NEPHROLOGY BOARD REVIEW MANUAL

PUBLISHING STAFF
PRESIDENT, GROUP PUBLISHER

Bruce M. White

Acute Renal Failure:

Pathophysiology and Treatment

EDITORIAL DIRECTOR

Debra Dreger
EDITOR

Robert Litchkofski
EDITORIAL ASSISTANT

Karen Meadows
SPECIAL PROGRAMS DIRECTOR

Barbara T. White
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PRODUCTION ASSOCIATES

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Series Editor and Contributing Author:

Stanley Goldfarb, MD, FACP
Professor of Medicine
Interim Chairman
Department of Medicine
University of Pennsylvania School of Medicine
Philadelphia, PA

Contributing Author:
Scott H. Adler, MD
Instructor, Renal-Electrolyte and Hypertension Division
Department of Medicine
University of Pennsylvania School of Medicine
Philadelphia, PA

PRODUCTION ASSISTANT

Stacey Caiazzo

Table of Contents

ADVERTISING/PROJECT MANAGER

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NOTE FROM THE PUBLISHER:

This publication has been developed without
involvement of or review by the American
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endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in
medical education as they affect residency programs and clinical hospital practice.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Etiology and Epidemiology . . . . . . . . . . . . . . . . . . . . 2
Diagnosis and Clinical Evaluation . . . . . . . . . . . . . . . 4
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Management of Ischemic Acute Renal Failure . . . . . 7
Renal Replacement Therapy. . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Cover Illustration by Scott Holladay

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Nephrology Volume 4, Part 3 1

NEPHROLOGY BOARD REVIEW MANUAL

Acute Renal Failure:

Pathophysiology and Treatment
Series Editor and Contributing Author:
Stanley Goldfarb, MD, FACP
Professor of Medicine
Interim Chairman
Department of Medicine
University of Pennsylvania School of Medicine
Philadelphia, PA

Contributing Author:
Scott H. Adler, MD
Instructor, Renal-Electrolyte and Hypertension Division
Department of Medicine
University of Pennsylvania School of Medicine
Philadelphia, PA

INTRODUCTION

ETIOLOGY AND EPIDEMIOLOGY

Acute renal failure (ARF) is a clinical syndrome characterized by an acute fall in glomerular filtration rate
(GFR), resulting in decreased clearance of metabolic
waste products from the blood. ARF can be caused by a
number of diseases and pathophysiologic mechanisms.
Most cases of ARF, however, occur in the most seriously
ill, who often have complex comorbid illnesses, such as
sepsis and multisystem organ failure. Despite many advances in critical care medicine, mortality in patients
with ARF remains high; in some studies it is greater
than 80%. This review discusses pathophysiologic
mechanisms involved in the development of ARF, pharmacologic agents with potential therapeutic benefit,
and issues surrounding the selection of a modality for
renal replacement therapy in ARF patients.

ETIOLOGY
The causes of ARF are typically divided into 3 categories: prerenal, renal, and postrenal (Table 1). Prerenal ARF results from an abnormality in glomerular
perfusion that reduces the GFR in the absence of any
pathology of the renal parenchyma. It is important to
note that this form of renal failure is rapidly reversed
when the hypoperfusion is corrected. Postrenal ARF
results from obstruction of urinary collection and,
again, occurs in the absence of any direct insult to the
renal parenchyma. This form of ARF is also completely reversible when the obstruction is relieved.
Finally, renal (or intrinsic) ARF occurs when there is
direct damage to the renal parenchyma itself; it can

2 Hospital Physician Board Review Manual

Acute Renal Failure

be induced by damage to the vasculature, glomeruli,
tubules, or interstitium. Intrinsic ARF is due to ischemia in 50% of cases, nephrotoxins in 35%, and
interstitial nephritis or glomerulonephritis in 15%.
The majority of intrinsic ARF cases are associated
with acute tubular necrosis (ATN). ATN is the histologic term used to describe the tubular-epithelial cell necrosis and regeneration seen in biopsy specimens of kidney following an ischemic or toxic insult. Patients with
ARF, however, usually do not undergo biopsy, and ATN
is typically diagnosed based upon a comprehensive clinical evaluation. Most cases of ATN are seen in the critically ill intensive care patient and are usually multifactorial in origin (eg, hypotension, nephrotoxic drug
exposure, sepsis, and cardiac, respiratory, or liver failure). Ischemia is the cause of most cases of ATN in hospitalized patients. The development of ATN is closely
related to prerenal azotemia, as both are related to
hypoperfusion of the kidney. In most cases, the extent
of renal hypoperfusion will determine the extent of
ATN, and the underlying renal function may play an
important role in determining the extent of renal
parenchymal damage.

Table 1. Causes of Acute Renal Failure

MORBIDITY AND MORTALITY

ARF occurs in approximately 5% of all hospitalized
patients, and, historically, it has been associated with a
high risk of mortality.1 Following the introduction of
dialysis therapy more than 50 years ago, patient mortality fell from 90% to 50%. However, recent studies have
shown that the mortality rate for patients with ARF has
not changed significantly, ranging from 50% to 80%.2
With new advances in intensive care medicine, it has
become clear that the current mortality rate is dependent upon underlying comorbid illness. In patients with
simple ARF and no underlying comorbidities, the mortality rate is between 7% and 23%; in intensive care
patients with other comorbidities it is between 50% and
80%. Several epidemiologic studies have shown that the
mortality rate in intensive care patients is correlated
with the number of other organ systems in failure
(Figure 1).2
In addition to being a surrogate marker for severe illness, ARF has been shown to be an independent risk
factor for mortality. In a recent study involving patients
who received intravenous contrast dye, the mortality
rate was 34% in those who developed ARF but only 7%
in those who did not develop ARF.3 After adjusting for
comorbid factors, renal failure was associated with an
odds ratio of dying of 5.5.
Need for hemodialysis also has an impact on mortality in patients with ARF, as demonstrated in a prospec-

Glomerulonephritis: rapidly progressive glomerulonephritis,

Goodpastures syndrome, Wegeners granulomatosis,
microscopic polyangiitis, pauci-immune, systemic lupus,
post-streptococcal, immunoglobulin A nephropathy,
Henoch-Schnlein purpura, endocarditis

Prerenal
Hypovolemia
Hemorrhage
Fluid loss
Hypoalbuminemia
Third-space losses
Cardiac failure: myocardial dysfunction, valvular dysfunction,
cardiac tamponade, pulmonary hypertension
Systemic vasodilatation: sepsis, cirrhosis, anaphylaxis,
anesthesia, pharmacologic vasodilation
Afferent arteriolar vasoconstriction: sepsis, hypercalcemia,
hepatorenal syndrome, drugs
Efferent arteriolar vasoconstriction: angiotensin-converting
enzyme inhibitors, angiotensin-receptor blockers
Renal
Renal artery occlusion: acute or chronic embolization, acute
or chronic thrombosis, renal artery aneurysms, aortic
dissection, acute or chronic renal artery stenosis
Intrarenal artery occlusion: thrombotic microangiopathies,
vasculitis, atheroemboli

Ischemic acute tubular necrosis

Toxic acute tubular necrosis
Interstitial: drugs, autoimmune, malignant infiltration, acute
pyelonephritis, other infections
Intrarenal obstruction: casts, crystals
Postrenal
Urinary tract obstruction
Adapted with permission from Woolfson RAH. Causes of acute renal
failure. In: Johnson J, editor. Comprehensive clinical nephrology.
London: Mosby; 2000:16.2.

tive study of 43,642 patients undergoing open heart

surgery.4 In this study, the mortality rate for patients
with ARF requiring dialysis (n = 460; 1.05% of total) was
63.7%, compared with 4.3% for patients without ARF.
Thus, patients with ARF requiring dialysis have a
15-fold increased risk of death compared with patients
without ARF. These data underscore the fact that ARF
is a serious condition that must be treated aggressively
at the earliest signs of renal insufficiency.
Severity of illness in the critically ill assessed by the use

Nephrology Volume 4, Part 3 3

100

100

80

80
Mortality, %

Mortality, %

Acute Renal Failure

60
40
20

Figure 1. Mortality in acute renal failure

is correlated with comorbidity. ARF =
acute renal failure; ICU = intensive care
unit. (Adapted with permission from Star
RA. Treatment of acute renal failure. Kidney Int 1998;54:181731.)

60
40
20

0
Simple
ARF

ICU
setting

1
2
3
4
Number of failed organs

of APACHE scores has not been a good predictor of outcome in patients with ARF.5 A major advance in the ability to predict mortality in renal failure patients has come
from the studies of the Liano Severity of Illness score
(Table 2). In this index, renal dysfunction accounts for
21% of mortality (compared with 4% in the APACHE
scoring system) and correlates with outcome.2

DIAGNOSIS AND CLINICAL EVALUATION

ARF is typically diagnosed after serial screening reveals
a rise in blood urea nitrogen (BUN) and plasma creatinine concentrations, or after a decrease in urine output
is observed over a period of hours to days. Once the diagnosis of ARF is suspected, it is important to correlate the
laboratory diagnosis (creatinine value) with renal function. However, plasma creatinine is a suboptimal indicator of renal function during ARF because the creatinine
level is influenced by many nonrenal events, such as creatinine generation, volume of distribution, nutritional
status, infection, and creatinine excretion. In addition,
the relationship between plasma creatinine and GFR is
dynamic. Changes in GFR are not reflected in the plasma
creatinine value until the creatinine level has stabilized,
which can take several days. Therefore, when the GFR is
changing (during the early phases of ARF and during
recovery from renal failure), plasma creatinine levels are
poor indicators of renal function. In such cases, the GFR
should be considered to be less than 10 mL/min.
Despite the shortcomings of the creatinine value as a clinical indicator of renal function, it will continue to be used
until a more effective indicator becomes widely available.
HISTORY AND PHYSICAL EXAMINATION
The clinical evaluation of all patients with ARF should

4 Hospital Physician Board Review Manual

include a careful and complete history and physical

examination. The medical records of hospitalized
patients often provide an important source of information regarding the etiology of renal failure, including
drug exposures, vital signs, intravenous fluid records,
weights, and urine output. The physical examination
should focus on assessment of the patients volume status, including evaluation of the patients neck veins and
cardiac and pulmonary examinations. In some cases,
hemodynamic monitoring may be necessary for an accurate evaluation of volume status. On skin examination,
findings suggestive of an allergic reaction to a drug associated with acute interstitial nephritis should be sought.
Other skin findings such as purpura and livedo reticularis are suggestive of vasculitides or atheroemboli. The
abdominal examination may reveal ascites associated
with liver disease and heart failure. Renal bruits are often
heard in patients with renal artery stenosis, and a distended bladder can be palpated when bladder outlet
obstruction is present.
LABORATORY TESTS
As mentioned, the diagnosis of ARF typically is
based on identification of a rise in BUN and creatinine.
These measures also can be used in the differential
diagnosis of ARF. The BUN-to-creatinine ratio will be
high (> 20:1) during states of decreased urea excretion
or increased urea production (eg, prerenal azotemia,
urinary tract obstruction, catabolic states, gastrointestinal bleeding, corticosteroid administration, or increased protein intake). Conversely, the ratio is low
(< 10:1) when there is reduced urea production, increased release of creatinine, and decreased tubular
secretion of creatinine. Other serum chemistries (eg,
sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus, uric acid) are helpful for the acute

Acute Renal Failure

management of ARF. Urinalysis is essential for evaluating patients with ARF. In particular, microscopic evaluation of the urinary sediment is critical in the diagnosis
of an acute glomerulonephritis, acute interstitial
nephritis, or ATN. Renal ultrasonography is useful in
identifying obstruction of the urinary system. Findings
regarding renal size and echogenicity also can be of
some diagnostic help (eg, detecting anatomic abnormalities such as solitary kidney, previous undiagnosed
chronic renal disease, asymmetric kidney size suggestive
of renal artery stenosis).

PATHOPHYSIOLOGY
The pathophysiology of ARF is very complex and
corresponds to the complexity of the syndromes differential diagnosis (Table 1). Studies using both in vitro
and in vivo models of ATN have identified several cellular and molecular events that may contribute to kidney dysfunction seen in patients with ARF. Ischemiareperfusion, one of the most widely studied models, is
discussed in the following sections. Knowledge regarding some mechanisms of the ischemia-reperfusion
model remains incomplete, and this model is not
applicable to all causes of ARF. Nonetheless, understanding the events of ischemia-reperfusion provides
insight into ARF pathophysiology.
HEMODYNAMIC AND VASCULAR FACTORS
An ischemic injury is the near loss or complete lack of
blood flow to an organ. A decrease in the effective arterial
blood flow to the kidney results in the release of vasoactive
mediators aimed at altering glomerular hemodynamics
in an effort to maintain renal perfusion and glomerular
filtration. Systemically, epinephrine, vasopressin, and
angiotensin II are elaborated to cause vasoconstriction of
the efferent arteriole, while prostacyclin and nitric oxide
(NO) are produced locally to maintain afferent arteriolar
vasodilation (Figure 2).6 This protective response, known
as autoregulation, is maintained as long as the mean arterial pressure stays above 70 mm Hg. When the arterial
pressure falls below this level, however, renal blood flow
and glomerular filtration cannot be maintained and the
vasoconstrictive forces supervene, further decreasing
renal blood flow. If renal hypoperfusion persists, ischemia
develops and leads to the local production of endothelin
and NO, 2 factors important in the regulation of the renal
microvascular circulation.
Endothelin-1 (ET-1) is a potent vasoconstrictor that
plays an important role in ischemic ARF.7 It is synthesized by renal endothelial, epithelial, and mesangial

Table 2. Liano Acute Renal Failure Severity of Illness

Score
Constant

Add 21

Age

Add (3 decade)

Female

Add 9

Oliguria

Add 11

Hypotension

Add 12

Jaundice

Add 12

Coma

Add 15

Mechanical ventilation

Add 18

Pure nephrotoxic

Subtract 11

Alert mental status

Subtract 15

Expected % mortality

Total

Adapted with permission from Star RA. Treatment of acute renal failure. Kidney Int 1998;54:181731.

cells as a preprohormone and is enzymatically converted to its active form, which binds to 1 of 2 receptors:
ETA or ETB. ETA engagement leads to vasoconstriction,
further decreasing blood flow, but it also acts as a
growth factor, inducing cellular proliferation and
matrix deposition in cultured cells. Signaling through
ETB leads to vasodilatation and NO release as well as
increased synthesis of endothelin.
Exposure to endotoxin, tumor necrosis factor-
(TNF-), platelet-derived growth factor, transforming
growth factor-, radiocontrast dye, and cyclosporine
produces physiologic changes in renal blood flow similar to those seen with ischemic insults, including enhanced renal expression of ET-1 and decreased renal
perfusion. In an experimental model of ischemic
ARF, blocking the endothelin pathway using either an
angiotensin-converting enzyme (ACE) inhibitor, an
anti-endothelin neutralizing antibody, or an endothelinreceptor blocker decreased functional renal injury.8
When this approach was translated to a clinical study
in humans undergoing cardiac catheterization, the
same effect was not observed.9
NO has a complex role in renal hemodynamics and
in ischemia-reperfusion injuries seen in the kidney. NO
is produced by endothelial cells through the actions of
endogenous nitric oxide synthase (eNOS) in response
to decreases in renal blood flow. Vasodilation occurs following the release of NO, resulting in increased blood
flow in the renal microcirculation. However, the increased blood flow is short-lived, as the NO is inactivated by oxygen-derived free radicals induced during the
primary ischemic insult. The protective role of NO was

Nephrology Volume 4, Part 3 5

Acute Renal Failure

Vasoconstrictor
influences
Nonsteroidal
anti-inflammatory
agents
Cyclosporine
Tacrolimus
Thromboxane A2

Sympathetic
nervous system
Vasopressin
Angiotensin II

Afferent
arteriole

Efferent
arteriole

Vasodilator
influences
Glomerular capillary
hydrostatic pressure
Nitric oxide

Figure 2. Glomerular hemodynamic autoregulation. ACE = angiotensin-converting

enzyme; AT1 = angiotensin I. (Reprinted
with permission from Iglesias J, Lieberthal
W. Clinical evaluation of acute renal failure.
In: Johnson RJ, Feehally J, editors. Comprehensive clinical nephrology. London:
Mosby; 2000:15.4.)

ACE inhibitors
AT1 receptor
antagonists

Prostacyclin

Glomerular
filtration rate

demonstrated in an experimental ischemia model in

which the infusion of NO reduced reperfusion injury.10
Patients with chronic renal failure, diabetes mellitus, atherosclerosis, hypertension, and sepsis have been observed to have defective endothelium-dependent
vasodilation, which may contribute to their increased
vulnerability to ATN.
In contrast to its beneficial effects, NO also can have
deleterious effects on renal function. The kidney can
produce large amounts of NO via a form of nitric oxide
synthase (iNOS) that can be induced by cytokines and
endotoxin. The excess NO reacts with oxygen-derived
free radicals generated by injured endothelial cells and
adherent leukocytes to form toxic hydroxyl radicals,
which in turn cause further renal damage. Because NO
has a potential dual role in ARF, inhibiting nitric oxide
synthase (eNOS and/or iNOS) may have different
effects depending on the model studied. To date, NOS
inhibitors have had no beneficial effects in humans.
In summary, the initial ischemic insult leads to the
production of vasoactive factors that exacerbate renal
ischemia, and these ischemic events precipitate damage
to the renal tubular epithelium.

6 Hospital Physician Board Review Manual

TUBULAR EPITHELIAL CELL INJURY AND DEATH

Injury to and death of renal tubule cells contribute to
the alterations in GFR following an ischemic insult. The
severity of the injury, in part, relies upon the extent of
ischemia. In most cases of ischemic ATN, a range of
pathology is seen, from sublethal injury, to apoptosis, to
necrosis. Intracellular depletion of adenosine triphosphate (ATP), upon which all cellular processes are
dependent, is the hallmark of ischemia. Following depletion of ATP, the function of ATPase is lost and cell
homeostasis fails, resulting in cell swelling and acid-base
dysregulation, which in turn causes increased levels of
intracellular calcium. The increased calcium activates
specific enzymes, such as phospholipases, proteases, and
endonucleases, that cause loss of cell regulation, cellular
detachment, membrane degradation, and cell death.
The epithelial-cell barrier loses the ability to regulate its
function and loses its polarity and brush border. The loss
of function of cellular proteins as well as the activation of
destructive proteins leads to cell injury or death and
sloughing into the lumen of the nephron. Cell sloughing causes luminal obstruction, increased tubular pressure, and decreased single-nephron GFR. The loss of

Acute Renal Failure

Ischemia and
reperfusion

Tubular
lumen
Normal epithelium with brush
border

Calcium
Reactive oxygen
species
Purine depletion
Phospholipases

Loss of polarity
and brush
border

Proliferation, differentiation, and

reestablishment
of polarity

Apoptosis

Growth
factors

Cell death

Figure 3. Tubular-cell injury and repair in

ischemic acute renal failure. (Reprinted
with permission from Thadhani R, Pascual
M, Bonventre JV. Acute renal failure. N
Engl J Med 1996;334:144860.)

Spreading and
dedifferentiation of
viable cells

Sloughing of viable
and dead cells,
with luminal
obstruction

Necrosis

Integrin
Na+/K+ATPase
Necrosis

tubular lumen epithelium results in tubular fluid backleakage, further decreasing the effective GFR. Following
this injury, the kidney has the ability to repair itself
through the proliferation and differentiation of new
epithelium, a process that is likely promoted by growth
factors. Some of the cellular events associated with
ischemic ATN are summarized in Figure 3.11

MANAGEMENT OF ISCHEMIC ACUTE RENAL

FAILURE
PREVENTION
Ischemic ATN is best avoided by maintaining systemic hemodynamics and renal perfusion and carefully
monitoring the dosing of potentially nephrotoxic drugs.
Nonetheless, in most cases of ARF the ischemic insult is

unavoidable and the onset is unpredictable. In some

clinical situations, the ischemic insult is iatrogenic and
occurs when patients are administered intravenous
radiocontrast material. Much progress has been made in
the prevention of contrast-induced nephropathy, which
is caused in part by an acute ischemic injury.12 In patients at high risk for contrast nephropathy, the administration of intravenous saline has been used to ameliorate reductions in renal function; calcium antagonists,
theophylline, dopamine, and atrial natriuretic peptide
have been studied in clinical trials and have not been
shown to ameliorate reductions in renal function.13 The
rationale for administering saline is that it corrects any
subclinical intravascular volume depletion, thereby minimizing ischemia induced by the dye. Saline also can prevent intravascular volume depletion induced by the
diuresis of the osmotic load. The administration of intravenous fluids has not been studied in a randomized

Nephrology Volume 4, Part 3 7

Acute Renal Failure

controlled fashion, but some benefits have been suggested by both retrospective and uncontrolled studies.
Most protocols recommend half-normal saline given at
a rate of 1 mL/kg/hr beginning 1 to 2 hours before the
procedure and lasting for 24 hours. Studies of other
agents administered to induce diuresis following intravenous radiocontrast have not shown a clinical benefit.
In 2 trials that evaluated the effects of furosemide on
renal function in the context of dye exposure, renal
impairment was more common in the furosemide
group than in the control group.14,15 This effect is likely
due to the intravascular volume depletion induced by
diuresis and the ischemic effects on renal blood flow.
Therefore, furosemide cannot be recommended for the
prophylaxis of contrast nephropathy. Mannitol also
showed no benefit in preventing the effects of dyeinduced nephropathy.
In recent studies, reactive oxygen species have been
shown to play an important role in contrast-induced
ischemia to the kidney. The antioxidant acetylcysteine
was evaluated in a randomized controlled clinical trial
designed to block reactive oxygen species in patients at
high risk for developing contrast-induced nephropathy. In this trial, 12% of the placebo-controlled patients
had an increase in creatinine levels compared with 2%
of the acetylcysteine treated patients.16 Thus, prophylactic oral administration of a reducing agent may
decrease the risk of contrast-induced renal failure in a
high-risk patient population.
PHARMACOLOGIC TREATMENT OF ESTABLISHED ATN
The primary therapeutic goals in the treatment of
established ischemic ATN are to restore renal perfusion,
minimize epithelial damage, relieve tubule obstruction,
and promote epithelial repair and regeneration. Many
agents shown to be beneficial in experimental models
have failed to produce significant beneficial effects in
human clinical trials. The following sections briefly discuss some of the potential pharmacologic agents and
the rationale for their use in acute ischemic ATN.
Dopamine
Agents aimed at restoring renal hemodynamics have
been a main focus of attention in the treatment of ATN.
Renal-dose dopamine is commonly prescribed in the
early phase of ARF to enhance renal blood flow and
induce diuresis. Dopamine is an endogenous catecholamine, and it acts as a nonspecific vasoactive agonist. It
activates both dopaminergic and adrenergic receptors in
a dose-dependent manner. At doses of 0.5 to 1.0 g/
kg/min, dopamine primarily acts upon the dopamine
receptors, leading to vasodilation and increased renal

8 Hospital Physician Board Review Manual

blood flow. At doses greater than 2 to 3 g/kg/min, the

1 receptors are stimulated, increasing cardiac output and
further augmenting renal blood flow. With doses greater
than 10 g/kg/min, the -adrenergic receptors are stimulated, causing vasoconstriction.
The dopamine receptors are classified into 2 subtypes:
D1 and D2. D1 receptors are located in the proximal
tubule, macula densa, and renal arteries, while the D2 receptors are located in brush border and basolateral membranes of the tubules and the renal vasculature. Activation
of both results in renal arterial vasodilation. In addition to
its vasoactive properties, dopamine inhibits the function
of the sodium-hydrogen exchanger and Na+K+ATPase
and inhibits the release of antidiuretic hormone, resulting in diuresis. Based on these physiologic effects, dopamine has theoretic purpose in the treatment of ARF.
There have been several uncontrolled case series that
have reported increases in urine output and improvements in renal function, but no improvements on
mortality or the need for renal replacement therapy.17
Recently, the largest prospective randomized placebocontrolled trial comparing low-dose dopamine in the setting of ARF was published.18 In this trial, 328 patients with
systemic inflammatory response syndrome and ARF were
studied. Statistically powered to detect a difference of
more than 25% in peak serum creatinine between the
2 groups, this study found no difference in peak serum
creatinine, need for renal replacement therapy, length of
intensive care unit or hospital stay, or mortality.
Dopamine has clinically significant side effects. It can
suppress respiratory drive, increase myocardial oxygen
demand, and trigger myocardial ischemia or arrhythmias. The drug also can induce hypokalemia and hypophosphatemia and predispose to gut ischemia. There
also is evidence that it can suppress T cell function and
increase the risk of infection. Because of these potential
adverse side effects, low-dose dopamine should not be
administered to critically ill patients for the recovery of
renal function.
Dopamine Agonists
Despite the lack of evidence supporting the use of
dopamine, interest remains in dopamine agonists for the
prevention and treatment of ARF. Fenoldopam is a selective dopaminergic (D1) agonist that is currently approved for the treatment of hypertensive emergencies.
The drug increases renal perfusion at doses that do not
lower systemic blood pressure in normal volunteers.19 As
fenoldopam is selective for the D1 receptor, it does not
cross-react with the adrenergic receptors and does not
exhibit the potential disadvantages of dopamine. In a
recent canine study, fenoldopam was shown to ablate the

Acute Renal Failure

prerenal tubular response, thus maintaining renal perfusion and GFR in the presence of hypovolemia. This finding suggests that a selective dopamine agonist may confer renal protection during renal ischemia.20 The true
test of the effectiveness of this drug will have to await a
well-powered randomized controlled study.
Anaritide
Anaritide, a synthetic form of atrial natriuretic peptide, has shown great promise in animal and early
human studies in the treatment of ARF. This drug has
several characteristics that make it theoretically beneficial in the treatment of ARF. Anaritide increases GFR by
dilating afferent arterioles while constricting efferent
tubules. It also blocks tubular reabsorption of sodium
and chloride, redistributes renal medullary blood flow,
disrupts glomerulotubular feedback, and reverses
endothelin-mediated vasoconstriction. Anaritide also
has been shown to increase glomerular filtration and
urinary output in animals with acute renal dysfunction.
In the first open-label clinical trial, which involved
53 patients with ATN, infusion of anaritide increased
creatinine clearance and reduced the need for dialysis.21 This finding led to a large multicenter randomized, placebo-controlled trial in 504 critically ill patients. The administration of anaritide did not improve
the overall rate of dialysis-free survival in critically ill
patients with ATN.22
COMPLICATIONS
A number of life-threatening complications can
develop in patients with ARF, and these need to be anticipated from the earliest recognition of renal insufficiency. Measures aimed at preventing these complications
must be initiated when a physician first evaluates the
patient with ARF. Most medical therapy includes supportive care directed at the management of cardiovascular and respiratory stability. In addition, the metabolic complications must be addressed and managed
throughout the course of renal failure (Table 3). Should
medical management be unsuccessful at correcting
some of the metabolic complications of ARF, renal replacement therapy is indicated. Currently, dialysis is the
only FDA-approved treatment for ARF; it is required in
about 85% of patients with nonoliguric ARF and 30% of
those with oliguric ARF.

RENAL REPLACEMENT THERAPY

The indications for dialysis are symptoms and signs
of uremia, volume overload, hyperkalemia, and meta-

Table 3. Management of Complications of Acute

Renal Failure
Complication

Potential Treatment

Extracellular volume
overload

Salt restriction, diuretics, ultrafiltration

Hyponatremia

Restriction of oral water and hypotonic

intravenous fluid

Hyperkalemia

Restriction of dietary K+; elimination

of K+ supplements and K+-sparing
diuretics; administration of K+binding resins, glucose and insulin,
sodium bicarbonate, calcium gluconate, dialysis

Metabolic acidosis

Restriction of dietary protein; administration of sodium bicarbonate,

dialysis

Hyperphosphatemia

Restriction of dietary phosphate;

administration of phosphate binders

Hypocalcemia

Calcium supplementation

Hyperuricemia

Allopurinol, diuresis, dialysis

Nutrition

Enteral or parenteral nutrition

Drug dosing

Adjust doses for GFR < 10 mL/min;

avoid NSAIDs, ACE inhibitors,
ARBs, radiocontrast, nephrotoxic
antibiotics, other nephrotoxins

ACE = angiotensin-converting enzyme; ARB = adrenergic-receptor

binder; GFR = glomerular filtration rate; IV = intravenous; NSAID =
nonsteroidal anti-inflammatory drug.
Adapted with permission from Brady HR, Singer GG. Acute renal failure. Lancet 1995;346:1533 40.

bolic acidosis that is refractory to medical therapy. One

of the more difficult issues in the management of ARF
is determining the modality of renal replacement therapy. The form of dialytic therapy may affect patient
morbidity and mortality and has been the subject of
intense investigation in clinical nephrology over the
past several years.
INTERMITTENT HEMODIALYSIS
Intermittent hemodialysis (IHD) has been the standard form of dialysis used to treat ARF, but some have
suggested that this form of renal replacement therapy
may actually prolong the course of ARF. It has been
hypothesized that intravascular fluid shifts and decreases
in blood pressure can exacerbate renal ischemia and
delay the recovery of ARF. These hemodynamic effects of
IHD may be associated with focal areas of ATN in the
recovering kidney.

Nephrology Volume 4, Part 3 9

Acute Renal Failure

Daily 1HD
GU = 13.79 mg/min
Kt/V = 1.23
Kd = 216 mL/min
Td = 240 minutes

Urea nitrogen (mg/dL)

120
100

CVVHD
GU = 13.79 mg/min
Kd = 39 mL/min
Kt/V = 1.33

Kd = 26 mL/min
Kt/V = 0.89

80
60
40
20
Monday Tuesday

Wednesday

Thursday Friday

0
0

3
4
Time (min 1000)

The role of biocompatibility and delivered dialysis

dose are 2 of the many clinical aspects of IHD that have
not been adequately studied in the outcomes of patients
with ARF.23 Biocompatibility refers to the magnitude of
the activation of the plasma and cellular components of
the blood after exposure to the dialysis membrane.
These changes are due to activation of complement and
the coagulation cascade. In addition, neutrophils, macrophages, and monocytes also are activated. The clinical
sequelae of this activation remain speculative, but they
may play a role in prolonging recovery of ATN. Several
clinical studies have been performed to study the effects
of biocompatibility in ARF, and there is some suggestion
that biocompatible membranes are beneficial.24
Assessment of dialysis adequacy also is an essential
issue in the management of patients with ARF. Mortality
is inversely related to dialysis adequacy in patients with
end-stage renal disease as determined by Kt/V measurements.25,26 In recent years, similar studies have begun to
emerge for patients with ARF.23 These studies suggest
that patients with ARF are underdialyzed, as the delivered dose of dialysis falls short of the prescribed dose.
Dialysis adequacy, some argue, may be a factor contributing to the high mortality seen in ARF. The reasons
for the discrepancy between delivered and prescribed
dose of dialysis are related to temporary vascular access,
catheter recirculation, hypotension, dialyzer clotting,
and poor urea clearances.
CONTINUOUS RENAL REPLACEMENT THERAPY
Continuous renal replacement therapy (CRRT) can
potentially correct some of the problems associated with
IHD. This modality has several theoretical advantages
over IHD.27 First, CRRT avoids water, electrolyte, and

10 Hospital Physician Board Review Manual

Figure 4. Sawtooth pattern of blood urea

nitrogen level across time in daily intermittent
hemodialysis (IHD) and smooth decline of solute concentration of continuous venovenous
hemodialysis (CVVHD) in a 70-kg patient
with a protein catabolic rate of 2 g/kg body
weight/day and a urea generation rate (GU) of
13.79 mg/min. Kt/V is defined as the dialyzer
clearance of urea (K) multiplied by the duration of the dialysis treatment (t, in minutes)
divided by the volume of distribution of urea
in the body (V, in mL [approximately total
body water]). (Adapted with permission from
Manns M, Sigler MH, Teehan BP. Continuous
renal replacement therapies: an update. Am J
Kidney Dis 1998;32:185207.)

urea fluctuations. During ARF, metabolites that are normally excreted at relatively constant rates accumulate in
the blood. With IHD, these substances are cleared over a
period of hours, but they rapidly reaccumulate in the
absence of renal function, resulting in a sawtooth pattern of metabolite increases and decreases. CRRT provides a more physiologic clearance pattern, avoiding fluctuations in levels of metabolites (Figure 4). A second
advantage is that CRRT can be used in patients with
hemodynamic stability. Many patients with ARF are
hemodynamically unstable and cannot tolerate IHD,
which is associated with intermittent hypotension. In
addition, these patients sometimes cannot tolerate the
rapid ultrafiltration that is often required with IHD because they are markedly volume overloaded and require
more than 2 L of intravenous fluid and nutrition daily.
Continuous therapies allow for an almost unlimited ability to remove fluid. Third, CRRT allows for elimination of
septic mediators. CRRTs have been shown to remove
proinflammatory mediators such as TNF-, thromboxane B2, interleukin-1, and platelet activating factor.
Removal of these factors may play a role in treating
underlying causes of ARF.
There are several different CRRT modalities
(Table 4).28 Historically, the arterial circulation was used to
provide the force to move blood across the dialyzer. Due
to the need for arterial access and inherent complications,
such as ischemia, atheroemboli, bleeding, and pseudoaneurysm and the technical improvement in venovenous
therapies, these methods have been largely abandoned.
The venovenous modalities differ primarily in the methods of clearance. Slow continuous ultrafiltration (SCUF)
is a method employed to remove volume by taking off
fluid filtered by a dialysis membrane by convective force.

Acute Renal Failure

Table 4. Comparison of Continuous Renal Replacement Therapy Modalities
Modality

Dialysate

Replacement Fluid

Urea Clearance (L/d)

No

No

1 to 4

Continuous venovenous hemofiltration

No

Yes

22 to 24

Continuous venovenous hemodialysis

Yes

No

24 to 30

Continuous venovenous hemodiafiltration

Yes

Yes

36 to 38

Slow continuous ultrafiltration

Adapted with permission from Manns M, Sigler MH, Teehan BP. Continuous renal replacement therapies: an update. Am J Kidney Dis 1998;32:
185207.

Continuous venovenous hemodialysis (CVVHD) provides clearance using diffusive clearance by running
dialysate across the membrane. Continuous venovenous hemofiltration (CVVHF) removes fluid by convection (as in SCUF) and then provides replacement
fluid back to the patient. Finally, continuous venovenous hemodiafiltration combines the clearance properties of CVVHD and CVVHF.
OUTCOMES OF CRRT AND IHD
Much has been published in the last several years
regarding the potential advantages of CRRT versus
IHD. To date there is no clear consensus as to whether
outcomes are improved in patients treated with CRRT,
but clinical trials addressing this specific question are
difficult to perform. In a recent study performed in
patients with severe ARF requiring dialysis, mortality
was almost solely attributed to the underlying medical
condition. After adjusting for severity of illness, patients
who received CRRT and those who received IHD were
equally likely to survive.29
Even though there is no definite advantage of CRRT
versus IHD, it is becoming clear that the amount of dialysis delivered to the patient with ARF is important for
patient outcome. In a recent trial, the dose of delivered
dialysis was shown to impact patient survival in a dosedependent manner.30 Critically ill patients requiring
CRRT were randomized into 3 groups, each receiving an
increased dose of dialysis (20, 35, and 45 mL/hour/kg of
ultrafiltration by CVVHF). The survival rate for the
3 groups was 41%, 57%, and 58%, respectively, demonstrating a significant difference in survival for those
patients receiving more dialysis. The authors concluded
that ICU patients with ARF requiring CRRT should
receive at least 35 mL/hour/kg of ultrafiltration.
Despite the potential advantages of CRRT, this therapy has several disadvantages, including the need for anticoagulation, patient immobility, and intensive nursing
and expense. Furthermore, this form of dialysis is not
available at all centers providing renal replacement ther-

apy. Because of these factors, a group recently published

a report using conventional dialysis machines in a technique they call extended daily dialysis (EDD).31 With this
technique, a conventional dialysis machine is employed
and patients are dialyzed for 6 to 8 hours at low blood
flow, mimicking CRRT. Their study (not randomized)
was done in a controlled fashion in which patients
undergoing EDD were compared to a group of patients
undergoing CRRT. There were no significant differences between the 2 groups regarding several clinical
parameters. Mortality was not a primary end-point in
this study; however, 84% of the patients receiving EDD
died compared with 65% of those receiving CRRT. Further study of this dialysis technique will have to be performed to determine if it has any clinical benefit.
SUMMARY
Medical management of ARF remains a challenge for
clinicians. Increased understanding of some of the pathophysiologic mechanisms of ARF has led to the study of
many pharmacologic agents in its treatment. Because of
the complex etiology of the syndrome, the benefit of most
of these agents has not been recognized. Until further
clinical trials are performed, we will not know the true
benefit of pharmacologic treatments to prevent or treat
ARF. In addition, renal replacement therapies are now
available to support ARF patients; determining which
therapies improve survival outcomes will be beneficial.

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12 Hospital Physician Board Review Manual