Nephrology

Lecture 1

Matthew B. Wilkinson, PhD, M4

Mount Sinai School of Medicine

NP01-.1 1
 Renal Embryology

Pronephros
• Develops at the 4th week from mesoderm
• Canalizes to form the nephric tubules
• Degenerates by the 4th week
Mesonephros
• Develops at the 5th week from mesoderm
• Forms Bowman’s capsule, glomerulus, and
mesonephric (Wolffian) duct
• The mesonephric duct drains into the hindgut
• Mesonephric tubules function temporarily then
degenerate
• The remainder of the mesonephric ducts persist
and forms:
• Men: ureters, ductus epididymis, ductus deferens Kaplan Anatomy: Figure III-3-21
and ejaculatory duct
• Females: ureters

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 Renal Embryology

Metanephros
• Develops at the 5th week
• Origin of the kidneys
• Develops from two sources:
• Ureteric bud (a diverticulum of the
mesonephric duct)
• Metanephric mass (or blastema) - also
originates from mesoderm

Kaplan Anatomy: Figure III-3-21

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 Renal Embryology

Ureteric bud
• Develops from the drainage
component of the urinary system
• Invaginates into the metanephric mass
• Condenses around the diverticulum to
form the metanephrogenic cap
• Dilates forming the renal collecting
system:
• Pelvis, calyces (major and minor)
• Pyramids (formed by collecting tubules)
• Nephrons (proximal and distal tubules
and loop of Henle)
• Kidneys develop in the pelvis
Kaplan Anatomy: Figure III-3-22
• Ascend into the abdomen
• Arterial inflow arises from the aorta

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 Renal Embryology

Bladder Development
• Develops from the urogenital sinus
(a protrusion of the endoderm)
• Caudal mesonephric duct joins the
developing bladder to form the
trigone of the bladder
• The mesonephric ducts form the
ureters in both sexes, and also the
ejaculatory ducts in males

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 Congenital Abnormalities

Renal agenesis
• Failure of one or both kidneys to develop
• Due to early degeneration of the ureteric bud
• Unilateral (common)
• Bilateral (fatal) associated with:
• Oligohydramnios
• Potter sequence
• Clubbed feet
• Pulmonary hypoplasia
• Craniofacial anomalies: flattened nose, low-set
ears, recessed chin
Pelvic kidney
• Failure of kidney ascent into the abdomen
• Not associated with a higher risk of pathology
Horseshoe kidney
• Fusion at the inferior poles Hufeisenniere CT axial.jpg, commons.wikimedia.org.
Used with permission.
• Incomplete ascent with entrapment at the
inferior mesenteric artery
• Associated with normal renal function, renal
calculi and Turner syndrome

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 Congenital Abnormalities

Double ureter
• Due to early splitting of the ureteric bud
• Development of two separate buds
Patent urachus
• Failure of allantois to obliterate
• Allantois is an embryological structure that connects bladder to
umbilicus
• Normally the lumen is obliterated
• Results in drainage of urine through the umbilicus

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 Anatomy of the Kidney

Cortex
• Outer aspect of the kidney
• Might delve into the parenchyma (renal
columns)
• Divided into lobules
• Contains glomeruli, nephrons and connective
tissue
• Cortical nephrons
• Juxtamedullary nephrons
Medulla
• Divided in outer and inner medulla
• Organized in radially arranged pyramids
• Straight tubules (run from the cortex to the
papilla)
• The apex of each pyramid directs urine →
minor calyx → major calyx → renal pelvis →
ureter
Hilum
• Located medially
• Point of entry and exit for the renal artery,
vein, and ureter

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 Fluid Compartments
Kidney processes
• Filtration, reabsorption , secretion, and
excretion
Fluid balance
• Normal fluid distribution
• 60% of TBW = Body water
• 40% of TBW= Non-water tissue mass
2/3rds 1/3rd
• ICF compartment
• Contains most of K+ stores
• Contains lesser fraction of Na+ and Cl-
• ECF compartment
• Contains high fraction of Na+ and Cl-
• Contains lesser fraction of K+ stores
• Divided in plasma (1/4th) and interstitium (3/4ths)
• Osmolarity is the same in all fluid compartments (290mOsm)
• Fluid compartment osmolarity determines water distribution
• Ions and solutes that contribute to osmolarity differ in each compartment

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 Fluid Compartments Measurement
Characteristics of tracers
• Tracer substances are used to measure body compartment volume
• Injected intravenously
• Diffuse until a barrier is encountered (e.g. capillary endothelial membranes, cell membranes)
• Requirements of a tracer
• Must disperse evenly within a fluid compartment
• Disperse only within the compartment of interest
• Intravascular fluid compartment tracers:
• Not permeable to capillary endothelial cell membranes
• 125I-albumin, Evans blue dye, 51Cr-red blood cells
• ECF tracers:
• Permeable to capillary endothelial membranes but not to cell membranes
• Inulin, mannitol, 22Na, and sucrose
• TBW tracers:
• Permeable to cappilary endothelial membranes and cell membranes
• Heavy water, tritiated water, antipyrine, and urea

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 Sample Fluid Calculation

A person in hemorrhagic shock is resuscitated with 0.5L of 500g/L of radiolabeled

albumin. 10 minutes later, the plasma concentration of this marker is 5g/dL. What
is the effective plasma volume for this patient?

A = (0.5L)(500g/L) = 250 g albumin administered

C = 5g/dL = 50g/L
V = (250g)/(50g/L) = 5 liters
Effective plasma volume: 5 liters

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 Filtration

Glomerular apparatus
• Blood enters via the afferent arteriole
• Glomerular membrane
• Fenestrated capillary endothelial wall
• Glomerullar basement membrane aligned
with heparan sulfate (negative charge)
• Epithelial layer of podocyte foot
processes
• Mesangium (similar to monocytes)

• Permeable to water and dissolved

solutes
• Impermeable to large proteins
• Blood exits via the efferent arteriole

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 Filtration
Materials freely filtered
• Electrolytes

• Metabolic waste products (urea, creatinine)

• Metabolites (glucose, amino acids, organic acids)

• Low weight proteins and peptides (insulin and

myoglobin)

Material not freely filtered

• Large molecular weight proteins (e.g. albumin)

• Lipid soluble substances attached to plasma proteins

(e.g. bilirubin, thyroxine, other hormones)

Bowman’s space
• Fluid entering has the same concentration of
dissolved substances as the plasma minus the
proteins which were not filtered

• Ultrafiltrate osmolarity 290 mOsm/L

• Substance freely filtered: ratio of filtrate

concentration = 1
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 Filtration

Factors effecting filtration

• Glomerular membrane permeability
• Surface area
• Hydrostatic and oncotic Starling forces
Filtration fraction (FF)
• Fraction of plasma solute filtered into Bowman’s space
• FF = GFR/RPF
• Normal: 20%
Filtered load (amount/time)
• GFR x plasma concentration of the substance being filtered
• RPF is regulated by afferent or efferent arteriolar constriction
• The longer the plasma remains within glomerular capillaries,
the greater percentage of plasma that is filtered
• RPF: (volume/time)

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 Filtration
Sympathetic stimulation
• Vasoconstriction of arterioles
• Decreased fluid filtered, GFR and RPF leading to
• Increased FF
• Increased oncotic pressure within peritubular
capillaries
• Increased reabsorption in the proximal tubule
Angiotensin II
• Constriction of Efferent > Afferent constriction
• Preserved glomerular capillary pressure
• Increased resistance within the glomerular apparatus
• Decreased RPF
• Increased GFR
• Increased FF
NSAIDS
• Inhibit prostaglandins (maintain dilated vascular tone)
• Afferent arteriolar constriction
• Decreased GFR and RPF
• No changes in FF

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 Filtration Pressure

Starling forces
• Glomerular capillary hydrostatic
pressure

• Glomerular oncotic pressure

• Bowman’s space hydrostatic pressure

• Bowman’s space oncotic pressure

(under normal conditions equals zero)

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 Starling Forces

Starling equation of fluid movement (Qf):

• Qf = k[(PC+πI)-(PI+πC)]
• K = filtration coefficient
• PC = capillary hydrostatic pressure
• PI = Interstitial hydrostatic pressure
• πC = Capillary oncotic pressure
• πI = Interstitial oncotic pressure
• Compares the forces that favor fluid filtration
with the forces that oppose it
• Net filtration pressure = PGC- πGC- PBS
• PGC = capillary hydrostatic pressure
• PBS = Bowman’s space hydrostatic pressure
• πC = Capillary oncotic pressure
• *πBS = Bowman’s space oncotic pressure = zero

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 Glomerular Flow Regulation

Afferent capillary constriction

• ↓RPF
• ↓Glomerular filtration pressure (as PBS ↓)
• ↓GFR
Efferent capillary constriction
• ↓RPF
• ↑ PBS
• ↑Glomerular filtration pressure
• ↑GFR

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 Glomerular Filtration Rate

Characteristics
• Used as marker for kidney filtration function
• The rate at which fluid is filtered into Bowman’s space
• Units: volume/time
• GFR in the young/healthy:120 mL/min = 180L/day
• With nephron loss (e.g. nephrectomy) the remaining nephrons compensate
and GFR decreases by only 25%

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 Clearance
Characteristics
• Volume of plasma cleared of a solute or drug per
unit of time
• Affected by
• GFR
• Nephron secretion
• Nephron reabsorption
• Inulin clearance = GFR
• Neither secreted nor reabsorbed
• Renal clearance of inulin is direct
measurement of GFR
• Creatinine (product of muscle breakdown)
• Small amount secreted
• Not reabsorbed
• Creatinine clearance ≈ GFR

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 Serum Creatinine and GFR

Characteristics
• ↓GFR = ↑ plasma creatinine

• Plasma creatinine not a sensitive measure of

reduced GFR

• Will reveal large changes in GFR

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 Effective Renal Plasma Flow

Para-aminohippuric acid (PAH)

• Filtered and secreted
• Not reabsorbed
• Used as reflection of RPF (PAH clearance = RPF)
• Urine and plasma concentration of PAH and urine flow
rate are used to calculate effective renal plasma flow
ERPF = UPAH x V/PPAH = CPAH
• Effective renal plasma flow differs from renal blood flow
• PAH clearance is a measure of 90% of true renal
plasma flow (effective renal plasma flow)
RBF = RPF/(1-hematocrit)

Example
If RPF is 600mL/min and Hct is 50%, then RBF equals 1200 mL/min

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 Key Concepts and Equations
• Filtered load = (GFR) x (plasma concentration of the substance being
cleared)
• Excretion rate = (urine flow rate) x (urine substance concentration)
• Reabsorption = (amount filtered) – (amount excreted)
• Secretion = (amount excreted) – (amount filtered)

(urine concentration of x)(urine flow rate)

• Clearance =
(plasma concentration of x)

• Clearance < GFR: net tubular reabsorption

• Clearance > GFR: net tubular secretion
• Clearance = GFR: no net secretion or reabsorption

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Renal 2

Matthew B. Wilkinson, PhD, M4

Mount Sinai School of Medicine

NP02.1- 1
 Solute Transport
Types of solute transport
• Simple diffusion
• Solute movement via electrochemical gradient

• Facilitated diffusion
• Solute movement down electrochemical gradient

• Via a membrane-bound protein

• Active transport
• ATP mediated solute movement

• Via a membr

• Secondary active transport

• Solute movement driven by the electrochemical gradient generated by the active
transport of another solute

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 Protein-Mediated Transport

Uniport
• Facilitated transport
• One transporter moves 1 solute
Symport
• Co-transporter
• Coupled transport of ≥2 solutes in
same direction
Antiport
• Counter transport
• Coupled transport of ≥2 solutes in
opposite directions

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 Protein-Mediated Transport

Characteristics
• Solutes can be transported at higher rates than that achieved by simple diffusion
• Nephrons are able to regulate solute reabsorption and clearance
• Saturation kinetics apply
• Transport rate ↑ with solute concentration until Tmax is reached
• Entire filtered load of a substance is reabsorbed until carriers are saturated
• Excess is excreted in urine

• Transport maximum systems:

• Glucose
• Ketone bodies
• Amino acids • Calcium
• Small peptides • Phosphate
• Proteins

• Transporters are chemically specific; selectively bind to substances based on

chemical structure
• Competition for same transporter can occur between substances of similar chemical structure

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 Types of Active Transport

Primary active transport

• ATP is consumed directly by transporting
protein
• Na+/K+-ATPase pump
Secondary active transport
• Indirect, ATPase-dependent, transport
• Na+-glucose co-transport

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 Nephron Tubular Secretion

Characteristics
• Tubules secrete solutes from peritubular
capillaries into the nephron lumen

• Secretion is via TM systems

• Classic example is the tubular secretion of

p-aminohippuric acid, or PAH

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 Nephron Tubular Secretion

Characteristics
• Secretion of organic anions and cations
occur via non-specific carriers
• Potential for competition
• Organic anions secreted by tubules
• Penicillin
• Furosemide
• Acetazolamide
• Salicylate
• Organic cations secreted by tubules
• Atropine
• Morphine
• Procainamide
• Cimetidine
• Amiloride

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 Proximal Tubule

Characteristics
• Receives isotonic ultrafiltrate from Bowman’s
capsule
• Osmolarity of 300 mOsm/L (concentration of
freely filtered substances equal to the plasma)
• Active transport via primary active transport
(Na+/K+-ATPase)
• Pump located along basal and basolateral
borders
• Responsible for 2/3 of all solute reabsorption
• Leaky tight junctions
• Co-transported with sodium via secondary
co-transport:
• Carbohydrates
• Proteins
• Peptides
• Amino acids
• Ketone bodies

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 Proximal Tubule

Characteristics
• 80–90% of HCO3- reabsorption
• Facilitated by
• Luminal and intracellular
carbonic anhydrase
• Na+/H+ antiporter
• CO2 diffusion
• Facilitated HCO3- transport
• Secretion of
• Organic anions
• Organic cations

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 Glucose Transport

Characteristics
• Glucose clearance is 0 at normal serum levels
• All filtered glucose is reabsorbed in the
proximal tubule (Na+/glucose co-transport)
• Glucose transporters near saturation when
plasma levels 160-200 mg/dL (glucosuria)
• Glucosuria indicates hyperglycemia
(e.g., diabetes)
• All nephron glucose transporters reach Tmax
at plasma glucose 350 mg/dL

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 Amino Acids Transport

Reabsorption
• Proximal tubule by secondary active transport
• Via Na+/AA co-transporter
Hartnup disease
• ↓ AA reabsorption and aminoaciduria
• Autosomal recessive
• Impaired neutral AA transport (tryptophan) in brush
border of small intestine and proximal tubules
Clinical manifestations
• Pellagra-like skin lesions (↓ tryptophan)
• Cerebellar ataxia
• Peptide reabsorption can compensate à
phenotypic variability

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 Proximal Tubule Reabsorption

Characteristics
• Increased TF/P = increased H2O reabsorption
• Inulin is neither secreted nor reabsorbed
• PAH is filtered and secreted, not reabsorbed
• TF/P = 1
• Solutes and water reabsorbed equally
• TF/P >1
• Solutes reabsorbed more slowly than water
• Net solute secretion
• TF/P <1
• Solutes reabsorb more quickly than water

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 Transport in Loop of Henle

Loop of Henle
• Receives isotonic fluid
• Corresponds to 1/3 of volume filtered
• Functions as a countercurrent
multiplier
• Creates a medullary interstitial osmolar
gradient
• Facilitates tubular reabsorbtion
• Accumulates
• Sodium
• Chloride
• Urea

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 Transport in Loop of Henle
Characteristics
• Opposite directional flow in descending and

Kaplan Physiology 2010: Figure VIII-1-1

ascending limbs
• Descending limb is permeable to H2O and
less to solute
• Ascending limb is permeable to solute, not
H2O
• Via Na+/K+/2Cl- symporter and Na+/H+ antiporter
• Medullary interstitial osmolar gradient as well
as back diffusion of K+ induces paracellular
reabsorption of Mg2+ and Ca2+
• Slow tubular fluid flow facilitates generation
and maintenance of osmolar gradient
• Loop of Henle reabsorbs
• 25% of filtered electrolytes
• 15% of filtered H2O

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 Early Distal Tubule

Characteristics
• Impermeable to H2O
• Site of Na+, Cl-, Ca2+ reabsorption
• Apical Na+/Cl- symporter
• Na+ is pumped across the basal
membrane via Na+/K+-ATPase protein
• Chloride diffuses through channels down
its electrochemical gradient
• Ca2+ enters the luminal surface passively,
through calcium channels
• Ca2+ can also be actively extruded into the
peritubular fluid via a Ca2+-ATPase protein
or Na+/Ca2+ antiporter
• Parathyroid hormone acts upon apical
Ca2+ channels

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 Distal Tubule and Collecting Ducts

Characteristics
• Membrane composition similar to that of
collecting ducts
• Contain principal and intercalated cells
• Principal cells:
• Reabsorb Na+, Cl-, and H2O
• Secrete K+

• Site of aldosterone action

• Active reabsorption of Na+
• Activate Na+/K+-ATPase pumps
• Induce Na+ channel insertion

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 Distal Tubule and Collecting Ducts

Intercalated cells
• Represented by 2 cell types
• Type 1 secretes H+ into the tubular
lumen; used to generate new
bicarbonate to be secreted into
circulation
• Type 2 secretes bicarbonate into the
tubular lumen
• Both contribute to the kidney’s role in
acid-base regulation

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 Distal Tubule and Collecting Ducts

Characteristics
• Eliminate fixed acids produced by
body metabolism
• Secreted H+ binds HPO42- and NH3,
facilitating their excretion
• Ratio of excreted H+ to reabsorbed
HCO3- 1:1
• NH3 made from glutamine to buffer H+

• Contain basolateral ADH receptors

• Induce the insertion of water channels
onto apical surface
• Allows free water reabsorption

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 Atrial Natriuretic Peptide (ANP)

Characteristics
• Found in the heart, mainly in the right atrium
• Secretion stimulated by stretch associated with hypervolemia and
increased salt intake
• Increases GFR
• Dilates afferent arteriole
• Constricts efferent arteriole
• Increases natriuresis and diuresis
• Na+ and H2O reabsorption in the collecting ducts
• Physiological function is unknown
• Might play a role in extracellular fluid osmolarity and volume regulation
• Antagonizes ATII and ADH action

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 Parathyroid Hormone (PTH)

Characteristics
• Secretion stimulated by
• Decrease of serum free calcium
concentration
• Action
• Increases distal tubule Ca2+ reabsorption
• Decreases proximal tubule phosphate
reabsorption
• Increases proximal tubule
1,25 dihydroxyvitamin D formation
• Net effect of PTH function
• Increases serum calcium
• Decreases serum phosphate

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 Renin-Angiotensin-Aldosterone System

Juxtaglomerular cells
• Modified smooth muscle cells of the
afferent arteriole

Macula densa
• Portion of distal convoluted tubule that senses
Na+ concentration

Juxtaglomerular cell renin secretion

stimulated by
• Decreased Na+ delivery to macula densa
• Decreased blood pressure at JG cells
• Increased β1 stimulation of JG cells

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 Renin-Angiotensin-Aldosterone System

• Renin converts circulating angiotensinogen into angiotensin I

• Angiotensin I is converted into angiotensin II in the lungs
• Angiotensin II induces:
• Peripheral arteriolar vasoconstriction (increasing TPR)
• Efferent arteriole constriction, leading to increased GFR and FF with compensatory
Na+ reabsorption in the proximal and distal nephron
• Thirst (via the hypothalamus)
• Adrenal aldosterone secretion leading to increased Na+ reabsorption by principal cells
of the collecting duct via:
• Increased insertion of Na + /K + -ATPase pumps
• Increased insertion of luminal Na+ channels
• Water is reabsorbed along with sodium, increasing the extracellular fluid volume of the
plasma, raising cardiac output and blood pressure
• K+ loss occurs by way of increased Na+ reabsorption
• H+ secretion by way of intercalated cells H+ ATPase activity

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 Anti-Diuretic Hormone (ADH)

• Also known as vasopressin

• Secretion stimulated by
• Increased plasma osmolarity
• Decreased blood volume
• Binds to receptors on collecting duct
principal cells
• Induces insertion of water channels
(aquaporins)
• Increases reabsorption of free water
• Restores plasma volume and osmolarity

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 Erythropoietin

Characteristics
• Glycoprotein hormone

• Produced in peritubular cells

• Secreted in response to hypoxia

Functions

• Protects RBCs from hypoxemia-induced apoptosis

• Increases RBC production (adaptive polycythemia)

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 Potassium Homeostasis

• Excretion must match intake

• 98% of K+ intracellular, 2% is extracellular

• Normal plasma concentration: 3.5–5 mEq/L

• >5 mEq/L = hyperkalemia

• <3.5 mEq/L= hypokalemia

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 Potassium Homeostasis

Characteristics
• Concentration gradients across cell membranes
maintained by
K+
• Negative intracellular potential within cells H+

• Permeability of cell membranes to potassium

• Cell membrane potential maintained by
Na+/K+-ATPase pumps
Factors influencing K+ homeostasis
• Postprandial, insulin, and epinephrine-induced
K+ shift intracellularly
• Long-term K+ balance via aldosterone on distal
tubule and collecting duct

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 Potassium Homeostasis

Transcelluar potassium shifts

• Causing shifts out of cells
• Acidosis (in exchange for hydrogen ions)
K+
• Hyperosmolarity (e.g., hyperglycemia)

• Cell lysis or muscle trauma

H+
• Insulin deficiency or resistance (decreased
Na+/K+-ATPase activity)

• Beta antagonist (decreased Na+/K+-ATPase activity)

• Causing shifts into cells

• Insulin use (increased Na+/K+-ATPase activity)

• β-agonists (increased Na+/K+-ATPase activity)

• Alkalosis (increased activity of cell membrane

K+/H+ pumps)

• Hypo-osmolar states

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 Potassium Homeostasis

Main factors affecting renal K+ secretion

• Increased tubular fluid flow
• Increased tubular fluid negative potential
Other factors

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 Hyperkalemia

Etiology
• Transcellular shifts
• Renal failure (decreased GFR)
• Hypoaldosteronism
• Excess dietary intake (rare)
Clinical manifestations
• Muscle weakness
ECG_in_hyperkalemia,
• Fatigue commons.wikimedia.org.

• Cardiac arrhythmias
• Peaked T waves
• Widened QRS
• V-fib
• Worsening metabolic acidosis

FA 2013: 487 • FA 2012: 509 • FA 2011: 462 NP02.5 - 5

ME 3e: 318 • ME 4e: 318
 Hypokalemia

Etiology
• Transcellular shifts (metabolic alkalosis)
• Increases of insulin and catecholamines
U-wave
• Diarrhea and vomiting
• Diuretics (increased fluid flow)
• Hyperaldosteronism (adrenal adenoma,
renal artery stenosis)
• Renal tubular acidosis types I and II
Clinical manifestations
• Muscle weakness
• Fatigue
• Cardiac arrhythmias
• Flattened T waves
• U waves

FA 2013: 487 • FA 2012: 509 • FA 2011: 462 NP02.5 - 6

ME 3e: 318 • ME 4e: 318
 Other Electrolyte Disturbances

Hyponatremia
• Mental status changes: confusion, stupor, coma
Hypernatremia
• Mental status changes: irritability, delirium, coma
Hypochloremia
• Excessive vomiting, prolonged nasogastric tube suctioning, metabolic
alkalosis, hypovolemia, cystic fibrosis, and hyperaldosteronism
Hyperchloremia
• Non-anion gap acidosis

FA 2013: 487 • FA 2012: 509 • FA 2011: 462 NP02.5 - 7

ME 3e: 316 • ME 4e: 316
 Other Electrolyte Disturbances

Hypocalcemia
• Tingling and numbness, muscle cramps, tetany, neuromuscular instability, fatigue,
irritability, depression, seizures
Hypercalcemia
• Delirium, renal stones, abdominal pain
Hypomagnesemia
• Neuromuscular irritability, cardiac arrhythmias
Hypermagnesemia
• Delirium, decreased deep tendon reflexes, and cardiopulmonary arrest
Hypophosphatemia
• Bone loss and osteomalacia
Hyperphosphatemia
• Renal stones and metastatic calcifications

FA 2013: 487 • FA 2012: 509 • FA 2011: 462 NP02.5 - 8

ME 3e: 316 • ME 4e: 316
 Acid-Base Disorders

Bicarbonate buffer system

• Predominant pH regulating system
• Controls the concentration of H+
• Functions to maintain a normal serum pH
Four primary acid-base disturbances
• Respiratory acidosis
• Respiratory alkalosis
• Metabolic acidosis
• Metabolic alkalosis

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 1

ME 3e: 323 • ME 4e: 323
 Respiratory Acidosis

Etiology
• Decreased alveolar ventilation relative to total CO 2 production
• Increased H+ and HCO3-
• Decreased plasma pH
Labs
• For every 10 mm Hg increase in PaCO2:
• HCO3- increases by 1
• pH decreases by 0.08

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 2

ME 3e: 323 • ME 4e: 323
 Respiratory Alkalosis
Etiology
• Increased alveolar ventilation relative to total CO2 production (e.g., hyperventilation)
• Decreased CO2
• Decreased H+
• Decreased HCO3-
• Increased pH
Labs
• For every 10 mm Hg decrease in PaCO2:
• HCO3- decreases by 2
• pH increases by 0.08

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 3

ME 3e: 323 • ME 4e: 323
 Metabolic Acidosis
Etiology
• Increased plasma fixed acid (lactic acidosis and ketoacidosis)
• Bicarbonate loss (renal tubular acidosis type II and in diarrhea)
Labs
• Net gain in plasma hydrogen ion concentration
• Relative decrease in plasma bicarbonate concentration
• Decrease of plasma pH

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 4

ME 3e: 323 • ME 4e: 323
 Metabolic Alkalosis
Etiology
• Loss of plasma fixed acid and/or loss of HCO3-
• Excessive vomiting
• Nasogastric tube suctioning
• Loop and thiazide diuretic use
• Conditions causing H+ shifts
Labs
• Relative increase of plasma bicarbonate
• Rise in arterial pH

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 5

ME 3e: 323 • ME 4e: 323
 Acid–Base Disturbances

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 6

ME 3e: 323 • ME 4e: 323
 Respiratory Compensation in Acidosis

• Respiratory compensation occurs only in metabolic disturbances

• Can begin immediately
• In metabolic acidosis, the respiratory system compensates by hyperventilating
• Serves to reduce CO2
• Shifts toward the consumption of hydrogen ions

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 7

ME 3e: 323 • ME 4e: 323
 Respiratory Compensation in Alkalosis

• In metabolic alkalosis, the respiratory system’s compensation involves

hypoventilation
• Increases plasma CO2 concentration
• Shifts acid-base balance toward the production of hydrogen ions

Expected é CO2 = 0.7 mmHg for each 1 mEq/L é of HCO3-

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 8

ME 3e: 323 • ME 4e: 323
 Renal Compensation

• Kidneys compensate for respiratory and metabolic disturbances

• Mechanism

• Excretion of HCO3- or synthesis de novo in distal tubule and collecting ducts

• H+ excretion (further compensation)

• Slower than respiratory compensation

Compensation in chronic respiratory acidosis

• Expected HCO3- = 0.4 × (↑ in PaCO2)

Compensation in chronic respiratory alkalosis

• Expected HCO3- = 0.4 × (↓ in PaCO2)

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 9

ME 3e: 323 • ME 4e: 323
 Plasma Anion Gap

• Plasma cations charges equals plasma anions charges

• Anion gap equation only considers major plasma anions
• Expected (normal) gap: 12 ± 2 mEq/L
• Plasma anion gap = (Na+) – (Cl- + HCO3-)
• Major cation used for calculating anion gap is plasma Na+
• Major anions used for calculating anion gap is plasma Cl- and HCO3-
Normal Values
• Na+ = 140 mEq/L
• Cl- = 104 mEq/L
• HCO3- = 24 mEq/L

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 10

ME 3e: 323 • ME 4e: 323
 Plasma Anion Gap

Plasma anion gap = (Na+) – (Cl- + HCO3-)

Characteristics
• AG useful for diagnosing causes of metabolic acidosis
• AG increases with anion accumulation (other than Cl-)
• Organic acids (e.g., lactic acidosis or ketoacidosis)
• Anion ingestion (e.g., salicylates, ethylene glycol, EtOH, methanol)
• AG not elevated in a primary metabolic acidosis
Causes of AG acidosis: “MUDPILES”
• M – methanol • I – iron tablets or INH
• U – uremia • L – lactic acidosis
• D – diabetic ketoacidosis • E – ethylene glycol
• P – paraldehyde or phenformin • S - salicylates

FA 2013: 487-488 • FA 2012: 513 • FA 2011: 465 NP02.6 - 11

ME 3e: 323 • ME 4e: 323
 Renal Tubular Acidosis (RTA)

Classifications: types 1, 2, and 4

RTA type 1
• Inability of distal nephron to secrete/excrete fixed acid
• Impaired H+ and HCO3- transport systems
• Increased permeability of tubular apical membranes

Etiology
• Sporadic
• Secondary to autoimmune disease (e.g., lupus)
• Drugs (e.g., amphotericin, lithium)

FA 2013: 488 • FA 2012: 514 • FA 2011: 466 NP02.7 - 1

ME 3e: 323 • ME 4e: 323
 RTA Type 1

Clinical manifestations
• Metabolic acidosis
• Increased urine pH
• Secondary hyperaldosteronism
• Decreased K+
• In chronic acidemia:
• HCO3- buffer system is exhausted
• Ca2+ salts mobilized from bone to serve as plasma buffer
• Hypercalcemia + decreased acidosis: impairment of proximal/distal Ca2+ reabsorption

• Hypercalcuria
• Nephrocalcinosis
• Nephrolithiasis (due to reduction in urinary citrate levels and persistent alkaline urine)

FA 2013: 488 • FA 2012: 514 • FA 2011: 466 NP02.7 - 2

ME 3e: 323 • ME 4e: 323
 RTA Type 2

• Decreased proximal tubule HCO3- reabsorption

Clinical manifestations
• Decreased plasma HCO3-
• Decreased urine pH
• Decreased reabsorption of glucose, Ca2+, PO3-4, citrate, uric acid, lysozymes,
and amino acids
• Associated with other defects of proximal tubular function
Associated conditions
• Hypophosphatemic rickets • Vitamin D deficiency
• Fanconi’s syndrome • Secondary hypoparathyroidism
• Wilson’s disease • Chronic hepatitis
• Amyloidosis • Systemic lupus erythematosis
• Multiple myeloma • Carbonic anhydrase inhibitor use

FA 2013: 488 • FA 2012: 514 • FA 2011: 466 NP02.7 - 3

ME 3e: 323 • ME 4e: 323
 RTA Type 4

Pathophysiology
• Hypoaldosteronism
• Lack of collecting tubule response to aldosterone
• Associated with a mild metabolic acidosis
• ↓ proximal tubular ammoniagenesis and excretion
• Decrease in urine buffering capacity
Other etiologies
• Drugs
• Spironolactone, ACE inhibitors, ARBs
• Trimethoprim
• Pentamidine
• Diseases
• Diabetic nephropathy
• HIV/AIDS
• Lupus
• Adrenal disease

FA 2013: 488 • FA 2012: 514 • FA 2011: 466 NP02.7 - 4

ME 3e: 323 • ME 4e: 323
 RTA Type 4

Clinical manifestations
• Hyperkalemia (helps to distinguish it from the other types)
• Metabolic acidosis
• Decreased urine pH

FA 2013: 488 • FA 2012: 514 • FA 2011: 466 NP02.7 - 5

ME 3e: 323 • ME 4e: 323
Renal 3

Matthew B. Wilkinson, PhD, M4

Mount Sinai School of Medicine

NP03.1- 1
 Urinary Casts

Definition
• Sediments formed in distal convoluted tubule or collecting duct
• Dislodge with tubular fluid flow into the urine
• Detected by cytology
• Specifically indicative of renal disease

Classification
• Acellular casts
• Hyaline, granular, fatty, and waxy
• Cellular casts
• Red blood cell, white blood cell, and epithelial cell

FA 2013: 489 • FA 2012: 514 • FA 2011: 466 NP03.1- 2

ME 3e: 328 • ME 4e: 328
 Hyaline Casts

Characteristics
• Most common cast type
• Composed of solidified Tamm-Horsfall mucoprotein secreted from tubular
epithelial cells
• Formation precipitated by
• Low tubular fluid flow
• Concentrated tubular fluid
• Acidic tubular fluid
Cytology
• Cylindrical and clear
• Other casts types formed via adhesion to hyaline cast bases

FA 2013: 489 • FA 2012: 514 • FA 2011: 466 NP03.1- 3

ME 3e: 328 • ME 4e: 328
 Granular Casts

Characteristics
• Second most common cast type
• Formed by
• Breakdown of cellular casts
• Inclusion of plasma protein or immunoglobulin light chain aggregates into
a hyaline cast base
Cytology
• Cigar-shaped
• Muddy brown
• Non-specific markers of underlying kidney disease

FA 2013: 489 • FA 2012: 514 • FA 2011: 466 NP03.1- 4

ME 3e: 328 • ME 4e: 328
 Fatty and Waxy Casts

Fatty casts
• Seen when lipid is within the urine (e.g., nephrotic syndrome)
Waxy casts
• Represent the end product of cast evolution
• Suggest slowed and/or stasis of tubular fluid flow characteristic of
chronic kidney disease
Cytology
• Large
• Cylindrical
• Sharp edges and fractures

FA 2013: 489 • FA 2012: 514 • FA 2011: 466 NP03.1- 5

ME 3e: 328 • ME 4e: 328
 Red Blood Cell Casts

Cytology
• Red blood cell clumps
Characteristics
• Strongly indicative of glomerular damage
• Primary glomerular disease
• Secondary glomerular damage (e.g., severe hypertension)

FA 2013: 489 • FA 2012: 514 • FA 2011: 466 NP03.1- 6

ME 3e: 328 • ME 4e: 328
 White Blood Cell Casts

Cytology
• White blood cell clumps
Characteristics
• Indicative of
• Tubulointerstitial inflammation
• Acute pyelonephritis
• Graft rejection in transplanted kidneys

FA 2013: 489 • FA 2012: 514 • FA 2011: 466 NP03.1- 7

ME 3e: 328 • ME 4e: 328
 Glomerular Diseases

Classification: nephritic syndrome and nephrotic syndrome

FA 2013: 489 • FA 2012: 515 • FA 2011: 466 NP03.2- 1

ME 3e: 328 • ME 4e: 328
 Acute Poststreptococcal Glomerulonephritis

Characteristics
• Proliferative glomerulonephritis or
postinfectious glomerulonephritis
• Occurs 2-4 weeks after a
streptococcal throat or skin infection
• Children > adults
Risk factors
• ß-hemolytic, group A streptococci
• Other bacterial infections
• Viral and parasite infections Post-infectious glomerulonephritis - very high mag,
commons.wikimedia.org.

• Systemic disease (e.g., SLE,

polyarteritis nodosa)

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 2

ME 3e: 328 • ME 4e: 328
 Acute Poststreptococcal Glomerulonephritis

Diagnosis
• Positive antistreptolysin O (ASO) titers
• ê serum complement
• Biopsy findings
• Light microscopy
• Hypercellular glomeruli
(neutrophils, monocytes)
• RBC casts within tubules
• Immunofluorescence
• Granular deposits of IgG, IgM, C3
• Electron microscopy
Post-infectious glomerulonephritis - very high mag.
• Hump-shaped, subepithelial commons.wikimedia.org.

immune complex deposition

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 3

ME 3e: 328 • ME 4e: 328
 Acute Poststreptococcal Glomerulonephritis

Treatment
• Conservative IV fluid management
Prognosis
• 95% of children and 60% of adults
recover completely
• Those who don’t recover develop
chronic renal failure or rapidly
progressive glomerulonephritis Post-infectious glomerulonephritis - very high
mag.jcommons.wikimedia.org.

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 4

ME 3e: 328 • ME 4e: 328
 Goodpasture’s Syndrome

Characteristics
• Also called Anti-GBM disease
• Anti-body mediated against:
• Glomerular basement membrane
• Type IV collagen (non-collagenous
components)
• Key: associated lung parenchymal
damage also present
Risk factors
• Young men (age 20-40)
Clinical presentation Crescentic glomerulonephritis - very high mag.
commons.wikimedia.org.
• Nephritic syndrome
• Hemoptysis
• Pulmonary hemorrhage

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 5

ME 3e: 328 • ME 4e: 328
 Goodpasture’s Syndrome

Diagnosis
• Biopsy findings
Crescent-shaped pattern
• Light microscopy
• Glomerular hypercellularity

• Fibrin deposition (crescent-shaped

pattern)

• Immunoflorescence
• Smooth, linear pattern of IgG and C3
deposition in glomerular basement
membrane

• Electron microscopy Crescentic glomerulonephritis - very high mag,

commons.wikimedia.org.

• Disrupted-appearing glomerular
basement membrane

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 6

ME 3e: 328 • ME 4e: 328
 Goodpasture’s Syndrome

Treatment
• Plasma exchange
• IV steroids
• Cytotoxic drugs
Prognosis
• Poor
• Most patients develop rapidly
progressive glomerulonephritis Crescentic glomerulonephritis - very high mag,
commons.wikimedia.org.

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 7

ME 3e: 328 • ME 4e: 328
 Rapidly Progressive Glomerulonephritis

Characteristics
• Also called crescentic glomerulonephritis

• Causes rapid renal failure (weeks to months)

• May occur in association with:

• Goodpasture’s syndrome

• Other forms of glomerulonephritis

• Vasculitides (e.g., Wegener’s granulomatosis)

© Katsumi M. Miyai, M.D., Ph.D., Regents of the

University of California. Used with permission.

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 8

ME 3e: 328 • ME 4e: 328
 Rapidly Progressive Glomerulonephritis

Diagnosis
•Biopsy findings
• Light microscopy
• Glomerular hypercellularity
• Bowman’s capsule crescent formation
pattern
• Immunoflorescence
• Granular or linear Ig and complement
deposits
• Electromicroscopy
• Variable pattern of
electron-dense deposits
• Glomerular basement membrane © Katsumi M. Miyai, M.D., Ph.D., Regents of the
University of California. Used with permission.
discontinuity

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 9

ME 3e: 328 • ME 4e: 328
 Rapidly Progressive Glomerulonephritis

Treatment
• Steroids
• Cyclophosphamide

Prognosis
• Poor
• Most patients progress to acute renal
failure and end-staged renal disease

© Katsumi M. Miyai, M.D., Ph.D., Regents of the

University of California. Used with permission.

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 10

ME 3e: 328 • ME 4e: 328
 IgA Nephropathy
Characteristics
• Also called Berger disease
• Most common cause of
glomerulonephritis worldwide
• High incidence in:
• France • Italy
• Japan • Austria

Risk factors
• Male sex
• 1-2 days following a respiratory infection
(post-strep GN occurs 1-2 weeks later)
• Celiac sprue
Pathogenesis
IgA nephritis immunostaining, jpgcommons.
wikimedia.org.
• Unknown
• Glomerular entrapment of Ig with
complement activation

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 11

ME 3e: 328 • ME 4e: 328
 IgA Nephropathy
Diagnosis
• Biopsy findings
• Light microscopy
• Can be normal
• Mesangial proliferation can be
seen
• Immunofluorescence
• Mesangial IgA and C3 deposits
• Electron microscopy
• Mesangial immune complex
deposits
Treatment
• No proven effective treatment
• ACE inhibitors or angiostensin receptor
blockers
• Steroids IgA nephritis immunostaining, commons. wikimedia.org.

Prognosis
• 40-50% progress to renal failure, which
can manifest after decades

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 12

ME 3e: 328 • ME 4e: 328
 Membranoproliferative Glomerulonephritis

Characteristics
• Affects the mesangium and basement
membrane
Clinical presentation
• Variable; can have nephritic and/or nephrotic
syndrome
Risk factors
• Occurring secondary to:
• SLE
• Endocarditis
• Hepatitis B and C
• HIV
• Chronic lymphocytic leukemia
Labs
• Serum C3
• C3 nephritic factor (stabilized C3 convertase) Membranoproliferative glomerulonephritis - very high mag,
commons.wikimedia.org.

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 13

ME 3e: 328 • ME 4e: 328
 Membranoproliferative Glomerulonephritis

Diagnosis
•Biopsy findings
• Light microscopy
• Lobulated appearing glomerulus due to
mesangial and endothelial proliferation
• Subendothelial Ig deposition
• Basement membrane splitting
(“tram-tracking”) on silver or PAS stains
• Immunofluorescence
• Granular pattern of C3
• Deposition of IgG, C1q, and C4
•Electron microscopy
• Subendothelial and mesangial Ig
deposition Membranoproliferative glomerulonephritis - very high
mag,commons.wikimedia.org.
• Dense basement membrane deposits

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 14

ME 3e: 328 • ME 4e: 328
 Membranoproliferative Glomerulonephritis

Treatment
• Dipyridamole
• Aspirin
Prognosis
• Slow progression to chronic renal failure
(10+ years)
• High recurrence following kidney
transplant

Membranoproliferative glomerulonephritis - very high

mag, commons.wikimedia.org.

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 15

ME 3e: 328 • ME 4e: 328
 Alport Syndrome

Characteristics
• Also known as hereditary nephritis
• Rare X-linked disorder
• Genetic mutation of the C0L4A5 gene: defective type IV collagen production
Clinical presentation
• Hereditary nephritis in childhood
• Sensorineural hearing loss
• Ocular abnormalities of the lens and cornea
Diagnosis
• Biopsy
• Electron microscopy
• Alternating thickening and thinning of basement membrane with lamina densa splitting
Prognosis
• 90% develop end stage renal disease by age 40

FA 2013: 492 • FA 2012: 516 • FA 2011: 467 NP03.2- 16

ME 3e: 328 • ME 4e: 328
 Nephrotic Syndrome

Characteristics
• Noninflammatory glomerular injury
• Podocyte and basement membrane damage
• porosity protein NOT cell filtration
Treatment
• Monitoring to ensure euvolemia
• Loop diuretics for edema
• ACE inhibitors for proteinuria and blood
pressure control
• Management of hyperlipidemia
• Steroids
• Cyclophosphamide or mycophenolate
• Azathioprine

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.3- 1

ME 3e: 328 • ME 4e: 328
 Membranous Glomerulonephritis

Characteristics
• One of the most common causes of
nephrotic syndrome in adults
• Most cases are idopathic
Risk factors
• Drugs (e.g., penicillamine)
• Infections (e.g., hepatitis B & C, syphilis)
• Systemic disease (e.g., SLE, diabetes)
• Malignant carcinomas (e.g., lung and colon)

© Katsumi M. Miyai, M.D., Ph.D., Regents of the

University of California. Used with permission.

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.3- 2

ME 3e: 328 • ME 4e: 328
 Membranous Glomerulonephritis

Diagnosis
• Biopsy findings
• Light microscopy
• Glomerular capillary wall thickening
• Basement membrane projections
(silver stain)

• Immunofluorescence
• Granular and linear IgG and C3
deposition

• Electron microscopy
• Subepithelial deposits along
the BM
• Podocyte foot process effacement © Katsumi M. Miyai, M.D., Ph.D., Regents
of the University of California. Used with
permission.

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.3- 3

ME 3e: 328 • ME 4e: 328
 Membranous Glomerulonephritis

Prognosis
• One-third show spontaneous remission
• One-third have persistent proteinuria,
preserved renal function
• One-third progress to end-stage
renal disease

© Katsumi M. Miyai, M.D., Ph.D., Regents of the

University of California. Used with permission.

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.3- 4

ME 3e: 328 • ME 4e: 328
 Minimal Change Disease

Characteristics
• Also called lipoid nephrosis and nil disease
• Most common cause of nephrotic syndrome
in children (15% in adults)
• Etiology unclear
• Complement, Ig, and immune complex
deposition not involved

Pathophysiology
• Altered cell-mediated T-cell response
• glomerular BM anions
© Katsumi M. Miyai, M.D., Ph.D., Regents of the
• Increased glomerular membrane University of California. Used with permission.

permeability

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.3- 5

ME 3e: 328 • ME 4e: 328
 Minimal Change Disease

Diagnosis
• Biopsy findings
• Light microscopy
• Normal glomeruli
• Lipid accumulation in proximal tubule
cells (lipoid nephrosis)
• Immunofluorescence
• Normal-appearing
• Electron microscopy
• Podocyte foot process effacement
• Microvillous transformation
• No immune complex deposits
Treatment: corticosteroids
© Katsumi M. Miyai, M.D., Ph.D., Regents of the

Prognosis: excellent University of California. Used with permission.

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.3- 6

ME 3e: 328 • ME 4e: 328
 Focal Segmental Glomerulosclerosis

Characteristics
• One of the most common causes of
nephrotic syndrome in adults
• Occurs at any age
• African American predominance in
the United States
• Can be idopathic
Risk factors
• Associated with:
• Other glomerular diseases
• Sickle cell anemia
• Heroin use
• AIDS Focal segmental glomerulosclerosis - high
mag.jpg,commons.wikimedia.org. Used with
• Morbid obesity permission.

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.3- 7

ME 3e: 328 • ME 4e: 328
 Focal Segmental Glomerulosclerosis
Diagnosis
• Biopsy findings
• Light microscopy
• Variable
• Focal segmental to global capillary
collapse, sclerosis, and hyalinization
• Immunofluorescence
• IgM and C3 deposition in sclerotic
segments
• Electron microscopy
• Podocyte foot process effacement in
non-sclerotic regions
• mesangial matrix in sclerotic regions Focal areas of
sclerosis and
Prognosis hyalinization

• Poor response to corticosteroids

• Most patients progress to chronic renal
failure Focal segmental glomerulosclerosis - high
mag,commons.wikimedia.org.

• High recurrence rate following transplant

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.3- 8

ME 3e: 328 • ME 4e: 328
 Secondary Glomerulopathy

Diabetes
• Glomerular pathology
• Nodular glomerulosclerosis
• Hyaline arteriosclerosis
• Microangiopathy
• Clinical presentation
• Microalbuminuria progressing to nephrotic syndrome
Systemic lupus erythematosus (SLE)
• Associated with various glomerular pathologies
• Clinical presentation
• Hematuria
• Nephritic and nephrotic syndrome
• May progress to renal failure

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.4- 1

ME 3e: 328 • ME 4e: 328
 Secondary Glomerulopathy

Amyloidosis
• Extra and intracellular deposition of insoluble
amyloid fibrils which alter normal function
• The result of various chronic inflammatory
disorders, systemic disease, neoplasms
• Glomerular accumulation nephrotic syndrome
• Light microscopy
• H&E: amorphous eosinophilic deposition
• Congo Red staining: apple-green birefringence
• Electron microscopy
• Fibrillar appearance

Treatment
• Treat underlying, predisposing condition © Katsumi M. Miyai, M.D., Ph.D., Regents of the
University of California. Used with permission.
• Support renal function

FA 2013: 490-491 • FA 2012: 517 • FA 2011: 468 NP03.4- 2

ME 3e: 328 • ME 4e: 328
Renal 4

Matthew B. Wilkinson, PhD, M4

Mount Sinai School of Medicine
NEPH4_1- 1
 Acute Tubular Necrosis

Characteristics
• Acute renal failure due to potentially reversible injury to the tubular epithelium
• Most common cause of acute renal failure in the United States
Clinical presentation
• Oliguria
• Increased BUN and creatinine
• Metabolic acidosis
• Hyperkalemia
• Urine cytology: muddy brown granular casts and epithelial casts

FA 2013: 496 • FA 2012: 522 • FA 2011: 470 NEPH4_1- 2

ME 3e: 329 • ME 4e: 329
 Acute Tubular Necrosis

Etiologies: ischemic (most common) and nephrotoxic

Ischemic ATN
• Due to a disruption of renal blood flow
• Associated with severe renal vasoconstriction, severe dehydration, and shock states
(hemorrhage and/or hypovolemia)
Nephrotoxic ATN
• Drugs (e.g., polymyxin, methicillin, gentamicin, sulfonamides)
• Radiographic contrast dyes
• Heavy metals
• Ethylene glycol
• Toxins (mushrooms, phenol, pesticides)
• Myoglobin
Prognosis: renal function recovers if patient survives the insult

FA 2013: 496 • FA 2012: 522 • FA 2011: 470 NEPH4_1- 3

ME 3e: 329 • ME 4e: 329
 Pyelonephritis

Characteristics
• Acute or chronic
• May be due to ascending bacterial UTI
• May involve renal pelvis, tubules, and interstitium
• Women > men
• Causative organisms:
• E. coli
• Proteus
• Klebsiella
• Enterobacterium
Histology
• Acute: inflammatory changes of interstitium and tubules
• Chronic: inflammation and fibrosis © Katsumi M. Miyai, M.D., Ph.D., Regents of the
University of California. Used with permission.
Risk factors
• Uretheral instrumentation
• Urinary obstruction
• Diabetes mellitus
• Vesicoureteral reflux
• Benign prostatic hypertrophy
• Pregnancy

FA 2013: 495 • FA 2012: 521 • FA 2011: 470 NEPH4_1- 4

ME 3e: 329 • ME 4e: 329
 Pyelonephritis

Signs and symptoms

• Fever • Frequency
• Chills • Urgency
• Malaise • Costovertebral angle
tenderness
• Dysuria
Labs
• Serum: increased WBC
• Urinalysis: pyuria and WBC casts
Treatment
• Antibiotics © Katsumi M. Miyai, M.D., Ph.D., Regents of the
University of California. Used with permission.
• Obstruction relief
• Supportive care

FA 2013: 495 • FA 2012: 521 • FA 2011: 470 NEPH4_1- 5

ME 3e: 329 • ME 4e: 329
 Tubulointerstitial Nephritis

Characteristics
• Acute or chronic inflammatory disease process
• Involves the tubules and interstitium
• Precipitated by various causes:
• Medications
• Infections
• Acute pyelonephritis
• SLE
• Lead poisoning
• Urate nephropathy
• Multiple myeloma
Treatment
• Treat the primary cause
• Supportive care

FA 2013: 495 • FA 2012: 521 • FA 2011: 470 NEPH4_1- 6

ME 3e: 329 • ME 4e: 329
 Drug-induced Interstitial Nephritis

Characteristics
• Drug-induced, acute, or chronic inflammatory disease process
• Analgesic nephropathy (most common cause of chronic disease)
• Acute drug-induced interstitial nephritis can be precipitated by diuretics, NSAIDs,
penicillin derivatives, sulfonamides, or rifampin
Pathophysiology
• Drugs act as haptens, inducing a hypersensitivity inflammatory response
• Can present up to 1-2 weeks following administration
Presentation: azotemia and pyuria with eosinophils
Complications
• Papillary necrosis
• Hypertension
• Chronic renal failure
• Transitional cell carcinoma

FA 2013: 495 • FA 2012: 521 • FA 2011: 470 NEPH4_1- 7

ME 3e: 329 • ME 4e: 329
 Urate Nephropathy

Characteristics
• Due to toxicity from elevated serum uric acid levels and deposition of urate
crystals into renal tubules and interstitium
Etiology
• Gout
• Lead poisoning
• Chemotherapy for leukemia and lymphoma (tumor lysis syndrome)
Clinical presentation: acute renal failure
Treatment
• Treat primary condition
• Support renal function
• IV fluids and allopurinol (with tumor lysis syndrome)

FA 2013: 493 • FA 2012: 519 • FA 2011: 470 NEPH4_1- 8

ME 3e: 329 • ME 4e: 329
 Renal Papillary Necrosis

Characteristics
• The sequelae of a multi-focal ischemic process in the papillae, causing
necrosis
• Multiple conditions are working synergistically to magnify the ischemic state
• Precipitated by previous renal inflammatory disease
• Parenchymal edema and compressed medullary vasculature
• Necrosis develops and is complicated by secondary infection, tissue-sloughing,
and urinary tract obstruction
• Classified as focal or diffuse depending on degree of vascular impairment
• Bilateral is most common form
• Disease is limited to inner medulla and papilla

FA 2013: 496 • FA 2012: 522 • FA 2011: 470 NEPH4_1- 9

ME 3e: 329 • ME 4e: 329
 Renal Papillary Necrosis

Clinical presentation
• Variable: acute or chronic (most common)
• Acute: rapidly progressive acute renal failure and sepsis
• Chronic: asymptomatic (may present with urinary tract obstruction or
pyelonephritis)
Treatment
• Adequate hydration to ameliorate ischemia
• Re-establish urinary drainage
• Stop nephrotoxic drugs
• Antibiotics
Prognosis
• Depends on etiology, number of factors involved, dispersal of necrosis, and
overall patient health

FA 2013: 496 • FA 2012: 521 • FA 2011: 470 NEPH4_1- 10

ME 3e: 329 • ME 4e: 329
 Diffuse Cortical Necrosis

Characteristics
• Acute, generalized cortical infarction
• Unilateral or bilateral
• Due to vasospasm and disseminated intravascular coagulation
• Associated with:
• Obstetric complication (e.g., abruptio placentae)
• Septic shock

Treatment
• Early dialysis after hemodynamic stabilization

FA 2013: 495 • FA 2012: 521 • FA 2011: 470 NEPH4_1- 11

ME 3e: 329 • ME 4e: 329
 Nephrolithiasis

Urolithiasis
• Affects 6% of the population: men>women
• Renal colic may occur if small stones pass into the ureter
• May also cause hematuria and urinary obstruction and predispose to infection
Calcium stones • 75% stones: most patients have hypercalciuria without hypercalcemia
• Calcium stones are radiopaque, they are the only ones that can be seen on x-
ray
Magnesium- • 15% of stones: occur after infection by urease-producing bacteria, such as
Proteus
ammonium • Urine becomes alkaline, resulting in precipitation of magnesium- ammonium
phosphate stones phosphate salts; may form large stones (e.g. staghorn calculi)

Uric acid stones • Seen in gout, leukemia and patients with acidic urine

Cystine stones • Very rare

• Associated with autosomal recessive amino acid transport disorder leading to
cystinuria
• Most stones are unilateral and formed in calyx, pelvis, bladder

FA 2013: 493 • FA 2012: 521 • FA 2011: 470 NEPH4_2- 1

ME 3e: 330 • ME 4e: 330
 Calcium Stones

Characteristics
• Settings that cause hypercalcuria:
• Cancer
• Hyperparathyroidism
• Ethylene glycol (i.e. antifreeze) or vitamin C abuse
• Can be seen on X-ray (radiopaque)

Calcium stones • 75% stones: most patients have hypercalciuria without

hypercalcemia
• Calcium stones are radiopaque, they are the only ones that can be
seen on x-ray

FA 2013: 493 • FA 2012: 521 • FA 2011: 470 NEPH4_2- 2

ME 3e: 330 • ME 4e: 330
 Renal Stones

Magnesium- • 15% of stones: occur after infection by urease-producing bacteria, such as

Proteus
ammonium • Urine becomes alkaline, resulting in precipitation of magnesium- ammonium
phosphate stones phosphate salts; may form large stones (e.g. staghorn calculi)

Uric acid stones • Seen in gout, leukemia and patients with acidic urine

Cystine stones • Very rare

• Associated with autosomal recessive amino acid transport disorder
leading to cystinuria
• Most stones are unilateral and formed in calyx, pelvis, bladder

FA 2013: 493 • FA 2012: 521 • FA 2011: 470 NEPH4_2- 3

ME 3e: 330 • ME 4e: 330
 Nephrolithiasis

Characteristics
• Mostly unilateral
• Formed in the calyx, pelvis, and bladder
Clinical presentation
• Renal colic
• Acute renal failure
Treatment
• Correct dehydration
• Treat infections
• Manage acute renal failure
• Remove with lithotripsy or endoscope

FA 2013: 493 • FA 2012: 521 • FA 2011: 470 NEPH4_2- 4

ME 3e: 330 • ME 4e: 330
 Benign Tumors

Cortical adenoma
• Small, encapsulated cortical nodules

• <3 cm

• Often asymptomatic

Angiomyolipoma
• Hamartoma

• Composed of fat, smooth muscle, and

blood vessels

• Associated with tuberous sclerosis Angiomyolipome der Niere CT., commons.wikimedia.org.

FA 2013: 494 • FA 2012: 520 • FA 2011: 469 NEPH4_3- 1

ME 3e: 331 • ME 4e: 331
 Renal Cell Carcinoma
Characteristics
• Also called hypernephroma
• Most commonly presents age 50-70
• Men > women
Risk factors
• Cigarette smoking
• Chronic analgesic use
• Asbestos
• Chronic renal failure
• Acquired cystic disease
• Von Hippel-Lindau disease
Presentation
• Commonly on the upper pole
• Usually solitary
• Contains areas of necrosis and hemorrhage
• Often invades renal vein and extend to the vena cava and heart

FA 2013: 494 • FA 2012: 520 • FA 2011: 469 NEPH4_3- 2

ME 3e: 331 • ME 4e: 331
 Renal Cell Carcinoma

Clinical presentation
• Hematuria, palpable mass, flank pain (10%)
• Symptoms from a paraneoplastic syndrome:
• Erythropoietin à polycythemia
• Renin à hypertension
• Corticosteroids à Cushing syndrome
• Parathyroid hormone à hypercalcemia
• Gonadotropin à feminization or
masculinization
• Amyloidosis
• Leukemoid reaction
• Eosinophilia
• Metastasis

FA 2013: 494 • FA 2012: 520 • FA 2011: 469 NEPH4_3- 3

ME 3e: 331 • ME 4e: 331
 Wilms’ Tumor

Characteristics
• Also called nephroblastoma
• Presents as abdominal mass in children age 2-5
• Most common renal malignancy of early childhood
• Due to deletion of tumor suppressor genes WT-1 and
WT-2 on chromosome 11

Risk factors
• WAGR syndrome
• Wilms’ tumor

• Aniridia (absence of the iris)

• Genital anomalies
© Katsumi M. Miyai, M.D., Ph.D., Regents of the
• Mental retardation University of California. Used with permission.

• Beckwith-Wiedemann syndrome

FA 2013: 494 • FA 2012: 520 • FA 2011: 469 NEPH4_3- 4

ME 3e: 331 • ME 4e: 331
 Wilms’ Tumor

Histology
Epithelial element
• Three elements:

• Metanephric blastemas

• Epithelial elements
(immature glomeruli and
Metanephric
tubules) blastema element

• Stromal elements
Stromal
element

Wilms’ tumor, commons.wikimedia.org.

FA 2013: 494 • FA 2012: 520 • FA 2011: 469 NEPH4_3- 5

ME 3e: 331 • ME 4e: 331
 Wilms’ Tumor

Characteristics
• Large, tan, often solitary
Treatment
• Surgery
• Chemotherapy
• Radiation
Prognosis
• Variable, long-term survival rates of up to 90%

© Katsumi M. Miyai, M.D., Ph.D., Regents of the

University of California. Used with permission.

FA 2013: 494 • FA 2012: 520 • FA 2011: 469 NEPH4_3- 6

ME 3e: 331 • ME 4e: 331
 Transitional Cell Carcinoma

Characteristics
• Most common tumor of the urinary tract
• Appears in renal calyces, pelvis, ureters, bladder
Risk factors
• Cigarette smoking
• Aniline dye exposure
• Phenacetin or cyclophosphamide exposure
Clinical presentation: hematuria
Treatment
• Surgery if indicated
• Chemotherapy
• Immunotherapy

FA 2013: 494 • FA 2012: 520 • FA 2011: 469 NEPH4_3- 7

ME 3e: 331 • ME 4e: 331
 Autosomal Recessive Polycystic Kidney Disease

Characteristics
• Also called childhood polycystic kidney disease

• Rare

• Presents in infancy with progressive renal failure

• Bilaterally enlarged kidneys

• Cortex and medullary cysts of the collecting ducts

• Associated with hepatic cysts and fibrosis

FA 2013: 498 • FA 2012: 523 • FA 2011: 472 NEPH4_4- 1

ME 3e: 327 • ME 4e: 327
 Autosomal Dominant Polycystic Kidney Disease

Characteristics
• Also called adult polycystic kidney disease
• Mutation of:
• PKD1 gene on chromosome 16
• PKD2 gene on chromosome 4
Clinical presentation
• Often asymptomatic until middle age
• Renal insufficiency
• Hematuria
• Hypertension
• Abdominal mass
• Flank pain
• Seen on ultrasound or CT © Katsumi M. Miyai, M.D., Ph.D., Regents of the University of
California. Used with permission.

FA 2013: 498 • FA 2012: 523 • FA 2011: 472 NEPH4_4- 2

ME 3e: 327 • ME 4e: 327
 Autosomal Dominant Polycystic Kidney Disease

Gross appearance
• Enlarged
• Bulging cysts
• Serous, turbid, or hemorrhagic fluid
Microscopic appearance
• Arise from tubular structures
• Surrounded by normal nephrons
Associated findings
• Liver cysts
• Circle of Willis berry aneurysms
• Mitral valve prolapse
• Colonic diverticula
Prognosis: most progress to end-stage © Katsumi M. Miyai, M.D., Ph.D., Regents of the University of
California. Used with permission.
renal failure by age 70

FA 2013: 498 • FA 2012: 523 • FA 2011: 472 NEPH4_4- 3

ME 3e: 327 • ME 4e: 327
 Other Cystic Diseases

Acquired polycystic kidney disease

• Seen in dialysis patients
• Associated with renal cell carcinoma
Medullary sponge kidney disease
• Causes multiple collecting duct cysts
• Associated with progressive fibrosis and renal insufficiency
Simple retention cysts
• Affects adults
• Benign
• Often found incidentally on CT scan
• Thin, non-enhancing
• Cortical
• Fluid-filled

FA 2013: 498 • FA 2012: 523 • FA 2011: 472 NEPH4_4- 4

ME 3e: 327 • ME 4e: 327
 Renal Failure

• Categorized by location and cause: prerenal, intrarenal, and post-renal

Prerenal
• Often due to impaired renal perfusion
• Hypotensive states (e.g., shock)
• Structural lesions (e.g., renal artery stenosis)
• Drug effect

Intrarenal
• Due to diseases that cause organ damage
Post-renal
• Due to urinary tract obstruction
Patient receiving dialysis 02.jpg, commons.wikimedia.org.

FA 2013: 496 • FA 2012: 523 • FA 2011: 472 NEPH4_5- 1

ME 3e: 370 • ME 4e: 370
 Renal Failure

Impaired waste-product excretion

• Uremia
Signs and symptoms
• Increased BUN and creatinine
• Vomiting
• Dyspnea
• Headache
• Convulsions
• Pericarditis
• Asterixis
• Encephalopathy
• Platelet dysfunction
• Coma

FA 2013: 496 • FA 2012: 523 • FA 2011: 472 NEPH4_5- 2

ME 3e: 370 • ME 4e: 370
 Renal Failure

Impaired regulation of Na+ and H2O balance

• Hyper- and hyponatremia
• Volume overload
Impaired regulation of K+
• Hyperkalemia

Impaired regulation of acid-base balance

• ↓ ability to excrete fixed-acid end products of metabolism
• Anion gap, metabolic acidosis

Impaired renal endocrine function

• ↓ activation of vitamin D
• Secondary hyperparathyroidism
• Renal osteodystrophy
• ↓ erythropoietin production à anemia

FA 2013: 497 • FA 2012: 522 • FA 2011: 472 NEPH4_5- 3

ME 3e: 370 • ME 4e: 370
 Acute Renal Failure

Acute pre-renal failure

• Acute onset hypovolemia (e.g., hemorrhage)
• Severe dehydration
• Congestive heart failure
• Initially, no intrinsic renal damage
• Can be fully reversible if etiology is treated
Acute intra-renal failure
• Etiologies vary:
• Glomerulonephritis
• Interstitial nephritis
• Ischemia
• Rhabdomyolysis
• Sepsis
Acute post-renal failure
• Acute urinary obstructive processes

FA 2013: 497 • FA 2012: 522 • FA 2011: 472 NEPH4_5- 4

ME 3e: 370 • ME 4e: 370
 Chronic Renal Failure

Characteristics
• Two common causes: uncontrolled hypertension and diabetes
• Chronic differs from acute in that organ damage is irreversible
• Surviving nephrons compensate for nephrons lost
• ↑ glomerular capillary pressure
• Hyperfiltration
• Compensatory mechanism promotes further nephron injury
• Chronic failure is categorized by:
• Level of GFR
• Presence or absence of proteinuria
• GFR ↓ to 20% à ↑ BUN

FA 2013: 497 • FA 2012: 522 • FA 2011: 472 NEPH4_5- 5

ME 3e: 370 • ME 4e: 370
 Chronic Renal Failure

Signs and symptoms

• Na+ and H2O retention à hypertension, CHF, peripheral edema
• Hyperkalemia
• Initially compensated by ↑ aldosterone secretion
• Progressive disease outpaces compensatory mechanisms
• End-stage patients require dialysis for K+ clearance
• Other symptoms:
• Normocytic anemia
• Platelet dysfunction
• Renal osteodystrophy

FA 2013: 497 • FA 2012: 522 • FA 2011: 472 NEPH4_5- 6

ME 3e: 370 • ME 4e: 370
 Renal Pharmacology

Matthew B. Wilkinson, PhD, M4

Mount Sinai School of Medicine

1 NEPH5_1-
 Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors

• Acetazolamide
• Dorzolamide
Function
• Block CA in proximal convoluted tubule
(brush border and intracellularly)
Uses
• Glaucoma (↓ aqueous humor production)
• Acute mountain sickness
• Metabolic alkalosis
• Urinary alkalinization to assist acidic
drug/toxin excretion
Side effects
• Acidosis
• Sulfa allergy
• Hypokalemia
• Parasthesia
• Hyperchloremia
• Ammonia toxicity
• Renal stones

FA 2013: 500 • FA 2012: 525 • FA 2011: 474 NEPH5_1- 2

ME 3e: 326 • ME 4e: 326
 Mannitol

Characteristics
• Freely filtered, poorly absorbed
• Increases tubular fluid osmolarity
• Prevents H2O reabsorption
Uses
• Induces osmotic diuresis in solute overload
states (e.g., hemolysis, rhabdomyolysis)
• Decreases intracranial pressure (head
trauma)
• Decreases intraocular pressure (glaucoma)
Side effects
• Pulmonary edema
• Hypovolemia
• Hypernatremia
• Nausea, vomiting

FA 2013: 500 • FA 2012: 525 • FA 2011: 474 NEPH5_1- 3

ME 3e: 326 • ME 4e: 326
 Loop Diuretics

• Furosemide, ethacrynic acid, torsemide

Function
• Inhibit Na+/K+/2Cl- co-transporter in the
thick ascending limb of loop of Henle
Uses
• Edematous states (e.g., CHF)
• Pulmonary edema
• Hypertension
• Hypercalcemia
Side effects
• Hypokalemic metabolic alkalosis
• Hypovolemia
• Ototoxicity
• Sulfa allergic reaction (furosemide)
• Use ethacrynic acid with sulfa allergy

FA 2013: 500 • FA 2012: 525 • FA 2011: 474 NEPH5_1- 4

ME 3e: 326 • ME 4e: 326
 Thiazide Diuretics

• Hydrochlorothiazide, metolazone
Function
• Inhibit Na/Cl- co-transporter in the
distal convoluted tubule
Uses
• HTN
• Edematous states
Side effects
• Hyponatremia
• Hypokalemic metabolic alkalosis
• Hyperglycemia
• Hyperuricemia
• Hypercalcemia
• Hyperlipidemia
• Sulfa allergic reaction

FA 2013: 501 • FA 2012: 525 • FA 2011: 474 NEPH5_1- 5

ME 3e: 326 • ME 4e: 326
 Potassium Sparing Diuretics

• Spironolactone, eplerenone, amiloride,

triamterene
Function
• Act on cortical collecting tubules
• Block aldosterone receptors
(spironolactone and eplerenone)
• Block sodium channels (amiloride and
triamterene)
Uses
• HTN and edema (to prevent K+loss)
• Aldosterone excess states
(spironolactone)
• Androgen excess states
Side effects
• Hyperkalemia
• Gynecomastia
• Excessive anti-androgen effect
FA 2013: 501 • FA 2012: 525 • FA 2011: 474 NEPH5_1- 6
ME 3e: 326 • ME 4e: 326
 ACE Inhibitors

• Captopril, enalapril, lisinopril

Function
• Inhibits angiotensin-converting enzyme
• Promotes vasodilation and diuresis (decreasing aldosterone)

Uses
• HTN
• CHF
• Diabetic nephropathy

FA 2013: 502 • FA 2012: 527 • FA 2011: 474 NEPH5_1- 7

ME 3e: 326 • ME 4e: 326
 ACE Inhibitors

Side effects
• Chronic cough
• Angioedema
• Proteinuria
• Taste changes
• Hypotension
• Fetal renal damage
• Rash
• Hypokalemia
Contraindications
• Bilateral renal artery stenosis (prevent efferent arteriolar constriction GFR)
Alternatives
• Losartan
• Angiotensin II receptor antagonists
• Used when ACE inhibitors are not tolerated or contraindicated
• Do not cause chronic cough

FA 2013: 502 • FA 2012: 527 • FA 2011: 474 NEPH5_1- 8

ME 3e: 326 • ME 4e: 326