nephron to retain electrolytes (and
consequently water), thereby increasing the amount of urine produced.
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Additional images
Distribution of
blood vessels in
cortex of kidney.
(Although the
figure labels the
efferent vessel as a
vein, it is actually
an arteriole.)
Glomerulus is red;
Bowman's capsule
is white.
Kidney tissue
Glomerulus
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Nephrons
[2] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=253#p1223
[3] Ecology & Evolutionary Biology - University of Colorado at Boulder. "The Kidney Tubule I: Urine Production." URL: (http:/ / www.
colorado. edu/ eeb/ web_resources/ cartoons/ nephrex1. html). Accessed on: March 6, 2007.
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Glomerulus
Glomerulus
The glomerulus is the network (tuft) of capillaries in red. Blood flows in via the afferent arteriole and out via the efferent arteriole
(arrows). The round, double-walled structure in white is Bowman's capsule. The liquid component of blood (plasma)is filtered by
passing through the glomerular membrane, which consists of the capillary wall and the epithelial layer of Bowman's capsule. The
filtered blood leaves through the tubule at the top.
glomerulus renis
Gray's
Precursor
Metanephric blastema
MeSH
Kidney+Glomerulus
[1]
[1]
In the kidney, a tubular structure called the nephron filters blood to form urine. At the beginning of the nephron, the
glomerulus /lmrls/ is a network (tuft) of capillaries that performs the first step of filtering blood.
The glomerulus is surrounded by Bowman's capsule. The blood plasma is filtered through the capillaries of the
glomerulus into the Bowman's capsule. The Bowman's capsule empties the filtrate into a tubule that is also part of
the nephron.
A glomerulus receives its blood supply from an afferent arteriole of the renal circulation. Unlike most other capillary
beds, the glomerulus drains into an efferent arteriole rather than a venule. The resistance of these arterioles results in
high pressure within the glomerulus, aiding the process of ultrafiltration, where fluids and soluble materials in the
blood are forced out of the capillaries and into Bowman's capsule.
A glomerulus and its surrounding Bowman's capsule constitute a renal corpuscle, the basic filtration unit of the
kidney. The rate at which blood is filtered through all of the glomeruli, and thus the measure of the overall renal
function, is the glomerular filtration rate (GFR).
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
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Afferent circulation
The afferent arteriole that supplies the capillaries of a glomerulus branches off an interlobular artery in the renal
cortex. Glomerular capillary pressure, and thus glomerular filtration rate, can be influenced by constriction or
relaxation of the afferent arteriole, resulting in decreases or increases in pressure. As an example, one study
involving rats found that having narrowed afferent arterioles contributed to the development of increased blood
pressure. Sympathetic nervous system action as well as hormones can also impact glomerular filtration rate by
modulating afferent arteriole diameter.
Layers
If a substance has passed through the glomerular capillary endothelial cells, glomerular basement membrane, and
podocytes, then it enters the lumen of the tubule and is known as glomerular filtrate. Otherwise, it exits the
glomerulus through the efferent arteriole and continues circulation as discussed below and as shown on the picture.
Endothelial cells
The endothelial cells of the glomerulus
contain numerous pores (fenestrae)
that, unlike those of other fenestrated
capillaries, are not spanned by
diaphragms.
The
cells
have
fenestrations that are 70 to 100 nm in
diameter. Since these pores are
relatively large, they allow for the free
filtration of fluid, plasma solutes and
protein. However they are not large
enough that red blood cells can be
filtered.
Glomerular basement
membrane
Scheme of filtration barrier (blood-urine) in the kidney. A. The endothelial cells of the
glomerulus; 1. pore (fenestra).
B. Glomerular basement membrane: 1. lamina rara interna 2. lamina densa 3. lamina rara
externa
C. Podocytes: 1. enzymatic and structural protein 2. filtration slit 3. diaphragma
The glomerular endothelium sits on a very thick (250350 nm) glomerular basement membrane.
Podocytes
Podocytes line the other side of the glomerular basement membrane and form part of the lining of Bowman's space.
Podocytes form a tight interdigitating network of foot processes (pedicels) that control the filtration of proteins from
the capillary lumen into Bowman's space.
The space between adjacent podocyte foot processes is spanned by a slit diaphragm formed by several proteins
including podocin and nephrin. In addition, foot processes have a negatively charged coat (glycocalyx) that limits the
filtration of negatively charged molecules, such as serum albumin.
The podocytes are sometimes considered the "visceral layer of Bowman's capsule", rather than part of the
glomerulus.
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Selectivity
The structures of the layers determine their permeability-selectivity permselectivity. The factors that influence
permselectivity are the negative charge of the basement membrane and the podocytic epithelium, and the effective
pore size of the glomerular wall (8nm). As a result, large and/or negatively charged molecules will pass through far
less frequently than small and/or positively charged ones. For instance, small ions such as sodium and potassium
pass freely, while larger proteins, such as hemoglobin and albumin have practically no permeability at all.
Efferent circulation
Blood is carried out of the glomerulus by an efferent arteriole instead of a venule, as is observed in most other
capillary systems. This provides tighter control over the blood flow through the glomerulus, since arterioles dilate
and constrict more readily than venules, owing to arterioles' larger smooth muscle layer (tunica media).
Efferent arterioles of juxtamedullary nephrons (i.e., the 15% of nephrons closest to the medulla) send straight
capillary branches that deliver isotonic blood to the renal medulla. Along with the loop of Henle, these vasa recta
play a crucial role in the establishment of the nephron's countercurrent exchange system.
The efferent arteriole, into which the glomerulus delivers blood, empties into an interlobular vein.
Juxtaglomerular cells
The walls of the afferent arteriole contain specialized smooth muscle cells that synthesize renin. These
juxtaglomerular cells play a major role in the renin-angiotensin system, which helps regulate blood volume and
pressure.
History
In 1666, Malpighi first described the glomeruli and demonstrated their continuity with the renal vasculature
(281,282). About 175 years later, Bowman elucidated in detail the capillary architecture of the glomerulus and the
continuity between its surrounding capsule and the proximal tubule .[2] .
Additional images
1 Glomerulus, 2
proximal tubule, 3 distal
tubule
Glomerulus.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Glomerulus
32
Renal corpuscle
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Kidney+ Glomerulus
[2] "lippicotts histology for pathologesits; satcey e. mills
External links
Image and article at FGCU (http://coe.fgcu.edu/faculty/greenep/kidney/Glomerulus.html)
Histology at KUMC epithel-epith02 (http://www.kumc.edu/instruction/medicine/anatomy/histoweb/epithel/
epith02.htm) "Kidney (Glomerulus)"
Organology at UC Davis Urinary/mammal/cortex1/cortex1 (http://trc.ucdavis.edu/mjguinan/apc100/modules/
Urinary/mammal/cortex1/cortex1.html) - "Mammal, kidney cortex (LM, Medium)"
BU Histology Learning System: 16010loa (http://www.bu.edu/histology/p/16010loa.htm)
UNC Nephropathology (http://www.uncnephropathology.org)
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Bowman's capsule
33
Bowman's capsule
Bowman's capsule
capsula glomeruli
Gray's
Precursor
Metanephric blastema
MeSH
Bowman+Capsule
[1]
[2]
The Bowman's capsule (or capsula glomeruli, glomerular capsule) is a cup-like sac at the beginning of the tubular
component of a nephron in the mammalian kidney that performs the first step in the filtration of blood to form urine.
A glomerulus is enclosed in the sac. Fluids from blood in the glomerulus are collected in the Bowman's capsule (i.e.,
glomerular filtrate) and further processed along the nephron to form urine. This process is known as
ultrafiltration.[citation needed] The Bowman's capsule is named after Sir William Bowman, who identified it in 1842.
Anatomy
Outside the capsule, there are two "poles":
The vascular pole is the side with the afferent arteriole and efferent arteriole.
the urinary pole is the side with the proximal convoluted tubule.
Inside the capsule, the layers are as follows, from outside to inside:[citation needed]
Parietal layer -- A single layer of simple squamous epithelium. Does not function in filtration.
Bowman's space (or "urinary space", or "capsular space") -- Between the visceral and parietal layers, into which
the filtrate enters after passing through the filtration slits.
Visceral layer -- Lies just above the thickened glomerular basement membrane and is made of podocytes.
Beneath the visceral layer lie the glomerular capillaries.[citation needed]
Filtration barrier -- The filtration barrier is composed of the fenestrated endothelium of the glomerular
capillaries, the fused basal lamina of the endothelial cells and podocytes, and the filtration slits of the podocytes.
The barrier permits the passage of water, ions, and small molecules from the bloodstream into the Bowman's
space. The barrier prevents the passage of large and/or negatively charged proteins (such as albumin). The basal
lamina of the filtration barrier is composed of three layers. The first layer is the lamina rara externa, adjacent to
the podocyte processes. The second layer is the lamina rara interna, adjacent to the endothelial cells. The final
layer is the lamina densa which is a darker central zone of the basal lamina. It consists of the meshwork of type
IV collagen and laminin which act as a selective macromolecular filter.[citation needed]
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Bowman's capsule
34
A - Renal corpuscle
B - Proximal tubule
C - Distal convoluted tubule
D - Juxtaglomerular apparatus
1. Basement membrane (Basal lamina)
2. Bowman's capsule - parietal layer
3. Bowman's capsule - visceral layer
3a. Pedicels (podocytes)
3b. Podocyte or sometimes called Bowman's
cells
4. Bowman's space (urinary space)
5a. Mesangium - Intraglomerular cell
5b. Mesangium - Extraglomerular cell
6. Granular cells (Juxtaglomerular cells)
7. Macula densa
8. Myocytes (smooth muscle)
9. Afferent arteriole
10. Glomerulus Capillaries
11. Efferent arteriole
Physiology
The process of filtration of the blood in the Bowman's capsule is ultrafiltration (or glomerular filtration), and the
normal rate of filtration is 125 ml/min, equivalent to 80 times the daily blood volume.[citation needed]
Any proteins under roughly 30 kilodaltons can pass freely through the membrane, although there is some extra
hindrance for negatively charged molecules due to the negative charge of the basement membrane and the
podocytes.[citation needed]
Any small molecules such as water, glucose, salt (NaCl), amino acids, and urea pass freely into Bowman's space, but
cells, platelets and large proteins do not.[citation needed]
As a result, the filtrate leaving the Bowman's capsule is very similar to blood plasma in composition as it passes into
the proximal convoluted tubule.[citation needed]
Clinical significance
Measuring the glomerular filtration rate (GFR) is a diagnostic test of kidney function.[citation needed]
A decreased GFR may be a sign of renal failure.[citation needed]
A number of diseases can result in various problems within the glomerulus. Examples include acute proliferative
(endocapillary)
glomerulonephritis,
mesangioproliferative
glomerulonephritis,
mesangiocapillary
(membranoproliferative)
glomerulonephritis,
acute
crescentic
glomerulonephritis,
focal
segmental
[citation needed]
glomerulonephritis, and diabetic glomerulosclerosis.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Bowman's capsule
35
Eponym
Bowman's capsule is named after Sir William Bowman (1816-1892), a British surgeon and anatomist.[citation needed]
Together with the glomerulus it is known as a renal corpuscle, or a Malpighian corpuscle, named after Marcello
Malpighi (1628-1694), an Italian physician and biologist. This name is not used widely anymore, probably to avoid
confusion with Malpighian bodies of the spleen.[citation needed]
Additional images
Glomerulus.
References
[1] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=253#p1222
[2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Bowman+ Capsule
External links
BU Histology Learning System: 16006loa (http://www.bu.edu/histology/p/16006loa.htm)
Diagram at ircc.edu (http://faculty.ircc.edu/faculty/tfischer/images/Bowman's capsule.jpg)
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal physiology
Renal physiology
Renal physiology (Latin rns, "kidney") is
the study of the physiology of the kidney.
This encompasses all functions of the
kidney, including reabsorption of glucose,
amino acids, and other small molecules;
regulation of sodium, potassium, and other
electrolytes; regulation of fluid balance and
blood pressure; maintenance of acid-base
balance; the production of various hormones
including erythropoietin, and the activation
of vitamin D
Much of renal physiology is studied at the
This illustration demonstrates the normal kidney physiology. It also includes
level of the nephron, the smallest functional
illustrations showing where some types of diuretics act, and what they do.
unit of the kidney. Each nephron begins
with a filtration component that filters blood entering the kidney. This filtrate then flows along the length of the
nephron, which is a tubular structure lined by a single layer of specialized cells and surrounded by capillaries. The
major functions of these lining cells are the reabsorption of water and small molecules from the filtrate into the
blood, and the secretion of wastes from the blood into the urine.
Proper function of the kidney requires that it receives and adequately filters blood. This is performed at the
microscopic level by many hundreds of thousands of filtration units called renal corpuscles, each of which is
composed of a glomerulus and a Bowman's capsule. A global assessment of renal function is often ascertained by
estimating the rate of filtration, called the glomerular filtration rate (GFR).
Secretion of hormones
Secretion of erythropoietin, which regulates red blood cell production in the bone marrow.
Secretion of renin, which is a key part of the renin-angiotensin-aldosterone system.
Secretion of the active form of vitamin D (calcitriol) and prostaglandins.
36
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal physiology
37
Gluconeogenesis
The kidney in humans is capable of producing glucose from lactate, glycerol and glutamine. The kidney is
responsible for about half of the total gluconeogenesis in fasting humans. The regulation of glucose production in the
kidney is achieved by action of insulin, catecholamines and other hormones. Renal gluconeogenesis takes place in
the renal cortex. The renal medulla is incapable of producing glucose due to absence of necessary enzymes.
Extracellular homeostasis
The kidney is responsible for maintaining a balance of the following substances:
Substance
Description
Proximal tubule
Loop of Henle
Distal tubule
Collecting duct
Glucose
reabsorption (almost
100%) via
sodium-glucose transport
[2]
proteins (apical) and
GLUT (basolateral).
Oligopeptides,
proteins, and
amino acids
reabsorption
Urea
Regulation of osmolality.
[4][5]
Varies with ADH
secretion
reabsorption in medullary
collecting ducts
Sodium
reabsorption (65%,
isosmotic)
reabsorption
(25%, thick
ascending,
Na-K-2Cl
symporter)
reabsorption (5%,
sodium-chloride
symporter)
reabsorption (5%,
principal cells), stimulated
by aldosterone via ENaC
Chloride
reabsorption
Water
absorbed osmotically
along with solutes
reabsorption
(descending)
reabsorption (regulated by
ADH, via arginine
vasopressin receptor 2)
Bicarbonate
reabsorption (8090%)
[8]
reabsorption
(thick ascending)
[9]
reabsorption (intercalated
cells, via band 3 and
pendrin)
Protons
secretion (intercalated
cells)
Potassium
reabsorption (65%)
reabsorption
(20%, thick
ascending,
Na-K-2Cl
symporter)
Calcium
reabsorption
reabsorption
(thick ascending)
via passive
transport
reabsorption in
response to PTH and
reabsorption with
Thiazide Diuretics.
[10]
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal physiology
38
Magnesium
reabsorption
(thick ascending)
reabsorption
Phosphate
Carboxylate
reabsorption (100%
via carboxylate
transporters.
The body is very sensitive to its pH. Outside the range of pH that is compatible with life, proteins are denatured and
digested, enzymes lose their ability to function, and the body is unable to sustain itself. The kidneys maintain
acid-base homeostasis by regulating the pH of the blood plasma. Gains and losses of acid and base must be balanced.
Acids are divided into "volatile acids"[12] and "nonvolatile acids".[13] See also titratable acid.
The major homeostatic control point for maintaining this stable balance is renal excretion. The kidney is directed to
excrete or retain sodium via the action of aldosterone, antidiuretic hormone (ADH, or vasopressin), atrial natriuretic
peptide (ANP), and other hormones. Abnormal ranges of the fractional excretion of sodium can imply acute tubular
necrosis or glomerular dysfunction.
Mechanisms
The kidney's ability to perform many of its
functions depends on the three fundamental
functions of filtration, reabsorption, and
secretion, whose sum is renal excretion.
That is:
Urinary excretion rate = Filtration rate
Reabsorption rate + Secretion
rate[14]
Filtration
The blood is filtered by nephrons, the
functional units of the kidney. Each nephron
begins in a renal corpuscle, which is
composed of a glomerulus enclosed in a
Bowman's capsule. Cells, proteins, and
other large molecules are filtered out of the
glomerulus by a process of ultrafiltration,
leaving an ultrafiltrate that resembles
plasma (except that the ultrafiltrate has
negligible plasma proteins) to enter
Bowman's space. Filtration is driven by
Starling forces.
The ultrafiltrate is passed through, in turn, the proximal convoluted tubule, the loop of Henle, the distal convoluted
tubule, and a series of collecting ducts to form urine.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal physiology
Reabsorption
Tubular reabsorption is the process by which solutes and water are removed from the tubular fluid and transported
into the blood. It is called reabsorption (and not absorption) because these substances have already been absorbed
once (particularly in the intestines).
Reabsorption is a two-step process beginning with the active or passive extraction of substances from the tubule fluid
into the renal interstitium (the connective tissue that surrounds the nephrons), and then the transport of these
substances from the interstitium into the bloodstream. These transport processes are driven by Starling forces,
diffusion, and active transport.
Indirect reabsorption
In some cases, reabsorption is indirect. For example, bicarbonate (HCO3-) does not have a transporter, so its
reabsorption involves a series of reactions in the tubule lumen and tubular epithelium. It begins with the active
secretion of a hydrogen ion (H+) into the tubule fluid via a Na/H exchanger:
In the lumen
The H+ combines with HCO3- to form carbonic acid (H2CO3)
Luminal carbonic anhydrase enzymatically converts H2CO3 into H2O and CO2
CO2 freely diffuses into the cell
In the epithelial cell
Cytoplasmic carbonic anhydrase converts the CO2 and H2O (which is abundant in the cell) into H2CO3
H2CO3 readily dissociates into H+ and HCO3 HCO3- is facilitated out of the cell's basolateral membrane
Hormones
Some key regulatory hormones for reabsorption include:
aldosterone, which stimulates active sodium reabsorption (and water as a result)
antidiuretic hormone, which stimulates passive water reabsorption
Both hormones exert their effects principally on the collecting ducts.
Secretion
Tubular secretion is the transfer of materials from peritubular capillaries to renal tubular lumen. Tubular secretion is
caused mainly by active transport.
Usually only a few substances are secreted. These substances are present in great excess, or are natural poisons.
Many drugs are eliminated by tubular secretion. Further reading: Table of medication secreted in kidney
39
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal physiology
Measurement
40
Calculation
Details
renal plasma
flow
[15]
(HCT is hematocrit)
glomerular
filtration rate
filtration fraction
anion gap
[16]
AG = [Na+] ([Cl] + [HCO3])
Clearance (other
than water)
free water
clearance
Net acid
excretion
or
[18]
References
[1] Sect. 7, Ch. 6: Characteristics of Proximal Glucose Reabsorption (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www. lib. mcg.
edu/ edu/ eshuphysio/ program/ section7/ 7ch06/ 7ch06p11. htm). lib.mcg.edu
[2] Sect. 7, Ch. 5: Cotransport (Symport) (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www. lib. mcg. edu/ edu/ eshuphysio/
program/ section7/ 7ch05/ 7ch05p13. htm). lib.mcg.edu
[3] Sect. 7, Ch. 6: Proximal Reabsorption of Amino Acids: Site of Reabsorption (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www.
lib. mcg. edu/ edu/ eshuphysio/ program/ section7/ 7ch06/ 7ch06p17. htm). lib.mcg.edu
[4] Sect. 7, Ch. 6: Proximal Reabsorption of Urea (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www. lib. mcg. edu/ edu/
eshuphysio/ program/ section7/ 7ch06/ 7ch06p10. htm). lib.mcg.edu
[5] V. Excretion of Organic Molecules (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www2. kumc. edu/ ki/ physiology/ course/ five/
5_1. htm). lib.mcg.edu
[6] VI. Mechanisms of Salt & Water Reabsorption (http:/ / www2. kumc. edu/ ki/ physiology/ course/ six/ 6_1. htm)
[7] Sect. 7, Ch. 6: Proximal Reabsorption of Bicarbonate (http:/ / web. archive. org/ web/ 20070219065040/ http:/ / lib. mcg. edu/ edu/
eshuphysio/ program/ section7/ 7ch06/ 7ch06p08. htm). lib.mcg.edu
[8] Sect. 7, Ch. 12: Proximal Tubular Reabsorption of Bicarbonate (http:/ / web. archive. org/ web/ 20070715121612/ http:/ / www. lib. mcg. edu/
edu/ eshuphysio/ program/ section7/ 7ch12/ 7ch12p21. htm). lib.mcg.edu
[9] Sect. 7, Ch. 12: Bicarbonate Reabsorption, Thick Limb of Henles Loop (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www. lib.
mcg. edu/ edu/ eshuphysio/ program/ section7/ 7ch12/ 7ch12p22. htm). lib.mcg.edu
[10] en.wikipedia.org/wiki/Distal_convoluted_tubule
[11] Page 799
[12] Sect. 7, Ch. 12: Physiological Definition of Acids: Volatile Acid (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www. lib. mcg.
edu/ edu/ eshuphysio/ program/ section7/ 7ch12/ 7ch12p12. htm). lib.mcg.edu
[13] Sect. 7, Ch. 12: Nonvolatile Acids (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www. lib. mcg. edu/ edu/ eshuphysio/ program/
section7/ 7ch12/ 7ch12p13. htm). lib.mcg.edu
[14] p 314, Guyton and Hall, Medical Physiology, 11th edition
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Renal physiology
41
[15] Sect. 7, Ch. 4: Measurement of Renal Plasma Flow; Renal Clearance of PAH (http:/ / web. archive. org/ web/ 20070715122822/ http:/ /
www. lib. mcg. edu/ edu/ eshuphysio/ program/ section7/ 7ch04/ 7ch04p28. htm). lib.mcg.edu
[16] Sect. 7, Ch. 4: Filtration Fraction (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www. lib. mcg. edu/ edu/ eshuphysio/ program/
section7/ 7ch04/ 7ch04p17. htm). lib.mcg.edu
[17] IV. Measurement of Renal Function (http:/ / web. archive. org/ web/ 20090124041511/ http:/ / www2. kumc. edu/ ki/ physiology/ course/
four/ 4_2. htm). kumc.edu
[18] Sect. 7, Ch. 8: Free water clearance (CH2O) (http:/ / web. archive. org/ web/ 20070715122822/ http:/ / www. lib. mcg. edu/ edu/ eshuphysio/
program/ section7/ 7ch08/ 7ch08p21. htm). lib.mcg.edu
Overview table
Characteristics of Glucose reabsorption
Characteristic
proximal tubule
S1
reabsorption (%)
S2
[2]
98
reabsorption (mmoles/day)
Concentration
apical transport proteins
SGLT2
SGLT1
GLUT2
GLUT1
References
[1] Sect. 7, Ch. 6: Characteristics of Proximal Glucose Reabsorption (http:/ / www. lib. mcg. edu/ edu/ eshuphysio/ program/ section7/ 7ch06/
7ch06p11. htm)
[2] Page 793
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Proximal tubule
Most of the reabsorption (65%) occurs in the proximal tubule. In the latter part it is favoured by an electrochemical
driving force, but initially it needs the cotransporter SGLT and the Na-H antiporter. Water is reabsorbed to the same
degree, resulting in the concentration in the end of the proximal tubule being the same as in the beginning. In other
words, the reabsorption in the proximal tubule is isosmotic.
Loop of Henle
Sodium is reabsorbed in the thick ascending limb of loop of Henle, by Na-K-2Cl symporter and Na-H antiporter. It
goes against its chemical driving force, but the high electrical driving force renders the overall electrochemical
driving force positive anyway, availing some sodium to diffuse passively either the transcellular or paracellular way.
Distal tubule
In the distal convoluted tubule sodium is transported against an electrochemical gradient by sodium-chloride
symporters.
Collecting duct
The principal cells are the sodium-transporting cells in the collecting duct system.
Regulation
Although only a fragment of total reabsorption happens here, it is the main part of intervention. This is e.g. done by
endogenous production of aldosterone, increasing reabsorption. Since the normal excretion rate of sodium is
~100mmoles/day, then a regulation of the absorption of still more than 1000 mmoles/day entering the collecting duct
system has a substantial influence of the total sodium excreted.
Overview table
42
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
43
proximal tubule
S1
S2 S3
reabsorption
(%)
67%
reabsorption
(mmoles/day)
~17,000
Concentration
(mM)
142
electrical
driving force
(mV)
chemical
driving force
(mV)
loop of Henle
descending thin
limb
ascending
limb
Distal
convoluted
tubule
thick
ascending
limb
25%
5%
3%
~6,400
~1,300
~700
142
100
70
40
-3
+3
+15
-5 to +5
-40
-9
-19
-34
+3
+6
-24 to -14
-74
[]
[2]
electrochemical -3
driving force
(mV)
apical transport
proteins
SGLT,
Na-H
[3]
antiporter
basolateral
transport
proteins
Na+/K+-ATPase
Other
reabsorption
features
isosmotic
ENaC
References
[1] VI. Mechanisms of Salt & Water Reabsorption (http:/ / www2. kumc. edu/ ki/ physiology/ course/ six/ 6_1. htm)
[2] Page 777
[3] Page 778
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
44
Overview table
Characteristics of Cl reabsorption
Characteristic
proximal tubule
S1
S2 S3
loop of Henle
Distal
convoluted
tubule
descending thin
thick ascending
limb
ascending limb
limb
reabsorption
(%)
reabsorption
(mmoles/day)
Concentration
(mM)
115
electrical
driving force
(mV)
[1]
135
+3
+15
5 to +5
40
chemical
driving force
(mV)
electrochemical (positive)
[2]
driving force
(mV)
apical transport (passively)
proteins
Cl-formate
exchanger
Cl-oxalate
exchanger
Cl/HCO3
exchanger
Cl-OH
exchanger
Na-K-2Cl
cotransporter
Na-Cl
cotransporter
chloride
channels
chloride
channels
chloride
channels
Cl-K
[]
cotransporter
chloride channels
intercalated
cells: ClHCO3
exchanger
basolateral
transport
proteins
Other
reabsorption
features
principal
cells:
paracellularily
medullary
collecting
ducts
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
45
References
[1] Page 777
[2] Page 779
Overview table
Characteristics of oligopeptide reabsorption
Characteristic
proximal tubule
S1
reabsorption (%)
S2
[]
99
reabsorption (mmoles/day)
Concentration
apical transport
References
endocytosis
amino acid transporter
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
46
Significant bilateral nephrocalcinosis (calcification of the kidneys) on a frontal X-ray (radiopacities (white) in the right upper and left upper
quadrant of the image), as seen in distal renal tubular acidosis.
[1]
ICD-10
N25.8
ICD-9
588.89
OMIM
179800
DiseasesDB
11687
eMedicine
med/1071
MeSH
D000141
[2]
[3]
[4]
11673
[5]
11705
[6]
[7]
[8]
Renal tubular acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a
failure of the kidneys to appropriately acidify the urine. When blood is filtered by the kidney, the filtrate passes
through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other solutes before it drains
into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by failure to recover
sufficient (alkaline) bicarbonate ions from the filtrate in the early portion of the nephron (proximal tubule) or by
insufficient secretion of (acid) hydrogen ions into the latter portions of the nephron (distal tubule). Although a
metabolic acidosis also occurs in those with renal insufficiency, the term RTA is reserved for individuals with poor
urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have
different syndromes and different causes.
The word acidosis refers to the tendency for RTA to lower the blood's pH. When the blood pH is below normal
(7.35), this is called acidemia. The metabolic acidosis caused by RTA is a normal anion gap acidosis.
An overview of types 1, 2, and 4 is presented below (type 3 is usually excluded from modern classifications):
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Type
47
Type 1
Type 2
Type 4
Location
Distal tubules
Proximal tubules
Adrenal
Acidosis?
Yes (severe)
Yes
Potassium
Hypokalemia
Hypokalemia
Hyperkalemia
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
48
Type 4 RTA
Type 4 RTA is not actually a tubular disorder at all nor does it have a
clinical syndrome similar to the other types of RTA described above. It
was included in the classification of renal tubular acidoses as it is
associated with a mild (normal anion gap) metabolic acidosis due to a
physiological reduction in proximal tubular ammonium excretion
(impaired ammoniagenesis), which is secondary to hypoaldosteronism,
and results in a decrease in urine buffering capacity. Its cardinal feature
is hyperkalemia, and measured urinary acidification is normal, hence it
is often called hyperkalemic RTA or tubular hyperkalemia.
Causes include:
History
Renal tubular acidosis was first described in 1935 by Lightwood and 1936 by Butler et al. in children. Baines et al.
first described it in adults in 1945.
It has been postulated the Dickens character, Tiny Tim in A Christmas Carol, was suffering from renal tubular
acidosis. [9]
References
[1]
[2]
[3]
[4]
[5]
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ N25. 8
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=588. 89
http:/ / omim. org/ entry/ 179800
http:/ / www. diseasesdatabase. com/ ddb11687. htm
http:/ / www. diseasesdatabase. com/ ddb11673. htm
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
49
OMIM
179830
DiseasesDB
11687
MedlinePlus
000497
MeSH
D000141
[4]
[2]
[8]
Proximal renal tubular acidosis (pRTA) or Type 2 Renal tubular acidosis (RTA) is a type of RTA caused by a
failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate
wasting and subsequent acidemia. The distal intercalated cells function normally, so the acidemia is less severe than
dRTA and the urine can acidify to a pH of less than 5.3. pRTA also has several causes, and may occasionally be
present as a solitary defect, but is usually associated with a more generalised dysfunction of the proximal tubular
cells called Fanconi's syndrome where there is also phosphaturia, glycosuria, aminoaciduria, uricosuria and tubular
proteinuria. The principal feature of Fanconi's syndrome is bone demineralization (osteomalacia or rickets) due to
phosphate wasting.
Causes
Familial disorders
Cystinosis
Galactosemia
Glycogen storage disease (type I)
Hereditary fructose intolerance
Lowe syndrome
Tyrosinemia
Wilson's disease
Acquired disorders
Amyloidosis
Multiple myeloma
Paroxysmal nocturnal hemoglobinuria
Toxins, such as HAART, ifosfamide, lead, and cadmium
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Treatment
Again this depends on oral bicarbonate supplementation. However, this will increase urinary bicarbonate wasting
and may well promote a bicarbonate diuresis. The amount of bicarbonate given may have to be very large, to stay
ahead of the urinary losses. Correction with oral bicarbonate may exacerbate urinary potassium losses and precipitate
hypokalemia. As with dRTA, reversal of the chronic acidosis should reverse bone demineralization.
Thiazide diuretics can also be used as treatment by making use of contraction alkalosis caused by them.
References
[1] http:/ / omim. org/ entry/ 179830
[2] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000497. htm
50
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
51
OMIM
179800
MedlinePlus
000493
MeSH
D000141
[1]
[8]
Symptoms
Because renal excretion is the primary means of eliminating acid from
the body, there is consequently a tendency towards acidemia. This
leads to the clinical features of dRTA;.
Normal anion gap metabolic acidosis/acidemia
Hypokalemia
Urinary stone formation (related to alkaline urine, hypercalciuria,
and low urinary citrate).
Nephrocalcinosis (deposition of calcium in the substance of the
kidney)
Bone demineralisation (causing rickets in children and osteomalacia
in adults)
The symptoms and sequelae of dRTA are variable and range from being completely asymptomatic, to loin pain and
hematuria from kidney stones, to failure to thrive and severe rickets in childhood forms as well as possible renal
failure and even death.
dRTA commonly leads to sodium loss and volume contraction, which causes a compensatory increase in blood
levels of aldosterone. Aldosterone causes increased resorption of sodium and loss of potassium in the collecting duct
of the kidney, so these increased aldosterone levels cause the hypokalemia which is a common symptom of dRTA.
Diagnosis
The acidosis is variable, and one may have dRTA with alpha intercalated cell failure without necessarily being
acidemic; this is termed incomplete dRTA. The diagnosis of dRTA can be made by the observation of a urinary pH of
greater than 5.3 in the face of a systemic acidemia (usually taken to be a serum bicarbonate of 20 mmol/l or less). In
the case of an incomplete dRTA, failure to acidify the urine following an oral acid loading challenge is often used as
a test. The test usually performed is the short ammonium chloride test, in which ammonium chloride capsules are
used as the acid load. More recently, an alternative test using furosemide and fludrocortisone has been described.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
52
Interestingly, dRTA has been proposed as a possible diagnosis for the unknown malady plaguing Tiny Tim in
Charles Dickens' A Christmas Carol.
Causes
Autoimmune disease. Classically Sjgren's syndrome, but it is also
associated with systemic lupus erythematosus, rheumatoid arthritis
and even hypergammaglobulinemia. Hypokalaemia is often severe
in these cases.
Hereditary causes include mutations of Band 3 the basolateral
bicarbonate transporter of the intercalated cell, which may be
transmitted in an autosomal dominant fashion in western European
cases, or in an autosomal recessive fashion in South East Asian
cases. The South East Asian cases are associated with more severe
hypokalemia. Other hereditary causes include mutations of subunits
of the apical proton pump vH+-ATPase, which are transmitted in an
autosomal recessive fashion, and may be associated with
sensorineural deafness.
Liver cirrhosis.
Nephrocalcinosis. While it is a consequence of dRTA, it can also be a cause; related to calcium-induced damage
of the cortical collecting duct.
Renal transplantation.
Sickle cell anemia.
Toxins, including ifosfamide (more commonly causing pRTA than dRTA), toluene, lithium carbonate and
amphotericin B.
Chronic urinary tract obstruction.
Possible side effect of IV-administered bisphosphonates, such as zoledronate (~10%)
Treatment
This is relatively straightforward. It involves correction of the acidemia with oral sodium bicarbonate, sodium citrate
or potassium citrate. This will correct the acidemia and reverse bone demineralisation. Hypokalemia and urinary
stone formation and nephrocalcinosis can be treated with potassium citrate tablets which not only replace potassium
but also inhibit calcium excretion and thus do not exacerbate stone disease as sodium bicarbonate or citrate may do.
References
[1] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000493. htm
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
53
Overview table
Characteristic
proximal
tubule
S1
S2
S3
loop of Henle
descending
limb
Distal
convoluted
tubule
connecting initial
cortical
medullary
tubule
collecting collecting collecting
tubule
ducts
ducts
reabsorption (% 50[]
compared to
filtered amount)
70
secretion (%
compared to
filtered amount)
60
reabsorption
(mmoles/day)
Concentration
electrical
driving force
(mV)
[1]
-3
+3
+15
-5 to +5
-40
chemical
driving force
(mV)
electrochemical
driving force
(mV)
apical transport
proteins
solvent drag
unknown
transporter
Urea
transporter
2?
unknown
transporter
urea
transporter
1
basolateral
transport
proteins
unknown
transporter
Urea
transporter
2?
unknown
transporter
urea
transporter
4
Other
reabsorption
features
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Ammonia
68
Ammonia
Redox properties of liquid ammonia
Li+ + e Li
2.24
3.04
K+ + e K
1.98
2.93
Na+ + e Na
1.85
2.71
Zn2+ + 2e Zn
0.53
0.76
NH4+ + e H2 + NH3
0.00
Cu2+ + 2e Cu
+0.43
+0.34
Ag+ + e Ag
+0.83
+0.80
The range of thermodynamic stability of liquid ammonia solutions is very narrow, as the potential for oxidation to
dinitrogen, E (N2 + 6NH4+ + 6e 8NH3), is only +0.04V. In practice, both oxidation to dinitrogen and reduction
to dihydrogen are slow. This is particularly true of reducing solutions: the solutions of the alkali metals mentioned
above are stable for several days, slowly decomposing to the metal amide and dihydrogen. Most studies involving
liquid ammonia solutions are done in reducing conditions; although oxidation of liquid ammonia is usually slow,
there is still a risk of explosion, particularly if transition metal ions are present as possible catalysts.
Biosynthesis
In certain organisms, ammonia is produced from
atmospheric nitrogen by enzymes called nitrogenases.
Main symptoms of hyperammonemia (ammonia reaching toxic
The overall process is called nitrogen fixation.
concentrations).
Although it is unlikely that biomimetic methods that
are competitive with the Haber process will be
developed, intense effort has been directed toward understanding the mechanism of biological nitrogen fixation. The
scientific interest in this problem is motivated by the unusual structure of the active site of the enzyme, which
consists of an Fe MoS ensemble.
7
Ammonia is also a metabolic product of amino acid deamination catalyzed by enzymes such as glutamate
dehydrogenase 1. Ammonia excretion is common in aquatic animals. In humans, it is quickly converted to urea,
which is much less toxic, particularly less basic. This urea is a major component of the dry weight of urine. Most
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Ammonia
reptiles, birds, insects, and snails excrete uric acid solely as nitrogenous waste.
In physiology
Ammonia also plays a role in both normal and abnormal animal physiology. It is biosynthesised through normal
amino acid metabolism and is toxic in high concentrations. The liver converts ammonia to urea through a series of
reactions known as the urea cycle. Liver dysfunction, such as that seen in cirrhosis, may lead to elevated amounts of
ammonia in the blood (hyperammonemia). Likewise, defects in the enzymes responsible for the urea cycle, such as
ornithine transcarbamylase, lead to hyperammonemia. Hyperammonemia contributes to the confusion and coma of
hepatic encephalopathy, as well as the neurologic disease common in people with urea cycle defects and organic
acidurias.
Ammonia is important for normal animal acid/base balance. After formation of ammonium from glutamine,
-ketoglutarate may be degraded to produce two molecules of bicarbonate, which are then available as buffers for
dietary acids. Ammonium is excreted in the urine, resulting in net acid loss. Ammonia may itself diffuse across the
renal tubules, combine with a hydrogen ion, and thus allow for further acid excretion.
Excretion
Ammonium ions are a toxic waste product of the metabolism in animals. In fish and aquatic invertebrates, it is
excreted directly into the water. In mammals, sharks, and amphibians, it is converted in the urea cycle to urea,
because it is less toxic and can be stored more efficiently. In birds, reptiles, and terrestrial snails, metabolic
ammonium is converted into uric acid, which is solid, and can therefore be excreted with minimal water loss.
Reference ranges for blood tests, comparing blood content of ammonia (shown in yellow near middle) with other
constituents
69
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Ammonia
References
"Aqua Ammonia" (http://www.airgasspecialtyproducts.com/Libraries/
Aqua_Ammonia_Technical_Data_Manual/Physical_Properties.sflb.ashx). airgasspecialtyproducts.com.
Archived (http://web.archive.org/web/20101119084300/http://airgasspecialtyproducts.com/Libraries/
Aqua_Ammonia_Technical_Data_Manual/Physical_Properties.sflb.ashx) from the original on 19 November
2010. Retrieved 28 November 2010.
Attribution
This articleincorporates text from a publication now in the public domain:Chisholm, Hugh, ed. (1911).
"Ammonia" (http://www.1911encyclopedia.com/Ammonia). Encyclopdia Britannica (11th ed.). Cambridge
University Press
Further reading
Bretherick, L., ed. (1986). Hazards in the Chemical Laboratory (4th ed.). London: Royal Society of Chemistry.
ISBN0-85186-489-9. OCLC 16985764 (http://www.worldcat.org/oclc/16985764).
Greenwood, Norman N.; Earnshaw, Alan (1997). Chemistry of the Elements (2nd ed.). ButterworthHeinemann.
ISBN0080379419.
Housecroft, C. E.; Sharpe, A. G. (2000). Inorganic Chemistry (1st ed.). New York: Prentice Hall.
ISBN978-0582310803.
Weast, R. C., ed. (1972). Handbook of Chemistry and Physics (53rd ed.). Cleveland, OH: Chemical Rubber Co.
External links
International Chemical Safety Card 0414 (http://www.inchem.org/documents/icsc/icsc/eics0414.htm)
(anhydrous ammonia), ilo.org.
International Chemical Safety Card 0215 (http://www.inchem.org/documents/icsc/icsc/eics0215.htm)
(aqueous solutions), ilo.org.
CID 222 (http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=222) from PubChem
"Ammoniac et solutions aqueuses" (http://www.inrs.fr/fichetox/ft16.html). Institut National de Recherche et
de Scurit. (French)
Emergency Response to Ammonia Fertilizer Releases (Spills) (http://www.ammoniaspills.org/) for the
Minnesota Department of Agriculture.ammoniaspills.org
National Institute for Occupational Safety and Health Ammonia Page (http://www.cdc.gov/niosh/topics/
ammonia), cdc.gov
NIOSH Pocket Guide to Chemical Hazards - Ammonia (http://www.cdc.gov/niosh/npg/npgd0028.html),
cdc.gov
73
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Urine
74
Urine
Urine (from Latin Urina, ae, f.) is a typically sterile liquid by-product of the body secreted by the kidneys through a
process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products,
many rich in nitrogen, that require elimination from the bloodstream. These by-products are eventually expelled
from the body during urination, the primary method for excreting water-soluble chemicals from the body. These
chemicals can be detected and analyzed by urinalysis. Certain disease conditions can result in
pathogen-contaminated urine.[1]
Physiology
Most animals have excretory systems for elimination of soluble toxic
wastes. In humans, soluble wastes are excreted primarily by the urinary
system and, to a lesser extent in terms of urea removed, by
perspiration. The urinary system consists of the kidneys, ureters,
urinary bladder, and urethra. The system produces urine by a process
of filtration, reabsorption, and tubular secretion. The kidneys extract
the soluble wastes from the bloodstream, as well as excess water,
sugars, and a variety of other compounds. The resulting urine contains
high concentrations of urea and other substances, including toxins.
Urine flows from the kidney through the ureter, bladder, and finally the
urethra before passing from the body.
Composition
Exhaustive detailed description of the composition of human urine can
be found in NASA Contractor Report No. NASA CR-1802, D. F.
Putnam, July 1971.[2] That report provided detailed chemical analyses
for inorganic and organic constituents, methods of analysis, chemical
and physical properties and its behavior during concentrative processes
such as evaporation, distillation and other physiochemical operations.
Urine is an aqueous solution of greater than 95% water, with the
remaining constituents, in order of decreasing concentration urea 9.3
g/L, chloride 1.87 g/L, sodium 1.17 g/L, potassium 0.750 g/L,
creatinine 0.670 g/L and other dissolved ions, inorganic and organic
compounds.
Urine is sterile until it reaches the urethra, where epithelial cells lining
the urethra are colonized by facultatively anaerobic Gram negative
rods and cocci. Subsequent to elimination from the body, urine can
acquire strong odors due to bacterial action,[citation needed] and in
particular the release of ammonia from the breakdown of urea.
Some diseases alter the quantity and consistency of urine, such as
diabetes introducing sugar. Consuming beets can result in beeturia
(pink/red urine containing betanin) for some 1014% of the population.
Urea structure
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Urine
75
Hazards
Healthy urine is not toxic.[3] However, it contains compounds
eliminated by the body as undesirable, and can be irritating to skin and
eyes. After suitable processing it is possible to extract potable water
from urine.
Characteristics
Chemical analysis
Urine is principally water. It also contains an assortment of inorganic
salts and organic compounds, including proteins, hormones, and a wide
range of metabolites, varying by what is introduced into the body.
Color
Urine varies in appearance, depending principally upon a body's level
of hydration, as well as other factors. Normal urine is a transparent
solution ranging from colorless to amber but is usually a pale yellow.
In the urine of a healthy individual the color comes primarily from the
presence of urobilin. Urobilin in turn is a final waste product resulting
from the breakdown of heme from hemoglobin during the destruction
of aging blood cells.
Colorless urine indicates over-hydration, generally preferable to
dehydration (though it can remove essential salts from the body).
Colorless urine in drug tests can suggest an attempt to avoid detection
of illicit drugs in the bloodstream through over-hydration.
Dark yellow urine is often indicative of dehydration.
Yellowing/light orange may be caused by removal of excess B
vitamins from the bloodstream.
Certain medications such as rifampin and phenazopyridine can cause orange urine.
Bloody urine is termed hematuria, a symptom of a wide variety of medical conditions.
Dark orange to brown urine can be a symptom of jaundice, rhabdomyolysis, or Gilbert's syndrome.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Urine
Odor
The odor of normal human urine can reflect what has been consumed or specific diseases. For example, an
individual with diabetes mellitus may present a sweetened urine odor. This can be due to kidney diseases as well,
such as kidney stones.
Eating asparagus can cause a strong odor reminiscent of the vegetable caused by the body's breakdown of
asparagusic acid. Likewise consumption of saffron, alcohol, coffee, tuna fish, and onion can result in telltale
scents.[citation needed] Particularly spicy foods can have a similar effect, as their compounds pass through the kidneys
without being fully broken down before exiting the body.[4]
Turbidity
Turbid (cloudy) urine may be a symptom of a bacterial infection, but can also be caused by crystallization of salts
such as calcium phosphate.[citation needed]
pH
The pH of urine can vary between 4.6 and 8, with neutral (7) being norm. In persons with hyperuricosuria, acidic
urine can contribute to the formation of stones of uric acid in the kidneys, ureters, or bladder. Urine pH can be
monitored by a physician or at home.
A diet high in citrus, vegetables, or dairy can increase urine pH (more basic).[5] Some drugs also can increase urine
pH, including acetazolamide, potassium citrate, and sodium bicarbonate.[citation needed]
A diet high in meat can decrease urine pH (more acidic).[citation needed] Cranberries, popularly thought to decrease the
pH of urine, have actually been shown not to acidify urine. Drugs that can decrease urine pH include ammonium
chloride, chlorothiazide diuretics, and methenamine mandelate.[6][7]
Volume
Average urine production in adult humans is about 1 2 L per day, depending on state of hydration, activity level,
environmental factors, weight, and the individual's health. Producing too much or too little urine needs medical
attention. Polyuria is a condition of excessive production of urine (> 2.5 L/day), oliguria when < 400 mL are
produced, and anuria one of < 100 mL per day.
76
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Urine
Urine in medicine
Examination
Many physicians in ancient history have resorted
to the inspection and examination of the urine of
their patients. Hermogenes wrote about the color
and other attributes of urine as indicators of certain
diseases. Abdul Malik Ibn Habib of Andalusia
d.862 AD, mentions numerous reports of urine
examination throughout the Umayyad empire.[8]
Diabetes mellitus got its name because the urine is
plentiful and sweet. A urinalysis is a medical
examination of the urine and part of routine
examinations. A culture of the urine is performed
A Doctor Examining Urine. Trophime Bigot.
when a urinary tract infection is suspected. A
microscopic examination of the urine may be
helpful to identify organic or inorganic substrates and help in the diagnosis.
The color and volume of urine can be reliable indicators of hydration level. Clear and copious urine is generally a
sign of adequate hydration. Dark urine is a sign of dehydration. The exception occurs when diuretics or excessive
amounts of alcohol[citation needed] or caffeine[citation needed] are consumed, in which case urine can be clear and
copious and the person still be dehydrated.
Source of Medications
Urine contains proteins and other substances that are useful for medical therapy and are ingredients in many
prescription drugs (e.g., Ureacin, Urecholine, Urowave).[citation needed] Urine from postmenopausal women is rich in
gonadotropins that can yield follicle stimulating hormone and luteinizing hormone for fertility therapy.[9] One such
commercial product is Pergonal.[10] Urine from pregnant women contains enough human chorionic gonadotropins
for commercial extraction and purification to produce hCG medication. Pregnant mare urine is the source of
estrogens, namely Premarin. Urine also contains antibodies, which can be used in diagnostic antibody tests for a
range of pathogens, including HIV-1.[11]
Other uses
Agriculture
Urine contains large quantities of nitrogen (mostly as urea), as well as significant quantities of dissolved phosphates
and potassium, the main macronutrients required by plants, with urine having plant macronutrient percentages (i.e.
NPK) of approximately 11-1-2 by one study or 15-1-2 by another report, illustrating that exact composition varies
with diet. Undiluted, it can chemically burn the roots of some plants, but it can be used safely as a source of
complementary nitrogen in carbon-rich compost.
When diluted with water (at a 1:5 ratio for container-grown annual crops with fresh growing medium each season, or
a 1:8 ratio for more general use), it can be applied directly to soil as a fertilizer. The fertilization effect of urine has
been found to be comparable to that of commercial fertilizers with an equivalent NPK rating. Urine contains most
(94% according to Wolgast) of the NPK nutrients excreted by the human body. Conversely, concentrations of heavy
metals such as lead, mercury, and cadmium, commonly found in solid human waste, are much lower in urine (though
not low enough to qualify for use in organic agriculture under current EU rules). The more general limitations to
77
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Urine
using urine as fertilizer then depend mainly on the potential for buildup of excess nitrogen (due to the high ratio of
that macronutrient), and inorganic salts such as sodium chloride, which are also part of the wastes excreted by the
renal system. The degree to which these factors impact the effectiveness depends on the term of use, salinity
tolerance of the plant, soil composition, addition of other fertilizing compounds, and quantity of rainfall or other
irrigation.
Urine typically contains 70% of the nitrogen and more than half the phosphorus and potassium found in urban waste
water flows, while making up less than 1% of the overall volume. Thus far, source separation, or urine diversion and
on-site treatment has been implemented in South Africa, China, and Sweden among other countries with the Bill and
Melinda Gates Foundation provided some of the funding implementations.[12] China reportedly had 685,000
operating source separation toilets spread out among 17 provinces in 2003.[13]
"Urine management" is a relatively new way to view closing the cycle of agricultural nutrient flows and reducing
sewage treatment costs and ecological consequences such as eutrophication resulting from the influx of nutrient rich
effluent into aquatic or marine ecosystems. Proponents of urine as a natural source of agricultural fertilizer claim the
risks to be negligible or acceptable. Their views seem to be backed by research showing there are more
environmental problems when it is treated and disposed of compared with when it is used as a resource.[14]
It is unclear whether source separation, urine diversion, and on-site urine treatment can be made cost effective; nor
whether required behavioral changes would be regarded as socially acceptable, as the largely successful trials
performed in Sweden may not readily generalize to other industrialized societies. In developing countries the use of
whole raw sewage (night soil) has been common throughout history, yet the application of pure urine to crops is rare.
Increasingly there are calls for urine's use as a fertilizer, such as a Scientific American article "Human urine is an
effective fertilizer".[15]
Cleaning
In pre-industrial times urine, being rich in ammonia, was used in the form of lant as a cleaning fluid.[16] Urine
was also used for whitening teeth in Ancient Rome.
Gunpowder
Urine was used before the development of a chemical industry in the manufacture of gunpowder. Urine, a nitrogen
source, was used to moisten straw or other organic material, which was kept moist and allowed to rot for several
months to over a year. The resulting salts were washed from the heap with water, which was evaporated to allow
collection of crude saltpeter crystals, that were usually refined before being used in making gunpowder.
Survival uses
The US Army Field Manual,[17] advises against drinking urine for survival. These guides explain that drinking urine
tends to worsen, rather than relieve dehydration due to the salts in it, and that urine should not be consumed in a
survival situation, even when there is no other fluid available. In hot weather survival situations where other sources
of water are not available, soaking cloth (a shirt for example) in urine and putting it on the head can help cool the
body.
During World War I the Germans experimented with numerous poisonous gases for use during war. After the first
German chlorine gas attacks, Allied troops were supplied with masks of cotton pads that had been soaked in urine. It
was believed that the ammonia in the pad neutralized the chlorine. These pads were held over the face until the
soldiers could escape from the poisonous fumes, although it is now known that chlorine gas reacts with urine to
produce toxic fumes (see chlorine and use of poison gas in World War I).[citation needed] The Vickers machine gun,
used by the British Army during World War 1, required water for cooling when fired so soldiers would resort to
urine if water was unavailable.
78
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Urine
Urban myth states that urine works well against jellyfish stings, and this scenario was demonstrated on a Season 4
episode of the NBC-TV show Friends, "The One With the Jellyfish", an early episode of the CBS-TV show Survivor
and the documentary film The Real Cancun. At best, it is ineffective and in some cases this treatment may make the
injury worse.[18][19][20]
Tanning
Tanners soaked animal skins in urine to remove hair fibersa necessary step in the preparation of leather.[citation
needed]
Textiles
Urine has often been used as a mordant to help prepare textiles, especially wool, for dyeing. In Scotland, the process
of "walking" (stretching) tweed cloth is preceded by soaking in urine.[21]
Metals
Because of its high nitrogen content, urine can be used to harden metal. In 1983, in an effort to cope with the high
pressures reached in a turbocharged racing engine, the BMW formula 1 engineering team strengthened their cars'
engine blocks by urinating on them.[22]
References
Notes
[1] Does a reservoir need emptying if someone urinates in it? (http:/ / www. bbc. co. uk/ news/ magazine-13874089). BBC Magazine. 22 June
2011. Retrieved on 2011-06-22.
[2] David F. Putnam Composition and Concentrative Properties of Human Urine (http:/ / ntrs. nasa. gov/ archive/ nasa/ casi. ntrs. nasa. gov/
19710023044_1971023044. pdf). NASA Contractor Report. July 1971
[3] Urine therapy (http:/ / www. vanderbilt. edu/ AnS/ psychology/ health_psychology/ Urine_Therapy. htm). Vanderbilt.edu (1992-10-16).
Retrieved on 2011-04-27.
[4] Foods that Affect the Odor of Urine (http:/ / web. archive. org/ web/ 20110713222322/ http:/ / www. livestrong. com/ article/
248141-foods-that-affect-the-odor-of-urine/ ). livestrong.com. December 27, 2010.
[5] Urine pH is an indicator of dietary acid-base load, fruit and vegetables and meat intakes: results from the European Prospective Investigation
into Cancer and Nutrition (EPIC)-Norfolk population study Br J Nutr. 2008 Jun;99(6):1335-43. Epub 2007 Nov 28 (http:/ / www. ncbi. nlm.
nih. gov/ pubmed/ 18042305)
79
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Urine
[6] Urine pH: MedlinePlus Medical Encyclopedia (http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 003583. htm). Nlm.nih.gov
(2011-03-28). Retrieved on 2011-04-27.
[7] Discovery Health "Urine PH Medical Dictionary" (http:/ / healthguide. howstuffworks. com/ urine-ph-dictionary. htm).
Healthguide.howstuffworks.com (2007-05-16). Retrieved on 2011-04-27.
[8] Ibn Habib, Abdul Malik d.862CE/283AH "Kitaab Tib Al'Arab" (The Book of Arabian Medicine), Published by Dar Ibn Hazm, Beirut,
Lebanon 2007(Arabic)
[9] Carrell, D.T., & Peterson, C. M. eds. (2010). Chapter 31, Artificial insemination: intrauterine insemination. 31.3.1.2 Gonadotrophins,
Reproductive endocrinology and infertility.(Excerpt, p. 489), New York, New York: Springer. DOI 10.1007/978-1-4419-1436-1 (http:/ /
books. google. ca/ books?id=lcBEheiufVcC& pg=PA489& lpg=PA489& dq=urine-derived+ gonadotropins& source=bl& ots=bcwNoc6zP3&
sig=5rt-D-RU9ipfKL3dvGbUHz9VWY0& hl=en& sa=X& ei=6odTUYWFB-eY2AXT7IHoCA& sqi=2& ved=0CFkQ6AEwBg#v=onepage&
q=urine-derived gonadotropins& f=false). Retrieved on 2013-03-26.
[10] [Adelson, Andrea. Wall Street; A Fertility Drug Grows Scarce. http:/ / www. nytimes. com/ 1995/ 02/ 26/ business/
wall-street-a-fertility-drug-grows-scarce. html New York Times 1995-02-26 Retrieved 2013-03-27.].
[11] Urine Antibody Tests: New Insights into the Dynamics of HIV-1 Infection Urnovitz et al. 45 (9): 1602 Clinical Chemistry (http:/ / www.
clinchem. org/ cgi/ content/ abstract/ 45/ 9/ 1602). Clinchem.org. Retrieved on 2011-04-27.
[12] South African city looks to turn urine into fertilizer, UN Office for the Coordination of Humanitarian Affairs, November 2010 (http:/ / www.
sanitationfinance. org/ blog/ urine-fertilizer-south-africa). Sanitationfinance.org (2010-11-13). Retrieved on 2011-12-07.
[13] water- and sanitation-related activities of GTZ focus on ecosan projects (http:/ / www. iwc-berlin. de/ medienpool/
iwc_m77_61000000012/ iwc_20071011140736_1_840856. pdf). (PDF) Retrieved on 2011-12-07.
[14] UDD-Toilets and urine management (http:/ / ecosanservices. org/ pdf/ UDD-ToiletsTraining material. pdf). (PDF). ecosanservices.org.
Retrieved on 2011-12-07.
[15] Mara Grunbaum Shown to be an effective agricultural fertilizer (http:/ / www. scientificamerican. com/ article.
cfm?id=human-urine-is-an-effective-fertilizer), Scientific American, July 2010. Retrieved on 2011-12-07.
[16] Sueton, Vespasian 23 English (http:/ / penelope. uchicago. edu/ Thayer/ E/ Roman/ Texts/ Suetonius/ 12Caesars/ Vespasian*. html#23),
Latin (http:/ / penelope. uchicago. edu/ Thayer/ L/ Roman/ Texts/ Suetonius/ 12Caesars/ Vespasian*. html#23). Cf. Dio Cassius, Roman
History, Book 65, chapter 14,5 English (http:/ / penelope. uchicago. edu/ Thayer/ E/ Roman/ Texts/ Cassius_Dio/ 65*. html#14),
Greek/French (66, 14) (http:/ / remacle. org/ bloodwolf/ historiens/ Dion/ livre66. htm)
[17] Water Procurement (http:/ / www. equipped. com/ 21-76/ ch6. pdf), US Army Field Manual
[18] Old Wives' Tale? Urine as Jellyfish Sting Remedy (http:/ / abcnews. go. com/ Health/ story?id=2283933& page=1). ABC News
(2006-08-08). Retrieved on 2011-04-27.
[19] Fact or Fiction?: Urinating on a Jellyfish Sting is an Effective Treatment (http:/ / www. sciam. com/ article. cfm?chanID=sa004&
articleID=EEC8FE59-E7F2-99DF-3F08DA1A6F42454F& ref=rss). Scientific American. 4 January 2007. Retrieved on 2011-04-27.
[20] Jellyfish Sting Treatment How to Treat a Jellyfish Sting (http:/ / firstaid. about. com/ od/ bitesstings/ ht/ 06_jellyfish. htm).
Firstaid.about.com. 22 August 2010. Retrieved on 2011-04-27.
[21] Mentioned by an interviewee in Lomax the Songhunter, a 2004 documentary film.
[22] Turbocharged Engines in Formula One. (http:/ / www. autoevolution. com/ news/ turbocharged-engines-in-formula-one-18108. html)
Autoevolution. 16 March 2010. Retrieved on 2013-10-31.
Further reading
Definition of oliguria and anuria (http://medres.med.ucla.edu/curriculum/lectures/acute_oliguria.htm)
Hermogenes on urine (http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&
ProduktNr=223979&Ausgabe=225203&ArtikelNr=13449)
"Urine." Oxford English Dictionary. October 29, 2008 OED.com (http://dictionary.oed.com/entrance.dtl)
Geoffrey Chaucer, Department of English. Dept. home page. October 3, 2006. Harvard University October 27,
2008 Harvard.edu (http://www.courses.fas.harvard.edu/~chaucer/)
Kelly, John F. " The Urine Cure and Other Curious Medical Treatments (http://www.wfmu.org/LCD/19/
urine.html)" Hippocrates Magazine. (May/June 1988)
80
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Urine
81
External links
Urinanalysis (http://www-medlib.med.utah.edu/WebPath/TUTORIAL/URINE/URINE.html) at the
University of Utah Eccles Health Sciences Library
Urine Chemistry (http://www.drugs.com/enc/urine-chemistry.html) at drugs.com
Urinary Health Education (http://www.redurine.com/urine.html) at redurine.com
Clearance (medicine)
In medicine, the clearance is a pharmacokinetic measurement of the renal excretion ability. Although clearance may
also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance.
Each substance has a specific clearance that depends on its filtration characteristics. Clearance is a function of
glomerular filtration, secretion from the peritubular capillaries to the nephron, and reabsorption from the nephron
back to the peritubular capillaries. Clearance is constant in first-order kinetics because a constant fraction of the drug
is eliminated per unit time, but it is variable in zero-order kinetics, because a constant amount of drug is eliminated
per unit time.[1]
Definition
When referring to the function of the
kidney, clearance is considered to be the
amount of liquid filtered out of the blood
that gets processed by the kidneys or the
amount of blood cleaned per time because it
has the units of a volumetric flow rate [
volume / time ]. However, it does not refer
to a real value; "the kidney does not
completely remove a substance from the
total renal plasma flow."[2] From a mass
transfer perspective and physiologically,
volumetric blood flow (to the dialysis
machine and/or kidney) is only one of
several factors that determine blood
concentration and removal of a substance
from the body. Other factors include the
mass transfer coefficient, dialysate flow and
dialysate
recirculation
flow
for
hemodialysis, and the glomerular filtration
rate and the tubular reabsorption rate, for the
kidney. A physiologic interpretation of
clearance (at steady-state) is that clearance
is a ratio of the mass generation and blood
(or plasma) concentration.
Its definition follows from the differential equation that describes exponential decay and is used to model kidney
function and hemodialysis machine function:
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Clearance (medicine)
82
Where:
is the mass generation rate of the substance - assumed to be a constant, i.e. not a function of time (equal to
zero for foreign substances/drugs) [mmol/min] or [mol/s]
t is dialysis time or time since injection of the substance/drug [min] or [s]
V is the volume of distribution or total body water [L] or [m]
K is the clearance [mL/min] or [m/s]
C is the concentration [mmol/L] or [mol/m] (in the USA often [mg/mL])
Derivation of equation
Equation 1 is derived from a mass balance:
where:
is a period of time
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Clearance (medicine)
83
and
and divides by
equation:
Where:
Co is the concentration at the beginning of dialysis or the initial concentration of the substance/drug (after it has
distributed) [mmol/L] or [mol/m]
e is the base of the natural logarithm
Steady-state solution
The solution to the above differential equation (9) at time infinity (steady state) is:
The above equation (10b) makes clear the relationship between mass removal and clearance. It states that (with a
constant mass generation) the concentration and clearance vary inversely with one another. If applied to creatinine
(i.e. creatinine clearance), it follows from the equation that if the serum creatinine doubles the clearance halves and
that if the serum creatinine quadruples the clearance is quartered.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Clearance (medicine)
Where:
When the substance "C" is creatinine, an endogenous chemical that is excreted only by filtration, the calculated
clearance is equivalent to the glomerular filtration rate. Inulin clearance is also used to estimate glomerular filtration
rate.
Note - the above equation (11) is valid only for the steady-state condition. If the substance being cleared is not at a
constant plasma concentration (i.e. not at steady-state) K must be obtained from the (full) solution of the differential
equation (9).
References
[1] Kaplan Step1 Pharmacology 2010, page 14
[2] Available at: (http:/ / www. sin-italy. org/ jnonline/ Vol17n1/ 166. html). Accessed on: Sept 2, 2007.
[3] Basic clinical pharmacokinetics, Page 32: Plasma protein binding (http:/ / books. google. dk/ books?id=JIajn4ebtq0C& pg=PA32&
lpg=PA32& dq=Plasma+ Protein+ Binding) By Michael E. Winter Edition: 4, illustrated Published by Lippincott Williams & Wilkins, 2003
ISBN 0-7817-4147-5, ISBN 978-0-7817-4147-7 511 pages
[4] Full Text (http:/ / ndt. oxfordjournals. org/ cgi/ reprint/ 13/ suppl_6/ 10)
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85
Blood pressure
Blood pressure
Diagnostics
D001795
[1]
Blood pressure (BP), sometimes referred to as arterial blood pressure, is the pressure exerted by circulating blood
upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification,
"blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, blood
pressure varies between a maximum (systolic) and a minimum (diastolic) pressure. The blood pressure in the
circulation is principally due to the pumping action of the heart. Differences in mean blood pressure are responsible
for blood flow from one location to another in the circulation. The rate of mean blood flow depends on the resistance
to flow presented by the blood vessels. Mean blood pressure decreases as the circulating blood moves away from the
heart through arteries and capillaries due to viscous losses of energy. Mean blood pressure drops over the whole
circulation, although most of the fall occurs along the small arteries and arterioles. Gravity affects blood pressure via
hydrostatic forces (e.g., during standing), and valves in veins, breathing, and pumping from contraction of skeletal
muscles also influence blood pressure in veins.
Blood pressure without further specification usually refers to the systemic arterial pressure measured at a person's
upper arm and is a measure of the pressure in the brachial artery, the major artery in the upper arm. A persons blood
pressure is usually expressed in terms of the systolic pressure over diastolic pressure and is measured in millimetres
of mercury (mmHg), for example 120/80.
Blood pressure varies in healthy people and animals, but its variation is under control by the nervous and endocrine
systems. Blood pressure that is pathologically low is called hypotension, and that which is pathologically high is
hypertension. Both have many causes and can range from mild to severe.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Blood pressure
86
Hypotension
< 90
< 60
Desired
90119
6079
Prehypertension
120139
8089
Stage 1 Hypertension
140159
9099
Stage 2 Hypertension
160179
100109
Hypertensive Emergency
180
110
The table on the right shows the classification of blood pressure adopted by the American Heart Association for
adults who are 18 years and older. It assumes the values are a result of averaging blood pressure readings measured
at two or more visits to the doctor.
In the UK, blood pressures are usually categorised into three groups; low (90/60 or lower), high (140/90 or higher),
and normal (values above 90/60 and below 130/80).[2][3]
Normal range of blood pressure
While average values for arterial pressure could be computed for a given population, there is often a large variation
from person to person; arterial pressure also varies in individuals from moment to moment. Additionally, the average
of any given population may have a questionable correlation with its general health; thus the relevance of such
average values is equally questionable. However, in a study of 100 human subjects with no known history of
hypertension, an average blood pressure of 120/80mmHg was found, which are currently classified as desirable or
"normal" values. Normal values fluctuate through the 24-hour cycle, with highest readings in the afternoons and
lowest readings at night.[4]
Various factors, such as age and sex, influence a person's average blood pressure and variations in it. In children, the
normal ranges are lower than for adults and depend on height.[5] As adults age, systolic pressure tends to rise and
diastolic tends to fall.[6] In the elderly, blood pressure tends to be above the normal adult range,[7] largely because of
reduced flexibility of the arteries. Also, an individual's blood pressure varies with exercise, emotional reactions,
sleep, digestion, time of day and circadian rhythm.
Differences between left and right arm blood pressure measurements tend to be random and average to nearly zero if
enough measurements are taken. However, in a small percentage of cases there is a consistent difference greater than
10mmHg which may need further investigation, e.g. for obstructive arterial disease.
The risk of cardiovascular disease increases progressively above 115/75mmHg. In the past, hypertension was only
diagnosed if secondary signs of high arterial pressure were present, along with a prolonged high systolic pressure
reading over several visits. Regarding hypotension, in practice blood pressure is considered too low only if
noticeable symptoms are present.
Clinical trials demonstrate that people who maintain arterial pressures at the low end of these pressure ranges have
much better long term cardiovascular health. The principal medical debate concerns the aggressiveness and relative
value of methods used to lower pressures into this range for those who do not maintain such pressure on their own.
Elevations, more commonly seen in older people, though often considered normal, are associated with increased
morbidity and mortality.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Blood pressure
87
75100 5070
80110 5080
School age
6 to 12 years
85120 5080
Adolescents
13 to 18 years
95140 6090
Physiology
There are many physical factors that influence arterial pressure. Each
of these may in turn be influenced by physiological factors, such as:
diet, exercise, disease, drugs or alcohol, stress, and obesity.
Some physical factors are:
Volume of fluid or blood volume, the amount of blood that is
present in the body. The more blood present in the body, the higher
the rate of blood return to the heart and the resulting cardiac output.
There is some relationship between dietary salt intake and increased
blood volume, potentially resulting in higher arterial pressure,
though this varies with the individual and is highly dependent on
autonomic nervous system response and the renin-angiotensin
system.
Resistance. In the circulatory system, this is the resistance of the blood vessels. The higher the resistance, the
higher the arterial pressure upstream from the resistance to blood flow. Resistance is related to vessel radius (the
larger the radius, the lower the resistance), vessel length (the longer the vessel, the higher the resistance), blood
viscosity, as well as the smoothness of the blood vessel walls. Smoothness is reduced by the build up of fatty
deposits on the arterial walls. Substances called vasoconstrictors can reduce the size of blood vessels, thereby
increasing blood pressure. Vasodilators (such as nitroglycerin) increase the size of blood vessels, thereby
decreasing arterial pressure. Resistance, and its relation to volumetric flow rate (Q) and pressure difference
between the two ends of a vessel are described by Poiseuille's Law.
Viscosity, or thickness of the fluid. If the blood gets thicker, the result is an increase in arterial pressure. Certain
medical conditions can change the viscosity of the blood. For instance, anemia (low red blood cell concentration),
reduces viscosity, whereas increased red blood cell concentration increases viscosity. It had been thought that
aspirin and related "blood thinner" drugs decreased the viscosity of blood, but instead studies found that they act
by reducing the tendency of the blood to clot.
In practice, each individual's autonomic nervous system responds to and regulates all these interacting factors so that,
although the above issues are important, the actual arterial pressure response of a given individual varies widely
because of both split-second and slow-moving responses of the nervous system and end organs. These responses are
very effective in changing the variables and resulting blood pressure from moment to moment.
Moreover, blood pressure is the result of cardiac output increased by peripheral resistance: blood pressure = cardiac
output X peripheral resistance. As a result, an abnormal change in blood pressure is often an indication of a problem
affecting the heart's output, the blood vessels' resistance, or both. Thus, knowing the patient's blood pressure is
critical to assess any pathology related to output and resistance.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
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88
Pulse pressure
The up and down fluctuation of the arterial pressure results from the
pulsatile nature of the cardiac output, i.e. the heartbeat. The pulse
pressure is determined by the interaction of the stroke volume of the
heart, compliance (ability to expand) of the aorta, and the resistance to
flow in the arterial tree. By expanding under pressure, the aorta absorbs
some of the force of the blood surge from the heart during a heartbeat.
In this way, the pulse pressure is reduced from what it would be if the
aorta wasn't compliant.[10] The loss of arterial compliance that occurs
with aging explains the elevated pulse pressures found in elderly
patients.
The pulse pressure can be simply calculated from the difference of the
measured systolic and diastolic pressures,
Armleg gradient
The armleg (blood pressure) gradient is the difference between the blood pressure measured in the arms and that
measured in the legs. It is normally less than 10 mmHg, but may be increased in e.g. coarctation of the aorta.
Vascular resistance
The larger arteries, including all large enough to see without magnification, are conduits with low vascular resistance
(assuming no advanced atherosclerotic changes) with high flow rates that generate only small drops in pressure. The
smaller arteries and arterioles have higher resistance, and confer the main blood pressure drop across major arteries
to capillaries in the circulatory system.
Vascular pressure wave
Modern physiology developed the concept of the vascular pressure wave (VPW). This wave is created by the heart
during the systole and originates in the ascending aorta. Much faster than the stream of blood itself, it is then
transported through the vessel walls to the peripheral arteries. There the pressure wave can be palpated as the
peripheral pulse. As the wave is reflected at the peripheral veins, it runs back in a centripetal fashion. When the
reflected wave meets the next outbound pressure wave, the pressure inside the vessel rises higher than the pressure in
the aorta. This concept explains why the arterial pressure inside the peripheral arteries of the legs and arms is higher
than the arterial pressure in the aorta, and in turn for the higher pressures seen at the ankle compared to the arm with
normal ankle brachial pressure index values.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Blood pressure
Regulation
The endogenous regulation of arterial pressure is not completely understood, but the following mechanisms of
regulating arterial pressure have been well-characterized:
Baroreceptor reflex: Baroreceptors in the high pressure receptor zones detect changes in arterial pressure. These
baroreceptors send signals ultimately to the medulla of the brain stem, specifically to the Rostral ventrolateral
medulla (RVLM). The medulla, by way of the autonomic nervous system, adjusts the mean arterial pressure by
altering both the force and speed of the heart's contractions, as well as the total peripheral resistance. The most
important arterial baroreceptors are located in the left and right carotid sinuses and in the aortic arch.[11]
Renin-angiotensin system (RAS): This system is generally known for its long-term adjustment of arterial
pressure. This system allows the kidney to compensate for loss in blood volume or drops in arterial pressure by
activating an endogenous vasoconstrictor known as angiotensin II.
Aldosterone release: This steroid hormone is released from the adrenal cortex in response to angiotensin II or high
serum potassium levels. Aldosterone stimulates sodium retention and potassium excretion by the kidneys. Since
sodium is the main ion that determines the amount of fluid in the blood vessels by osmosis, aldosterone will
increase fluid retention, and indirectly, arterial pressure.
Baroreceptors in low pressure receptor zones (mainly in the venae cavae and the pulmonary veins, and in the
atria) result in feedback by regulating the secretion of antidiuretic hormone (ADH/Vasopressin), renin and
aldosterone. The resultant increase in blood volume results an increased cardiac output by the FrankStarling law
of the heart, in turn increasing arterial blood pressure.
These different mechanisms are not necessarily independent of each other, as indicated by the link between the RAS
and aldosterone release. Currently, the RAS is targeted pharmacologically by ACE inhibitors and angiotensin II
receptor antagonists. The aldosterone system is directly targeted by spironolactone, an aldosterone antagonist. The
fluid retention may be targeted by diuretics; the antihypertensive effect of diuretics is due to its effect on blood
volume. Generally, the baroreceptor reflex is not targeted in hypertension because if blocked, individuals may suffer
from orthostatic hypotension and fainting.
Measurement
Arterial pressure is most commonly measured via a
sphygmomanometer, which historically used the height of a column of
mercury to reflect the circulating pressure. Blood pressure values are
generally reported in millimetres of mercury (mmHg), though aneroid
and electronic devices do not contain mercury.
For each heartbeat, blood pressure varies between systolic and diastolic
pressures. Systolic pressure is peak pressure in the arteries, which
occurs near the end of the cardiac cycle when the ventricles are
contracting. Diastolic pressure is minimum pressure in the arteries,
A medical student checking blood pressure using
which occurs near the beginning of the cardiac cycle when the
a sphygmomanometer and stethoscope.
ventricles are filled with blood. An example of normal measured
values for a resting, healthy adult human is 120mmHg systolic and 80mmHg diastolic (written as 120/80 mmHg,
and spoken as "one-twenty over eighty").
Systolic and diastolic arterial blood pressures are not static but undergo natural variations from one heartbeat to
another
and
throughout
the
day
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IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Blood pressure
90
Measuring pressure invasively, by penetrating the arterial wall to take the measurement, is much less common and
usually restricted to a hospital setting.
Noninvasive
The noninvasive auscultatory and oscillometric measurements are simpler and quicker than invasive measurements,
require less expertise, have virtually no complications, are less unpleasant and less painful for the patient. However,
noninvasive methods may yield somewhat lower accuracy and small systematic differences in numerical results.
Noninvasive measurement methods are more commonly used for routine examinations and monitoring.
Palpation
A minimum systolic value can be roughly estimated by palpation, most often used in emergency situations, but
should be used with caution. It has been estimated that, using 50% percentiles, carotid, femoral and radial pulses are
present in patients with a systolic blood pressure > 70 mmHg, carotid and femoral pulses alone in patients with
systolic blood pressure of > 50 mmHg, and only a carotid pulse in patients with a systolic blood pressure of > 40
mmHg.
A more accurate value of systolic blood pressure can be obtained with a sphygmomanometer and palpating the radial
pulse.[12] The diastolic blood pressure cannot be estimated by this method.[13] The American Heart Association
recommends that palpation be used to get an estimate before using the auscultatory method.
Auscultatory
The auscultatory method (from the Latin word for "listening") uses a
stethoscope and a sphygmomanometer. This comprises an inflatable
(Riva-Rocci) cuff placed around the upper arm at roughly the same
vertical height as the heart, attached to a mercury or aneroid
manometer. The mercury manometer, considered the gold standard,
measures the height of a column of mercury, giving an absolute result
without need for calibration and, consequently, not subject to the errors
and drift of calibration which affect other methods. The use of mercury
manometers is often required in clinical trials and for the clinical
measurement of hypertension in high-risk patients, such as pregnant
women.
A cuff of appropriate size is fitted smoothly and snugly, then inflated manually by repeatedly squeezing a rubber
bulb until the artery is completely occluded. Listening with the stethoscope to the brachial artery at the elbow, the
examiner
slowly
releases
the
pressure
in
the
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Blood pressure
cuff. When blood just starts to flow in the artery, the turbulent flow
creates a "whooshing" or pounding (first Korotkoff sound). The
pressure at which this sound is first heard is the systolic blood pressure.
The cuff pressure is further released until no sound can be heard (fifth
Korotkoff sound), at the diastolic arterial pressure.
The auscultatory method is the predominant method of clinical
measurement.[14]
Oscillometric
The oscillometric method was first demonstrated in 1876 and involves
the observation of oscillations in the sphygmomanometer cuff
pressure[15] which are caused by the oscillations of blood flow, i.e., the
Mercury manometer
pulse. The electronic version of this method is sometimes used in
long-term measurements and general practice. It uses a
sphygmomanometer cuff, like the auscultatory method, but with an electronic pressure sensor (transducer) to observe
cuff pressure oscillations, electronics to automatically interpret them, and automatic inflation and deflation of the
cuff. The pressure sensor should be calibrated periodically to maintain accuracy.
Oscillometric measurement requires less skill than the auscultatory technique and may be suitable for use by
untrained staff and for automated patient home monitoring.
The cuff is inflated to a pressure initially in excess of the systolic arterial pressure and then reduced to below
diastolic pressure over a period of about 30seconds. When blood flow is nil (cuff pressure exceeding systolic
pressure) or unimpeded (cuff pressure below diastolic pressure), cuff pressure will be essentially constant. It is
essential that the cuff size is correct: undersized cuffs may yield too high a pressure; oversized cuffs yield too low a
pressure. When blood flow is present, but restricted, the cuff pressure, which is monitored by the pressure sensor,
will vary periodically in synchrony with the cyclic expansion and contraction of the brachial artery, i.e., it will
oscillate. The values of systolic and diastolic pressure are computed, not actually measured from the raw data, using
an algorithm; the computed results are displayed.
Oscillometric monitors may produce inaccurate readings in patients with heart and circulation problems, which
include arterial sclerosis, arrhythmia, preeclampsia, pulsus alternans, and pulsus paradoxus [citation needed].
In practice the different methods do not give identical results; an algorithm and experimentally obtained coefficients
are used to adjust the oscillometric results to give readings which match the auscultatory results as well as possible.
Some equipment uses computer-aided analysis of the instantaneous arterial pressure waveform to determine the
systolic, mean, and diastolic points. Since many oscillometric devices have not been validated, caution must be given
as most are not suitable in clinical and acute care settings.
The term NIBP, for non-invasive blood pressure, is often used to describe oscillometric monitoring equipment.
Continuous noninvasive techniques (CNAP)
Continuous Noninvasive Arterial Pressure (CNAP) is the method of measuring arterial blood pressure in real-time
without any interruptions and without cannulating the human body. CNAP combines the advantages of the following
two clinical gold standards: it measures blood pressure continuously in real-time like the invasive arterial catheter
system and it is noninvasive like the standard upper arm sphygmomanometer. Latest developments in this field show
promising results in terms of accuracy, ease of use and clinical acceptance.
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Non-occlusive techniques: the Pulse Wave Velocity (PWV) principle
Since the 1990s a novel family of techniques based on the so-called pulse wave velocity (PWV) principle have been
developed. These techniques rely on the fact that the velocity at which an arterial pressure pulse travels along the
arterial tree depends, among others, on the underlying blood pressure. Accordingly, after a calibration maneuver,
these techniques provide indirect estimates of blood pressure by translating PWV values into blood pressure values.
The main advantage of these techniques is that it is possible to measure PWV values of a subject continuously
(beat-by-beat), without medical supervision, and without the need of inflating brachial cuffs. PWV-based techniques
are still in the research domain and are not adapted to clinical settings.
White-coat hypertension
For some patients, blood pressure measurements taken in a doctor's office may not correctly characterize their typical
blood pressure. In up to 25% of patients, the office measurement is higher than their typical blood pressure. This
type of error is called white-coat hypertension (WCH) and can result from anxiety related to an examination by a
health care professional. The misdiagnosis of hypertension for these patients can result in needless and possibly
harmful medication. WCH can be reduced (but not eliminated) with automated blood pressure measurements over 15
to 20 minutes in a quiet part of the office or clinic.[16]
Debate continues regarding the significance of this effect.[citation needed] Some reactive patients will react to many
other stimuli throughout their daily lives and require treatment. In some cases a lower blood pressure reading occurs
at the doctor's office.[17]
Home monitoring
Ambulatory blood pressure devices that take readings every half hour throughout the day and night have been used
for identifying and mitigating measurement problems like white-coat hypertension. Except for sleep, home
monitoring could be used for these purposes instead of ambulatory blood pressure monitoring. Home monitoring
may be used to improve hypertension management and to monitor the effects of lifestyle changes and medication
related to blood pressure. Compared to ambulatory blood pressure measurements, home monitoring has been found
to be an effective and lower cost alternative, but ambulatory monitoring is more accurate than both clinic and home
monitoring in diagnosing hypertension. Ambulatory monitoring is recommended for most patients before the start of
antihypertensive drugs.[18]
Aside from the white-coat effect, blood pressure readings outside of a clinical setting are usually slightly lower in the
majority of people. The studies that looked into the risks from hypertension and the benefits of lowering blood
pressure in affected patients were based on readings in a clinical environment.
When measuring blood pressure, an accurate reading requires that one not drink coffee, smoke cigarettes, or engage
in strenuous exercise for 30minutes before taking the reading. A full bladder may have a small effect on blood
pressure readings; if the urge to urinate arises, one should do so before the reading. For 5minutes before the reading,
one should sit upright in a chair with one's feet flat on the floor and with limbs uncrossed. The blood pressure cuff
should always be against bare skin, as readings taken over a shirt sleeve are less accurate. During the reading, the
arm that is used should be relaxed and kept at heart level, for example by resting it on a table.
Since blood pressure varies throughout the day, measurements intended to monitor changes over longer time frames
should be taken at the same time of day to ensure that the readings are comparable. Suitable times are:
immediately after awakening (before washing/dressing and taking breakfast/drink), while the body is still resting,
immediately after finishing work.
Automatic self-contained blood pressure monitors are available at reasonable prices, some of which are capable of
Korotkoff's measurement in addition to oscillometric methods, enabling irregular heartbeat patients to accurately
measure their blood pressure at home.
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Invasive
Arterial blood pressure (BP) is most accurately measured invasively through an arterial line. Invasive arterial
pressure measurement with intravascular cannulae involves direct measurement of arterial pressure by placing a
cannula needle in an artery (usually radial, femoral, dorsalis pedis or brachial).
The cannula must be connected to a sterile, fluid-filled system, which is connected to an electronic pressure
transducer. The advantage of this system is that pressure is constantly monitored beat-by-beat, and a waveform (a
graph of pressure against time) can be displayed. This invasive technique is regularly employed in human and
veterinary intensive care medicine, anesthesiology, and for research purposes.
Cannulation for invasive vascular pressure monitoring is infrequently associated with complications such as
thrombosis, infection, and bleeding. Patients with invasive arterial monitoring require very close supervision, as
there is a danger of severe bleeding if the line becomes disconnected. It is generally reserved for patients where rapid
variations in arterial pressure are anticipated.
Invasive vascular pressure monitors are pressure monitoring systems designed to acquire pressure information for
display and processing. There are a variety of invasive vascular pressure monitors for trauma, critical care, and
operating room applications. These include single pressure, dual pressure, and multi-parameter (i.e. pressure /
temperature). The monitors can be used for measurement and follow-up of arterial, central venous, pulmonary
arterial, left atrial, right atrial, femoral arterial, umbilical venous, umbilical arterial, and intracranial pressures.
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therefore the resistance is low.
In addition, flow rate (Q) is also the product of the cross-sectional area of the vessel and the average velocity
(Q=AV). Flow rate is directly proportional to the pressure drop in a tube or in this case a vessel. PQ. The
relationship is further described by Poisseulles equation P=8lQ/r4. As evident in the Poisseulles equation,
although flow rate is proportional to the pressure drop, there are other factors of blood vessels that contribute
towards the difference in pressure drop in bifurcations of blood vessels. These include viscosity, length of the vessel,
and radius of the vessel.
Factors that determine the flows resistance as described by Poiseuilles relationship:
P: pressure drop/gradient
: viscosity
l: length of tube. In the case of vessels with infinitely long lengths, l is replaced with diameter of the vessel.
Q: flow rate of the blood in the vessel
r: radius of the vessel
Assuming steady, laminar flow in the vessel, the blood vessels behavior is similar to that of a pipe. For instance if p1
and p2 are pressures are at the ends of the tube, the pressure drop/gradient is:
In the arterioles blood pressure is lower than in the major arteries. This is due to bifurcations, which cause a drop in
pressure. The more bifurcations, the higher the total cross-sectional area, therefore the pressure across the surface
drops. This is why the arterioles have the highest pressure-drop. The pressure drop of the arterioles is the product of
flow rate and resistance: P=Q xresistance. The high resistance observed in the arterioles, which factor largely in the
P is a result of a smaller radius of about 30m. The smaller the radius of a tube, the larger the resistance to fluid
flow.
Immediately following the arterioles are the capillaries. Following the logic obvserved in the arterioles, we expect
the blood pressure to be lower in the capillaries compared to the arterioles. Since pressure is a function of force per
unit area, (P=F/A), the larger the surface area, the lesser the pressure when an external force acts on it. Though the
radii of the capillaries are very small, the network of capillaries have the largest surface area in the vascular network.
They are known to have the largest surface area (485mm) in the human vascular network. The larger the total
cross-sectional area, the lower the mean velocity as well as the pressure.
Reynolds number also affects the blood flow in capillaries. Due to its smaller radius and lowest velocity compared
to other vessels, the Reynolds number at the capillaries is very low, resulting in laminar instead of turbulent flow.
The Reynolds number (denoted NR or Re) is a relationship that helps determine the behavior of a fluid in a tube, in
this case blood in the vessel. The equation for this dimensionless relationship is written as:
The Reynolds number is directly proportional to the velocity and diameter of the tube. Note that NR is directly
proportional to the mean velocity as well as the diameter. A Reynolds number of less than 2300 is laminar fluid
flow, which is characterized by constant flow motion, whereas a value of over 4000, is represented as turbulent flow.
Turbulent flow is characterized as chaotic and irregular flow.
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Disorders
Disregulation disorders of blood pressure control include: high blood pressure, low blood pressure, and blood
pressure that shows excessive or maladaptive fluctuation.
High
Arterial hypertension can be an indicator of
other problems and may have long-term
adverse effects. Sometimes it can be an
acute problem, for example hypertensive
emergency.
Levels of arterial pressure put mechanical
stress on the arterial walls. Higher pressures
increase heart workload and progression of
unhealthy tissue growth (atheroma) that
develops within the walls of arteries. The
higher the pressure, the more stress that is
present and the more atheroma tend to
progress and the heart muscle tends to
thicken, enlarge and become weaker over
time.
Persistent hypertension is one of the risk
factors for strokes, heart attacks, heart
Overview of main complications of persistent high blood pressure.
failure and arterial aneurysms, and is the
leading cause of chronic renal failure. Even moderate elevation of arterial pressure leads to shortened life
expectancy. At severely high pressures, mean arterial pressures 50% or more above average, a person can expect to
live no more than a few years unless appropriately treated.[20]
In the past, most attention was paid to diastolic pressure; but nowadays it is recognised that both high systolic
pressure and high pulse pressure (the numerical difference between systolic and diastolic pressures) are also risk
factors. In some cases, it appears that a decrease in excessive diastolic pressure can actually increase risk, due
probably to the increased difference between systolic and diastolic pressures (see the article on pulse pressure). If
systolic blood pressure is elevated (>140) with a normal diastolic blood pressure (<90), it is called "isolated systolic
hypertension" and may present a health concern.
For those with heart valve regurgitation, a change in its severity may be associated with a change in diastolic
pressure. In a study of people with heart valve regurgitation that compared measurements 2 weeks apart for each
person, there was an increased severity of aortic and mitral regurgitation when diastolic blood pressure increased,
whereas when diastolic blood pressure decreased, there was a decreased severity.
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Low
Blood pressure that is too low is known as hypotension. Hypotension is a medical concern if it causes signs or
symptoms, such as dizziness, fainting, or in extreme cases, shock.
When arterial pressure and blood flow decrease beyond a certain point, the perfusion of the brain becomes critically
decreased (i.e., the blood supply is not sufficient), causing lightheadedness, dizziness, weakness or fainting.
Sometimes the arterial pressure drops significantly when a patient stands up from sitting. This is known as
orthostatic hypotension (postural hypotension); gravity reduces the rate of blood return from the body veins below
the heart back to the heart, thus reducing stroke volume and cardiac output.
When people are healthy, the veins below their heart quickly constrict and the heart rate increases to minimize and
compensate for the gravity effect. This is carried out involuntarily by the autonomic nervous system. The system
usually requires a few seconds to fully adjust and if the compensations are too slow or inadequate, the individual will
suffer reduced blood flow to the brain, dizziness and potential blackout. Increases in G-loading, such as routinely
experienced by aerobatic or combat pilots 'pulling Gs', greatly increases this effect. Repositioning the body
perpendicular to gravity largely eliminates the problem.
Other causes of low arterial pressure include:
Sepsis
Shock is a complex condition which leads to critically decreased perfusion. The usual mechanisms are loss of blood
volume, pooling of blood within the veins reducing adequate return to the heart and/or low effective heart pumping.
Low arterial pressure, especially low pulse pressure, is a sign of shock and contributes to and reflects decreased
perfusion.
If there is a significant difference in the pressure from one arm to the other, that may indicate a narrowing (for
example, due to aortic coarctation, aortic dissection, thrombosis or embolism) of an artery .
Fluctuating blood pressure
Normal fluctuation in blood pressure is adaptive and necessary. Fluctuations in pressure that are significantly greater
than the norm are associated with greater white matter hyperintensity, a finding consistent with reduced local
cerebral blood flow[21] and a heightened risk of cerebrovascular disease.[22] Within both high- and low-blood
pressure groups, a greater degree of fluctuation was found to correlate with an increase in cerebrovascular disease
compared to those with less variability, suggesting the consideration of the clinical management of blood pressure
fluctuations, even among normotensive older adults. Older individuals and those who had received blood pressure
medications were more likely to exhibit larger fluctuations in pressure.
At other sites
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97
Site
Normal
pressure
range
[23]
(in mmHg)
38
1530
diastolic 38
Pulmonary artery pressure systolic
1530
diastolic 412
Pulmonary vein/
215
Pulmonary capillary wedge pressure
Left ventricular pressure
systolic
100140
diastolic 3-12
Blood pressure generally refers to the arterial pressure in the systemic circulation. However, measurement of
pressures in the venous system and the pulmonary vessels plays an important role in intensive care medicine but
requires an invasive central venous catheter.
Pulmonary pressure
Normally, the pressure in the pulmonary artery is about 15 mmHg at rest.[24]
Increased blood pressure in the capillaries of the lung cause pulmonary hypertension, with interstitial edema if the
pressure increases to above 20 mmHg, and to frank pulmonary edema at pressures above 25 mmHg.[25]
where
P is the blood pressure
t is the wall thickness
r is the inside radius of the cylinder.
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Blood pressure
98
For the thin-walled assumption to be valid the vessel must have a wall thickness of no more than about one-tenth
(often cited as one twentieth) of its radius.
The cylinder stress, in turn, is the average force exerted
circumferentially (perpendicular both to the axis and to the radius of
the object) in the cylinder wall, and can be described as:
where:
F is the force exerted circumferentially on an area of the cylinder
wall that has the following two lengths as sides:
t is the radial thickness of the cylinder
l is the axial length of the cylinder
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D001795
[2] NHS choices: What is blood pressure? (http:/ / www. nhs. uk/ chq/ pages/ what-is-blood-pressure. aspx?categoryid=201&
subcategoryid=201) Retrieved 2012-03-27
[3] NHS choices: High blood pressure (hypertension) (http:/ / www. nhs. uk/ conditions/ Blood-pressure-(high)/ Pages/ Introduction. aspx)
Retrieved 2012-03-27
[4] Table: Comparison of ambulatory blood pressures and urinary norepinephrine and epinephrine excretion measured at work, home, and during
sleep between EuropeanAmerican (n = 110) and AfricanAmerican (n = 51) women (http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/
PMC2655229/ table/ T2/ )
[5] (Note that the median blood pressure is given by the 50th percentile and hypertension is defined by the 95th percentile for a given age, height,
and gender.)
[6] See Isolated Systolic Hypertension.
[7] "...more than half of all Americans aged 65 or older have hypertension."
[8] PEDIATRIC AGE SPECIFIC (http:/ / hr. uclahealth. org/ workfiles/ AgeSpecificSLM-Peds. pdf), page 6. Revised 6/10. By Theresa
Kirkpatrick and Kateri Tobias. UCLA Health System
[9] Archived version 2009-10-03 (http:/ / www. webcitation. org/ 5kGLMdqnn)
[10] Archived version 2009-10-03 (http:/ / www. webcitation. org/ 5kGLuC47S)
[11] Archived version 2009-10-03 (http:/ / www. cvphysiology. com/ Blood Pressure/ BP012. htm)
[12] Interpretation Blood Pressure Vitals (http:/ / bcs. medinfo. ufl. edu/ sample/ page06. html), University of Florida
[13] G8 Secondary Survey (http:/ / www. gov. mb. ca/ health/ ems/ guidelines/ G8. pdf), "Manitoba"
[14] See Blood Pressure Measurement Methods.
[15] See The Oscillometric Technique.
[16] See White Coat Hypertension or Isolated Office Hypertension.
[17] See Masked Hypertension or Isolated Ambulatory Hypertension.
[18] Kate Lovibond, Sue Jowett, Pelham Barton, Mark Caulfield et al. " Cost-effectiveness of options for the diagnosis of high blood pressure in
primary care: a modelling study (http:/ / www. thelancet. com/ journals/ lancet/ article/ PIIS0140-6736(11)61184-7/ fulltext)", The Lancet, 24
August 2011. Retrieved 24 August 2011.
[19] Sharon, S. M. & Emily, S. M.(2006). Foundations of Maternal-Newborn Nursing. (4th ed p.476). Philadelphia:Elsevier.
[20] Textbook of Medical Physiology, 7th Ed., Guyton & Hall, Elsevier-Saunders, ISBN 0-7216-0240-1, page 220.
[21] Thomas, A.J., Perry, R., Barber, R., Kalaria, R.N., OBrien, J.T. (2002)
" Pathologies and pathological mechanisms for white matter hyperintensities in depression (http:/ / www3.
interscience.wiley.com/journal/120778635/abstract)," '
'Ann N Y Acad Sci., 977:333339.
[22] Brickman AM, Reitz C, Luchsinger JA, Manly JJ, Schupf N, Muraskin J, DeCarli C, Brown TR, Mayeux R.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Blood pressure
PMCID PMC2917204 Free Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917204/?tool=pubmed
NIHMSID NIHMS216309
http://archneur.ama-assn.org/cgi/content/short/67/5/564
[23] Table 30-1 in:
[24] What Is Pulmonary Hypertension? (http:/ / www. nhlbi. nih. gov/ health/ dci/ Diseases/ pah/ pah_what. html) From Diseases and Conditions
Index (DCI). National Heart, Lung, and Blood Institute. Last updated September 2008. Retrieved on 6 April 2009.
[25] Chapter 41, page 210 in: Cardiology secrets (http:/ / books. google. com/ books?id=IYFAsxAUA_MC& printsec=frontcover#PPR3,M1) By
Olivia Vynn Adair Edition: 2, illustrated Published by Elsevier Health Sciences, 2001 ISBN 1-56053-420-6, ISBN 978-1-56053-420-4
Further reading
Pickering, TG; Hall, JE; Appel, LJ et al. (2005). "Recommendations for blood pressure measurement in humans
and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the
Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood
Pressure Research" (http://hyper.ahajournals.org/cgi/content/full/45/1/142). Hypertension 45 (5): 14261.
doi: 10.1161/01.HYP.0000150859.47929.8e (http://dx.doi.org/10.1161/01.HYP.0000150859.47929.8e).
PMID 15611362 (http://www.ncbi.nlm.nih.gov/pubmed/15611362). Retrieved 2009-10-01.
External links
Blood Pressure Association (UK)ension/ Pulmonary Hypertension (http://www.bpassoc.org.uk), Cleveland
Clinic Center for Continuing Education
About High Blood Pressure (http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/
AboutHighBloodPressure/About-High-Blood-Pressure_UCM_002050_Article.jsp), American Heart Association
Control of Blood Pressure (http://pie.med.utoronto.ca/CA/CA_content/CA_cardiacPhys_intro.html),
Toronto General Hospital
Blood Pressure Chart (http://www.vaughns-1-pagers.com/medicine/blood-pressure.htm), Vaughn's
Summaries
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Erythropoietin
100
Erythropoietin
Erythropoietin
Available structures
PDB Ortholog search: PDBe [1], RCSB [2]
List of PDB id codes
1BUY
[3]
, 1CN4
[4]
, 1EER
[5]
Identifiers
[6]
Symbols
EPO
External IDs
OMIM: 133170
; EP; MVCD2
[7]
MGI: 95407
[8]
HomoloGene: 624
[9]
ChEMBL: 5837
[10]
[11]
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101
Gene Ontology
Molecular function erythropoietin receptor binding [12]
[13]
hormone activity
[14]
protein binding
[15]
protein kinase activator activity
[16]
eukaryotic cell surface binding
Cellular component extracellular region [17]
[18]
extracellular space
Biological process
[19]
apoptotic process
[20]
signal transduction
[21]
embryo implantation
[22]
aging
[23]
blood circulation
[24]
positive regulation of cell proliferation
[25]
response to salt stress
[26]
negative regulation of sodium ion transport
[27]
peptidyl-serine phosphorylation
[28]
negative regulation of ion transmembrane transporter activity
[29]
response to lipopolysaccharide
[30]
negative regulation of myeloid cell apoptotic process
[31]
response to vitamin A
[32]
cellular response to stress
[33]
response to testosterone stimulus
[34]
positive regulation of tyrosine phosphorylation of Stat5 protein
[35]
hemoglobin biosynthetic process
[36]
negative regulation of apoptotic process
[37]
erythrocyte maturation
[38]
response to estrogen stimulus
[39]
positive regulation of neuron differentiation
[40]
positive regulation of DNA replication
[41]
positive regulation of transcription, DNA-dependent
[42]
positive regulation of Ras protein signal transduction
[43]
response to axon injury
[44]
response to electrical stimulus
[45]
response to hyperoxia
regulation of transcription from RNA polymerase II promoter in response to hypoxia
[46]
[47]
response to interleukin-1
[48]
cellular response to hypoxia
[49]
cellular hyperosmotic response
Sources: Amigo
[50]
/ QuickGO
[51]
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Erythropoietin
102
[52]
Orthologs
Species
Human
Mouse
Entrez
2056
Ensembl
ENSG00000130427
UniProt
P01588
RefSeq (mRNA)
NM_000799
RefSeq (protein)
NP_000790
[53]
13856
[55]
[57]
[54]
ENSMUSG00000029711
P07321
[59]
[61]
[58]
NM_007942
NP_031968
[60]
[62]
Chr 5:
[64]
137.48 137.53 Mb
PubMed search
[66]
[65]
[56]
Function
Primary role in red blood cell production
Erythropoietin is an essential hormone for red cell production. Without it, definitive erythropoiesis does not take
place. Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red
blood cells by targeting CFU-E, proerythroblast and basophilic erythroblast subsets in the differentiation.
Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone
marrow in humans) by promoting their survival through protecting these cells from apoptosis.
Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., IL-3, IL-6,
glucocorticoids, and SCF) involved in the development of erythroid lineage from multipotent progenitors. The
burst-forming unit-erythroid (BFU-E) cells start erythropoietin receptor expression and are sensitive to
erythropoietin. Subsequent stage, the colony-forming unit-erythroid (CFU-E), expresses maximal erythropoietin
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Erythropoietin
receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the
proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it.
Mechanism of action
Erythropoietin has been shown to exert its effects by binding to the erythropoietin receptor (EpoR).
EPO is highly glycosylated (40% of total molecular weight), with half-life in blood around five hours. EPO's
half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other
alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring
less frequent injections). EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a
JAK2 signaling cascade. Erythropoietin receptor expression is found in a number of tissues, such as bone marrow
and peripheral/central nervous tissue. In the bloodstream, red cells themselves do not express erythropoietin receptor,
so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin
levels has been reported, a process termed neocytolysis.
Medical uses
Erythropoietins available for use as therapeutic agents are produced by recombinant DNA technology in cell culture,
and include Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa); they are used in treating anemia resulting
from chronic kidney disease, inflammatory bowel disease (Crohn's disease and ulcer colitis) and myelodysplasia
from the treatment of cancer (chemotherapy and radiation), but include boxed warnings of increased risk of death,
myocardial infarction, stroke, venous thromboembolism, tumor recurrence, and other severe off-target effects.
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104
Available forms
Recombinant EPO has a variety of glycosylation patterns giving rise to alfa, beta, delta, and omega forms:
epoetin alfa:
epoetin beta:
epoetin delta:
Darbepoetin (Aranesp)
Epocept (Lupin pharma)
Nanokine (Nanogen Pharmaceutical biotechnology, Vietnam
Epofit (Intas pharma)
Epogen, made by Amgen
Epogin
Eprex, made by Janssen-Cilag
Binocrit, made by Sandoz
Procrit
Silapo (Stada)
Retacrit (Hospira)
Miscellaneous:
epoetin omega:
Epomax
Darbepoetin alfa is a form created by five substitutions (Asn-57, Thr-59, Val-114, Asn-115 and Thr-117) that create
two new N-glycosylation sites.
More recently, a novel erythropoiesis-stimulating protein (NESP) has been produced. This glycoprotein
demonstrates anti-anemic capabilities and has a longer terminal half-life than erythropoietin. NESP offers chronic
renal-failure patients a lower dose of hormones to maintain normal hemoglobin levels.
Blood doping
Erythropoiesis-stimulating agents (ESAs) have a history of use as blood doping agents in endurance sports, such as
horseracing, boxing, cycling, rowing, distance running, race walking, snowshoeing, cross country skiing, biathlon,
and triathlon. The overall oxygen delivery system (blood oxygen levels, as well as heart stroke volume,
vascularization, and lung function) is one of the major limiting factors to muscles' ability to perform endurance
exercise. Therefore, the primary reason athletes may use ESAs is to improve oxygen delivery to muscles, which
directly improves their endurance capacity. With the advent of recombinant erythropoietin in the 1990s, the practice
of autologous and homologous blood transfusion has been partially replaced by injecting erythropoietin such that the
body naturally produces its own red cells. ESAs increase hematocrit (% of blood volume that is red cell mass) and
total red cell mass in the body, providing a good advantage in sports where such practice is banned. In addition to
ethical considerations in sports, providing an increased red cell mass beyond the natural levels reduces blood flow
due to increased viscosity, and increases the likelihood of thrombosis and stroke. Due to dangers associated with
using ESAs, their use should be limited to the clinic where anemic patients are boosted back to normal hemoglobin
levels (as opposed to going above the normal levels for performance advantage, leading to an increased risk of
death).
Though EPO was believed to be widely used in the 1990s in certain sports, there was no way at the time to directly
test for it, until in 2000, when a test developed by scientists at the French national antidoping laboratory (LNDD) and
endorsed by the World Anti-Doping Agency (WADA) was introduced to detect pharmaceutical EPO by
distinguishing it from the nearly identical natural hormone normally present in an athlete's urine.
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Erythropoietin
In 2002, at the Winter Olympic Games in Salt Lake City, Dr. Don Catlin, the founder and then-director of the UCLA
Olympic Analytical Lab, reported finding darbepoetin alfa, a form of erythropoietin, in a test sample for the first
time in sports. At the 2012 Summer Olympics in London, Alex Schwazer, the gold medalist in the 50-kilometer race
walk in the 2008 Summer Olympics in Beijing, tested positive for EPO and was disqualified.[67]
Since 2002, EPO tests performed by US sports authorities have consisted of only a urine or "direct" test. From
20002006, EPO tests at the Olympics were conducted on both blood and urine. However, several compounds have
been identified that can be taken orally to stimulate endogenous EPO production. Most of the compounds stabilize
the hypoxia-inducible transcription factors which activate the EPO gene. The compounds include oxo-glutarate
competitors, but also simple ions such as cobalt(II) chloride. [68]
Cycling
Synthetic EPO is believed to have come into use in cycling about 1990. In theory, EPO use can increase VO2max by
a significant amount, making it useful for endurance sports like cycling. Italian antidoping advocate Sandro Donati
has claimed that the history of doping in cycling can be traced to the Italian Dr Francesco Conconi at the University
of Ferrara. Conconi had worked on the idea of giving athletes tranfusions of their own blood in the 1980s. Donati felt
this work "opened the road to EPO . . . because blood doping was a trial to understand the role of EPO".
Dr Michele Ferrari, a former student and mentee of Conconi, had a controversial interview mentioning the drug in
1994, just after his Gewiss-Ballan team had a remarkable performance in the La Flche Wallonne race. Ferrari told
l'Equipe journalist Jean-Michel Rouet that EPO had no "fundamental" effect on performance and that if his riders
used it, it wouldn't "scandalize" himself. After the journalist pointed out several riders were suspected of dying from
EPO, Ferrari said EPO was not dangerous, and only abuse of it was dangerous, saying, "It's also dangerous to drink
10 liters of orange juice." The 'orange juice' comment has been widely misquoted.[69] Ferrari was fired shortly after,
but continued to work in the industry. That same year, Sandro Donati, working for the Italian National Olympic
Committee, presented a report accusing Conconi of being linked to the use of EPO in the sport.
In 1997, the Union Cycliste Internationale (UCI) instituted a new rule that riders testing above 50% haematocrit
were not allowed to race. Robert Millar, former racer, later wrote for Cycling News that the 50% limit was "an open
invitation to dope to that level", pointing out that normally haematocrit levels would start "around 40-42%" and drop
during the course of a "grand tour", but after EPO, they were staying at 50% for "weeks at a time". By 1998, EPO
use had become widespread, and the Festina affair tarnished the 1998 Tour de France. One manager offered a
270,000-franc-per-month raise to Christophe Bassons if he would use EPO, but Bassons refused.
In the 1998 Tour de France Stuart O'Grady won one stage, held the Tour de France yellow jersey for three days, and
came second in the points classification with the assistance of EPO. In 2010, Floyd Landis admitted to using
performance-enhancing drugs, including EPO, throughout his career as a professional cyclist. In 2012, the USADA
released a report on its investigation into the US Postal Service cycling team and blood doping. The report contained
affidavits from numerous riders on the team, including Frankie Andreu, Tyler Hamilton, George Hincapie, Floyd
Landis, Levi Leipheimer, and others, outlining that they, and Lance Armstrong, used a cocktail of
performance-enhancing substances for the Tour de France, most notably EPO, during the 1999 tour. Armstrong was
later stripped of his seven tour wins by USADA, and the UCI concurred with the decision. Tour organisers have
removed Armstrong's name and results from the race's history. Witnesses testified that code words used for EPO
included "Edgar", "Poe", "Edgar Allen Poe", and "Zumo" (Spanish for 'juice').
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History
In 1905, Paul Carnot, a professor of medicine in Paris, and his assistant, Clotilde Deflandre, proposed the idea that
hormones regulate the production of red blood cells. After conducting experiments on rabbits subject to bloodletting,
Carnot and Deflandre attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called
hemopoietin. Eva Bonsdorff and Eeva Jalavisto continued to study red cell production and later called the
hemopoietic substance 'erythropoietin'. Further studies investigating the existence of EPO by K.R. Reissman
(unknown location) and Allan J. Erslev (Thomas Jefferson Medical College) demonstrated that a certain substance,
circulated in the blood, is able to stimulate red blood cell production and increase hematocrit. This substance was
finally purified and confirmed as erythropoietin, opening doors to therapeutic uses for EPO in diseases such as
anemia.
Haematologist John Adamson and nephrologist Joseph W. Eschbach looked at various forms of renal failure and the
role of the natural hormone EPO in the formation of red blood cells. Studying sheep and other animals in the 1970s,
the two scientists helped establish that EPO stimulates the production of red cells in bone marrow and could lead to a
treatment for anemia in humans. In 1968, Goldwasser and Kung began work to purify human EPO, and managed to
purify milligram quantities of over 95% pure material by 1977. Pure EPO allowed the amino acid sequence to be
partially identified and the gene to be isolated. Later, an NIH-funded researcher at Columbia University discovered a
way to synthesize EPO. Columbia University patented the technique, and licensed it to Amgen. Controversy has
ensued over the fairness of the rewards that Amgen reaped from NIH-funded work, and Goldwasser was never
financially rewarded for his work.
In the 1980s, Adamson, Joseph W. Eschbach, Joan C. Egrie, Michael R. Downing and Jeffrey K. Browne conducted
a clinical trial at the Northwest Kidney Centers for a synthetic form of the hormone, Epogen, produced by Amgen.
The trial was successful, and the results were published in the New England Journal of Medicine in January 1987.
In 1985, Lin et al isolated the human erythropoietin gene from a genomic phage library and were able to characterize
it for research and production. Their research demonstrated the gene for erythropoietin encoded the production of
EPO in mammalian cells that is biologically active in vitro and in vivo. The industrial production of recombinant
human erythropoietin (RhEpo) for treating anemia patients would begin soon after.
In 1989, the US Food and Drug Administration approved the hormone Epogen, which remains in use today.
References
[1] http:/ / www. ebi. ac. uk/ pdbe/ searchResults. html?display=both&
term=P01588%20or%20P33707%20or%20P48617%20or%20P07321%20or%20Q0VED9%20or%20P29676%20or%20B1N8Y1
[2] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=UpAccessionIdQuery&
accessionIdList=P01588,P33707,P48617,P07321,Q0VED9,P29676,B1N8Y1
[3] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1BUY
[4] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1CN4
[5] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1EER
[6] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=3415
[7] http:/ / omim. org/ entry/ 133170
[8] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:95407
[9] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=624
[10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ target/ inspect/ CHEMBL5837
[11] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=2056
[12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005128
[13] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005179
[14] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005515
[15] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030295
[16] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043499
[17] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005576
[18] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005615
[19] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006915
106
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Erythropoietin
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007165
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007566
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007568
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008015
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008284
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0009651
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0010766
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0018105
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032413
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032496
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0033033
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0033189
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0033554
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0033574
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042523
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042541
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043066
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043249
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043627
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045666
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045740
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045893
[42] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0046579
[43] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0048678
[44] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051602
[45] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0055093
[46] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0061418
[47] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0070555
[48] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0071456
[49] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0071474
[50] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P01588
[51] http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P01588
[52] http:/ / biogps. org/ gene/ 2056/
[53] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=2056& rn=1
[54] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=13856& rn=1
[55] http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000130427;db=core
[56] http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000029711;db=core
[57] http:/ / www. uniprot. org/ uniprot/ P01588
[58] http:/ / www. uniprot. org/ uniprot/ P07321
[59] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_000799
[60] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_007942
[61] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_000790
[62] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_031968
[63] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr7:100318423-100321323
[64] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr5:137482259-137533242
[65] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=2056
[66] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=13856
[67] "Ousted Olympic race walk champion says he bought EPO in Turkey, hid it in refrigerator at home" (http:/ / www. washingtonpost. com/
sports/ olympics/ 2008-olympic-race-walk-champ-i-bought-epo-in-turkey-hid-doping-from-kostner-im-destroyed/ 2012/ 08/ 29/
5c7b3c7a-e14d-11e1-89f7-76e23a982d06_story. html) Associated Press story in the Washington Post (August 8, 2012)
[68] W. Jelkmann: The disparate roles of cobalt in erythropoiesis, and doping relevance. Open Journal of Hematology, 2012, 3-6. http:/ /
rossscience. org/ ojhmt/ 2075-907X-3-6. php
[69] 10 liters of orange juice: see the article on Water intoxication, for example.
107
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Erythropoietin
Further reading
Takeuchi M, Kobata A (1992). "Structures and functional roles of the sugar chains of human erythropoietins".
Glycobiology 1 (4): 33746. doi: 10.1093/glycob/1.4.337 (http://dx.doi.org/10.1093/glycob/1.4.337).
PMID 1820196 (http://www.ncbi.nlm.nih.gov/pubmed/1820196).
Semba RD, Juul SE (2002). "Erythropoietin in human milk: physiology and role in infant health". Journal of
human lactation : official journal of International Lactation Consultant Association 18 (3): 25261. PMID
12192960 (http://www.ncbi.nlm.nih.gov/pubmed/12192960).
Ratcliffe PJ (2003). "From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia
signal pathway". Blood Purif. 20 (5): 44550. doi: 10.1159/000065201 (http://dx.doi.org/10.1159/
000065201). PMID 12207089 (http://www.ncbi.nlm.nih.gov/pubmed/12207089).
Westenfelder, Christof (2002). "Unexpected renal actions of erythropoietin". Exp. Nephrol. 10 (56): 2948. doi:
10.1159/000065304 (http://dx.doi.org/10.1159/000065304). PMID 12381912 (http://www.ncbi.nlm.nih.
gov/pubmed/12381912).
Becerra SP, Amaral J (2002). "Erythropoietin--an endogenous retinal survival factor". N. Engl. J. Med. 347 (24):
196870. doi: 10.1056/NEJMcibr022629 (http://dx.doi.org/10.1056/NEJMcibr022629). PMID 12477950
(http://www.ncbi.nlm.nih.gov/pubmed/12477950).
Genc S, Koroglu TF, Genc K (2004). "Erythropoietin and the nervous system". Brain Res. 1000 (12): 1931.
doi: 10.1016/j.brainres.2003.12.037 (http://dx.doi.org/10.1016/j.brainres.2003.12.037). PMID 15053948
(http://www.ncbi.nlm.nih.gov/pubmed/15053948).
Fandrey J (2004). "Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression". Am. J.
Physiol. Regul. Integr. Comp. Physiol. 286 (6): R97788. doi: 10.1152/ajpregu.00577.2003 (http://dx.doi.org/
10.1152/ajpregu.00577.2003). PMID 15142852 (http://www.ncbi.nlm.nih.gov/pubmed/15142852).
Juul S (2004). "Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models". Clinics
in perinatology 31 (1): 12942. doi: 10.1016/j.clp.2004.03.004 (http://dx.doi.org/10.1016/j.clp.2004.03.
004). PMID 15183662 (http://www.ncbi.nlm.nih.gov/pubmed/15183662).
Buemi M, Caccamo C, Nostro L, et al. (2005). "Brain and cancer: the protective role of erythropoietin". Med Res
Rev 25 (2): 24559. doi: 10.1002/med.20012 (http://dx.doi.org/10.1002/med.20012). PMID 15389732
(http://www.ncbi.nlm.nih.gov/pubmed/15389732).
Sytkowski AJ (2007). "Does erythropoietin have a dark side? Epo signaling and cancer cells". Sci. STKE 2007
(395): e38. doi: 10.1126/stke.3952007pe38 (http://dx.doi.org/10.1126/stke.3952007pe38). PMID 17636183
(http://www.ncbi.nlm.nih.gov/pubmed/17636183).
Goldwasser, Eugene. A Bloody Long Journey: Erythropoietin and the Person Who Isolated It. Xlibris, 2011.
ISBN 978-1-4568-5737-0
External links
NYT - 1987 announcement of Epogen's clinical success (http://query.nytimes.com/gst/fullpage.
html?res=9B0DE2D81138F93BA35752C0A961948260&sec=&spon=&partner=permalink&
exprod=permalink)
108
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Calcium metabolism
109
Calcium metabolism
Calcium metabolism or calcium
homeostasis is the mechanism by
which the body maintains adequate
calcium levels. Derangements of this
mechanism lead to hypercalcemia or
hypocalcemia, both of which can have
important consequences for health.
Calcium
Biological functions
Structural function: Supporting material in bones. Present as calcium phosphate.
Signalling function: Intracellular calcium functions as a second messenger for the secretion of some hormones
and neurotransmitters. Also acts as an intracellular permeation regulator and mediator of muscle contraction.
Enzymatic function: Calcium acts as a coenzyme for clotting factors.
Calcium also causes the release of Acetylcholine from pre-synaptic terminals in the transmission of nerve impulses.
Calcium causes the contraction of muscles, removing the Triosephosphate isomerase (TPI) subunit from Myosin
head which has ATPase activity to cause contraction.
Normal ranges
The plasma level of calcium is closely regulated with a normal total calcium of 2.2-2.6mmol/L (9-10.5mg/dL) and
a normal ionized calcium of 1.1-1.4mmol/L (4.5-5.6mg/dL). The amount of total calcium varies with the level of
serum albumin, a protein to which calcium is bound. The biologic effect of calcium is determined by the amount of
ionized calcium, rather than the total calcium. Ionized calcium does not vary with the albumin level, and therefore it
is useful to measure the ionized calcium level when the serum albumin is not within normal ranges, or when a
calcium disorder is suspected despite a normal total calcium level.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Calcium metabolism
Effector organs
Absorption
About 25 mmol of calcium enters the body in a normal diet. Of this, about 40% (10mmol) is absorbed in small
intestine, and 5mmol leaves the body in feces, netting 5mmol of calcium a day.[1]
Calcium is absorbed across the intestinal brush border membrane, passing through ion channels such as TRPV6.
Calbindin is a vitamin D-dependent calcium-binding protein inside intestinal epithelial cells which functions together
with TRPV6 and calcium pumps (PMCA1) in the basal membrane to actively transport calcium into the body.
Active transport of calcium occurs primarily in the duodenum portion of the intestine when calcium intake is low;
and through passive paracellular transport occurs in the jejunum and ileum parts when calcium intake is high,
independent of Vitamin D level.[2]
Excretion
The kidney excretes 250mmol a day in pro-urine, and resorbs 245mmol, leading to a net loss in the urine of
5mmol/d. In addition to this, the kidney processes Vitamin D into calcitriol, the active form that is most effective in
assisting intestinal absorption. Both processes are stimulated by parathyroid hormone.
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Calcium metabolism
111
Boron[citation needed]
Regulatory organs
Primarily calcium is regulated by the actions of
1,25-Dihydroxycholecalciferol, parathyroid hormone
(PTH) and calcitonin and direct exchange with the bone
matrix. Plasma calcium levels are regulated by
hormonal and non-hormonal mechanisms. After
ingestion of substantial amounts of calcium the short
term control that prevents calcium spiking in the serum
is absorption by the bone matrix. After about an hour,
PTH will be released and not peak for about 8 hours.[4]
The PTH is, over time, a very potent regulator of
plasma calcium, and controls the conversion of vitamin
D into its active form in the kidney. The parathyroid
glands are located behind the thyroid, and produce
parathyroid hormone in response to low calcium levels.
The parafollicular cells of the thyroid produce
calcitonin in response to high calcium levels, but its
significance is much smaller than that of PTH.
[3]
Pathology
Hypocalcemia and hypercalcemia are both serious medical disorders.
Renal osteodystrophy is a consequence of chronic renal failure related to the calcium metabolism.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Calcium metabolism
Osteoporosis and osteomalacia have been linked to calcium metabolism disorders.
References
[1] Barrett KE, Barman SM, Boitano S, Brooks H, "Chapter 23. Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of
Bone" (Chapter). Barrett KE, Barman SM, Boitano S, Brooks H: Ganong's Review of Medical Physiology, 23e: http:/ / www. accessmedicine.
com/ content. aspx?aID=5244785.
[2] http:/ / www. vivo. colostate. edu/ hbooks/ pathphys/ digestion/ smallgut/ absorb_minerals. html
[3] Page 1094 (The Parathyroid Glands and Vitamin D) in:
[4] Medical Physiology; Guyton, Saunders and Co. 1976pp.1062
[5] Potency-Man (http:/ / www. inra. fr/ reseau-nacre/ sci-memb/ corpet/ Data/ table. php?file=Potency-Man. txt)
[6] Calcium meta-analysis Colon Cancer chemoprevention systematic review (http:/ / www. inra. fr/ reseau-nacre/ sci-memb/ corpet/
MAcalcium. html)
External links
Calcium (http://labtestsonline.org/understanding/analytes/calcium/tab/test) at Lab Tests Online
Physiology at MCG 5/5ch6/5ch6line (http://web.archive.org/web/20080401093403/http://www.lib.mcg.
edu/edu/eshuphysio/program/section5/5ch6/5ch6line.htm)
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IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Fluid balance
Fluid balance
Fluid balance is the concept of human homeostasis that the amount of fluid lost from the body is equal to the
amount of fluid taken in. Euvolemia is the state of normal body fluid volume. Water is necessary for all life on Earth.
Humans can survive for 46 weeks without food, but for only a few days without water.
The amount of water varies with the individual, as it depends on the condition of the subject, the amount of physical
exercise, and on the environmental temperature and humidity. In the US, the reference daily intake (RDI) for water is
3.7 litres per day (l/day) for human males older than 18, and 2.7 l/day for human females older than 18[1] including
water contained in food, beverages, and drinking water. The common misconception that everyone should drink two
litres (68 ounces, or about eight 8-oz glasses) of water per day is not supported by scientific research. Various
reviews of all the scientific literature on the topic performed in 2002 and 2008 could not find any solid scientific
evidence that recommended drinking eight glasses of water per day.[2][3] For example, people in hotter climates will
require greater water intake than those in cooler climates. An individual's thirst provides a better guide for how much
water they require rather than a specific, fixed number. A more flexible guideline is that a normal person should
urinate 4 times per day, and the urine should be a light yellow color.
A constant supply is needed to replenish the fluids lost through normal physiological activities, such as respiration,
perspiration and urination. Food contributes 0.5 to 1 l/day, and the metabolism of protein, fat, and carbohydrates
produces another 0.25 to 0.4 l/day,[4] which means that 2 to 3 l/day of water for men and 1 to 2 l/day of water for
women should be taken in as fluid, i.e. drunk, in order to meet the Recommended Daily Intake (RDI). In terms of
mineral nutrients intake, it is unclear what the drinking water contribution is. However, inorganic minerals generally
enter surface water and ground water via storm water runoff or through the Earth's crust. Treatment processes also
lead to the presence of some minerals. Examples include calcium, zinc, manganese, phosphate, fluoride and sodium
compounds.[5] Water generated from the biochemical metabolism of nutrients provides a significant proportion of
the daily water requirements for some arthropods and desert animals, but provides only a small fraction of a human's
necessary intake. There are a variety of trace elements present in virtually all potable water, some of which play a
role in metabolism. For example sodium, potassium and chloride are common chemicals found in small quantities in
most waters, and these elements play a role (not necessarily major) in body metabolism. Other elements such as
fluoride, while beneficial in low concentrations, can cause dental problems and other issues when present at high
levels. Water is essential for the growth and maintenance of our bodies, as it is involved in a number of biological
processes.
Profuse sweating can increase the need for electrolyte (salt) replacement. Water intoxication (which results in
hyponatremia), the process of consuming too much water too quickly, can be fatal.
The human kidneys will normally adjust to varying levels of water intake. The kidneys will require time to adjust to
the new water intake level. This can cause someone who drinks a lot of water to become dehydrated more easily than
someone who routinely drinks less.
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Fluid balance
Input
A constant supply is needed to replenish the fluids lost through normal physiological activities, such as respiration,
sweating and urination. Water generated from the biochemical metabolism of nutrients provides a significant
proportion of the daily water requirements for some arthropods and desert animals, but provides only a small fraction
of a human's necessary intake.
In the normal resting state, input of water through ingested fluids is approximately 1200 ml/day, from ingested foods
1000 ml/day and from aerobic respiration 300 ml/day, totaling 2500 ml/day.[7]
Regulation of input
Input of water is regulated mainly through ingested fluids, which, in turn, depends on thirst. An insufficiency of
water results in an increased osmolarity in the extracellular fluid. This is sensed by osmoreceptors in the organum
vasculosum of the lamina terminalis, which trigger thirst. Thirst can to some degree be voluntarily resisted, as during
fluid restriction.
Output
The majority of fluid output occurs via the urine, approximately 1500 ml/day (approx 1.59 qt/day) in the normal
adult resting state.
Some fluid is lost through perspiration (part of the body's temperature control mechanism) and as water vapor in
expired air. These are termed "insensible fluid losses" as they cannot be easily measured. Some sources say
insensible losses account for 500 to 650 ml/day (0.5 to 0.6 qt.) of water in adults, while other sources put the
minimum value at 800 ml (0.8 qt.).[8] In children, one calculation used for insensible fluid loss is 400ml/m2 body
surface area.
In addition, an adult loses approximately 100ml/day of fluid through feces.
For females, an additional 50 ml/day is lost through vaginal secretions.
These outputs are in balance with the input of ~2500 ml/day.
Regulation of output
The body's homeostatic control mechanisms, which maintain a constant internal environment, ensure that a balance
between fluid gain and fluid loss is maintained. The hormones ADH (Anti-diuretic Hormone, also known as
vasopressin) and Aldosterone play a major role in this.
If the body is becoming fluid-deficient, there will be an increase in the secretion of these hormones, causing fluid
to be retained by the kidneys and urine output to be reduced.
Conversely, if fluid levels are excessive, secretion of these hormones is suppressed, resulting in less retention of
fluid by the kidneys and a subsequent increase in the volume of urine produced.
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Fluid balance
Antidiuretic hormone
If the body is becoming fluid-deficient, this will be sensed by osmoreceptors in the organum vasculosum of lamina
terminalis and subfornical organ. These areas project to the supraoptic nucleus and paraventricular nucleus, which
contain neurons that secrete the antidiuretic hormone, vasopressin, from their nerve endings in the posterior pituitary.
Thus, there will be an increase in the secretion of antidiuretic hormone, causing fluid to be retained by the kidneys
and urine output to be reduced.
Aldosterone
A fluid-insufficiency causes a decreased perfusion of the juxtaglomerular apparatus in the kidneys. This activates the
renin-angiotensin system. Among other actions, it causes renal tubules (i.e. the distal convoluted tubules and the
cortical collecting ducts) to reabsorb more sodium and water from the urine. Potassium is secreted into the tubule in
exchange for the sodium, which is reabsorbed. The activated renin-angiotensin system stimulates zona glomerulosa
of the adrenal cortex which in turn secretes hormone aldosterone. This hormone stimulates the reabsorption of
sodium ions from distal tubules and collecting ducts. Water in the tubular lumen cannot follow the sodium
reabsorption osmotically, as this part of the kidney is impermeable to water; release of AHD (vasopressin) is
required to increase expression of aquaporin channels in the cortical collecting duct, allowing reabsorption of water.
Effects of illness
When a person is ill, fluid may also be lost through vomiting, diarrhea, and hemorrhage. An individual is at an
increased risk of dehydration in these instances, as the kidneys will find it more difficult to match fluid loss by
reducing urine output (the kidneys must produce at least some urine in order to excrete metabolic waste.)
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Fluid balance
Trace elements
There are a variety of trace elements present in virtually all potable water, some of which play a role in metabolism;
for example sodium, potassium and chloride are common chemicals found in very small amounts in most waters, and
these elements play a major role in body metabolism. Water is essential for the growth and maintenance of our
bodies, as it is involved in a number of biological processes.
References
[1] US daily reference intake values (http:/ / iom. edu/ Reports/ 2004/ Dietary-Reference-Intakes-Water-Potassium-Sodium-Chloride-and-Sulfate.
aspx)
[2] Research debunks health value of guzzling water (http:/ / www. reuters. com/ article/ healthNews/ idUSN0236679720080402). Reuters, April
2008.
[3] H. Valtin, Drink at least eight glasses of water a day." Really? Is there scientific evidence for "8 8"? (http:/ / ajpregu. physiology. org/ cgi/
content/ full/ 283/ 5/ R993) Am J Physiol Regul Integr Comp Physiol 283: R993-R1004, 2002.
[4] Swedish DFA (http:/ / www. slv. se/ templates/ SLV_Page. aspx?id=13974& epslanguage=SV) (in Swedish)
[5] World Health Organization (http:/ / www. who. int/ en/ ) (WHO). Geneva, Switzerland. Joyce Morrissey Donohue, Charles O. Abernathy,
Peter Lassovszky, George Hallberg. "The contribution of drinking-water to total dietary intakes of selected trace mineral nutrients in the
United States." (http:/ / www. who. int/ entity/ water_sanitation_health/ dwq/ nutintakes. pdf) Draft, August 2004.
[6] Saladin, Kenneth S. Water, Electrolyte, and Acid-Base Balance (New York: McGraw-Hill Companies, Inc., 2010), 943-944.
[7] Page 829
[8] 3.2 Insensible Water Loss (http:/ / www. anaesthesiamcq. com/ FluidBook/ fl3_2. php)
116
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Vasopressin
117
Vasopressin
Arginine vasopressin
[3]
, 1jk6
[4]
, 1npo
[5]
, 2bn2
[6]
Identifiers
[7]
Symbols
AVP
External IDs
OMIM: 192340
MGI: 88121
[9]
HomoloGene: 417
[10]
[11]
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
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118
Gene Ontology
Molecular function protein kinase activity [12]
[13]
signal transducer activity
[14]
receptor binding
[15]
neuropeptide hormone activity
[16]
neurohypophyseal hormone activity
[17]
V1A vasopressin receptor binding
[18]
V1B vasopressin receptor binding
[19]
cysteine-type endopeptidase inhibitor activity involved in apoptotic process
Cellular component extracellular region [17]
[18]
extracellular space
[20]
cytosol
[21]
secretory granule
[22]
dendrite
Biological process
[23]
[48]
[57]
/ QuickGO
[58]
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Vasopressin
119
RNA expression pattern
[59]
Orthologs
Species
Human
Mouse
Entrez
551
Ensembl
ENSG00000101200
UniProt
P01185
RefSeq (mRNA)
NM_000490
RefSeq (protein)
NP_000481
Location (UCSC)
Chr 20:
[70]
3.06 3.07 Mb
Chr 2:
[71]
130.58 130.58 Mb
PubMed search
[72]
[73]
[60]
11998
[64]
[62]
[61]
ENSMUSG00000037727
P35455
[66]
[68]
[63]
[65]
NM_009732
NP_033862
[67]
[69]
Arginine vasopressin (AVP), also known as vasopressin, argipressin or antidiuretic hormone (ADH), is a
neurohypophysial hormone found in most mammals. Its two primary functions are to retain water in the body and to
constrict blood vessels. Vasopressin regulates the body's retention of water by acting to increase water absorption in
the collecting ducts of the kidney nephron. Vasopressin is a peptide hormone that increases water permeability of the
kidney's collecting duct and distal convoluted tubule by inducing translocation of aquaporin-CD water channels in
the kidney nephron collecting duct plasma membrane. It also increases peripheral vascular resistance, which in turn
increases arterial blood pressure. It plays a key role in homeostasis, by the regulation of water, glucose, and salts in
the blood. It is derived from a preprohormone precursor that is synthesized in the hypothalamus and stored in
vesicles at the posterior pituitary. Most of it is stored in the posterior pituitary to be released into the bloodstream.
However, some AVP may also be released directly into the brain, and accumulating evidence suggests it plays an
important role in social behavior, sexual motivation and bonding, and maternal responses to stress. It has a very short
half-life between 16-24 minutes.
Physiology
Function
One of the most important roles of AVP is to regulate the body's retention of water; it is released when the body is
dehydrated and causes the kidneys to conserve water, thus concentrating the urine and reducing urine volume. At
high concentrations, it also raises blood pressure by inducing moderate vasoconstriction. In addition, it has a variety
of neurological effects on the brain, having been found, for example, to influence pair-bonding in voles. The
high-density distributions of vasopressin receptor AVPr1a in prairie vole ventral forebrain regions have been shown
to facilitate and coordinate reward circuits during partner preference formation, critical for pair bond formation.
A very similar substance, lysine vasopressin (LVP) or lypressin, has the same function in pigs and is often used in
human therapy.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
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120
Kidney
Vasopressin has two main effects by which it contributes to increased urine osmolarity (increased concentration) and
decreased water excretion:
1. Increasing the water permeability of distal tubule and collecting duct cells in the kidney, thus allowing water
reabsorption and excretion of more concentrated urine, i.e., antidiuresis. This occurs through insertion of water
channels (Aquaporin-2) into the apical membrane of distal tubule and collecting duct epithelial cells. Aquaporins
allow water to move down their osmotic gradient and out of the nephron, increasing the amount of water
re-absorbed from the filtrate (forming urine) back into the bloodstream.
V2 receptors, which are G protein-coupled receptors on the basolateral plasma membrane of the epithelial cells,
couple to the heterotrimeric G-protein Gs, which activates adenylyl cyclases III and VI to convert ATP into
cAMP, plus 2 inorganic phosphates. The rise in cAMP then triggers the insertion of aquaporin-2 water channels
by exocytosis of intracellular vesicles, recycling endosomes. Vasopressin also increases the concentration of
calcium in the collecting duct cells, by episodic release from intracellular stores. Vasopressin, acting through
cAMP, also increases transcription of the aquaporin-2 gene, thus increasing the total number of aquaporin-2
molecules in collecting duct cells.
Cyclic-AMP activates protein kinase A (PKA) by binding to its regulatory subunits and allowing them to detach
from the catalytic subunits. Detachment exposes the catalytic site in the enzyme, allowing it to add phosphate
groups to proteins (including the aquaporin-2 protein), which alters their functions.
2. Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface
expression of urea transporters, which facilitates its reabsorption into the medullary interstitium as it travels down
the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and
outer medullary collecting duct.
Cardiovascular system
Vasopressin increases peripheral vascular resistance (vasoconstriction) and thus increases arterial blood pressure.
This effect appears small in healthy individuals; however it becomes an important compensatory mechanism for
restoring blood pressure in hypovolemic shock such as that which occurs during hemorrhage.
Central nervous system
Vasopressin released within the brain has many actions:
It has been implicated in memory formation, including delayed
reflexes, image, short- and long-term memory, though the
mechanism remains unknown; these findings are controversial.
However, the synthetic vasopressin analogue desmopressin has
come to interest as a likely nootropic.
[74]
Avp
is expressed in the periventricular
region of the hypothalamus in the adult mouse.
Allen Brain Atlases
temperature regulation.
It is likely that vasopressin acts in conjunction with corticotropin-releasing hormone to modulate the release of
corticosteroids from the adrenal gland in response to stress, particularly during pregnancy and lactation in
mammals.
Selective AVPr1a blockade in the ventral pallidum has been shown to prevent partner preference in prairie voles,
suggesting that these receptors in this ventral forebrain region are crucial for pair bonding.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Vasopressin
Recent evidence suggests that vasopressin may have analgesic effects. The analgesia effects of vasopressin were
found to be dependent on both stress and gender.
Evidence for this comes from experimental studies in several species, which indicate that the precise distribution of
vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In
particular, there are consistent differences between monogamous species and promiscuous species in the distribution
of AVP receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely related
species are compared. Moreover, studies involving either injecting AVP agonists into the brain or blocking the
actions of AVP support the hypothesis that vasopressin is involved in aggression toward other males. There is also
evidence that differences in the AVP receptor gene between individual members of a species might be predictive of
differences in social behavior. One study has suggested that genetic variation in male humans affects pair-bonding
behavior. The brain of males uses vasopressin as a reward for forming lasting bonds with a mate, and men with one
or two of the genetic alleles are more likely to experience marital discord. The partners of the men with two of the
alleles affecting vasopressin reception state disappointing levels of satisfaction, affection, and cohesion. Vasopressin
receptors distributed along the reward circuit pathway, to be specific in the ventral pallidum, are activated when
AVP is released during social interactions such as mating, in monogamous prairie voles. The activation of the reward
circuitry reinforces this behavior, leading to conditioned partner preference, and thereby initiates the formation of a
pair bond.
Control
Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume, in response to
increases in the plasma osmolality, and in response to cholecystokinin (CCK) secreted by the small intestine:
Secretion in response to reduced plasma volume is activated by pressure receptors in the veins, atria, and carotids.
Secretion in response to increases in plasma osmotic pressure is mediated by osmoreceptors in the hypothalamus.
Secretion in response to increases in plasma CCK is mediated by an unknown pathway.
The neurons that make AVP, in the hypothalamic supraoptic nuclei (SON) and paraventricular nuclei (PVN), are
themselves osmoreceptors, but they also receive synaptic input from other osmoreceptors located in regions adjacent
to the anterior wall of the third ventricle. These regions include the organum vasculosum of the lamina terminalis
and the subfornical organ.
Many factors influence the secretion of vasopressin:
Ethanol (alcohol) reduces the calcium-dependent secretion of AVP by blocking voltage-gated calcium channels in
neurohypophyseal nerve terminals.
Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body.
Atrial natriuretic peptide inhibits AVP secretion, in part by inhibiting Angiotensin II-induced stimulation of AVP
secretion.
Secretion
The main stimulus for secretion of vasopressin is increased osmolality of plasma. Reduced volume of extracellular
fluid also has this effect, but is a less sensitive mechanism.
The AVP that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland
(except in cases of AVP-secreting tumours). Vasopressin is produced by magnocellular neurosecretory neurons in
the Paraventricular nucleus of hypothalamus (PVN) and Supraoptic nucleus (SON). It then travels down the axon
through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of
the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until
released into the blood. However there are two other sources of AVP with important local effects:
121
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AVP is also synthesized by parvocellular neurosecretory neurons at the PVN, transported and released at the
median eminence, which then travels through the hypophyseal portal system to the anterior pituitary where it
stimulates corticotropic cells synergistically with CRH to produce ACTH (by itself it is a weak secretagogue).
Vasopressin is also released into the brain by several different populations of smaller neurons.
Receptors
Below is a table summarizing some of the actions of AVP at its four receptors, differently expressed in different
tissues and exerting different actions:
Type
Locations
AVPR1A
AVPR1B
or AVPR3
AVPR2
Adenylate cyclase/cAMP
VACM-1
Actions
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Argipressin (AVP,
ADH)
Most mammals
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2
Lypressin (LVP)
Cys-Phe-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2
Phenypressin
Some marsupials
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2
Vasotocin
Non-mammals
Oxytocin (OXT)
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Pro-Gly-NH2
Prol-Oxytocin
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Ile-Gly-NH2
Mesotocin
Cys-Tyr-Ile-Gln-Ser-Cys-Pro-Ile-Gly-NH2
Seritocin
Frogs
Cys-Tyr-Ile-Ser-Asn-Cys-Pro-Ile-Gly-NH2
Isotocin
Bony fishes
Cys-Tyr-Ile-Ser-Asn-Cys-Pro-Gln-Gly-NH2
Glumitocin
Skates
Sharks
Diuretic Hormone
Locust
Cys-Phe-Val-Arg-Asn-Cys-Pro-Thr-Gly-NH2
Annetocin
Earthworm
Cys-Phe-Ile-Arg-Asn-Cys-Pro-Lys-Gly-NH2
Lys-Connopressin
Geography & imperial cone snail, pond snail, sea hare, leech
Cys-Ile-Ile-Arg-Asn-Cys-Pro-Arg-Gly-NH2
Arg-Connopressin
Cys-Tyr-Phe-Arg-Asn-Cys-Pro-Ile-Gly-NH2
Cephalotocin
Octopus
Cys-Phe-Trp-Thr-Ser-Cys-Pro-Ile-Gly-NH2
Octopressin
Octopus
Role in disease
Lack of AVP
Decreased AVP release or decreased renal sensitivity to AVP leads to diabetes insipidus, a condition featuring
hypernatremia (increased blood sodium concentration), polyuria (excess urine production), and polydipsia (thirst).
Excess AVP
High levels of AVP secretion may lead to hyponatremia. In many cases, the AVP secretion is appropriate (due to
severe hypovolemia), and the state is labelled "hypovolemic hyponatremia". In certain disease states (heart failure,
nephrotic syndrome) the body fluid volume is increased but AVP production is not suppressed for various reasons;
this state is labelled "hypervolemic hyponatremia". A proportion of cases of hyponatremia feature neither hyper- nor
hypovolemia. In this group (labelled "euvolemic hyponatremia"), AVP secretion is either driven by a lack of cortisol
or thyroxine (hypoadrenalism and hypothyroidism, respectively) or a very low level of urinary solute excretion
(potomania, low-protein diet), or it is entirely inappropriate. This last category is classified as the syndrome of
inappropriate antidiuretic hormone (SIADH).
SIADH in turn can be caused by a number of problems. Some forms of cancer can cause SIADH, particularly small
cell lung carcinoma but also a number of other tumors. A variety of diseases affecting the brain or the lung
(infections, bleeding) can be the driver behind SIADH. A number of drugs has been associated with SIADH, such as
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
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124
certain antidepressants (serotonin reuptake inhibitors and tricyclic antidepressants), the anticonvulsant
carbamazepine, oxytocin (used to induce and stimulate labor), and the chemotherapy drug vincristine. It has also
been associated with fluoroqionolones, moxifloxacin and ciprofloxacin. Finally, it can occur without a clear
explanation.
Hyponatremia can be treated pharmaceutically through the use of vasopressin receptor antagonists.
Pharmacology
Vasopressin analogues
Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue
desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some
forms of von Willebrand disease and in mild haemophilia A) and in extreme cases of bedwetting by children.
Terlipressin and related analogues are used as vasoconstrictors in certain conditions. Use of vasopressin analogues
for esophageal varices commenced in 1970.
Vasopressin infusion has also been used as a second line of management in septic shock patients not responding to
high dose of inotropes (e.g., dopamine or norepinephrine).
Table 1. Meta-analysis of outcomes for patients treated with vasopressin versus epinephrine
RR (95% CI)
Failure of ROSC
0.81 (0.58-1.12)
0.72 (0.38-1.39)
0.74 (0.38-1.43)
0.96 (0.87-1.05)
Although both vasopressors, vasopressin and epinephrine differ in that vasopressin does not have direct effects on
cardiac contractility as epinephrine does. Thus, vasopressin is theorized to be of increased benefit over epinephrine
in cardiac arrest due to its properties of not increasing myocardial and cerebral oxygen demands. This idea has led to
the advent of several studies searching for the presence of a clinical difference in benefit of these two treatment
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
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125
choices. Initial small studies demonstrated improved outcomes with vasopressin in comparison to epinephrine.
However, subsequent studies have not all been in agreement. Several randomized controlled trials have been unable
to reproduce positive results with vasopressin treatment in both return of spontaneous circulation (ROSC) and
survival to hospital discharge, including a systematic review and meta-analysis completed in 2005 that found no
evidence of a significant difference with vasopressin in five studied outcomes (see Table 1).
Vasopressin and epinephrine vs. epinephrine alone
p value
ROSC
1.42 (1.14-1.77)
In subgroup: PEA
3.69 (1.52-8.95)
There is no current evidence of significant survival benefit with improved neurological outcomes in patients given
combinations of both epinephrine and vasopressin during cardiac arrest. A systematic review from 2008 did,
however, find one study that showed a statistically significant improvement in ROSC and survival to hospital
discharge with this combination treatment; unfortunately, those patients that survived to hospital discharge had
overall poor outcomes and many suffered permanent, severe neurological damage. A more recently published
clinical trial out of Singapore has shown similar results, finding combination treatment to only improve the rate of
survival to hospital admission, especially in the subgroup analysis of patients with longer "collapse to emergency
department" arrival times of 15 to 45 minutes. Table 2 lists all statistically significant findings of a correlation
between combined treatment and positive outcomes found in these two studies.
2010 American Heart Association Guidelines
The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care recommend the consideration of vasopressor treatment in the form of epinephrine in adults with
cardiac arrest (Class IIb, LOE A recommendation). Due to the absence of evidence that vasopressin administered
instead of or in addition to epinephrine has significant positive outcomes, the guidelines do not currently contain
vasopressin as a part of the cardiac arrest algorithms. It does, however, allow for one dose of vasopressin to replace
either the first or second dose of epinephrine in the treatment of cardiac arrest (Class IIb, LOE A recommendation).
References
[1] http:/ / www. ebi. ac. uk/ pdbe/ searchResults. html?display=both&
term=P01185%20or%20P01180%20or%20Q3UUQ5%20or%20P35455%20or%20P24787%20or%20Q8AV79
[2] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=UpAccessionIdQuery&
accessionIdList=P01185,P01180,Q3UUQ5,P35455,P24787,Q8AV79
[3] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1jk4
[4] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1jk6
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Vasopressin
[5] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1npo
[6] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2bn2
[7] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=894
[8] http:/ / omim. org/ entry/ 192340
[9] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:88121
[10] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=417
[11] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=551
[12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0004672
[13] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0004871
[14] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005102
[15] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005184
[16] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005185
[17] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031894
[18] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031895
[19] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043027
[20] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005829
[21] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030141
[22] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030425
[23] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0002125
[24] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0003084
[25] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006091
[26] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006468
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
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[38]
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[45]
[46]
[47]
[48]
[49]
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[51]
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[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006833
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007204
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007267
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007621
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007625
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007626
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0010628
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0014049
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030307
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030819
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031394
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032849
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0033138
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0035094
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0035176
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0035813
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042310
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042538
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042711
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043084
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043154
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043252
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045471
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045907
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0050891
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051970
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0055085
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0070371
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0070528
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0090201
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P01185
http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P01185
http:/ / biogps. org/ gene/ 551/
http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=551& rn=1
[61] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=11998& rn=1
[62] http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000101200;db=core
[63] http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000037727;db=core
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IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Vasopressin
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
Further reading
Rector, Floyd C.; Brenner, Barry M. (2004). Brenner & Rector's the kidney (http://home.mdconsult.com/das/
search/openres/56203699-5?searchisbn=460046813) (7th ed.). Philadelphia: Saunders. ISBN0-7216-0164-2.
External links
Molecular neurobiology of social bonding: Implications for autism spectrum disorders (http://videocast.nih.
gov/Summary.asp?File=15521) a lecture by Prof. Larry Young, Jan. 4, 2010.
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IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Aldosterone
128
Aldosterone
Aldosterone
Identifiers
[1]
CAS number
52-39-1
PubChem
5839
ChemSpider
5633
UNII
4964P6T9RB
DrugBank
DB04630
KEGG
C01780
MeSH
Aldosterone
ChEBI
CHEBI:27584
ChEMBL
CHEMBL273453
ATC code
H02 AA01
Jmol-3D images
Image 1
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Properties
Molecular formula
C H O
Molar mass
360.44 g mol1
21 28 5
(verify)
[12]
(what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)
Infobox references
Aldosterone is a steroid hormone (mineralocorticoid family) produced by the outer section (zona glomerulosa) of
the adrenal cortex in the adrenal gland.[13] It plays a central role in the regulation of blood pressure mainly by acting
on the distal tubules and collecting ducts of the nephron, increasing reabsorption of ions and water in the kidney, to
cause the conservation of sodium, secretion of potassium, increased water retention, and increased blood pressure.
When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular
and renal disease. Aldosterone has exactly the opposite function of the atrial natriuretic hormone secreted by the
heart.
Drugs that interfere with the secretion or action of aldosterone are in use as antihypertensives, like Lisinopril; which
lowers blood pressure by blocking the Angiotensin Converting Enzyme (ACE), leading to lower aldosterone
secretion; its net effect is to reduce sodium and water retention, but increase retention of potassium. Aldosterone is
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Aldosterone
part of the renin-angiotensin system. Another example is spironolactone, a potassium sparing diuretic, which
decreases blood pressure by releasing fluid from the body, while retaining potassium.
It was first isolated by Simpson and Tait in 1953.
Synthesis
The corticosteroids are synthesized from cholesterol within the adrenal cortex. Most steroidogenic reactions are
catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require
adrenodoxin as a cofactor (except 21-hydroxylase and 17-hydroxylase).
Aldosterone and corticosterone share the first part of their biosynthetic pathways. The last parts are mediated either
by the aldosterone synthase (for aldosterone) or by the 11-hydroxylase (for corticosterone). These enzymes are
nearly identical (they share 11-hydroxylation and 18-hydroxylation functions), but aldosterone synthase is also able
to perform a 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of
the adrenal cortex; 11-hydroxylase is found in the zona fasciculata and reticularis.
Note: aldosterone synthase is absent in
other sections of the adrenal gland.
Stimulation
Aldosterone synthesis is stimulated by
several factors:
increase in the plasma concentration
of angiotensin III, a metabolite of
angiotensin II
increase in plasma angiotensin II,
ACTH, or potassium levels, which
are present in proportion to plasma
sodium deficiencies. (The increased
potassium level works to regulate
aldosterone synthesis by
depolarizing the cells in the zona
glomerulosa, which opens the
Steroidogenesis, showing aldosterone synthesis at upper-right corner
voltage-dependent calcium
channels.) The level of angiotensin
II is regulated by angiotensin I, which is in turn regulated by renin, an enzyme secreted in the kidneys. Potassium
levels are the most sensitive stimulator of aldosterone.
the ACTH stimulation test, which is sometimes used to stimulate the production of aldosterone along with cortisol
to determine whether primary or secondary adrenal insufficiency is present. However, ACTH has only a minor
role in regulating aldosterone production; with hypopituitarism there is no atrophy of the zona glomerulosa.
plasma acidosis
the stretch receptors located in the atria of the heart. If decreased blood pressure is detected, the adrenal gland is
stimulated by these stretch receptors to release aldosterone, which increases sodium reabsorption from the urine,
sweat, and the gut. This causes increased osmolarity in the extracellular fluid, which will eventually return blood
pressure toward normal.
adrenoglomerulotropin, a lipid factor, obtained from pineal extracts. It selectively stimulates secretion of
aldosterone.
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Aldosterone
The secretion of aldosterone has a diurnal rhythm.
Function
Aldosterone is the primary of several endogenous members of the class of mineralocorticoids in humans.
Deoxycorticosterone is another important member of this class. Aldosterone tends to promote Na+ and water
retention, and lower plasma K+ concentration by the following mechanisms:
1. Acting on the nuclear mineralocorticoid receptors (MR) within the principal cells of the distal tubule and the
collecting duct of the kidney nephron, it upregulates and activates the basolateral Na+/K+ pumps, which pumps
three sodium ions out of the cell and two potassium ions into the cell. This results in reabsorption of sodium (Na+)
ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into the urine (lumen of
collecting duct).
2. Aldosterone upregulates epithelial sodium channels (ENaCs), increasing apical membrane permeability for Na+.
3. Cl is reabsorbed in conjunction with sodium cations to maintain the system's electrochemical balance.
4. Aldosterone stimulates the secretion of K+ into the tubular lumen.
5. Aldosterone stimulates Na+ and water reabsorption from the gut, salivary and sweat glands in exchange for K+.
6. Aldosterone stimulates secretion of H+ in exchange for Na+ in the intercalated cells of the cortical collecting
tubules, regulating plasma bicarbonate (HCO3) levels and its acid/base balance.
Aldosterone is responsible for the reabsorption of about 2% of filtered sodium in the kidneys, which is nearly equal
to the entire sodium content in human blood under normal glomerular filtration rates.
Aldosterone, probably acting through mineralocorticoid receptors, may positively influence neurogenesis in the
dentate gyrus.
Location of receptors
Steroid receptors are intracellular. The aldosterone mineralcorticoid receptor complex binds on the DNA to specific
hormone response element, which leads to gene specific transcription.
Some of the transcribed genes are crucial for transepithelial sodium transport, including the three subunits of the
epithelial sodium channel (ENaC), the Na+/K+ pumps and their regulatory proteins serum and
glucocorticoid-induced kinase, and channel-inducing factor, respectively.
The mineralcorticoid receptor is stimulated by both aldosterone and cortisol, but a mechanism protects the body from
excess aldosterone receptor stimulation by glucocorticoids (such as cortisol), which happen to be present at much
higher concentrations than mineralcorticoids in the healthy individual. The mechanism consists of an enzyme called
11 -hydroxysteroid dehydrogenase (11 -HSD). This enzyme co-localizes with intracellular adrenal steroid
receptors and converts cortisol into cortisone, a relatively inactive metabolite with little affinity for the MR.
Liquorice, which contains glycyrrhetinic acid, can inhibit 11 -HSD and lead to a mineralcorticoid excess syndrome.
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Aldosterone
Miscellaneous regulators
The role of sympathetic nerves
The aldosterone production is also affected to one extent or another by nervous control, which integrates the inverse
of carotid artery pressure,[] pain, posture, and probably emotion (anxiety, fear, and hostility) (including surgical
stress). Anxiety increases aldosterone, which must have evolved because of the time delay involved in migration of
aldosterone into the cell nucleus.[17] Thus, there is an advantage to an animal's anticipating a future need from
interaction with a predator, since too high a serum content of potassium has very adverse effects on nervous
transmission.
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Aldosterone
The role of baroreceptors
Pressure-sensitive baroreceptors are found in the vessel walls of nearly all large arteries in the thorax and neck, but
are particularly plentiful in the sinuses of the carotid arteries and in the arch of the aorta. These specialized receptors
are sensitive to changes in mean arterial pressure. An increase in sensed pressure results in an increased rate of firing
by the baroreceptors and a negative feedback response, lowering systemic arterial pressure. Aldosterone release
causes sodium and water retention, which causes increased blood volume, and a subsequent increase in blood
pressure, which is sensed by the baroreceptors.[18] To maintain normal homeostasis these receptors also detect low
blood pressure or low blood volume, causing aldosterone to be released. This results in sodium retention in the
kidney, leading to water retention and increased blood volume.[19]
The plasma concentration of sodium
Aldosterone is a function of the inverse of the sodium intake as sensed via osmotic pressure. The slope of the
response of aldosterone to serum potassium is almost independent of sodium intake. Aldosterone is much increased
at low sodium intakes, but the rate of increase of plasma aldosterone as potassium rises in the serum is not much
lower at high sodium intakes than it is at low. Thus, the potassium is strongly regulated at all sodium intakes by
aldosterone when the supply of potassium is adequate, which it usually is in primitive diets.
Aldosterone feedback
Feedback by aldosterone concentration itself is of a nonmorphological character (that is, other than changes in the
cells' number or structure) and is poor, so the electrolyte feedbacks predominate, short term.
Hyperaldosteronism
Primary aldosteronism, also known as primary hyperaldosteronism, is characterized by the overproduction of
aldosterone by the adrenal glands, when not a result of excessive renin secretion. It leads to arterial hypertension
(high blood pressure) associated with hypokalemia, usually a diagnostic clue. Secondary hyperaldosteronism, on the
other hand, is due to overactivity of the renin-angiotensin system.
Conn's syndrome is primary hyperaldosteronism caused by an aldosterone-producing adenoma.
Depending on cause and other factors, hyperaldosteronism can be treated by surgery and/or medically, such as by
aldosterone antagonists.
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Aldosterone
133
Hypoaldosteronism
An ACTH stimulation test for aldosterone can help in determining the cause of hypoaldosteronism, with a low
aldosterone response indicating a primary hypoaldosteronism of the adrenals, while a large response indicating a
secondary hypoaldosteronism.
Additional images
Corticosterone
References
External Links
Aldosterone at Lab Tests Online (http://labtestsonline.org/understanding/analytes/aldosterone/tab/test)
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Countercurrent multiplication
Countercurrent multiplication
A countercurrent multiplier system is a mechanism that expends energy to create a concentration gradient.
It is found widely in nature and especially in mammalian organs. For example, it can refer to the process that is
underlying the process of urine concentration, that is, the production of hyperosmotic urine by the mammalian
kidney.[citation needed] The ability to concentrate urine is also present in birds, but involves another mechanism which
is not comparable.[citation needed]
Countercurrent multiplication is frequently mistaken for countercurrent exchange, a similar but different
mechanism where gradients are maintained, but not established.
Physiological principles
The term derives from the form and function of the loop of Henle, which consists of two parallel limbs of renal
tubules running in opposite directions, separated by the interstital space of the renal medulla.[citation needed]
The descending limb of the loop of Henle is permeable to water but impermeable to solutes, due to the presence
of aquaporin 1 in its tubular wall. Thus water moves across the tubular wall into the medullary space, making the
urine hypertonic.[citation needed]
The ascending limb is impermeable to water (because of a lack of aquaporin, a common transporter protein for
water channels in all cells except the walls of the ascending limb of the loop of Henle) but permeable to solutes,
but here Na+, Cl, and K+ are actively transported into the medullary space, making the filtrate hypotonic (with a
higher water potential). This constitutes the single effect of the countercurrent multiplication process.[citation
needed]
Active transport of these ions from the thick ascending limb creates an osmotic pressure drawing water from the
descending limb into the hyperosmolar medullary space, making the filtrate hypertonic (with a lower water
potential).[citation needed]
The countercurrent flow within the descending and ascending limb thus increases, or multiplies the osmotic
gradient between tubular fluid and interstitial space.[citation needed]
Details
Countercurrent multiplication was originally studied as a mechanism whereby urine is concentrated in the nephron.
Initially studied in the 1950s by Gottschalk and Mylle following Werner Kuhn's postulations, this mechanism gained
popularity only after a series of complicated micropuncture experiments.
The proposed mechanism consists of pump, equilibration, and shift steps. In the proximal tubule, the osmolarity is
isomolar to plasma (300 mOsm/L). In a hypothetical model where there was no equilibration or pump steps, the
tubular fluid and interstitial osmolarity would be 300 mOsm/L as well.{Respicius Rwehumbiza, 2010}
Pump: The Na+/K+/2Cl transporter in the ascending limb of the loop of Henle helps to create a gradient by shifting
Na+ into the medullary interstitium. The thick ascending limb of the loop of Henle is the only part of the nephron
lacking in aquaporina common transporter protein for water channels. This makes the thick ascending limb
impermeable to water. The action of the Na+/K+/2Cl transporter therefore creates a hypoosmolar solution in the
tubular fluid and a hyperosmolar fluid in the interstitium, since water cannot follow the solutes to produce osmotic
equilibrium.[citation needed]
Equilibration: Since the descending limb of the loop of henle consists of very leaky epithelium, the fluid inside the
descending limb becomes hyperosmolar.[citation needed]
Shift: The movement of fluid through the tubules causes the hyperosmotic fluid to move further down the loop.
Repeating many cycles causes fluid to be near isosmolar at the top of Henle's loop and very concentrated at the
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Countercurrent multiplication
bottom of the loop. Interestingly, animals with a need for very concentrated urine (such as desert animals) have very
long loops of Henle to create a very large osmotic gradient. Animals that have abundant water on the other hand
(such as beavers) have very short loops. The vasa recta have a similar loop shape so that the gradient does not
dissipate into the plasma.[citation needed]
The mechanism of counter current multiplication works together with the vasa recta's counter current exchange to
prevent the wash out of salts and maintain a high osmolarity at the inner medulla.[citation needed]
References
The Loop of Henle: Concentration (http://www.liv.ac.uk/~petesmif/teaching/1bds_mb/notes/kidney/loop.
htm) at University of Liverpool
Countercurrent Multiplier Animation (http://www.colorado.edu/intphys/Class/IPHY3430-200/
countercurrent_ct.html) at University of Colorado
Osmoregulation
Osmoregulation is the active regulation of the osmotic pressure of an organism's fluids to maintain the homeostasis
of the organism's water content; that is, it keeps the organism's fluids from becoming too diluted or too concentrated.
Osmotic pressure is a measure of the tendency of water to move into one solution from another by osmosis. The
higher the osmotic pressure of a solution, the more water tends to move into it. Pressure must be exerted on the
hypertonic side of a selectively permeable membrane to prevent diffusion of water by osmosis from the side
containing pure water.
Organisms in aquatic and terrestrial environments must maintain the right concentration of solutes and amount of
water in their body fluids; this involves excretion (getting rid of metabolic wastes and other substances such as
hormones that would be toxic if allowed to accumulate in the blood) through organs such as the skin and the kidneys.
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IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Osmoregulation
salt out from the gills. Most fish are stenohaline, which
means they are restricted to either salt or fresh water and
cannot survive in water with a different salt concentration
than they are adapted to. However, some fish show a
tremendous ability to effectively osmoregulate across a
broad range of salinities; fish with this ability are known as
euryhaline species, e.g., salmon. Salmon has been observed
to inhabit two utterly disparate environments marine
and fresh water and it is inherent to adapt to both by
bringing in behavioral and physiological modifications.
136
Some marine fish, like sharks, have adopted a different, efficient mechanism to conserve water, i.e., osmoregulation.
They retain urea in their blood in relatively higher concentration. Urea is damaging to living tissue so, to cope with
this problem, some fish retain trimethylamine oxide. This provides a better solution to urea's toxicity. Sharks, having
slightly higher solute concentration (i.e., above 1000 mOsm which is sea solute concentration), do not drink water
like fresh water fish.
Osmoregulation in plants
While there are no specific osmoregulatory organs in higher plants, the stomata are important in regulating water
loss through evapotranspiration, and on the cellular level the vacuole is crucial in regulating the concentration of
solutes in the cytoplasm. Strong winds, low humidity and high temperatures all increase evapotranspiration from
leaves. Abscisic acid is an important hormone in helping plants to conserve water it causes stomata to close and
stimulates root growth so that more water can be absorbed.
Plants share with animals the problems of obtaining water but, unlike in animals, the loss of water in plants is crucial
to create a driving force to move nutrients from the soil to tissues. Certain plants have evolved methods of water
conservation.
Xerophytes are plants that can survive in dry habitats, such as deserts, and are able to withstand prolonged periods of
water shortage. Succulent plants such as the cacti store water in the vacuoles of large parenchyma tissues. Other
plants have leaf modifications to reduce water loss, such as needle-shaped leaves, sunken stomata, and thick, waxy
cuticles as in the pine. The sand-dune marram grass has rolled leaves with stomata on the inner surface.
Hydrophytes are plants in water habitats. They mostly grow in water or in wet or damp places. In these plants the
water absorption occur through the whole surface of the plant, e.g. the water lily.
Halophytes are plants living in marshy areas (close to sea). They have to absorb water from such a soil which has
higher salt concentration and therefore lower water potential(higher osmotic pressure). Halophytes cope with this
situation by activating salts in their roots. As a consequence,the cells of the roots develop lower water potential
which brings in water by osmosis. The excess salt can be stored in cells or excreted out from salt glands on leaves.
The salt thus secreted by some species help them to trap water vapours from the air, which is absorbed in liquid by
leaf cells. Therefore this is another way of obtaining additional water from air, e.g. glasswort and cord-grass.
Mesophytes [1] are plants living in lands of temperate zone, which grow in well watered soil. They can easily
compensate the water lost by transpiration through absorbing water from the soil. To prevent excessive transpiration
they have developed a water proof external covering called cuticle.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Osmoregulation
137
Osmoregulation in animals
Kidneys play a very large role in human osmoregulation by regulating the amount of water reabsorbed from
glomerular filtrate in kidney tubules, which is controlled by hormones such as antidiuretic hormone (ADH),
aldosterone, and angiotensin II. For example, a decrease in water potential of blood is detected by osmoreceptors in
hypothalamus, which stimulates ADH release from pituitary gland to increase the permeability of the wall of the
collecting ducts in the kidneys. Therefore a large proportion of water is reabsorbed from fluid to prevent a fair
proportion of water from being excreted.
A major way animals have evolved to osmoregulate is by controlling the amount of water lost through the excretory
system.
Osmoregulation in protists
Amoeba make use of contractile vacuoles to collect excretory waste,
such as ammonia, from the intracellular fluid by diffusion and active
transport. As osmotic action pushes water from the environment into
the cytoplasm, the vacuole moves to the surface and disposes the
contents into the environment.
Osmoregulation in bacteria
Prokaryotes respond via altered gene expression to changes in the
osmotic environment. The model organism E. coli's osmoregulation is
well described.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Osmoregulation
References
E. Solomon, L. Berg, D. Martin, Biology 6th edition. Brooks/Cole Publishing. 2002
References
[1] http:/ / en. wikipedia. org/ wiki/ Mesophyte
138
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Loop of Henle
139
Loop of Henle
Loop of Henle
Scheme of renal tubule and its vascular supply. (Loop of Henle visible center-left.)
Latin
Ansa nephroni
Gray's
Precursor
Metanephric blastema
MeSH
loop+of+henle
[2]
[1]
In the kidney, the loop of Henle (or Henle's loop, nephron loop [2] or its Latin counterpart ansa nephroni) is the
portion of a nephron that leads from the proximal convoluted tubule to the distal convoluted tubule. Named after its
discoverer F. G. J. Henle, the loop of Henle's main function is to create a concentration gradient in the medulla of the
kidney.
By means of a countercurrent multiplier system, which utilizes electrolyte pumps, the loop of Henle creates an area
of high urea concentration deep in the medulla, near the collecting duct. Water present in the filtrate in the collecting
duct flows through aquaporin channels out of the collecting duct, moving passively down its concentration gradient.
This process reabsorbs water and creates a concentrated urine for excretion.
Anatomy
It can be divided into four parts:
Thin descending limb of loop of Henle
The thin descending limb has low permeability to ions and urea, while being highly permeable to water. The
loop has a sharp bend in the renal medulla going from descending to ascending thin limb.
Thin ascending limb of loop of Henle
The thin ascending limb is impermeable to water, but it is permeable to ions.
Thick ascending limb of loop of Henle
Sodium (Na+), potassium (K+) and chloride (Cl-) ions are reabsorbed from the urine by secondary active
transport by a Na-K-Cl cotransporter (NKCC2). The electrical and concentration gradient drives more
reabsorption of Na+, as well as other cations such as magnesium (Mg2+) and calcium (Ca2+).
Cortical thick ascending limb
The cortical thick ascending limb drains urine into the distal convoluted tubule.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Loop of Henle
140
Blood supply
The loop of Henle is supplied by blood in a series of straight capillaries
descending from the cortical efferent arterioles. These capillaries
(called the vasa recta; recta is from the Latin for "straight") also have a
countercurrent multiplier mechanism that prevents washout of solutes
from the medulla, thereby maintaining the medullary concentration. As
water is osmotically driven from the descending limb into the
interstitium, it readily enters the vasa recta. The low bloodflow through
the vasa recta allows time for osmotic equilibration, and can be altered
by changing the resistance of the vessels' efferent arterioles.[citation needed]
Also, the vasa recta still has the large proteins and ions which were not filtered through the glomerulus, which
provides an oncotic pressure for ions to enter the vasa recta from the interstitium.[citation needed]
The main function of the Loop of Henle is to set up a concentration gradient.[citation needed]
Physiology
The descending loop of Henle receives isotonic (300 mOsm/L) fluid from the proximal convoluted tubule (PCT).
The fluid is isotonic because as ions are reabsorbed by the gradient time system, water is also reabsorbed
maintaining the osmolarity of the fluid in the PCT. Substances reabsorbed in the PCT include urea, water, potassium,
sodium, chloride, glucose, amino acids, lactate, phosphate, and bicarbonate. Since water is also reabsorbed the
volume of fluid in the loop of Henle is less than the PCT, approximately one-third of the original volume.
The interstitium of the kidney increases in osmolarity outside as the loop of Henle descends from 600 mOsm/L in the
outer medulla of the kidney to 1200 mOsm/L in the inner medulla. The descending portion of the loop of Henle is
extremely permeable to water and is less permeable to ions, therefore water is easily reabsorbed here and solutes are
not readily reabsorbed. The 300 mOsm/L fluid from the loop loses water to the higher concentration outside the loop
and increases in tonicity until it reaches its maximum at the bottom of the loop. This area represents the highest
concentration in the nephron, but the collecting duct can reach this same tonicity with maximum ADH effect.
The ascending limb of the loop of Henle receives an even lower volume of fluid and has different characteristics
compared to the descending limb. In the ascending portion, the loop becomes impermeable to water and the cells of
the loop actively reabsorb solutes from the luminal fluid; therefore water is not reabsorbed and ions are readily
reabsorbed. As ions leave the lumen via the Na-K-2Cl symporter and the Na-H antiporter, the concentration becomes
more and more hypotonic until it reaches approximately 100-150 mOsm/L. The ascending limb is also called the
diluting segment of the nephron because of its ability to dilute the fluid in the loop from 1200 mOsm/L to 100
mOsm/L.
Flow of the fluid through the entire loop of Henle is considered slow. As flow increases, the ability of the loop to
maintain its osmolar gradient is reduced. The vasa recta (capillary loops) also have a slow flow as well. Increases in
vasa recta flow wash away metabolites and cause the medulla to lose osmolarity as well. Increases in flow will
disrupt the kidney's ability to form concentrated urine.
Overall the loop of Henle resorbs about 25% of filtered ions and 20% of the filtered water in a normal kidney. These
ions are mostly Na, Cl, K, Ca and HCO3. The powering force is the Na/K ATPase on the basolateral membrane
which maintains the ion concentrations inside the cells. On the luminal membrane Na enters the cells passively
utilizing the Na-K-2Cl symporter. Then the Na/K ATPase will pump 3 Na out into the peritubular fluid and 2 K into
the cell on the non-lumen side of the cell. This gives the lumen of the fluid in the loop a positive charge in
comparison and creates a Na concentration gradient, which both push more Na into the cell via the Na-H antiporter.
The hydrogen for the antiporter comes from the enyzme carbonic anhydrase, which takes water and carbon dioxide
and forms bicarbonate and hydrogen. The hydrogen is exchanged for the Na in the tubular fluid of the loop of Henle.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Loop of Henle
141
Additional images
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=loop+ of+ henle
[2] http:/ / www. unifr. ch/ ifaa/ Public/ EntryPage/ ViewTH/ THh306. html
Further reading
Douglas C. Eaton, John Pooler (2004). Vander's Renal Physiology (6th edition ed.). McGraw-Hill Medical.
ISBN0-07-135728-9.
Lote, Christopher J. (2000). "The loop of Henle, distal tubing and collecting duct" (http://books.google.com/
books?id=-joihQfwXzwC&pg=PA70). Principles of Renal Physiology. Springer. p.70.
ISBN978-0-7923-6178-7.
External links
Loop of Henle physiology (http://www.acbrown.com/renal/OutLoop.htm)
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Water-electrolyte imbalance
142
Water-electrolyte imbalance
Water-electrolyte
imbalance
Classification and external resources
[1]
ICD-10
E86
ICD-9
276
MeSH
D014883
-E87
[2]
[3]
[4]
Electrolytes play a vital role in maintaining homeostasis within the body. They help to regulate myocardial and
neurological function, fluid balance, oxygen delivery, acid-base balance and much more. Electrolyte imbalances can
develop by the following mechanisms: excessive ingestion; diminished elimination of an electrolyte; diminished
ingestion or excessive elimination of an electrolyte. The most common cause of electrolyte disturbances is renal
failure.
The most serious electrolyte disturbances involve abnormalities in the levels of sodium, potassium, and/or calcium.
Other electrolyte imbalances are less common, and often occur in conjunction with major electrolyte changes.
Chronic laxative abuse or severe diarrhoea or vomiting (Gastroenteritis) can lead to electrolyte disturbances along
with dehydration. People suffering from bulimia or anorexia nervosa are at especially high risk for an electrolyte
imbalance.
General function
Electrolytes are important because they are what cells (especially nerve, heart, muscle) use to maintain voltages
across their cell membranes and to carry electrical impulses (nerve impulses, muscle contractions) across themselves
and to other cells. Kidneys work to keep the electrolyte concentrations in blood constant despite changes in your
body. For example, during heavy exercise, electrolytes are lost in sweat, particularly sodium and potassium. These
electrolytes must be replaced to keep the electrolyte concentrations of the body fluids constant.
References
[1]
[2]
[3]
[4]
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ E86
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ E87
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=276
http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D014883
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hyponatremia
143
Hyponatremia
Hyponatremia
Classification and external resources
Sodium
[1]
ICD-10
E87.1
ICD-9
276.1
DiseasesDB
6483
MedlinePlus
000394
eMedicine
emerg/275
MeSH
D007010
[2]
[3]
[4]
[5]
med/1130
[6]
ped/1124
[7]
[8]
Hyponatremia (American English) or hyponatraemia (British English) is an electrolyte disturbance in which the
sodium ion concentration in the plasma is lower than normal. Sodium is the dominant extracellular cation (positive
ion) and cannot freely cross from the interstitial space into the cell, because charged sodium ions attract up to 25
water molecules around them, creating a large polar structure that is too large to pass through the cell membrane. Its
homeostasis (stability of concentration) inside the cell is vital to the normal function of any cell. Normal serum
sodium levels are between approximately 135 and 145 mEq/L (135 - 145 mmol/L). Hyponatremia is generally
defined as a serum level of less than 135 mEq/L and is considered severe when the serum level is below 125 mEq/L.
Many conditions including congestive heart failure, liver failure, kidney failure and pneumonia can have an
associated hyponatremia. It can also be caused by overhydration from drinking too much water (polydipsia).
In the vast majority of cases, hyponatremia occurs as a result of a proportional excess of water relative to the plasma
sodium (salt level in the blood). Lack of sodium (salt) alone is very rarely the cause of hyponatremia, although it can
promote hyponatremia indirectly. In particular, sodium loss can lead to a state of volume depletion (loss of blood
volume in the body), with volume depletion serving as a signal for the release of ADH (anti-diuretic
hormone).[citation needed] As a result of ADH-stimulated water retention (too much water in the body), blood sodium
becomes diluted and hyponatremia results.
Exercise-associated hyponatremia (EAH), however, is common at marathons and other endurance events.
Researchers found, for instance, that 13% of the athletes who finished the 2002 Boston Marathon were in a clinically
hyponatremic condition, i.e. their salt levels in their blood had fallen below an acceptable level. Tim Noakes' 2012
book "Waterlogged" addresses this phenomenon clearly.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hyponatremia
Causes
Based on the above classification, some of the many specific causes of hyponatremia can be listed as follows:
Hypervolemic hyponatremia Both sodium & water content increase: Increase in sodium content leads to
hypervolemia and water content to hyponatremia. Total body water and sodium are regulated independently
Euvolemic hyponatremia total body water increases, but the body's sodium content stays the same
Hypovolemic hyponatremia The hypovolemia (extracellular volume loss) is consequent on total body sodium loss
but, overall, total body water is decreased and is the aetiology of the hyponatremia
any cause of hypovolemia such as prolonged vomiting, decreased oral intake, severe diarrhea
diuretic use (due to the diuretic causing a volume depleted state and thence ADH release, and not a direct result of
diuretic-induced urine sodium loss)
Addison's disease in which the adrenal glands do not produce sufficient steroid hormones (combined
glucocorticoid and mineralocorticoid deficiency)
Miscellaneous causes of hyponatremia that are not included under the above classification scheme include:
144
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hyponatremia
factitious hyponatremia (due to massive increases in blood triglyceride levels, extreme elevation of
immunoglobulins as may occur in multiple myeloma, and extreme hyperglycemia)
hypothyroidism and adrenal insufficiency (both thyroid hormone and cortisol are required to excrete free water)
beer potomania and other malnourished states where poor dietary protein intake leads to inadequate urine solute
formation thereby impeding the kidney's ability to excrete free water
primary polydipsia (where the amount of urine solute required to excrete huge quantities of ingested water
exceeds the body's ability to produce it; this typically occurs when 12 or more litres of water are ingested per day)
Diagnosis
Examination includes taking vital signs when lying, sitting, and standing, and an assessment of how much blood is in
the body. This determination (i.e. hypervolemic, euvolemic, hypovolemic) helps guide treatment decisions. A full
assessment of other medical conditions (comorbidity) is also taken, because heart and brain conditions affect the
results and the treatment decisions.
Pathophysiology
The hyponatremia can be spurious (false) and/or artifactual hyponatremia in which case there is no hypotonicity.
Hypertonic hyponatremia, caused by resorption of water drawn by molecules such as glucose (hyperglycemia or
diabetes) or mannitol (hypertonic infusion). Isotonic hyponatremia, more commonly called "pseudohyponatremia,"
is caused by measurement error due to hypertriglyceridemia (most common) or paraproteinemia. It occurs when
using techniques that measure the amount of sodium in a specified volume of serum/plasma, or that dilute the sample
before analysis.
True hyponatremia is Hypotonic hyponatremia and is by far the most common type, and is often simply referred to
as "hyponatremia." Hypotonic hyponatremia is categorized in 3 ways based on the patient's blood volume status.
Each category represents a different underlying reason for the increase in ADH that led to the water retention and
thence hyponatremia:
Hypervolemic hyponatremia, wherein there is decreased effective circulating volume (less blood flowing in the
body) even though total body volume is increased (by the presence of edema or swelling, especially in the
ankles). The decreased effective circulating volume stimulates the release of anti-diurectic hormone(ADH), which
in turn leads to water retention. Hypervolemic hyponatremia is most commonly the result of congestive heart
failure, liver failure (cirrhosis), or kidney disease (nephrotic syndrome).
Euvolemic hyponatremia, wherein the increase in ADH is secondary to either physiologic but excessive ADH
release (as occurs with nausea or severe pain) or inappropriate and non-physiologic secretion of ADH, i.e.
syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). Often categorized under euvolemic is
hyponatremia due to inadequate urine solute (not enough chemicals or electrolytes to produce urine) as occurs in
beer potomania or "tea and toast" hyponatremia, hyponatremia due to hypothyroidism or central adrenal
insufficiency, and those rare instances of hyponatremia that are truly secondary to excess water intake (i.e.,
extreme psychogenic polydipsia)
Hypovolemic hyponatremia, wherein ADH secretion is stimulated by or associated with volume depletion (not
enough water in the body).
The volemic classification fails to include spurious (fake) and/or artifactual hyponatremia, which is addressed in the
osmolar classification. This includes hyponatremia that occurs in the presence of massive hypertriglyceridemia,
severe hyperglycemia, and extreme elevation of immunoglobulin levels.
In chronic hyponatremia, sodium (salt) levels drop gradually over several days or weeks and symptoms and
complications are typically moderate. Chronic hyponatremia is often called asymptomatic hyponatremia in clinical
settings because it is thought to have no symptoms; however, emerging data suggests that "asymptomatic"
145
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hyponatremia
hyponatremia is not actually asymptomatic.
In acute hyponatremia sodium (salt) levels drop rapidly, resulting in potentially dangerous effects, such as rapid
brain swelling, which can result in coma and death.
Treatment
The treatment of hyponatremia depends on the underlying cause and whether the patient's blood volume status is
hypervolemic, euvolemic, or hypovolemic. In the setting of hypovolemia, intravenous administration of normal
saline (salt) is usual, careful care taken not to raise the serum sodium level (salt level in the blood) too quickly (see
below). Euvolemic hyponatremia is usually managed by fluid restriction and treatment to abolish any stimuli for
ADH secretion such as nausea. Likewise, drugs causing SIADH are discontinued if possible. Patients with
euvolemic hyponatremia that persists despite those measures may be candidates for a so-called vaptan drug as
discussed below. Hypervolemic hyponatremia is usually treated by addressing the underlying heart or liver failure. If
it is not be possible to do so, the treatment becomes the same as that for euvolemic hyponatremia (i.e. fluid
restriction and/or use of a vaptan drug).
Hyponatremia is corrected slowly in order to lessen the chance of the development of central pontine myelinolysis
(CPM), a severe neurological disease involving a breakdown of the myelin sheaths covering parts of nerve cells. In
fact, overly rapid correction of hyponatremia is the most common cause of that potentially devastating disorder.
During treatment of hyponatremia, the serum sodium (salt level in the blood) is not allowed to rise by more than
8mmol/l over 24 hours (i.e. 0.33mmol/l/h rate of rise). In practice, too rapid correction of hyponatremia and thence
CPM is most likely to occur during the treatment of hypovolemic hyponatremia. In particular, once the hypovolemic
state has been corrected, the signal for ADH release disappears. At that point, there will be an abrupt water diuresis
(an increase in urination since there is no longer any ADH acting to retain the water). A rapid and profound rise in
serum sodium (salt level in the blood) can then occur. Should the rate of rise of serum sodium exceed 0.33mmol/l/h
over several hours, vasopressin may be administered to prevent ongoing rapid water diuresis (excessive urination).
Pharmaceutically, vasopressin receptor antagonists can be used in the treatment of hyponatremia, especially in
patients with SIADH, congestive heart failure or liver cirrhosis. A vasopressin receptor antagonist is an agent that
interferes with the action at the vasopressin receptors. A new class of medication, the "vaptan" drugs has been
specifically developed to inhibit the action of vasopressin on its receptors (V1A, V1B, and V2). These receptors
have a variety of functions, with the V1A and V2 receptors are expressed peripherally and involved in the
modulation of blood pressure and kidney function respectively, while the V1A and V1B receptors are expressed in
the central nervous system. V1A is expressed in many regions of the brain, and has been linked to a variety of social
behaviors in humans and animals.
Vaptan drugs
The vaptan class of drugs contains a number of compounds with varying selectivity, several of which are either
already in clinical use or in clinical trials as of 2010.
Unselective (mixed V1A, V2)
Conivaptan
V1A selective
Relcovaptan
V1B selective
Nelivaptan
V2 selective
Lixivaptan
146
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hyponatremia
Mozavaptan
Satavaptan
Tolvaptan
The V2-receptor antagonists tolvaptan and conivaptan allow excretion of electrolyte free water and are effective in
increasing serum sodium in euvolemic and hypervolemic hyponatremia.
Complications
Chronic hyponatremia can lead to such complications as neurological impairments. These neurological impairments
most often affect gait (walking) and attention, and can lead to falls, osteoporosis, and decreased reaction time.
Complications for chronic hyponatremia are most dangerous for geriatric patients. Falls are the leading cause of
deaths related to injury among people 65 years or older. In a recent study the incidence of hyponatremia in elderly
patients with large-bone fractures was more than double that of non-fracture patients. Recent work by Verbalis et al.
suggests that hyponatremia induces osteoporosis and found the adjusted odds ratio for developing osteoporosis to be
2.87 times higher among adults with mild hyponatremia compared to those without.
Acute hyponatremia can lead to much more serious complications including brain disease, brain herniation,
cardiopulmonary arrest, cerebral edema (brain swelling), seizures, coma, and death.
Epidemiology
Hyponatremia is the most common electrolyte disorder. Electrolytes are sodium (salt), potassium, calcium,
magnesium, chloride, hydrogen phosphate, and hydrogen carbonate. The disorder is more frequent in females, the
elderly, and in patients who are hospitalized. The incidence of hyponatremia depends largely on the patient
population. A hospital incidence of 1520% is common, while only 35% of patients who are hospitalized have a
serum sodium level (salt blood level) of less than 130 mEq/L. Hyponatremia has been reported in up to 30% of
elderly patients in nursing homes and is also present in approximately 30% of depressed patients on selective
serotonin reuptake inhibitors.
References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ E87. 1
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=276. 1
http:/ / www. diseasesdatabase. com/ ddb6483. htm
http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000394. htm
http:/ / www. emedicine. com/ emerg/ topic275. htm
http:/ / www. emedicine. com/ med/ topic1130. htm#
http:/ / www. emedicine. com/ ped/ topic1124. htm#
http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D007010
147
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hyponatremia
External links
Sandy Craig, Erik D Schraga, Francisco Talavera, Howard A Bessen, John D Halamka (2010-04-13).
"Hyponatremia in Emergency Medicine" (http://emedicine.medscape.com/article/767624-overview).
Medscape.
James L. Lewis, III, MD (May 2009). "Hyponatremia" (http://www.merckmanuals.com/professional/sec12/
ch156/ch156d.html#CIHEIHHA). Merck Manual of Diagnosis and Therapy.
Kugler JP, Hustead T (June 2000). "Hyponatremia and hypernatremia in the elderly" (http://www.aafp.org/afp/
20000615/3623.html). Am Fam Physician 61 (12): 362330. PMID 10892634 (http://www.ncbi.nlm.nih.
gov/pubmed/10892634).
Elizabeth Quinn (2011-03-07). "What Is Hyponatremia: Hyponatremia or water intoxication Can Athletes
Drink Too Much Water?" (http://sportsmedicine.about.com/od/hydrationandfluid/a/Hyponatremia.htm).
About.com.
"Salt and the ultraendurance athlete" (http://www.rice.edu/~jenky/sports/salt.html). SportsMed Web. 1997.
Sean Rothwell (2010-06-07). "Kokoda Medicine" (http://lifeinthefastlane.com/2010/06/kokoda-medicine/).
Hyponatremia (http://www.mayoclinic.com/health/hyponatremia/DS00974/DSECTION=causes) Mayo
Clinic
Sodium (http://labtestsonline.org/understanding/analytes/sodium/tab/test) at Lab Tests Online
148
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hypernatremia
149
Hypernatremia
Hypernatremia
Classification and external resources
Sodium
[1]
ICD-10
E87.0
ICD-9
276.0
DiseasesDB
6266
eMedicine
emerg/263
[2]
[3]
[4]
Hypernatremia or hypernatraemia (see American and British English spelling differences) is an electrolyte
disturbance that is defined by an elevated sodium level in the blood. Hypernatremia is generally not caused by an
excess of sodium, but rather by a relative deficit of free water in the body. For this reason, hypernatremia is often
synonymous with the less precise term, dehydration.
Water is lost from the body in a variety of ways, including perspiration, imperceptible losses from breathing, and in
the feces and urine. If the amount of water ingested consistently falls below the amount of water lost, the plasma
sodium level will begin to rise, leading to hypernatremia. Rarely, hypernatremia can result from massive salt
ingestion,[5][6] such as may occur from drinking seawater or excessive amounts of a salty liquid like soy sauce.[7][8]
Ordinarily, even a small rise in the plasma sodium concentration above the normal range results in a strong sensation
of thirst, an increase in free water intake, and correction of the abnormality. Therefore, hypernatremia most often
occurs in people such as infants, those with impaired mental status, or the elderly, who may have an intact thirst
mechanism but are unable to ask for or obtain water.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hypernatremia
150
Cause
Common causes of hypernatremia include:
Hypovolemic
Inadequate intake of free water associated with total body
sodium depletion. Typically in elderly or otherwise disabled
patients who are unable to take in water as their thirst dictates
and also are sodium depleted. This is the most common cause of
hypernatremia.
Excessive losses of water from the urinary tract, which may be
caused by glycosuria, or other osmotic diuretics - leads to a
combination of sodium and free water losses.
Water losses associated with extreme sweating.
Severe watery diarrhea
Euvolemic
Excessive excretion of water from the kidneys caused by
diabetes insipidus, which involves either inadequate production
of the hormone vasopressin, from the pituitary gland or impaired
responsiveness of the kidneys to vasopressin.
Management of hypernatremia
Hypervolemic
Intake of a hypertonic fluid (a fluid with a higher concentration of solutes than the remainder of the body) with
restricted free water intake. This is relatively uncommon, though it can occur after a vigorous resuscitation
where a patient receives a large volume of a concentrated sodium bicarbonate solution. Ingesting seawater also
causes hypernatremia because seawater is hypertonic and free water is not available. There are several
recorded cases of forced ingestion of concentrated salt solution in exorcism rituals leading to death.
Mineralcorticoid excess due to a disease state such as Conn's syndrome usually does not lead to hypernatremia
unless free water intake is restricted.
Treatment
The cornerstone of treatment is administration of free water to correct the relative water deficit. Water can be
replaced orally or intravenously. Water alone cannot be administered intravenously (because of osmolarity issue),
but rather can be given with addition to dextrose or saline infusion solutions. However, overly rapid correction of
hypernatremia is potentially very dangerous. The body (in particular the brain) adapts to the higher sodium
concentration. Rapidly lowering the sodium concentration with free water, once this adaptation has occurred, causes
water to flow into brain cells and causes them to swell. This can lead to cerebral edema, potentially resulting in
seizures, permanent brain damage, or death. Therefore, significant hypernatremia should be treated carefully by a
physician or other medical professional with experience in treatment of electrolyte imbalance, specific treatment like
ACE inhibitors in heart failure and corticosteroids in nephropathy also can be used.[9]
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Hypernatremia
151
References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ E87. 0
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=276. 0
http:/ / www. diseasesdatabase. com/ ddb6266. htm
http:/ / www. emedicine. com/ emerg/ topic263. htm
Ofran, Y., Lavi, D., Opher, D., Weiss, T. A. and Elinav, E. (2004), Fatal voluntary salt intake resulting in the highest ever documented
sodium plasma level in adults (255 mmol L1): a disorder linked to female gender and psychiatric disorders. Journal of Internal Medicine,
256: 525528. doi: 10.1111/j.1365-2796.2004.01411.x
http:/ / dx. doi. org/ 10. 1016/ S0379-0738(98)00179-0
http:/ / www. huffingtonpost. com/ 2013/ 06/ 07/ soy-sauce-overdose-coma-hypernatremia_n_3402726. html
Survival of Acute Hypernatremia Due to Massive Soy Sauce Ingestion (http:/ / www. jem-journal. com/ article/ S0736-4679(13)00202-3/
abstract), The Journal of Emergency Medicine
Hypernatremia NEJM (http:/ / www. nejm. org/ doi/ full/ 10. 1056/ NEJM200005183422006)
External links
Sodium (http://labtestsonline.org/understanding/analytes/sodium/tab/test) at Lab Tests Online
Acidbase homeostasis
Acids and bases
Brnsted
Lewis
Mineral
Organic
Strong
Superacids
Weak
Base types
Brnsted
Lewis
Organic
Strong
Superbases
Non-nucleophilic
Weak
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Acidbase homeostasis
Acidbase homeostasis is the part of human homeostasis concerning the proper balance between acids and bases,
also called body pH. The body is very sensitive to its pH level, so strong mechanisms exist to maintain it. Outside
the acceptable range of pH, proteins are denatured and digested, enzymes lose their ability to function, and death
may occur.
Mechanism
The body's acidbase balance is normally tightly regulated, keeping
the arterial blood pH between 7.38 and 7.42. Several buffering agents
that reversibly bind hydrogen ions and impede any change in pH exist.
Extracellular buffers include bicarbonate and ammonia, whereas
proteins and phosphate act as intracellular buffers. The bicarbonate
buffering system is especially key, as carbon dioxide (CO2) can be
shifted through carbonic acid (H
2CO
3) to hydrogen ions and bicarbonate (HCO
3) as shown below.
Imbalance
Acidbase imbalance occurs when a significant insult causes the blood pH to shift out of the normal range (7.35 to
7.45). In the fetus, the normal range differs based on which umbilical vessel is sampled (umbilical vein pH is
normally 7.25 to 7.45; umbilical artery pH is normally 7.18 to 7.38). An excess of acid in the blood is called
acidemia and an excess of base is called alkalemia. The process that causes the imbalance is classified based on the
etiology of the disturbance (respiratory or metabolic) and the direction of change in pH (acidosis or alkalosis). There
are four basic processes: metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. One
or a combination may occur at any given time.
152
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Acidbase homeostasis
References
External links
153
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Acidosis
154
Acidosis
Acidosis
Classification and external resources
[1]
ICD-10
E87.2
ICD-9
276.2
DiseasesDB
87
MedlinePlus
001181
[2]
[3]
[4]
Acidosis is an increased acidity in the blood and other body tissue (i.e. an increased hydrogen ion concentration). If
not further qualified, it usually refers to acidity of the blood plasma.
Acidosis is said to occur when arterial pH falls below 7.35 (except in the fetus - see below), while its counterpart
(alkalosis) occurs at a pH over 7.45. Arterial blood gas analysis and other tests are required to separate the main
causes.
The term acidemia describes the state of low blood pH, while acidosis is used to describe the processes leading to
these states. Nevertheless, the terms are sometimes used interchangeably. The distinction may be relevant where a
patient has factors causing both acidosis and alkalosis, wherein the relative severity of both determines whether the
result is a high or a low pH.
The rate of cellular metabolic activity affects and, at the same time, is affected by the pH of the body fluids. In
mammals, the normal pH of arterial blood lies between 7.35 and 7.50 depending on the species (e.g. healthy
human-arterial blood pH varies between 7.35 and 7.45). Blood pH values compatible with life in mammals are
limited to a pH range between 6.8 and 7.8. Changes in the pH of arterial blood (and therefore the extracellular fluid)
outside this range result in irreversible cell damage.[5]
Metabolic acidosis
Metabolic acidosis may result from increased
production of metabolic acids or disturbances in the
ability to excrete acid via the kidneys. Renal acidosis is
associated with an accumulation of urea and creatinine
as well as metabolic acid residues of protein
catabolism.
An increase in the production of other acids may also
produce metabolic acidosis. For example, lactic
acidosis may occur from:
1. severe (PaO2 <36mm Hg) hypoxemia causing a fall
in the rate of oxygen diffusion from arterial blood to
tissues
2. hypoperfusion (e.g., hypovolemic shock) causing an
inadequate blood delivery of oxygen to tissues.
[6][7]
General symptoms of acidosis.
These usually accompany
symptoms of another primary defect (respiratory or metabolic).
A rise in lactate out of proportion to the level of pyruvate, e.g. in mixed venous blood, is termed "excess lactate", and
may also be an indicator of fermentation due to anaerobic metabolism occurring in muscle cells, as seen during
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Acidosis
strenuous exercise. Once oxygenation is restored, the acidosis clears quickly. Another example of increased
production of acids occurs in starvation and diabetic acidosis. It is due to the accumulation of ketoacids (ketosis) and
reflects a severe shift from glycolysis to lipolysis for energy needs.
Acid consumption from poisoning such as hypercapnia, elevated levels of iron in the blood, and chronically
decreased production of bicarbonate may also produce metabolic acidosis.
Metabolic acidosis is compensated for in the lungs, as increased exhalation of carbon dioxide promptly shifts the
buffering equation to reduce metabolic acid. This is a result of stimulation to chemoreceptors, which increases
alveolar ventilation, leading to respiratory compensation, otherwise known as Kussmaul breathing (a specific type of
hyperventilation). Should this situation persist, the patient is at risk for exhaustion leading to respiratory failure.
Mutations to the V-ATPase 'a4' or 'B1' isoforms result in distal renal tubular acidosis, a condition that leads to
metabolic acidosis, in some cases with sensorineural deafness.
Arterial blood gases will indicate low pH, low blood HCO3, and normal or low PaCO2. In addition to arterial blood
gas, an anion gap can also differentiate between possible causes.
The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. The
amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate
of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of
the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected.
Treatment of uncompensated metabolic acidosis is focused upon correcting the underlying problem. When metabolic
acidosis is severe and can no longer be compensated for adequately by the lungs, neutralizing the acidosis with
infusions of bicarbonate may be required.
Respiratory acidosis
Respiratory acidosis results from a build-up of carbon dioxide in the blood (hypercapnia) due to hypoventilation. It is
most often caused by pulmonary problems, although head injuries, drugs (especially anaesthetics and sedatives), and
brain tumors can cause this acidemia. Pneumothorax, emphysema, chronic bronchitis, asthma, severe pneumonia,
and aspiration are among the most frequent causes. It can also occur as a compensatory response to chronic
metabolic alkalosis.
One key to distinguish between respiratory and metabolic acidosis is that in respiratory acidosis, the CO2 is increased
while the bicarbonate is either normal (uncompensated) or increased (compensated). Compensation occurs if
respiratory acidosis is present, and a chronic phase is entered with partial buffering of the acidosis through renal
bicarbonate retention.
However, in cases where chronic illnesses that compromise pulmonary function persist, such as late-stage
emphysema and certain types of muscular dystrophy, compensatory mechanisms will be unable to reverse this
acidotic condition. As metabolic bicarbonate production becomes exhausted, and extraneous bicarbonate infusion
can no longer reverse the extreme buildup of carbon dioxide associated with uncompensated respiratory acidosis,
mechanical ventilation will usually be applied.
155
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Acidosis
References
[1]
[2]
[3]
[4]
[5]
[6]
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ E87. 2
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=276. 2
http:/ / www. diseasesdatabase. com/ ddb87. htm
http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001181. htm
Needham, A. 2004. Comparative and Environmental Physiology. Acidosis and Alkalosis.
Answers.com Medical Encyclopedia: Metabolic Acidosis: Causes and symptoms (http:/ / www. answers. com/ topic/
metabolic-acidosis-causes-and-symptoms) By Altha Roberts Edgren. Retrieved on April 13, 2009
[7] Symptoms mentioned in both metabolic and respiratory acidosis from the following two references: - Wrongdiagnosis.com > Symptoms of
Metabolic Acidosis (http:/ / www. wrongdiagnosis. com/ m/ metabolic_acidosis/ symptoms. htm#symptom_list) Retrieved on April 13, 2009 Wrongdiagnosis.com > Symptoms of Respiratory acidosis (http:/ / www. wrongdiagnosis. com/ r/ respiratory_acidosis/ symptoms.
htm-symptom_list) Retrieved on April 13, 2009
Notes
Hobler KE, Carey LC. Effect of acute progressive hypoxemia on cardiac output and plasma excess lactate. Ann
Surg. 1973 Feb;177(2):199-202.
Hobler KE, Napodano RJ, Tolerance of swine to acute blood volume deficits.
J Trauma. 1974 Aug;14(8):716-8.
Clinical Physiology of Acid-Base and Electrolyte Disorders by Rose, Post (http://books.mcgraw-hill.com/
getbook.php?isbn=0071346821&template=medical)
Intensive Care Medicine by Irwin and Rippe (http://www.lww.com/product/?0-7817-3548-3)
The ICU Book by Marino (http://www.lww.com/product/?0-683-05565-8)
156
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Alkalosis
157
Alkalosis
Alkalosis
Classification and external resources
[1]
ICD-10
E87.3
ICD-9
276.3
DiseasesDB
32458
MedlinePlus
001183
MeSH
D000471
[2]
[3]
[4]
[5]
Alkalosis refers to a condition reducing hydrogen ion concentration of arterial blood plasma (alkalemia). Generally,
alkalosis is said to occur when pH of the blood exceeds 7.45. The opposite condition is acidosis (when pH falls
below 7.35).
Types
Alkalosis can refer to:
Respiratory alkalosis
Metabolic alkalosis
Causes
The main cause of respiratory alkalosis is hyperventilation, resulting in a loss of carbon dioxide. Compensatory
mechanisms for this would include increased dissociation of the carbonic acid buffering intermediate into hydrogen
ions, and the related excretion of bicarbonate,[citation needed] both of which lower blood pH.
Metabolic alkalosis can be caused by prolonged vomiting, resulting in a loss of hydrochloric acid with the stomach
content. Severe dehydration, and the consumption of alkali are other causes. It can also be caused by administration
of diuretics and endocrine disorders such as Cushing's syndrome. Compensatory mechanism for metabolic alkalosis
involve slowed breathing by the lungs to increase serum carbon dioxide, a condition leaning toward respiratory
acidosis. As respiratory acidosis often accompanies the compensation for metabolic alkalosis, and viceversa, a
delicate balance is created between these two conditions.
Complications
Metabolic alkalosis is usually accompanied with hypokalemia, causing, e.g., muscular weakness, myalgia, and
muscle cramps (from disturbed function of the skeletal muscles), and muscle spasms (from disturbed function of
smooth muscles).
It may also cause hypocalcemia. As the pH of blood increases, blood transport proteins, such as albumin, become
more ionised into anions. This causes the free calcium present in blood to bind more strongly with albumin. If
severe, it may cause tetany (alkalotic tetany).
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Alkalosis
References
IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:
(2006) "alkalosis [6]".
References
[1]
[2]
[3]
[4]
[5]
[6]
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ E87. 3
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=276. 3
http:/ / www. diseasesdatabase. com/ ddb32458. htm
http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001183. htm
http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D000471
http:/ / goldbook. iupac. org/ A00221. html
158
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Glomerulonephritis
159
Glomerulonephritis
Glomerulonephritis
Classification and external resources
Photomicrograph of a kidney biopsy from a patient with crescentic glomerulonephritis showing prominent fibrocellular crescent formation and
moderate mesangial proliferation in a glomerulus. Hematoxylin and eosin stain.
ICD-10
ICD-9
580
DiseasesDB
5245
MedlinePlus
000484
MeSH
D005921
[1]
-582
[2]
[3]
[4]
[5]
Glomerulonephritis, also known as glomerular nephritis, is a term used to refer to several renal diseases (usually
affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or small
blood vessels in the kidneys, hence the name, but not all diseases necessarily have an inflammatory component.
As it is not strictly a single disease, its presentation depends on the specific disease entity: it may present with
isolated hematuria and/or proteinuria (blood or protein in the urine); or as a nephrotic syndrome, a nephritic
syndrome, acute renal failure, or chronic renal failure.
They are categorized into several different pathological patterns, which are broadly grouped into non-proliferative or
proliferative types. Diagnosing the pattern of GN is important because the outcome and treatment differs in different
types. Primary causes are intrinsic to the kidney. Secondary causes are associated with certain infections (bacterial,
viral or parasitic pathogens), drugs, systemic disorders (SLE, vasculitis), or diabetes.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Glomerulonephritis
160
Nephrotic syndrome
The nephrotic syndrome is characterised by the finding of oedema in a
patient that has increase protein in the urine and decreased protein in
the blood, with increased fat in the blood. Inflammation that affects the
cells surrounding the glomerulus, podocytes, increases the permeability
to proteins, resulting in an increased in excreted proteins. When the
amount of proteins excreted in the urine exceeds the liver's ability to
compensate, less proteins are detected in the blood - in particular
albumin, which makes up the majority of circulating proteins. With
decreased proteins in the blood, there is a decrease in the osmotic
A glomerulus, a functional unit that represents the
pressure of the blood. This results in oedema, as the osmotic pressure
first step in the filtration of blood and generation
of urine.
in tissue remains the same. This is worsened by the secretion of the
hormone Aldosterone by the kidney, which is secreted in response to
the decrease in circulating blood and causes sodium and water retention. Hyperlipidemia is thought to be a result of
the increased activity of the liver. :549
Nephritic syndrome
The nephritic syndrome is characterised by blood in the urine and a
decrease in the amount of urine in the presence of hypertension. In this
syndrome, inflammatory damage to cells lining the glomerulus are
thought to result destruction of the epithelial barrier, leading to blood
being found in the urine. At the same time, reactive changes
Wikipedia:Avoid weasel words may result in a decrease in renal
perfusion, resulting in a decrease in the production of urine. The
renin-angiotensin system may be subsequently activated, because of
the decrease in perfusion of juxtaglomerular apparatus, which may
result in hypertension. :554
Nonproliferative
This is characterised by forms of glomerulonephritis in which the number of cells is not changed. These forms
usually result in the nephrotic syndrome. Causes include:
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Glomerulonephritis
the glomerulus. It is typically managed with corticosteroids and does not progress to chronic kidney disease. :500 :550
Membranous glomerulonephritis
Membranous glomerulonephritis may cause either nephrotic or a nephritic picture. About two-thirds are associated
with auto-antibodies to phospholipase A2 receptor, but other associations include cancers of the lung and bowel,
infections such as hepatitis B and malaria, drugs including penicillamine, and connective tissue diseases such as
systemic lupus erythematosus. Individuals with cerebral shunts are at risk of developing shunt nephritis, which
frequently produces MGN.
Microscopically, MGN is characterized by a thickened glomerular basement membrane without a hypercellular
glomerulus. Immunofluorescence demonstrates diffuse granular uptake of IgG. The basement membrane may
completely surround the granular deposits, forming a "spike and dome" pattern. Tubules also display the symptoms
of a typical Type III hypersensitivity reaction, which causes the endothelial cells to proliferate, which can be seen
under a light microscope with a PAS stain.
Prognosis follows the rule of thirds: one-third remain with MGN indefinitely, one-third remit, and one-third progress
to end-stage renal failure. As the glomerulonephritis progresses, the tubules of the kidney become infected, leading
to atrophy and hyalinisation. The kidney appears to shrink. Treatment with corticosteroids is attempted if the disease
progresses.
In extremely rare cases, the disease has been known to run in families, usually passed down through the females.
This condition, similarly, is called Familial Membranous Glomerulonephritis. There have only been about nine
documented cases in the world.
Proliferative
Proliferative glomerulonephritis is characterised by an increased number of cells in the glomeruls. These forms
usually present with a triad of blood in the urine, decreased urine production, and hypertension, the nephritic
syndrome. These forms usually progress to end-stage renal failure (ESRF) over weeks to years (depending on type).
161
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Glomerulonephritis
162
IgA nephropathy
IgA nephropathy, also known as Berger's disease, is the most common type of glomerulonephritis, and generally
causes a nephritic syndrome characterised by protein in the urine, and visible blood in the urine. IgA nephropathy is
classically described as a self-resolving form in young adults several days after a respiratory infection. It is
characterised by deposits of IgA in the space between glomerular capillaries. :501:554-555
Henoch-Schonlein purpura refers to a form of IgA nephropathy, typically affecting children, chararcterised by a rash
of small bruises affecting the buttocks and lower legs, with abdominal pain. :501
Post-infectious
Post-infectious glomerulonephritis can occur after essentially any infection, but classically occurs after infection
with the bacteria Streptococcus pyogenes. It typically occurs 1-4 weeks after a pharyngeal infection with this
bacterium, and is likely to present with malaise, a slight fever, nausea and a mild nephritic syndrome of moderately
increased blood pressure, gross haematuria, and smoky-brown urine. Circulating immune complexes that deposit in
the glomerules may lead to an inflammatory reaction. :554-555
Diagnosis may be made on clinical findings or through antistreptolysin O antibodies found in the blood. A biopsy is
seldom done, and the disease is likely to self-resolve in children in 1-4 weeks, with a poorer prognosis if adults are
affected. :501
Membranoproliferative
Membranoproliferative GN (MPGN), also known as mesangiocapillary glomerulonephritis,:502 is characterised by
an increase in the number of cells in the glomerulus, and alterations in the glomerular basement membrane. These
forms present with the nephrotic syndrome, hypocomplementemia, and have a poor prognosis. Two primary
subtypes exist: :552-553
Type 1 MPGN is caused by circulating immune complexes, typically secondary to systemic lupus erythematosis,
hepatitis B and C, or other chronic or recurring infections. Circulating immune complexes may activate the
complement system, leading to inflammation and an influx of inflammatory cells.:552-553
Type 2 MPGN, also known as Dense Deposit Disease, is characterised by an excessive activation of the
complement system. The C3 Nephritic Factor autoantibody stabilises C3-convertase, which may lead to an
excessive activation of complement. :553
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Glomerulonephritis
Type 2 is characterised by immune-complex-mediated damage, and
may be associated with systemic lupus erythematosis, post-infective
glomerulonephritis, IgA nephropathy, and Henoch-Scholein
purpura. :558
Type 3 rapidly progressive glomerulonephritis, also called
pauciimmune type, is associated with causes of vascular
inflammation including Wegener granulomatosis and microscopic
polyangitis. No immune deposits can be seen on staining, however
blood tests may be positive for the ANCA antibody. :558-559
Photomicrograph of renal biopsy showing
Histopathology: The majority of glomeruli present "crescents".
crescent formation and tuft narrowing. Periodic
Formation of crescents is initiated by passage of fibrin into the
acid silver methenamine stain.
Bowman space as a result of increased permeability of glomerular
basement membrane. Fibrin stimulates the proliferation of endothelial
cells of Bowman capsule, and an influx of monocytes. Rapid growing and fibrosis of crescents compresses the
capillary loops and decreases the Bowman space, which leads to renal failure within weeks or months. [citation needed]
Investigations
Some forms of glomerulonephritis are diagnosed clinically, based on findings on history and examination. Other
tests may include:
Urine examination
Blood tests investigating the cause, including FBC, inflammatory markers and special tests including (ASLO,
ANCA, Anti-GBM, Complement levels, Antinuclear antibodies
Biopsy of the kidney
References
[1] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=580
[2] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=582
[3] http:/ / www. diseasesdatabase. com/ ddb5245. htm
[4] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000484. htm
[5] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D005921
163
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Interstitial nephritis
164
Interstitial nephritis
Interstitial nephritis
Classification and external resources
[1]
ICD-10
N10
ICD-9
580.89
DiseasesDB
6854
-N12
[2]
[3]
, 581.89
[4]
, 582.89
[5]
, 583.89
[6]
[7]
med/1596
MeSH
D009395
[9]
[10]
Interstitial nephritis (or Tubulo-interstitial nephritis) is a form of nephritis affecting the interstitium of the
kidneys surrounding the tubules. This disease can be either acute, meaning it occurs suddenly, or chronic, meaning it
is ongoing and eventually ends in kidney failure.
Etiologies
Common causes include infection, or reaction to medication (such as an analgesic or antibiotics such as Methicillin
(Meticillin). Reaction to medications causes 71% to 92% of cases.
This disease is also caused by other diseases and toxins that do damage to the kidney. Both acute and chronic
tubulointerstitial nephritis can be caused by a bacterial infection in the kidneys, known as pyelonephritis. The most
common cause is by an allergic reaction to a drug. The drugs that are known to cause this sort of reaction are
antibiotics such as penicillin and cephalexin, and nonsteroidal anti-inflammatory drugs, such as aspirin, as well as
rifampin, sulfa drugs, quinolones, diuretics, allopurinol, and phenytoin. The time between exposure to the drug and
the development of acute tubulointerstitial nephritis can be anywhere from 5 days to 5 months (fenoprofen induced).
Diagnosis
At times there are no symptoms of this disease, but when they do occur they are widely varied and can occur rapidly
or gradually. When caused by an allergic reaction, the symptoms of acute tubulointerstitial nephritis are fever (27%
of patients), rash (15% of patients), and enlarged kidneys. Some people experience dysuria, and lower back pain. In
chronic tubulointerstitial nephritis the patient can experience symptoms such as nausea, vomiting, fatigue, and
weight loss. Other conditions that may develop include hyperkalemia, metabolic acidosis, and kidney failure.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Interstitial nephritis
Blood tests
About 23% of patients have eosinophilia.
Urinary findings
Urinary findings include:
Eosinophiluria: sensitivity is 67% and specificity is 83%. The sensitivity is higher in patients with interstitial
nephritis induced by methicillin or when the Hansel's stain is used.
Isosthenuria.
Hematuria
Sterile pyuria: white blood cells and no bacteria
Gallium scan
The sensitivity of an abnormal gallium scan has been reported to range from 60% to 100%.
Treatment
Remove the etiology such as an offending drug. Corticosteroids do not clearly help. Nutrition therapy consists of
adequate fluid intake, which can require several liters of extra fluid.
Prognosis
The kidneys are the only body system that are directly affected by tubulointerstitial nephritis. Kidney function is
usually reduced; the kidneys can be just slightly dysfunctional, or fail completely.
In chronic tubulointerstitial nephritis, the most serious long-term effect is kidney failure. When the proximal tubule
is injured, sodium, potassium, bicarbonate, uric acid, and phosphate reabsorption may be reduced or changed,
resulting in low bicarbonate, known as metabolic acidosis, low potassium, low uric acid known as hypouricemia, and
low phosphate known as hypophosphatemia. Damage to the distal tubule may cause loss of urine-concentrating
ability and polyuria.
In most cases of acute tubulointerstitial nephritis, the function of the kidneys will return after the harmful drug is not
taken anymore, or when the underlying disease is cured by treatment. If the illness is caused by an allergic reaction, a
corticosteroid may speed the recovery kidney function; however, this is often not the case.
Chronic tubulointerstitial nephritis has no cure. Some patients may require dialysis. Eventually, a kidney transplant
may be needed.
References
[1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ N10
[2] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ N12
[3] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=580. 89
[4] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=581. 89
[5] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=582. 89
[6] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=583. 89
[7] http:/ / www. diseasesdatabase. com/ ddb6854. htm
[8] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000464. htm
[9] http:/ / www. emedicine. com/ med/ topic1596. htm
[10] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D009395
165
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Interstitial nephritis
166
External links
Merck Manual (http://www.merck.com/mmpe/sec17/ch236/ch236c.html)
Diabetic nephropathy
Diabetic nephropathy
Classification and external resources
ICD-9
250.4
MedlinePlus
000494
MeSH
D003928
[1]
[2]
[3]
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Diabetic nephropathy
167
headache
frequent hiccups
The first laboratory abnormality is a positive microalbuminuria test. Most often, the diagnosis is suspected when a
routine urinalysis of a person with diabetes shows too much protein in the urine (proteinuria). The urinalysis may
also show glucose in the urine, especially if blood glucose is poorly controlled. Serum creatinine and BUN may
increase as kidney damage progresses.
A kidney biopsy confirms the diagnosis, although it is not always necessary if the case is straightforward, with a
documented progression of proteinuria over time and presence of diabetic retinopathy on examination of the retina of
the eyes.
Cause
The word diabetes means "passing through", referring to the polyuria (abnormal increase of urine production), a
symptom historically present in those affected by the disease. When the level of blood glucose rises beyond the
kidney's capacity to reabsorb glucose from the renal ultrafiltrate, glucose remains diluted in the fluid, raising its
osmotic pressure and causing more water to be carried out, thus, increasing the excreted urine volume. The increased
volume dilutes the sodium chloride in the urine, signalling the macula densa to release more renin, causing
vasoconstriction, a survival mechanism to retain water by passing less blood through the kidneys. Because the
kidney is nurtured exclusively by the blood it filtrates, the vasoconstriction also reduces the nutrients supplied to it,
causing infarct of its tissues and reduction of renal function.
Pathophysiology
The earliest detectable change in the course of diabetic nephropathy is
a thickening in the glomerulus. At this stage, the kidney may leak more
serum albumin (plasma protein) than normal in the urine
(albuminuria), and this can be detected by sensitive medical tests for
albumin. This stage is called "microalbuminuria". As diabetic
nephropathy progresses, increasing numbers of glomeruli are destroyed
by progressive nodular glomerulosclerosis. Consequently, urine
albumin increases to the point that it may be detected by ordinary
urinalysis techniques. At this stage, a kidney biopsy generally clearly
shows diabetic nephropathy.
The Armanni-Ebstein change (or Armanni-Ebstein cells) consists of deposits of glycogen in the tubular epithelial
cells (pars straight of proximal convoluted tubule and loop of Henle). Because most diabetics are treated before this
stage, it is very rare to see it at the present time. It appears in decompensated diabetics with glycemia higher than
500mg/dL and in the presence of severe glycosuria; it is a reversible alteration without functional manifestations.
The interstitium shows nonspecific chronic changes.
Treatment
The goals of treatment are to slow the progression of kidney damage and control related complications. The main
treatment, once proteinuria is established, is ACE inhibitor drugs, which usually reduces proteinuria levels and slows
the progression of diabetic nephropathy. Several effects of the ACEIs that may contribute to renal protection have
been related to the association of rise in Kinins which is also responsible for some of the side effects associated with
ACEIs therapy such as dry cough. The renal protection effect is related to the antihypertensive effects in normal and
hypertensive patients, renal vasodilatation resulting in increased renal blood flow and dilatation of the efferent
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Diabetic nephropathy
arterioles.[4] Many studies have shown that related drugs, angiotensin receptor blockers (ARBs), have a similar
benefit. However, combination therapy, according to the ONTARGET study, is known to worsen major renal
outcomes, such as increasing serum creatinine and causing a greater decline in estimated glomerular filtration rate
(eGFR).
Blood-glucose levels should be closely monitored and controlled. This may slow the progression of the disorder,
especially in the very early ("microalbuminuria") stages. Medications to manage diabetes include oral hypoglycemic
agents and insulin injections. As kidney failure progresses, less insulin is excreted, so lesser doses may be needed to
control glucose levels.
Diet may be modified to help control blood-sugar levels. Modification of protein intake can affect hemodynamic and
nonhemodynamic injury.
High blood pressure should be aggressively treated with antihypertensive medications, in order to reduce the risks of
kidney, eye, and blood vessel damage in the body. It is also very important to control lipid levels, maintain a healthy
weight, and engage in regular physical activity.
Patients with diabetic nephropathy should avoid taking the following drugs:
Contrast agents containing iodine
Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen, or COX-2
inhibitors like celecoxib, because they may injure the weakened kidney.
Urinary tract and other infections are common and can be treated with appropriate antibiotics.
Dialysis may be necessary once end-stage renal disease develops. At this stage, a kidney transplantation must be
considered. Another option for type 1 diabetes patients is a combined kidney-pancreas transplant.
C-peptide, a by-product of insulin production, may provide new hope for patients suffering from diabetic
nephropathy.
Several compounds are in development for diabetic kidney disease. These include, but are not limited to,
bardoxolone methyl,[5] olmesartan medoxomil, sulodexide, and avosentan.[6]
Prognosis
Diabetic nephropathy continues to get gradually worse. Complications of chronic kidney failure are more likely to
occur earlier, and progress more rapidly, when it is caused by diabetes than other causes. Even after initiation of
dialysis or after transplantation, people with diabetes tend to do worse than those without diabetes.
Possible complications include:
168
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Diabetic nephropathy
169
Epidemiology
The syndrome can be seen in patients with diabetes (usually less than 15 years after onset) after about 5 years in type
1 diabetes. Clinical nephropathy secondary to glomerular disease usually manifests 1525 years after diagnosis of
diabetes and affects 25-35% of patients under the age of 30 years. It is the leading cause of premature death in young
diabetic patients (between 50 and 70 years old). The disease is progressive and may cause death two or three years
after the initial lesions, and is more frequent in men. Diabetic nephropathy is the most common cause of chronic
kidney failure and end-stage kidney disease in the United States. People with both type 1 and type 2 diabetes are at
risk. The risk is higher if blood-glucose levels are poorly controlled. Furthermore, once nephropathy develops, the
greatest rate of progression is seen in patients with poor control of their blood pressure. Also people with high
cholesterol level in their blood have much more risk than others.
History
The syndrome was discovered by British physician Clifford Wilson (19061997) andGerman-born American
physician Paul Kimmelstiel (19001970) and was published for the first time in 1936.
Additional images
Histopathological image of
diabetic glomerulosclerosis with
nephrotic syndrome. H&E stain.
Histopathological image of
diabetic glomerulosclerosis with
nephrotic syndrome. Another
glomerulus. H&E stain.
Histopathological image of
diabetic glomerulosclerosis with
nephrotic syndrome. Another
glomerulus. H&E stain.
Histopathological image of
diabetic glomerulosclerosis with
nephrotic syndrome. PAS stain.
Histopathological image of
diabetic glomerulosclerosis with
nephrotic syndrome. PAM stain.
Histopathological image of
diabetic glomerulosclerosis with
nephrotic syndrome. PAM stain.
Histopathological image of
diabetic glomerulosclerosis with
nephrotic syndrome. PAS stain.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Diabetic nephropathy
References
[1]
[2]
[3]
[4]
External links
Diabetic nephropathy (http://www.healthcentral.com/mhc/top/000494.cfm). HealthCentral.
Diabetic nephropathy (http://www.nlm.nih.gov/medlineplus/ency/article/000494.htm). MedlinePlus
Medical Encyclopedia. Text from this public domain article was partially used here.
Texas University Classification (http://www.podomedic.it/modules/news/article.php?storyid=108)
170
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
171
Pathologic kidney specimen showing marked pallor of the cortex, contrasting to the darker areas of surviving medullary tissue. The patient died
with acute kidney injury.
[1]
ICD-10
N17
ICD-9
584
DiseasesDB
11263
MedlinePlus
000501
eMedicine
med/1595
MeSH
D058186
[2]
[3]
[4]
[5]
[6]
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a rapid loss of kidney function.
Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the
kidney, and obstruction of the urinary tract. AKI is diagnosed on the basis of characteristic laboratory findings, such
as elevated blood urea nitrogen and creatinine, or inability of the kidneys to produce sufficient amounts of urine.
AKI may lead to a number of complications, including metabolic acidosis, high potassium levels, uremia, changes in
body fluid balance, and effects to other organ systems. Management includes supportive care, such as renal
replacement therapy, as well as treatment of the underlying disorder.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
172
Inability to excrete sufficient fluid from the body can cause accumulation of fluid in the limbs (peripheral edema)
and the lungs (pulmonary edema), as well as cardiac tamponade as a result of fluid effusions.
Causes
AKI can be caused by disease, crush injury, contrast agents, some antibiotics, and more.
The causes of acute kidney injury are commonly categorized into prerenal, intrinsic, and postrenal.
BUN/Cr
Prerenal
>20
Intrinsic
>15
Prerenal
Prerenal causes of AKI ("pre-renal azotemia") are those that decrease effective blood flow to the kidney. These
include systemic causes, such as low blood volume, low blood pressure, heart failure, and local changes to the blood
vessels supplying the kidney. The latter include renal artery stenosis, or the narrowing of the renal artery which
supplies the kidney with blood, and renal vein thrombosis, which is the formation of a blood clot in the renal vein
that drains blood from the kidney.
Renal ischaemia ultimately results in functional disorder, depression of GFR, or both. These causes stem from the
inadequate cardiac output and hypovolemia or vascular diseases causing reduced perfusion of both kidneys. Both
kidneys need to be affected as one kidney is still more than adequate for normal kidney function.
Intrinsic
Sources of damage to the kidney itself are dubbed intrinsic. Intrinsic AKI can be due to damage to the glomeruli,
renal tubules, or interstitium. Common causes of each are glomerulonephritis, acute tubular necrosis (ATN), and
acute interstitial nephritis (AIN), respectively. A cause of intrinsic acute renal failure is tumor lysis syndrome.
Postrenal
Postrenal AKI is a consequence of urinary tract obstruction. This may be related to benign prostatic hyperplasia,
kidney stones, obstructed urinary catheter, bladder stone, bladder, ureteral or renal malignancy. It is useful to
perform a bladder scan or a post void residual to rule out urinary retention. In post void residual, a catheter is
inserted immediately after urinating to measure fluid still in the bladder. 50-100ml suggests neurogenic bladder. A
renal ultrasound will demonstrate hydronephrosis if present. A CT scan of the abdomen will also demonstrate
bladder distension or hydronephrosis, however, in case of acute renal failure, the use of IV contrast is
contraindicated. On the basic metabolic panel, the ratio of BUN to creatinine may indicate post renal failure.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Diagnosis
Detection
The deterioration of renal function may be discovered by a measured decrease in urine output. Often, it is diagnosed
on the basis of blood tests for substances normally eliminated by the kidney: urea and creatinine. Both tests have
their disadvantages. For instance, it takes about 24 hours for the creatinine level to rise, even if both kidneys have
ceased to function. A number of alternative markers has been proposed (such as NGAL, KIM-1, IL18 and cystatin
C), but none are currently established enough to replace creatinine as a marker of renal function.
Further testing
Once the diagnosis of AKI is made, further testing is often required to determine the underlying cause. These may
include urine sediment analysis, renal ultrasound and/or kidney biopsy. Indications for renal biopsy in the setting of
AKI include:
1. Unexplained AKI
2. AKI in the presence of the nephritic syndrome
3. Systemic disease associated with AKI
Classification
Acute kidney injury is diagnosed on the basis of clinical history and laboratory data. A diagnosis is made when there
is rapid reduction in kidney function, as measured by serum creatinine, or based on a rapid reduction in urine output,
termed oliguria.
Definition
Introduced by the Acute Kidney Injury Network (AKIN), specific criteria exist for the diagnosis of AKI:
1. Rapid time course (less than 48 hours)
2. Reduction of kidney function
Rise in serum creatinine, defined by either:
Absolute increase in serum creatinine of 0.3mg/dl (26.4 mol/l)
Percentage increase in serum creatinine of 50%
Reduction in urine output, defined as <0.5ml/kg/h for more than 6 hours
Staging
The RIFLE criteria, proposed by the Acute Dialysis Quality Initiative (ADQI) group, aid in the staging of patients
with AKI:
Risk: GFR decrease >25%, serum creatinine increased 1.5 times or urine production of <0.5ml/kg/h for 6 hours
Injury: GFR decrease >50%, doubling of creatinine or urine production <0.5ml/kg/h for 12 hours
Failure: GFR decrease >75%, tripling of creatinine or creatinine >355mol/l (with a rise of >44) (>4mg/dl)
OR urine output below 0.3ml/kg/h for 24 hours
Loss: persistent AKI or complete loss of kidney function for more than 4 weeks
End-stage renal disease: need for renal replacement therapy (RRT) for more than 3 months
173
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Treatment
The management of AKI hinges on identification and treatment of the underlying cause. In addition to treatment of
the underlying disorder, management of AKI routinely includes the avoidance of substances that are toxic to the
kidneys, called nephrotoxins. These include NSAIDs such as ibuprofen, iodinated contrasts such as those used for
CT scans, many antibiotics such as gentamicin, and a range of other substances.
Monitoring of renal function, by serial serum creatinine measurements and monitoring of urine output, is routinely
performed. In the hospital, insertion of a urinary catheter helps monitor urine output and relieves possible bladder
outlet obstruction, such as with an enlarged prostate.
Specific therapies
In prerenal AKI without fluid overload, administration of intravenous fluids is typically the first step to improve
renal function. Volume status may be monitored with the use of a central venous catheter to avoid over- or
under-replacement of fluid.
Should low blood pressure prove a persistent problem in the fluid-replete patient, inotropes such as norepinephrine
and dobutamine may be given to improve cardiac output and hence renal perfusion. While a useful pressor, there is
no evidence to suggest that dopamine is of any specific benefit, and may be harmful.
The myriad causes of intrinsic AKI require specific therapies. For example, intrinsic AKI due to Wegener's
granulomatosis may respond to steroid medication. Toxin-induced prerenal AKI often responds to discontinuation of
the offending agent, such as aminoglycoside, penicillin, NSAIDs, or paracetamol.
If the cause is obstruction of the urinary tract, relief of the obstruction (with a nephrostomy or urinary catheter) may
be necessary.
Diuretic agents
The use of diuretics such as furosemide, is widespread and sometimes convenient in ameliorating fluid overload, and
is not associated with higher mortality (risk of death).
Complications
Metabolic acidosis, hyperkalemia, and pulmonary edema may require medical treatment with sodium bicarbonate,
antihyperkalemic measures, and diuretics.
Lack of improvement with fluid resuscitation, therapy-resistant hyperkalemia, metabolic acidosis, or fluid overload
may necessitate artificial support in the form of dialysis or hemofiltration.
Prognosis
Depending on the cause, a proportion of patients will never regain full renal function, thus entering end-stage renal
failure and requiring lifelong dialysis or a kidney transplant. Patients with AKI are more likely to die prematurely
after they were discharged from hospital even if their kidney function has recovered.
174
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Epidemiology
New cases of AKI are unusual but not rare, affecting approximately 0.1% of the UK population per year (2000
ppm/year), 20x incidence of new ESRD. AKI requiring dialysis (10% of these) is rare (200 ppm/year), 2x incidence
of new ESRD.
Acute kidney injury is common among hospitalized patients. It affects some 3-7% of patients admitted to the
hospital and approximately 25-30% of patients in the intensive care unit.
Acute renal failure was one of the most expensive conditions seen in U.S. hospitals in 2011, with an aggregated cost
of nearly $4.7 billion for approximately 498,000 hospital stays.[7] This was a 346% increase in hospitalizations from
1997, when there were 98,000 acute renal failure stays.[8]
History
Before the advancement of modern medicine, acute kidney injury was referred to as uremic poisoning while uremia
was contamination of the blood with urine. Starting around 1847, uremia came to be used for reduced urine output, a
condition now called oliguria, which was thought to be caused by the urine's mixing with the blood instead of being
voided through the urethra.[citation needed]
Acute kidney injury due to acute tubular necrosis (ATN) was recognised in the 1940s in the United Kingdom, where
crush injury victims during the London Blitz developed patchy necrosis of renal tubules, leading to a sudden
decrease in renal function. During the Korean and Vietnam wars, the incidence of AKI decreased due to better acute
management and administration of intravenous fluids.
References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ N17
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=584
http:/ / www. diseasesdatabase. com/ ddb11263. htm
http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000501. htm
http:/ / www. emedicine. com/ med/ topic1595. htm
http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D058186
Torio CM, Andrews RM. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011. HCUP Statistical Brief #160.
Agency for Healthcare Research and Quality, Rockville, MD. August 2013. (http:/ / hcup-us. ahrq. gov/ reports/ statbriefs/ sb160. jsp)
[8] Pfuntner A., Wier L.M., Stocks C. Most Frequent Conditions in U.S. Hospitals, 2011. HCUP Statistical Brief #162. September 2013. Agency
for Healthcare Research and Quality, Rockville, MD. (http:/ / www. hcup-us. ahrq. gov/ reports/ statbriefs/ sb162. jsp)
175
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
176
ICD-10
N17.0
ICD-9
584.5
DiseasesDB
11263
MedlinePlus
000512
eMedicine
med/39
MeSH
D007683
[2]
[3]
[3]
[4]
ped/28
[5]
[6]
Acute tubular necrosis (ATN) is a medical condition involving the death of tubular cells that form the tubule that
transports urine to the ureters while reabsorbing 99% of the water (and highly concentrating the salts and metabolic
byproducts). Tubular cells continually replace themselves and if the cause of ATN is removed then recovery is
likely. ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. The presence of
"muddy brown casts" of epithelial cells found in the urine during urinalysis is pathognomonic for ATN.
Classification
It may be classified as either toxic or ischemic. Toxic ATN occurs when the tubular cells are exposed to a toxic
substance (nephrotoxic ATN). Ischemic ATN occurs when the tubular cells do not get enough oxygen, a condition
that they are highly sensitive and susceptible to, due to their very high metabolism.
Diagnosis
Acute tubular necrosis is classified as a "renal" (i.e. not pre-renal or post-renal) cause of acute kidney injury.
Diagnosis is made by a FENa (fractional excretion of sodium) > 3% and presence of muddy casts (a type of granular
cast) in urinalysis. On histopathology, there is usually tubulorrhexis, that is, localized necrosis of the epithelial lining
in renal tubules, with focal rupture or loss of basement membrane.[7] Proximal tubule cells can shed with variable
viability and not be purely "necrotic". 40_75%
Toxic ATN
Toxic ATN can be caused by free hemoglobin or myoglobin, by medication such as antibiotics such as
aminoglycoside and cytoxic drugs such as cisplatin, or by intoxication (ethylene glycol, "anti-freeze").
Histopathology: Toxic ATN is characterized by proximal tubular epithelium necrosis (no nuclei, intense eosinophilic
homogeneous cytoplasm, but preserved shape) due to a toxic substance (poisons, organic solvents, drugs, heavy
metals). Necrotic cells fall into the tubule lumen, obturating it, and determining acute renal failure. Basement
membrane is intact[citation needed], so the tubular epithelium regeneration is possible. Glomeruli are not affected.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Ischemic ATN
Ischemic ATN can be caused when the kidneys are not sufficiently perfused for a long period of time (i.e. renal
artery stenosis) or during shock. Hypoperfusion can also be caused by embolism of the renal arteries. Ischemic ATN
specifically causes skip lesions through the tubules.
External links
Photo at: Atlas of Pathology [8]
References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ N17. 0
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=584. 5
http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000512. htm
http:/ / www. emedicine. com/ med/ topic39. htm
http:/ / www. emedicine. com/ ped/ topic28. htm#
http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D007683
TheFreeDictionary > tubulorrhexis (http:/ / medical-dictionary. thefreedictionary. com/ tubulorrhexis) Citing: The American Heritage
Medical Dictionary 2007
[8] http:/ / www. pathologyatlas. ro/ toxic-tubular-necrosis. php
177
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
178
Uremic frost on the forehead and scalp of a young man who presented with complaints of chronic anorexia and fatigue with blood urea nitrogen and
serum creatinine levels of approximately 100 and 50 mg/dL respectively.
[1]
ICD-10
N18
ICD-9
585.9
DiseasesDB
11288
MedlinePlus
000471
eMedicine
article/238798
MeSH
D007676
[2]
585.1-585.5
[3]
403
[4]
[5]
[6]
[7]
[8]
Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal function over a
period of months or years. The symptoms of worsening kidney function are non-specific, and might include feeling
generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of
screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and
those with a blood relative with chronic kidney disease. Chronic kidney disease may also be identified when it leads
to one of its recognized complications, such as cardiovascular disease, anemia or pericarditis. It is differentiated from
acute kidney disease in that the reduction in kidney function must be present for over 3 months.
Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine indicate a lower
glomerular filtration rate and as a result a decreased capability of the kidneys to excrete waste products. Creatinine
levels may be normal in the early stages of CKD, and the condition is discovered if urinalysis (testing of a urine
sample) shows that the kidney is allowing the loss of protein or red blood cells into the urine. To fully investigate the
underlying cause of kidney damage, various forms of medical imaging, blood tests and often renal biopsy (removing
a small sample of kidney tissue) are employed to find out if there is a reversible cause for the kidney malfunction.
Recent professional guidelines classify the severity of chronic kidney disease in five stages, with stage 1 being the
mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated.
Stage 5 CKD is often called end stage renal disease (ESRD), end stage renal failure (ESRF), or end-stage kidney
disease (ESKD) and is synonymous with the now outdated terms chronic kidney failure (CKF) or chronic renal
failure (CRF).
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
179
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Causes
The three most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis.[9] Together,
these cause approximately 75% of all adult cases.
Historically, kidney disease has been classified according to the part of the renal anatomy that is involved.[citation
needed]
Vascular, includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as
ischemic nephropathy, hemolytic-uremic syndrome and vasculitis
Glomerular, comprising a diverse group and subclassified into
Primary Glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy (or nephritis)
Secondary Glomerular disease such as diabetic nephropathy and lupus nephritis
Tubulointerstitial including polycystic kidney disease, drug and toxin-induced chronic tubulointerstitial nephritis
and reflux nephropathy
Obstructive such as with bilateral kidney stones and diseases of the prostate
On rare cases, pin worms infecting the kidney can also cause nephropathy.
non traditional causes of CKD are denoted if the common causes of CKD are not present, e.g. in El Salvador [10],
Nicaragua, ... in rural communities with agriculture.
Diagnosis
In many CKD patients, previous renal disease or other underlying
diseases are already known. A small number present with CKD of
unknown cause. In these patients, a cause is occasionally identified
retrospectively.[citation needed]
It is important to differentiate CKD from acute renal failure (ARF)
because ARF can be reversible. Abdominal ultrasound, in which the
size of the kidneys is measured, is commonly performed. Kidneys with
12-lead ECG of a person with chronic renal
CKD are usually smaller (< 9cm) than normal kidneys, with notable
disease and a severe electrolyte imbalance:
hyperkalemia
(7.4 mmol/l) with hypocalcemia
exceptions such as in diabetic nephropathy and polycystic kidney
(1.6 mmol/l). The T-waves are peaked and the
disease. Another diagnostic clue that helps differentiate CKD from
QT interval is prolonged.
ARF is a gradual rise in serum creatinine (over several months or
years) as opposed to a sudden increase in the serum creatinine (several
days to weeks). If these levels are unavailable (because the patient has been well and has had no blood tests), it is
occasionally necessary to treat a patient briefly as having ARF until it has been established that the renal impairment
is irreversible.[citation needed]
Additional tests may include nuclear medicine MAG3 scan to confirm blood flows and establish the differential
function between the two kidneys. DMSA scans are also used in renal imaging; with both MAG3 and DMSA being
used chelated with the radioactive element Technetium-99.[citation needed]
In chronic renal failure treated with standard dialysis, numerous uremic toxins accumulate. These toxins show
various cytotoxic activities in the serum, have different molecular weights and some of them are bound to other
proteins, primarily to albumin. Such toxic protein bound substances are receiving the attention of scientists who are
interested in improving the standard chronic dialysis procedures used today.[citation needed]
180
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
181
Stages
CKD Stage GFR level (mL/min/1.73 m2)
Stage 1
90
Stage 2
60 89
Stage 3
30 59
Stage 4
15 29
Stage 5
< 15
All individuals with a glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for 3 months are classified as having
chronic kidney disease, irrespective of the presence or absence of kidney damage. The rationale for including these
individuals is that reduction in kidney function to this level or lower represents loss of half or more of the adult level
of normal kidney function, which may be associated with a number of complications.
All individuals with kidney damage are classified as having chronic kidney disease, irrespective of the level of GFR.
The rationale for including individuals with GFR > 60 mL/min/1.73 m2 is that GFR may be sustained at normal or
increased levels despite substantial kidney damage and that patients with kidney damage are at increased risk of the
two major outcomes of chronic kidney disease: loss of kidney function and development of cardiovascular disease.
The loss of protein in the urine is regarded as an independent marker for worsening of renal function and
cardiovascular disease. Hence, British guidelines append the letter "P" to the stage of chronic kidney disease if there
is significant protein loss.
Stage 1
Slightly diminished function; kidney damage with normal or relatively high GFR (90 mL/min/1.73 m2). Kidney
damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine test
or imaging studies.
Stage 2
Mild reduction in GFR (6089 mL/min/1.73 m2) with kidney damage. Kidney damage is defined as pathological
abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.
Stage 3
Moderate reduction in GFR (3059 mL/min/1.73 m2). British guidelines distinguish between stage 3A (GFR 4559)
and stage 3B (GFR 3044) for purposes of screening and referral.
Stage 4
Severe reduction in GFR (1529 mL/min/1.73 m2) Preparation for renal replacement therapy
Stage 5
Established kidney failure (GFR <15 mL/min/1.73 m2, permanent renal replacement therapy (RRT), or end stage
renal disease (ESRD)
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Screening
Screening those who neither have symptoms or risk factors for chronic kidney disease is not recommended. Those
who should be screened include: those with hypertension or history of cardiovascular disease, those with diabetes or
marked obesity, those aged > 60 years, subjects with indigenous racial origin, those with a history of renal disease in
the past, as well as subjects who have relatives who had kidney disease requiring dialysis. Screening should include
calculation of estimated GFR/1.73 m2 from the serum creatinine level, and measurement of urine-to-albumin
creatinine ratio in a first-morning urine specimen as well as dipstick screen for hematuria. Guidelines for
nephrologist referral vary among different countries. Nephrology referral is useful when eGFR/1.73m2 is less than 30
or decreasing by more than 3 mL/min/year, when urine albumin-to-creatinine ratio is more than 30mg/g, when
blood pressure is difficult to control, or when hematuria or other findings suggest either a primarily glomerular
disorder or secondary disease amenable to specific treatment. Other benefits of early nephrology referral include
proper patient education regarding options for renal replacement therapy as well as pre-emptive transplantation, and
timely workup and placement of an arteriovenous fistula in those patients opting for future hemodialysis.
Treatment
The presence of chronic kidney disease confers a markedly increased risk of cardiovascular disease, and people with
CKD often have other risk factors for heart disease, such as hyperlipidemia. The most common cause of death in
people with CKD is therefore cardiovascular disease rather than renal failure. Aggressive treatment of
hyperlipidemia is warranted.
Apart from controlling other risk factors, the goal of therapy is to slow down or halt the progression of CKD to stage
5. Control of blood pressure and treatment of the original disease, whenever feasible, are the broad principles of
management. Generally, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists
(ARBs) are used, as they have been found to slow the progression of CKD to stage 5. Although the use of ACE
inhibitors and ARBs represents the current standard of care for patients with CKD, patients progressively lose kidney
function while on these medications, as seen in the IDNT and RENAAL studies, which reported a decrease over time
in estimated glomerular filtration rate (an accurate measure of CKD progression, as detailed in the K/DOQI
guidelines) in patients treated by these conventional methods.
Currently, several compounds are in development for CKD. These include, but are not limited to, bardoxolone
methyl, olmesartan medoxomil, sulodexide, and avosentan.
Replacement of erythropoietin and calcitriol, two hormones processed by the kidney, is often necessary in people
with advanced disease. Guidelines[11] recommend treatment with parenteral iron prior to treatment with
erythropoietin. A target hemoglobin level of 9-12 g/dL is recommended. Phosphate binders are also used to control
the serum phosphate levels, which are usually elevated in advanced chronic kidney disease. Zerenex(TM), a very
promising new drug developed by Keryx Biopharma will have the ability to treat both elevated serum phosphate
levels and anemia in CKD patients likely reducing or eliminating the need for other drugs i.e. IV iron and ESA's.
When one reaches stage 5 CKD, renal replacement therapy is usually required, in the form of either dialysis or a
transplant.
The normalization of hemoglobin has not been found to be of any benefit to the CKD but does significantly improve
the patient's quality of life in reducing symptoms such as fatigue and can improve other co-morbidities that might be
present, such as chronic heart failure (CHF).[citation needed] Although the evidence for them is limited,
phosphodiesterase-5 inhibitors and zinc show potential for helping men with sexual dysfunction.
182
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Prognosis
The prognosis of patients with chronic kidney disease is guarded as epidemiological data has shown that all cause
mortality (the overall death rate) increases as kidney function decreases. The leading cause of death in patients with
chronic kidney disease is cardiovascular disease, regardless of whether there is progression to stage 5.
While renal replacement therapies can maintain patients indefinitely and prolong life, the quality of life is severely
affected. Renal transplantation increases the survival of patients with stage 5 CKD significantly when compared to
other therapeutic options; however, it is associated with an increased short-term mortality due to complications of the
surgery. Transplantation aside, high intensity home hemodialysis appears to be associated with improved survival
and a greater quality of life, when compared to the conventional three times a week hemodialysis and peritoneal
dialysis.
Cancer risk
Patients with end-stage renal disease are at increased overall risk for cancer. This risk is particularly high in younger
patients and gradually diminishes with age. Medical specialty professional organizations recommend that physicians
not perform routine cancer screening in patients with limited life expectancies due to ESRD because evidence does
not show that such tests lead to improved patient outcomes.
Epidemiology
Chronic kidney disease globally resulted in 735,000 deaths in 2010 up from 400,000 deaths in 1990.
In Canada 1.9 to 2.3 million people have chronic kidney disease. In the US, the Centers for Disease Control and
Prevention found that CKD affected an estimated 16.8% of adults aged 20 years and older, during 1999 to 2004. UK
estimates suggest that 8.8% of the population of Great Britain and Northern Ireland have symptomatic CKD.[12]
Chronic kidney disease (CKD) is a major concern in African Americans, mostly due to increased prevalence of
hypertension. As an example, 37% of end-stage renal disease cases in African Americans can be attributed to high
blood pressure, compared with 19% among caucasians. Treatment efficacy also differs between racial groups.
Administration of anti-hypertensive drugs generally halts disease progression in white populations, but has little
effect in slowing renal disease among blacks, and additional treatment such as bicarbonate therapy is often required.
While lower socioeconomic status contributes to prevalence of CKD, there are still significant differences in CKD
prevalence between African Americans and whites when controlling for environmental factors. Studies have shown
that there is a true association between history of chronic renal failure in first or second-degree relatives, and risk of
disease. In addition, African Americans may have higher serum levels of human leukocyte antigens (HLA). High
HLA concentrations can contribute to increased systemic inflammation, which indirectly may lead to heightened
susceptibility for developing kidney disease. Lack of nocturnal reduction in blood pressure among groups of African
Americans is also offered as an explanation, which lends further credence to a genetic etiology of CKD racial
disparities.
A high and so-far unexplained incidence of chronic kidney disease, referred to as the Mesoamerican nephropathy,
has been noted among male workers in Central America, mainly in sugar cane fields in the low-lands of El Salvador
and Nicaragua. Heat stress from long hours of piece-rate work at high average temperatures[13][14][15] (in the range
of 96F) is suspected as are agricultural chemicals and other factors.
183
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Organizations
In the USA, the National Kidney Foundation is a national organization representing patients and professionals who
treat kidney diseases. The American Kidney Fund (AKF) is a national non-profit organization providing
treatment-related financial assistance to 1 out of every 5 dialysis patients each year. The Renal Support Network
(RSN) is a nonprofit, patient-focused, patient-run organization that provides non-medical services to those affected
by CKD. The American Association of Kidney Patients (AAKP) is a non-profit, patient-centric group focused on
improving the health and well-being of CKD and dialysis patients. The Renal Physicians Association (RPA) is an
association representing nephrology professionals.
In the United Kingdom, the UK National Kidney Federation represents patients, and the Renal Association
represents renal physicians and works closely with the National Service Framework for kidney disease.
Kidney Health Australia serves that country.
The International Society of Nephrology is an international body representing specialists in kidney diseases.
References
[1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ N18
[2] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=585. 9
[3] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=585. 1-585. 5
[4] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=403
[5] http:/ / www. diseasesdatabase. com/ ddb11288. htm
[6] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000471. htm
[7] http:/ / emedicine. medscape. com/ article/ 238798-overview
[8] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D007676
[9] http:/ / www. usrds. org/
[10] http:/ / www. youtube. com/ watch?v=wO2crSCFE08
[11] NICE: Anaemia management in people with chronic kidney disease (CG114)
[12] The Association of Public Health Observatories Chronic Kidney Disease Prevalence Estimates. 2007 [cited 1/3/2010]; Available from:
http:/ / www. apho. org. uk/ resource/ item. aspx?RID=63798.
[13] http:/ / ajkdblog. org/ 2013/ 07/ 29/ mesoamerican-nephropathy-a-new-entity/
[14] Wesseling C, Crowe J, Hogstedt C, Jakobsson K, Lucas R, Wegman DH. The Epidemic of Chronic Kidney Disease of Unknown Etiology in
Mesoamerica: A Call for Interdisciplinary Research and Action. Am J Public Health. 2013 Sep 12. [Epub ahead of print]
[15] Johnson RJ, Snchez-Lozada LG. Chronic kidney disease: Mesoamerican nephropathy-new clues to the cause. Nat Rev Nephrol. 2013
Oct;9(10):560-1. doi: 10.1038/nrneph.2013.174. [Epub ahead of print]
External links
National Kidney Foundation (http://www.kidney.org/)
Dialysis Complications of Chronic Renal Failure (http://emedicine.medscape.com/article/1918879-overview)
at eMedicine
The Kidney Foundation of Canada (http://www.kidney.ca)
184
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Dialysis
185
Dialysis
Dialysis
Intervention
ICD-9-CM
39.95
MeSH
D006435
MedlinePlus
007434
[2]
[3]
In medicine dialysis (from Greek dialusis,"", meaning dissolution, dia, meaning through, and lysis,
meaning loosening or splitting) is a process for removing waste and excess water from the blood, and is used
primarily as an artificial replacement for lost kidney function in people with renal failure. Dialysis may be used for
those with an acute disturbance in kidney function (acute kidney injury, previously acute renal failure), or
progressive but chronically worsening kidney functiona state known as chronic kidney disease stage 5 (previously
chronic renal failure or end-stage renal disease). The latter form may develop over months or years, but in contrast to
acute kidney injury is not usually reversible, and dialysis is regarded as a "holding measure" until a renal transplant
can be performed, or sometimes as the only supportive measure in those for whom a transplant would be
inappropriate.[4]
The kidneys have important roles in maintaining health. When healthy, the kidneys maintain the body's internal
equilibrium of water and minerals (sodium, potassium, chloride, calcium, phosphorus, magnesium, sulfate). The
acidic metabolism end-products that the body cannot get rid of via respiration are also excreted through the kidneys.
The kidneys also function as a part of the endocrine system, producing erythropoietin and calcitriol. Erythropoietin is
involved in the production of red blood cells and calcitriol plays a role in bone formation.[5] Dialysis is an imperfect
treatment to replace kidney function because it does not correct the compromised endocrine functions of the kidney.
Dialysis treatments replace some of these functions through diffusion (waste removal) and ultrafiltration (fluid
removal).
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Dialysis
186
History
Dr. Willem Kolff, a Dutch physician, constructed the first working dialyzer in
1943 during the Nazi occupation of the Netherlands.[6] Due to the scarcity of
available resources, Kolff had to improvise and build the initial machine
using sausage casings, beverage cans, a washing machine, and various other
items that were available at the time. Over the following two
years,[1943-1945] Kolff used his machine to treat 16 patients suffering from
acute kidney failure, but the results were unsuccessful. Then, in 1945, a
67-year-old comatose woman regained consciousness following 11 hours of
hemodialysis with the dialyzer, and lived for another seven years before dying
of an unrelated condition. She was the first-ever patient successfully treated with dialysis.
Principle
Dialysis works on the principles of the diffusion of solutes and
ultrafiltration of fluid across a semi-permeable membrane. Diffusion is
a property of substances in water; substances in water tend to move
from an area of high concentration to an area of low concentration.[7]
Blood flows by one side of a semi-permeable membrane, and a
dialysate, or special dialysis fluid, flows by the opposite side. A
semipermeable membrane is a thin layer of material that contains holes
of various sizes, or pores. Smaller solutes and fluid pass through the
membrane, but the membrane blocks the passage of larger substances
(for example, red blood cells, large proteins). This replicates the
filtering process that takes place in the kidneys, when the blood enters
the kidneys and the larger substances are separated from the smaller
ones in the glomerulus.
The two main types of dialysis, hemodialysis and peritoneal dialysis,
remove wastes and excess water from the blood in different ways.
Hemodialysis removes wastes and water by circulating blood outside
A hemodialysis machine
the body through an external filter, called a dialyzer, that contains a
semipermeable membrane. The blood flows in one direction and the
dialysate flows in the opposite. The counter-current flow of the blood and dialysate maximizes the concentration
gradient of solutes between the blood and dialysate, which helps to remove more urea and creatinine from the blood.
The concentrations of solutes (for example potassium, phosphorus, and urea) are undesirably high in the blood, but
low or absent in the dialysis solution, and constant replacement of the dialysate ensures that the concentration of
undesired solutes is kept low on this side of the membrane. The dialysis solution has levels of minerals like
potassium and calcium that are similar to their natural concentration in healthy blood. For another solute,
bicarbonate, dialysis solution level is set at a slightly higher level than in normal blood, to encourage diffusion of
bicarbonate into the blood, to act as a pH buffer to neutralize the metabolic acidosis that is often present in these
patients. The levels of the components of dialysate are typically prescribed by a nephrologist according to the needs
of the individual patient.
In peritoneal dialysis, wastes and water are removed from the blood inside the body using the peritoneal membrane
of the peritoneum as a natural semipermeable membrane. Wastes and excess water move from the blood, across the
peritoneal membrane, and into a special dialysis solution, called dialysate, in the abdominal cavity which has a
composition similar to the fluid portion of blood.
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Dialysis
Types
There are three primary and two secondary types of dialysis: hemodialysis (primary), peritoneal dialysis (primary),
hemofiltration (primary), hemodiafiltration (secondary), and intestinal dialysis (secondary).
Hemodialysis
In hemodialysis, the patient's blood is
pumped
through
the
blood
compartment of a dialyzer, exposing it
to a partially permeable membrane.
The dialyzer is composed of thousands
of tiny synthetic hollow fibers. The
fiber wall acts as the semipermeable
membrane. Blood flows through the
fibers, dialysis solution flows around
the outside of the fibers, and water and
wastes move between these two
solutions.[8] The cleansed blood is then
returned via the circuit back to the
body. Ultrafiltration occurs by
increasing the hydrostatic pressure
across the dialyzer membrane. This
usually is done by applying a negative
pressure to the dialysate compartment
Hemodialysis schematic
of the dialyzer. This pressure gradient
causes water and dissolved solutes to move from blood to dialysate, and allows the removal of several litres of
excess fluid during a typical 4-hour treatment. In the US, hemodialysis treatments are typically given in a dialysis
center three times per week (due in the US to Medicare reimbursement rules); however, as of 2007 over 2,500 people
in the US are dialyzing at home more frequently for various treatment lengths. Studies have demonstrated the
clinical benefits of dialyzing 5 to 7 times a week, for 6 to 8 hours. This type of hemodialysis is usually called
"nocturnal daily hemodialysis", which a study has shown a significant improvement in both small and large
molecular weight clearance and decrease the requirement of taking phosphate binders.[9] These frequent long
treatments are often done at home while sleeping, but home dialysis is a flexible modality and schedules can be
changed day to day, week to week. In general, studies have shown that both increased treatment length and
frequency are clinically beneficial.[10]
Hemodialysis was one of the most common procedures performed in U.S. hospitals in 2011, occurring in 909,000
stays (a rate of 29 stays per 10,000 population).[11]
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Dialysis
Peritoneal dialysis
In peritoneal dialysis, a sterile solution containing glucose
(called dialysate) is run through a tube into the peritoneal
cavity, the abdominal body cavity around the intestine, where
the peritoneal membrane acts as a partially permeable
membrane. The peritoneal membrane or peritoneum is a layer
of tissue containing blood vessels that lines and surrounds the
peritoneal, or abdominal, cavity and the internal abdominal
organs (stomach, spleen, liver, and intestines).[12] Diffusion
and osmosis drive waste products and excess fluid through the
peritoneum into the dialysate until the dialysate approaches
equilibrium with the body's fluids. Then the dialysate is
drained, discarded, and replaced with fresh dialysate.[13]
This exchange is repeated 4-5 times per day; automatic
systems can run more frequent exchange cycles overnight.
Peritoneal dialysis is less efficient than hemodialysis, but
Schematic diagram of peritoneal dialysis
because it is carried out for a longer period of time the net
effect in terms of removal of waste products and of salt and
water are similar to hemodialysis. Peritoneal dialysis is carried out at home by the patient, often without help. This
frees patients from the routine of having to go to a dialysis clinic on a fixed schedule multiple times per week.
Peritoneal dialysis can be performed with little to no specialized equipment (other than bags of fresh dialysate).
Hemofiltration
Hemofiltration is a similar treatment to hemodialysis, but it makes use of a different principle. The blood is pumped
through a dialyzer or "hemofilter" as in dialysis, but no dialysate is used. A pressure gradient is applied; as a result,
water moves across the very permeable membrane rapidly, "dragging" along with it many dissolved substances,
including ones with large molecular weights, which are not cleared as well by hemodialysis. Salts and water lost
from the blood during this process are replaced with a "substitution fluid" that is infused into the extracorporeal
circuit during the treatment. Hemodiafiltration is the combining of hemodialysis and hemofiltration in one process.
Hemodiafiltration
Hemodiafiltration is a combination of hemodialysis and hemofiltration.
Intestinal dialysis
In intestinal dialysis, the diet is supplemented with soluble fibres such as acacia fibre, which is digested by bacteria
in the colon. This bacterial growth increases the amount of nitrogen that is eliminated in fecal waste. An alternative
approach utilizes the ingestion of 1 to 1.5 liters of non-absorbable solutions of polyethylene glycol or mannitol every
fourth hour.
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Dialysis
Starting indications
The decision to initiate dialysis or hemofiltration in patients with renal failure depends on several factors. These can
be divided into acute or chronic indications.
Indications for dialysis in the patient with acute kidney injury are summarized with the vowel acronym of
"AEIOU":
1. Acidemia from metabolic acidosis in situations in which correction with sodium bicarbonate is impractical or
may result in fluid overload
2. Electrolyte abnormality, such as severe hyperkalemia, especially when combined with AKI
3. Intoxication, that is, acute poisoning with a dialyzable substance. These substances can be represented by the
mnemonic SLIME: salicylic acid, lithium, isopropanol, Magnesium-containing laxatives, and ethylene glycol
4. Overload of fluid not expected to respond to treatment with diuretics
5. Uremia complications, such as pericarditis, encephalopathy, or gastrointestinal bleeding.
Chronic indications for dialysis:
1. Symptomatic renal failure
2. Low glomerular filtration rate (GFR) (RRT often recommended to commence at a GFR of less than 10-15
mls/min/1.73m2). In diabetics, dialysis is started earlier.
3. Difficulty in medically controlling fluid overload, serum potassium, and/or serum phosphorus when the GFR
is very low
References
[1]
[2]
[3]
[4]
[5]
[6]
http:/ / icd9cm. chrisendres. com/ index. php?srchtype=procs& srchtext=39. 95& Submit=Search& action=search
http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D006435
http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 007434. htm
Pendse S, Singh A, Zawada E. Initiation of Dialysis. In: Handbook of Dialysis. 4th ed. New York, NY; 2008:1421
Brundage D. Renal Disorders. St. Louis, MO: Mosby; 1992
Willem Kolff, Doctor Who Invented Kidney and Heart Machines, Dies at 97. http:/ / www. nytimes. com/ 2009/ 02/ 13/ health/ 13kolff.
html?pagewanted=all; New York Times, 2009
[7] Mosbys Dictionary of Medicine, Nursing, & Health Professions. 7th ed. St. Louis, MO; Mosby: 2006
[8] Ahmad S, Misra M, Hoenich N, Daugirdas J. Hemodialysis Apparatus. In: Handbook of Dialysis. 4th ed. New York, NY; 2008:59-78.
[9] Rocco MV.More frequent hemodialysis: back to the future? In: Advances in Chronic Kidney Disease. Volume 14, issue 3; 2007:e1-9.
[10] Daily therapy study results compared (http:/ / www. homedialysis. org/ learn/ types/ )
[11] Pfuntner A., Wier L.M., Stocks C. Most Frequent Procedures Performed in U.S. Hospitals, 2011. HCUP Statistical Brief #165. October
2013. Agency for Healthcare Research and Quality, Rockville, MD. (http:/ / www. hcup-us. ahrq. gov/ reports/ statbriefs/ sb165. jsp).
[12] Blake P, Daugirdas J. Physiology of Peritoneal Dialysis. In: Handbook of Dialysis. 4th ed. New York, NY; 2008:323-338
[13] Kallenbach J.Z. In: Review of hemodialysis for nurses and dialysis personnel. 7th ed. St. Louis, Missouri:Elsevier Mosby; 2005.
External links
Machine Cleans Blood While You Wait (http://books.google.com/books?id=ZyEDAAAAMBAJ&
pg=PA103#v=onepage&f=true)1950 article on early use of Dialysis machine at Bellevue Hospital New York
Cityi.e. example of how complex and large early dialysis machines were
Home Dialysis Museum (http://www.homedialysis.org/home-dialysis-basics/machines-and-supplies/
dialysis-museum)History and pictures of dialysis machines through time
Introduction to Dialysis Machines (http://www.maximintegrated.com/app-notes/index.mvp/id/
4698)Tutorial describing the main subfunctions of dialysis systems.
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Kidney transplantation
190
Kidney transplantation
Kidney transplantation
Intervention
[1]
ICD-10-PCS
OTY
ICD-9-CM
55.6
MeSH
D016030
OPS-301code:
5-555
MedlinePlus
003005
[2]
[3]
[4]
[5]
Kidney transplantation or renal transplantation is the organ transplant of a kidney into a patient with end-stage
renal disease. Kidney transplantation is typically classified as deceased-donor (formerly known as cadaveric) or
living-donor transplantation depending on the source of the donor organ. Living-donor renal transplants are further
characterized as genetically related (living-related) or non-related (living-unrelated) transplants, depending on
whether a biological relationship exists between the donor and recipient. Exchanges and chains are a novel approach
to expand the living donor pool.
History
The first kidney transplantation in the United States was performed on June 17, 1950, on Ruth Tucker, a 44-year-old
woman with polycystic kidney disease, at Little Company of Mary Hospital in Evergreen Park, Illinois. Although the
donated kidney was rejected ten months later because no immunosuppressive therapy was available at the timethe
development of effective antirejection drugs was years awaythe intervening time gave Tucker's remaining kidney
time to recover and she lived another five years.
The first kidney transplants between living patients were undertaken in 1954 in Boston and Paris. The Boston
transplantation, performed on December 23, 1954, at Brigham Hospital was performed by Joseph Murray, J.
Hartwell Harrison, John P. Merrill and others. The procedure was done between identical twins Ronald and Richard
Herrick to eliminate any problems of an immune reaction. For this and later work, Dr. Murray received the Nobel
Prize for Medicine in 1990. The recipient, Richard Herrick, died eight years after the transplantation.
The first kidney transplantation in the United Kingdom did not occur until 1960, when Michael Woodruff performed
one between identical twins in Edinburgh. Until the routine use of medications to prevent and treat acute rejection,
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney transplantation
introduced in 1964, deceased donor transplantation was not performed. The kidney was the easiest organ to
transplant: tissue typing was simple, the organ was relatively easy to remove and implant, live donors could be used
without difficulty, and in the event of failure, kidney dialysis was available from the 1940s. Tissue typing was
essential to the success: early attempts in the 1950s on sufferers from Bright's disease had been very unsuccessful.
The major barrier to organ transplantation between genetically non-identical patients lay in the recipient's immune
system, which would treat a transplanted kidney as a "non-self" and immediately or chronically, reject it. Thus,
having medications to suppress the immune system was essential. However, suppressing an individual's immune
system places that individual at greater risk of infection and cancer (particularly skin cancer and lymphoma), in
addition to the side effects of the medications.
The basis for most immunosuppressive regimens is prednisolone, a corticosteroid. Prednisolone suppresses the
immune system, but its long-term use at high doses causes a multitude of side effects, including glucose intolerance
and diabetes, weight gain, osteoporosis, muscle weakness, hypercholesterolemia, and cataract formation.
Prednisolone alone is usually inadequate to prevent rejection of a transplanted kidney. Thus other, non-steroid
immunosuppressive agents are needed, which also allow lower doses of prednisolone.
Indications
The indication for kidney transplantation is end-stage renal disease (ESRD), regardless of the primary cause. This is
defined as a glomerular filtration rate <15ml/min/1.73 sq.m. Common diseases leading to ESRD include malignant
hypertension, infections, diabetes mellitus, and focal segmental glomerulosclerosis; genetic causes include
polycystic kidney disease, a number of inborn errors of metabolism, and autoimmune conditions such as lupus.
Diabetes is the most common cause of kidney transplantation, accounting for approximately 25% of those in the US.
The majority of renal transplant recipients are on dialysis (peritoneal dialysis or hemofiltration) at the time of
transplantation. However, individuals with chronic renal failure who have a living donor available may undergo
pre-emptive transplantation before dialysis is needed.
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Kidney transplantation
Sources of kidneys
Since medication to prevent rejection is so effective, donors do not need to be similar to their recipient. Most donated
kidneys come from deceased donors; however, the utilization of living donors in the United States is on the rise. In
2006, 47% of donated kidneys were from living donors.[6] This varies by country: for example, only 3% of kidneys
transplanted during 2006 in Spain came from living donors.[7]
Living donors
Approximately one in three donations in the US, UK, and Israel is now from a live donor.[8][9] Potential donors are
carefully evaluated on medical and psychological grounds. This ensures that the donor is fit for surgery and has no
disease which brings undue risk or likelihood of a poor outcome for either the donor or recipient. The psychological
assessment is to ensure the donor gives informed consent and is not coerced. In countries where paying for organs is
illegal, the authorities may also seek to ensure that a donation has not resulted from a financial transaction.
The relationship the donor has to the recipient has evolved over the years. In the 1950s, the first successful living
donor transplants were between identical twins. In the 1960s-1970s, live donors were genetically related to the
recipient. However, during the 1980s-1990s, the donor pool was expanded further to emotionally related individuals
(spouses, friends). Now the elasticity of the donor relationship has been stretched to include acquaintances and even
strangers ("altruistic donors").
The acceptance of altruistic donors has enabled chains of transplants to form. Kidney chains [10] are initiated when
an altruistic donor donates a kidney to a patient who has a willing but incompatible donor. This incompatible donor
then "pays it forward" and passes on the generosity to another recipient who also had a willing but incompatible
donor. Michael Rees from the University of Toledo developed the concept of open-ended chains.[11] This was a
variation of a concept developed at Johns Hopkins University.[12] On July 30, 2008, an altruistic donor kidney was
shipped via commercial airline from Cornell to the University of California, Los Angeles, thus triggering a chain of
transplants.[13] The shipment of living donor kidneys, computer-matching software algorithms, and cooperation
between transplant centers has enabled long-elaborate chains to be formed.[14]
There is good evidence that kidney donation is not associated with long-term harm to the donor. Traditionally, the
donor procedure has been through a single incision of 47 inches (1018cm), but live donation is being increasingly
performed by laparoscopic surgery. This reduces pain and accelerates recovery for the donor. Operative time and
complications decreased significantly after a surgeon performed 150 cases. Live donor kidney grafts have higher
long-term success rates than those from deceased donors. Since the increase in the use of laparoscopic surgery, the
number of live donors has increased. Any advance which leads to a decrease in pain and scarring and swifter
recovery has the potential to boost donor numbers. In January 2009, the first all-robotic kidney transplant was
performed at Saint Barnabas Medical Center through a two-inch incision. In the following six months, the same team
performed eight more robotic-assisted transplants.[15]
In 2004 the FDA approved the Cedars-Sinai High Dose IVIG therapy which reduces the need for the living donor to
be the same blood type (ABO compatible) or even a tissue match. The therapy reduced the incidence of the
recipient's immune system rejecting the donated kidney in highly sensitized patients.
In 2009 at the Johns Hopkins Medical Center, a healthy kidney was removed through the donor's vagina. Vaginal
donations promise to speed recovery and reduce scarring. The first donor was chosen as she had previously had a
hysterectomy. The extraction was performed using natural orifice transluminal endoscopic surgery, where an
endoscope is inserted through an orifice, then through an internal incision, so that there is no external scar. The
recent advance of single port laparoscopy requiring only one entry point at the navel is another advance with
potential for more frequent use.
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Kidney transplantation
Organ trade
In the developing world some people sell their organs. Such people are often in grave poverty or are exploited by
salespersons. The people who travel to make use of these kidneys are often known as "transplant tourists." This
practice is opposed by a variety of human rights groups, including Organs Watch, a group established by medical
anthropologists, which was instrumental in exposing illegal international organ selling rings. These patients may
have increased complications owing to poor infection control and lower medical and surgical standards. One surgeon
has said that organ trade could be legalized in the UK to prevent such tourism, but this is not seen by the National
Kidney Research Fund as the answer to a deficit in donors.[16]
Deceased donors
Deceased donors can be divided in two groups:
Brain-dead (BD) donors
Donation after Cardiac Death (DCD) donors
Although brain-dead (or "beating heart") donors are considered dead, the donor's heart continues to pump and
maintain the circulation. This makes it possible for surgeons to start operating while the organs are still being
perfused. During the operation, the aorta will be cannulated, after which the donor's blood will be replaced by an
ice-cold storage solution, such as UW (Viaspan), HTK, or Perfadex. Depending on which organs are transplanted,
more than one solution may be used simultaneously. Due to the temperature of the solution, and since large amounts
of cold NaCl-solution are poured over the organs for a rapid cooling, the heart will stop pumping.
"Donation after Cardiac Death" donors are patients who do not meet the brain-dead criteria but, due to the unlikely
chance of recovery, have elected via a living will or through family to have support withdrawn. In this procedure,
treatment is discontinued (mechanical ventilation is shut off). After a time of death has been pronounced, the patient
is rushed to the operating room where the organs are recovered. Storage solution is flushed through the organs. Since
the blood is no longer being circulated, coagulation must be prevented with large amounts of anti-coagulation agents
such as heparin. Several ethical and procedural guidelines must be followed; most importantly, the organ recovery
team should not participate in the patient's care in any manner until after death has been declared.
Compatibility
In general, the donor and recipient should be ABO blood group and crossmatch (HLA antigen) compatible. If a
potential living donor is incompatible with their recipient, the donor could be exchange for a compatible kidney.
Kidney exchange, also known as "kidney paired donation" or "chains" had recently gained popularity over the past
few years.
In an effort to reduce the risk of rejection during incompatible transplantation, ABO-incompatible and
densensitization protocols utilizing intravenous immunoglobulin (IVIG) have been developed, with the aim to reduce
ABO and HLA antibodies that the recipient may have to the donor.
In the 1980s, experimental protocols were developed for ABO-incompatible transplants using increased
immunosuppression and plasmapheresis. Through the 1990s these techniques were improved and an important study
of long-term outcomes in Japan was published ([17]). Now, a number of programs around the world are routinely
performing ABO-incompatible transplants.
The level of sensitization to donor HLA antigens is determined by performing a panel reactive antibody test on the
potential recipient. In the United States, up to 17% of all deceased donor kidney transplants have no HLA mismatch.
However, HLA matching is a relatively minor predictor of transplant outcomes. In fact, living non-related donors are
now almost as common as living (genetically)-related donors.
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Kidney transplantation
Procedure
In most cases the barely functioning existing kidneys are not removed, as this has been shown to increase the rates of
surgical morbidities. Therefore, the kidney is usually placed in a location different from the original kidney, often in
the iliac fossa, so it is often necessary to use a different blood supply:
The renal artery of the kidney, previously branching from the abdominal aorta in the donor, is often connected to
the external iliac artery in the recipient.
The renal vein of the new kidney, previously draining to the inferior vena cava in the donor, is often connected to
the external iliac vein in the recipient.
There is disagreement in surgical textbooks regarding which side of the recipients pelvis to use in receiving the
transplant. Campbell's Urology (2002) recommends placing the donor kidney in the recipients contralateral side (i.e.
a left sided kidney would be transplanted in the recipient's right side) to ensure the renal pelvis and ureter are anterior
in the event that future surgeries are required. In an instance where there is doubt over whether there is enough space
in the recipients pelvis for the donor's kidney the textbook recommends using the right side because the right side
has a wider choice of arteries and veins for reconstruction. Smith's Urology (2004) states that either side of the
recipient's pelvis is acceptable, however the right vessels are more horizontal with respect to each other and
therefore easier to use in the anastomoses. It is unclear what is meant by the words more horizontal. Glen's
Urological Surgery (2004) recommends putting the kidney in the contralateral side in all circumstances. No reason is
explicitly put forth; however, one can assume the rationale is similar to that of Campbell'sto ensure that the renal
pelvis and ureter are most anterior in the event that future surgical correction becomes necessary.
Kidney-pancreas transplant
Occasionally, the kidney is transplanted together with the pancreas.
University of Minnesota surgeons Richard Lillehei and William Kelly
perform the first successful simultaneous pancreas-kidney transplant in
the world in 1966. This is done in patients with diabetes mellitus type
1, in whom the diabetes is due to destruction of the beta cells of the
pancreas and in whom the diabetes has caused renal failure (diabetic
nephropathy). This is almost always a deceased donor transplant. Only
a few living donor (partial) pancreas transplants have been done. For
individuals with diabetes and renal failure, the advantages of earlier
transplant from a living donor (if available) are far superior to the risks
of continued dialysis until a combined kidney and pancreas are
available from a deceased donor.[citation needed] A patient can either
receive a living kidney followed by a donor pancreas at a later date
(PAK, or pancreas-after-kidney) or a combined kidney-pancreas from a
donor (SKP, simultaneous kidney-pancreas).
Transplanting just the islet cells from the pancreas is still in the
Kidney-pancreas transplant
experimental stage, but shows promise. This involves taking a
deceased donor pancreas, breaking it down, and extracting the islet
cells that make insulin. The cells are then injected through a catheter into the recipient and they generally lodge in
the liver. The recipient still needs to take immunosuppressants to avoid rejection, but no surgery is required. Most
people need two or three such injections, and many are not completely insulin-free.
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Kidney transplantation
Post operation
The transplant surgery takes about three hours. The donor kidney will be placed in the lower abdomen and its blood
vessels connected to arteries and veins in the recipient's body. When this is complete, blood will be allowed to flow
through the kidney again. The final step is connecting the ureter from the donor kidney to the bladder. In most cases,
the kidney will soon start producing urine.
Depending on its quality, the new kidney usually begins functioning immediately. Living donor kidneys normally
require 35 days to reach normal functioning levels, while cadaveric donations stretch that interval to 715 days.
Hospital stay is typically for 47 days. If complications arise, additional medications (diuretics) may be administered
to help the kidney produce urine.
Immunosuppressant drugs are used to suppress the immune system from rejecting the donor kidney. These
medicines must be taken for the rest of the patient's life. The most common medication regimen today is a cocktail of
tacrolimus, mycophenolate, and prednisone. Some patients may instead take cyclosporine, sirolimus, or azathioprine.
Cyclosporine, considered a breakthrough immunosuppressive when first discovered in the 1980s, ironically causes
nephrotoxicity and can result in iatrogenic damage to the newly transplanted kidney. Blood levels must be monitored
closely and if the patient seems to have declining renal function, a biopsy may be necessary to determine whether
this is due to rejection or cyclosporine intoxication.
Postoperative diet
Kidney transplant recipients are discouraged from consuming grapefruit, pomegranate and green tea products. These
food products are known to interact with the transplant medications, specifically tacrolimus, cyclosporin and
sirolimus; the blood levels of these drugs may be increased, potentially leading to an overdose.
Acute rejection occurs in 1025% of people after transplant during the first 60 days.[citation needed] Rejection does not
necessarily mean loss of the organ, but it may necessitate additional treatment and medication adjustments.
Complications
Problems after a transplant may include:
A patient's age and health condition before transplantation affect the risk of complications. Different transplant
centers have different success at managing complications and therefore, complication rates are different from center
to center.
The average lifetime for a donated kidney is ten to fifteen years. When a transplant fails, a patient may opt for a
second transplant, and may have to return to dialysis for some intermediary time.
Infections due to the immunosuppressant drugs used in people with kidney transplants most commonly occurs in
mucocutaneous areas (41%), the urinary tract (17%) and the respiratory tract (14%).[18] The most common infective
agents are bacterial (46%), viral (41%), fungal (13%), and protozoan (1%). Of the viral illnesses, the most common
agents are human cytomegalovirus (31.5%), herpes simplex (23.4%), and herpes zoster (23.4%). Infection is the
cause of death in about one third of people with renal transplants, and pneumonias account for 50% of the patient
deaths from infection.
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Prognosis
Kidney transplantation is a life-extending procedure. The typical patient will live 10 to 15 years longer with a kidney
transplant than if kept on dialysis.[19] The increase in longevity is greater for younger patients, but even 75-year-old
recipients (the oldest group for which there is data) gain an average four more years of life. People generally have
more energy, a less restricted diet, and fewer complications with a kidney transplant than if they stay on
conventional dialysis.
Some studies seem to suggest that the longer a patient is on dialysis before the transplant, the less time the kidney
will last. It is not clear why this occurs, but it underscores the need for rapid referral to a transplant program. Ideally,
a kidney transplant should be preemptive, i.e., take place before the patient begins dialysis.
At least four professional athletes have made a comeback to their sport after receiving a transplant: New Zealand
rugby union player Jonah Lomu, German-Croatian Soccer Player Ivan Klasni, and NBA basketballers Sean Elliott
and Alonzo Mourning.[citation needed]
Statistics
Statistics by country, year and donor type
Country Year Cadaveric donor Living donor Total transplants
Canada 2000
724
388
1,112
France 2003
1,991
136
2,127
Italy 2003
1,489
135
1,624
[20] 2010
208
1276
2,484
Spain 2003
1,991
60
2,051
1,297
439
1,736
[21] 2008
10,551
5,966
16,517
1,854
1,932
Japan
United States
Bill Thompson is the longest-surviving American kidney recipient from an unrelated donor, having received his
kidney in 1966 at age 15; it has survived over 40 years.
Denice Lombard of Washington, D.C., received her father's kidney on August 30, 1967, at age 13 and is still alive
and healthy 45 years, 9 months later as of 5-5-13. Her father will turn 85 in October and is still healthy and active.
Robert Brice of Adelaide, South Australia received a cadaver kidney in September 1981 at the age of 42 and is
alive and healthy in 2013.
John Dan of Nairobi, Kenya, was the known longest-surviving kidney recipient in East Africa. He received a
kidney from his brother in 1984 and lived for 27 years.
Chakravarthy from Chennai, India, received kidney from his brother on 2 May 1983 at the age of 29, is still alive
and healthy 27 years later.
Annemarie Grosskopf of Johannesburg, South Africa, received a kidney from a deceased donor in 1981 at the age
of 21, and is alive and healthy 32 years later.
In addition to nationality, transplantation rates differ based on race, sex, and income. A study done with patients
beginning long-term dialysis showed that the sociodemographic barriers to renal transplantation present themselves
even before patients are on the transplant list. For example, different groups express definite interest and complete
pretransplant workup at different rates. Previous efforts to create fair transplantation policies had focused on patients
currently on the transplantation waiting list.
IVMS Basic Mecdial Science of the Kidney, The Scientific Basis of Clinical Disease
Kidney transplantation
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Danovitch, Gabriel M.; Delmonico, Francis L. (2008). "The prohibition of kidney sales and organ markets should
remain" [25]. Current Opinion in Organ Transplantation 13 (4): 386394. doi:10.1097/MOT.0b013e3283097476
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El-Agroudy, Amgad E.; El-Husseini, Amr A.; El-Sayed, Moharam; Ghoneim, Mohamed A. (2003). "Preventing
Bone Loss in Renal Transplant Recipients with Vitamin D" [27]. Journal of the American Society of Nephrology
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El-Agroudy, Amgad E.; Sabry, Alaa A.; Wafa, Ehab W.; Neamatalla, Ahmed H.; Ismail, Amani M.; Mohsen,
Tarek; Khalil, Abd Allah; Shokeir, Ahmed A. et al. (2007). "Long-term follow-up of living kidney donors: a
longitudinal study" [30]. BJU International 100 (6): 13511355. doi:10.1111/j.1464-410X.2007.07054.x [31].
ISSN1464-4096 [32]. PMID17941927 [33].
Kerry Grens, "Living kidney donations favor some patient groups: study", 'Reuters', Apr 9, 2012. http://www.
reuters.com/article/2012/04/10/health-kidney-donations-idUSL3E8FA0A720120410
John L. Gore, et al., "The Socioeconomic Status of Donors and Recipients of Living Unrelated Renal Transplants
in the United States", 'The Journal of Urology', Volume 187, Issue 5, May 2012, Pages 17601765. http://www.
sciencedirect.com/science/article/pii/S0022534711060617
Notes
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
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Kidney transplantation
[12] Montgomery, R. A., Gentry, S. E., Marks, W. H., Warren, D. S., Hiller, J., Houp, J., et al. (2006). Domino paired kidney donation: a strategy
to make best use of live non-directed donation" Lancet 368(9533), 419421.
[13] Butt, F. K., Gritsch, H. A., Schulam, P., Danovitch, G. M., Wilkinson, A., Del Pizzo, J., et al. (2009). Asynchronous, Out-of-Sequence,
Transcontinental Chain Kidney Transplantation: A Novel Concept. American Journal of Transplantation, 9(9), 21802185.
[14] Sack, Kevin. "60 Lives, 30 Kidneys, All Linked." The New York Times. 19 Feb. 2012. http:/ / www. nytimes. com/ 2012/ 02/ 19/ health/
lives-forever-linked-through-kidney-transplant-chain-124. html?pagewanted=all& _r=0. 22 Oct 2013.
[15] New Robot Technology Eases Kidney Transplants (http:/ / wcbstv. com/ health/ da. vinci. robot. 2. 1055154. html), CBS News, June 22,
2009 - accessed July 8, 2009
[16] http:/ / news. bbc. co. uk/ 1/ hi/ health/ 3041363. stm Call to legalise live organ trade
[17] http:/ / www. centerspan. org/ pubs/ transplantation/ 1998/ 0127/ tr029800224o. pdf
[18] Renal Transplants > Renal Transplantation Complications (http:/ / emedicine. medscape. com/ article/ 778255-overview#aw2aab6b7) from
eMedicine. Author: Mert Erogul, MD; Chief Editor: Erik D Schraga, MD. Updated: Dec 5, 2008
[19] Wolfe RA, Ashby VB, Milford EL, et al. Comparison of Mortality in All Patients on Dialysis, Patients on Dialysis Awaiting
Transplantation, and Recipients of a First Cadaveric Transplant. NEJM 1999: 341, 1725-1730.
[20] "Kidney Transplantation Factbook 2011" (http:/ / www. asas. or. jp/ jst/ pdf/ factbook/ factbook2011. pdf)
[21] (the link is to a query interface; Choose Category = Transplant, Organ = Kidney, and select the 'Transplant by donor type' report link)
[22] Official Website of Sindh Institute of Urology & Transplant
[23] http:/ / dx. doi. org/ 10. 1016%2FS1479-666X%2803%2980065-3
[24] http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 15570790
[25] http:/ / journals. lww. com/ co-transplantation/ Abstract/ 2008/ 08000/ The_prohibition_of_kidney_sales_and_organ_markets. 11. aspx
[26] http:/ / dx. doi. org/ 10. 1097%2FMOT. 0b013e3283097476
[27] http:/ / jasn. asnjournals. org/ cgi/ content/ full/ 14/ 11/ 2975
[28]
[29]
[30]
[31]
[32]
[33]
External links
Kidney transplantation (http://www.dmoz.org/Health/Conditions_and_Diseases/Genitourinary_Disorders/
Kidney/End_Stage_Disease/Transplantation//) at the Open Directory Project
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License
License
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