Competency-Based Critical Care

Series Editors
John Knighton, MBBS, MRCP, FRCA Paul Sadler, MBChB, FRCA
Consultant Consultant
Intensive Care Medicine & Anaesthesia Critical Care Medicine & Anaesthesia
Portsmouth Hospitals NHS Trust Queen Alexandra Hospital
Portsmouth Portsmouth
UK UK

Founding Editor
John SP Lumley
Emeritus Professor of Vascular Surgery
University of London
London
UK
and
Honorary Consultant Surgeon
Great Ormond Street Hospital for Children NHS Trust (GOSH)
London
UK

Other titles in this series

Sepsis
Simon Baudouin (Ed.)
Sara Blakeley (Ed.)

Renal Failure and

Replacement
Therapies
Sara Blakeley, BM, MRCP, EDIC
Queen Alexandra Hospital
Portsmouth
Hampshire, UK

British Library Cataloguing in Publication Data

Renal Failure and Replacement Therapies.—(Competency-based critical care)
1. Kidneys—Diseases 2. Kidneys—Diseases—Treatment
3. Acute renal failure 4. Acute renal failure—Treatment
I. Blakeley, Sara
616.6′1
ISBN-13: 9781846289361

Library of Congress Control Number: 2007927934

Competency-Based Critical Care Series ISSN 1864-9998

ISBN: 978-1-84628-936-1 e-ISBN: 978-1-84628-937-8

© Springer-Verlag London Limited 2008

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Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

Chapter 1 Assessment of Renal Function . . . . . . . . . . . . . . . . . . . . . 1

Mohan Arkanath

Chapter 2 Imaging of Acute Renal Failure—A Problem-Solving

Approach for Intensive Care Unit Physicians . . . . . . . . 7
Tom Sutherland

Chapter 3 Drug-Induced Renal Injury . . . . . . . . . . . . . . . . . . . . . . . . 14

Sara Blakeley

Chapter 4 Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Sara Blakeley

Chapter 5 Medical Management of Acute Renal Failure . . . . . . . . 26

Nerina Harley

Chapter 6 Acute Renal Failure in the Surgical Patient . . . . . . . . . . 33

Marlies Ostermann

Chapter 7 Rhabdomyolysis and Compartment Syndrome . . . . . . . 38

Laurie Tomlinson and Stephen Holt

Chapter 8 Multisystem Causes of Acute Renal Failure . . . . . . . . . . 42

Tim Leach

Chapter 9 Therapeutic Plasma Exchange . . . . . . . . . . . . . . . . . . . . . 49

Tim Leach

Chapter 10 Renal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . 51

John H. Reeves

Chapter 11 Technical Aspects of Renal Replacement Therapy . . . . 57

Sara Blakeley

v
vi Contents

Chapter 12 End-Stage Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Emile Mohammed

Chapter 13 Clinical Hyperkalemia and Hypokalemia . . . . . . . . . . . . 71

Harn-Yih Ong

Chapter 14 Clinical Hyponatremia and Hypernatremia . . . . . . . . . . 77

Himangsu Gangopadhyay

Chapter 15 Clinical Metabolic Acidosis and Alkalosis . . . . . . . . . . . 81

Sara Blakeley

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Contributors

Mohan Arkanath, MRCP School of Clinical Medicine and Research

Consultant Nephrologist Queen Elizabeth Hospital & Cavehill Campus
Doncaster Royal Infi
firmary Bridgetown, Barbados
Doncaster, UK
Harn-Yih Ong
Sara Blakeley, BM, MRCP, EDIC Registrar Intensive Care
Queen Alexandra Hospital St Vincent’s Hospital
Portsmouth Melbourne, Victoria
Hampshire, UK Australia
Nerina Harley, MBBS, MD, PGDIPEcho,
FRACP, FJFICM Marlies Ostermann
Intensive Care Consultant Consultant Nephrology and Critical Care
The Royal Melbourne Hospital Intensive Care Unit
Victoria, Australia St Thomas’ Hospital
London, UK
Stephen Holt, PhD, FRCP
Consultant Nephrologist and Honorary John H. Reeves, MD, MBBS, FANZCA, FJFICM,
Senior Lecturer EDIC
Sussex Kidney Unit Consultant in Intensive Care and Anaesthetics
Brighton and Sussex University Hospitals Department of Anaesthesia and Pain
Royal Sussex County Hospital Management
Brighton, UK Alfred Hospital
Melbourne, Victoria
Himangsu Gangopadhyay, MD, MBBS, Australia
FFARCS(Ireland), FJFICM
Consultant in Intensive Care
Tom Sutherland, MBBS (Hons)
Frankston Hospital
Radiology Registrar
Frankston, Victoria, Australia
St Vincent’s Hospital
Tim Leach, BM, FRCP Melbourne, Victoria
Consultant Nephrologist Australia
Wessex Renal and Transplant Unit
Queen Alexandra Hospital Laurie Tomlinson, MRCP
Portsmouth, UK Specialist Registrar Nephrology
Sussex Kidney Unit
Emile Mohammed, MB, ChB, MRCP (UK) Brighton and Sussex University Hospitals
Lecturer in Medicine (University of the West Royal Sussex County Hospital
Indies) and Consultant Nephrologist Brighton, UK

vii
1
Assessment of Renal Function
Mohan Arkanath
Normal Functions of the Kidney
To be able to assess a degree of renal function or
dysfunction, it is important to first
fi consider the
normal functions of the kidney:
1. Maintenance of body composition: The
volume of fl fluid in the body, its osmolarity, elec-
trolyte content, concentration, and acidity are all
regulated by the kidney via variation in urine
excretion of water and ions. Electrolytes regulated
by changes in urinary excretion include sodium,
potassium, chloride, calcium, magnesium, and
phosphate.
2. Excretion of metabolic end products and
foreign substances: The most notable are urea and
a number of toxins and drugs.
3. Production and secretion of enzymes and
hormones:
a. Renin: See Figure 1.1.
b. Erythropoietin: A glycosylated, 165-amino
acid protein produced by renal cortical
interstitial cells that stimulates maturation
of erythrocytes in the bone marrow.
c. 1, 25-Dihydroxyvitamin D3: The most active
form of vitamin D3, it is formed by proximal
tubule cells. This steroid hormone plays an
important role in the regulation of body
calcium and phosphate balance.
The Role of the Kidney in Homeostasis
Maintenance of body fluid fl composition and
volume are important for many functions of the
body. For example, cardiac output and blood pres-
sure are dependent on optimum plasma volume,
and most enzymes function best in narrow ranges
of pH or ion concentration.
The kidneys take up the role of correcting any
alterations in the composition and volume of body
fluids that occur as a consequence of food intake,
fl
metabolism, environmental factors, and exercise.
In healthy individuals, these corrections occur in
a matter of hours, and body fluid
fl volume and the
concentration of most ions return to normal set
points. In many disease states, however, these
regulatory processes are disturbed, resulting in
persistent deviations in body fl fluid volume and
composition.
Body Fluid Composition
A large proportion of the human body is com-
posed of water (Table 1.1). Adipose tissue is low in
water content and, hence, obese individuals have
a lower body water fraction than lean individuals.
Because of slightly greater fat content, women
generally contain less water than men.
Clinical Evaluation of Renal Function
Glomerular filtration
fi rate (GFR) is generally con-
sidered the best measure of renal function; it is the
sum of filtration
fi rates of all of the functioning
nephrons. It is defined
fi as the renal clearance of a
particular substance from plasma, and is expressed
as the volume of plasma that can be completely
cleared of that substance in a unit of time. In the
following sections, we will compare the advantages
1
2 M. Arkanath

Renin TABLE 1.2. Other factors altering blood urea or serum creatininea
Angiotensinogen Angiotensin Salt balance Increased level Decreased level
(Plasma globulin) (Vasoconstrictor) and blood
Urea Prerenal causes (e.g., Cirrhosis
pressure
control congestive heart failure, Protein malnutrition
volume contraction) lead Water excess (e.g.,
FIGURE 1.1. Production and secretion of enzymes and hormones to increased tubular SIADH, saline
for renin. reabsorption infusion) leads to
• Gastrointestinal bleeding reduced tubular
• Catabolic state reabsorption
• Corticosteroids
• Hyperalimentation
and disadvantages of the various methods avail- • Tetracyclines
able for GFR estimation or quantification.
fi Creatinine Overproduction (e.g., Decreased muscle
rhabdomyolysis, vigorous mass
Clearance Urine mg/dL Volume mL/min ) sustained exercise,
= anabolic steroids, dietary
(mL/min
/ i ) Plasma mg/dL ) supplements such as
creatine)
Where x is the substance being cleared. Blocked tubular secretion
Features of an ideal marker for GFR (e.g., drugs such as
trimethoprim and
determination:
cimetidine)
• Appears endogenously in the plasma at a con- Assay interference (e.g.,
ketosis and drugs such as
stant rate
cephalosporins, flucytosine,
• Is freely filtered by the glomerulus methyldopa, levodopa,
• Does not undergo reabsorption or secretion by and ascorbic acid)
the renal tubule a
SIADH, syndrome of inappropriate ADH secretion.
• Is not eliminated by extrarenal routes

Urea
Creatinine
Urea was first isolated in 1773, and urea clearance
as a surrogate marker for GFR introduced in 1929. Creatinine is a metabolite of creatine and phos-
Although urea measurement is performed fre- phocreatine found in skeletal muscle. It is a
quently, it is well recognized that its many draw- small molecule that is not protein bound and,
backs make it a poor measure of renal function hence, freely filtered by the glomerulus. It does,
(see Table 1.2). For example, the rate of production however, undergo tubular secretion which is
is influenced
fl by factors such as the availability variable (see Table 1.2). Creatinine production
of nitrogenous substrates, and the rate of reab- can vary in an individual over time with
sorption in the tubules can be affected by volume muscle mass changes or acutely with massive
status. myocyte turnover. There are also age- and sex-
associated differences in serum creatinine (Sα)
concentration; it is lower in the elderly and in
women.
TABLE 1.1. Body fluid compartment volumesa The ratio between serum urea and creatinine
Example for a 60-kg patient can be useful when assessing the patient with
TBW = 60% × body weight 60% × 60 kg = 36 L
acute renal failure. Under normal circumstances,
ICW = 2/3 TBW / × 36 L = 24 L
23 the ratio between urea and creatinine is 10 : 1 but
ECW = 1/3 TBW 1/3× 36 L = 12 L this value can rise to greater than 20 : 1 when the
Plasma water = 1/4 ECW 1/4 × 12 L = 3 L
extracellular volume is contracted. A volume-con-
Blood volume = Plasma water ÷ 3 L ÷ (1 − 0.40) = 6.6 L tracted state ((prerenal) is a “sodium avid” state
(1 − hematocrit)
and promotes proximal tubular and distal nephron
a
TBW, total body water; ICW, intracellular water; ECW, extracellular water. reabsorption of urea but not creatinine. Acute
1. Assessment of Renal Function
tubular necrosis (ATN) will have a urea-to-creati-
nine ratio of 10 : 1 because tubular reabsorption of
urea is not preferentially increased.
Assessment of GFR
Sα has become a standard measure of renal func-
tion because of its convenience and low costs;
however, it is crude marker of GFR. A 24-hour
creatinine clearance (Cα) is often used in practice
as a measure of the GFR because creatinine is
freely fi
filtered and not reabsorbed by the tubule.
However, approximately 15% of urinary creati-
nine is a result of tubular secretion and, thus, this
method overestimates GFR. The other problems
with Cα are incomplete urine collection and
increasing creatinine secretion. Inulin clearance
is traditionally considered the “gold standard”
for the measurement of GFR (1). It is one of the
most accurate measures of renal function, but
the inconvenience of administration, cost, and
limited supply of inulin preclude its use in routine
practice.
Estimated Ca: The Cockroft and Gault
Formula (2)
This formula is used to estimate Cα at the bedside
using age of the patient and Sα value (both corre-
late inversely with GFR), and the ideal body weight
(IBW) of the patient.
This formula can used only when the Sα value
is in a steady state and not when it is rapidly
changing, as in acute renal failure. It has also been
shown that Sα and estimations of GFR using
various formulae are often inaccurate in critically
ill patients (3). Although they may give an esti-
mate, their limitations should be remembered
when assessing renal function in patients on the
intensive care unit. Other factors, such as urine
output, clearance of acid and electrolytes, and rate
of change of serum urea and creatinine should all
be considered together.
The Cockroft and Gault formula is:
(140 − patient age weight in kg )
Estimated C α =
(Sα in μmol/L )
Multiply by 0.85 for women, 1.23 if male.
3
Urinalysis (4, 5)
The microscopic examination of the urinary sedi-
ment is an indispensable part of the work-up of
patients with renal insuffificiency, proteinuria, hema-
turia, urinary tract infections, or kidney stones. A
careful urinalysis has been referred to as a “poor
man’s renal biopsy.” The urine should be collected
as a midstream catch or fresh catheter specimen,
and because the urine sediment can degenerate
with time, it should be examined soon after collec-
tion. Urinalysis should include a dipstick examina-
tion for specifi fic gravity, pH, protein, hemoglobin,
glucose, ketones, nitrites, and leucocytes. This
should be followed by microscopic examination if
there are positive fi findings. Microscopic examina-
tion should check for all formed elements: crystals,
cells, casts, and infecting organisms.
Appearance
Normal urine is clear, with a faint yellow tinge
caused by the presence of urochromes. As it be-
comes more concentrated, its color deepens. Biliru-
bin, other pathologic metabolites, and a variety of
drugs may discolor the urine or change its smell.
Specific Gravity
The urine specificfi gravity is a conveniently deter-
mined but inaccurate surrogate of osmolality. Spe-
cific
fi gravities of 1.001 to 1.035 correspond to an
osmolality range of 50 to 1000 mOsm/kg. A spe-
cific
fi gravity near 1.010 connotes isosthenuria
(urine osmolality matching plasma).
The specific fi gravity is used to determine
whether the urine is, or can be, concentrated.
During a solute diuresis accompanying hypergly-
cemia, diuretic therapy, or relief of obstruction,
the urine is isosthenuric. In contrast, with a water
diuresis caused by overhydration or diabetes
insipidus, the specifi
fic gravity is low. It is also useful
in differentiating between prerenal cause of renal
failure (high) and ATN.
Volume
In health, the volume of urine passed is primarily
determined by diet and fluid
fl intake. The mini-
mum amount passed to stay in fluid fl balance is
4 M. Arkanath

determined by the amount of solute being excreted TABLE 1.3. Causes of hematuriaa
(mainly urea and electrolytes), and the concen- Glomerular disease Mesangial IgA nephropathy
trating ability of the kidneys. In disease, impair- Thin basement membrane disease
ment of concentrating ability requires increased Mesangial proliferative GN
volumes of urine to be passed for the same solute Membranoproliferative GN
Crescentic GN
output.
Systemic lupus erythematosus
Post streptococcal GN
• Oliguria is defifined as the excretion of less than Infective endocarditis
300 mL/d of urine, and is often caused by intrin- Alport’s syndrome
sic renal disease or obstructive uropathy. Vascular and Acute hypersensitivity interstitial nephritis
tubulointerstitial Tumors (renal cell carcinoma, Wilm’s tumor,
• Anuria suggests urinary tract obstruction until
disease leukemia)
proven otherwise. Polycystic kidney disease
• Polyuria is a persistent, large increase in urine Malignant hypertension
output, usually associated with nocturia. Poly- Analgesic nephropathy
uria is a result of excessive intake of water (e.g., Diabetes mellitus
Obstructive uropathy
compulsive water drinking), increased excretion
Urinary tract diseases Carcinoma (renal pelvis, ureter, bladder,
of solute (hyperglycemia and glycosuria), a urethra, prostate)
defective renal concentrating ability, or failure Calculi
of production of antidiuretic hormone (ADH). Retroperitoneal fibrosis
Tuberculosis
Cystitis
Chemical Testing Drugs (e.g., cyclophosphamide)
Trauma
Blood Benign prostatic hypertrophy
Urethritis
Hematuria may be macroscopic or microscopic Platelet defects (e.g., idiopathic or drug
(Table 1.3). Currently used dipstick tests for blood induced thrombocytopenic purpura)
are very sensitive, being positive if two or more a
GN, glomerulonephritis.
red cells are visible under the high-power fi field
(HPF) of a light microscope. A disadvantage is that
dipstick testing cannot distinguish between blood
and free hemoglobin. A positive dipstick has to be
concentration of 150 mg/L or more in urine. They
followed by microscopy of fresh urine to confirm fi
react primarily to albumin and are insensitive to
the presence of red cells and to exclude rare condi-
globulin or Bence-Jones protein. False-positive
tions such as hemoglobinuria and myoglobinuria.
results are common with iodinated contrast
In female patients, it is essential to enquire whether
agents; hence, urine testing should be repeated
the patient is menstruating.
after 24 hours. The normal rate of excretion of
Abnormal numbers of erythrocytes in the urine
protein in urine is 80 ± 24 mg/24 h in healthy indi-
may arise from anywhere from the glomerular
viduals, but protein excretion rates are somewhat
capillaries to the tip of the distal urethra. Dysmor-
higher in children, adolescents, and in pregnancy.
phic erythrocytes tend strongly to be associated
Fever, severe exercise, and the acute infusion of
with a glomerular source. Abnormal proteinuria
hyperoncotic solutions or certain pressor agents
along with dysmorphic erythrocytes is a reliable
(e.g., angiotensin II or norepinephrine) may
sign of glomerular disease. Urinary tract abnor-
transiently cause abnormal protein excretion
malities lead to microscopic or macroscopic
in normal individuals.
hematuria but the erythrocytes exhibit normal
The protein in normal and abnormal urine is
morphology.
derived from three sources:
Protein
1. Plasma proteins filtered
fi at the glomerulus and
Proteinuria is one the most common signs of renal escaping proximal tubular reabsorption.
disease (Table 1.4). Most reagent strips detect a 2. Proteins normally secreted by renal tubules.
1. Assessment of Renal Function 5

TABLE 1.4. Causes of proteinuria based on pathophysiologic mechanisma

Glomerular proteinuria Primary glomerular disease Secondary glomerular disease
• Minimal change disease • Drugs: e.g., mercurials, gold compounds, heroin,
• Mesangial proliferative GN penicillamine, probenecid, captopril, lithium, NSAID
• Focal and segmental glomerulosclerosis (FSGS) • Allergens: bee sting, pollen, milk
• Membranous GN • Infections: bacterial, viral, protozoal, fungal, helminthic
• Mesangiocapillary GN • Neoplastic: solid tumors, leukemia
• Fibrillary GN • Multisystem: SLE, Henoch-Schonlein purpura, amyloidosis
• Crescentic GN • Heredofamilial: diabetes mellitus, congenital nephritic
syndrome, Fabry’s disease, Alport’s syndrome
• Others: febrile proteinuria, postexercise proteinuria, benign
orthostatic proteinuria
Tubular proteinuria Endogenous toxins: light chain damage to
proximal tubular, lysozyme (leukemia)
Exogenous toxins and drugs: mercury, lead,
cadmium, outdated tetracycline
Tubulointerstitial disease SLE
Acute hypersensitivity interstitial nephritis
Acute bacterial pyelonephritis
Obstructive uropathy
Chronic interstitial nephritis
Overflow proteinuria Multiple myeloma
Light chain disease
Amyloidosis
Hemoglobinuria
Myoglobinuria
Certain colonic or pancreatic carcinomas
Tissue proteinuria Acute inflammation of urinary tract
Uroepithelial tumors
a
GN, glomerulonephritis; NSAID, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus.

3. Proteins derived from the lower urinary tract Bacteriuria

or leaking into the urine as a result of tissue
Dipsticks detect nitrites produced from the reduc-
injury or inflammation.
fl
tion of urinary nitrate by bacteria and also leuco-
cyte esterase, an enzyme specificfi for neutrophils.
Most patients with persistent proteinuria should
Detection of both nitrites and leucocytes on dip-
undergo a quantitative measurement of protein
stick has a high predictive value for urinary tract
excretion, with a 24-hour urine measurement.
infection.
A protein excretion rate greater than 3.5 g/d
(nephrotic range proteinuria) should prompt
further investigations to ascertain the exact cause Urine Microscopy
of the proteinuria with measurements of urea,
An unspun sample of urine may be examined
creatinine, liver function tests (most impor-
under low- or high-power microscopy, however, a
tantly, serum albumin), and a full blood count.
spun sample is a more accurate. Urine is centri-
A defifinitive diagnosis has to be achieved with a
fuged, the supernatant is discarded, and an aliquot
renal biopsy. Nephrotic syndrome is definedfi as a
of the residue is placed on a glass slide using a
combination of proteinuria in excess of 3 g/d,
Pasteur pipet. All patients suspected of having
hypoalbuminemia, edema, and hyperlipidemia.
renal disease should have urine microscopy.

Glucose White Blood Cells

Renal glycosuria is uncommon and any positive The presence of 10 or more white blood cells per
test requires evaluation of diabetes mellitus. cubic millimeter is abnormal and indicates an
6 M. Arkanath
infl
flammatory reaction within the urinary tract.
Most commonly this represents a urinary tract
infection but it may also be found with a sterile
sample in patients on antibiotic therapy, or with
kidney stones, tubulointerstitial nephritis, papil-
lary necrosis, or tuberculosis.
Red Blood Cells
As mentioned previously, erythrocytes can find fi
their way into the urine from any source between
the glomerulus to the urethral meatus. The pres-
ence of more than two to three red blood cells per
HPF is usually pathological. Erythrocytes origi-
nating in the renal parenchyma are dysmorphic,
whereas those originating in the collecting system
retain their uniform biconcave shape.
Casts
Based on their shape and origin, casts are appro-
priately named. Hyaline casts are found in con-
centrated urine, during febrile illnesses, after
strenuous exercise, and with diuretic therapy.
They are not indicative of renal disease. Red cell
casts indicate acute glomerulonephritis. White cell
casts indicate infection or infl
flammation, and are
seen in pyelonephritis and interstitial nephritis.
Renal tubular casts are found in cases of ATN and
interstitial nephritis. Coarse granular casts are
nonspecificfi and represent the degeneration of a
cast with a cellular element. Finally, broad waxy
casts are indicative of stasis in the collecting
tubules and are seen in chronic renal failure.
References
1. Brown SC, O’Reilly PH. Iohexol clearance for the
determination of glomerular filtration
fi rate in clinical
practice: evidence for a new gold standard. J Urol.
1991; 146(3): 675–679.
2. Cockroft DW, Gault MH. Prediction of creatinine
clearance from serum creatinine. Nephron. 1976; 16:
31–41.
3. Hoste EA, Damen J, Vanholder RC, et al. Assessment
of renal function in recently admitted critically ill
patients with normal serum creatinine. Nephrol Dial
Transplant. 2005; 20(4): 747–753.
4. Henry JB, Lauzon RB, Schaumann GB. Basic exami-
nation of the urine. Clinical Diagnosis and Manage-
ment by Laboratory Methods. 19th ed. Philadelphia:
Saunders. 1991.
5. Graff L. A Handbook of Routine Urinalysis. Philadel-
phia: Lippincott. 1983.
Suggested Reading
Davison AM, Cameron S, Grunfeld J-P, et al. Oxford
Textbook of Clinical Nephrology. 3rd ed. Oxford:
Oxford University Press. 2005.
Greenberg A, Cheung AK, Coffman TM, et al. Primer on
Kidney Diseases. 3rd Ed. London: Academic Press.
2001.
Guyton AC. Textbook of Physiology. 8th Ed. New York:
Saunders. 1991.
2
Imaging of Acute Renal Failure—A
Problem-Solving Approach for Intensive
Care Unit Physicians
Tom Sutherland
Acute renal failure (ARF) is a common problem in
hospitalized patients. It has a variety of causes,
traditionally divided into prerenal, renal, and
postrenal. A further classification
fi can be made
into medical and surgical causes, with the later
defined
fi as patients who will benefifit from mechan-
ical intervention.
Acute tubular necrosis (ATN) is the most
common cause of ARF (approximately 45%) and
postrenal obstruction accounts for roughly 10% of
presentations (1). A variety of imaging modalities
may be used to help diagnose the cause, or, if this
is not possible, to differentiate medical from sur-
gical causes. ARF in renal transplants will not be
addressed.
Acute or Chronic Renal Failure?
This is best answered by clinical assessment rather
than with imaging. Imaging findingsfi in chronic
renal failure are nonspecific fi and essentially char-
acterized by small kidneys. X-rays can show the
renal outline, calcifi fication, renal bone disease and
effects of hyperparathyroidism. Ultrasound is an
excellent modality for structural imaging because
it is able to detect reduced renal parenchyma, scar-
ring (usually secondary to previous refluxfl nephro-
pathy), calcification,
fi and polycystic kidneys. The
echogenicity of the cortex can be assessed with a
hyperechoic cortex (normal cortex is hypoechoic
to liver), present in most causes of chronic renal
failure; adult polycystic kidney disease being the
notable exception. Noncontrast computed tomo-
graphic (CT) and magnetic resonance imaging
(MRI) scans analyze renal structure and renal
artery calcifification, and dynamic gadolinium-
enhanced MRI renal studies allow functional
assessment. Other functional studies, such as mer-
captoacetyltriglycine (MAG3) and diethylene tri-
amine pentaacetic acid (DTPA) show reduced renal
uptake and delayed excretion of tracer.
A further role of imaging is to determine the
number of present and functioning kidneys. For
ARF to occur in previously normal kidneys, the
underlying cause must be a bilateral process, or
else a single functioning kidney must be compro-
mised (Figure 2.1).
Acute Tubular Necrosis
Ultrasound will usually show enlarged kidneys
with a smooth contour caused by interstitial
edema, no hydronephrosis, and renal arterial and
venous flow. The examination of choice in sus-
pected ATN is a MAG3 nuclear medicine study.
Scintigraphic examinations in ATN using Tc-
99m-MAG3 demonstrate relatively well-preserved
on-time renal perfusion, and delayed tracer
uptake, often with a continuing activity accumula-
tion curve. If the activity curve does have a
maximum, the time to maximum is delayed (2).
Excretion of tracer into the collecting system is
delayed and reduced, but there is no obstruction
to drainage of the collecting systems. If excre-
tion and drainage occur, the time from maximal
activity to half-maximal activity (or another
quantitative measure of tracer excretion) is pro-
longed. What underlies this scintigraphic pattern
7
 8 T. Sutherland

Liver Renal sinus Liver Renal cortex Dialysis fluid

A B

FIGURE 2.1. A, ultrasound of a normal kidney. Smooth cortex, hypoechoic to liver. B, chronic renal failure with a small irregular kidney
with hyperechoic cortex compared with liver (anechoic area around the liver is peritoneal dialysis fluid).

FIGURE 2.2. MAG3 study showing progressive accumulation of peak as the kidneys are perfused and then activity declines as
tracer in the renal cortex indicating normal perfusion but no excre- tracer is excreted and passes into the bladder. Lt, left; Rt, right;
tion, consistent with ATN. A normal activity curve should initially Bkg, background.
2. Imaging of Acute Renal Failure
is parenchymal retention of MAG3 by the remain-
ing viable tubular cells, whereas tubular obstruc-
tion prevents drainage of tracer into the collecting
system. The tubular cells continue to take up tracer
while they are viable and, thus, the cortical activity
can be used to monitor disease progress, with pro-
gressive loss of cortical activity being a poor prog-
nostic indicator (Figure 2.2).
If a MAG3 study cannot be performed, ultra-
sound will demonstrate a cortex of normal echo-
genicity with either a normal or hypoechoic
medulla. The renal arteries can also be interro-
gated for the renal index (RI), which is an objec-
tive measure of the resistance to renal perfusion.
RI is defifined as (systolic velocity minus diastolic
velocity) divided by systolic velocity, and has
been heavily investigated to determine whether
elevation in RI can differentiate ATN from renal
hypoperfusion not yet complicated by ATN. Unfor-
tunately, there have been mixed results and, gener-
ally, RI has inadequate specifi ficity for routine
clinical use.
Glomerulonephritis and Acute
Interstitial Nephritis
Clinical history and urinalysis plays a vital role in
differentiating GN and acute interstitial nephritis
(AIN) with the “gold standard” diagnostic test
being a renal biopsy. The main role of imaging is
to detect structural signs of chronic renal disease
and to exclude other causes of ARF. MAG3 studies
will show poorly functioning kidneys, but no
accumulation pattern and also no obstruction
to drainage. Edema can sometimes be demon-
strated with ultrasound, manifest as hypoechoic
large kidneys. If there is a clinical suspicion to
direct imaging, a careful search may also find fi
other signs of the underlying cause, for example,
pulmonary hemorrhage in Goodpasture’s syn-
drome and pulmonary nodules in Wegener’s
granulomatosis.
Ureteric Obstruction
For obstruction to produce ARF it must be bilat-
eral or affecting a single functioning kidney. This
is the classical cause of surgical ARF.
9
Ultrasound is the first-line
fi test for obstruction.
It is radiation free, portable, is not nephrotoxic,
and can simultaneously gather other structural
information. Obstructed kidneys are typically
normal sized with dilated ureters, renal pelvis, and
calyceal systems. These urine-filled fi structures
appear as anechoic areas with posterior acoustic
enhancement. Caution is required in interpreta-
tion because a ureter and renal pelvis may be
dilated without being obstructed (a false positive).
This can occur after previous obstruction that
leaves a residual “baggy” collecting system, or as
an anatomical variant (enlarged extrarenal pelvis).
Differentiation can often be made by examining
the bladder for ureteric jets, which are the periodic
expulsion of urine from the ureter into the bladder,
which can be detected by Doppler imaging. If ure-
teric jets are present, then there is not a complete
obstruction on that side (3). False negatives can
occur in the hyperacute setting if the renal collect-
ing system has not had time to dilate, or if the
system has spontaneously decompressed by forni-
ceal or renal pelvis rupture (Figure 2.3).
Noncontrast CT scan is the gold standard for
detecting ureteric calculi (4). The ureters can
usually be traced between the kidney and bladder,
and a hyperdense stone can be seen at the distal
site of hydroureter. More than 99% of renal calculi
are radiopaque on CT scan, however, xanthine
calculi may be radiolucent and stones associated
with indinavir are radiolucent. The obstructed
kidney is typically edematous (i.e., swollen) with
Cortex Renal pelvis Calyx
FIGURE 2.3. Ultrasound of a hydronephrotic kidney. Size is normal
with dilated renal pelvis and calyces (the anechoic central part).
10
perirenal stranding. The administration of con-
trast is contraindicated in ARF because of its
potential nephrotoxicity. Although not as helpful
as a contrast-enhanced CT scanning, a non-
contrast study can usually detect many extrinsic
compressing masses, such as retroperitoneal
tumors, or cervical or colon carcinomas, that
may produce bilateral obstruction. Complications
related to trauma, such as urinoma or renal pedicle
avulsions, are also visible even without contrast
(Figure 2.4).
Scintigraphic imaging with either Tc-99m-
MAG3 or Tc-99m-DTPA can detect ureteric
obstruction by showing a dilated collecting system
with delayed drainage of tracer. The collecting
system is outlined down to the level of the obstruc-
tion with no or limited tracer draining beyond
this. The negative predictive value of nuclear med-
icine scanning is extremely high, with a normal
study virtually excluding obstruction. Of course,
sufficient
fi tracer must be present in the collecting
system to reach the obstruction point. Reduced
urine production associated with renal failure
may deliver so little tracer into the collecting
system that obstruction cannot be excluded. The
lower the patients glomerular fi filtration rate (GFR),
the higher the probability of having an indetermi-
nate study (5). Further, an enlarged but non-
obstructed collecting system may mimic delayed
drainage. In this latter situation, the specifificity of
the examination is increased by administering
20 mg (or sometimes 40 mg) of frusemide IV, and
scanning for a further 20 minutes. A baggy non-
obstructed system will promptly wash out, and the
delay in washout after frusemide correlates with
Arrow heads are fatty stranding. Right ureteric calculus
T. Sutherland
the degree of obstruction. Once again, it must be
stressed that the only way mechanical obstruction
can produce ARF in previously normal kidneys is
by affecting a solitary functioning kidney, or by
blocking both kidneys simultaneously.
Renal Artery Dissection or Occlusion
Each kidney is normally supplied by a single renal
artery that arises from the aorta before dividing
into an average of five segmental end-arterial
branches. Arterial dissection and occlusion is
another surgical cause of ARF. Renal infarction
may be caused by blunt trauma with avulsion of
the renal pedicle or penetrating trauma transect-
ing the renal artery. Renal artery dissection may
be iatrogenic, occurring during endovascular
intervention. Bilateral dissection or exclusion
from the circulation can occur secondary to an
aortic dissection. Suspicion of a dissection or
occlusion is virtually the only differential diagno-
sis that warrants the administration of intra-
venous CT contrast in the setting of ARF in which
MRI scanning is unavailable. An arterial phase CT
scan highlights the renal artery anatomy, demon-
strating the intimal fl
flap of dissection and can also
detect signs of renal infarction and lacerations (6)
(Figure 2.5).
Magnetic resonance angiography (MRA) has
excellent sensitivity and specifi ficity for detecting
dissection and occlusion of proximal renal arter-
ies. Segmental arteries are less well visualized,
however, unilateral or isolated segmental pathol-
ogy will not produce ARF. MR contrast is much
Inferior pole left kidney
FIGURE 2.4. Noncontrast CT scan with
complete right-sided and moderate left-
sided obstruction secondary to bilateral
ureteric calculi (left calculus not shown).
Edematous fatty stranding around each
kidney with the right calculus in the
dilated ureter. Arrowheads indicate fatty
stranding.
2. Imaging of Acute Renal Failure
FIGURE 2.5. Contrast enhanced CT scan Contrast in the aorta
(magnified view of the left kidney) with
no renal parenchymal enhancement or
renal vascular enhancement secondary
to an occlusive renal artery embolus.
less nephrotoxic than CT contrast. MRI scanning
is logistically difficult
fi for most intensive care unit
(ICU) patients, and has a considerably longer scan
time and, therefore, CT scanning remains a more
practical modality.
MAG3 examinations will reveal an absence of
perfusion (segmental or unilateral or bilateral, as
the case may be) but not the cause.
Renal Vein Thrombosis
Bilateral renal vein thrombosis (RVT) will present
with ARF, but is very rare. If discovered, it should
trigger a search for a mass compressing both renal
veins or the suprarenal inferior vena cava (IVC)
and a coagulopathy screen. Unilateral RVT is more
frequent in contrast, but will not produce ARF if
both kidneys are initially normal.
Usually, a single renal vein exists on each side,
but up to 30% of patients will have multiple renal
veins. RVT is most common on the left because
this vein is three times longer than the right vein
and is more liable to extrinsic compression as it
passes between the superior mesenteric artery
and the aorta. RVT may be caused by hypercoagu-
lable states, dehydration (particularly in infants),
sepsis, or trauma and occurs in up to 40% of
patients with nephrotic syndrome.
Ultrasound can show a distended renal vein
with echogenic thrombus within that vein that
may extend into the IVC. Absent fl flow or a thin cuff
11
left kidney
of blood flowing around the thrombus is shown
on color Doppler imaging (7). The kidney itself
may have reduced corticomedullary differentia-
tion, be enlarged, and contain focal areas of
increased echogenicity related to edema and hem-
orrhage. Contrast-enhanced CT scanning has a
similar appearance in the acute setting, with a
dilated renal vein with hypodense thrombus
within. Secondary findings,
fi such as perirenal
stranding, dilated gonadal vein, prolonged nephro-
gram, and complications such as retroperitoneal
hemorrhage may also be present. As the chronicity
increases, the thrombus contracts and multiple
collateral vessels develop.
Renal veins are well demonstrated by MRI scan-
ning, with the thrombus appearing hyperintense
on both T1- and T2-weighted images. The kidney
appears swollen with loss of corticomedullary dif-
ferentiation on T1-weighted images, with both
cortex and medulla having low signal secondary
to prolonged T1 and T2 relaxation times.
Venography is the gold standard and can accu-
rately determine the presence of thrombus and its
extent. A catheter inserted in the common femoral
vein allows selection of the renal vein as it enters
the IVC and, with contrast injection, a fi
filling defect
or complete occlusion can be demonstrated.
Therapeutic measures, such as the instillation
of localized thrombolytics and the placement of
an IVC filter if the thrombus is extensive, can be
performed during the diagnostic procedure.
Complications include damage to vessels and
 12

? ARF with previously normal kidneys or acute on chronic renal

failure
Answer with history clinical findings and Laboratory tests

Acute on chronic renal

ARF with Previously normal kidneys failure

Prerenal Renal Postrenal

Surgical
Medical
Medical Surgical
REGION
ANATOMICAL

US US

?ATN ? Aortic or renal ? Renal vein ? Glomerulonephritis or ? Obstruction

artery thrombosis acute interstitial nephritis
DDx

dissection/occlusion
CLINICAL

US – largely US US to confirm chronic

MRI or angiography to exclude changes, scars etc. +/-
if high pretest other MAG3 for function.
probability diagnoses

MRI or
Contrast enhanced Non contrast CT for
CT* obstructing mass or
MAG3 Non contrast CT for stone
? obstructing mass
TEST TO ANSWER
CLINICAL QUESTION

FIGURE 2.6. Diagnostic algorithm for imaging in ARF. US, ultrasound.

T. Sutherland
2. Imaging of Acute Renal Failure
dislodgement of thrombus resulting in pulmonary
embolism, and require the administration of
potentially nephrotoxic intravenous contrast.
Renal Artery Stenosis
Renal artery stenosis (RAS) is most commonly
associated with hypertension and is usually caused
by atherosclerotic plaques and less commonly by
fibromuscular dysplasia. It can exacerbate renal
fi Kidney Int 1996; 50: 811–818.
hypoperfusion and is a cause of chronic renal
impairment. In these cases, signs of chronic renal
impairment, as previously mentioned, will usually
be present. It is extremely unlikely to be the caus-
ative factor for ARF presenting de novo. In patients
presenting with acute-on-chronic renal failure, it
is one of the many possible causes of the preexist-
ing renal failure and enters the differential diag-
nosis in this fashion.
Conclusion
Clinical assessment in ARF is vital to construct a
differential diagnosis list. Imaging can then have
a targeted role to answer questions and enable the
13
fi
final diagnosis to be made. Using the above dis-
cussion, a potential diagnostic algorithm is given
in Figure 2.6.
I thank Professor Alexander Pitman for his
assistance and guidance with this work.
References
1. Liano F, Pascual J. Epidemiology of acute renal failure:
a prospective, multicenter, community-based study.
2. Dahnert W. Radiology review manual. 5th ed.
Philadelphia: Lippincott Williams & Wilkins. 2003.
3. Middleton WD, Kurtz AB, Hertzberg BS. Ultrasound—
The requisites. 2nd ed. St. Louis: Mosby. 2004.
4. Sheafor DH et al. Non-enhanced helical CT and US
in the emergency evaluation of patients with renal
colic: Prospective comparison. Radiology 2000; 217:
792–797.
5. Brant WE, Helms CA. Fundamentals of diagnostic
radiology. 2nd ed. Philadelphia: Lippincott Williams
& Wilkins. 1999.
6. Urban BA, Ratner LE, Fishman EK. Three-dimensional
volume-rendered CT angiography of the renal arter-
ies and veins: Normal anatomy, variants, and clinical
applications. Radiographics 2001; 21: 373–386.
7. Pitman AG, Major NM, Tello R. Radiology core review.
Edinburgh: Saunders. 2003.
3
Drug-Induced Renal Injury
Sara Blakeley
Drug-induced nephrotoxicity contributes to 8 to
60% of all cases of in-hospital acute kidney injury
(AKI) and 1 to 23% of cases of AKI seen on the
intensive care unit (ICU) (1). The wide variations
are caused by different definitions
fi of AKI and dif-
ferent patient populations. Drug-induced nephrop-
athies are often underdiagnosed, and should be
considered in every type of renal failure, both acute
renal failure and chronic renal failure (CRF).
Risk Factors for Nephrotoxicity
Many patients may be taking a potentially nephro-
toxic drug. For example, 55% of patients admitted
to a general medical ward were taking one or
more of either an angiotensin-converting enzyme
inhibitor (ACEI) or angiotensin receptor antago-
nist (ARB), a diuretic, or a nonsteroidal anti-
infl
flammatory drug (NSAID) (2). More than 25% of
patients were taking two or three of these drugs.
Not all patients will develop renal failure; whether
a drug is nephrotoxic or not depends on patient-
and drug-related factors (Tables 3.1 and 3.2).
Methods of Prevention
The following general principles should be
adhered to:
1. Appropriate dose alteration in patients depending
on renal function, age, and ideal body weight.
2. Awareness of drug interactions.
3. Close attention to flfluid balance and hemody-
namic status.
14
4. Monitoring of drug levels (where appropriate).
5. Discontinuation or change of mediation when
possible.
6. Consider specific
fi therapies, e.g., N-acetylcysteine
N
(NAC; contrast), rasburicase, and allopurinol
(tumor lysis syndrome), urinary alkalinization
(drug-induced rhabdomyolysis).
7. Close liaison with ICU pharmacist.
Nonsteroidal Anti-Inflammatory
Drugs
NSAIDs are widely used and overall renal com-
plications are uncommon, however, their use
in the community has been shown to increase
the risk of hospitalization with AKI by up to
four-fold (4, 5). Renal effects are predominately
caused by their effect on the production of renal
prostaglandins.
Effects on Renal Prostaglandins
Membrane-bound phospholipids are converted to
arachidonic acid by phospholipase A. Arachidonic
acid then enters the cyclooxygenase pathway
under the action of cyclooxygenase enzyme (COX)
forming prostaglandins, or enters the lipoxygen-
ase pathway, forming leukotrienes.
In health, renal prostaglandins have a number
of effects: control of renin release, regulation of
renal blood flow
fl (RBF) through vascular tone, and
control of salt and water transport in the renal
tubules. They have both vasodilatory (prostaglan-
din [PG]-E2, PGI2) and vasoconstrictor (throm-
3. Drug-Induced Renal Injury
TABLE 3.1. Mechanism of drug-induced AKI
Mechanism
Altered intraglomerular
hemodynamics: drugs that
interfere with the normal
regulatory alterations in
preglomerular and postglomerular
arteriolar resistance can
compromise renal blood flow and
glomerular filtration rate, especially
in times of hemodynamic instabilit
Drug-induced glomerulopathy: this
usually presents with nephrotic
syndrome or proteinuria. Renal
function need not be impaired
Drug-induced thrombotic
microangiopathy: rare
Direct tubular cell toxicity
Tubular damaged caused by osmotic
nephrosis: tubule cells take up
nonmetabolizable molecules,
creating an osmotic gradient.
Water rapidly accumulates in
the cell, causing swelling and
vacuolation, thereby disrupting cell
integrity. Cellular debris causes
tubular obstruction
Tubular damage caused by cast
deposition: rhabdomyolysis
Interstitial nephritis: drugs can cause
an acute allergic interstitial
nephritis or chronic interstitial
damage
Note: This list is not exhaustive.
Source: Schetz et al., 2005; and Perazella, 2003.
boxane A2) effects. In certain situations associated
with high levels of circulating vasoconstrictors
(such as angiotensin II [ATII], endothelin, cate-
cholamines), vasodilatory renal prostaglandins
15
are crucial to maintain RBF and GFR. Patients
Drug examples who fall into this high-risk category are those with
parenchymal renal disease or renal impairment,
Calcineurin inhibitors
Vasopressors hypovolemic patients, those with congestive
Amphotericin cardiac failure or liver disease (because of activa-
Contrast agents tion of the renin-angiotensin system), and the
NSAIDs, ACEI/ARBs elderly. There are two isomers of the COX enzyme
(6). “Traditional” NSAIDs are nonselective COX
inhibitors, whereas newer “coxibs” selectively
target the production of proinfl flammatory prosta-
Gold, D-penicillamine glandins by COX-2. They have fewer gastric and
NSAIDs platelet side effects, but it is now clear that they
Mesalazine
have the same effects on renal prostaglandins (7);
Cyclosporin A, OKT3, therefore, caution should be still be taken in high-
tacrolimus risk individuals.
Clopidogrel, ticlopidine NSAID-induced salt and water retention occurs
Cocaine and the effect of loop diuretics is also diminished.
Quinine
This may lead to pedal edema or hypertension, but
Aminoglycosides
Amphotericin can precipitate overt cardiac failure in at-risk
Calcineurin inhibitors patients.
Cisplatin
Methotrexate
Cocaine Other Renal Effects
Contrast media
Palmidronate 1. Acute tubulointerstitial nephritis (TIN) is
Mannitol less common, occurring after 3 to 5 days, or
Dextrans even after years, of drug use. It occurs in an
Intravenous
immunoglobulin
Hydroxyethyl starch TABLE 3.2. Risk factors for development of drug-induced AKI
Patient-related factors Drug-related factors
Increased age Inherent nephrotoxic potential
Preexisting chronic kidney Dose (important for drugs
Statins disease inducing crystal deposition,
Diabetes mellitus causing tubular damage,
β-lactams, quinolones, Intravascular volume depletion: and drugs altering renal
rifampicin, macrolides, absolute (e.g., dehydration) hemodynamics)
sulfonamides or effective (e.g., massive Prolonged duration of
NSAIDs ascites, nephrotic syndrome) treatment
Thiazide and loop diuretics Peripheral vascular disease Frequency of administration
Phenytoin (this increasesthe risk of Time of administration
Cimetidine, ranitidine renovascular disease)
Allopurinol Sepsis Rate of administration
Antivirals Concomitant use of diuretics (important fordrugs causing
Cocaine and other nephrotoxic drugs crystal nephropathy)
Metabolic disturbances: sodium Route of administration (e.g.,
depletion, hypoalbuminemia, intravenous versus oral
acid-base disturbances (which contrast)
may exacerbate intrarenal Combination of drugs causing
crystal deposition), multiple nephrotoxic synergy (e.g.,
myeloma cephalosporins and
aminoglycosides,
aminoglycosides
vancomycin and
vancomycin,
aminoglycosides)
16
idiosyncratic, non-dose-dependent manner. The
classic features of fever, rash, arthralgia, and
eosinophilia are often not present. The diagnosis
is made on renal biopsy. Treatment is to stop the
drug and support the patient. Corticosteroids are
sometimes administered, but the evidence is
lacking.
2. Renal papillary necrosis.
3. Nephrotic syndrome.
4. Hyperkalemia caused by hyporeninemic
hypoaldosteronism generally occurs in patients
with CRF, diabetes mellitus, and type IV renal
tubular acidosis.
ACEIs and ARBs
ATII is a potent vasoconstrictor causing constric-
tion of the efferent arteriole, increasing trans-
glomerular pressure, and, thus, GFR. It also causes
systemic vasoconstriction, increasing systemic
blood pressure and improving renal perfusion. In
certain situations, GFR is very dependent on this
postglomerular constriction and, consequently,
blocking this mechanism by the use of ACEI/ARBs
may lead to a marked reduction in GFR (3).
If, after starting an ACEI/ARB, there is a small,
but nonprogressive rise in the serum creatinine,
this is generally related to alterations in intrarenal
hemodynamics rather than structural injury (8).
If the initial serum creatinine rises by more than
30% or if there is a progressive increase in creati-
nine after starting the drug, the drug should be
stopped and a reason sought. This situation may
arise in patients with bilateral renal artery steno-
sis (or stenosis of a single functioning kidney), but
is also seen when there is a reduction in the abso-
lute or effective circulating volume, in the pres-
ence of sepsis, and with the concomitant use of
other drugs (e.g., NSAIDs). These factors should
be addressed before restarting the drug.
Aminoglycosides
Aminoglycoside toxicity is caused by partial
reabsorption of the drug by the proximal renal
tubular cells, and the first
fi indication of renal
involvement is the development of polyuria
because of a defect in the urinary concentrating
S. Blakeley
ability. There is then a slow rise in serum creati-
nine over several days.
The risks of toxicity are increased with high
initial peak serum levels, prolonged treatment,
hypovolemia, increasing age, liver dysfunction,
hypoalbuminemia, and in combination with other
drugs (e.g., diuretics, NSAIDs, ACEIs, cephalospo-
rins) (9).
Once daily dosing is associated with less neph-
rotoxicity than dosing multiple times daily, but
may not be suitable for all patient groups (e.g.,
controversial in the treatment of bacterial endo-
carditis). The risk of nephrotoxicity is reduced
when the once daily dose is given during periods
of activity (daytime) or when taking food, possi-
bly related to changes in urinary pH. Levels should
still be monitored carefully according to local
practice.
Contrast Nephropathy
Incidence and Outcome
Contrast nephropathy (CN) is the third leading
cause of AKI in hospitalized patients (10), account-
ing for 12% of cases of AKI. It is defined
fi as an
acute decline in renal function, with a rise in
serum creatinine of greater than 25% from base-
line (or an absolute rise of 44 μmol/L), occurring
24 to 48 hours after contrast. Creatinine usually
peaks at 5 days and returns to baseline by 10 days.
Incidence is varied depending on definitions
fi used
and patient populations studied. Overall incidence
is less than 3% (11, 12), but rises in the setting
of increasing number of risk factors (13), up to
50% with the combination of diabetes and renal
failure (14).
Risk factors for development of CN:
• Preexisting renal impairment
• Diabetes mellitus
• Absolute (e.g., dehydration) or effective volume
depletion (e.g., congestive cardiac failure,
nephrotic syndrome, liver disease)
• Left ventricular ejection fraction less than 40%
• Concurrent use of nephrotoxic drugs (e.g.,
NSAIDs, aminoglycosides)
• High volume, high osmolar, ionic contrast given
intravenously
3. Drug-Induced Renal Injury
• Pre procedure shock (e.g., hypotension, intra-
aortic balloon pump)
• Increasing age
Renal failure is normally nonoliguric and
resolves with supportive care. Up to 12% of
patients need renal replacement therapy (11).
The development of CN increases mortality. It
is unclear whether this is because of renal failure
itself, or is simply a marker of increased disease
severity and underlying comorbidity. In one study,
the development of AKI increased mortality from
7 to 34% (11).
Methods of Prevention
Intravenous Hydration
Volume expansion with intravenous fluid fl before
and after contrast is proven to be beneficial.fi
Timing, dose, and type of fluid
fl administered are
less well defined.
fi Isotonic fluid (using sodium
bicarbonate) may be better than hypotonic fl fluid
because of better volume expansion, urinary alka-
linization, and reduction of free radical-mediated
injury (15).
N-Acetylcysteine
NAC counteracts renal vasoconstriction but also
scavenges oxygen free radicals, thereby preventing
direct oxidative tissue damage after exposure to
contrast media (16).
Data from a series of meta-analyses are mixed
because of the lack of a standardized definition
fi of
CN, study heterogeneity, and publication bias.
Despite this, NAC seems to reduce the risk of renal
injury in high-risk patients.
Type of Contrast Used
Studies compared high, low and iso-osmolar prep-
arations. In high-risk patients, iso-osmolar com-
pounds are associated with a reduced incidence of
CN (17). Nonionic rather than ionic compounds
have also been found to be less nephrotoxic.
Other Therapies (18, 19)
A recent meta-analysis found no evidence that
periprocedural renal replacement therapy reduced
the incidence of CN (20). Loop diuretics may
17
reduce the potential for ischemic injury by inter-
fering with active transport and decreasing the
oxygen demands of tubules, however, evidence is
lacking. There is no evidence that mannitol, atrial
natriuretic peptide, dopamine, or fenoldopam
(a dopamine 1 agonist) are better than standard
hydration. Calcium channel antagonists gained
some interest but were not supported by large
trials. Despite its properties as an adenosine
antagonist, there is no evidence that theophylline
is more effective, and work continues on the anti-
oxidant, ascorbic acid.
Suggestions for High-Risk Patients
• Identify high-risk patients, correct modifiable
fi
risks, and consider the risk/benefit
fi to the patient
of the procedure
• 600 to 1200 mg NAC twice daily for 2 days before
procedure and two doses after the procedure
• Intravenous hydration with saline at 1 mL/kg/h
for 6 to 12 hours before and after the
procedure
Or
5% dextrose and H2O + 154 mEq/L sodium
bicarbonate at 3 mL/kg/h for 1 hour before the
procedure and 6 hours after the procedure (add
154 mL of 1000 mEq/L sodium bicarbonate to
846 mL of 5% dextrose in H2O)
• Use the minimum volume of iso-osmolar or low
osmolar contrast
References
1. Schetz M, Dasta J, Goldstein S, Golper T. Drug-
induced acute kidney injury. Curr Opin Crit Care.
2005; 11: 555–565.
2. Loboz KK, Shenfieldfi GM. Drug combinations and
impaired renal function—the “triple whammy”.
Br J Clin Pharm. 2005; 59(2): 239–243.
3. Perazella MA. Drug induced renal failure: Update on
new medications and unique mechanisms of neph-
rotoxicity. Am J Med Sci. 2003; 325(6): 349–362.
4. Perez Gutthann S, Garcia Rodriguez LA, Raiford DS,
et al. Nonsteroidal anti-infl
flammatory drugs and the
risk of hospitalization for acute renal failure. Arch
Intern Med. 1996; 156: 2433–2439.
5. Griffifin MR, Yared A, Ray WA. Nonsteroidal anti-
infl
flammatory drugs and acute renal failure in elderly
persons. Am J Epidemiol. 2000; 151: 488–496.
18
6. Barkin RL, Buvanendran A. Focus on the COX-1 and
COX-2 agents: Renal effects of nonsteroidal and
anti-infl
flammatory drugs—NSAIDs. Am J Thera-
peutics. 2004; 11: 124–129.
7. Gambaro G, Perazella MA. Adverse renal effects of
anti inflflammatory agents: Evaluation of selective
and non selective cyclooxygenase inhibitors. J Int
Med. 2003; 253: 643–652.
8. Palmer BF. Renal dysfunction complicating treat-
ment of hypertension. N Engl J Med. 2002; 347:
1256–1261.
9. Beauchamp D, Labrecque G. Aminoglycoside neph-
rotoxicity: Do time and frequency of administra-
tion matter? Curr Opin Crit Care. 2001; 7: 401–408.
10. Nash K, Hafeez A, Hou S. Hospital-acquired renal
insuffi
ficiency. Am J Kidney Dis. 2002; 39(5): 930–936.
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renal failure on mortality. A cohort analysis. JAMA.
1996; 275(19): 1489–1494.
12. Rudnick MR, Berns JS, Cohen RM, Goldfarb S.
Contrast-media associated nephrotoxicity. Semin
Nephrol. 1997; 17: 15–26.
13. Rich MW, Crecelius CA. Incidence, risk factors, and
clinical course of acute renal insuffi ficiency after
cardiac catheterization in patients 70 years of age or
older. A prospective study. Arch Intern Med. 1990;
150(6): 1237–1242.
14. Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast
nephropathy in azotemic diabetic patients undergo-
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ing coronary angiography. Am J Med. 1990; 89(5):
615–620.
15. Merten GJ, Burgess WP, Gray LV, et al. Prevention of
contrast induced nephropathy with sodium bicar-
bonate: a randomised controlled trial. JAMA. 2004;
291: 2328–2334.
16. Pannu N, Manns B, Lee H, Tonelli M. Systematic
review of the impact of N-acetylcysteine on
contrast nephropathy. Kidney Int. 2004; 65: 1366–
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17. Aspelin P, Aubry P, Fransson SG, Strasser R, Willen-
brock R, Berg KJ. Nephrotoxicity in high-risk
patients study of iso-osmolar and low-osmolar
non-ionic contrast media study investigators. Neph-
rotoxic effects in high-risk patients undergoing
angiography. N Engl J Med. 2003; 348(6): 491–
499.
18. Maeder M, Klein M, Fehr T, Rickli H. Contrast
nephropathy: Review focusing on prevention. J Am
Coll Cardiol. 2004; 44: 1763–1771.
19. Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies
for contrast nephropathy. JAMA. 2006; 295: 2765–
2779.
20. Cruz DN, Perazella MA, Bellomo R, Corradi V, de
Cal M, Kuang D, Ocampo C, Nalesso F, Ronco C.
Extracorporeal blood purifi fication therapies for pre-
vention of radiocontrast-induced nephropathy: a
systematic review. Am J Kidney Dis. 2006; 48(3):
361–367.
4
Acute Kidney Injury
Sara Blakeley
Patients may be admitted to the intensive care unit
(ICU) with acute kidney injury (AKI) or it may
develop during their stay. This chapter gives an over-
view of the definition
fi and epidemiology of AKI, along
with clinical features and initial investigations.
Definition of AKI
AKI is an abrupt (<7 d) and sustained decrease in
kidney function (1). It is accompanied by changes
in blood biochemistry (e.g., a rise in serum creati-
nine), in urine output, or both. There is a spec-
trum ranging from a mild transient rise in serum
creatinine, to overt renal failure needing renal
replacement therapy (RRT); hence, the term acute
kidney injury (AKI) is more precise than the term
“acute renal failure”.
Multiple definitions
fi of ARF exist, and the reader
is guided to a series of excellent reviews that high-
light this problem (1–5). A rise in serum creatinine
is often used as a marker of renal dysfunction, but
it is affected by extrarenal factors, such as age, sex,
race, and muscle bulk. It may lag behind changes
in glomerular filtration
fi rate (GFR), either in
decline or during recovery, and, therefore, does
not always give a true reflection
fl of the GFR. Urine
output can be used to definefi renal failure, but this
can be confounded by the use of diuretics, and
not all cases of renal failure are associated with
oliguria.
Efforts have been made to develop a universal
and practical way of defining
fi AKI via either serum
creatinine or urine output. One such recent pro-
posal is the RIFLE (5) system; an acronym for
three levels of renal dysfunction and two renal
outcomes. The levels of renal dysfunction can be
defined
fi by changes in serum creatinine, GFR, or
urine output.
Risk of Renal Dysfunction
• Serum creatinine increased 1.5 fold or
• GFR decreased by more than 25% or
• Less than 0.5 mL/kg/h of urine for 6 hours
Injury to the Kidney
• Serum creatinine doubled or
• GFR decreased greater than 50% or
• Less than 0.5 mL/kg/h of urine for 12 hours
Failure of Kidney Function
• Serum creatinine increased 3 fold or
• An acute rise in creatinine of greater than
44 μmol/L so that new creatinine is greater
than 350 μmol/L or
• GFR decreased more than 75% or
• Less than 0.3 mL/kg/h of urine for 24 hours or
anuria for 12 hours
• Note: This takes into consideration acute-on-
chronic renal failure
Loss of Kidney Function
• Complete loss of kidney function for longer
than 4 weeks
End-Stage Renal Disease
• The need for dialysis for longer than 3 months
Incidence and Outcome
AKI develops in 5 to 7% of hospitalized patients
(6, 7). Six to 25% of patients on the ICU develop
AKI (2, 8); overall, 4% of admissions require RRT.
19
20
This may underestimate the scale of the problem,
however, because when all degrees of kidney
dysfunction are considered using the RIFLE
criteria, 20% (9) of hospital patients and 67% of
ICU patients developed some form of kidney
injury (10).
The incidence and progression of AKI varies
depending on the patient group studied. For
example, up to 20% of cardiac surgery patients
will develop some evidence of renal injury (11),
but only 1% will need RRT (12).
AKI on the ICU is associated with a hospital
mortality of 13 to 80% (2, 8, 10–17) and 57 to 80%
if RRT is needed. Renal failure rarely occurs on
its own, with up to 80% of patients with renal
failure on the ICU having another organ system
failure (8). Various factors have been associated
with a worse outcome; including comorbidity,
increased severity of illness, presence of sepsis,
need for mechanical ventilation, oliguria, hospi-
talization before ICU, and delayed occurrence of
AKI (13–15).
The development of AKI dramatically increases
mortality across all patient populations studied
(8–10, 12, 14). Worsening levels of renal dysfunc-
tion, as described by the RIFLE criteria, correlate
well with increasing hospital mortality, with up to
a 10-fold risk of death with “failure.” AKI carries
an independent risk of death, but it is unclear
whether this is related to the systemic effects of
renal failure itself, the effects of its treatment, or
is simply a refl
flection of the severity of the under-
lying condition.
After AKI needing RRT, 10 to 32% of patients
are discharged from hospital still needing RRT
(2, 16, 18).
Causes of AKI
Causes of AKI can be divided into prerenal, intrin-
sic, and obstructive causes. One disease may be
associated with different causes of ARF, for
example, sepsis is a common cause of renal dys-
function on the ICU, accounting for up to 50% of
cases of AKI. AKI occurs in 23% of patients with
severe sepsis, and in 51% of patients with septic
shock when blood cultures are positive (19). Sepsis
is characterized by systemic vasodilation (prere-
( restoration of adequate renal perfusion. The
S. Blakeley
nall failure) but intrarenal vasoconstriction, which
could progress to tubular damage (intrinsicc renal
failure). Glomerular microthrombi are associated
with disseminated intravascular coagulation, and
can cause intrinsic AKI (20).
Prerenal Failure
Prerenal failure (Figure 4.1) accounts for 15 to
20% of cases of AKI on the ICU (13, 15). For the
kidneys to be perfused and, therefore, function,
adequate pressure, fl
flow, volume, and patent vessels
are needed.
The kidney autoregulates to maintain a con-
stant renal blood flow (RBF) through a mean arte-
rial pressure range of 65 to 180 mmHg. “Prerenal
failure” is an appropriate, albeit exaggerated,
physiological response to renal hypoperfusion.
Stimulation of the renin-angiotensin-aldosterone
system attempts to retain salt and water and,
therefore, maintain RBF. Because renal tissue is
still preserved, once renal perfusion is restored,
function should improve. A profound or prolonged
reduction in perfusion can, however, lead to isch-
emic acute tubular necrosis (ATN) (intrinsic renal
failure).
Conditions leading to reduced renal perfusion
and, therefore, causing prerenal failure are:
• Hypotension (relative or absolute) secondary to
vasodilation (e.g., certain drugs, loss of vascular
tone, and sepsis)
• Compromised cardiac function
• Intravascular volume depletion (absolute or
effective)
• Increased intra-abdominal pressure (abdominal
compartment syndrome)
Intrinsic Renal Failure
The commonest cause of intrinsic renal failure on
the ICU is ischemic ATN developing after pro-
found or prolonged prerenal failure (Figure 4.2).
Up to 80% of cases of AKI on the ICU are attrib-
uted to ATN (2, 13, 15). Although ATN is a histo-
logical diagnosis, its development is suggested
by the persistence of renal failure following the
4. Acute Kidney Injury 21

Pre re
Pre
Pr rena
nall fa
na faililur
fail ure
ur e

Hypottens
Hypo tensiion
i on Hypovo
Hypo volla
laemiia
laem ia Low card
Low
Lo rdi
dia
iac out
iac outp
tputt
(Reduced intravascular volume)

Tota
Tot
Total lo
tal loss
loss Volu
Vol
Volume red
lume edi
dis
istr
ist
tribut
tributitio
ion
ion

GI los
los
osss Redu
Red
Re duce
duce
cedd ef
eff
ffe
fect
cti
tiv
ive ci
ive circ
ircullat
ati
tin
ing
ing
(Vomiti
(Vom
(V iting,
g ddiiarr
iarrhoea
iarrhhoea, surgic
i all ffiistu
istul
t lae))
vollu
vo lume
lume
(Ascit
(Asc
(A ites, oed
oedema 3rdd spacing
dema, “3 cing”
i ”, conge
congestiv
stive
ti e cardia
rdiac
di c
failure)

Haem
Haem
Ha emor
orrh
rhag
hag
ge
(Visibl
(Vis
(Vi ible and
d occult)
lt)
Altte
Al tere
tere
redd va
vasc
scul
ular
lar cap
cap
pac
acit
itan
itance
ance
( psis:
(Sep
(S i shu
h ntin
nting
ti g
g, vasod
asodil
dilattatio
ti n.
n Hepat
p torenall
synd
y drome HRS
HRS))
Rena
Rena
Re nall lo
loss
loss
(Diureti
(Di retics
tics
cs, poly
l uria
uria)
i )

Skiin
Sk in los
los
osss
(
(Exc
(E essive
essi
ive sweat
weati
ting
ing
ing,
g, bur
burns))

FIGURE 4.1. Causes of prerenal failure. GI, gastrointestinal.

Intr
Int
Intrin
tri
insi
sic
ic re
rena
nall fa
na fail
fail
ilur
lur
ure
e

Glom
Glomer
omerul
ular
lar Tubular Inte
Int
In ters
ters
rsti
titi
ti tiall Vascul
Vasc
Va ular
lar
(Glo
(Glome
lo meru
merulo
rulone
lo neph
ne phri
ph riti
ri tis)
tis) (Aut
(A utoi
ut oimm
oi mmun
mm une
un e, tox
tox
oxic
ic, in
ic infe
fect
fe ctio
ct ious
io us))
us

Ischaemic Toxic Larg

Larg
La ge ve
vess
ssell Smal
Sm allll ve
vess
ssell
(E
Ext
xtreme
xtre me pre rren
enal
al, (Ren
(Renov
ovasascu
culla
lar di
lar diseseas ase
e, ((Vas
(V
Vas
ascu
culililiti
cu tiss, HRS
ti HRS
RS,
sepsis,, pa
p nc
n re
reat
atit
ati is
itis)) athe
at hero
he roem
ro embo
em bo
olilic)
c)) reno
re nova
no vasc
vasc
scul
ular
lar ar,
r, ma
malililign
gnan
gn
nan
ant
nt
hypertension)

Intrinsic toxins
( ha
(Rhabd
bdom
bdomyo
om y lyysi
yo siss, masassi
sive
sive hae
hae
aemomoly
mo lyysi
siss
tumo
tumo
tu mour
ur llys
ysiis
ys is myel
is, elom
loma))

Extrinsic toxins
(Rad
(Radio
io
o ccon
ontr
on tras
trastt,
as t, dru
dru
rugs
gs, an
gs antititibi
biot
bi otic
ot
tic
ics)
s))

FIGURE 4.2. Causes of intrinsic renal failure (red,

d commoner causes on the ICU). HRS, hepatorenal syndrome.
22
pathophysiology of ischemic ATN is reviewed
elsewhere (21, 22), but an alteration in glomerular
hemodynamics with marked afferent arteriolar
renal vasoconstriction causes a fall in glomerular
filtration pressure and subsequently causes isch-
fi (16). Volume overload may have deleterious effects
emia. This particularly affects the outer medulla.
Tubular damage leads to loss of normal cell-to-cell
adhesion and allows back leakage of filtrate
fi into
the interstitium. Shed cells precipitate, with
protein obstructing the tubules and further com-
promising tubular function. Local infl flammatory
mediators respond to cell injury, perpetuating the
process.
ATN can also develop secondary to a variety of
intrinsic or extrinsic renal toxins. Vascular causes
of renal failure may be present at a prerenal or
intrarenal level, and should be considered in vas-
culopaths. The more classic glomerular causes for
intrinsic renal failure are seen less frequently on
the ICU, but are important to recognize because
they require specificfi treatment.
Postrenal or Obstructive Renal Failure
Obstruction can occur at any level of the urinary
collecting system and can be caused by intrinsic
(e.g., stones, tumor) or extrinsic causes (e.g., sur-
rounding or infi filtrating tumor, large infl
flammatory
abdominal aortic aneurysms). Obstruction is an
infrequent cause of AKI on the ICU but is impor-
tant to be excluded in all cases.
Complications of AKI
AKI is a systemic disease, having effects on practi-
cally all organ systems (23). It is becoming increas-
ingly recognized that there is “cross talk” between
the injured kidney and other organs through the
release of proinfl flammatory cytokines. Complica-
tions related to other failing organs may be seen,
but complications specificfi to the failing kidney are
as follows.
Retention of Uremic Toxins
Accumulation of toxins, including urea, can lead
to nausea, vomiting, drowsiness, a bleeding ten-
dency, uremic flap, and, rarely, coma (uremic
encephalopathy) and a pericardial rub.
S. Blakeley
Volume Overload
Salt and water retention occurs early, and is a
common reason for initiating RRT on the ICU
on cardiac and respiratory function, with the
development of peripheral edema affecting wound
healing and pressure areas.
Acidosis
There is retention of organic anions (e.g., phos-
phate) and reduced production of bicarbonate
by the failing tubules. In critically ill patients,
this may be aggravated by the presence of a non-
renal acidosis, for example, lactic acidosis from
sepsis and respiratory acidosis from respiratory
failure.
Electrolyte and Mineral Disturbances
Hyponatremia, hyperkalemia, and hyperphospha-
temia are commonly seen.
Anemia
Anemia can develop because of inappropriate
levels of erythropoietin (decreased synthesis) or
increased red cell fragility, causing premature red
cell destruction. Uremia is also associated with
platelet dysfunction and increased risk of gastro-
intestinal bleeding.
Immunosuppression
Renal failure itself can impair humoral and cellu-
lar immunity, putting the patient at risk of infec-
tious complications.
Metabolic Consequences
Hyperglycemia occurs because of peripheral in-
sulin resistance and increased hepatic gluconeo-
genesis. Protein catabolism is also activated.
Drug Accumulation
Renal failure may be secondary to drugs, but, as
GFR falls, renal clearance of drugs and their
4. Acute Kidney Injury 23

metabolites also falls. Renal failure may be exac-
erbated by drug accumulation, or other side effects
can develop, such as morphine metabolites leading
to respiratory depression.
Investigation of the Cause of Renal
Failure (Table 4.1)
Laboratory Tests (Table 4.2)
Urinalysis
A standard dipstick for blood and protein should
be preformed and a fresh sample spun for casts:
hyaline casts (nonspecific
fi markers of renal injury),
brown/cellular casts (ATN), and red cell casts
(acute glomerulonephritis). An estimation of
protein excretion may be needed, either a 24-hour
urine collection or a spot urine protein-creatinine
ratio, depending on local resources.
Urine osmolality and urinary electrolytes can
be used to help distinguish prerenal failure from
intrinsic kidney disease (Table 4.3). They should
be interpreted in light of the clinical setting, but
can act as another tool in the assessment of intra-
vascular volume status.
Radiological Investigations
A chest x-ray will help assess volume status, but
patchy infifiltrates may also represent pulmonary
hemorrhage, as seen in certain forms of vasculitis.
A renal ultrasound scan should be performed;
the timing will depend on the likely cause of renal
failure and the patient’s clinical state. Further
imaging should be guided by the clinical scenario.
Conclusion
AKI is a significant
fi condition affecting critically
ill patients on the ICU. It is a systemic process
affecting all organs, and has a major impact on
patient morbidity and mortality. It is, therefore,
important to be able to promptly recognize its
development and institute the appropriate inves-
tigations to guide treatment.

TABLE 4.1. History and examination in AKI

A full history should be take with reference to the following:
• Presence of risk factors: known chronic renal disease, advanced age, diabetes mellitus, ischemic heart disease, hypertension, peripheral vascular
di
disease, liver
li disease,
di recentt hi
high-risk
h i k surgery
• Previous episodes of renal failure
• Family history of renal disease
• Rashes, joint aches, sinusitis, and hemoptysis suggesting a systemic condition
• Review blood pressure and anesthetic charts for periods of profound or prolonged hypotension in relation to the patients usual blood pressure
• Review fluid balance charts considering hidden losses, such as sweating or “third spacing.” The sudden onset of anuria suggests obstruction or a
catastrophic
t t hi vascular l event.t RRememberb that
th t di
diuretics
ti can make
k th
the urine
i output
t t llookk ““artificially
tifi i ll good”
d”
• Drug charts should be reviewed for intravenous contrast, chemotherapeutic agents, analgesics, antibiotics, and herbal remedies, including any
new medications taken in the past month
• Determine baseline creatine and pattern of change (i.e., sudden jump or gradual decline). The rate of change may be more important than the
absolute value
• Review any previous urinalyses for previous hematuria or proteinuria that may suggest chronic disease
A full examination should be performed with reference to the following:
• Pressure: mean arterial pressure in relation to the patients usual readings
• Flow: cardiac output studies and/or markers of end organ perfusion (e.g., lactate)
• Volume: overall volume status as well as intravascular volume status
• Patent vessels: evidence of generalized vascular disease
• Rashes or splinter hemorrhages suggesting vasculitis, cholesterol emboli, or infective endocarditis
• Palpable bladder or kidney, suggesting obstruction
• Raised intra-abdominal pressure or tense limbs, suggesting compartment syndrome
24 S. Blakeley

TABLE 4.2. Laboratory investigations for AKI

Finding Comment
Anemia Normochromic, normocytic suggests chronicity
Thrombocytopenia + microangiopathic hemolytic anemia Consider hemolytic uremic syndrome, thrombotic thrombocytopenic purpura,
disseminated intravascular coagulation (DIC)
Neutrophilia, “left shift” + thrombocytopenia Consider sepsis
Eosinophilia Consider vasculitis, allergic interstitial nephritis
Abnormal coagulation profile Sepsis, DIC, hepatorenal syndrome, systemic lupus erythematosus (SLE)
Elevated urea and creatinine Will rise with any cause of renal failure. A normal serum creatinine does not exclude
the presence of renal dysfunction, and conversely an elevated creatinine may
underestimate the degree of renal dysfunction
Elevated serum Cystatin C A newer marker of renal dysfunction, but needs further evaluation on ICU patients.
Freely filtered at the glomerulus, and fully metabolized by proximal tubular cells, if
GFR falls, levels rise
Hypercalcemia Elevated in malignancy (including hematological). Calcium may be high, low, or
normal in chronic kidney disease (CKD)
Hyperphosphatemia Extremely elevated in rhabdomyolysis and tumor lysis syndrome, but will rise with
any cause of low GFR. May be normal or high in CKD
Elevated creatinine kinase Rhabdomyolysis
Abnormal liver function tests Consider hepatorenal syndrome; sepsis; vasculitis; and hemolysis, elevated liver
enzymes, and low platelet count (HELLP) syndrome
Elevated uric acid Seen in preeclampsia but will rise with any fall in GFR
Abnormal immunoglobulins Look for myeloma and other hematological malignancies
Elevated antinuclear factor, double-stranded DNA, Investigate further for systemic diseases, such as SLE and vasculitis
antineutrophil cytoplasmic antibodies (ANCA),
antiglomerular basement membrane
antibodies, and low complement
Positive virology/serology/microbiology Certain forms of renal injury seen with specific infections, e.g., hepatitis B/C, HIV,
leptospirosis, verotoxin-producing Escherichia coli

TABLE 4.3. Urinary findings in prerenal failure and ATNa References

Prerenal Intrinsic
1. Kellum JA, Levin N, Bouman C, Lameire N. Devleop-
Urine Na <20 mmol/L >40 mmol/L
ing a concensus classification
fi for acute renal failure.
Urine : plasma (U : P) urea >20 <10
ratio
Curr Opin Crit Care. 2002; 8: 509–514.
U : P creatinine ratio >40 <10–20 2. Tillyard A, Keays R, Soni N. The diagnosis of acute
U : P osmolality >2.1 <1.2 renal failure in intensive care: mongrel or pedigree?
Specific gravity >1.020 <1.010 Anaesthesia. 2005; 60: 903–914.
Urine osmolality >500 <400 3. Hoste EA, Kellum JA. Acute kidney injury: epidemi-
Urine osmolality High (>serum + Low (<serum + ology and diagnostic criteria. Curr Opin Crit Care.
100 mOsm/L) 100 mOsm/L) 2006; 12: 531–537.
FE sodiumb <1% >1–2% 4. Mehta RL, Chertow GM. Acute renal failure defini- fi
a
These results should be interpreted with caution in patients who have had
tions and classifification: Time for a change? J Am Soc
diuretics, large volume resuscitation, the elderly, or patients with chronic Nephrol. 2003; 14: 2178–2187.
renal failure. 5. Bellomo R, Ronco C, Kellum JA et al. Acute renal
b
FE, fractional excretion of sodium: in a prerenal state, sodium is actively failure—Definition,
fi outcome measures, animal
reabsorbed by working tubules to maintain intravascular volume. The models, fluid therapy and information technology
kidney will, therefore, produce concentrated urine with a low concentra- needs. The Second International Consensus Con-
tion of sodium. Creatinine is still excreted, but relatively less sodium ference of the Acute Dialysis Quality Initiative
appears in the urine. Hence, if the tubules are intact, the amount of sodium (ADQI) group. Crit Care. 2004; 8: R204–R212.
excreted compared with creatinine (fractional excretion) falls. 6. Nash K, Hafeez A, Hou S. Hospital-acquired renal
Urine Na plasma creatinine insufficiency.
fi Am J Kid Dis. 2002; 39(5): 930–
FE Na = × 100
Plasma Na Urine creatinine 936.
4. Acute Kidney Injury
7. Hou SH, Bushinsky DA, Wish JB et al. Hospital-
acquired renal insuffi ficiency: a prospective study.
Am J Med. 1983; 74(2): 243–248.
8. Uchino S, Kellum JA, Bellomo R et al. Beginning and
Ending Supportive Therapy for the Kidney (BEST
Kidney) Investigators. Acute renal failure in criti-
cally ill patients: a multinational, multicenter study.
JAMA. 2005; 294(7): 813–818.
9. Uchino S, Bellomo R, Goldsmith D et al. An assess-
ment of the RIFLE criteria for acute renal failure in
hospitalized patients. Crit Care Med. 2006; 34(7):
1913–1917.
10. Hoste EA, Clermont G, Kersten A et al. RIFLE crite-
ria for acute kidney injury are associated with hos-
pital mortality in critically ill patients: a cohort
analysis. Crit Care. 2006; 10(3): R73.
11. Kuitunen A, Vento A, Suojaranta-Ylinen R, Pettila V.
Acute renal failure after cardiac surgery: evaluation
of the RIFLE classifi fication. Ann Thoracic Surg. 2006;
81(2): 542–546.
12. Chertow GM, Levy EM, Hammermeister KE et al.
Independent association between acute renal failure
and mortality following cardiac surgery. Am J Med.
1998; 104(4): 343–348.
13. Bagshaw SM, Laupland KB, Doig CJ et al. Prognosis
for longterm survival and renal revoery in critically
ill patients with severe acute renal failure: A popu-
lation based study. Crit Care. 2005; 9: R700–
709.
14. Metnitz PG, Krenn CG, Steltzer H et al. Effect of
acute renal failure requiring renal replacement
25
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15. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ.
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of critical illness in Australia. Crit Care Med. 2001;
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5
Medical Management of Acute Renal Failure
Nerina Harley

Acute renal failure (ARF) is both common and
associated with signifificant mortality in the inten-
sive care unit (ICU) setting (1). With an impact on
length of stay, likelihood of survival until dis-
charge, and cost of care, it is vital that the increas-
ing body of evidence in critical care nephrology is
used to refine
fi defi finitions, diagnosis, preventive
strategies, investigations, and management of
these patients (2).
The medical management of ARF relies on the
basic tenets of diagnosis, elimination of reversi-
ble factors, amelioration of exacerbating factors,
treatment of complications, and optimization of
the “kidney’s environment” to provide maximal
recovery.
Diagnosis of ARF
Major causes of renal disease are divided, for
simplicity, into three areas:
• Prerenal causes, caused by volume depletion
with or without relative hypotension (reduced
renal perfusion)
• Intrinsic renal causes, caused by vasculitis, glo-
merular disease, and tubulointerstitial disease
• Postrenal or obstructive causes
The most common causes of ARF have been
found to be acute tubular necrosis (ATN) (45%),
prerenal (21%), acute on chronic (13%), obstruc-
tion (10%), glomerulonephritis (GN), or vasculitis
(4%) (3).
Risk factors for the development of ARF are
given in Table 5.1.
Patients with renal disease have a variety of
clinical presentations:
• Asymptomatic
• Symptoms directly referable to the kidney,
e.g., hematuria, flank
fl pain
• Extrarenal symptoms, e.g., edema, hyperten-
sion, uremic symptoms, consequences of
hyperkalemia
• Manifestations of the underlying pathology
or etiology, e.g., sepsis, hypotension, rhabdo-
myolysis, systemic vasculitis
Investigations
Assessment of Renal Function
Although they lack sensitivity and specificity fi
serum creatinine and urine output are the most
useful parameters in clinical practice. Glomerular
filtration rate (GFR) assessment may be diffi
fi ficult
in nonsteady-state conditions. Comparison with
previous results is vital in determination of base-
line function, time course, and progression.
Urinalysis
Urine examination may demonstrate granular and
epithelial casts in ATN, eosinophils in acute inter-
stitial nephritis, and red cell casts in acute vascu-
litis or glomerulonephritis and/or proteinuria.
There are no prospective studies of the predictive
value of urine sediment in ATN. Urinary elec-
trolytes are of limited value in most clinical
situations because of the confounding effects of

26
5. Medical Management of Acute Renal Failure 27

TABLE 5.1. Risk factors for ARF inherent risks of bleeding should be weighed up
Risk factor Selected reference(s) in the setting of the risk-to-benefit
fi ratio.
Note: The “gold standard” for the diagnosis of
Older age Nash et al., 2002 (43)
Diabetes Parfrey et al., 1989 (44). a prerenal cause of ARF is resolution of renal
Underlying renal insufficiency impairment in response to fluid challenge. This is
Cardiac failure in contrast to significant
fi ATN, in which there is
Sepsis Brun-Buisson et al., 2004 (45) prolonged time to resolution.
Ricci et al., (46)
Absolute or relative hypovolemia
Hepatic failure Han and Hyzy, 2006 (47)
Nephrotoxins (including Barrett et al., 1993 (48) Primary Prevention
high-osmolality Aspelin et al., 2003 (49).
radiocontrast agents) McCullogh et al., 2006 (50) Primary prevention of ARF in the critically ill with
Cardiopulmonary bypass with Mangano et al., 1998 (51)
or without baseline risk factors consists of avoid-
aortic cross-clamping Chertow et al., 1998 (52)
(particularly valve surgery) ance, amelioration, and treatment of these factors
Nonrenal organ transplantation Lima et al., 2003 (53) wherever possible. Strategies can be divided into
Abdominal compartment syndrome McNelis et al., 2003 (54) nonpharmacological, for example, fluid
fl adminis-
tration to reduce the risk of contrast induced
nephropathy (6), and pharmacological. To date, no
treatments such as diuretics. Urine volume is of pharmacological strategies have conclusively dem-
little diagnostic value, although little or no output onstrated prevention of ARF from any insult (7).
is acutely useful with causes of anuria, including
shock, bilateral urinary obstruction, renal cortical
necrosis, and bilateral vascular occlusion.
Loop Diuretics
Although oliguria (<400 mL/24 h) is common in
ATN, anuria is rare and other etiologies must be
Other Markers of Renal Injury
considered. Nonoliguric patients have a better
These have been described but are not currently prognosis than oliguric patients in terms of a
generally available in the acute setting. For greater residual GFR (8), lower peak serum creati-
example, serum cystatin C has been recently nine, and dialysis-free survival at 21 days (9, 10),
proposed as a marker of ARF (4), predicting ARF possibly reflecting
fl less severe renal injury. A clini-
by at least 24 hours. cal issue of the use of loop diuretics often arises in
increasing the urine output of oliguric patients.
Experimentally, loop diuretics reduce active
Radiology
sodium chloride transport in the thick ascending
Renal ultrasound is the modality of choice to limb of the loop of Henle, decreasing energy
exclude obstruction. Reduced renal size and corti- requirements and, thus, protecting the cell in
cal thinning (although preserved in diabetic the setting of decreased energy availability. Only
nephropathy) is indicative of chronic renal impair- anecdotal human evidence suggests that the use
ment. A helical computed tomographic (CT) scan of loop diuretics may be beneficialfi in the first 24
may be useful in urolithiasis, but there are risks of hours in flushing tubular casts. There is no evi-
secondary injury with radiocontrast. dence of benefi fit in established ATN on duration
of renal failure, requirement for dialysis, or sur-
vival (11). The increase in urine output in this
Renal Biopsy
setting is caused by decreased tubular reabsorp-
Renal biopsy is considered when noninvasive eval- tion in residual functioning nephrons (not re-
uation has not established the diagnosis (5); the cruitment of nonfunctioning nephrons), volume
major indications include isolated hematuria with expansion (initial sodium retention), and urea
proteinuria, nephrotic syndrome, acute nephritic osmotic diuresis.
syndrome, and unexplained ARF. Percutaneous A number of studies have suggested worsened
biopsy is most commonly performed and the outcomes in ATN with the use of loop diuretics in
28
the setting of contrast media (9, 12) and cardiac
surgery. A systematic review (13, 14) comparing
fluids alone with diuretics found no evidence of
fl groups (20).
improvement in survival, incidence of ARF, or
need for renal replacement therapy (RRT). Deaf-
ness, possibly permanent, is a known complica-
tion of high-dose loop diuretics.
Mannitol
Mannitol may preserve mitochondrial function by
minimizing postinjury edema. Human trials have
failed to show benefifit in reducing ARF with man-
nitol versus fluid alone in rhabdomyolysis (15),
cardiac surgery (16), and vascular and biliary tract
surgery (17). A trend toward harm was noted in
the prevention of contrast nephropathy (12).
Dopamine Agonists
Dopamine has a number of effects in the kidney
via dopamine A1 and A2 receptors. In the proxi-
mal tubule, dopamine, via the generation of cyclic
AMP, decreases Na+-H+ exchange and the Na+-H+-
ATPase pump, thus, decreasing sodium reabsorp-
tion. In the collecting tubules, this effect on
Na+-H+-ATPase and decreased aldosterone secre-
tion reduces sodium reabsorption (18).
When infused in doses of 0.5 to 3 μg/kg/min,
dopamine causes afferent and efferent glomerular
arteriolar dilatation, increasing blood flow
fl with
little or no increase in GFR. At higher concentra-
tions, dopamine causes vasoconstriction via α-
adrenergic receptors.
There is no evidence in human studies for a
“renal protective effect” of dopamine.
• In 1994, Baldwin et al. studied the effect of post-
operative low-dose dopamine on renal function
after major elective vascular surgery. Patients
were administered saline or saline plus dopa-
mine as fluid replacement. No difference in renal
function was demonstrated between the two
groups (19).
• In the North American Study of the Safety
and Efficacy
fi of Murine Monoclonal Antibody
to Tumor Necrosis Factor for the Treatment
of Septic Shock (NORASEPT) II study, 400
patients with septic shock and oliguria nonran-
domly received no, low-, or high-dose dopamine.
N. Harley
The incidence of ARF and requirement for
RRT was not significantfi different between
• A large randomized controlled trial of low-dose
dopamine in 328 critically ill patients with
impaired creatinine, oliguria, and at least two
systemic infl flammatory response syndrome
(SIRS) criteria failed to show any benefit fi in
progression, need for RRT, or death (21).
• Studies of fenoldopam, a relatively selective
dopamine A1 receptor agonist, although shown
to increase sodium excretion and renal blood
flow in healthy and hypertensive patients, has
fl
not shown benefi fit in ARF in the critically ill
(22).
N-Acetylcysteine
N-Acetylcysteine (NAC) has been shown in a
N
number of studies to decrease the incidence of
contrast nephropathy in high-risk patients (23,
24), but without improvement in RRT require-
ment or survival. Importantly, NAC may decrease
creatinine via activation of creatinine kinase (25)
but not GFR. Promising studies have led to the
introduction of protocols in many institutions for
the prophylactic use of NAC in the prevention
of contrast-induced nephropathy. With few side
effects, low cost, and ease of administration (oral
or intravenous), many centers have erred on the
side of possible benefit
fi in the face of lack of hard
evidence of long-term benefit fi (26).
Others
Trials have failed to demonstrate benefi fit of natri-
uretic peptides (10, 27) or adenosine agonists (28).
Experimental therapies, such as antioxidants and
erythropoietin are unproven in humans.
In the absence of further evidence, flfluids, and
possibly NAC, are the gold standards of interven-
tional strategies.
Supportive Strategies
Fluid resuscitation and correction of hypotension
are clearly essential. There is no evidence of
advantage of one particular inotrope over another.
5. Medical Management of Acute Renal Failure
No evidence exists that reversing hypotension
with noradrenaline compromises mesenteric or
renal blood flow (29).
Van den Berghe demonstrated that tight glucose
control with intravenous therapy improved out-
comes in critically ill patients, including decreased
incidence of ARF (30, 31).
Nutritional supportt of the critically ill is the
basic standard of care, although not always
achieved. Early enteral nutrition is supported by
meta-analyses of Level II trials; benefits fi include
preservation of muscle mass, the maintenance of
the gastrointestinal mucosal barrier and immune
status, and a possible reduction in multiorgan
dysfunction (32–34). A Level I trial is currently
planned by the Australian and New Zealand Inten-
sive Care Society (ANZICS) clinical trials group
comparing early enteral nutrition with standard
care in 1470 critically ill patients intolerant of
early enteral nutrition (www.actr.org.au).
There is no evidence to support prophylactic
hemofiltration
fi to prevent contrast nephropathy,
despite fifiltration removal of contrast.
Early recognition and adequate management of
the deteriorating clinical condition of a patient is
fundamental in the prevention of morbidity and
mortality, including ARF. In a hospital-based
study of a medical emergency team (MET) system,
Bellomo et al. demonstrated reduced incidence of
postoperative adverse outcomes, mortality rate,
and mean hospital length of stay (35). This was
not validated in a larger cluster-randomized con-
trolled trial of 23 hospitals with no effect on inci-
dence of cardiac arrest, unplanned admissions to
ICU, or unexpected death (36). Nevertheless, the
principles of early recognition, monitoring, and
adequate response remain fundamental.
Postinjury Prevention of ARF
Secondary renal injury occurs after the primary
insult has triggered the initial injury to the
kidneys.
Strategies for postinjury prevention of ARF
overlap with those of primary prevention (37) as
described above. They include maintenance of
adequate intravascular volume, cardiac output,
mean arterial blood pressure (MAP), avoidance of
further insult, and supportive strategies.
29
Assessment and Correction of
Volume Depletion
Clinical signs of relative or absolute volume deple-
tion include loss of tissue turgor, hypotension,
postural hypotension, and decreased venous pres-
sure (reduced jugular venous pressure). Although
left ventricular end diastolic pressure (LVEDP)
is the most important determinant of left ventricu-
lar output and, thus, tissue perfusion, central
venous pressure is useful because it has a direct
relationship to LVEDP, with the exceptions of
pure left-sided or pure right-sided failure (cor
pulmonale). Other clinical manifestations may
be specifi fic to the source of depletion (losses
or third space sequestration), type of fl fluid lost,
and to the associated electrolyte and acid-base
abnormalities.
Recently, Vincent proposed a protocol for
routine flfluid challenge with defi fined rules based
on clinical response to the volumes infused,
allowing for prompt deficit fi correction while
minimizing risks of fluid
fl overload (38).
Maintenance of Adequate MAP and
Cardiac Output
There is currently insufficient
fi data to recommend
firm therapeutic targets, suffi
fi fice to say, Level III
evidence suggests failure to maintain systolic
blood pressure greater than 80 mmHg or MAP
greater than 50 mmHg is associated with increased
risk of developing ARF (39). A low cardiac output
is a major risk factor for ARF after cardiac surgery
(40), but supranormal cardiac output has no
beneficial
fi effect.
Avoidance of Further Insults
Appropriate dosage of medication and avoidance
(or protective strategies) of nephrotoxins is
advised.
Renal Replacement Therapy
Intermittent versus continuous renal replacement
strategies and dose delivery are discussed in a
later chapter.
30 N. Harley

TABLE 5.2. Summary of guidelines for management of ARF

Make diagnosis
Exclusion of prerenal causes
Exclusion of postrenal causes
Exclusion of intrinsic renal causes
Evaluation of urinary electrolytes
E.g., volume depletion, cardiac and liver disease, nephrotoxins
Renal ultrasound
E.g., review urinary sediment, consider renal biopsy
Only in the absence of diuretics

Treat reversible causes

Volume resuscitation Maintain fluid balance but avoid overload
Blood pressure support Inotropic if necessary, however no validated physiological targets or end points have been established
Treat electrolyte complications E.g., hyperkalemia
No dopamine

Address/avoid exacerbating factors

Treatment of underlying etiology E.g., treat sepsis, further investigation if diagnosis unclear, surgical referral if appropriate
Adjust medication dosage Discontinue any nephrotoxic drugs
Avoid further renal insult E.g., minimize contrast-induced injury with fluids and consider NAC

Optimize “kidney’s environment”

Maintain renal perfusion Maintain fluid balance, blood pressure, and cardiac output
Adequate nutrition
Glucose control
Appropriate RRT Timely introduction of RRT, avoidance of complications (e.g., hypotension, line-related sepsis,
biocompatible dialysis membranes), and appropriate dose of dialysis

Other
Constantly review diagnosis, which may Consider further investigations, e.g., renal biopsy and radiological investigations, as appropriate
multifactorial in nature
Appropriate medical review E.g., MET resources, nephrology input

Summary 3. Liano G, Pascual J. Acute renal failure. Madrid Acute

Measures of severity of illness are limited when
applied to patients with ARF and, at present, none
are currently adequate to predict mortality of ARF
(41). In the light of available evidence, guidelines
for the management of ARF have been formulated
and given in Table 5.2. Admiral efforts to clearly
defi
fine levels of injury in ARF and physiological
end points (42) will enable further research into
prevention, amelioration, and management of
ARF and, thus, impact on the significant
fi associ-
ated morbidity and mortality.
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6
Acute Renal Failure in the Surgical Patient
Marlies Ostermann
Acute renal failure (ARF) is a potential complica-
tion of any surgical procedure. In general, the risk
of ARF is increased in patients with underlying
vascular disease, diabetes mellitus, or chronic
kidney disease. High-risk situations include car-
diovascular, hepatobiliary, and trauma surgery,
especially if performed as an emergency.
Pathophysiology of ARF
The most common causes of postoperative renal
failure are hypotension (relative and absolute)
and/or volume depletion. Renal oxygen consump-
tion is determined by blood flow, making the
kidneys particularly vulnerable to ischemic injury
when flow is reduced. The kidneys receive 20 to
25% of the cardiac output. In healthy individuals,
renal blood flow
fl is regulated by a complex inter-
play between intrinsic autoregulation, and hor-
monal and neuronal influences.
fl This results in a
relatively constant renal blood fl flow when mean
arterial blood pressure (MAP) is 80 to 180 mmHg.
Outside of these limits, renal blood fl
flow becomes
pressure dependent, and glomerular filtration
fi
ceases when MAP is less than 40 to 50 mmHg. In
patients with long-standing hypertension, this
mechanism of autoregulation is lost, and renal
function is pressure dependent, often needing a
MAP of greater than 80 mmHg. As a result, these
patients need higher blood pressures to maintain
glomerular filtration
fi and are particularly vulner-
able to hypotension or volume depletion.
The whole kidney only extracts less than 10%
of the oxygen carried through the kidney. The
thick ascending limb of the loop of Henle in the
outer medulla is metabolically very active, despite
a relatively low oxygen delivery. As a consequence,
oxygen extraction in this region is approximately
80% and, in the event of ischemia, this area is often
the first part of the kidney to suffer injury.
Risk Factors for ARF in the Surgical
Patient (Table 6.1)
Effect of Anesthesia
Most inhalation and intravenous anesthetics cause
some degree of cardiac depression and/or vasodi-
lation, resulting in lowering of the blood pressure.
Similarly, spinal or epidural anesthesia can cause
hypotension as a result of increased venous ca-
pacitance and arterial vasodilation. In response,
compensatory changes lead to renal arterial vaso-
constriction and increased retention of sodium
and water. Maintenance of an adequate intravas-
cular volume and blood pressure in the range of
patient’s baseline blood pressure is essential to
prevent anesthesia-related renal impairment.
Effect of Drugs
Certain medication may be directly nephrotoxic
(e.g., aminoglycosides, amphotericin, nonsteroi-
dal anti-infl flammatory drugs) or may alter intra-
renal hemodynamics (e.g., angiotensin-converting
enzyme inhibitors, nonsteroidal anti-inflamma-fl
tory drugs). In rare situations, a drug-induced
interstitial nephritis may occur. This is most com-
monly caused by antibiotics or nonsteroidal anal-
gesics, but any drug can cause interstitial nephritis.
33
34 M. Ostermann

TABLE 6.1. Risk factors for ARF developing in surgical patients 25% or a fall in glomerular filtration rate by 25%.
Preoperative factors One to 5% of patients need renal replacement
State of hydration/adequate resuscitation preoperatively therapy. A combination of patient-specific fic comor-
Contrast media bidities and factors related to surgery usually con-
Preexisting sepsis tribute to the development of ARF.
Patient comorbidity
Patient-specific
fic risk factors may not be imme-
• Advanced age
• Diabetes mellitus diately obvious. A large study on 7310 patients
• Hypertension undergoing coronary artery bypass grafting
• Cardiovascular disease (CABG) demonstrated that 29.6% of patients
• Preexisting renal impairment reported being diabetic, but an additional 5.3% of
Operative factors patients were found to have previously undiag-
Related to anesthesia (see text) nosed diabetes. Similarly, among patients under-
Related to surgery going coronary angiography, 12% of patients were
• Emergency surgery
• Duration of cardiopulmonary bypass
found to have an undiagnosed renal artery steno-
• Clamping of renal arteries sis of greater than 75%.
• Suprarenal aortic cross clamping Risk factors related to surgery tend to be
Postoperative factors less predictable, but the risk of renal failure is
• Sepsis generally higher in patients undergoing combined
• Bleeding CABG and valve replacement compared with
• Nephrotoxic drugs patients who only need one procedure.
• Contrast media
Very recently, aprotinin was identified
fi as a risk
• Cardiovascular complications associated with a fall in cardiac
output
t t ((e.g., myocardial
di l iinfarction,
f ti pulmonary
l embolus,
b l factor for ARF. An observational study on 4374
pericardial effusion) patients undergoing revascularization showed
• Development of intra-abdominal compartment syndrome that the use of aprotinin was associated with a
doubling of the risk of renal failure requiring
dialysis when compared with aminocaprionic
Treatment consists of discontinuation of the acid, tranexamic acid, or no antifibrinolytic.
fi
offending drug and possibly steroid therapy.

Methods of Prevention of ARF

Development of Intra-abdominal
Compartment Syndrome Several studies have focussed on prevention of
ARF after cardiac surgery. To date, no magic bullet
Patients with severe ileus, bowel obstruction, has been identifi fied. Prophylactic therapy with
pancreatitis, or after trauma can develop increased dopamine, mannitol, theophylline, and diuretics
abdominal pressure leading to increased pressure has not been effective. There is some evidence that
in renal veins and renal parenchyma resulting in diuretic use after cardiac surgery increases the
decreased renal perfusion. There is a strong cor- risk of ARF. Data regarding the benefits fi of off-
relation between intra-abdominal pressure and pump surgery in patients at high risk of renal
ARF, with oliguria developing when the intra-
abdominal pressure is greater than 15 mmHg and
anuria developing when pressure is greater than TABLE 6.2. Risk factors after cardiac surgery
30 mmHg. Intra-abdominal decompression is the
Patient specific Surgery related
treatment of choice.
• Advanced age • Emergency surgery
• Diabetes mellitus • Reoperation
Type of Surgery • Hypertension • Prolonged duration of
• Preexisting renal impairment cardiopulmonary bypass
• Impaired left ventricular function • Reexploration for bleeding
Cardiac Surgery (Table 6.2) • Pericardial tamponade
• Deep sternal or systemic
Twenty to 40% of patients undergoing cardiac
infection
surgery experience a rise in serum creatinine by
6. Acute Renal Failure in the Surgical Patient
TABLE 6.3. Specific tests to consider in determining the cause of ARF in surgical patientsa
Blood tests Creatinine kinase
Full blood count
Urinalysis Dipstick
Biochemistry
Culture
Diagnostic imaging Ultrasound scan
Imaging of renal perfusion (e.g., renal
Dopplers, computed tomographic
angiogram, MAG3, DTPA)
Measurement of intravesical
pressure
a
MAG3, mercaptoacetyltriglycine; DTPA, diethylene triamine pentaacetic acid.
failure is still confl
flicting. Although low cardiac
output has been shown to be a strong risk factor
for ARF after cardiac surgery, there is no evidence
that increasing cardiac output from adequate to
supranormal has beneficial
fi renal effects.
Vascular Surgery
Patients undergoing vascular surgery generally
represent a high-risk group for renal failure. The
exact incidence of renal injury in this context is
unknown but, again, depends on the definition
fi of
renal injury, patient characteristics, and type of
surgery. Open surgical repair of abdominal aneu-
rysms is associated with a high risk of renal failure,
especially with suprarenal aortic cross clamping,
massive bleeding, or cholesterol embolization.
The emergence of endovascular repair has led to
a reduced incidence of ARF, however, the risk is
not completely abolished by vascular stents. In
rare instances, endovascular stents have been
found to migrate, resulting in occlusion of arterial
orifi
fices, including renal arteries.
Urological Surgery
Obstruction is a common cause of ARF in patients
with urological problems. Although this diagnosis
is usually made before surgery, it may occur
postoperatively (e.g., after renal transplantation
or ureteric surgery). In general, the majority of
ARF posturological surgery is because of acute
tubular necrosis precipitated by hypotension,
35
To exclude rhabdomyolysis especially after trauma
Eosinophilia is seen in 80% of patients with drug-induced interstitial
nephritis
Significant proteinuria/hematuria/casts suggest intrinsic renal
pathology
Urinary sodium and osmolality to help differentiate prerenal failure
from ATN
To exclude urinary tract infection
To exclude obstruction and to determine renal size
Renal vascular supply may be of concern after major abdominal aortic
surgery. Investigation will depend on patient stability and local
resources
To exclude intra-abdominal hypertension and compartment syndrome
volume depletion, bleeding complications, and/or
urosepsis.
Diagnosis (Table 6.3)
At present, there are no universally accepted cri-
teria for the definition
fi of ARF. Most arbitrary defi fi-
nitions are based on a rise in serum creatinine or
fall in calculated creatinine clearance. It is impor-
tant to remember that the glomerular fi filtration
rate has to fall to less than 50% before serum
creatinine rises, which means that any rise in
serum creatinine always implies significant
fi renal
injury.
Treatment
General Measures
• Restoration of renal perfusion pressure
• Correction of volume depletion
• Avoidance of hypotension (including relative
hypotension). Be guided by the patient’s preex-
isting blood pressure
• Fluid resuscitation, as appropriate, and use of
vasopressor agents if perfusing pressure still
inadequate
• Optimal treatment of sepsis/septic shock
• Avoidance of nephrotoxic medication if possi-
ble. Close monitoring of drug levels when ami-
noglycosides are necessary
36
• Renal replacement therapy in case of severe
metabolic acidosis, unresponsive fluid
fl overload,
resistant hyperkalemia, or pericarditis
• Early involvement of nephrologists if an intrinsic
cause of renal failure is a possibility or if the
patient is likely to require ongoing renal support
Specific Measures
• Removal of septic focus if possible (e.g. drainage
of intra-abdominal abscess)
• Relief of obstruction
• Management of abdominal compartment syn-
drome (including consideration of abdominal
decompression)
• Revascularization of kidneys, if appropriate
Treatments that Have Not Been Shown to
Alter the Course of ARF
• Diuretics (unless patient is fl
fluid overloaded)
• Low-dose dopamine
Vasopressor Agents and the Kidney
Vasopressor agents are often needed to manage
septic shock, and noradrenaline and dopamine are
good first-line drugs. Although there are few direct
comparison studies, patients with septic shock
tend to respond better to noradrenaline. Concern
regarding the potential for noradrenaline to impair
renal and mesenteric perfusion has been reduced
by studies showing that reversal of hypotension
with noradrenaline outweighed this effect and
increased renal and mesenteric perfusion.
Prevention
General Vigilance
Meticulous attention to fluid balance, blood pres-
sure, prescribed drugs, and treatment of sepsis are
the most important preventive measures. There is
insuffi
ficient evidence to recommend specifi fic phys-
iological targets (MAP, cardiac output, filling pres-
sures) that will ensure adequate renal perfusion.
Instead, therapy needs to be individualized based
on the baseline physiological condition of the
individual patient.
M. Ostermann
Early Resuscitation
Early recognition of patients at risk and timely
resuscitation has been shown to result in signifi-
fi
cant reduction of the development of ARF.
Prevention of Contrast-Induced
Nephropathy
The administration of fluids has been shown to be
the most important factor in prevention of con-
trast-induced renal injury. Although the optimal
fluid regimen is uncertain, available data support
fl
a regimen of 0.9% saline at 1 mL/kg/h intrave-
nously from up to 12 hours before administration
of contrast medium and for up to 12 hours after.
Studies on the prophylactic role of N-acetylcyste-
N
ine have had confl flicting results. Meta-analyses
have concluded that prophylactic N-acetylcysteine
N
was harmless and may prevent an acute rise of
serum creatinine after intravenous contrast, but
survival and need for dialysis were not affected.
Tight Glucose Control
A single-center randomized controlled trial on
intensive insulin therapy in postoperative
ventilated patients showed a 41% decrease in the
incidence of ARF requiring dialysis in the group
of patients whose blood sugars were tightly con-
trolled between 4.4 and 6.1 mmol/L compared
with patients whose blood sugar was allowed to
rise to 12 mmol/L before insulin was initiated.
Further studies are necessary to confirm
fi these
results.
Prophylactic Dopamine or Diuretics
A recent meta-analysis of 61 trials showed that
low-dose dopamine (<5 μg/kg/min) often increased
urine output but had no effect on renal function
or prevention of ARF.
Natriuretic Peptides
Urodilatin (renal natriuretic peptide) or anaritide
(synthetic form of atrial natriuretic peptide)
have failed to show any protective effect on the
kidney.
6. Acute Renal Failure in the Surgical Patient
Future Advances
At present, no agents have conclusively demon-
strated a protective effect against ARF or altera-
tion of the course of ARF. Strategies aimed at
modulating renal function and renal recovery
have focused on several mechanisms:
1. Reduction of renal metabolism and energy
consumption of the kidneys (i.e., induction of
hypothermia, use of insulin-like factor I).
2. Modulation of the inflammatory
fl system (i.e.,
up-regulation of the acute stress response,
manipulation of complement system, blockade
of adhesion molecules).
3. Ischemic preconditioning.
These strategies are clearly important areas of
research but not ready for clinical application.
References
1. Bahar I, Akgul A, Ozatik MA, Vural KM, Demirbag
AE, Boran M, Tasdemir O. Acute renal failure follow-
37
ing open heart surgery: risk factors and prognosis.
Perfusion 2005; 20: 317–322.
2. Barrett BJ, Parfrey PS. Preventing nephropathy
induced by contrast medium. N Engl J Med d 2006; 354:
379–386.
3. Chertow GM, Levy EM, Hammermeister KE, Grover
F, Daley J. Independent association between acute
renal failure and mortality following cardiac surgery.
Am J Med d 1998; 104: 343–348.
4. Friedrich JO, Adhikari N, Herridge MS, Beyene J.
Meta-analysis: low-dose dopamine increases urine
output but does not prevent renal dysfunction or
death. Ann Intern Med d 2005; 142: 510–524.
5. Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml
W, Hiesmayr M. Lack of renoprotective effects of
dopamine and furosemide during cardiac surgery.
J Am Soc Nephroll 2000; 11: 97–104.
6. Mangano DT, Tudor IC, Dietzel C. Multicenter Study
of Perioperative Ischemia Research Group; Ischemia
Research and Education Foundation. The risk associ-
ated with aprotinin in cardiac surgery. N Engl J Med
2006; 354: 353–365.
7. Van den Berghe G, Wouters PJ, Bouillon R, et al.
Intensive insulin therapy in critically ill patients.
N Engl J Med d 2001; 345: 1359–1367.
7
Rhabdomyolysis and
Compartment Syndrome
Laurie Tomlinson and Stephen Holt
Rhabdomyolysis occurs when an insult causing
myocyte necrosis results in release of intra-
cellular contents into the circulation. Renal dys-
function is caused by a combination of renal
vasoconstriction, tubular damage, and tubular
obstruction.
Causes
Rhabdomyolysis accounts for approximately 7%
of all causes of acute renal failure (ARF) during
peacetime. This figure is much higher after natural
disasters and in wartime. For example, after the
1998 Turkish earthquake, 12% of the hospitalized
population developed significant
fi renal dysfunc-
tion and 477 patients required dialysis.
Direct crush or compression injury and drugs
are the most important causes in clinical practice,
see Table 7.1. There are often predisposing factors,
for example, alcohol, which can presensitize myo-
cytes so they may be damaged by a more trivial
insult. A clinical scoring system exists (not widely
used) based on levels of phosphate, potassium,
albumin, creatine kinase (CK), and presence of
dehydration and sepsis.
Compartment Syndrome
After an appropriate precipitant, inflammation
fl
within a muscular compartment causes a vicious
cycle of increasing pressure. This leads to further
infl
flammation and damage, eventually compro-
mising blood supply, leading to further muscle
38
necrosis. There may be severe pain, with loss of
muscle function and loss of distal pulses. The
diagnosis may be occult, especially in the uncon-
scious patient. Direct pressure measurements
can be made by passing a needle connected to a
pressure manometer (e.g., central venous pressure
[CVP] transducer) into the affected muscle
compartment.
A fasciotomy should be considered if the pressure
exceeds 40 mmHg or greater than 30 mmHg above
diastolic pressure.
Diagnosis
Serum changes consequent on rhabdomyolysis:
Creatine Kinase
Very high levels of the muscle enzyme CK are
pathognomic of this condition. The degree of eleva-
tion is proportional to the degree of muscle injury.
Other muscle enzymes, such as aspartate transami-
nase (AST) and lactate dehydrogenase (LDH) are
also elevated. CK levels should decline by approxi-
mately 40% per day, a plateau or an increase should
prompt a search for ongoing muscle damage.
Hyperkalemia
Hyperkalemia caused by efflux
fl of potassium from
damaged cells is an early and life-threatening
consequence of rhabdomyolysis. It should be
aggressively treated.
7. Rhabdomyolysis and Compartment Syndrome 39

TABLE 7.1. Causes of rhabdomyolysis

Physical Trauma, hyperthermia, hypothermia, exercise, electric shock, seizures, delirium tremens
Toxins and drugs Alcohol, statins, amphetamines, aspirin (overdose), barium, barbiturates, caffeine, carbon monoxide, ecstasy, ethylene
glycol, LSD, malignant hyperpyrexia, neuroleptic malignant syndrome, opiates, toluene, snake/insect bites, vasopressin
Muscle ischemia Vascular ischemia, coma, sickle cell disease, surgery, vasoconstrictors, CO2 angiography
Infection Virtually any viral or bacterial infection (e.g., influenza, HIV, Epstein-Barr virus, Legionella, tetanus, malaria, Bacillus cereus)
Metabolic Hypernatremia/hyponatremia, hypokalemia, hypophosphatemia, diabetic ketoacidosis, diabetic hyperosmolar coma,
water intoxication, myxedema
Inherited Deficiency of carnitine palmityl transferase II, phosphofructokinase, myophosphorylase (McArdles), myoadenylate deaminase,
cytochrome oxidase, succinic dehydrogenase, coenzyme Q10 deficiency, King-Denborough Syndrome, Wilson’s disease
Immune Polymyositis, dermatomyositis

Acidosis rise in parathyroid hormone (a reflex

Metabolic acidosis may be caused by increased
lactate production and lactate release by damaged
muscle. Myoglobin (Mb) is considerably more
toxic in an acid milieu.
Early Hypocalcemia and Late Hypercalcemia
Serum calcium levels often fall dramatically,
with total calcium less than 1.7 mmol/L in the
early stages. This is caused by sequestration into
damaged muscle and reperfusion-induced cellu-
lar calcium uptake. In contrast, intracellular
calcium concentrations in damaged muscle may
rise by up to 10-fold. In the recovery phase of
rhabdomyolysis, serum calcium levels normalize
and may even “overshoot,” secondary to calcium
release by recovering myocytes and a transient
fl to the initial
hypocalcemia).
Symptoms of hypocalcemia are rare and treat-
ment with intravenous calcium should be avoided
unless tetany or cardiac dysfunction is present.
Pharmacologically administered calcium is taken
up avidly by the damaged muscle. It may be depos-
ited as inorganic complexes causing “heterotopic
calcification,”
fi which delays recovery and can lead
to long-term muscle dysfunction.
Hyperphosphatemia
Serum phosphate often exceeds 3 mmol/L.
Urinary Abnormalities
Urine dipsticks are usually positive for blood
because they detect the heme moiety present in
both hemoglobin (Hb) and Mb. On microscopy,
few red cells are seen (unless there is coexistent
trauma), instead, the characteristic “brown sugar
casts” of Mb are seen (Figure 7.1). When there is
uncertainty, Mb can be specifically
fi assayed in the
urine, although it has a short half-life. An assay
exists for myosin heavy chain, which remains pos-
itive for up to 12 days after the initial insult.

Pathophysiology of ARF
Suggested causes:
1. A reduction in renal blood flow
fl . There is a
FIGURE 7.1. “Brown sugar” Mb casts under light microscope are reduction in the effective blood volume caused
similar to granular casts but have a brown/rusty tinge. Additional by fluid
fl shifts from the intravascular to extracel-
red cells, tubular cells, and other debris are also present within lular fluid
fl compartments. Mb binds to nitric
the urine. oxide (NO), preventing intrarenal vasodilation
40 L. Tomlinson and S. Holt

(especially in the medulla) and, in addition, vaso-
dilators (e.g., endothelin) are increased.
2. Direct heme protein tubulotoxicityy occurs,
probably by free radical-mediated mechanisms.
3. Tubular cast formation. Urinary Mb and
Tamm-Horsfall protein (THP) complex and precip-
itate as tubular casts. These casts are less soluble in
acidic conditions. Although there is some evidence
that these complexes cause tubular obstruction,
micropuncture studies have shown relatively low
intratubular pressures, suggesting that these casts
are as a result of reduced tubular flflow and reduced
washout rather than by obstruction per se.
Treatment
• Bicarbonate solutions that are more concentrated
can be administered in small aliquots, e.g., 50 mL
of 8.4% NaHC03 via central access in patients
who are intravascularly full—remembering that
this is 1 mmol of sodium per milliliter of fluid
fl
and may cause sodium/fluid
fl overload
Mannitol
Mannitol promotes an osmotic diuresis and may
reduce pressure in a swollen muscle compartment,
but it also causes osmotically induced tubular
damage with vacuolation. There is no good evi-
dence that it is more effective than saline alone
and it has little scientifi
fic rationale to recommend
its routine use.

Intravascular Volume Expansion Dialysis/Hemofiltration

Intravascular volume expansion at the first
fi possi-
The circulating concentration of Mb can be
ble opportunity after the insult is the single most
reduced by hemofi filtration, plasma exchange, and
effective therapeutic maneuver in rhabdomyoly-
hemodialysis, with dialysis being somewhat less
sis. This not only prevents or limits renal damage
successful. It has not been shown that any physical
but may play a role in preventing acidosis and
therapy materially reduces renal Mb burden or
limiting ongoing damage caused by hypoperfu-
shortens the duration of renal replacement
sion. Very large volumes of fluid
fl can be lost into
therapy. Physical therapies may have a role, if
areas of muscle injury. In trauma situations in
commenced early, or if Mb release can be antici-
which there is a risk of crush injury, fl
fluid resusci-
pated, such as during arterial surgery.
tation should be commenced before the victim is
extricated.
Prognosis
Alkalinization
There is an unquantifiable
fi early mortality, mainly
There is much compelling evidence to suggest that
caused by hyperkalemia or the insult. Mortality
urinary alkalinization greatly reduces the nephro-
after diagnosis is up to 20%, usually caused by
toxicity of Mb. However, there are no large human
other associated conditions, e.g., sepsis. Survivors
trials that confirm
fi this consistent finding from
of the Japanese earthquake in 1995 arriving in
animal research. The potential benefits fi in this
hospital within 6 hours had an approximately 20%
setting include reduced renal vasoconstriction, a
chance of developing ARF, whereas all of those
dramatic reduction in the ability of Mb to cause
arriving after 40 hours developed renal failure. If
oxidant damage, and increased solubility of Mb-
the patient recovers from the initial insult, the
THP complex.
renal dysfunction almost always resolves, but can
Alkalinization can lower ionized calcium still
take up to 3 months.
further and, if administered, it is wise to periodi-
cally check the ionized calcium.
A suggested fluid
fl replacement regime would
be:
Summary
• Isotonic bicarbonate (1.26% sodium bicarbonate) • Rhabdomyolysis is a common cause of ARF, with
until urine pH is greater than 7 if the patient is important early biochemical changes that may
intravascularly volume deplete (which is usual) be fatal if treatment is not instituted quickly
7. Rhabdomyolysis and Compartment Syndrome
• Compartment syndromes can be occult and are
important to detect and monitor to protect
against further renal injury
• Early treatment with volume replacement
(±alkalinization) will reduce the risk of renal
failure and the need for renal replacement
therapy
41
Suggested Reading
Holt SG, Moore KP. Pathogenesis and treatment of renal
dysfunction in rhabdomyolysis. Intensive Care Med.
2001 May; 27(5): 803–811.
Zager R. Rhabdomyolysis and myohemoglobinuric acute
renal failure. Kidney Int. 1996 Feb; 49(2): 314–326.
8
Multisystem Causes of Acute
Renal Failure
Tim Leach
This chapter covers some of the more specialized
causes of acute renal failure, which, although more
likely to present to the nephrologist, could be
admitted to the intensive care unit as a conse-
quence of their illness or because of complications
of their treatment.
Systemic Vasculitis
Vasculitis is the term given to inflammation
fl of
blood vessels. Vasculitis is a rare condition, with
an incidence of approximately 6 people per million
(Western) population per year (1). Vessels can be
classified
fi according to their size (Table 8.1) (2).
Renal failure can occur in any vasculitis, but this
chapter focuses on those conditions that affect
renal function directly through inflammation
fl
within the glomeruli (small vessels), rather than
affecting the kidneys indirectly through a reduc-
tion of blood supply to the kidneys (large and
medium vessel diseases).
Etiology
Small vessel vasculitides separate into two broad
groups: those in which immune complexes are
deposited within the renal glomeruli and those
without evidence of deposition histologically. The
latter group are termed pauci-immune; lacking
(literally “few”) immune complexes. This distinc-
tion is useful for making a histological diagnosis
and for estimating prognosis, but the underlying
cause of these small vessel vasculitides is similar:
autoimmunity.
42
Normally, the immune system surveys cells and
tissues within the body, recognizing and ignoring
cells expressing “self” antigens while attacking
cells without these protective epitopes. In autoim-
mune conditions, the immune system does not
protect cells with “self” expression. Cells are
attacked and either inflflamed or killed, or circulat-
ing self-antigens are bound with antibody-forming
immune complexes. Immune complexes are very
large molecules that are often unable to pass
through capillaries because of their size. They can
induce local inflflammation and activate the com-
plement cascade.
Presentation
Symptoms
Renal failure as a result of fulminant small vessel
vasculitis will present acutely, and patients may
be systemically unwell, requiring organ support.
More often, however, there is an indolent presenta-
tion with several months of nonspecificfi symptoms
and signs (Table 8.2).
Signs
Fulminant systemic vasculitis presents with the
nephritic syndrome:
• Azotemia (more often with oligoanuria)
• Hypertension and edema from fl fluid overload
(but can present with circulatory collapse caused
by vasodilation and dehydration)
• Hematuria with red cell casts
8. Multisystem Causes of Acute Renal Failure 43

TABLE 8.1. Vasculitic conditions according to the vessel size

affected
Vessel size Condition
Large Takayasu’s arteritis
Giant cell arteritis
Medium Polyarteritis nodosa
Kawasaki disease
Small Pauci-immune:
• Wegener’s granulomatosis (WG)
• Microscopic polyangiitis (MPA)
• Churg-Strauss disease (CSD) Immune-complex
forming
• Goodpasture syndrome (GS) Immune-complex
depositing:
• SLE
• Henoch-Schönlein purpura (HSP)
• Cryoglobulins
• Rheumatoid arthritis FIGURE 8.1. Plain chest x-ray of fulminant pulmonary hemorrhage
of 17-year-old male patient with systemic vasculitis caused by
Source: Jeanette et al., 1994. Henoch-Schönlein purpura. The patchy diffuse alveolar shadowing
is clearly seen.
Other features include:
pneumonitis (Figure 8.1), or superadded
• Fever pneumonia
• Raised purpuric rash
• Respiratory failure secondary to pulmonary
edema, pulmonary hemorrhage from vasculitic Laboratory Investigations (Table 8.3)
TABLE 8.2. Nonrenal symptoms suffered in systemic vasculitis Imaging
Relative frequency Chest x-ray may be clear or show pulmonary
(some patients
edema or pulmonary hemorrhage (Figure 8.1).
System experienced more
affected than one) Symptoms Renal ultrasound will usually show normal-sized
kidneys with no obstruction.
Lower 63% Cough
respiratory Breathlessness (on
exertion/at Renal Biopsy
rest/orthopnea)
Hemoptysis The ultimate investigation for renal vasculitis is
Upper 50% Sinusitis the biopsy. Patients need to be hemodynamically
respiratory Nasal congestion
stable, normotensive, have a normal platelet count
Reduced hearing
Epistaxis and coagulation screen and be able to lie flat
fl (see
Skeletal 42% Arthralgia Figure 8.2).
Arthritis
Synovitis
Muscular 33% Myalgia
Myositis
Treatment
Muscle weakness
Dermatological 22% Rash (purpura/echinoses/ Treatments of patients with vasculitis fall into
malar flush) three main areas:
Neurological 14% Headache
Lethargy
Loss of concentration Resuscitation
Coma
Patients should be stabilized in terms of airway,
Source: Hedger et al., 2000. breathing, and circulation, as in any serious illness.
44 T. Leach

TABLE 8.3. Investigations for systemic vasculitis

Investigation Rationale Expected result
Urea and electrolytes Likely renal failure Elevated urea and creatinine
Potentially elevated potassium
Full blood count Anemia Anemia
Elevated white cell count
Normal/elevated platelet count (cff HUS)
Antineutrophil cytoplasmic antibody WG and MPA associated with positive ANCA Positive cANCA in WG
(ANCA) Positive pANCA in MPA
Otherwise negative
Antiglomerular basement antibody Goodpasture syndrome Positive in GS
(aGBM) Otherwise negative
Complement Involved in inflammation Usually mildly or significantly reduced levels of
C3 and C4
ESR/CRP Inflammatory markers Usually significantly elevated

ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Maintenance Disease-Specific Treatment

Maintenance of adequate oxygenation, circula-
tion, and fluid balance is vital to their recovery.
Hemofi filtration, hemodiafi filtration, or hemodialy-
sis depending on the patient’s hemodynamic
stability should be used to prevent and treat com-
plications that do not respond to standard medical
therapies. Infection, bleeding, and malnutrition
should be sought and remedied.
The disease is one of an abnormal immune
response inducing renal and other organ inflam-
fl
mation and treatment falls into three groups.
1. Reduction of inflammation
fl with corticoste-
roids (e.g., intravenous methylprednisolone fol-
lowed by oral prednisolone).
2. Reduction of antibody formation with
immunosuppressive agents (e.g., cyclophospha-
mide administered intravenously every 2 to 4
weeks or orally everyday).
3. Removal of the already-formed antibodies
with therapeutic plasma exchange if the patient has
pulmonary hemorrhage (potentially life threaten-
ing) or is requiring renal dialysis (severe disease).

FIGURE 8.2. Photomicrograph of renal biopsy from patient with
Wegener’s (cANCA-positive) renal vasculitis. Hematoxylin and
eosin stain with silver counterstain, showing features consistent
with the disease. The glomerulus (black arrow)
w shows segmental
fibrinoid change (red arrows) and crescent formation (yellow
( roids alone, but 90% of patients may develop renal
arrow).
w Some tubules contain red cells (white arrows). (Photo
reproduced with the kind permission of Dr. Nicholas Marley.)
Outcome
Renal vasculitis is a serious illness with significant
fi
morbidity and mortality. Before treatment, it was
universally fatal; with treatment, mortality is 10%
at 18 months. Up to 50% of patients require dialy-
sis with no renal recovery. If the patient did not
require dialysis at presentation, there is a 91%
chance of renal survival. If dialysis dependent at
presentation, 30% of patients may regain renal
function with cyclophosphamide and corticoste-
recovery with the addition of therapeutic plasma
exchange (3, 4).
8. Multisystem Causes of Acute Renal Failure 45

Infection is the most significant

fi side effect of
treatment. Bacterial sepsis, viral infections such as
herpes zoster and cytomegalovirus, fungal sepsis,
and Pneumocystis carinii pneumonitis (PCP)
occur in 40% of treated patients (5). Prophylaxis
against fungi and PCP is recommended.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multisys-
tem autoimmune condition of primarily young
(20–30 years old) women (Figure 8.3). The Ameri-
can College of Rheumatology definesfi the diagno-
sis of lupus for a patient presenting with four or
more of the following features at the same time, or
individually during a period of time:
1. Malar rash: redness or rash that may appear
in a butterflfly confi figuration across the nose
and cheeks. It can appear on one or both sides
of the face and is usually flat.
fl FIGURE 8.3. Magnetic resonance imaging scan of brain of 21-year-
2. Discoid rash: thick raised patches that can old woman with cerebral lupus. T2-weighted sagittal section
occur on any part of the body and may result shows increased white and grey matter signal, particularly in the
frontal and parietal regions, in keeping with cerebral vasculitis.
in scarring.
3. Sun sensitivity: a reaction to sunlight that is
more severe than just sunburn. interstitial pneumonitis, or aseptic meningitis. A
4. Oral ulcers: frequent development of mouth positive Coombs test, low complement levels, and
or nose ulcers. immune deposits at the dermal-epidermal junc-
5. Arthritis: pain, tenderness, or swelling in two tion on skin biopsy are also suggestive of lupus.
or more joints. Patients with SLE can present in extremis with
6. Pleurisy or pericarditis. any system involvement. The presence of a multi-
7. Nephritis: proteinuria or cellular casts in the system disease such as SLE should always be
urine. entertained in such patients.
8. Nervous system disorder: seizures or psy-
chotic behavior that cannot be attributed to
Laboratory Testing
drugs or metabolic dysfunction.
9. Blood system disorder: hemolytic anemia, leu- Tests that provide potentially diagnostically useful
kopenia, lymphopenia, or thrombocytopenia. information when SLE is suspected include:
10. Immunologic disorder: the presence of the
• Complete blood count and differential
lupus erythematosus (LE) cell, a false-positive
• Serum creatinine
reaction to the tests for syphilis, or the pre-
• Serum albumin
sence of autoantibodies.
• Serologic test for syphilis (falsely positive
11. Positive antinuclear antibodies (ANA): anti-
because of cross-reactivity)
bodies against the nucleus of cells, particu-
• Urinalysis
larly against double-stranded DNA.
• 24-hour urine collection for calculation of creati-
Lupus should also be suspected in young nine clearance and quantifification of proteinuria
women presenting with purpura, easy bruising, • Autoantibody testing: ANA, antibodies to phos-
diffuse lymphadenopathy, hepatosplenomegaly, pholipids, antibodies to double-stranded DNA,
peripheral neuropathy, endocarditis, myocarditis, and antibodies to Smith (Sm)
46
• Complement levels (total hemolytic comple-
ment [CH50], C3 and C4)
Imaging
This may be valuable but is not routinely obtained
unless indicated by the presence of symptoms,
clinical findings, or laboratory abnormalities.
Examples include:
• Plain radiographs of involved joints
• Renal ultrasound to assess kidney size and rule
out an obstructive post-renal cause when there
is evidence of acute renal failure
• Chest X ray
• Echocardiography (for suspected pericardial
involvement or to seek a source of emboli)
• CT scanning (for abdominal pain, suspected
pancreatitis, lymphadenopathy)
• Magnetic resonance imaging (for seizure activ-
ity, focal neurologic defificits or cognitive dys-
function/personality changes—see Figure 8.3)
• Contrast angiography may be valuable if vascu-
litis affecting medium-sized arteries is suspected
(mesenteric or limb-threatening ischemia).
Treatment
Treatment is broad and depends on the system
involved. General principles are:
• Reduce inflammation
fl with corticosteroids
• Prevent further autoantibody production with
immunosuppressant medications such as cyclo-
phosphamide or mycophenolate mofetil
• Remove circulating autoantibodies with thera-
peutic plasma exchange
Antiphospholipid antibodies and the presence
of the lupus anticoagulant increase coagulation
and lead to arterial and venous thromboses. Use
of antiplatelet drugs, thrombolytics, and antico-
agulation in these patients often prevents further
problems.
Fertility and pregnancy in lupus patients are
often problematic. Pregnancy alters the immune
state, often leading to fl
flares of lupus postpartum.
Coagulation abnormalities often lead to difficul-
fi be normal and will rarely have central neuro-
ties with conception and spontaneous abortion.
Primary infertility or recurrent miscarriages are
relatively common presenting features of SLE.
T. Leach
Thrombotic Microangiopathy
Thrombotic microangiopathy (TMA) covers the
acute syndrome of microangiopathic hemolytic
anemia, thrombocytopenia, and variable signs of
organ injury caused by platelet thromboses in
the microcirculation. Two clinically distinct but
pathologically identical syndromes are described:
hemolytic uremic syndrome (HUS) and throm-
botic thrombocytopenic purpura (TTP). HUS
usually affects children with renal failure but
minimal neurological involvement. TTP is a
disease of adults, with predominantly neurologi-
cal involvement and variable other organ disease.
The two syndromes often overlap and, thus, are
termed HUS/TTP.
Etiology
The mechanisms behind the development of
TMA are poorly understood but seem to involve
endothelial injury, which triggers events leading
to microvascular thrombosis, microangiopathic
hemolytic anemia, and platelet consumption.
Most causative factors lead to toxicity of the
endothelial cells: autoantibodies, exotoxins and
endotoxins, immune complexes, and certain
drugs.
The pathology of TMA consists of capillary and
arteriolar wall widening, with swelling and detach-
ment of the endothelium, and occlusion or severe
restriction of the lumen and platelet micro-
thrombi. In HUS, this occurs mainly in the kidney,
in TTP, mainly in the brain.
Presentation
HUS/TTP rarely causes specifi fic symptoms. In the
situations shown in Table 8.4, vomiting, pallor,
purpura, anuria, and/or neurological signs should
alert the clinician to the possibility of TMA.
Differential Diagnosis
• Systemic vasculitis will usually present with
arthralgia/arthritis, and the platelet count will
logical involvement.
• Disseminated intravascular coagulation (DIC)
is usually associated with shock or obstetric
8. Multisystem Causes of Acute Renal Failure 47

TABLE 8.4. Conditions and situations associated with the development of

HUS/TTP
Acquired Shigatoxin (Escherichia colii 0157)
Pregnancy
Pneumococcal infection
Systemic disease
Drug associated
Organ transplant
Genetic and familial forms
Idiopathic and atypical forms
HIV infection
SLE
Scleroderma
Malignancy
Mitomycin C, tamoxifen,
bleomycin, cisplatin,
clopidogrel, quinine, interferon,
OKT3, cyclosporine, tacrolimus
(among others)
De novo (usually drugs)
Recurrent posttransplant HUS

complications and will have consumption of all
of the clotting factors.
• Malignant hypertension will have classical
retinal changes, signifificant high blood pressure
(usually >210/130), and usually a history of
hypertension.
Laboratory Investigations
• Low hemoglobin (<7 g/dL)
• Thrombocytopenia (<80 × 109 cells/L)
• The blood filmfi will show red cell fragments
(schistocytes) and increased reticulocyte
counts
• Elevated lactate dehydrogenase and indirect
bilirubin (caused by hemolysis)
• Haptoglobin levels will usually be low because
of consumption
• Coombs test is negative
• Moderate proteinuria (1–2 g/d) with few red
cells and casts (ARF is secondary to occlusion of
capillaries rather than inflammation)
fl References
Treatment and Outcome
The epidemic or sporadic diarrhea-associated
HUS/TTP of young children is usually self-limiting
and mild. Renal failure requires dialysis in approxi-
mately 50% of patients, but otherwise supportive
treatment is all that is required. Ninety percent of
patients should recover completely. Up to 5% of
patients can die in the acute phase. Cerebrovascular
accidents, seizures, and coma occur in 25% of
patients, and residual impairment of renal
excretory function is present in up to 40% of
patients.
HUS/TTP in adults or children older than 14
years old usually requires treatment. In those with
an apparent cause (pregnancy, malignancy, infec-
tion, or drugs), removal of the cause is essential.
Supportive treatment is required. Specific fi treat-
ment of the condition revolves around therapeutic
plasma exchange or plasma infusion if TPE is
not available. There is no evidence of benefi fit of
immunosuppression with corticosteroids, immu-
noglobulins, or vincristine, or of benefit fi from
antithrombotic or antiplatelet agents.
Rescue therapies from severe refractory or
relapsing disease include bilateral nephrectomy
and/or splenectomy.
1. Hedger N, Stevens J, Drey N, Walker S, Roderick P.
Incidence and outcome of pauci-immune rapidly
progressive glomerulonephritis in Wessex, UK: a 10-
year retrospective study. Nephrol Dial Transplant
2000; 15(10): 1539–1539.
2. Jennette JC, Falk RJ, Andrassy K. Nomenclature of
systemic vasculitides. Proposal of an international
consensus conference. Arthritis Rheum 1994; 37:
187–192.
48
3. Andrassy K, Kuster S, Waldherr R, Ritz E. Rapidly pro-
gressive glomerulonephritis: analysis of prevalence
and clinical course. Nephron 1991; 59(2): 206–212.
4. Pusey CD, Rees AJ, Evans DJ, Peter DK, Lockwood
CM. Plasma exchange in focal necrotizing glomeru-
T. Leach
lonephritis without anti-GBM antibodies. Kidney Int
1991; 40(4): 757–763.
5. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener gran-
ulomatosis: an analysis of 158 patients. Ann Intern
Medd 1992; 116: 488–498.
9
Therapeutic Plasma Exchange
Tim Leach

Therapeutic plasma exchange (TPE) is an extra- • Of molecular weight greater than 15,000 kDa
corporeal blood purifi fication technique designed so it cannot be removed in any other way,
for the removal of large molecular weight sub- and/or
stances from plasma. Large molecular weight • Of suffi
ficient half-life that TPE is quicker than
substances equilibrate slowly between the vascu- endogenous removal, and/or
lar space and the interstitium. Calculations of • Acutely toxic and resistant to conventional
the rate of their removal by TPE follows fi first- therapy
order kinetics, i.e., approximately 60% is removed
by a single plasma volume exchange, and 75%
by an exchange equal to 1.4 times the plasma
volume.
Prescription (Table 9.1)
Blood is pumped through a highly permeable
Calculation of plasma volume:
filter, replacing the filtrate with fluid as indicated
fi
(Table 9.1). Venous access on the intensive care Estimated plasma volume (L) = 0.07 × Weight
unit (ICU) is via a double-lumen dialysis catheter, (kg) × (1 − hematocrit)
but can be via two wide-gauge peripheral venous
1. Before each treatment, measure serum potas-
cannulae. If chronic therapy is indicated, an arte-
sium calcium and clotting screen.
riovenous fifistula is used. The patient and filter are
2. Calculate the estimated plasma volume: Volume
anticoagulated during the procedure.
of exchange is measured in Patient Plasma
Volumes (∼3 L).
3. Prescribe the plasma exchange:
Indications (Table 9.2) a. Number and spacing of treatments
b. Volume and type of fl fluid
The basic premise of TPE is that removal of large
4. Electrolyte supplementation as needed (potas-
molecular weight substances from the circulation
sium and calcium).
will reduce further damage and may permit rever-
5. If coagulopathic consider, fresh-frozen plasma
sal of the pathological process.
(FFP) as the final exchange volume.
Other benefits
fi include unloading the reticulo-
endothelial system to permit further endogenous
removal of circulating toxins, stimulation of lym-
After Procedure
phocyte clones, and allowing re-infusion of large
volumes of plasma without the risk of volume • Repeat electrolytes and clotting after 2 hours
overload. and increase supplementation as needed
For TPE to be appropriate, the substance to be • FFP can be given as the final exchange volume
removed should be: if coagulopathic

49
50 T. Leach

TABLE 9.1. Example of TPE prescriptiona

Indication Plasma volumes Replacement fluid Number of exchanges Exchange frequency
Rapidly progressive 1 to 1.5 Albumin, with FFP if 7 to 10 Daily or alternate days
glomerulonephritis pulmonary hemorrhage
Acute renal failure caused
by myeloma kidney
Hyperviscosity 1 Albumin/saline mixtureb Until symptoms subside or Daily
Syndrome plasma viscosity
normal
Anti-glomerular basement 1.5 Albumin, with FFP if 7 to 10 Daily
membrane (GBM) disease pulmonary hemorrhage
Hemolytic uremic 1 to 2 All FFP Until platelets normal/no Once or twice daily
syndrome/thrombotic red cell fragments
thrombocytopenic purpura (usually 7 to 16)
Guillain-Barré Syndrome 2 Albumin 4 Alternate days
a
From: Wessex Renal and Transplant Unit, United Kingdom.
No more than one part saline to two parts albumin (i.e., ≤1 L saline for 2 L albumin).
b

TABLE 9.2. American Association of Blood Banks indications for Complications

TPE
1. Standard and acceptable
• Chronic inflammatory
demyelinating
polyneuropathy
• Cryoglobulinemia
• Anti-GBM disease
• Guillain-Barré syndrome
• Familial hypercholesterolemia
• Myasthenia gravis
• Posttransfusion purpura
• Thrombotic
thrombocytopenic purpura
3. Inconclusive evidence orr
uncertain benefit-to-risk ratio
• ABO-incompatible organ or
marrow transplantation
• Coagulation factor inhibitors
• Idiopathic thrombocytopenic
purpura
• Multiple sclerosis
• Progressive systemic sclerosis
• Thyroid storm
• Warm autoimmune
hemolytic anemia
2. Sufficient evidence to suggest • Hypotension: vasovagal, hypovolemia
efficacy/acceptable adjunct • Fluid overload
• Cold agglutinin disease
• Hypocalcemia causing tetany
• Protein-bound toxins
(drug overdose/ • Hypokalemia
poisonings) • Coagulopathy caused by removal of clotting
• Hemolytic uremic factors or thrombocytopenia with heparin
syndrome anticoagulation
• Rapidly progressive
• Protein-bound drug removal (administer drugs
glomerulonephritis
• Systemic vasculitis afterr TPE)
• Acute renal failure caused • ACE inhibitors may cause fl flushing and hypoten-
by myeloma kidney sion (stop 24 h before treatment)
4. No efficacy in trials
• AIDS
• Amyotrophic lateral
sclerosis
• Dermato/polymyositis
• Psoriasis
• Renal transplant rejection
• Rheumatoid arthritis
• Schizophrenia
10
Renal Replacement Therapy
John H. Reeves
Acute renal failure (ARF) occurs in 7% of patients
admitted to the intensive care unit (ICU) (1). Pre-
viously, mortality exceeded 91%, but with the
introduction of dialysis, this quickly fell to approx-
imately 50% (2). Overall mortality for ARF has
remained approximately 50%, associated with
increasing comorbidity (3).
There is no specifi
fic therapy for ARF other than
removal of the cause and ongoing supportive care
awaiting spontaneous recovery. Renal replacement
therapy (RRT) is the cornerstone of that support-
ive care.
The Basics
Extracorporeal RRT involves the passage of a
patient’s blood outside his/her body through a
dialysis or hemofilter
fi machine, where the removal
of unwanted solutes and excess water and the
replacement of lost bicarbonate (or buffer base)
take place. The “purified”
fi blood is returned to the
patient.
Clearance can be definedfi as that volume of
plasma completely cleared of a substance in a
given time. During extracorporeal RRT, net solute
clearance can be achieved by ultrafiltration
fi across
a porous membrane down a pressure gradient (fi (fil-
tration), or by diffusion across a semipermeable
membrane down a concentration gradient (dialy-
sis), or both. During fifiltration, the filtrate is dis-
carded and a replacement solution is added to the
blood to maintain fluid
fl and electrolyte equilib-
rium. During dialysis, a continuous stream of
dialysate is passed in the opposite direction to
blood, on the nonblood side of the membrane, to
51
maintain a concentration gradient favoring the
out-diffusion of unwanted solutes. Both dialysate
and replacement solutions contain electrolytes in
physiological concentrations and some form of
buffer base.
The hemofilter
fi r or dialysis membrane’s permea-
bility to water is determined by its surface area
(typically 0.5 to 2.0 m2) and the number and size
of its pores (typically 0.0055-μm diameter in a
high-flux
fl hemofi filter). The pore size determines
the size of molecules that are freely fi
filtered along
with water. Current hemofilters
fi freely filter sub-
stances up to approximately 5000-D molecular
weight and then in decreasing amounts up to a cut
off of approximately 20,000 Da. This minimizes
loss of important larger molecules, such as
albumin (molecular weight, 57,000 Da).
The ratio between the concentration of solute
in filtrate and that in plasma water is called the
sieving coefficient
fi , and this concept becomes
important in calculating the clearance of interme-
diate-sized molecules. The sieving coefficient
fi for
a small unbound solutes is one, decreasing to zero
as molecular size and or plasma protein binding
increases.
Theoretical small solute clearance can be pre-
dicted by knowledge of the blood flow
fl through the
extracorporeal circuit (QB) and the rate of ultrafil-
fi
tration (QF) and dialysate flow
fl (QD) (Figure 10.1).
During continuous RRT (CRRT), when blood
flow is signifi
fl ficantly higher than dialysate or ultra-
filtration rates, small solute clearance is deter-
fi
mined by dialysate and ultrafiltrate
fi flow. Assuming
complete concentration equilibrium between dial-
ysate and plasma water and a sieving coefficient
fi
equal to one:
52
Haemofiltration replacement ≅ QF
Blood flow
Membrane QB
Effluent Dialysate
QE QD
FIGURE 10.1. Predicting clearance during RRT.
Clearance during CRRT = QF + QD = QE
In contrast, during intermittentt hemodialysis
(IHD), dialysate flow is signifificantly higher than
blood flow, and blood flow becomes the limiting
factor for solute clearance. Small solute clearance
is proportional to the plasma flowfl through the
dialyzer:
Clearance during IHD ≅ QB × (1 − hematocrit)
This simplifified analysis only holds for small,
unbound solutes, such as urea and creatinine.
Increasing molecular weight decreases diffusive
clearance more signifi
ficantly than convective clear-
ance. Binding to macromolecules, such as albumin,
decreases convective and diffusive clearance (4).
Classification of RRT
In 1977, when Peter Kramer firstfi described con-
tinuous arteriovenous hemofi filtration (CAVH)
as a therapy for diuretic resistant flfluid overload
(5), the only other types of RRT were IHD and
peritoneal dialysis (PD). Since then, the classifica-
fi the clearance of the solute is convective—carried
tion of RRT has expanded (6). See the glossary in
Table 10.1.
Duration or Timing of Therapy
Continuous: CRRT aims to provide support 24 h/d,
but, in practice, is interrupted by factors such as
patient transfer out of the ICU or circuit failure.
Intermittent: IHD requires approximately 3 hours
per treatment. Patients with end-stage renal
failure (ESRF) may be maintained in the com-
munity with as few as three dialysis sessions per
J.H. Reeves
week. In contrast, ICU patients with ARF may
require daily treatment (7).
Hybrid: there is increasing interest in hybrid
approaches for extracorporeal RRT in the ICU
(8, 9). For example, during sustained low-
efficiency
fi dialysis (SLED), daily intermittent
therapy is reduced in intensity and extended in
duration up to 8 or 12 hours. The regular breaks
aid staffi
fing and free patients for investigations
and procedures. The reduced intensity reduces
the cardiorespiratory destabilization associated
with IHD.
Access
Arteriovenous: arteriovenous access involves can-
nulation of a medium-sized artery and large
vein—often the femoral artery and vein. Blood
flows passively from the artery through the
extracorporeal circuit (ECC) and back through
the vein, driven by the mean arterial pressure.
This method is reserved for situations in which
resources are limited.
Venovenous: venovenous access involves cannula-
tion of central veins, most commonly with a
double-lumen cannula in the femoral, internal
jugular, or subclavian vein. Blood flow
fl is driven
by a pump in the ECC. This increases reliability
of blood flow
fl and maximizes solute clearance,
but introduces the need for more complex safety
mechanisms to detect fault conditions, such as
air embolism or circuit occlusion.
Mechanism of Solute Removal
Convection: when solute is cleared by ultrafiltra-
fi
tion through a porous membrane, we say that
by the bulk flow of plasma water. During CRRT,
the process is called hemofiltration
fi .
Diffusion: when solute is cleared by diffusion
down a concentration gradient across a semi-
permeable membrane, we say that the clearance
of the solute is diffusive. The process is called
hemodialysis.
Combinations: diafiltration
fi is the term applied
when both convection and diffusion are operat-
ing to remove solute.
Adsorption: adsorption is the binding of sub-
stances to the membrane under molecular
10. Renal Replacement Therapy 53

TABLE 10.1. RRT: A glossarya

Acronym Full Name Notes Seed reference
SCUF Slow continuous ultrafiltration AV or VV Silverstein 1974 (12)
CAVH Continuous arteriovenous hemofiltration Kramer 1977 (5)
CAVHD Continuous arteriovenous hemodialysis
CAVHDF Continuous arteriovenous hemodiafiltration
CVVH Continuous venovenous hemofiltration
CVVHD Continuous venovenous hemodialysis
CVVHDF Continuous venovenous hemodiafiltration
CHFD Continuous high flux dialysis AV or VV Ronco 1996 (13)
HVHF High volume hemofiltration AV or VV Cole 2001 (14)
CPF Continuous plasma filtration AV or VV Reeves 1999 (15)
CPFA Coupled plasma filtration adsorption AV or VV Ronco 2003 (16)
SLED Sustained low efficiency dialysis Marshall 2004 (17)
EDD Extended daily dialysis Kumar 2000 (18)
PDIRRT Prolonged daily intermittent RRT Naka 2004 (9)
a
AV, arteriovenous; VV, venovenous.

attraction. Adsorption is used specifi fically for There is little information regarding what spe-
toxin removal using activated charcoal car- cific
fi threshold plasma concentrations of potas-
tridges (10) and it is being tested as a means of sium, bicarbonate, urea, or creatinine should be
blood purifification in sepsis (11). used for the institution of RRT. In a retrospective
comparison of early versus late CRRT in trauma
associated ARF, Gettings et al. (23) found that
Intensity of Therapy patients in whom CRRT was commenced at a
mean blood urea nitrogen (BUN) of 42.6 mg/dL
For example, slow continuous ultrafiltration
fi
(15.2 mmol/L) had a survival rate of 39% com-
(SCUF) is performed to simply remove excess
pared with 20% in patients in whom the
extracellular flfluid. High-volume hemofi filtration
mean BUN at commencement was 94.5 mg/dL
(HVHF) is used to intentionally accelerate the
(33.7 mmol/L).
clearance of target mediators, and high-fl
flux dialy-
sis (HFD) (dialysis performed with highly perme-
able membranes) is designed to accelerate the “Nonrenal” Indications
clearance of urea and larger molecules.
• Drug and toxin removal
• Sepsis and septic shock
• Inborn errors of metabolism
Indications for RRT • Congestive cardiac failure
• Cerebral edema
“Traditional” indications (19)
IHD can accelerate the elimination of small
• Diuretic resistant fluid overload
(<500 mw) unbound toxins with a low volume of
• Life-threatening hyperkalemia
distribution and minimal plasma protein binding
• Severe metabolic acidosis
(11), e.g., lithium, methanol, ethylene glycol, and
• Symptomatic uremia
salicylates. Continuous hemofiltration
fi has been
Kramer’s original description of CAVH involved used in lithium toxicity (24), with better hemody-
the treatment of diuretic resistant fl
fluid overload namic stability (25) but lower solute clearance
(5). During the intervening years, there has been than IHD.
controversy surrounding the use of diuretics in The use of extracorporeal blood purification
fi
ARF (20), but they may be helpful in the fl fluid techniques in sepsis and septic shock is attractive
management of ARF before the institution of RRT but unproven. There were early observations of
(21, 22). improved cardiovascular and respiratory function
54
in patients with severe sepsis after commence-
ment of continuous hemofiltration
fi (26). This,
together with the identification
fi of inflflammatory
mediators in filtrate
fi (27), led to efforts to increase
infl
flammatory mediator removal during RRT.
High-volume conventional hemofiltration
fi (14, 28),
large-pore hemofiltration
fi (29), and plasma filtra-
tion with (30) or without (15) coupled adsorption
have been examined in small clinical trials. There
is currently no Level I evidence for the use of
extracorporeal blood purifi fication therapy in
sepsis.
End-stage cardiac failure is characterized by
progressive fl fluid retention, renal impairment,
neurohumoral stimulation, and diuretic resistance
(31). It was shown that patients with advanced
cardiac failure can tolerate substantial fluid fl trial was controversial (37), it suggests that dialy-
removal during ultrafiltration
fi (12), with salutary
effects that persist beyond the time of fl fluid
removal. Improved renal function, decreased heart
failure scores, lowered B natriuretic peptide levels,
decreased hospital length of stay, and fewer read-
missions have all been observed in case-controlled
studies (32). Most recently, a small randomized
controlled study showed that early ultrafiltration
fi centration. During CRRT, if we know the volume
results in increased weight loss at 24 h compared
with diuretics alone (33). Larger studies are war-
ranted for this indication.
Cerebral edema can complicate IHD (34) and
contribute to the clinical picture of disequilib-
rium. In patients with hepatic encephalopathy,
early studies compared the effects of IHD and
CRRT (35). CRRT was associated with less decrease
in mean arterial pressure, less increase in intracra-
nial pressure, and less change in cerebral perfu-
sion pressure.
Choosing the Dose and Mode of RRT
Dialysis dose is a concept familiar to nephrologist
in the setting of ESRF: Kt/V.
K is clearance (the volume of solute, usually
urea, cleared in a given time), t is duration of treat-
ment, and V is volume of distribution of the solute.
Kt is the volume of plasma water cleared of solute
during the session, and Kt/V is Kt as a proportion
of its volume of distribution.
For example, a Kt/V of 1.0 for urea means that
a total volume of plasma water equal to the volume
J.H. Reeves
of distribution of urea was cleared during the
session. Using a single compartment exponential
washout model, we can predict that the final fi
concentration of the solute is approximately
37% of the starting concentration when the Kt/V
is 1.0.
In chronic renal failure, a minimum Kt/V of 1.2
should be delivered three times per week (36).
There has been one randomized controlled trial
assessing dose of dialysis in ARF (7). Schiffl fl com-
pared daily dialysis with alternate daily dialysis in
160 patients with ARF. The 28-day mortality using
intention-to-treat analysis was 28% in the daily
treated patients and 46% in the patients treated
every other day. Multiple other outcomes were
improved in the daily dialysis group. Although this
sis every second day is insufficient
fi in critically ill
patients with ARF.
Quantifi fication of clearance during CRRT can be
likened to the calculation of creatinine clearance,
which is described by the formula UV/P. U is the
urine concentration of the solute, V is the volume
collected in a given time, and P is the plasma con-
of efflfluent produced in a given time and the con-
centration of solute (e.g., urea) in both effluent
fl
and plasma, we can calculate its clearance (38).
The result is a value in milliliters per minute. To
simplify the estimate further, let us assume that
the sieving coefficient
fi is 1.0, and that there is full
concentration equilibrium between plasma water
and dialysate. Then the effluent
fl concentration will
equal the plasma concentration, and clearance is
simply equal to the rate of production of effluent
fl
from the hemofi filter.
Ronco, in 2000 (39), randomized 425 critically
ill patients with ARF to three different doses
(ultrafiltration
fi rates) of CRRT: 20, 35, or 45 mL/h/
kg. Fifteen-day survivals were 41%, 57%, and 58%,
respectively. This landmark study was one of the
first to formally adjust dose of CRRT based on
fi
patient weight. Importantly, it suggests that there
is a threshold minimum level of clearance required
for adequate CRRT of approximately 35 mL/h/kg.
Debate regarding the relative merits of CRRT
and IHD has continued for nearly 30 years. From
the outset (5), the attraction of CRRT was its sim-
plicity and cardiorespiratory stability compared
with IHD. Now that CRRT is as complex as IHD
10. Renal Replacement Therapy
and potentially more expensive to perform for
long periods, there is a paucity of good compara-
tive studies that report outcomes such as mortal-
ity or recovery of renal function. In 2001, Mehta
randomized 166 critically ill patients to CRRT or
IHD (40). The observed mortality was higher in
the group receiving CRRT, but this group had a
higher severity of illness. In 2002, Kellum pub-
lished a meta-analysis of 13 trials, 3 randomized
and 10 observational, comparing IHD and CRRT
(41). Overall, there was no difference in mortality,
but only six studies compared groups of equal
severity. In these six studies, the mortality was
lower in patients treated with CRRT. Since then, a
well-designed prospective randomized controlled
trial has been published comparing CRRT with
IHD in 80 critically ill patients with ARF. There
was no difference in survival or renal recovery
between the two groups. Although there was more
hemodynamic disturbance during IHD, this did
not translate to a survival benefifit for CRRT (42).
Summary
• RRT reduces the mortality of ARF from more
than 90% to approximately 50%.
• There is no proven difference in outcome
between intermittent and CRRTs, as long as a
minimum dose of Kt/V of 6 to 8 per week is
achieved during hemodialysis or a clearance
greater than 35 mL/kg/h is achieved during con-
tinuous hemofi filtration.
• New hybrid therapies (slow long extended daily
dialysis [SLEDD], extended daily dialysis [EDD],
and prolonged daily intermittent RRT [PDIRRT])
may avoid the destabilization associated with
IHD, and mitigate the cost and inconvenience of
continuous hemofiltration.
fi
References
1. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ.
Acute renal failure in intensive care units-causes,
outcome, and prognostic factors of hospital mortal-
ity; a prospective, multicenter study. French Study
Group on Acute Renal Failure. Crit Care Med 1996;
24(2): 192–198.
2. Smith LH, Post RS, et al. Post traumatic renal insuf-
ficiency in military casualties. II. Management, use
55
of an artifi ficial kidney, prognosis. Am J Med d 1955;
18:187.
3. Mehta RL, Pascual MT, Soroko S, et al. Spectrum of
acute renal failure in the intensive care unit: the
PICARD experience. Kidney Intt 2004; 66(4):
1613–1621.
4. Meyer TW, Walther JL, Pagtalunan ME, et al. The
clearance of protein-bound solutes by hemofiltra- fi
tion and hemodiafi filtration. Kidney Intt 2005; 68(2):
867–877.
5. Kramer P, Wigger W, Rieger J, et al. Arteriovenous
haemofi filtration: A new and simple method for
treatment of over-hydrated patients resistant to
diuretics. Klin Wschr 1977; 55: 1121–1122.
6. Ronco C, Bellomo R. Continuous renal replacement
therapy: evolution in technology and current nomen-
clature. Kidney Int Suppl 1998; 66: S160–164.
7. Schifflfl H, Lang SM, Fischer R. Daily hemodialysis
and the outcome of acute renal failure. N Engl J Med
2002; 346(5): 305–310.
8. Marshall MR, Golper TA, Shaver MJ, Chatoth DK.
Hybrid renal replacement modalities for the criti-
cally ill. Contrib Nephrol 2001(132): 252–257.
9. Naka T, Baldwin I, Bellomo R, Fealy N, Wan L. Pro-
longed daily intermittent renal replacement therapy
in ICU patients by ICU nurses and ICU physicians.
Int J Artif Organs 2004; 27(5): 380–387.
10. Zimmerman JL. Poisonings and overdoses in the
intensive care unit: general and specifi fic manage-
ment issues. Crit Care Med 2003; 31(12): 2794–
2801.
11. Nalesso F. Plasma filtration adsorption dialysis
(PFAD): a new technology for blood purification. fi
Int J Artif Organs 2005; 28(7): 731–738.
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Treatment of severe fl fluid overload by ultrafifiltration.
New Eng J Med d 1974; 291(15): 747–751.
13. Ronco C, Bellomo R, eds. Continuous high fl flux
dialysis: an effificient renal replacement. Heidelberg:
Springer Verlag; 1996.
14. Cole L, Bellomo R, Journois D, et al. High-volume
haemofi filtration in human septic shock. Intensive
Care Med 2001; 27(6): 978–986.
15. Reeves JH, Butt WW, Shann F, et al. Continuous plas-
mafi filtration in sepsis syndrome. Plasmafi filtration in
Sepsis Study Group. Crit Care Med d 1999; 27(10):
2096–2104.
16. Ronco C, Brendolan A, d’Intini V, et al. Coupled
plasma filtration
fi adsorption: rationale, technical
development and early clinical experience. Blood
Purif 2003; 21(6): 409–416.
17. Marshall MR, Ma T, Galler D, et al. Sustained low-
effificiency daily diafifiltration (SLEDD-f) for critically
ill patients requiring renal replacement therapy:
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towards an adequate therapy. Nephrol Dial Trans-
plantt 2004; 19(4): 877–884.
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daily dialysis: A new approach to renal replacement
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19. Palevsky PM. Renal replacement therapy I: indica-
tions and timing. Crit Care Clin 2005; 21(2): 347–
356.
20. Mehta RL, Pascual MT, Soroko S, Chertow GM.
Diuretics, mortality, and nonrecovery of renal func-
tion in acute renal failure. JAMA 2002; 288(20):
2547–2553.
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fi 39.
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and cerebral oedema. Nephron 2001; 87(2): 143–147.
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349(20): 1965.
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Am J Kidney Dis 2004; 44(6): 1000–1007.
11
Technical Aspects of Renal
Replacement Therapy
Sara Blakeley
Since its inception in 1977 (1), methods and equip-
ment used for the delivery of continuous renal
replacement therapy (CRRT) has undergone many
changes. Intermittent hemodialysis (IHD) is per-
formed on some intensive care units (ICU), but this
chapter will concentrate on continuous therapies.
Mode of CRRT
There is a spectrum of treatment available and
with choice comes debate; continuous versus
intermittent, convective versus diffusive therapy
(2, 3). Continuous therapies have been associated
with better renal survival compared with IHD,
although no compelling effect on overall mortality
has been seen (4).
Diffusion is the movement of molecules from
an area of high concentration (blood) to one of
a lower concentration (dialysis fl fluid circulating
in a counter current direction) across a semi-
permeable membrane. With convection a pressure
(transmembrane pressure) is applied across the
membrane, this drives water out and carries with
it dissolves solutes (solvent drag). The “waste” fl
fluid
produced is termed ultrafiltrate.
fi Both diffusive
and convective therapies are good at removing
small molecular weight molecules (<5000 Da),
such as urea and creatinine, but “middle mole-
cules” (10,000–50,000 Da) such as β2 microglobu-
lin and cytokines (5) may be better removed
by convection. Currently, there is no definitive
fi Continuous venovenous hemodialysis (CVVHD),
evidence to suggest one particular mode over
another, and choice is often guided by local
expertise.
CRRT on the ICU nowadays is almost exclu-
sively venovenous in nature; in other words, blood
is removed from a large vein and returned to a
large vein. The different modes of CRRT differ
mainly in their method of solute removal, and
most modern machines are capable of providing
the full range of modalities. Newer machines offer
greater ease in switching between modes.
There is much discussion regarding the rela-
tionship between dialysis dose delivered and sur-
vival (6). A prospective randomized study of post
dilution CVVH in critically ill patients found
improved survival with an ultrafiltration
fi dose of
35 ml/kg/hour (7). Ultrafiltration
fi rate is used as a
dose surrogate. This finding was not repeated in a
subsequent study (8) but a more recent study
found did find an improvement in survival when
adding a dialysis dose to CVVH (9). It is unclear
whether this survival advantage was due to a
higher dose of CRRT overall or due to the addition
of a diffusive therapy to a convective one. These
findings are being investigated further in other
fi
studies, to clarify what is the optimal dose and
means of delivery. In the mean time 35 ml/kg/hour
is often recommended as minimum that should be
provided (10–12).
Standard therapies in use are:
Continuous venovenous hemofi filtration (CVVH),
characterized by predominantly convective
solute clearance (Figure 11.1A).
characterized by predominantly diffusive solute
clearance but with some convection occurring
because of ultrafi
filtration.
57
 58 S. Blakeley

Effluent pump

Ultrafiltrate and Blood flow from patient

used dialysate - ‘arterial’ side
(waste)
Blood pump

Replacement fluid pump

Replacement fluid
entering pre filter (pre
dilution)

Blood flow to patient

- ‘venous’ side

Haemofilter
Pressure monitor
Air detector
A

Anticoagulation syringe
Effluent pump

Ultrafiltrate and Blood flow from patient

used dialysate - ‘arterial’ side
(waste)
Blood pump

Replacement fluid pump

Dialysate fluid
(running in a
counter current Replacement fluid
entering post filter
direction to blood (post dilution)
flow through the
haemofilter)

Dialysate pump Blood flow to patient

- ‘venous’ side

Haemofilter
Pressure monitor
Air detector
B

FIGURE 11.1. A, CVVH with prefilter replacement fluid delivery (predilution). B, CVVHDF with postfilter replacement fluid delivery
(postdilution).
11. Technical Aspects of Renal Replacement Therapy
Continuous venovenous hemodiafiltration
fi Infusion rates of replacement flfluid and/or dial-
(CVVHDF), characterized by a mixture of
diffusive and convective solute clearance
(Figure 11.1B).
Slow continuous ultrafifiltration (SCUF) is removal
of water in response to a pressure gradient, but
a degree of solute removal via convection will
also occur.
Therapeutic plasma exchange (TPE). Plasma is
separated, removed, and replaced with either
albumin or fresh frozen plasma.
Hemofiltration Machines (Figure 11.2)
All machines have a similar set up. Newer
machines differ in their degree of “user friendli-
ness,” their range of pump fl flow rates, and the
degree of monitoring.
A roller pump controls the flowfl of blood from
the patient through the fifiltration circuit and then
back to the patient. Blood flow
fl rate is set by the
operator but is limited by vascular access quality,
blood viscosity, patency of the hemofilter,
fi and car-
diovascular stability of the patient. The maximal
achievable blood flow
fl rate varies between differ-
ent makes of machine (50–450 mL/min).
FIGURE 11.2. Two examples of hemofiltration machines. The
Edwards’ Aquarius System (left)
t and Hospal Prisma (right).
t sterile fluid.
59
ysate are set, with newer machines offering
increased fluid removal rates (0–10 L/h) to perform
high-volume hemofiltration
fi (HVHF). A desired
net fl
fluid loss (0–1000 mL/h) is set by the operator
and constantly monitored by the machine. The
machine generally calculates the ultrafiltration
fi
rate depending on the rate of replacement fl fluid
and fluid
fl removal set by the operator. A bag then
collects the effl
fluent (waste), which is composed of
ultrafi
filtrate and spent dialysate (if being used).
A series of safety mechanisms are in place to
prevent the inadvertent introduction of air to the
patient and to detect blood leakage. Alarms warn
of pressure changes within the circuit:
• Access pressure: Pressure in the “arterial” limb
removing blood from the patient is a negative
pressure reflecting
fl blood suction. It is deter-
mined by blood flow,fl patient’s blood pressure,
and intravascular fluid status. Excessively
negative pressures (e.g., >300 mmHg) risk vascu-
lar injury and hemolysis and suggest occlusion
somewhere in the access limb of the blood circuit,
e.g., kinked line or blocked vascular access.
• Filter pressure: A rise in pressure indicates that
the filter may be starting to clot.
• Return pressure: Pressure in the “venous” limb
returning blood to the patient is a positive pres-
sure reflflecting resistance to venous return. Low
pressures may indicate disconnection but can be
seen with changes in position. High pressures
are seen with occlusion to flow, e.g., kinking or
clotting, but also if the blood fl flow rate is too
high.
Replacement and Dialysis Fluid
With convective therapies, large volumes of fl fluid
(effluent)
fl are removed from the patient per hour.
To maximize solute removal, prevent the patient
from becoming hypovolemic, and replace wanted
electrolytes, a replacement fluid
fl is infused. With
diffusive therapies, dialysate fluid
fl d is run in a
counterclockwise direction through the fluid fl
compartment of the fi filter, against the blood flow.
This flfluid can be formulated in-house, or more
commonly as commercially prepared bags of
60
The fluid contains a buffer, either lactate or
bicarbonate, and electrolytes (sodium, chloride,
magnesium, and calcium). Typically, replacement
fluids are potassium- and phosphate-free, and
fl phan) and synthetic fibers (e.g., polysulphone,
these may need to be replaced as clinically indi-
cated. Glucose is often not present.
Prefilter Versus Postfilter Infusion
Replacement fluid
fl is infused into the circuit either
before the filter (predilution) or after the filter
(postdilution). Predilution lowers the hematocrit
of the blood passing through the filter,
fi potentially
reducing anticoagulation needs and allowing
increased ultrafifiltration rates. This is at the expense
of less-effective solute clearance, therefore, an
increased ultrafifiltration rate is needed to achieve
similar solute clearances. Newer machines allow a
combination of predilution and postdilution.
Lactate Versus Bicarbonate Buffer
Both lactate- and bicarbonate-buffered solutions
have been shown to be effective in correcting
metabolic acidosis (11, 13). Bicarbonate is pre-
ferred in patients with a preexisting lactic acidosis
(e.g., septic shock) or with liver failure (11) because
these patients may be unable to metabolize an
exogenous lactate load normally, thus, worsening
the acidosis. Lactate levels are often seen to rise in
other patient groups who have a lactate buffer, but
the signifificance of this is unclear because hyper-
lactatemia is not always associated with an acido-
sis. Bicarbonate is a more physiological buffer, but,
because it is unstable in solution, it needs to be
added just before use. Studies have compared out-
comes of bicarbonate versus lactate buffers but
the evidence is inconclusive. Lactate intolerance
has been arbitrarily defi fined as a rise of greater
than 5 mmol/L during CRRT (14), and a change to
a bicarbonate buffer should be considered.
Hemofilters
Structure
Thousands of hollow fibers (membrane) are
bundled together forming a hemofilter fi with a
large surface area of 0.6 to 1.2 m2. Pores in the
membrane allow the passage of molecules with a
S. Blakeley
molecular weight less than 50,000 Daltons (Da),
i.e., smaller than albumin. Membranes are com-
posed of two substances, cellulose (e.g., cupro-
polyamide, or polyacrylonitrile).
Membrane Characteristics
Biocompatibility
Contact of blood with the fi
filter surface can lead to
complement and leucocyte activation, triggering
the coagulation cascade and infl flammatory
pathways. More “biocompatible” indicates less
complement/leucocyte activation. Activation of
infl
flammatory mediators has been suggested as
one mechanism leading to ongoing renal injury,
and, therefore, delay or nonreturn of renal func-
tion (4). Kidneys that have already been injured
because of reduced renal perfusion lose their
ability to autoregulate pressure changes and the
kidney becomes very sensitive to even small
changes in renal perfusion. Early reports that bio-
incompatible cellulose-based membranes led to a
worse outcome have been debated, but, currently,
the evidence is not robust enough to defi finitively
recommend a synthetic membrane over cellulose
or modifiedfi cellulose membrane (15). As it is,
most membranes used in CRRT are synthetic
because they have a greater degree of flflux.
Flux
This is a measure of ultrafifiltration capacity and is
based on the membrane ultrafiltration
fi coeffi
ficient.
A filter with a high permeability coeffi ficient to
water will allow more ultrafi filtration (high flux)
and, hence, more convective transport. Permeabil-
ity is a measure of the clearance of middle molec-
ular weight molecules and high permeability is
seen with high flflux membranes (synthetic mem-
branes). It should be noted that high permeability
does not always equate to high urea clearance
(efficiency).
fi
Vascular Access
When initially developed, CRRT used an arterial
and a venous catheter (arteriovenous) (1). A wide-
bore (11.5–13.5 French) dual-lumen vascular dial-
11. Technical Aspects of Renal Replacement Therapy
ysis (venovenous) catheter is now generally used.
Mostly composed of polyurethane, they can have
an antibiotic/antimicrobial coating.
Blood is pumped from the patient (arterial
side) through proximal side holes into one lumen,
and is then returned though a port at the distal tip
of the second lumen (venous side). High blood
flows without high pressures are ideal catheter
fl form of anticoagulation for the extracorporeal
design requirements, and the dual-lumen design
allows continuity and reduces recirculation.
Vascular catheters differ in length, diameter of
lumen, and positioning of ports, and some have an
extra lumen added for drug infusions. Remember:
always assume that EACH catheter limb contains
heparin and aspirate at least 5 mL of blood before
using. Cuffed dialysis catheters are generally not
used on the ICU, but may be indicated in stable
patients who are free of infection, and who require
ongoing renal replacement therapy (RRT) (Table
11.1).
Positioning
A correctly positioned catheter will have a better
blood flow; good access is the key to good dialysis.
The tip of a jugular or subclavian catheter should
extend to the superior vena cava and rest 1 to 2 cm
above the right atrium. Too short, and there is
the possibility of recirculation, whereas a catheter
that is too long risks atrial perforation. Femoral
catheters should be longer (>20 cm) to reach the
inferior vena cava, therefore, minimizing recircu-
lation and achieving better fl flow rates.
Site of Catheter
Debate continues regarding the ideal site for place-
ment of dialysis catheters in terms of safety of
insertion and infection risk. Where long term
dialysis is a possibility, there is concern that
subclavian catheters may be associated with an
increased incidence of subclavian stenosis/throm-
bosis, creating long-term problems for arteriove-
nous fistula formation.
Anticoagulation
As blood flows
fl through the filter and fluid is
removed, viscosity increases and there is a ten-
dency toward filter clotting. Passage of blood
61
through the circuit can also result in the formation
of platelet microthrombi, which can occlude the
filter. Loss of the filter through clotting can lead to
fi
ineffective dialysis and patient blood loss, as well
as being a drain on resources, both nursing and
financial. Methods such as predilution and ensur-
fi
ing adequate vascular access can be used, but some
circuit is often needed. Remember: circuit failure is
more often caused by inadequate vascular access
rather than inadequate anticoagulation.
No Anticoagulation
In the setting of deranged clotting (e.g., interna-
tional normalized ratio [INR] >2, activated partial
thromboplastin time [aPTT] >60 s) and/or throm-
bocytopenia (e.g., platelet count <50,000) or a
high risk of bleeding, further anticoagulation is
often not necessary or carries the risk of bleeding.
With adequate access and predilution, it is possi-
ble to run the circuit without any anticoagulation
for an acceptable period of time and achieve good
solute clearance.
Unfractionated Heparin
Unfractionated heparin (UFH) is the most com-
monly used extracorporeal anticoagulant. The
circuit is often primed with heparin (e.g., 1000–
10,000 IU) because it is highly negatively charged
and is absorbed onto the plastic circuit. Depend-
ing on the risk of bleeding, a bolus dose (e.g., 10–
20 IU/kg) can be administered and a continuous
infusion started. A low-dose infusion (<5 IU/kg/h)
aims NOT to prolong the aPTT. If clotting occurs,
a medium dose can be considered (5–10 IU/kg/h),
aiming for mild prolongation of the aPTT (1–1.4
times normal) (16). Prefilter
fi heparin can be neu-
tralized with postfilter
fi protamine (e.g., 1000 IU/h
to 10 mg/h), called regional heparinization. If
patients require formal heparinization for condi-
tions such as a pulmonary embolus, this should be
continued, no extra “fi filter” heparin is needed.
The methods, site of sampling, and frequency
of anticoagulation monitoring vary depending
on local protocols. Commonly used methods are
the activated coagulation time (ACT) and aPTT.
However, it should be remembered that there is
not always a linear correlation between dose of
heparin or degree of anticoagulation and filter
fi life.
62
Low Molecular Weight Heparin
Compared with UFH, low molecular weight
heparin (LMWH) is considered more effective in
reducing fibrin deposition on dialyzer membranes
and, thus, preventing circuit clotting, however, its
superiority to UFH has not been proven in trials.
There is a reduced incidence of heparin-induced
thrombocytopenia syndrome (HITS) compared
with UFH, but it is more costly. With more experi-
ence LMWH use has increased in popularity. Stan-
dard markers of anticoagulation are not reliable
and anti-Xa levels should be monitored with pro-
longed use (target, 0.25–0.35 U/mL) (16). However,
there is not always a correlation between anti-Xa
levels and filter life.
TABLE 11.1. Complications of RRTa
Access related
Complications during insertion
Infection
Catheter-related thrombosis
Patient immobility
Circuit related
Membrane bioincompatibility
Air embolism
Blood loss
Fluid balance errors
Hemolysis
Dialysis related
Hypotension
Anticoagulation-related complications
Electrolyte disturbances
Acid-base disturbances
Temperature disturbances
Vitamin and micronutrient depletion
Inappropriate prescribing of drugs
Further renal injury
a
ACEI, angiotensin converting enzyme inhibitor.
S. Blakeley
Regional Citrate Anticoagulation
Infused citrate complexes with calcium and pre-
vents activation of the coagulation cascade and
platelets. Post dialyser, calcium is reinfused.
Regional citrate anticoagulation (RCA) is an effec-
tive form of anticoagulation, and because only
the circuit is anticoagulated, it is safe to use in
patients at risk of bleeding. However, its side
effects and complex infusion protocol have limited
its widespread use. Side effects include citrate
toxicity if citrate is not metabolized rapidly
or adequately (e.g., in liver failure), hypernatre-
mia, hyper/hypocalcemia, and metabolic alkalosis
(each citrate molecule is metabolized to three
bicarbonates).
Bleeding, local trauma
Systemic or local
Particularly with femoral lines
See text
Caused by clotted filters (common) or disconnection (rare)
Hypovolemia secondary to total volume removal or speed of removal, i.e., not allowing body
compartments to equilibrate (commonest) t
High pump speeds may be enough to precipitate hypotension in unstable patients
Life-threatening anaphylactoid hypersensitivity reactions have been described with the use of certain
membranes (e.g., polyacrylonitrile membranes, such as AN69) with concurrent ACEI therapy
Activation of inflammatory and vasodilatory mediators (e.g., bradykinin) related to membrane
bioincompatibility
Local or systemic bleeding
Related to specific type of anticoagulant: e.g., HITS (heparin) and hypocalcemia (RCA)
Including hypokalemia, hypophosphatemia, and hypoglycemia
Metabolic acidosis related to lactate buffer in replacement fluid if unable to handle a large exogenous
lactate load (e.g., liver failure, septic shock)
Metabolic alkalosis related to RCA
A degree of cooling always occurs, this may lead to “normothermia” in febrile patients (i.e., masking a
pyrexia) or cause marked hypothermia
Water-soluble vitamins, trace minerals, certain hormones (e.g., glucocorticoids), amino acids
Generally leads to underdosing while a patient is on the filter
Systemic hypotension (see above) reducing already compromised renal perfusion
Because of release of inflammatory mediators triggered by blood coming into contact with the filter
and tubing
11. Technical Aspects of Renal Replacement Therapy
Prostacyclin
Prostaglandin (PG)-I2 is a natural anticoagulant
that is a potent antiplatelet agent and has been
shown to reduce platelet microthrombi during
dialysis. It is often used in patients with a high risk
of bleeding, but because it is a potent arterial
vasodilator, some patients develop symptomatic
hypotension. It has been used on its own and in
combination with low-dose heparin.
Other Anticoagulants
Heparinoids (e.g., danaparoid) have minimal
effects on platelets and can be used in HITS (but
remembering the potential cross reactivity in
5–10% of patients). However, standard markers of
anticoagulation are not reliable and its effect is
prolonged in renal failure. Factor Xa inhibitors
(e.g., fondaparinux) and direct thrombin inhibi-
tors (e.g., recombinant hirudin) can be safely used
in HITS, but, to date, have limited use in CRRT.
Comment
A recent systematic review (16) found that there
was no conclusive evidence to suggest one strat-
egy over another, but the chosen method should
take into account patient characteristics and local
facilities. Heparin (UFN and LMWH) has the
greatest evidence and experience behind it, but
RCA is increasing in popularity and ease of use.
References
1. Kramer P, Wigger W, Rieger J, et al. Arteriovenous
haemofi filtration: a new and simple method for treat-
ment of over-hydrated patients resistant to diuret-
ics. Klin Wochenschr. 1977; 55: 1121–1122.
2. Palevsky PM. Dialysis Modality and Dosing Strat-
egy in Acute Renal Failure. Sem Dialysis. 2006; 19:
165–170.
3. Van Biesen W, Vanholder R, Lameire N. Dialysis
strategies in critically ill acute renal failure patients.
Curr Opin Crit Care. 2003; 9: 491–495.
4. Palvesky PM, Baldwin I, Davenport A, et al. Renal
replacement therapy and the kidney: minimising
the impact of renal replacement therapy on recov-
63
ery of acute renal failure. Cur Opin Crit Care. 2005;
11: 548–554.
5. Ricci Z, Ronco C, Bachetoni A, et al. Solute removal
during continuous renal replacement therapy in
critically ill patients; convection versus diffusion.
Crit Care. 2006; 10: R67–R74.
6. Clark WR, Turk JE, Kraus MA, Gao D. Dose deter-
minants in continuous renal replacement therapy.
Artif Organs. 2003; 27: 815–820.
7. Ronco C, Bellomo R, Homal P, et al. Effects of dif-
ferent dose in continuous veno-venous haemofiltra-fi
tion on outcomes of acute renal failure: a prospective
randomised trial. Lancet. 2000; 356: 26–30.
8. Bouman C, et al. Effects of early high-volume con-
tinuous Venovenous hemofiltratin
fi of survival and
recovery of renal function in intensive care patients
with acute renal failure: a prospective randomized
trial. Crit Care Med. 2000; 30: 2205–2211.
9. Saudan P, et al. Adding a dialysis dose to continuous
hemofi filtration increases survival in patients with
acute renal failure. Kidney Int. 2006; 70: 1312–
1317.
10. Cariou A, Vinsonneau C, Dhainaut JF. Adjunctive
therapies in sepsis: an evidence-based review. Crit
Care Med. 2004; 32: S562–S570.
11. www.adqi.net
12. Ronco C. Renal replacement therapy for acute
kidney injury: let’s follow the evidence. Int J Artif
Organs. 2007; 30: 89–94.
13. Naka T, Bellomo R. Bench-to-bedside review: treat-
ing acid-base abnormalities in the intensive care
unit–the role of renal replacement therapy. Crit
Care. 2004; 8: 108–114.
14. Hilton PJ, Taylor J, Forni LG, Treacher DF. Bicarbo-
nate-based haemofiltration
fi in the management of
acute renal failure with lactic acidosis. QJM. 1998; 4:
279–283.
15. Teehan GS, Liangos O, Lau J, et al. Dialysis mem-
brane and modality in acute renal failure: under-
standing discordant meta-analyses. Sem Dialysis.
2003; 16: 356–360.
16. Oudemans-van Straaten HM, Wester JPJ, de Pont
ACJM, Schetz MRC. Anticoagulation strategies in
continuous renal replacement therapy: can the
choice be evidence based? Intensive Care Med. 2006;
32: 188–202.
Suggested Reading
Bellomo R, Baldwin I, Ronco C, Golper T. Atlas of Hemo-
fi
filtration. WB Saunders. 2002.
12
End-Stage Renal Disease
Emile Mohammed
There are now approximately one million people
on renal replacement therapy worldwide. In the
current era of chronic noncommunicable disease,
this number is set to double within the next
decade. Patients with end-stage renal disease
(ESRD) carry a significantly
fi higher cardiovascular
morbidity and mortality compared with the
general population. This is because of the “uremic”
cardiovascular factors (Table 12.1). The result is
that there will be a growing number of ESRD
patients being managed within the intensive care
unit (ICU) setting.
Hemodialysis and Peritoneal Dialysis
Mechanisms of Dialysis
There are two basic principles of dialysis that
allow the body’s homeostasis to be achieved in the
absence of a natural kidney. They are as follows:
• Convection, in which there is movement (in
large volumes) of solvent, which drags dissolved
solute across a membrane with a hydrostatic
pressure gradient.
• Diffusion, in which there is passive movement
of solute from a high- to a low-concentration
gradient across a membrane (Figure 12.1). Dif-
fusion depends not only on the transmembrane
gradient but the membrane characteristics (e.g.,
pore size).
Diffusion is more effective in clearing small
molecules and convection improves mid-size mol-
ecule clearance.
64
Hemodialysis
Many hemodialysis (HD) techniques have been
developed, particularly in the ICU setting, ranging
from conventional HD, high-fluxfl HD, hemodiafi fil-
tration, and hemofi filtration. These techniques
simply use varying degrees of convection or
diffusion. For example, hemofiltration
fi is a convec-
tive treatment with good clearance of mid-size
molecules but with poor small molecule clear-
ance. The converse holds for conventional inter-
mittent HD.
Peritoneal Dialysis
The peritoneum acts as a natural semipermeable
membrane. Dissolved waste products and water
pass from the blood, via the peritoneal capillaries,
through the mesothelial cells and interstitium to
the peritoneal dialysis (PD) fl fluid (PDF). This
process is referred to as ultrafi filtration (Figure
12.2). Water-soluble waste products pass down a
concentration gradient that is generated by an
osmotic gradient. This, in turn, is created by
glucose or glucose polymers added to the PDF.
PD regimens are all based on repetitions of a
basic cycle, which comprises inflow
fl of PDF, a dwell
time of the PDF within the peritoneal cavity, and
then drainage. The various types of PD are all
based on this principle. They include continuous
ambulatory PD (CAPD), automated PD (APD),
tidal PD, and intermittent PD. Typical regimes are
illustrated in Figure 12.3.
12. End-Stage Renal Disease 65

TABLE 12.1. Cardiovascular risk factors in the uremic patient

Traditional coronary risk factors Uremic-related cardiovascular
(The Framingham Study) risk factors
Hypertension Increased extracellular fluid
volume
High levels of low-density Calcification and high
lipoprotein calcium/phosphate product
Low levels of high-density Parathyroid hormone
lipoprotein
Smoking Anemia
Diabetes Oxidant stress
Older age Malnutrition
Male sex Pulse pressure
White race Triglycerides
Physical inactivity Lipoprotein remnants
Menopause Lipoprotein A
Left ventricular hypertrophy Homocysteine
Inflammation (C-reactive protein)
Sleep disorders

Clinical Parameters of Peritoneal Dialysis in Mexico (ADEMEX) study

Much debate surrounds the “optimal” dialysis
dose, although a minimal dialysis dose has been
universally accepted. Within the context of thrice-
weekly HD, there seems to be no added benefit fi of
high-dose dialysis compared with the conven-
tional dose of dialysis (the HEMO study) (1).
Dialysis adequacy is measured by urea kinetic
modeling (UKM) using the urea reduction ratio,
or Kt/V, where K is the dialyzer urea clearance, t
is the duration of dialysis, and V is the urea distri-
bution volume. In a well-nourished stable HD
patient, a Kt/V of 0.8 to 1.0 is the minimum accept-
able threshold per dialysis session. The Adequacy
(2) again reveals the same controversy of defining
fi
the optimal dialysis dose in PD patients. In this
study, there was a neutral effect on patient survival
between a control group on conventional CAPD
compared with a study group on a modified fi pre-
scription, which achieved increased small solute
clearance, measured by peritoneal creatinine
clearance and peritoneal Kt/V.
There are no “fi fixed targets” that determine
dialysis adequacy in the ICU setting. Dialysis
dose and duration must be determined by
balancing the clinical condition of the patient,
while achieving as normal a physiological state as
possible.

Blood flow (250-500ml/min)

Sodium Calcium, bicarbonate

Semi
em
mi-pe
-pe
-perme
perm
rmeab
rmeablle
memb
em
mbbran
ranee

Urea, creatinine Water Potassium

FIGURE 12.1. Diagrammatic representa-
tion of blood purification within the Dialysate flow (400-800ml/min)
dialyzer.
66 E. Mohammed

Interstitium Mesothelium Peritoneal cavity FIGURE 12.2. Ultrafiltration in PD.

Soluble waste products and water

Glucose

Capillary

Typcal CAPD regime

3
“Bag in”
2.5
PDF volume (litres)

1.5

0.5

0
Bag drained out Time (during day)

Typical APD regime

2.5

“Bag in”
PDF volume (litres)

1.5

0.5

0
wet day overnight exchanges FIGURE 12.3. PD regimes.
12. End-Stage Renal Disease
The following clinical parameters act as guide-
lines to achieve this:
• Target weight and blood pressure control. Target
weight is defifined as the patient’s weight in which
all the fluid compartments are physiologically
normal. Excess weight (which will be essentially
salt and water) results in hypertension. The
target weight is achieved by gradual weight
reduction on successive dialyses until the
patient is free from both pulmonary and peri-
pheral edema, but, below which, hypotension
occurs.
• Acid-base balance. Dialysis must be performed
frequently and long enough to maintain normal
acid-base balance.
• Bone biochemistry. Along with vitamin D sup-
plementation, serum calcium and phosphate
levels should be maintained within normal
limits.
• Nutritional state. It is important to remember
that a high proportion of ESRD patients within
the ICU will have a low serum albumin, low
body mass index, an infl flammatory and/or
hypercatabolic state, and a low dietary intake. It
is, therefore, necessary to obtain dietary advice,
treat correctable factors, give dietary supple-
ments, and have a low threshold for nasogastric
(NG), percutaneous endoscopic gastrostomy
(PEG), or even parenteral nutrition, if indicated.
Dialysis prescriptions must accommodate these
nutritional requirements.
A good starting point for prescribing dialysis
would be to continue the patient’s regular dialysis
regime and adjust the dose of dialysis, in conjunc-
tion with the nephrologists, to achieve the above
parameters.
Dialysis-Related Complications
Hemodialysis
• Hypotension. Hypotension can be minimized
with an accurate assessment of target weight,
judicious use of antihypertensive medications,
sodium restriction, increasing treatment dura-
tion, and careful choice of dialysis modality, e.g.,
hemodiafiltration
fi in the cardiovascularly unsta-
ble patient.
67
• Anaphylaxis. Anaphylaxis can occur by comple-
ment activation with the use of a bioincompati-
ble membrane and normally occurs within the
first 20 minutes of treatment.
• Catheter related-sepsis. Catheter related-sepsis
requires aggressive antibiotic treatment and
catheter removal. If temporary catheters are
being used, once weekly catheter changes are
recommended.
• Pyrogenic reactions. Uncommon if ultrapure
water is used.
• Dialysis equilibrium syndrome. Rare in estab-
lished dialysis patients. It can occur from overag-
gressive dialysis causing a rapid reduction in
serum osmolality and resulting in cerebral
edema.
• Modern fail-safe machines minimize other com-
plications such as air embolism and accidental
circuit disconnection.
Peritoneal Dialysis
Although PD is a technically safe procedure, there
may be clinical reasons to convert to temporary
HD.
These are as follows:
• Abdominal surgery
• Diaphragmatic fluid leak resulting in effusions
• Respiratory compromise from splinting of dia-
phragm by PDF
• Severe hypoalbuminemic state
• Peritonitis or catheter-related sepsis
• Inadequate ultrafiltration
fi in the context of
aggressive flfluid management and/or hypercata-
bolic state of the patient
Renal Transplantation
Renal transplantation represents the best mode of
therapy for ESRD patients, both in cost effective-
ness and quality of life (3). There have been many
improvements in renal transplantation, such as the
refi
finement of immunosuppression regimens, and
patient-donor selection and work-up as well as
their compatibilities. The major challenge facing
transplantation is that its demand far outstrips the
availability. Every effort should be made to increase
the number of donors. In parallel to this, there is
68
much research in the development of stem cell
transplantation and xenotransplantation.
Evaluation, Selection, and
Preparation of the Potential
Transplant Recipient
General Evaluation
There are few absolute contraindications to renal
transplantation. These are uncontrolled cancer,
HIV positivity, active systemic infections, and/or
any condition with a life expectancy of shorter
than 2 years. Conditions increasing the risk of
posttransplant morbidity and mortality include
long duration of dialysis, previous incidence of
recurrent infections, cardiovascular disease, and
gastrointestinal complications. Such patients
require a particularly careful work-up and aggres-
sive management of risk factors (e.g., hyper-
tension, obesity, and vascular disease) before
transplantation.
Psychological Evaluation
The use of psychiatric screening is not universally
adopted but may be useful in assessing compli-
ance with immunosuppressive regimes. Poor
compliance signifificantly worsens renal allograft
outcomes.
Recurrent Renal Disease
It is important to ascertain the underlying cause
of renal failure because some diseases recur in the
transplanted kidney, most notably, focal and seg-
mental glomerulosclerosis.
Immunological
ABO blood group must be compatible. HLA typing
of donors and recipients allows assessment of
compatibility. HLA DR is more important than
HLA B, which is more important than HLA A.
A lymphocyte cross-match is also performed: the
recipient is screened for preexisting antibodies to
donor lymphocytes, which arise in response to
previous blood transfusions, pregnancies, or renal
E. Mohammed
allografts. Such sensitization can cause severe
hyperacute rejection.
Evaluation and Selection of Donors
There are two sources of donors:
Cadaveric: Cadaveric kidneys may be either from
patients with brainstem death and a maintained
cardiac output or from nonheart-beating
donors. Donors with sepsis, malignancy, infec-
tion with hepatitis B, hepatitis C, HIV, or tuber-
culosis, or irreversible renal failure are not
considered for donation.
Live: The use of kidneys from living donors is
recommended for renal transplantation when-
ever possible, in light of the growing body of
evidence of favorable outcomes after transplan-
tation. Before being selected as a living donor,
thorough counseling, medical, physical, and
psychological evaluation is performed. Outcome
studies have revealed lower mortality rates in
living donors compared with the general popu-
lation. This is probably caused in part by patient
selection and the fact that this group of patients
receive long-term medical follow-up.
Immunosuppression
The immunosuppression regime is tailored to
each patient in an effort to minimize rejection
as well as side effects. The following is a brief
summary of drugs used, usually in combination.
The commonest regime is triple therapy, e.g.,
cyclosporin, azathioprine, and prednisolone.
Corticosteroids have broad but potent immuno-
suppressive actions. They are used in high doses
in induction therapy as well as for episodes of
acute rejection. They are tapered to small mainte-
nance doses or stopped completely over time.
Because of the broad actions of corticosteroids,
there are a large range of side effects.
Cyclosporin is a calcineurin inhibitor. Although
there is little myelotoxicity, cyclosporin is nephro-
toxic and does contribute to chronic allograft
rejection. It is an important agent, because its
introduction improved 1-year graft survival by 15
to 20%.
12. End-Stage Renal Disease
Tacrolimus is also a potent calcineurin inhibitor.
Its side effect profi
file is similar to cyclosporin but
seems to be more diabetogenic, particularly in the
black population.
Azathioprine has been widely used for trans-
plantation and it continues to be an integral part
of many immunosuppression regimens. It inhibits
purine metabolism and, therefore, cellular prolif-
eration. There is a significant
fi side-effect profi
file,
most notably its myelosuppressive effect, which is
worsened by concomitant use of other drugs such
as allopurinol.
Mycophenolate mofetill acts similarly to azathio-
prine but is more specifi fic for lymphocytes.
Myelosuppression must also be monitored and
mycophenolate mofetil has more gastrointestinal
side effects than azathioprine.
Daclizumab and basiliximab are anti-CD25
antibodies. They target activated T cells only and
are used as an induction agent to prevent early
rejection.
Polyclonal antibodies to T-cells, ALG and ATG, as
well as monoclonal antibody to T cells, OKT3, are
used to treat refractory acute rejection and some-
times used as an induction agent to prevent rejec-
tion. These drugs are used cautiously because their
administration is associated with cytokine release
syndrome and pulmonary edema. Other side
effects include subsequent infection and posttrans-
plantation lymphoproliferative disease (PTLD).
Complications of Transplantation
Immediate
• Acute tubular necrosis is the commonest cause
of early graft function and is more likely to
occur with prolonged ischemic times and asys-
tolic, hypotensive, or elderly donors.
• Surgical complications are now the commonest
cause of early graft loss. These include renal vein
and arterial thrombosis and urinary leaks. These
complications are surveyed for with Doppler
ultrasound and isotope scanning. Occasionally
renal angiography or surgical reexploration is
required in the anuric kidney.
• Hyperacute rejection is now very uncommon,
with the more meticulous screening for the
presence of preexisting antibodies. The only
available treatment is graft nephrectomy.
69
Early
• Acute rejection should be suspected in patients
with established graft function who then experi-
ence a rise in serum creatinine. A biopsy is
usually required to confirm
fi the clinical diagnosis
and the treatment involves high-dose steroids,
usually with some modification
fi of the immuno-
suppression regime. Antibodies are considered
in steroid-refractory acute rejection.
• Infectious complications tend to vary with time
after transplantation. Within the fi first month
after transplantation, most infections are sur-
gically related, such as atelectasis and wound
infection. From 1 to 6 months after transplanta-
tion, opportunistic infections can emerge, such
as Pneumocystis carinii and Aspergillus fumiga-
tus. Clinical infection caused by the effects of
modulating viruses, cytomegalovirus (CMV)
and Epstein-Barr virus (EBV) are serious com-
plications for which there should be surveillance
with prophylaxis administered where appropri-
ate. PTLD in the early period tends to be an
EBV-related malignancy.
• Mechanical complications, such as arterial and
ureteric stenoses and lymphoceles exerting local
pressure, sometimes evolve as a cause of deteri-
orating graft function.
Late
• Chronic rejection occurs secondary to a combi-
nation of immunological and nonimmunolo-
gical factors. The result is an irreversible
progressive decline in graft function and is often
associated with proteinuria.
• Recurrence of original disease may result in graft
failure. There is a particularly high rate of recur-
rence of focal and segmental glomerulosclerosis
but it is diffi
ficult to predict and, therefore, is not
a contraindication to transplantation.
• Cardiovascular disease is the main cause of
death in the transplant population and the rate
of cardiovascular disease is higher than in the
general population. This is because of the addi-
tional risk factors of the ESRD population (Table
12.1) as well as the adverse effects of the immu-
nosuppressive agents.
• Malignancy, in particular, skin cancer, is three
times more common than the general population.
70
Other cancers that should be screened for include
renal, cervical, and vaginal cancers.
Summary
ESRD and its complications are becoming more
commonplace, particularly in the ICU environ-
ment. The challenges associated with this group
of patients also continue to rise and requires a
multidisciplinary approach, which includes the
intensivist and the nephrologist.
References
1. Eknoyan G, Beck GJ, Cheung AK, et al. Hemodialysis
(HEMO) Study Group. Effect of dialysis dose and
E. Mohammed
membrane flux in maintenance hemodialysis. N Engl
J Med 2002; 347(25): 2010–2019.
2. Paniagua R, Amato D, Vonesh E, et al. Health-related
quality of life predicts outcomes but is not affected
by peritoneal clearance: The ADEMEX trial. Kidney
Intt 2005; 67(3): 1093–1104.
3. The EBPG Expert Group on Renal Transplantation.
European Best Practice Guidelines for Renal Trans-
plantation (Part 1). Nephrol Dial Transplantt 2000;
15(Supp 7): 1–85.
Suggested Reading
Davison AM, Cameron S, Grunfeld J-P, et al. Oxford
Textbook of Clinical Nephrology. 3rd edition. Oxford:
Oxford University Press. 2005.
Levy J, Brown E, Morgan J. Oxford Handbook of Dialy-
sis. Oxford: Oxford University Press. 2001.
13
Clinical Hyperkalemia and Hypokalemia
Harn-Yih Ong
Hyperkalemia
Hyperkalemia is defined
fi as a plasma potassium
concentration greater than 5.0 mmol/L and refers
to an excess concentration of potassium ions in
the extracellular fl
fluid (ECF) compartment.
Causes of Hyperkalemia
(Tables 13.1 and 13.2)
Because of the ability of the kidneys to excrete a
large amount of potassium, hyperkalemia caused
by accelerated exogenous intake usually indicates
the presence of a subtle or overt defect in renal
potassium handling or an altered transcellular
distribution.
Compartmental Shift
Potassium is the principal intracellular cation, and
maintenance of the normal distribution of potas-
sium between the intracellular and extracellular
compartments relies on several regulatory mecha-
nisms. Under normal conditions, ingested potas-
sium is absorbed into the portal circulation
and rapidly shifted into cells by Na+/K+-ATPase
under the influence
fl of insulin and circulating β-
adrenergic catecholamines. When these mecha-
nisms are perturbed, hyperkalemia may occur.
Decreased Renal Excretion
The renal system maintains external potassium
balance in the long term and is responsible for
excreting 90 to 95% of the daily potassium load.
Decreased renal excretion of potassium is, there-
fore, the most important cause of hyperkalemia.
Hyperkalemia may follow failure of glomerular
filtration or tubular secretion of potassium.
fi
Clinical Features
Hyperkalemia is often asymptomatic, but severe
hyperkalemia (potassium >6.5 mmol/L) may pre-
sent with neuromuscular disturbances such as
distal paresthesia, generalized muscle weakness,
an ascending flaccid
fl paralysis, or ventilatory
failure. Sudden cardiac death may occur when
plasma potassium concentration exceeds 7.0 to
7.5 mmol/L, and this may be the earliest and only
manifestation. Acute hyperkalemia is much less
well tolerated than chronic hyperkalemia.
Electrocardiogram Changes
Some patients may show a gradual progression
of electrocardiogram (ECG) findings
fi but may
progress rapidly without warning. Cardiac arrest
caused by asystole, ventricular tachycardia, or ven-
tricular fi
fibrillation may occur at any point along
this progression. Hyperkalemia can be life threat-
ening even if the ECG is normal. Approximately
50% of patients with potassium levels exceeding
6.0 mmol/L have a normal ECG.
• K+, 5 to 6 mmol/L: peaked T waves and short-
ened QT interval
71
72 H.-Y. Ong

TABLE 13.1. Extrarenal causes of hyperkalemia

Increased intake
Exogenous sources
Endogenous sources (tissue breakdown)
Compartmental shift
Inhibition of Na+/K+-ATPase
Altered transcellular electrochemical
K+ gradient
Increased conductance of K+ channels
Familial hyperkalemic periodic paralysis
Potassium supplements (especially with advanced age, diabetes mellitus, underlying renal
impairment, and/or the concurrent use of potassium-sparing diuretics)
Stored packed red blood cells. Cardiac tolerance to hyperkalemia is decreased by hypocalcemia
because of the presence of the anticoagulant, citrate
Potassium penicillin G
Salt substitutes
Rhabdomyolysis. Each kilogram of lean muscle mass contains more than 100 mmol of potassium
Hemolysis
Tumor lysis syndrome
Reperfusion syndrome. Ischemia results in acidosis in the affected area and an outflow of
intracellular potassium, this potassium is “washed out” when the region is reperfused
Catabolic states
Insulin resistance/deficiency
β2-adrenergic catecholamine deficiency or resistance; e.g., β-blockers
Drugs and toxins; e.g., cardiac glycosides
Inorganic metabolic acidosis
ECF hypertonicity or hyperosmolar states; e.g., hyperglycemia, hypertonic solutions such as mannitol,
hypertonic saline
Drugs; e.g., depolarizing muscle relaxants (succinylcholine)

• K+, 6 to 7 mmol/L: prolonged PR interval, AV Pseudohyperkalemia

dissociation, flattening
fl and loss of P wave, and
widening of QRS complex Pseudohyperkalemia is caused by the release of
• K+, greater than 7 to 8 mmol/L: sine wave pattern, potassium from damaged cells in vitro (during
ventricular fibrillation, and asystole or after the removal of the blood sample from

TABLE 13.2. Renal causes of hyperkalemia

Inadequate sodium delivery to the cortical collecting duct
Intravascular volume depletion Acute circulatory failure, e.g., vasodilatory or septic shock
Severe cardiac failure
Hepatic cirrhosis with ascites
Renal failure Acute (oliguric) and chronic renal failure
Secondary hypoaldosteronism
Low renin Suppressed renin secretion, e.g., cyclosporin, tacrolimus
Distal (type IV) renal tubular acidosis, e.g., associated with diabetic nephropathy, tubular interstitial nephritis,
inhibitors of prostaglandin production
Normal/high renin Impaired aldosterone production, e.g., heparin
Impaired angiotensin II production/action, e.g., angiotensin-converting enzyme inhibitors, angiotensin II
receptor blockers
Normal/high renin, low cortisol Primary adrenal insufficiency, e.g., Addison’s disease (autoimmune)
Impaired adrenal enzyme biosynthesis, e.g., azole antifungals (ketoconazole), congenital adrenal enzyme
defects (rare)
Primary hypoaldosteronism (rare)
Tubular hyperkalemia without aldosterone deficiency (aldosterone resistance)
Renal distal tubular potassium Aldosterone antagonists, e.g., spironolactone
secretory defect (acquired) Luminal sodium channel blockade, e.g., amiloride, cimetidine, trimethoprim, pentamidine
Inhibition of basolateral Na+/K+-ATPase, e.g., cyclosporine
Acute or chronic tubulointerstitial nephritis, e.g., diabetic nephropathy, obstructive uropathy, postrenal
transplant, lupus nephritis, sickle cell nephropathy, amyloidosis
Pseudohypoaldosteronism Type I and II. Rare
13. Clinical Hyperkalemia and Hypokalemia
the patient) and can produce a 1 to 2 mmol/L arti-
factual increase in potassium levels. The major
causes are:
• Contamination by drip site or laboratory error
• Hemolysis caused by mechanical trauma during
venipuncture
• Thrombocytosis (platelet count >900 × 1010
cells/L)
• Leukocytosis (white cell count >70 × 109 cells/L)
or mononucleosis (“leaky red blood cells”)
• Familial pseudohyperkalemia or other uncom-
mon genetic syndromes
Management
Severe hyperkalemia (plasma potassium
>6.5 mmol/L or with ECG changes) is a medical
emergency and therapy should begin
immediately.
Stabilization of Cardiac Membranes:
Intravenous Calcium
Although no randomized studies exist to support
the use of calcium salts administered intrave-
nously (e.g., 10 mL 10% calcium gluconate over
2–3 min into a large vein), it is still recommended
as first-line therapy in the presence of ECG changes
or arrhythmia. The protective effect of calcium is
evident within minutes and lasts for 30 to 60
minutes. Caution should be used in patients who
take digoxin because calcium has been reported
to worsen the myocardial effects of digoxin toxic-
ity. An alternative is to consider using magnesium
instead of calcium to stabilize the myocardium.
Calcium may reduce the immediate risk of cardiac
arrest, but represents a temporizing measure only.
Plasma potassium concentration is unaltered.
Transcellular Redistribution
• Insulin and dextrose: Administration of insulin
always causes a transient reduction in plasma
potassium because the activated insulin recep-
tor stimulates Na+/K+-ATPase, driving cellular
uptake of potassium. The use of insulin and
glucose (e.g., 50 mL of 50% glucose to prevent
hypoglycemia) for the emergency treatment of
73
hyperglycemia is effective and rapid in onset of
action. For example, 10 U intravenous insulin
can be expected to lower the plasma potassium
concentration by 0.5 to 1.5 mmol/L within 15
minutes, lasting 2 to 4 hours.
• Sodium bicarbonate: Increasing the pH of the
ECF compartment with sodium bicarbonate
(e.g., 100 mmol over 1–2 hours) will shift potas-
sium into cells as an acidosis is corrected. Its
effectiveness is debated, but it is still recom-
mended when hyperkalemia is associated with
severe inorganic metabolic acidosis. Ensur-
ing effective diuretic therapy fi
first lessens the
likelihood of developing volume overload as a
complication.
• Salbutamol: Meter-dose inhalers, nebulized, or
intravenous salbutamol seem equally effective
in reducing potassium levels.
Removal of Excess Potassium
Treatments that shift potassium into the cells have
no effect on total body potassium. Excess total
body potassium may be removed by gastrointes-
tinal elimination, renal excretion, or renal replace-
ment therapy.
• Renal excretion of potassium may be enhanced
with the use of diuretics, especially loop diuret-
ics, which increase the delivery of sodium and
the urine flow rate to the cortical collecting duct,
increasing tubular secretion of potassium. If the
patient is volume depleted, hydration with saline
can be administered with the diuretic.
• Although widely used clinically in the treatment
of hyperkalemia, cation exchange resins do not
seem to be effective at 4 hours and should not
be relied on for rapid effects.
• Hemodialysis or continuous renal replacement
therapies are the treatments of last resort, with
the exception of patients already receiving these
therapies.
Hypokalemia
Hypokalemia is usually defined
fi as a plasma potas-
sium concentration of less than 3.5 mmol/L, and
refers to a deficit
fi of potassium ions in the ECF
compartment.
74
Causes of Hypokalemia (Table 13.3)
Hypokalemia indicates a disruption of normal
potassium homeostasis and is almost always
caused by potassium depletion caused by increased
losses, either through the kidneys or gut. In either
case, drugs are the most common cause. Less fre-
quently, hypokalemia occurs because of an acute
shift of potassium from extracellular to intracel-
lular fluid (ICF) compartments (compartmental
shift). For any given cause, the magnitude of the
change is relatively small (usually <1.0 mmol/L),
but a combination of factors may lead to a signifi-fi
cant fall in plasma potassium.
TABLE 13.3. Causes of hypokalemia
Inadequate intake of potassium (rare)
Compartmental shift
Stimulation of Na+/K+-ATPase-mediated
cellular potassium uptake
Metabolic alkalosis
Inhibition or blockade of K+ conductance
channels and unopposed Na+/K+- ATPase
Accelerated loss of potassium (can be classified according to acid-base status)
Chloride-responsive metabolic alkalosis
(chloride depletion causes ECF
contraction with secondary
hyperaldosteronism, leading
to renal potassium wasting)
Chloride-resistant metabolic alkalosis
(the primary disturbance is
mineralocorticoid excess
resulting in sodium and water
retention, ECF expansion,
hypertension, metabolic
alkalosis, and the continuous
stimulation of potassium
secretion in the cortical
collecting duct)
Hyperchloremic metabolic acidosis
(non anion gap)
Organic metabolic acidosis (high anion gap)
Magnesium deficiency (normal acid-base
balance)
H.-Y. Ong
Familial Hypokalemic Periodic Paralysis
Familial Hypokalemic Periodic Paralysis is an
uncommon inherited (autosomal dominant) dis-
order characterized by recurrent episodes of
muscle paralysis that subside spontaneously after
6 to 24 hours. The primary defect is the gene encod-
ing the skeletal muscle dihydropyridine receptor, a
voltage-gated calcium channel. Acute attacks are
precipitated by a reduction in plasma potassium,
such as after carbohydrate-rich meals (increased
insulin) or rest after exertion (increased catechol-
amines). Administration of potassium is lifesaving
and should be administered to treat acute attacks.
Endogenous or exogenous insulin
β2-adrenergic receptors activation or indirect β2 sympathomimetics (e.g., salbutamol,
dobutamine)
Increased endogenous adrenaline release (e.g., delirium tremens, hypoglycemia, coronary
ischemia, after cardiopulmonary resuscitation)
Phosphodiesterase inhibition (e.g., xanthines: milrinone, theophylline, and caffeine)
Thyrotoxic hypokalemic periodic paralysis
Rapid cell growth (e.g., after vitamin B12 treatment for pernicious anemia)
In general, [K+]Plasma falls by 0.4 mmol/L per 0.1 U increase in ECF pH
Barium causes irreversible blockade of K+ conductance channels, preventing passive efflux of
K+ from cells
Chloroquine toxicity causes a dose-dependent reversible blockade of K+ channels
Familial hypokalemic periodic paralysis: K+ channels are normal but the muscle behaves as if
channels are blocked
Gastrointestinal loss (e.g., vomiting, gastric suctioning, colonic villous adenoma)
Renal loss (e.g., loop diuretics, Bartter’s syndrome, thiazide diuretics, Gitelman syndrome)
Primary hyperaldosteronism: high aldosterone, low renin, normal cortisol levels, e.g., adrenal
adenoma, bilateral adrenal hyperplasia
Glucocorticoid excess: normal aldosterone, normal renin and high cortisol levels, e.g., Cushing’s
syndrome
Syndrome of apparent mineralocorticoid excess: low aldosterone level, low renin level, and
normal cortisol, e.g., liquorice, Liddle syndrome
Congenital adrenal hyperplasia: low aldosterone, low renin, and low cortisol
Gastrointestinal loss of potassium, e.g., diarrhea, urinary diversion
Renal tubular acidosis
E.g., lactic acidosis, ketoacidosis
E.g., alcoholism, malabsorption, drugs: diuretics, gentamicin, cisplatin, amphotericin
13. Clinical Hyperkalemia and Hypokalemia
Magnesium Depletion
Concurrent hypomagnesemia coexists in up to
40% of cases of hypokalemia because of drugs or
disease processes that cause loss of both ions.
Whether hypokalemia is caused by magnesium
depletion or is an independent effect, it is difficult
fi Cardiovascular
to assess. Magnesium is essential in the stabiliza-
tion of cellular membranes, and hypomagnesemia
is associated with increased losses of intracellular
potassium, and increased fecal and urinary potas-
sium wasting. Regardless of the cause, hypokale-
mia becomes refractory when hypomagnesemia is
also present, especially with plasma magnesium
concentrations less than 0.6 mmol/L. In these cir-
cumstances, correction of hypokalemia requires
initial restoration of magnesium.
Clinical Effects
Hypokalemia alters the function of excitable
membranes, an effect more notable in skeletal
muscle than cardiac muscle. Renal and metabolic
effects are also seen. The likelihood of symptoms
seems to correlates with the rapidity of decrease
in plasma potassium.
Neuromuscular
Mild Hypokalemia
Mild hypokalemia (plasma potassium, 3.0–
3.5 mmol/L) is often asymptomatic. Skeletal
muscle weakness is not usually seen with potas-
sium greater than 3.0 mmol/L.
Moderate Hypokalemia
Symptoms of moderate hypokalemia (plasma
potassium, 2.5–3.0 mmol/L) are nonspecific:fi lassi-
tude, fatigue, constipation, weakness in the lower
extremities, and myalgia. A paralytic ileus can
occur.
Severe Hypokalemia
Ascending paralysis can occur in severe hypoka-
lemia (plasma potassium, ≤2.0–2.5 mmol/L). The
lower extremities are typically involved fi
first (par-
ticularly the quadriceps), followed by the trunk
75
and upper extremities, with eventual impairment
of respiratory muscle function and ventilatory
failure. Rhabdomyolysis can be seen with severe
hypokalemia.
Arrhythmias
The arrhythmogenic potential of hypokalemia is
significantly
fi increased in the presence of digoxin,
myocardial ischemia, congestive cardiac failure
(CCF), or left ventricular hypertrophy. Hypokale-
mia predisposes to serious ventricular ectopy and
is associated with increased frequency of primary
ventricular fifibrillation and mortality, particularly
in the setting of ischemic heart disease and acute
myocardial infarction.
ECG Changes
• Flattened T wave
• U wave (delayed ventricular and Purkinje
repolarization)
• Ventricular ectopics
• Note: When potassium is at ≤2.0 mmol/L, T and U
waves combine, creating a wave with greater
amplitude with risk of reentry circuits arising
during the prolonged relative refractory period,
leading to the development of tachyarrhythmias
Worsening of Cardiac Function
Chronic hypokalemia exacerbates CCF by impair-
ing the function and contractility of myocardial
muscle. This reduces stroke volume and cardiac
output. Cardiac necrosis has been described.
Renal and Metabolic
Ammoniagenesis and Metabolic Alkalosis
Chronic hypokalemia results in ICF acidification,
fi
which stimulates ammoniagenesis in the proximal
tubule. Increased ammonia trapping and net
acid excretion coupled to enhanced bicarbonate
production perpetuates metabolic alkalosis.
Increased ammoniagenesis may be clinically
important in patients with severe liver disease,
in whom hypokalemia may precipitate hepatic
encephalopathy.
76
Nephrogenic Diabetes Insipidus
Chronic hypokalemia commonly leads to irrevers-
ible tubulointerstitial changes resulting in neph-
rogenic diabetes insipidus (DI).
Diagnostic Approach to Hypokalemia
1. History of associated conditions, including
drug history.
2. Examination: assessment of extracellular
volume and acid-base status.
3. Investigations:
a. Urinary potassium.
i. Measured on a 24-hour urine collection,
urinary potassium should be less than 10
to 15 mmol/24 hours with hypokalemia
of extrarenall origin (indicating appro-
priate renal potassium conservation).
ii. Random urinary potassium may be
greater than 20 mmol/L in cases of renal
potassium wasting, but this cannot be
interpreted unambiguously because
urinary potassium reflects
fl the K+ to H2O
ratio (and depends mainly on the amount
of water reabsorbed).
b. Urinary anion gap.
4. Serum magnesium.
5. Plasma aldosterone, renin, and cortisol levels.
Treatment
The immediate objective of potassium supple-
mentation is to prevent life-threatening cardiac
and muscular complications, with the rate and
H.-Y. Ong
route of administration depending on the plasma
potassium as well as the presence and serious-
ness of the pathophysiological consequences of
hypokalemia. The underlying disorder should be
treated simultaneously.
Continuous ECG monitoring of cardiac rhythm
is indicated for plasma potassium ≤2.5 mmol/L or
intravenous infusion rates of at least 10 mmol/h.
Maximum rate of intravenous potassium admin-
istration should not exceed 20 mmol/h. Large
enteral doses of potassium are difficult
fi to deliver
because potassium salts are mucosal irritants,
with both tablet and liquid forms reported to
cause esophageal and gastrointestinal ulceration.
Suggested Reading
Gennari FJ. Current Concepts: Hypokalemia. N Engl J
Med. 1998; 339(7): 451–457.
Glover P. Hypokalaemia. Crit Care Resusc. 1999; 1:
239–251.
Halperin M, Kamel KS. Potassium. Lancett 1998; 352:
135–140.
Mahoney BA, Smith WAD, Lo DS, et al. Emergency Inter-
ventions for Hyperkalaemia. Cochrane Database Syst
Rev. 2006. Issue 1.
Peterson LN, Levi M (Edited by Robert W. Schrier).
Renal and Electrolyte disorders: Disorders of
Potassium Metabolism. 6th ed. Lippincott, Williams
and Wilkins. 2003.
Rastegar A, Soleimani M. Hypokalaemia and hyperka-
laemia. Postgrad Med J. 2001; 77: 759–764.
14
Clinical Hyponatremia and Hypernatremia
Himangsu Gangopadhyay
Hyponatremia
Hyponatremia reflects
fl an abnormal ratio of
sodium to water and is defi
fined as a serum sodium
less than 135 mmol/L. Mild to moderate hypona-
tremia (serum sodium 128–134 mmol/L) is seen in
20 to 30% of hospital inpatients. Severe hypona-
tremia (serum sodium less than 120 mmol/L) is
seen in only 2 to 5% of hyponatremic patients.
Classification (Table 14.1)
1. Hyponatremia with decreased sodium and
water (hypotonic dehydration). There is gener-
ally loss of sodium and water with inappropri-
ate fluid replacement.
2. Hyponatremia with normal body sodium and
normal or increased body water, the patient is
usually euvolemic. Plasma osmolality may be
normal, low, or high.
3. Hyponatremia with increased sodium and
water.
Pseudohyponatremia
Isosmolar hyponatremia (serum osmolality of
275–290 mOsm/kg) is usually caused by severe
hyperlipidemia or hyperproteinemia and has
been called “pseudohyponatremia.” Measurement
of plasma sodium by an ion-selective electrode is
not affected by the volume of plasma “solids” and,
therefore, will give a true sodium level.
Transurethral Resection of the Prostate
(TURP) Syndrome
• Hyponatremia
• Cardiovascular changes: hypertension/
hypotension, bradycardia
• Neurological changes: agitation, confusion,
fitting, visual disturbances, fixed dilated
pupils
Irrigating fluid usually containing 1.5% glycine
is absorbed during the procedure. Excess fl fluid
is absorbed and leads to an increase in total
body water and hyponatremia. There is an in-
crease in the osmolar gap. With the use of
glycine, other features may be seen: hypergly-
cinemia, hyperserinemia (a metabolite of
glycine), hyperammonemia, metabolic acidosis,
and hypocalcemia.
Syndrome of Inappropriate Antidiuretic
Hormone Secretion
Syndrome of inappropriate antidiuretic hormone
(ADH) secretion (SIADH) is diagnosed on the fol-
lowing features:
• Hypotonic hyponatremia
• Urine osmolality greater than plasma osmolal-
ity (inappropriately concentrated urine
osmolality)
• Urine sodium greater than 20 mmol/L
• Other causes of hyponatremia excluded (e.g.,
cardiac, endocrine)
• Normovolemia
77
78 H. Gangopadhyay

TABLE 14.1. Causes and classification of hyponatremia

Osmolality Volume status Other
Decreased sodium and water (hypotonic dehydration)
Extra renal sodium loss Excessive sweating Low Hypovolemic Urine Na < 20 mmol/L
Burns
Vomiting
Diarrhea
Renal sodium loss Osmotic diuretics Low Hypovolemic Urine Na > 20 mmol/L
Thiazide and loop diuretics
Mineralocorticoid deficiency
Salt-losing nephropathy
Diuretic phase of acute tubular
necrosis
Renal tubular acidosis
Normal body sodium and normal or increased body water
High plasma osmolality Hyperglycemia High Normal or hypovolemic
Mannitol
Glycerol
Glycine
Sorbitol
Normal plasma osmolality Hyperlipidemia Normal Normal
Hyperproteinemia
(pseudohyponatremia)
Low plasma osmolality Stress (physical, psychological) Low Normal Urine Na > 20 mmol/L
Antidiuretic drugs
Glucocorticoid deficiency
Myxedema
SIADH
Transurethral resection of prostate
Acute/chronic renal failure
Severe polydipsia Low Normal Urine Na < 20 mmol/L
Increased sodium and water
Edematous states Cardiac failure Low Edematous
Liver failure
Renal failure
Nephrotic syndrome

TABLE 14.2. Causes of SIADH

Ectopic ADH production Small cell bronchial carcinoma
Pancreatic adenocarcinoma
Leukemia
Lymphoma
Thymoma
Central nervous system disorders Trauma
Brain tumor
Central nervous system infection (meningitis, encephalitis,
abscess)
Subarachnoid hemorrhage
Acute intermittent porphyria
Guillain-Barré syndrome
Systemic lupus erythematous
Pulmonary diseases Pneumonia
Tuberculosis
Lung abscess
14. Clinical Hyponatremia and Hypernatremia
Treatment is with fluid restriction and treat-
ment of the underlying cause if possible. See Table
14.2 for a list of causes.
Clinical Presentation
Clinical presentation depends on the rapidity and
severity of the development of the hyponatremia
as well as the underlying condition. Mild
hyponatremia may be symptomless or present
with anorexia, nausea, lethargy, and apathy. Signs
and symptoms of severe hyponatremia include
disorientation, agitation, seizures, depressed
refl
flexes, focal neurological signs, and, eventually,
Cheyne-Stokes respiration.
Diagnosis
Diagnosis of the cause of hyponatremia involves:
1. History:
a. Medical history: cardiac disease, renal disease,
hepatic disease, endocrine disorders
b. Current and recent medication: diuretics,
antidepressants
2. Physical examination: volume status, evidence
of cardiac, renal, liver failure
3. Investigations:
a. Serum osmolality
b. Urine sodium and osmolality
c. Blood glucose
d. Serum lipids
e. Thyroid function
f. Plasma proteins
Treatment
Much has been mentioned regarding treatment of
hyponatremia and the potential complication of
central pontine myelinolysis (CPM). This is a
potentially fatal condition that can occur when
the serum sodium is corrected too quickly. CPM
can lead to mutism, dysphasia, spastic quadriple-
gia, pseudobulbar palsy, delirium coma, and even
death. Risk factors for its development are alco-
holism, burns, use of thiazide diuretics, a mal-
nourished state, and hypokalemia.
79
Asymptomatic Patients
It is important to fully assess the patient and treat
the underlying cause. The patient’s fluid fl status
should be assessed; hypovolemia should be treated
with normal saline, whereas hypervolemic states
(such as congestive cardiac failure) will require
salt and water restriction. With patients who are
euvolemic and asymptomatic, fluid fl restriction
may be adequate.
Symptomatic Patients
If the onset is acute and the patient is symptomatic
(e.g., fitting, altered conscious level) then aggres-
sive correction of sodium is required. This can be
performed by the cautious infusion of 3% saline
at a rate of 1 mL/kg/h until the sodium rises to 120
to 125 mmol/L. The patient should be closely mon-
itored during this period, and the presence of
seizure or coma may require airway protection,
anticonvulsants, and other supportive care before
the serum sodium is corrected appropriately.
Serum sodium should not be allowed to rise more
than 2 mmol/L/h and not more than 25 mmol in
48 hours. Frequent checking of serum sodium is,
therefore, important. In patients with chronic
hyponatremia, a more gradual rise of serum
sodium is appropriate.
Hypernatremia
Hypernatremia is defined
fi as serum sodium greater
than 145 mmol/L. It is always associated with a
hyperosmolar state.
Classification (Table 14.3)
1. Decreased total body sodium (extracellular
water and sodium loss with excess water
loss)
2. Normal total body sodium (extracellular water
deficiency
fi associated with minimal sodium
loss)
3. Increased total body sodium (extracellular
water and sodium gain with relatively excess
sodium gain)
80 H. Gangopadhyay

TABLE 14.3. Classification and causes of hypernatremia Evaluation of Hypernatremia

Decreased total body sodium (water greater than sodium loss)
Extra renal loss Vomiting Diagnosis of the cause of hypernatremia
Diarrhea involves:
Excessive sweating
Dialysis 1. History
Renal loss Osmotic diuretics (e.g., glucose, urea, a. Fluid loss/excessive water loss
mannitol)
b. Poor fluid intake
Normal total body sodium (water loss) c. Increased salt intake
Extra renal Unconscious state
d. Intravenous sodium bicarbonate or hyper-
Thirst center dysfunction
Mechanical obstruction tonic saline therapy
Inappropriate intravenous therapy e. Clinical scenario that can lead to neuro-
No access to water genic/nephrogenic diabetes insipidus
Renal loss Cranial diabetes insipidus 2. Physical examination: assessment of volume
Nephrogenic diabetes insipidus
status is most important
Increased total body sodium (sodium greater than water gain) 3. Investigations:
High sodium intake Sea water ingestion a. Serum osmolality
Accidental/intentional salt ingestion
Hypertonic saline
b. Urine sodium and osmolality
Sodium bicarbonate infusion
Low sodium output Mineralocorticoid excess
Interpretation of Urinary Osmolality
A serum osmolality greater than 290 mOsm/kg
should be accompanied by highly concentrated
urine if the concentrating mechanism of the
Mechanism tubules is intact and ADH release is adequate. A
urinary osmolality of less than 200 mOsm/kg
The defence mechanisms against hypernatremia usually suggests some form of diabetes insipidus.
are ADH release and thirst. Any clinical condition
affecting these mechanisms will lead to hyperna-
tremia if not addressed properly. Treatment
Treating underlying cause is very important. Fluid
Clinical Presentation therapy with pure water orally or nasogastrically
could be suffi
ficient in some situations, but intrave-
Clinical signs and symptoms are not seen until nous therapy with 5% dextrose or pure water
serum sodium reaches more than 155 mmol/L. through a central vein is often necessary.
Symptoms include fever, restlessness, irritability, A rapid decrease of serum sodium could be
drowsiness, lethargy, confusion, and coma. Con- equally detrimental, and a decrease of serum
vulsions are rarely seen. sodium by 2 mmol/L/h is acceptable.
15
Clinical Metabolic Acidosis and Alkalosis
Sara Blakeley
Acid-base disturbances are common on the inten-
sive care unit (ICU) and should always prompt a
search for the underlying cause (Tables 15.1–15.3).
Recently another, although not all that new (1),
way of understanding the mechanism behind
acid-base disorders has gained popularity. This
chapter starts with just a brief discussion of this
approach, because there are several excellent over-
views in the literature (2–6).
Traditional Versus Physiochemical
Approach to Acid-Base Disturbances
Most “traditional” views of acid-base balance rely
on the Henderson-Hesselbach equation, but there
has always been debate regarding quantification
fi the effective SID (SIDe). The SIDe is made up of
of the metabolic component. It can be described
using plasma bicarbonate and anion gap (AG) or
by using standard base excess (SBE). However,
SBE is affected by changes in sodium, chloride,
and albumin, and a significant
fi number of abnor-
mal AGs will be missed unless the effect of albumin
is considered (7–9). The third way of quantifying
the metabolic component is the strong ion differ-
ence (SID) (1), taking into consideration nonbi-
carbonate buffers, such as inorganic phosphate
and serum albumin, both of which may be abnor-
mal in critically ill patients.
Stewart’s (physiochemical) approach relies on
the principles of physical chemistry; electroneu-
trality, conservation of mass, and dissociation of
electrolytes (1). It considers three independent
variables for pH: the SID, pCO2 and total weak acid
concentration (ATOT). H+ or HCO3− can only change
if one or more of these three variables changes,
rather than bicarbonate itself being the main deter-
minant of change, as in the traditional approach.
“Strong ions” are ions that exist completely dis-
sociated (charged) in water. There are more strong
cations than anions and this difference is called
the SID. SID has an electrochemical effect on water
dissociation; as SID becomes more negative, H+
increases and pH falls.
“Weak ions” exist as dissociated (A−) or associ-
ated forms (HA), and together they make up ATOT.
Nonvolatile weak acids, mainly albumin but also
inorganic phosphate and bicarbonate, dissociate
in body fluids forming weak anions.
To maintain electrical neutrality, the SID must
be balanced by an equal and opposite charge,
predominately weak acids (A−) and CO2 (Equation
15.1). If the SID is calculatedd from the measured
plasma strong ion concentrations (Equation 15.2),
it is termed the apparent SID (SIDa). However, this
will not be precise if there are unmeasured anions
or cations present. If the SIDe and the SIDa do not
match (strong ion gap [SIG]) then unmeasured
ions mustt be present. SIG should be zero, although,
in practice, there is a degree of normal variability.
If SIG is positive, there must be more unmeasured
strong anions (e.g., ketones, sulfates), and if it is
negative, more unmeasured cations.
Equation 15.1:
SIDe = A− + HCO3−
Equation 15.2:
SIDa = ([Na+] + [K+] + [Ca2+] + [Mg2+]) − ([Cl−] +
[lactate])
81
82 S. Blakeley

TABLE 15.1. Classification of metabolic acidosis according to AG

High AG (unmeasured anions)
Lactate
Ketones Diabetic, alcoholic, or starvation ketoacidosis
Renal failure
Ingested toxins E.g., salicylate, paracetamol, formaldehyde, ethylene glycol, methanol
Non-AG (hyperchloremic)
Gastrointestinal bicarbonate loss E.g., diarrhea, ureterosigmoidostomy, jejunal/ileal loop, small bowel fistulae, pancreatic
fistulae, biliary fistulae
Renal bicarbonate loss Renal tubular acidosis
Exogenous acid load
Loss of potential bicarbonate E.g., ketosis with ketone excretion
Cation exchange resins
Low AG
Hypoalbuminemia
Increased concentration of unmeasured cations E.g., magnesium, calcium, lithium
Accumulation of positively charged compounds E.g., cationic antibiotics, IgG myeloma
normally absent from serum
Interference with measurement E.g., hyperlipidemia
+ + − −
AG = ([Na ] + [K ]) + ([Cl ] + [HCO ]) (Normal, 10–18 mmol/L)
3
AGadjusted = AGobserved + 0.25 × ([normal albumin in g/L] − [observed albumin in g/L])

TABLE 15.2. Pathological classification of causes of metabolic alkalosis

Exogenous or endogenous bicarbonate load
Acute alkali administration
Milk alkali syndrome
Recovery from lactic acidosis or ketoacidosis Caused by excess regeneration of HCO3
Massive blood transfusion Caused by metabolism of citrate
Chloride depletion
Vomiting, high gastric drainage
Gastrocystoplasty
Diuretics
Posthypercapnia
Diarrhea secondary to villous adenoma Villous adenomas are usually associated with hyperchloremic metabolic acidosis, but some can
secrete chloride
Cystic fibrosis
Potassium deficiency
Primary hyperaldosteronism Caused by adenoma, carcinoma; idiopathic or hyperplasia
Secondary hyperaldosteronism E.g., Cushing syndrome/disease, exogenous corticosteroids, accelerated hypertension, renal
artery stenosis
Drugs E.g., carbenoxolone, liquorice
Primary hyperaldosteronism Caused by adenoma, carcinoma; idiopathic or hyperplasia
Secondary hyperaldosteronism E.g., Cushing syndrome/disease, exogenous corticosteroids, accelerated hypertension, renal
artery stenosis
Bartter’s syndrome
Gitelman syndrome
Magnesium or potassium deficiency
High-dose intravenous penicillins Caused by distal delivery of nonreabsorbable anions with an absorbable cation such as sodium
Other
Severe hypoalbuminemia E.g., nephrotic syndrome
15. Clinical Metabolic Acidosis and Alkalosis 83

TABLE 15.3. Clinical effects of metabolic acidosis and metabolic alkalosis

Metabolic acidosis
Cardiac • Reduced myocardial contractility and cardiac failure
(but unclear association in clinical practice)
• Resistance to catecholamines
• Increased risk of arrhythmias
Respiratory • Stimulation of the carotid body and aortic
chemoreceptors causing hyperventilation
(Kussmaul respiration)
Neurological • Impaired consciousness (mechanism not fullyy
understood and not clearly correlating with the
degree of acidosis)
• Intracerebral vasodilation (may be clinicallyy
significant in the setting of already raisedd
intracranial pressure)
Metabolic and immune • Hyperkalemia (extracellular potassium shifts)
• Glucose intolerance (inhibition of glycolysis andd
hepatic gluconeogenesis)
• Immune activation
Metabolic alkalosis
• Decreased myocardial perfusion caused by arteriolar
constriction
• Reduced angina threshold
• Increased risk of arrhythmias
• Depressed ventilation (causing compensatory respiratory
acidosis), which could lead to failure to wean a patient
from mechanical ventilation
• Decreased cerebral blood flow caused by arteriolar
constriction
• Headache, confusion, mental obtundation
• Neuromuscular excitability: seizures and tetany (related to
reduction in ionized calcium level)l
• Hypokalemia
• Hypomagnesemia
• Hypophosphatemia
• Stimulation of aerobic glycolysis leading production of
lactic acid and ketoacids
• Decreased plasma ionized calcium concentration

Note: the effects of severe alkalemia (pH > 7.60) appear more pronounced with respiratory rather than metabolic alkalosis.

Equation 15.3: lactate can be produced under aerobic conditions,

SIDa − SIDe = SIG (equals zero unless especially in the setting of infl flammatory pro-
unmeasured anions or cations cesses. In sepsis, infl flammatory mediators can
present) accelerate aerobic glycolysis, leading to increased
glucose turnover and increased lactate production
By using this approach, a change in the balance
(12, 13). Specifific organs are also capable of pro-
between strong anions and cations accounts for
ducing excess lactate under times of stress, for
acid-base disturbances seen on the ICU. For
example, the lungs and gut (12, 13).
example, excess chloride from a high-volume
Elevated lactate levels may also indicate
saline infusion reduces the SID, causing an acido-
decreased clearance (12). Lactate is mostly metab-
sis. A loss of chloride from a large nasogastric
olized by the liver (50%), and decreased clearance
output increases the SID, causing an alkalosis.
can occur with impaired liver function or
The modern debate now centers on which is the
decreased liver blood flow.
best and most practical method of assessing acid-
Unless lactate levels are specifi
fically measured,
base disorders in critically ill patients, and, in par-
an elevated level may be “missed” by the AG or
ticular, detecting the presence of unmeasured anions:
SBE because of factors such as hypoalbuminemia.
the SIG. To date, neither the SIG, corrected AG, or
In addition, hyperlactatemia is not always accom-
corrected SBE has been found to be overwhelmingly
panied by an acidosis.
superior to the other, but all have been found to be
Elevated lactate levels, particularly those that
predictors of increased mortality (10, 11).
fail to clear during the fifirst 24 hours, have been
repeatedly shown to correlate with a poor outcome
Lactic Acidosis (Table 15.4) (11, 14, 15).

When more lactate is produced than is metabo-

lized, hyperlactatemia occurs. Elevated levels are
generally taken to indicate anaerobic metabolism
caused by generalized or regional tissue hypoxia
(12). However, it is important to remember that
Use of Sodium Bicarbonate
Controversy exists regarding the use of alkali
therapy (e.g., sodium bicarbonate) to treat meta-
bolic acidosis (16). No clinical studies have shown
84 S. Blakeley

TABLE 15.4. Classification of lactic acidosis

Type A (hypoxic)
Circulatory insufficiency (e.g., shock, cardiac arrest)
Regional hypoperfusion
Carbon monoxide and cyanide poisoning (caused by mitochondrial enzyme inhibition)
Severe hypoxia
Severe exercise/prolonged seizures (caused by increased muscle activity)
Severe anemia
Type B (nonhypoxic)
Sepsis in general (caused by accelerated aerobic glycolysis and mitochondrial dysfunction) and with specific infections (e.g., cholera, falciparum
malaria, AIDS)
Thiamine deficiency (thiamine is a cofactor of pyruvate dehydrogenase)
Fulminant hepatic failure, severe liver disease
Alcoholism (ethanol oxidation increases the conversion of pyruvate to lactate and inhibits of pathways of pyruvate metabolism)
Severe renal failure
Malignancy, leukemia, and lymphoma
Short bowel syndrome (D lactic acidosis)
Diabetic ketoacidosis (ketones may inhibit hepatic lactate uptake)
Type B: drug induced
Phenformin/metformin
Ethanol, methanol, ethylene glycol
Salicylate poisoning
Paracetamol poisoning
Intravenous fructose, sorbitol
Cyanide
β-agonists (e.g., salbutamol, adrenaline, caused by increased glyconeogenesis, glycogenolysis, lipolysis, and cyclic AMP activity)
Type B: inborn errors of metabolism
Glucose 6 phosphatase deficiency
Fructose 1,6 diphosphatase deficiency
Deficiency of enzymes of oxidative phosphorylation

a benefifit on outcome in patients with lactic acido-
sis, but it is diffi
ficult to separate the effects of the
acidosis from the effects of the underlying patho-
logical condition.
Sodium bicarbonate is not without risks,
including:
• Acute fluid overload.
• Alkaline “overshoot” caused by subsequent
metabolism of organic salts increasing the bicar-
bonate concentration.
• Paradoxical intracellular acidosis. CO2 released
diffuses more quickly than bicarbonate ions into
cells, therefore, initially lowering the intracellu-
lar pH. There is debate regarding whether this is
clinically significant.
fi
Use of Renal Replacement Therapy
In acute renal failure, the daily production of
mineral acids is adequately matched by the effi-
fi reason for the increased mortality.
cacy of renal replacement therapy (RRT) tech-
niques, therefore, the acidosis can be cleared
within 48 hours (16). Despite the fact that lactate
has a low molecular weight and it is easily removed
by continuous therapies, RRT has been shown to
contribute to only less than 3% of total lactate
clearance (17). It may be that RRT plays a role in
improving the overall clinical situation (e.g.,
hemodynamic and fluid fl status), therefore, pro-
moting the clearance of lactate, rather than actu-
ally removing it.
Metabolic Alkalosis
Metabolic alkalosis is common, but carries an
associated mortality that increases with increas-
ing pH, especially pH higher than 7.55 (18). The
cause, rather than the alkalosis itself, may be the
15. Clinical Metabolic Acidosis and Alkalosis
Metabolic alkalosis can be classified
fi clinically
(Table 15.2) or according to the underlying
pathophysiology: initiating process or perpetuat-
ing processes (18).
Initiating Processes
1. Loss of hydrogen ions through the kidney
(e.g., loop diuretics, primary hyperaldosteronism)
or gastrointestinal tract (e.g., vomiting, nasogas-
tric suctioning).
2. Accumulation of alkali from exogenous (e.g.,
sodium bicarbonate in the setting of renal insuf-
ficiency) or endogenous sources (e.g., metabolism
fi References
of ketones after diabetic ketoacidosis).
The kidneys have a large capacity to excrete
excess bicarbonate and are mostly able to correct
the alkalosis; however, in certain situations, the
kidney will retain rather than excrete alkali, there-
fore, perpetuatingg the alkalosis. The persistence of
a metabolic alkalosis suggests there is an ongoing,
untreated process.
Perpetuating Factors
1. Hypovolemia. Decreased renal perfusion stimu-
lates the renin-angiotensin-aldosterone system
(RAAS), therefore, increasing sodium absorp-
tion and hydrogen ion secretion.
2. Chloride depletion. Stimulation of the RAAS
leads to increased bicarbonate reabsorption in
the absence of adequate chloride.
3. Severe hypokalemia. Caused by an intracellu-
lar shift of hydrogen ions in exchange for
potassium.
4. Reduced glomerular fi filtration rate (GFR).
Reduction in GFR causes a decrease in filtered
fi 9. Story DA, Poustie S, Bellomo R. Estimating unmea-
bicarbonate.
Treatment
1. Correct the primary cause if possible, e.g.,
stop or reduce diuretics.
2. Address perpetuating factors. Most forms of
metabolic alkalosis are chloride responsive, and
isotonic sodium chloride will correct both chlo-
ride and volume depletion. As the chloride deficitfi
is corrected, there will be an alkaline diuresis and
the plasma bicarbonate will start to normalize.
85
3. Consider specificfi treatments, e.g., surgery
for an adrenal adenoma or spironolactone for
hyperaldosteronism.
4. Other:
a. Hydrochloric acid: rarely used.
b. Acetazolamide: increases bicarbonate loss,
but only if GFR is adequate.
c. RRT: in patients with severe cardiac or renal
disease, RRT may assist volume and electro-
lyte correction. Standard replacement flfluids
will need modifification as they contain bicar-
bonate or its precursor lactate.
1. Stewart PA. Modern quantitative acid-base chemis-
try. Can J Pharmacol. 1983; 61: 1444–1461.
2. Story DA. Bench-to-bedside review: A brief
history of clinical acid-base. Crit Care. 2004; 8:
253–258.
3. Kellum JA. Determinants of blood pH in health and
disease. Crit Care. 2000; 4: 6–14.
4. Kaplan LJ, Frangos S. Clinical review: Acid-base
abnormalities in the intensive care unit. Crit Care.
2005; 9: 198–203.
5. Morgan TJ. Clinical review: The meaning of acid-
base abnormalities in the intensive care unit—
effects of fl
fluid administration. Crit Care. 2005; 9:
204–211.
6. Morgan TJ. What exactly is the strong ion gap, and
does anybody care? Crit Care Resusc. 2004; 6: 155–
166.
7. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and
hypoproteinaemia. Crit Care Med. 1998; 26: 1807–
1810.
8. Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of
metabolic acid-base disturbances in critically ill
patients. Am J Resp Crit Care Med. 2000; 162:
2246–2251.
sured anions in critically ill patients: anion gap,
base deficit
fi and strong ion gap. Anaesthesia. 2002;
57: 1102–1133.
10. Kaplan LJ, Kellum JA. Initial pH, base deficit,
fi lactate,
anion gap, strong ion difference, and strong ion gap
predict outcome from major vascular injury. Crit
Care Med. 2004; 32: 1120–1124.
11. Smith I, Kumar P, Molloy S, et al. Base excess and
lactate as prognostic indicators for patients ad-
mitted to intensive care. Intensive Care Med. 2001;
27: 74–83.
12. De Backer D. Lactic acidosis. Intensive Care Med.
2003; 29: 699–702.
86
13. Bellomo R, Ronco C. The pathogenesis of lactic aci-
dosis in sepsis. Curr Opin Crit Care. 1999; 5: 452–457.
14. Stacpoole PW, Wright EC, Baumgartner TG, et al. for
the DCA-Lactic acidosis Study Group: Natural
history and course of acquired lactic acidosis in
adults. Am J Med. 1994; 97: 47–54.
15. Husain FA, Martin MJ, Mullenix PS, et al. Serum
lactate and base defi ficit as predictors of mortality
and morbidity. Am J Surg. 2003; 185(5): 485–491.
S. Blakeley
16. Levraut J, Grimaud D. Treatment of metabolic
acidosis. Curr Opin Crit Care. 2003; 9: 260–
265.
17. Levraut J, Ciebiera JP, Jambou P, et al. Effect of con-
tinuous venovenous hemofiltration
fi with dialysis on
lactate clearance in critically ill patients. Crit Care
Med. 1997; 25(1): 58–62.
18. Galla JH. Metabolic alkalosis. J Am Soc Nephrol.
2000; 11: 369–375.
Index
A Aneurysms, abdominal, 22, 35
N-Acetylcysteine, 17, 28, 36
N Angiotensin, 2
Acid-base disturbances. See also
Acidosis; Alkalosis
traditional versus
physiochemical approach
to, 81–84
Acidosis, 22, 39
lactic, 83–84
metabolic, 60, 82, 83, 84
Acute kidney injury (AKI), 19–25
causes of, 20–22
investigation of, 23, 24
complications of, 22–23
defifinition of, 19
incidence and outcome of, 19–20
Acute tubular necrosis (ATN), 3, 20,
22
casts in, 6, 23
imaging of, 7–9
as oliguria cause, 27
as renal failure cause, 7, 21, 26,
27–28
urea-to-creatinine ratio in, 2–3
Adenosine agonists, 28
Alcohol, as rhabdomyolysis cause,
39
Alkalosis, metabolic, 74, 75, 82,
84–85
Allopurinol, 15
Aminoglycosides, nephrotoxicity
of, 16, 33
Ammoniagenesis, 75
Anaphylaxis, dialysis-related, 67
Anemia, acute kidney injury-
related, 22, 24
Anesthesia, effect on renal
function, 33
Angiotensin-converting enzyme
inhibitors (ACEIs), 14, 16,
33
Angiotensin receptor blockers,
nephrotoxicity of, 16
Anion gap, 81, 82, 83
Anticoagulation, in renal
replacement therapy, 61–63
Antidiuretic hormone (ADH), 4,
80
Anuria, 4, 19, 27
Aprotinin, as acute renal failure
risk factor, 34
Aspartate transaminase, 38
Azathioprine, 68
Azotemia, 42
B Complement, 44, 46
Bacteriuria, 5
Bicarbonate, 40, 51, 60, 73, 83–84,
84, 85
Biopsy, renal
for acute renal failure diagnosis,
27
“poor man’s,” 3
for vasculitis diagnosis, 43
Blood flow, renal
effect of prostaglandins on, 14
regulation of, 33
in rhabdomyolysis, 38, 39–40
C Creatinine clearance, 3
Calcifi
fication, heterotopic, 39
Calcium. See also Hypercalcemia;
Hypocalcemia
as hyperkalemia treatment, 73
Calcium channel antagonists, 17
Calculi, ureteric, imaging studies
of, 9–10
Cardiac arrest, hyperkalemia-
related, 71, 73
Cardiac output, 29
Cardiac surgery, as acute renal
failure risk factor, 34–35
Casts, 6, 23, 26, 39
Cation exchange resins, 73
Central pontine myelinolysis, 79
Chemical testing, of urine, 4–5
Chloride depletion, 82, 83
Coagulopathy, therapeutic plasma
exchange-related, 50
Cockroft and Gault formula, for
creatinine clearance, 3
Compartment syndromes, 20, 34,
38–39, 41
Compression injuries, as
rhabdomyolysis cause, 38
Computed tomography (CT), renal,
7, 9–11
Contrast agents, nephrotoxicity of,
10, 11, 13, 16–17, 27–28, 36
Corticosteroids, 68
Creatine kinase, 38
Creatinine, 2–3
as acute kidney injury marker,
19
renal failure-related increase in,
24
Crush injuries, as rhabdomyolysis
cause, 38
Cyclooxygenase inhibitors, 15
Cyclosporin, 68
87
88
D F
Daclizumab, 69
Dextrose, 17, 73
Diabetes insipidus, nephrogenic, 76
Diabetes mellitus, 6, 33, 34
Dialysis
optimal dose in, 65–67
peritoneal, 64–67
principles of, 64
as renal vasculitis treatment, 44
for urinary myoglobin
reduction, 39–40
Dialysis equilibrium syndrome, 67
Diethylene triamine pentaacetic
acid (DTPA) studies, 7, 10
Digoxin, toxicity of, 73
1,25-Dihydroxyvitamin D3, 1
Disseminated intravascular
coagulation, 46–47
Diuretics
as acute renal failure
prophylaxis, 34, 36
as acute renal failure treatment,
36
loop, 15, 17, 27–28
nephrotoxicity of, 16
Dopamine, as renal failure
prophylaxis, 36
Dopamine agonists, 28
Drugs. See also names of specificfi
drugs
as hypokalemia cause, 74
impaired renal clearance of, 23–24
nephrotoxicity of, 14–18, 23,
33–34, 38, 39
as rhabdomyolysis cause, 38, 39
E reduction, 39–40
Edema
pulmonary, 43
renal, 9
Electrocardiography
in hyperkalemia, 71–72
in hypokalemia, 75
Electrolyte disturbances. See also
specific
fi electrolyte
disturbances
acute kidney injury-related, 22
Encephalopathy, uremic, 22
Enteral support, in critically ill
patients, 29
Eosinophilia, 24
Erythropoietin, 1, 22
Excretion, urinary, 1
Familial hypokalemic periodic
paralysis, 74
Fasciotomy, 38
Fluid composition, of the body, 1,
2 Hypoperfusion, renal, 9, 20.6
Fluid resuscitation, in acute renal
failure patients, 28–29
G dialysis-related, 67
Glomerular filtration,
fi cessation of,
33
Glomerular filtration
fi rate (GFR), 2
in acute kidney injury, 19
assessment of, 3
in metabolic alkalosis, 85
Glomerulonephritis, 6, 9, 26
Glucose control, tight, 29, 36
Glycosuria, renal, 5
Goodpasture’s syndrome, 9
H 7–13. See also Computed
Hematuria, 4, 26, 42
Hemodiafiltration,
fi 64
continuous venovenous, 59
Hemodialysis, 64
complications of, 67
continuous, 57–63
as hyperkalemia treatment, 74
intermittent, 52, 54, 60
Hemofi filters, 50
Hemofi filtration, 52, 64
continuous venovenous, 52, 57,
59
high-volume, 53
prophylactic, 29
for urinary myoglobin
Hemofi filtration machines, 58,
59–60
Hemolytic uremic syndrome, 46,
47
Hemorrhage, gastrointestinal, 23
Henoch-Schönlein purpura, 43
Heparin, 61–62
Homeostasis, role of the kidney in,
1
Hypercalcemia, 24
Hyperglycemia, 22
Hyperkalemia, 16, 22, 71–73
Hypernatremia, 79–80
Hyperphosphatemia, 22, 24, 39
Hypertension, 13, 42
malignant, 47
Index
Hypocalcemia, 39, 50
Hypokalemia, 50, 74–76, 82, 85,
8575, 73076
Hypomagnesemia, 75
Hyponatremia, 22, 77–79, 79
Hypotension
acute renal failure-related, 26, 29
anesthesia-related, 33
as postoperative renal failure
cause, 33
prerenal failure-related, 20
relative, 36
in surgical patients, 33
therapeutic plasma exchange-
related, 50
Hypovolemia, 21, 49, 85
I
Imaging, of acute renal failure,
tomography (CT); Magnetic
resonance angiography
(MRA); Magnetic resonance
imaging (MRI);
Scintigraphic imaging
diagnostic algorithm for, 12
Immunosuppression, renal failure-
related, 22
Immunosuppressive therapy, in
renal transplant recipients,
68–69
Infection
in renal transplant recipients, 69
as rhabdomyolysis cause, 38
Inotrope therapy, for acute renal
failure, 29
Insulin therapy, 36, 73
Intensive care unit (ICU) patients
acute kidney injury in, 19
acute renal failure in, 26
intrinsic renal failure in, 20, 21
obstructive renal failure in, 22
Inulin clearance, 3
Ischemia, renal, 33
K
Kidney
hydronephrotic, 9
normal, ultrasound imaging of,
7, 8
normal functions of, 1
polycystic, 7
Index
L Pregnancy, in systemic lupus
Lactate, 60, 82, 83
Lactate dehydrogenase, 38
Left ventricular end diastolic
pressure (LVEDP), 29
M renal failure, 23, 24
Magnetic resonance angiography
(MRA), renal, 10–11
Magnetic resonance imaging
(MRI), renal, 7
Mannitol, 28, 34
Mean arterial pressure (MAP), 29,
33
Mercaptoacetyltriglycerine (MAG3)
studies, 7, 8, 9, 10, 11
Microangiopathy, thrombotic,
46–47
Mineral disturbances, acute kidney
injury-related, 22
Mycophenolate mofetil, 69
Myoglobin, in urine, 39–40
N kidney injury (AKI)
Natriuretic peptides, 28, 36
Nephritic syndrome, 42–43
Nephritis
interstitial, 6, 9, 15, 33–34
systemic lupus erythromatosus-
related, 45
Nephrotic syndrome, 5, 11, 16
Neutrophilia, 24
Nonsteroidal anti-infl flammatory
drugs, nephrotoxicity of,
14–16, 33
Nutrition/nutritional support, 29,
67
O multisystem causes of, 42–48
Oliguria, 4, 27, 34
Oxygen consumption, renal, 33
P risk factors for, 26, 27, 33–34
Peritoneal dialysis, 64–67
Plasma exchange, therapeutic,
49–50, 59
Plasma volume, calculation of, 49
Polyclonal antibodies, 69
Polyuria, 4
Postrenal failure, 7
Potassium. See also Hyperkalemia;
Hypokalemia
renal excretion of, 71, 73
Potassium supplementation, 76
erythromatosus patients, 46
Prerenal failure, 7, 21
as acute kidney injury cause, 20
defifinition of, 20
differentiated from intrinsic
Prostacyclin, 63
Prostaglandins, renal, 14–15
Proteinuria, 4–5
Pseudohyperkalemia, 72–73
Pseudohyponatremia, 77
Purpura, thrombotic
thrombocytopenic, 46, 47
R basics of, 51–52
Red blood cells, in urine, 6
Renal artery, dissection or
occlusion of, 10–11, 13, 16
Renal disease, end-stage, renal
replacement therapy for,
64–70
Renal dysfunction. See also Acute
RIFLE classifi fication system for,
19, 20
Renal failure
acute
acute kidney injury-related, 19
diagnosis of, 26, 35–36
differentiated from chronic
renal failure, 7
drug-related, 14–18
imaging of, 7–13
laboratory investigations of,
26–27
medical management of,
26–32
pathophysiology of, 33
prevention of, 27–30, 36–37
rhabdomyolysis-related, 38
supportive strategies for, 28–29
in surgical patients, 33–37
treatment of, 35–36
chronic
differentiated from acute renal
failure, 7
imaging of, 8
intrinsic, 20–21
differentiated from prerenal
failure, 23, 24
postrenal or obstructive, 22
89
Renal function
abrupt and sustained decrease
in. See Acute kidney injury
(AKI)
assessment of, 1–6, 26
Renal index (RI), 9
Renal injury. See also Acute kidney
injury (AKI)
drug-induced, 14–18
Renal replacement therapy, 28,
51–56. See also Dialysis;
Hemodialysis; Renal
transplantation
for acute kidney injury, 20
anticoagulation in, 62
continuous, 51, 52, 53, 54, 57–59,
61
for hyperkalemia, 74
effect on lactic acidosis, 84
for end-stage renal disease, 64–70
hemofi filters in, 60
hybrid, 52
indications for, 53–54
intermittent, 51, 53, 54
replacement and dialysis fluid
fl
in, 59–60
selection of dosage and mode in,
54–55
technical aspects of, 57–63
vascular access in, 52, 60–61
for volume overload, 22
Renal transplantation, 67–69
Renal vein, thrombosis of, 11, 13
Renin, 1, 2
Respiratory failure, 43
Resuscitation, in surgical patients,
36
Rhabdomyolysis, 28, 38–41
diagnosis of, 38–39
drug-related, 14
treatment of, 40
RIFLE system, for renal
dysfunction classification,
fi
19, 20
S
Salbutamol, 73
Scintigraphic imaging
diethylene triamine pentaacetic
acid (DTPA) studies, 7, 10
mercaptoacetyltriglycerine
(MAG3) studies, 7, 8, 9, 10, 11
of ureteric obstruction, 10
90
Sepsis
dialysis-related, 67
treatment of, 53
Sodium bicarbonate, 40, 73, 84
Statins, as rhabdomyolysis cause,
39
Strong ion difference (SID), 81, 83
Surgical patients
acute kidney injury in, 20
acute renal failure in, 33–37
Syndrome of inappropriate
antidiuretic hormone
secretion (SIADH), 77, 78,
79
Systemic lupus erythromatosus,
45–46
T interstitial nephritis
Tacrolimus, 68
Tamm-Horsfall protein, 40
Thrombocytopenia, 24
Toxins
as rhabdomyolysis cause, 38
uremic, retention of, 22
Transurethral resection of the
prostate (TURP) syndrome,
77
Tubulointerstitial disease, 26
Tumor lysis syndrome, 14
U specifific gravity of, 3, 24
Ultrafi
filtration, slow continuous, 53,
59
Ultrasound, renal, 7, 23, 27
of normal kidneys, 7, 8
of renal vein thrombosis, 11
of ureteric obstruction, 9
Urea
accumulation of, 22, 24
measurement of, 2
Urea-to-creatinien ratio, 2–3
Uremia, 22–23
Uremic patients, cardiovascular
risk factors in, 65
Ureteric obstruction, imaging
studies of, 9–10
Urinalysis, 3–6
for acute kidney injury
evaluation, 23, 24
for acute renal failure evaluation,
26–27
for glomerulonephritis/acute
differentiation, 9
in surgical patients, 35
for systemic lupus
erythromatosus evaluation,
45
Urine
alkalinization of, 14, 40, 41
appearance of, 3
chemical testing of, 4–5
microscopy of, 5–6
in rhabdomyolysis, 39, 40
osmolality of, 23, 24, 80
volume of, 3–4, 27
Urine output, in acute kidney
injury, 19–20
Urolithiasis, 27
Index
Urological surgery, as acute renal
failure risk factor, 35
V
Vascular surgery, as acute renal
failure risk factor, 34
Vasculitis
as acute renal failure cause, 26,
42–45
clinical presentation of, 42–43
etiology of, 42
treatment of, 43–44
Wegener’s renal, 44
Venography, of renal vein
thrombosis, 11
Volume depletion
as acute renal failure cause, 26
assessment and correction of, 29
as postoperative renal failure
cause, 33
prerenal failure-related, 21
Volume expansion, intravascular,
40
Volume overload, acute kidney
injury-related, 22
W
Wegener’s granulomatosis, 9
Wegener’s renal vasculitis, 44
White blood cells, in urine, 5–6
X
X-rays
chest, 23, 44
renal, 7