Acs0807 Acute Renal Failure

© 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 7 ACUTE RENAL FAILURE — 1

7 ACUTE RENAL FAILURE
Sean M. Bagshaw, M.D., M.SC., F.R.C.P.C., and Rinaldo Bellomo, M.D., F.R.A.C.P., F.J.F.I.C.M.

Acute renal failure (ARF) remains one of the major therapeutic changes in nitrogen intake, and changes in protein catabolic rate)
challenges facing the modern physician.The term describes a syn- and that varies more rapidly.The creatinine level is a more reliable
drome characterized by a rapid decrease (occurring within hours marker of the glomerular filtration rate (GFR) and is commonly
to days) in the kidney’s ability to eliminate waste products, regu- used to define the presence or absence of ARF; however, it does
late extracellular volume, and maintain electrolyte and acid-base not change in direct proportion to the loss of nephron mass and is
homeostasis.This loss of excretory function is manifested clinical- not a real-time descriptor of the GFR. Nonetheless, using urea
ly by the accumulation of end products of nitrogen metabolism and creatinine levels to define ARF seems a practical and reason-
(e.g., urea and creatinine). Other typical clinical manifestations able approach to the biochemical definition of this condition.The
include decreased urine output (which is not always present), the problem, however, is that in current practice, there are too many
accumulation of nonvolatile acids, and an increased serum potas- essentially arbitrary biochemical cutoff values for the definition of
sium concentration. ARF.This point was highlighted by a review of 28 studies of post-
In the literature, the incidence of ARF has been variable, operative ARF, in which each study used a different definition of
depending on the criteria used to define the condition. ARF has this condition.1 The lack of agreement on the operative definition
been reported to occur in approximately 5% to 8% of hospitalized of ARF has significantly hindered research in this field, especially
patients and 15% to 30% of patients admitted to an intensive care with regard to the design and execution of randomized, controlled
unit. Despite the advances that have been made in understanding trials. In 2004, however, the work of the Acute Dialysis Quality
the pathophysiology of ARF and developing extracorporeal thera- Initiative (ADQI) (http://www.ADQI.net) led to the development
pies, the mortality associated with this condition continues to be and publication of a consensus definition of ARF. It is hoped that
alarmingly high. Moreover, there is evidence to suggest that the acceptance and use of this definition will lead to more consistent,
mortality is even higher in patients with ARF that is severe enough reproducible, and generalizable results from epidemiologic and
to warrant initiation of renal replacement therapy (RRT). interventional studies of ARF [see Figure 1].2
The term acute tubular necrosis (ATN) has frequently been
ASSESSMENT OF RENAL FUNCTION
used in the context of ARF, but current evidence suggests that this
term has limited clinical relevance, in that it describes only the
Waste Product Levels
histopathology and is not reliably linked with differences in patient
management. The concept of ATN comes from animal models As noted (see above), to establish that ARF is present, one must
that do not accurately reflect clinical situations and from old biop- be able to measure renal function and detect that it has been
sy data. Even in cases where the term seems appropriate, the so- altered; however, the complexity of renal function can make this a
called necrosis is frequently patchy and mostly isolated to the thick difficult undertaking. Accordingly, in the clinical context, moni-
ascending loop of Henle. Furthermore, cells found in the urinary toring of renal function is limited to indirect assessment of the
tubular casts of such patients are viable on staining studies, a find- GFR through measurement of urea and creatinine levels in blood.
ing that partly invalidates the use of the term necrosis. These levels are relatively inaccurate markers of GFR and are
heavily influenced by patient age, patient sex, nutritional status,
steroid use, and the presence of GI bleeding or muscle injury.
General Principles Furthermore, they generally only become abnormal once the
GFR has fallen by 50% or more; they do not reflect real-time
DEFINITION OF ACUTE RENAL FAILURE
dynamic changes in the GFR and can be grossly modified by
A logical approach to organ failure might reasonably begin by aggressive fluid resuscitation. Determining creatinine clearance by
defining what a particular organ does. In the case of the kidney, the means of 2-hour or 4-hour collections or calculating clearance by
list of functions is long. Many of these functions, however, are either means of formulas adjusted for body weight, sex, or age may
shared with other organs (e.g., acid-base control, which is shared increase the accuracy of the results, but it rarely, if ever, changes
with the lung) or require complex neurohormonal interactions that clinical management. Sophisticated radionuclide-based tests are
involve other organs (e.g., the renin-angiotensin-aldosterone axis). available, but they are cumbersome and are useful only for re-
Other renal functions are not routinely measured (e.g., small pep- search purposes.
tide excretion, tubular metabolism, and hormonal production).
Urine Output
There are only two functions that are routinely and easily mea-
sured in patients and are unique to the kidney: (1) production of Urine output is a commonly measured parameter of renal func-
urine and (2) excretion of waste products of nitrogen metabolism. tion and often is more sensitive to changes in renal hemodynam-
Accordingly, clinicians have focused on these two functions in ics than biochemical markers of solute clearance are. However,
their efforts to define the presence of so-called ARF. urine output is also of limited sensitivity and specificity; some
The two waste products whose levels are routinely measured in patients have severe ARF, as indicated by a markedly elevated
patients are urea and creatinine. The urea level is the one that is serum creatinine level, while maintaining normal urine output (so-
affected more by extrarenal factors (e.g., gastrointestinal blood, called nonoliguric ARF). Because nonoliguric ARF has a lower


GFR Criteria UO Criteria

SCr increased 1.5✕
R Risk or UO < 0.5 ml/kg/hr
for 6 hr
GFR decreased by > 25% Figure 1 Depicted is the RIFLE (Risk, Injury,
Failure, Loss, End stage) classification scheme for
SCr increased 2✕ High ARF.2 The classification system includes separate
UO < 0.5 ml/kg/hr Sensitivity
I Injury or criteria for GFR and urine output (UO). Those cri-
for 12 hr
GFR decreased by > 50% teria that lead to the worst possible classification of
renal failure should be used. The designation
SCr increased 3✕ RIFLE-F (for failure) is appropriate even if there is
or a less than threefold increase in the serum creati-
UO < 0.3 ml/kg/hr nine concentration (SCr), provided that the new SCr

Oliguria
GFR decreased by 75% for 24 hr
is higher than 4.0 mg/dl (350 µmol/L) in the setting
F Failure or or of an acute increase of at least 0.5 mg/dl (44
SCr ≥ 4 mg/dl in Anuria for 12 hr µmol/L). In this case, the designation RIFLE-FC
setting of acute rise should be used to denote acute-on-chronic disease.
of ≥ 0.5 mg/dl Similarly, when the presence of renal failure
(RIFLE-F) is determined on the basis of urine out-
put criteria only, the designation RIFLE-FO should
Persistent ARF = complete loss of be used to denote oliguria. The shape of the figure
L Loss illustrates the point that more patients are included
kidney function for > 4 wk
in the mild category (top), including some who do
High
Specificity not have renal failure (higher sensitivity, lower
specificity). In the severe category (bottom), the
End-stage kidney disease criteria are strict and therefore specific, but some
E End Stage
(> 3 mo) patients with renal dysfunction may be missed
(higher specificity, lower sensitivity).

mortality than oliguric ARF, urine output is frequently used as a lars of the diagnosis of ARF.They accept and understand the inac-
means of distinguishing varieties of ARF.3 Classically, oliguria has curacy of these tests because they recognize that in this setting,
been defined (approximately) as a urine output of less than 5 to 6 obtaining absolute values is less important than detecting change
ml/kg/day or less than 0.5 ml/kg/hr. Often, changes in urine out- and identifying the direction of change.
put can develop before biochemical changes in renal function
CLASSIFICATION OF ACUTE RENAL FAILURE
become apparent.
The classification of ARF into clinically useful etiologic cate-
Serum and Urine Biomarkers
gories remains challenging and problematic, for several reasons.
Overall, it would be highly desirable to have markers of renal First, several of the test results that are time-honored and com-
function that would enable physicians to diagnose true reductions monly cited classifiers of ARF—such as a relatively high fraction-
in function associated with renal injury; the ability to diagnose al excretion of sodium (FENa), a high urinary sodium level, a low
such functional impairments would allow the identification of specific gravity, the presence of casts, and a relatively low urinary
those patients in whom early intervention might be justified. osmolality—have yet to be validated against a widely accepted def-
In the past few years, several serum and urine biomarkers have inition of ARF or a gold-standard test. Second, these test results
been developed for use in the detection of early renal dysfunction have not been characterized in blinded, controlled, or standard-
or injury. One such biomarker is cystatin C, a cysteine proteinase ized studies.Third, classification of ARF on the basis of these test
inhibitor of low molecular weight. This substance has many fea- results has not been shown to alter either patient management or
tures that would make it an ideal tool for the assessment of renal outcome. Nevertheless, despite their limitations, these test results
function, especially its constant rate of production (which appears are widely used in the literature to classify and define ARF.
to be independent of any pathologic states), its exclusively renal Unfortunately, there is no easy solution to the problems associ-
excretion, and the good inverse correlation of its blood levels with ated with classification of ARF. Clearly, more research is necessary
radionuclide-derived measurements of the GFR.4,5 Another bio- before our understanding of ARF reaches the point where more
marker is kidney injury molecule–1 (KIM-1), a transmembrane reliable and objective subdivisions can be created (as has been
protein that is present in the proximal renal tubule and is marked- done with pneumonia). The comprehensive process initiated by
ly upregulated and excreted in the urine in response to injury.6 the ADQI (see above) should facilitate such research.2
Several other urinary biomarkers have been described that also These classification difficulties notwithstanding, there does exist
appear to have potential for the detection of renal injury, includ- a practical and useful approach to stratifying patients presenting
ing interleukin-18 (IL-18), Na+/H+ exchanger isoform 3 (NHE3), with ARF.Traditionally, ARF is classified according to the proba-
and neutrophil gelatinase-associated lipocalin (NGAL).7-9 ble source of renal injury: prerenal, renal (parenchymal), or post-
These biomarkers are all promising; however, they are still rel- renal (obstructive) [see Table 1].
atively new, and thus, their roles in the diagnosis and management
Prerenal
of ARF have not yet been assessed in large multicenter studies. At
present, therefore, clinicians continue to rely on serum creatinine Prerenal ARF is by far the most common type of ARF. The
levels, plasma urea levels, and urine output as the three clinical pil- term prerenal typically indicates that the kidney is malfunctioning


predominantly as a result not of reasons intrinsic to the kidney but
of systemic factors, which, through variable mechanisms, can alter
renal blood flow (RBF) or intraglomerular hemodynamics and Table 2 Drugs Capable of Precipitating
result in a decrease in GFR. Acute Renal Failure
Clinicians frequently use terms such as prerenal azotemia or
Radiocontrast media ACE inhibitors
prerenal ARF to indicate not only that the cause or trigger of ARF Aminoglycosides Methotrexate
is external to the renal parenchyma but also that a given patient β-Lactam antibiotics Cisplatin
has functional loss of GFR (i.e., loss of GFR without structural Trimethoprim-sulfamethoxazole Cyclosporine
cell injury) as opposed to structural loss. In cases of suspected Amphotericin FK-506 (tacrolimus)
structural injury to the kidney, they typically use the term ATN NSAIDs
instead. This clinical distinction probably does not reflect a true ACE—angiotensin-converting enzyme NSAIDs—nonsteroidal anti-inflammatory
difference between two separate pathophysiologic states; more drugs
likely, these states simply represent two different points on a con-
tinuum of renal injury. Furthermore, no biopsy studies of ARF in
patients treated in the ICU have been conducted to demonstrate
(especially in critically ill patients) are sepsis and septic shock,
that so-called ATN is the histopathologic basis of prolonged renal
which account for more than 50% of all cases of ARF.12-14
dysfunction.10
If the systemic cause of prerenal ARF is rapidly removed or cor-
Common systemic causes of ARF include a low cardiac output
rected, renal function usually improves, returning to near-normal
state (e.g., myocardial infarction, tamponade, or valvular disease),
or baseline levels over a period of days. If intervention is delayed
cardiac surgery, major vascular surgery, trauma with hypovolemia,
or unsuccessful, however, renal injury can become established,
shock of any type (anaphylactic, hemorrhagic, or hypovolemic),
and RRT may have to be initiated. In these circumstances, if the
hemodynamic instability associated with surgery, hepatic failure,
patient survives, it frequently takes several days or weeks to achieve
increased intra-abdominal pressure, intra-abdominal hyperten-
renal recovery with independence from RRT.13,15-17
sion, and rhabdomyolysis.3,11 The mechanisms by which these
events induce ARF vary according to the causative trigger and are Parenchymal
poorly understood; however, they are likely to be complex and to
Parenchymal ARF is generally less common than prerenal ARF.
involve multiple pathways of renal injury. By far the most signifi-
The term parenchymal ARF is used to define a syndrome in which
cant systemic factors contributing to ARF in developed countries
the principal source of damage is within the kidney and in which
typical structural changes can be seen on microscopy. This syn-
drome can result from any of a number of disorders that affect the
Table 1—Differential Diagnosis of microvasculature, the glomerulus, the tubules, or the interstitium
[see Table 1].
Acute Renal Failure
Nephrotoxic drugs are a particularly important cause of paren-
chymal ARF, especially in hospitalized patients.3,11 Many patients
Probable Source with drug-induced ARF show rapid improvement once the of-
Differential Diagnosis
of Renal Injury
fending agent is removed. The drugs most commonly implicated
States of low cardiac output (myocardial, valvular, peri- in the development of ARF are aminoglycosides, penicillin or peni-
cardial, or arrhythmic disease; pulmonary hypertension; cillin derivatives, nonsteroidal anti-inflammatory drugs (NSAIDs),
pulmonary embolism; mechanical ventilation)
States of decreased intravascular volume (dehydration; trimethoprim-sulfamethoxazole, amphotericin B, cyclosporine,
hemorrhage; burns; GI losses from vomiting, diarrhea, chemotherapeutic agents, and angiotensin-converting enzyme
Prerenal or surgery; renal losses from diuretics, osmotic diuresis, (ACE) inhibitors [see Table 2].11 Not uncommonly, patients may
or diabetes insipidus)
States of low systemic vasodilation (sepsis or septic
be receiving several potentially nephrotoxic drugs concurrently.
shock; anaphylaxis; drugs; HRS) Accordingly, in all patients with ARF, a thorough history of drug
States of altered renal hemodynamics (from antiprostaglan- administration is mandatory.
din agents, ACE inhibitors, or exogenous vasopressors) Other conditions that can cause parenchymal ARF include
Glomerulonephritis or vasculitis glomerulonephritis, vasculitis, interstitial nephropathy, malignant
Renovascular disease (renal artery or vein occlusion; hypertension, pelvicaliceal infection, bilateral cortical necrosis,
malignant hypertension) amyloidosis, and trauma.
Exposure to toxins, either endogenous (myoglobin;
hemoglobin; uric acid) or exogenous (radiocontrast Postrenal
media; antimicrobials; chemotherapeutic agents;
Renal immunosuppressive agents; ethylene glycol) Obstruction to urine outflow gives rise to postrenal ARF, which
(parenchymal)
Interstitial nephritis (from antimicrobials, diuretics, malig- is the most common cause of functional renal impairment in the
nancy, or infection) community (i.e., in nonhospitalized patients) and is usually sec-
Tubular deposition or obstruction (from bilateral cortical
necrosis, multiple myeloma, or amyloidosis) ondary to prostatic hypertrophy. Obstructive ARF is also seen in
Renal allograft rejection hospitalized patients, albeit less commonly; typical causes in this
Trauma population include prostatic hypertrophy, pelvic tumors, retroperi-
toneal fibrosis, papillary necrosis, and large calculi [see Table 1].
Obstruction of ureter (from compression or kinking of The clinical presentation of obstruction may be acute or acute-
ureters or pelvicaliceal area, calculi, malignancy, or
Postrenal external compression [e.g., retroperitoneal fibrosis]) on-chronic in patients with long-standing renal calculi; oliguria is
(obstructive) Obstruction of bladder (from prostatic hypertrophy, not always present. If obstruction is suspected, ultrasonography
calculi, malignancy, blood clot, or neurogenic bladder) can be easily performed at the bedside. However, in some cases of
Obstruction of urethra (from stricture, phimosis, or trauma) acute obstruction, the ultrasonogram is abnormal, and in many
ACE—angiotensin-converting enzyme HRS—hepatorenal syndrome cases, the obstruction occurs in conjunction with other renal


insults (e.g., staghorn calculi and severe sepsis of renal origin), so with the broader utilization of radiocontrast media for diagnostic
that the renal dysfunction is actually caused by a combination of and interventional procedures.3,11 CIN results in prolonged hospi-
factors. talization, higher mortality, excessive health care costs, and, possi-
bly, long-term kidney impairment.23-25 In addition, CIN (or con-
Specific Syndromes
cerns regarding the risk of CIN) may result in delay or cancella-
Hepatorenal syndrome Hepatorenal syndrome (HRS) is a tion of important diagnostic or therapeutic procedures.
form of ARF that typically occurs in the setting of advanced cir- Experimental studies suggest that the pathophysiologic basis of
rhosis but can also occur in the setting of severe liver dysfunction CIN is the interplay among direct tubular epithelial cell toxicity,
caused by alcoholic hepatitis or in association with other forms of alterations in renal hemodynamics with ensuing ischemia, and
acute hepatic failure.18 concomitant atheroembolic showers of the renovasculature after
The pathophysiologic hallmark of HRS is profound renal vaso- procedures involving exposure to radiocontrast media.
constriction in the setting of systemic and splanchnic vasodilation. Several different definitions of CIN appear in the literature.
The pathogenesis of HRS is incompletely understood; however, Generally, however, CIN is defined as an acute decline in kidney
there are several mechanisms that may contribute to its develop- function occurring after the administration of intravascular radio-
ment, including (1) activation of the renin-angiotensin system in contrast media in the absence of other precipitants of renal dys-
response to systemic hypotension; (2) activation of the sympathet- function. Although it may seem obvious that CIN is the cause of
ic nervous system in response to systemic hypotension and the renal dysfunction, other important possible causes (e.g., athero-
increased intrahepatic sinusoidal pressure; (3) increased release of embolic disease, renal ischemia, and other nephrotoxic agents)
arginine vasopressin in response to systemic hypotension; and (4) should be considered before the diagnosis is made.26 For research
reduced hepatic clearance of various vascular mediators (e.g., purposes and for better generalizability of results and outcomes
endothelin, prostaglandins, and endotoxin).18,19 across clinical studies, CIN has traditionally been defined as a
HRS can occur spontaneously in patients with advanced cirrho- 25% or greater (or ≥ 0.5 mg/dl [44 μmol/L]) increase in the serum
sis. Much more frequently, however, it is caused by other precipi- creatinine level from the baseline value.27,28
tating conditions, including sepsis (specifically, spontaneous bacte- Patients with CIN typically present with an acute rise in the
rial peritonitis), paracentesis-induced hypovolemia, elevated intra- serum creatinine level within 24 to 48 hours after injection of a
abdominal pressure (from tense ascites), GI bleeding, diuretic-in- radiocontrast agent. Oliguria is usually absent, and FENa may be
duced or lactulose-induced hypovolemia, and various combinations low initially.29 Urine studies may reveal granular brown casts,
of these. Other contributing factors to ARF should be routinely tubular epithelial cells, and minimal proteinuria (< 300 mg/day).
sought, including cardiomyopathy related to alcoholism, nutrition- The presentation may vary, however. In some cases, there is no sig-
al deficiencies, viral infection, and exposure to nephrotoxins. nificant increase in the serum creatinine level, but urinalysis yields
Typically, HRS patients have advanced cirrhosis and show evi- abnormal results or markers of renal tubular injury are present. In
dence of portal hypertension with ascites in the absence of other other cases, there is a clear increase in the serum creatinine level,
apparent causes of ARF.They generally are oligoanuric, with pro- but results of urinalysis are bland and nondiagnostic. As a rule, the
gressive increases in serum creatinine or blood urea nitrogen lev- serum creatinine level peaks within 3 to 5 days after radiocontrast
els and bland urinary sediment. These patients experience pro- injection and returns to baseline within 7 to 10 days. In some
found sodium and water retention, with significant hyponatremia, patients, however, kidney function does not return to baseline, and
a urine osmolality higher than the plasma osmolality, and a very a degree of renal impairment persists.
low urinary sodium concentration (< 10 mEq/L). Although transient declines in renal function have been report-
ed after administration of radiocontrast media in almost all pa-
Rhabdomyolysis-associated ARF Rhabdomyolysis-in- tients, clinically important declines are exceedingly uncommon in
duced ARF is estimated to occur in about 1% of hospitalized patients with normal baseline kidney function. In general, clinical-
patients; however, it may account for close to 5% to 7% of cases ly important declines in renal function are associated with the
of ARF in critically ill patients, depending on the setting.11,14,20 The presence of preexisting risk factors. In several epidemiologic stud-
pathogenesis of this condition involves the interplay of prerenal, ies, multivariate analyses suggested that the presence of preexist-
parenchymal, and postrenal factors, including concurrent hypo- ing chronic kidney disease (GFR < 60 ml/min/1.73 m2), a diag-
volemia, renal ischemia, direct tubular toxicity mediated by the nosis of diabetes mellitus, the administration of a substantial quan-
heme pigment in myoglobin, and intratubular obstruction.21,22 tity of radiocontrast media, the presence of hypotension or hyper-
The causes of muscle injury that can result in rhabdomyolysis tension, increased age, anemia, a recent acute myocardial infarc-
include major trauma or compression, a drug overdose, vascular tion, a history of congestive heart failure, the use of an intra-aortic
embolism, prolonged seizures, malignant hyperthermia, neurolep- balloon pump, and the presence of shock were independently
tic malignant syndrome, various infections (e.g., pyomyositis, nec- associated with a risk of the development of CIN.30-34
rotizing fasciitis, influenza, and HIV infection), severe exertion,
alcoholism, and certain drug interactions (e.g., the combination of
a macrolide antibiotic or cyclosporine with a statin). Clinical Evaluation
Clinically, rhabdomyolysis is variably manifested by an elevated In all patients presenting with renal failure, it is important to
serum creatine kinase level, pigmented granular urinary casts, and determine whether the reduction in kidney function is truly acute
a red-to-brown color in the urine.Various electrolyte disorders may or whether chronic kidney disease was already present. In this con-
also develop as a result of muscle breakdown, including hyper- text, it is worth noting that more than one third of patients in
phosphatemia, hyperkalemia, hypocalcemia, and hyperuricemia. whom ARF develops have some degree of preexisting chronic kid-
ney disease with chronic parenchymal changes (e.g., as a result of
Contrast-induced nephropathy Contrast-induced nephrop- aging, long-standing hypertension, diabetes, or atheromatous dis-
athy (CIN) is currently the third most frequent cause of ARF in ease of the renal vessels). Such patients may also have preexisting
hospitalized patients, and its incidence is likely to increase further elevations of the serum creatinine concentration; however, this is


Table 3 Laboratory Tests Used to Help are often used to restore mean arterial pressure (MAP) to accept-
Diagnose Established Acute Renal Failure able levels (typically, 70 to 75 mm Hg or higher). Improvement
may be noted over time, and urine output may return, with or
without the assistance of diuretic agents. If urine output does not
Test Result in Prerenal ARF Result in
Established ARF return, however, early implementation of RRT should be consid-
ered. If the cause of ARF has been removed or resolved and the
Urine sediment Normal Epithelial casts patient has become physiologically stable, renal recovery may
Specific gravity > 1.020 < 1.020
occur slowly, over a period as short as 4 to 5 days or as long as 3
or 4 weeks. In some cases, even after renal recovery occurs, urine
UNa < 10 mEq/L > 20 mEq/L output continues to be higher than normal for several days. If the
FENa < 1% > 1%
cause of ARF has not been adequately remedied, the patient
remains gravely ill, the kidneys do not recover, and death from
Urinary osmolality > 500 mOsm/kg H2O < 300 mOsm/kg H2O multiple organ dysfunction syndrome (MODS) commonly ensues.
UCr/PCr ratio > 40 < 10

Plasma urea/ Investigative Studies
High Normal
creatinine ratio
As noted (see above), it is vital to identify the underlying condition
ARF—acute renal failure FENa—fractional excretion of sodium PCr—plasma creatinine or conditions responsible for ARF. The diagnosis may be obvious
concentration UCr—urinary creatinine concentration UNa—urinary sodium concentration
from the results of the clinical assessment; however, in many patients,
it is best to consider all possibilities and to exclude common treat-
not always the case. Often, an insult that would be considered rel- able causes by performing some simple investigative studies.
atively trivial and incapable of fully explaining the onset of ARF in LABORATORY TESTS
a normal patient is in fact sufficient to unmask a lack of renal func-
tional reserve in another patient. A key study is microscopic examination of the urinary sedi-
In general, diagnosis and management of ARF should always be ment. Urinalysis is an essential and simple noninvasive test that
based on four principles: (1) confirmation of the probable cause, can yield important diagnostic information and highlight patterns
(2) elimination of potential contributing factors, (3) institution of suggestive of specific syndromes. For example, the finding of dys-
disease-specific therapy if appropriate, and (4) prevention and morphic red blood cells (RBCs) or RBC casts is virtually diag-
management of the complications of ARF. nostic of active glomerulonephritis or vasculitis. Similarly, the find-
In most cases, important clues to the cause of ARF in a given ing of heavy proteinuria suggests some form of glomerular disease.
patient and an accurate working diagnosis can be obtained from a The finding of white blood cell (WBC) casts can suggest either
careful review of the medical record (with particular attention to interstitial nephropathy or infection. A urinalysis that yields no
medications administered, exposure to potential nephrotoxins, and abnormal findings can also provide important diagnostic informa-
recent events in the hospital, including any operative or other pro- tion, suggesting that ARF is prerenal or obstructive. Finally, exam-
cedures undergone), in conjunction with physical examination and ination of the urine helps the clinician determine whether a uri-
selected radiologic and laboratory investigations [see Investigative nary tract infection is present.
Studies, below]. In these cases, one can proceed to a therapeutic Several measures of urine and blood biochemistry have tradi-
trial without having to resort to renal biopsy. tionally been used to help clinicians distinguish between prerenal
An important caveat in the workup of a patient with ARF is that ARF and so-called ATN or established ARF [see Table 3]. One
one should not assume that ARF can always be correctly or sim- such measure is the FENa.35,36 In the setting of prerenal ARF, fil-
ply attributed to a single mechanism. As an example, patients with tered sodium is avidly reabsorbed from glomerular filtrate in the
postrenal obstruction frequently have some degree of sepsis, often renal tubules, resulting in an FENa lower than 1%, whereas in the
are hypotensive, and sometimes are hypovolemic and underresus- setting of renal tubular injury in established ARF, the resulting
citated. As another example, patients with crescentic glomeru- FENa is higher than 1%. However, the diagnostic utility of FENa
lonephritis are often systemically unwell and may have pulmonary has been questioned, and several reports have concluded that
disease with hypoxemia or hypotension (from volume depletion FENa must be interpreted with caution.37,38 For example, FENa is
caused by inadequate oral intake or from the vasodilatory effect of often higher than 1% in patients who have received diuretic ther-
inflammation). The possibility that several mechanisms can con- apy, regardless of the effective circulating volume (ECV).39,40
tribute to ARF in a single patient underscores the importance of Furthermore, FENa may be lower than 1% in patients with condi-
careful clinical assessment in the approach to the patient with ARF tions associated with parenchymal ARF (e.g., sepsis, rhabdomyol-
of recent onset. ysis, and exposure to radiocontrast media), perhaps reflecting non-
ARF patients frequently are critically ill and require admission homogeneous injury to the renal parenchyma and preservation of
to an ICU. Such patients often have sustained a major systemic tubular function in some regions.41-43
insult. Upon transfer and admission to the ICU, fluid resuscitation Overall, the clinical utility of these tests in hospitalized and crit-
either is well under way or has already been completed. Despite ically ill patients who receive fluids in massive amounts, loop
such efforts, patients often are profoundly oliguric or anuric, with diuretics, or vasopressors is untested and questionable. Further-
a rising serum creatinine level and developing metabolic acidosis. more, it is important to keep in mind that, as noted [see Classi-
Potassium and phosphate levels may be rising as well. Concomi- fication of Renal Failure, above], prerenal ARF and established
tant multiple organ dysfunction (signaled by the need for mechan- ARF are part of a continuum of disease and that separating the
ical ventilation and vasoactive drugs) is common in ARF patients. two conditions, though conceptually valid, is of only limited clini-
Fluid resuscitation is typically continued or reinstituted under the cal relevance. In general terms, therapy is the same for prerenal
guidance of invasive hemodynamic monitoring. Vasoactive drugs ARF as for established ARF: one treats the underlying cause while


promptly resuscitating the patient, using hemodynamic monitor- centration (≥ 8 g/dl) must be maintained or immediately restored
ing to guide therapy. during the acute phase of resuscitation. Some patients remain
In certain circumstances, other laboratory investigations may be hypotensive (MAP < 75 mm Hg) even after intravascular volume
necessary to establish the diagnosis. Marked anemia in the absence has been restored. In these patients, autoregulation of RBF may be
of blood loss may suggest acute hemolysis, thrombotic microan- impaired or lost. Restoration of MAP to near-normal levels is like-
giopathy, or paraproteinemia related to malignancy. If thrombotic- ly to improve RBF and increase GFR. Such restoration requires
thrombocytopenic purpura or another cause of microangiopathic the administration of vasopressor drugs. In patients with hyper-
hemolytic anemia is suspected, a peripheral blood smear should be tension or renovascular disease, a MAP of 75 to 80 mm Hg may
obtained and examined for evidence of hemolysis or schistocytes, still be inadequate.
and levels of lactic dehydrogenase, haptoglobin, unconjugated Despite these measures, progressive ARF may still develop in
bilirubin, and free hemoglobin should be measured. If parapro- patients whose cardiac output is inadequate. To improve cardiac
teinemia from multiple myeloma or lymphoma is suspected, serum output may require a variety of interventions, such as the addition
and urine protein electrophoresis should be done and the serum of inotropic drugs or the application of ventricular assist devices.
calcium concentration measured. A history of cancer or chemo- Whether additional fluid therapy in a patient with normal or
therapy should prompt measurement of uric acid to detect possible increased cardiac output and adequate blood pressure provides
tumor lysis syndrome. any significant renal protection is questionable; such therapy may
In patients with a potential mechanism of muscle injury, crea- in fact contribute to excess accumulation of extravascular fluid,
tine kinase and free myoglobin levels should be determined. If an resulting in pulmonary edema.
elevated–anion gap metabolic acidosis is present and there is evi- Once hemodynamic resuscitation has been accomplished and
dence that a toxin may have been ingested, ethylene glycol or nephrotoxins removed, it is unclear whether additional pharmaco-
methanol levels should be measured. logic measures provide any further benefit to the kidneys. So-
Systemic eosinophilia suggests the possibility of systemic vascu- called renal-dose (or low-dose) dopamine therapy is still frequent-
litis, allergic interstitial nephritis, or atheroembolic disease. Mea- ly used.There is little evidence that this regimen is effective in crit-
surements of levels of specific antibodies (e.g., anti–glomerular base- ically ill patients47-49; however, dopamine is a tubular diuretic that
ment membrane [GBM] antibodies, antineutrophil cytoplasmic an- occasionally increases urine output,50 and the increased output may
tibodies [ANCAs], antinuclear antibodies [ANAs], anti-DNA be incorrectly interpreted as an increase in GFR.51 A large phase
antibodies, or anti–smooth muscle antibodies) or cryoglobulins are III trial that examined the use of low-dose dopamine in critically
extremely useful screening tests to support the diagnosis of vasculi- ill patients showed it to be no better than placebo for prevention
tis, certain types of collagen vascular diseases, or glomerulonephritis. of renal dysfunction.52 In patients with low cardiac output, how-
ever, higher-dose dopamine may increase cardiac output, RBF,
IMAGING
and GFR (as might dobutamine or milrinone).
Renal ultrasonography is a rapid, noninvasive imaging modali- Fenoldopam is a selective D1 dopamine receptor agonist with
ty that is designed primarily to look for evidence of obstruction, no affinity for adrenergic D2, α, or β receptors. It has been shown
stones, cysts, masses, or overt renovascular disease. Doppler ultra- to reduce systemic vascular resistance while increasing RBF
sonography or magnetic resonance imaging can be useful in through reversal of the vasoconstrictive effects of angiotensin II
screening for renovascular occlusion. A chest x-ray may be indi- and endothelin.53 Fenoldopam improves both renal cortical and
cated, either to assess possible pulmonary complications of ARF renal medullary blood flow and decreases sodium reabsorption in
or to help confirm or rule out a diagnosis of systemic vasculitis. the proximal tubule.54 In a randomized, controlled trial of pro-
phylactic continuous infusion of fenoldopam in critically ill pa-
BIOPSY
tients with sepsis, this measure led to a reduction in the incidence
On rare occasions, percutaneous renal biopsy is necessary to of ARF; however, it had no impact on the need for RRT or on
confirm the diagnosis, determine the severity of renal injury, guide mortality.55 At present, the clinical implications of this study are
therapy, and estimate the potential for renal recovery.44,45 Renal uncertain; a clearer understanding of the role of fenoldopam pro-
biopsy is indicated when a thorough noninvasive investigation has phylaxis will have to await the results of a larger clinical trial.
failed to yield the diagnosis, after prerenal and postrenal causes There is a biologic rationale for the use of mannitol in this set-
have been excluded, and before aggressive immunosuppressive ting, as there is for the use of dopamine. Whereas animal experi-
therapy is initiated.The biopsy is generally performed under ultra- ments have yielded some encouraging findings, there are as yet no
sonographic guidance, using local anesthesia. As a rule, the risk data from controlled human studies to support the clinical appli-
associated with performing a renal biopsy in a critically ill patient cation of mannitol.56 The value of mannitol as a renal-protective
undergoing mechanical ventilation is comparable to that associat- agent remains questionable.
ed with performing a biopsy under standard conditions.46 Loop diuretics may protect the loop of Henle from ischemia by
reducing its transport-related workload through inhibition of the
Na+/K+/2 Cl− pump.57 The results of animal studies have been
Prevention encouraging, as have those of ex vivo experiments.58 To date, how-
ever, no double-blind, randomized, controlled studies of suitable
GENERAL MEASURES
size have definitively shown that these agents reduce the incidence
The fundamental principle of ARF prevention is to eliminate of ARF in humans.59-62 A few studies, however, have suggested
and treat precipitating causes of renal dysfunction. If prerenal fac- that loop diuretics can induce polyuria, which may translate into
tors are contributing to the problem, they must be identified, and prevention or easier control of volume overload, metabolic acido-
hemodynamic resuscitation must be quickly instituted. Intravas- sis, and hyperkalemia—the three major triggers of RRT.59,60 When
cular volume must be maintained or rapidly restored; this is often RRT can be avoided, treatment is simpler and less costly. Thus,
best done with the help of invasive hemodynamic monitoring. loop diuretics may be useful for the purposes of prophylaxis, espe-
Oxygenation must be maintained. An adequate hemoglobin con- cially if given via continuous infusion.63,64


Management
Other agents, such as adenosine antagonists (e.g., theophylline)
and atrial natriuretic peptides (e.g., urodilatin and anaritide), have The fundamental principles of the management of ARF are (1)
also been suggested for prevention of ARF.65-68 In a randomized, to identify, treat, and remove any precipitating factors and (2) to
controlled trial that included 504 critically ill patients with ARF, maintain physiologic homeostasis while renal recovery takes place.
administration of atrial natriuretic peptide did not yield any over-
all improvement in dialysis-free survival.66 Subgroup analysis sug- PREVENTION OR TREATMENT OF COMPLICATIONS
gested that this measure was of some benefit in patients with oli- Complications of ARF such as encephalopathy, pericarditis,
guric ARF; however, a follow-up study of 222 critically ill patients severe electrolyte disturbances (e.g., hyperkalemia), serious meta-
with oliguric ARF found no differences in dialysis-free survival or bolic disturbances (e.g., severe metabolic acidosis), myopathy,
overall mortality between those who received atrial natriuretic neuropathy, or major fluid derangements should never be permit-
peptide and those who received placebo.67 ted to occur in a modern hospital setting. Prevention of these com-
plications may entail several different measures, which may vary in
SPECIFIC SYNDROMES
complexity from fluid restriction to the initiation of extracorpore-
al RRT.
Rhabdomyolysis-Associated ARF
Extracellular fluid expansion is a common complication in pa-
The principles of prevention of rhabdomyolysis-associated tients with ARF, particularly in those who have a diminished ca-
ARF are based primarily on animal studies, retrospective data, pacity for sodium and water excretion as a consequence of oligu-
small case series, and multivariate logistic regression analyses; to ria. Accumulation of extracellular fluid is manifested by weight
date, no randomized, controlled trials have been conducted. gain, dependent interstitial edema, elevated central venous pres-
These principles include (1) identification and elimination of sure, pleural effusion and ascites, and pulmonary interstitial and
potential causative agents or correction of underlying compart- alveolar edema. Extracellular fluid overload can be further exacer-
ment syndromes; (2) prompt and aggressive fluid resuscitation bated in patients who require large volumes of parenteral medica-
to restore vascular volume and maintenance of polyuria (> 300 tions or nutritional formulas. If a patient is nonoliguric, fluid over-
ml/hr) to flush obstructing cellular casts (if present); and (3) load can generally be prevented through judicious use of loop
alkalinization of the urine (to a pH > 6.5) to reduce renal toxic- diuretics. If a patient is oliguric, however, the only way of averting
ity from myoglobin-induced lipid peroxidation and improve the dangerous fluid overload is to institute RRT at an early stage.
solubility of myoglobin.22 Experimental studies suggest that Marked azotemia (urea concentration > 112 mg/dl [40
mannitol may act as a scavenger of free radicals and thereby mmol/L] or serum creatinine concentration > 4.5 mg/dl [400
reduce cellular toxicity; however, the role of forced diuresis with μmol/L]) is undesirable and should probably be treated with RRT
mannitol remains controversial. unless (1) recovery is imminent or already under way and (2) a
return toward baseline or normal values is expected within 24
Contrast-Induced Nephropathy
hours. It should be recognized, however, that to date, no random-
Measures aimed at preventing CIN have been studied in sev- ized, controlled trials have defined the ideal time at which inter-
eral randomized trials; to date, however, few prophylactic or vention with artificial renal support should be initiated.
therapeutic interventions have conclusively been shown to Hyperkalemia (potassium concentration > 6 mEq/L) is anoth-
reduce the incidence of CIN, and no therapeutic intervention er frequent complication of ARF. Obviously, patients with ARF
has been found to be efficacious once CIN is established. The and oliguria should never receive any potassium-containing solu-
most prudent method of preventing CIN is to identify patients tion, either orally or via continuous infusion. Spurious hyper-
with risk factors before radiocontrast media are administered, kalemia secondary to hemolysis, thrombocytosis, and a very high
then to consider either delaying the diagnostic or interventional WBC count may occur and must be excluded. Genuine hyper-
procedure until kidney function can be optimized or switching to kalemia must be promptly treated to prevent the development of
an alternative imaging modality. At the same time, every effort a life-threatening cardiac dysrhythmia. Patients should receive
should be made to identify and correct underlying volume deple- insulin with dextrose, bicarbonate (if acidosis is present), nebu-
tion and discontinue potential nephrotoxins. If the procedure is lized salbutamol, or all three together. If the serum potassium level
performed, the volume of radiocontrast media employed should exceeds 7 mEq/L or there are electrocardiographic signs of hyper-
be kept to a minimum. kalemia, calcium gluconate (10 ml of a 10% solution I.V.) should
The adoption of periprocedural hydration protocols and the also be immediately administered. These measures are temporiz-
use of nonionic iso-osmolar radiocontrast media (e.g., iodixanol) ing actions only; urgent RRT should be arranged.
have reduced the incidence and severity of radiocontrast-associ- Metabolic acidosis is almost always present as a consequence
ated renal injury.69-72 In the first few years of the 21st century, of reduced excretion of nonvolatile acids produced through
randomized trials assessed the efficacy of N-acetylcysteine for metabolism of dietary protein. In itself, the metabolic acidosis is
the prevention of CIN, with highly variable results.73-82 These rarely severe enough to necessitate treatment, but it can be great-
results were further analyzed in several meta-analyses, which ly exacerbated by a host of concomitant processes when the kid-
concluded that there appears to be a potential reduction in re- ney’s capacity for generation of bicarbonate is diminished.
nal injury with N-acetylcysteine (though this conclusion re- Increased endogenous production of acid can occur in all types
mains controversial).83-87 It is reasonable to use N-acetylcys- of shock, with elevated lactate production, severe sepsis, diabet-
teine for prevention of CIN in routine care, in view of its relative ic or starvation ketoacidosis, and liver disease. In addition, vari-
ease of use, its low cost, and its good safety profile, especially in ous exogenous sources can worsen metabolic acidosis, including
patients at high risk for CIN.There is also some evidence to sug- toxins (e.g., ethylene glycol and salicylates) and solutions con-
gest that adenosine antagonists may confer some protection taining large amounts of chloride. When refractory severe meta-
against CIN; however, further evidence is required to confirm bolic acidosis (pH < 7.1) is present, early initiation of RRT
that the benefit is real.88,89 should be considered.


ARF can also result in the development of anemia via any of
several mechanisms, including bleeding, hemodilution, hemolysis, Table 4 Modern Criteria for Initiation of
decreased RBC lifespan, and reduced erythropoiesis. One large Renal Replacement Therapy*
randomized study suggested that a restrictive transfusion protocol
for correction of hemoglobin levels higher than 7 g/dl in critically Anuria (no urine output for ≥ 6 hr)
ill patients with anemia is adequate.90 However, more liberal and Oliguria (urine output < 200 ml/12 hr)
aggressive transfusion may be necessary, depending on the results Serum urea concentration > 28 mmol/L or BUN > 80 mg/dl
of individual patient assessments. Serum creatinine concentration > 3 mg/dl (265 μmol/L)
Serum potassium concentration ≥ 6.5 mEq/L or rapidly rising
Nutritional support must be started early and must contain an
Pulmonary edema unresponsive to diuretics
adequate amount of calories (30 to 35 kcal/kg/day) in a mixture of
Uncompensated refractory metabolic acidosis (pH < 7.1)
carbohydrates and lipids. Sufficient protein (about 1 to 2 g/kg/day) Any uremic complication (encephalopathy, myopathy, neuropathy, or
must be administered. There is no evidence that specific renal pericarditis)
nutritional solutions are useful. Vitamins and trace elements Temperature ≥ 40° C (104° F)
should be administered in amounts that at least match the recom- Overdose with a dialyzable toxin (e.g., lithium or salicylates)
mended dietary allowance. The role of the newer immunonutri-
* If one criterion is met, RRT should be considered. If two criteria are met simulta-
tional solutions remains controversial. The enteral route is gener- neously, RRT is strongly recommended.
ally preferred to the parenteral route. BUN—blood urea nitrogen

All drug regimens must be adjusted to take into account the
effect of the decreased clearances associated with impaired renal
function. Finally, assiduous attention should be paid to the pre- dialysis (IHD), and peritoneal dialysis (PD). The basis of all of
vention of infection. these RRT techniques is the removal of unwanted solutes and
water through a semipermeable membrane. Such a membrane
MANAGEMENT OF HEPATORENAL SYNDROME
may be either biologic (i.e., the peritoneum) or artificial (i.e.,
Management of HRS remains challenging. In general, it should hemodialysis or hemofiltration membranes); each type has its
include systematic identification and prompt treatment of any advantages, disadvantages, and limitations.
potentially reversible precipitating factors (especially infections and In general, RRT for ARF should be initiated early, before com-
volume depletion). Prevention of hypovolemia by administering plications develop. The commonly expressed concerns regarding
albumin to patients with spontaneous bacterial peritonitis has been early RRT stem from the adverse effects of conventional IHD with
shown to decrease the incidence of HRS and improve outcome.91 cuprophane membranes (in particular, hemodynamic instability)
One small nonrandomized study found that treating HRS pa- and from the risks and limitations associated with CRRT or PD.
tients with a combination of midodrine and octreotide resulted in In the past few years, however, improved use of CRRT and the
improved kidney function and outcome.92 Another small uncon- development of new hybrid techniques adapted from convention-
trolled study suggested that I.V. N-acetylcysteine might improve al IHD (e.g., sustained low-efficacy dialysis [SLED] and extend-
GFR in patients with HRS through reductions in splanchnic vaso- ed daily dialysis [EDD]) have reduced the incidence of these
dilatation achieved by decreasing the formation of nitric oxide and adverse effects.100-102
oxygen free radicals.93 The criteria governing the initiation of RRT in patients with
There is some evidence to suggest that vasopressin derivatives chronic renal failure may be inappropriate for patients with ARF,
(ornipressin and terlipressin) may improve GFR in patients with particularly if they are critically ill. Accordingly, a set of modern
HRS. In a small uncontrolled trial, administration of ornipressin, in criteria for the initiation of RRT has been developed [see Table 4].
conjunction with volume expansion, reduced plasma renin and With either CRRT or IHD, the available data are insufficient
norepinephrine levels and improved RBF, GFR, and urinary sodi- to establish precisely what constitutes adequate intensity of dial-
um excretion.94 In other small studies, the combination of terli- ysis; however, there is some evidence that a higher prescribed
pressin and volume expansion led to similar improvements in sys- dose of RRT may improve survival.103,104 At a minimum, RRT
temic hemodynamics and kidney function, with a suggestion of should be of sufficient intensity to maintain homeostasis at all
improved short-term outcome.95,96 At present, however, the precise levels. An appropriate target urea level is 42 to 70 mg/dl (15 to
role of these agents in the management of HRS remains unclear. 25 mmol/L), with a protein intake of about 1.5 g/kg/day.This tar-
Transjugular intrahepatic portosystemic shunting (TIPS) [see get level can easily be achieved by using CRRT at urea clear-
5:10 Portal Hypertension] has been associated with modest ances of 30 to 40 L/day (depending on patient size and catabol-
improvements in kidney function in HRS patients, may improve ic rate).104 If IHD is employed, daily treatment and extended
outcome, and thus may be an option for patients who are not can- treatment become desirable.103
didates for transplantation or are awaiting transplantation.97-99 In There remains considerable controversy regarding which mo-
general, however, the ideal solution for reversal of ARF in HRS dality of RRT is ideal for reducing mortality and enhancing renal
patients is to improve hepatic function by treating the underlying recovery, in particular for patients who are hemodynamically
primary liver disease, to refer patients for orthotopic liver trans- unstable or critically ill. A major reason for the controversy is the
plantation, or both. difficulty of comparing the results of various small randomized,
controlled trials that made use of different techniques.13,105-107
RENAL REPLACEMENT THERAPY
Large trials of sufficient statistical power would be hard to conduct
When ARF is severe, resolution can take days to weeks. In and may never be performed. In the absence of such trials, RRT
these situations, extracorporeal techniques of blood purification techniques should be judged on the basis of the following criteria:
often must be applied to prevent complications [see Prevention (1) biocompatibility, (2) hemodynamic side effects, (3) uremic con-
or Treatment of Complications, above]. Such techniques, collec- trol, (4) ability to control fluid status, (5) ability to control acido-
tively referred to as renal replacement therapy, include continu- sis, (6) ability to allow full nutritional support, (7) risk of infection,
ous renal replacement therapy (CRRT), intermittent hemo- (8) absence of specific side effects, and (9) cost.


CRRT and SLED may offer many advantages over conven- catheters in the subclavian position pose particular problems; larg-
tional IHD and PD; however, the necessary technology and exper- er (13.5 French) catheters in the femoral position appear to func-
tise are not available everywhere, and practice preferences vary tion more reliably.118 The choice of membrane is a matter of some
widely from one country to another.108 Therefore, it will be worth- debate. There are several biosynthetic membranes on the market
while to review certain salient features of CRRT and IHD. (e.g., those made of AN69, polyamide, polysulfone, or cellulose
triacetate) that have excellent biocompatibility. To date, however,
Continuous Renal Replacement Therapy
no controlled studies have shown any of them to possess a clinical
CRRT was initially performed as an arteriovenous procedure advantage over any of the others.
(i.e., continuous arteriovenous hemofiltration [CAVH]), in which
Intermittent Hemodialysis
blood flow through the hemofilter was driven by the patient’s
blood pressure. A drawback of this approach was that the cannu- In IHD, as in CRRT, vascular access is typically obtained via a
lation of an artery was associated with a morbidity of 15% to 20%. double-lumen catheter. Also as in CRRT, the circuit consists of
Accordingly, CRRT is now more commonly performed as a ve- venovenous blood flow driven by a peristaltic pump. As in CVVH,
novenous procedure using double-lumen catheters and peristaltic countercurrent dialysate flow is employed; however, standard IHD
blood pumps (continuous venovenous hemofiltration [CVVH]), differs from CVVH in that it uses high dialysate flows (300 to 400
with or without control of the ultrafiltration rate. In a venovenous ml/min), generates dialysate by using purified water and concen-
system, dialysate can also be delivered against the direction of trate, and is applied for short periods (3 to 4 hours).These differ-
blood flow (a technique known as continuous venovenous hemo- ences have important implications. First, volume removal must be
diafiltration [CVVHDF]) to achieve either almost pure diffusive completed within a short time, and this process may be poorly tol-
clearance or a mixture of diffusive and convective clearance. No erated by patients who are hemodynamically unstable or critically
matter which CRRT technique is used, the following outcomes ill. There is a high incidence of hypotension in such patients, and
are predictable: (1) a high level of biocompatibility, (2) hemody- repeated hypotensive episodes may contribute to delayed renal
namic stability, (3) continuous control of fluid balance, (4) control recovery.119 Second, solute removal is episodic, resulting in inferi-
of acid-base status, (5) control of electrolytes (including phosphate or uremic and acid-base control, decreased therapeutic efficacy,
and calcium), (6) the ability to provide protein-rich nutrition while and a lower delivered dose of RRT. Suboptimal fluid and uremic
achieving uremic control, (7) a minimal risk of infection, and (8) control imposes unnecessary limitations on nutritional support.
prevention of dangerous swings in intracerebral water balance. Furthermore, rapid solute shifts increase brain water content and
Generally, performance of CRRT is restricted to ICUs and raise intracranial pressure.120
requires that specifically trained nursing and medical staff mem- The issue of membrane bioincompatibility has given rise to a
bers be available 24 hours a day. Many small ICUs cannot provide great deal of controversy. In comparison with high-flux synthetic
this level of support. If CRRT is only performed five to 10 times a membranes (also used for CVVH), standard low-flux dialyzing
year, the cost of training may not be economically justifiable, and membranes made of cuprophane have been found to trigger the
expertise may be hard to maintain. Furthermore, depending on how activation of several inflammatory pathways. It is possible that this
patient care is organized at a particular institution, CRRT may be proinflammatory effect contributes to further renal damage and
more expensive than IHD.109 In addition, the need for continuous delays recovery or even affects mortality. The controversy has not
anticoagulation of the extracorporeal circuit during CRRT raises the yet been resolved.
issues of possible hemorrhage, immune thrombotic thrombocy- The limitations of conventional IHD in the setting of ARF led
topenia, and increased transfusion requirements.110-112 In view of to the development of the new hybrid techniques SLED and
these concerns, it is essential to consider the risks and benefits of EDD,100,101 which adapt IHD to specific clinical circumstances so
more or less intensive anticoagulation and of alternative strategies. as to make it easier to tolerate and more effective. At present, PD
In the vast majority of patients, low-dose heparin (< 500 IU/hr) is rarely used in the treatment of adult ARF in developed coun-
is sufficient to achieve an adequate filter lifespan, is relatively easy tries; however, it may be a reasonable option in developing coun-
and cheap to administer, and has almost no effect on coagulation test tries or in the treatment of children when alternatives are unavail-
results. In some patients, a higher dose is necessary. In others (e.g., able or are considered too expensive or invasive.108
those with pulmonary embolism or myocardial ischemia), full hep-
BLOOD PURIFICATION FOR INDICATIONS OTHER THAN
arinization may be indicated. Regional citrate anticoagulation is
ACUTE RENAL FAILURE
highly effective but somewhat complex, in that it requires a special
dialysate or replacement fluid.113 Regional heparin or protamine There is growing interest in the possibility that blood purifica-
anticoagulation is also somewhat complex, but it may be helpful if tion, by removing circulating mediators, may provide a clinically
frequent filter clotting occurs and further anticoagulation of the pa- significant benefit for patients who are in a severe septic state.121-123
tient is considered dangerous. Low-molecular-weight heparin Various techniques, including plasmapheresis, high-volume hemo-
(LMWH) is easy to administer but is more expensive than stan- filtration, very-high-volume hemofiltration, and coupled plasma fil-
dard heparin.114 The LMWH dose must be adjusted for the loss of tration adsorption, are currently being assessed in animal studies
renal function, which is difficult to monitor. Heparinoids and pros- and in phase I and II human studies.124,125 Initial findings suggest
tacyclin may be useful if the patient has heparin-induced thrombo- that continued exploration of this therapeutic option is worth-
cytopenia and thrombosis.115 Finally, in perhaps 10% to 20% of pa- while126; however, randomized, controlled trials of sufficient statis-
tients, anticoagulation is contraindicated because of endogenous coag- tical power have not yet been performed. Blood purification tech-
ulopathy or recent surgery. In such patients, mean filter lives longer nology, in combination with the use of bioreactors containing either
than 24 hours can be achieved, provided that blood flow is kept at human or porcine liver cells, is also under active investigation as a
about 200 ml/min and reliable vascular access is maintained.116 form of artificial liver support for patients with fulminant or acute-
Particular attention must be paid to the adequacy and ease of on-chronic liver failure.127 Some promising results have been
flow through the double-lumen catheter.117 Smaller (11.5 French) reported.


Discussion

Pathogenesis of Acute Renal Failure al useful observations can be made about the epidemiology of this
The pathogenesis of ARF varies, depending on the primary condition.
mechanism and contributing factors underlying the acute decline First, some degree of acute renal injury (manifested by albu-
in kidney function. minuria; the loss of small tubular proteins; the inability to excrete
For postrenal or obstructive ARF, the pathogenesis typically a water, sodium, or amino acid load; or any combination of these)
involves several humoral responses, as well as a host of mechani- can be demonstrated in most ICU patients.The manifestations of
cal factors. As a rule, a single functioning kidney has adequate renal injury may be seen in patients who are undergoing simple
capacity for clearance of daily nitrogenous waste and maintenance and successful cardiac surgery with cardiopulmonary bypass, as
of water and acid-base homeostasis.Therefore, for postrenal ARF well as in patients who have severe sepsis but a normal serum cre-
to develop, urinary flow must be obstructed in the urethra, in the atinine concentration. Their significance is unclear, beyond the
bladder, or in both ureters (one ureter if the patient has only a sin- observation that some of them (e.g., albuminuria) have been asso-
gle kidney). These mechanical factors can arise from within the ciated with increased mortality.
genitourinary system (e.g., stones or strictures) or from extrinsic Second, ARF is common in hospitalized patients, affecting
causes (e.g., ureteral compression or kinking) [see Table 1]. When between 5% and 8% (depending on the specific population being
urinary flow is obstructed, glomerular filtration initially continues, assessed and the criteria being used to define ARF).3,11 In a report
gradually elevating the intraluminal pressures proximal to the site from the Madrid ARF Study Group, the overall annual incidence
of obstruction. Over time, the elevated pressures result in progres- of ARF was 209 cases/million, with ARF defined as either (1) a
sive distention and dilation of the proximal ureter, the renal pelvis, sudden increase in the serum creatinine concentration to 2.0
and the calyx and directly cause GFR to decline. mg/dl (177 μmol/L) or higher in a patient with normal premorbid
The pathogenesis of parenchymal ARF is typically immunolog- renal function or (2) a 50% or greater increase in the serum crea-
ic. It is a complicated process that includes a wide variety of pos- tinine concentration in a patient with chronic kidney disease.128 In
sible causative conditions (including glomerulonephritis, vasculi- several other population-based epidemiologic studies, the annual
tis, and interstitial nephropathy) and involves an extraordinary incidence of ARF ranged from 20 to 187 cases/million (again,
array of cell-mediated and humoral mechanisms, discussion of depending on the operative definition of ARF used).15,129-131 If
which exceeds the scope of this chapter. these general observations are applied to the more economically
The pathogenesis of prerenal ARF is of greater direct rele- developed countries, which have a total population of approxi-
vance to the surgeon. Traditionally, prerenal ARF is, by defini- mately 1 billion people, it may be estimated that about 200,000
tion, the result of a reduction in ECV and a concomitant reduc- cases of ARF occur in this population each year. Unfortunately, lit-
tion in renal perfusion. A reduction in ECV is frequently accom- tle information is available on the incidence of ARF in the less
panied by a reduction in MAP, which can stimulate several developed countries.
humoral and neural processes by activating arterial and cardiac Third, current trends suggest that the incidence of and mortal-
baroreceptors. Increased activity in these baroreceptors stimu- ity attributable to ARF may actually be increasing, particularly in
lates the sympathetic nervous system and the renin-angiotensin- critically ill patients, despite advances in the understanding of
aldosterone system and triggers the release of arginine vaso- the pathophysiology of ARF and the development of new and
pressin from the posterior pituitary in an attempt to compensate improved methods for its treatment. One explanation for this
for any reduction in GFR. increase may be that ARF as a manifestation of single-organ dys-
At the level of the kidney, there are several mechanisms that may function is becoming less common, whereas MODS with associ-
play a major role in the development of prerenal injury, including ated ARF is becoming more common.132 In a multinational, mul-
(1) ischemia of the outer medulla, (2) activation of the tubuloglo- ticenter study carried out by the Beginning and Ending
merular feedback system (afferent arteriolar constriction), (3) Supportive Therapy for the Kidney (BEST Kidney) Investigators,
tubular obstruction from cell casts, (4) interstitial edema secondary it was estimated that ARF associated with admission to an ICU
to back-diffusion of fluid, (5) inflammatory response to cell injury develops in approximately 6% of critically ill patients worldwide.12
and local release of mediators, (6) disruption of normal cellular ARF was severe enough to warrant initiation of RRT in approxi-
adhesion to the basement membrane, (7) oxygen free radical–induced mately 70% of the patients studied.12 In other studies, the annual
apoptosis, and (8) phospholipase A2–induced cell membrane in- incidence of ARF severe enough to necessitate RRT has been esti-
jury. It must be kept in mind, however, that to date, most of these mated to range from 40 to 130 cases/million.12-14,132,133
mechanisms have been demonstrated to be operative only in ani- Fourth, large epidemiologic studies have identified a number of
mal models. Because such models bear limited resemblance to the risk factors for the development of ARF, including greater age,
clinical scenarios in which ARF develops in humans, the relevance male sex, preexisting illness, severe sepsis or septic shock, major
of these findings to human disease remains highly speculative. Even surgery (in particular, cardiac surgery), cardiogenic shock, hypo-
if these experimentally proven mechanisms are operative in humans, volemia, and exposure to various nephrotoxic drugs.12,13 Smaller
their hierarchy and their time sequence remain unknown, which cohort studies have shown that ARF is common in the setting of
makes the development of specific therapeutic targets for preven- MODS, specifically when there is concomitant acute circulatory,
tion and management a difficult task. pulmonary, and hepatic organ dysfunction.134-137
Fifth, although the studies cited above suggest that ARF may in
part be an expression of overall illness severity, there is evidence that
Epidemiology of Acute Renal Failure ARF, in and of itself, significantly and independently increases
As noted [see General Principles, Definition of Acute Renal mortality.138 The overall hospital mortality for patients with ARF
Failure, above], defining ARF can be problematic. Even so, sever- is estimated to be about 20%; however, the hospital mortality for

Acs0807 Acute Renal Failure

Recommended

Recommended

More Related Content

What's hot

What's hot (18)

Similar to Acs0807 Acute Renal Failure

Similar to Acs0807 Acute Renal Failure (20)

More from medbookonline

More from medbookonline (20)

Acs0807 Acute Renal Failure