DISEASE OF THE MONTH

Hospital-Acquired Acute Renal Failure

CHARLES R. NOLAN and ROBERT J. ANDERSON

Department of Medicine, University of Colorado Health Sciences Center and Denver Veterans Affairs Medical

Center, Denver. Colorado.

Acute renal failure (ARF) is the abrupt loss of renal function

sufficient to decrease urinary elimination of nitrogenous waste

(urea nitrogen and creatinine). Although there is consensus

about this general definition, few agree on the magnitude of the

rise in serum eneatinine necessary to ascribe a diagnosis of

ARF (1,2). These differences in definition plus variances in

methods of patient accrual, populations analyzed, and eatego-

rization of causes render development of a broad-based over-

view of ARF difficult. However. two generalizations about

contemporary ARF are compelling. First, ARF is predomi-

nantly a hospital-acquired disorder (1-3). Second, the high

mortality of patients with ARF is not explained entirely by

comonbid conditions. Recent data indicate that ARF per se

increases the risk of development of multiple nonrenal condi-

tions that lead to death and disability (4). Thus, ARF should not

always be considered a treatable condition that complicates

advanced disease. Together, these two generalizations prompt

this review, which focuses on the causes, diagnosis, preven-

tion, and management of hospital-acquired ARF.

Causes and Clinical Settings of Hospital-Acquired ARF

Categorization of the cause(s) of hospital-acquired ARF has

traditionally involved determining which general physiologic

mechanism (prerenal, postrenal, or intrarenal) is responsible

for the decline of glomerulan filtration (Figure 1). This method

has the advantage of providing a well accepted diagnostic

framework that guides the clinician to comprehensively eon-

siden most potential causes of deteriorating renal function ( 1 ,5).

Prerenal factors (e.g. , extracellulan fluid volume loss and/or

sequestration and impaired cardiac function) contribute to 30 to

60% of all cases of ARF. Postrenal factors (e.g., intra- or

extrarenal obstruction of urine flow) are much less frequently

encountered causes of hospital-acquired ARF ( 1 to 10%) but

are almost always amenable to therapy. When considering

renal causes of ARF, it is helpful to think of each renal

anatomic compartment (vasculature, glomeruli, intenstitium,

and tubules) as a potential contributor to the renal failure.

Although acute vascular (e.g. , atheroemboli, vaseulitis, throm-

bosis), glomerular (e.g. , glomerulonephritis), and interstitial

Correspondence to Dr. Robert J. Anderson, University of Colorado HealthSciences Center. Box B 180. 4200 East Ninth Avenue. Denver. CO 80262.

1046-6673/09()4-07 l0$03.00/0Journal of the American Society of Nephrology

Copyright 0 1998 by the American Society of Nephrology

(e.g. , allergic interstitial nephritis) processes occasionally

cause hospital-acquired ARF, the major cause is acute tubular

injury. This tubular damage is most often due to either is-

ehemia (e.g., prolonged prerenal insult) or a nephrotoxin.

Sometimes acute tubular injury occurs in the setting of pig-

mentunia (e.g. , myogbobinunia or hemogbobinuria).

A recent study by Liano and Pascual provides a reasonable

overview of the causes of hospital-associated ARF (3). This

experience was based on more than 740 eases of ARF that were

either referred to or occurred within 13 tertiary care facilities in

Madrid, Spain. Of these eases, 45% were attributed to acute

tubular necrosis, 21% to prenenal causes, 10% to postrenal

causes, 3% to renal vascular disorders, 3% to glomerulonephri-

tis, and 2% to acute interstitial nephritis (3). In the study by

Brivet ci a!. drawn from 20 French multidisciplinary intensive

care units (ICUs), the type of ARF was pnerenal in I 7%, renal

(usually acute tubular injury) in 78%, and postrenal in 5% (6).

From a more pragmatic standpoint, general hospital-ac-

quired ARF is usually encountered within a relatively narrow

context of settings. These settings include the postoperative

state, advanced cardiovascular disease, neoplastie disease, HIV

infection, multiple organ failure, systemic infection, and solid

organ transplantation. The hospital-acquired ARF that occurs

in these disparate settings is usually associated with one or

more of three renal insults, including prerenal events (extra-

cellular fluid volume defects and hemodynamie instability),

exposure to nephrotoxins, and sepsis.

The postoperative period is currently one of the most prey-

alent settings of ARF. For example, 27% of the 748 eases of

ARF reported by Liano and Pascual were encountered in the

postoperative setting (3). Older studies by Charlson et a!.

indicated that 25% of elective, noneardiac surgical procedures

were complicated by an acute rise in serum ereatinine of 20%

or greater (7). In 1 1 % of these patients, a 50% decline in

endogenous ereatinine clearance occurred (7). More recent

studies by Chertow ci’ a!. , using Veterans Affairs patient data-

bases, indicate that the development of ARF sufficient to

require renal replacement therapy occurs in 0.4 to 7.5% of

patients undergoing cardiac surgery and 0.6% of patients un-

dergoing general surgery, and is dependent on a number of

preoperative risk factors (8,9).

What underlies the relatively high frequency of ARF that

occurs in relation to elective surgical procedures? In many

eases, underlying comorbidity (diabetes mellitus, chronic hy-

pertension, vascular disease, congestive heart failure) leads to

diminished baseline GFR and reduced renal reserve (7-9).

With this background, the “surgical experience” appears to

Figure 1. Acute renal failure.

Hospital-Acquired ARF 71 1

potentially induce afferent arteriolar renal vasoconstrietion and

diminished GFR (10,1 1). If an additional renal insult is en-

countered, clinical ARF occurs (7-9). These additional renal

insults are often referred to as “second hits” and include

reoperation, sepsis, nephrotoxin exposure, circulatory/volume

deficits, and heart failure (7-9).

A high percentage of contemporary hospital-acquired ARF

occurs in patients in the ICU. For example, 27% of the 748

eases of ARF reported by Liano and Pascual were encountered

in the ICU (3), and the frequency of ARF in patients admitted

to ICUs ranges from 6 to 23% (reviewed in reference 1). In

most eases of ICU-acquired ARF, the ARF occurs in the

setting of multiple organ failure. For example, more than 90%

of cases of ICU-aequired ARF have failure of one or more

additional organ systems, and the failure of these other systems

nearly always precedes the development of ARF (reviewed in

reference 1). In the recent ICU experience of Brivet ci’ a!.,

failure of another organ system was nearly uniformly present in

patients with ARF (6). In all series of ICU-associated ARF,

hemodynamie instability, nephrotoxins, and sepsis are eon-

comitantly present in more than two-thirds of all patients

(1-3,6).

ARF is commonly encountered in patients with HIV infee-

tion (12). Valeri and Neusy found that more than half of 246

HIV-infeeted patients had one or more episodes of a rise in

serum ereatinine of 0.3 mg/dl or greater ( 1 2). The causes of

ARF in the HIV population are diverse and include prerenal

conditions, postrenal failure (due to either intratubular micro-

crystallization from sulfa drugs/protease inhibitors or ureterie

obstruction from lymphoma), and renal disorders, including

thrombotie mieroangiopathy, HIV-associated nephropathy,

gbomerulopathy, interstitial nephritis, and acute tubular injury

occurring in the setting of sepsis and/or nephrotoxins (12,13).

Patients with neoplastie disease are also at high-risk for

hospital-acquired ARF (1,14). The frequency of development

of ARF in patients with hematobogic malignancies may be up

to 40% in some series (14). Sepsis, tumor-lysis syndrome,

hyperealeemia, hyperunicemia, nephrotoxins, and prerenal fac-

tons are the predominant causes of ARF in patients with ma-

lignancies. Less commonly encountered causes include tumor

infiltration, obstructive uropathy, and glomerubopathy.

Two of the most common conditions predisposing to hospi-

tab-acquired ARF are sepsis and nephrotoxin exposure. A ease-

control study identified sepsis as the single factor associated

with the greatest risk of developing hospital-acquired ARF

(15), and sepsis was the most common factor (48% of eases)

predisposing to development of ICU-associated ARF in the

study of Brivet ci’ a!. (6). Not only is hospital-acquired sepsis

often linked to ARF, but community-acquired sepsis is also

commonly associated with ARF (I 6). The experience of

Rayner et a!. found that 24% of 239 patients with community-

acquired bacteremia doubled their serum ereatinine coneentra-

tions (16).

In every analysis, nephrotoxie agents have been found to

contribute to hospital-acquired ARF (1-4,17). The number of

potential nephrotoxins is large, and the mechanisms by which

nephrotoxins contribute to ARF are diverse (Figure 2). More-

over, new agents (e.g. , protease inhibitors, immune globulin,

tacrolimus) are continually being added to the ever-expanding

list of foods, plants, animal venoms, and diagnostic and then-

apeutic drugs capable of inducing ARF, emphasizing the need

for a comprehensive review of medication/exposure history in

each ease (1,17,18).

Diagnosis of Hospital-Acquired ARFThe time-honored approach to evaluating a patient with ARF

is to exclude prerenal and postrenal causes and then, if neces-

sary, initiate an examination to determine potential renal eti-

obogies. We favor a four-step approach to this process, as

outlined in Figure 3. In our experience, the cause(s) of ARF is

usually apparent after step 1 . A thorough review of the medical

record is mandatory to identify potential nephnotoxie drugs on

other insults, such as volume depletion, hypotension, radiocon-

trast studies, or surgical interventions. A careful historical and

physical examination for clues to volume status is imperative,

because prerenal azotemia is a correctable condition, and care-

ful volume repletion may be of value even in established ARF.

Occasionally, hemodynamie monitoring, i.e., noting changes in

cardiac output, capillary wedge pressure, or urine output in

response to a trial of either volume expansion or inotropie

agents, may be useful in the process of excluding prerenal

azotemia.

Urinalysis performed by the physician is usually a key tool

in the diagnostic evaluation of ARF. A normal urinalysis is

most compatible with pre- or postrenal forms of ARF. Numen-

ous pigmented granular casts or the finding of abundant tubular

epithelial cells helps support a diagnosis of isehemia/nephro-

toxin-induced ARF. The detection of heme-pigment by dip-

stick screening, which is out of proportion to the number of

erythrocytes on microscopic examination, suggests the pres-

ence of pigmentunia due to rhabdomyolysis on intravascular

hemolysis. Significant proteinuria, hematunia, on the finding of

red blood cell casts suggests an underlying gbomerubonephnitis

or vasculitis. White blood cell casts may be seen in the setting

of acute pyebonephritis, interstitial nephritis, or gbomerulone-

phritis. The finding of eosinophiluria by Hansel’s stain sug-

gests that the ARF is not due to acute tubular injury. However,

in the absence of systemic signs of an allergic reaction (fever,

rash, peripheral eosinophilia), the finding of eosinophiluria is

suggestive, but clearly not diagnostic, of drug-induced acute

NEPHROTOXIC

ACUTE RENAL FAiLURE

DextranMannitol

DiureticsInterleukinsCEIsAntihypertensive

agents

CyclosponineMitomycin CTacrolimusCocaineEstrogenQuinine

MethotrexateAcyclovirTniamtereneEthylene glycolProtease

inhibitors

GoldPenicillamineNSAIDsOthers

Multipleetiologies

AminoglycosidesCisplatinVancomycinFoscarnetPentamidineRadio contrast

agentsAmphotenicinHeavy metals

IV immuneglobulin

DextranMaltoseSucroseMannitol

NSAIDs

Radiocontrastagents

Amphotenicin

CEIsAngiotensin II

receptorantagonists

Multipleetiologies

Multipleetiologies

712 Journal of the American Society of Nephrology

Figure 2. Nephnotoxic acute renal failure.

interstitial nephritis ( I 9). Moreover, the finding of eosinophi-

lunia in a patient with ARF after an arteriographie procedure or

in patients with severe peripheral vascular disease supports a

diagnosis of atheroembolic renal disease, which should prompt

investigation for systemic evidence of atheroembolism (livedo

reticulanis, purple toes, or Hollenhonst plaques) (see reference

I ).

Urinary diagnostic indices have become a standard tool in

the evaluation of patients with acute azotemia (Figure 4) (re-

viewed in reference 1 ). Patients with oliguria due to prerenal

azotemia tend to have intact tubular function, whereas patients

with established acute tubular injury typically have urine mdi-

ces compatible with diminished tubular reabsorption of Se-

bected solutes and water ( I ). However, the term “urinary diag-

nostie indices” is a misnomer because urinary electrolyte

results are often indeterminate, and the results must always be

interpreted in light of the clinical situation. For example, pa-

tients receiving diuretic therapy, i.e. , patients with either bi-

earbonaturia or an osmotic diuresis induced by glucose, urea,

on nadiocontrast agents, and patients with primary adrenal

insufficiency may have prenenal ARF with elevated FENa de-

spite profound volume depletion. Likewise, patients with

chronic renal insufficiency on interstitial disease may be unable

to conserve sodium despite volume depletion with superim-

posed prerenal azotemia. Also, low urinary indices do not

always indicate reversible prerenal azotemia. For example,

early in the course of intrinsic renal damage due to radiocon-

trast agents, rhabdomyolysis, or sepsis, urinary indices often

suggest intact tubular function. Urinary diagnostic indices are

not reliable in patients with urinary tract obstruction, gbomer-

ubonephnitis, or acute interstitial nephritis, and these disorders

must be excluded on other grounds.

Prevention of Hospital-Acquired ARFBecause contemporary hospital-acquired ARF is associated

with substantial mortality and morbidity, major efforts should

be directed toward prevention. Potential preventive strategies

are outlined in Table I . A high percentage of hospital-acquired

ARF occurs in the context of nosocomial infection with sepsis

(1-3,15). Thus, although not always germane to the consultant

nephrologist, maneuvers designed to prevent hospital-acquired

infection (Table 1 ) are common sense, low-cost, low-tech

maneuvers that potentially decrease the frequency of sepsis-

related ARF.

One or more nephrotoxins potentially contribute to at least

25% of all cases of hospital-acquired ARF ( I -6,15-17,20,21).

The best strategy is avoidance. For example, there are currently

multiple antimicrobial alternatives to potentially nephrotoxie

aminoglycosides. Although recent studies suggest low nephro-

toxic risk from nonsteroidal anti-inflammatory drugs in the

postoperative state (22), the potential renal vasoconstrietive

effect of these agents should be kept in mind in selected

patients, such as those with sepsis, heart failure, cirrhosis,

nephrosis, volume depletion, and hypoalbuminemia (1,20).

rSTEP 1� STEP 2 � STEP 3� � STEP�

URINARY DIAGNOSTIC INDICESIN ACUTE RENAL FAILURE

PRERENAL RENAL

Hyaline casts +- Urinalysis

> 1.020 +- SpecificGravity

> 500 �- Uosmol (mosmol/kg H2O)

< 20 �- UNa (mEq/L)

<1 �- FENa(%)

<7 4- FEuricacid(%)

<7 4- FElithium(%)

-3 Abnormal

-3 -.1.010

-+ >300

-3 >40

-3 >2

-4 >15

-). >20

Hospital-Acquired ARF 713

Figure 4. Urinary diagnostic indices in acute renal failure.

STEPWISE APPROACH TO

DIAGNOSIS OF ACUTE RENAL FAILURE

#{149}History

#{149}Recordreview

#{149}Physical examination

#{149}Uninarybladder catheterization

(if oligo-anuric)

#{149}Uninalysis

#{149}Consider urinary

diagnostic indices

(Table 4)

#{149}Considerif further

evaluation needed to

exclude urinary tract

obstruction (e.g., ultrasound)

#{149}Consider ifmore data

needed to assess

intravascular volume/

cardiac output status

(e.g., invasive monitoring)

#{149}Consider if additional

blood tests needed

(e.g., tests for

gbomerubopathy, and/or

plasma cell dyserasia

#{149}Considen if status of

renal vasculature

needs evaluation

(e.g., isotope scans,

Doppler flow studies,

angiography)

‘Consider selectedtherapeutic trials

(e.g., volume

expansion, inotropic

agents, reliefof

obstructive uropathy)

‘Consider renal biopsy

#{149}Consider empiric therapy

for suspected diagnoses

Figure 3. Stepwise approach to diagnosis of acute renal failure.

Many nephrotoxins exert dose-dependent toxicity. This ap-

pears particularly true for radiocontrast agents, aminoglyco-

sides, cisplatin, and amphotericin B. Thus, for nadiocontrast

agents, carefully limiting the dose given appears to be the best

means of prevention of nephrotoxieity (23). Alterations in

dosing strategy may also affect nephrotoxieity of selected

agents such as the aminoglycosides. Animal studies demon-

strate equivalent antimicrobial efficacy with lower renal tissue

levels and less nephrotoxicity when aminoglycosides are given

once daily as opposed to multiple times a day. Meta-analysis of

human studies also demonstrates a small effect of single daily

dosing of aminoglycosides to decrease nephrotoxieity (20,24).

Formulation and structure modifications of potential nephro-

toxins might also reduce ARF. The two best examples are

nonionie contrast agents and lipid emulsified amphotericin B,

which may be associated with reduced nephrotoxieity (25,26).

In selected eases (e.g. , radiocontrast agents, amphotericin B,

cisplatin, and drugs that induce erystalluria) (Figure 2), modest

714 Journal of the American Society of Nephrology

Table I. Potential strategies to prevent hospital-acquired

ARF

Diminish risk of nosocomial infection

conservative use and rapid removal of intravascular and

intravesiculan catheters

cautious use of antibiotics based on culture data with

automatic stop-orders to ensure brief usage

aspiration pneumonia precautions (elevated head of bed,

attention to gastric residual volume, conservative use

of sedatives and hypnotics)

meticulous hand-washing

Prevention of nephrotoxieity

avoidance of known nephrotoxins

dosing modification of selected agents

formulation modification

extracellular fluid volume expansion

notification systems that allow early intervention

Pharmacologic manipulations

extracellular fluid volume expansion

renal vasodilatons

calcium channel blockers

growth factors

Pre- and postsungieal interventions

preoperative hemodynamic optimization

selected pharmacologic manipulation

increase tissue oxygen delivery to supranormal levels in

selected eases

volume expansion appears on the basis of substantial retro-

speetive and anecdotal observations to protect against the de-

vebopment of nephrotoxieity (17,20).

Another approach to prevention of nephrotoxin-induced

ARF is the use of modern information systems that link labo-

ratory and pharmacy databases (27). In a recent prospective

study, electronic mail notification of clinicians regarding mild

rises in serum ereatinine in their patients on either a potential

nephrotoxin or a nenally excreted agent resulted in a faster

response time to stop the drug and lessened the frequency of

development of severe ARF (27). This low-cost method could

be even more effective in the context of a more powerful

intervention (e.g. , mandatory clinician notification and/or au-

tomatie drug stop order).

Pharmacologic manipulations to prevent hospital-acquired

ARF, with the exception of modest volume expansion, have, in

general, not met with great success. From a medical perspec-

tive, use of furosemide, mannitol, dopamine, and atnial natni-

uretic peptide to prevent contrast-associated ARF has been

disappointing (28,29). From a general surgical perspective,

intraopenative diltiazem and alpha-adrenengic antagonists can

reduce the modest intnaoperative fall in GFR that accompanies

cardiac surgery, but these maneuvers have not yet been dem-

onstrated to prevent ARF (10, 1 1 ). To date, the effective use of

low-dose dopamine to prevent ARF in several operative set-

tings, including intrarenal aortic clamping, elective major vas-

eular surgery, and biliary tract surgery, has not been demon-

strated (reviewed in reference 1).

One pharmacologic intervention of great interest and prom-

ise in the prevention of ARF is the use of growth factors. To

date, substantial experimental evidence on the use of growth

factors to accelerate recovery from ARF is available. In the

only reported study earned out in humans (n = 54), in which

a growth factor has been used, insulin-like growth factor I

exerted a modest but significant effect to prevent the fall in

GFR in high-risk supranenal aortie and renal artery surgery

(30). For example, a smaller percentage of treated patients

(22%) had a postoperative decline in ereatinine clearance than

did untreated patients (33%). Whether such therapy prevents

postoperative ARF, however, remains to be determined.

With regard to high-risk surgical candidates, Berlauk and

colleagues found that preoperative optimization of hemody-

namie parameters, guided by Swan-Ganz catheterization, was

helpful in patients undergoing limb salvage vascular surgery

(3 1). In this small prospective study, mortality, graft loss, and

frequency of development of postoperative ARF were dimin-

ished by the optimization procedure (3 1). Confirmation of

these results and delineation and definition of high-risk popu-

lations for which this strategy is potentially helpful are needed.

With regard to other critically ill patients, it has been sug-

gested that fluid volume and pharmacologic therapy designed

to increase cardiac index and delivery and consumption of

oxygen to supranormal levels can prevent tissue hypoxia. From

a very simplified perspective, this enhanced oxygen delivery

might protect end organs from isehemie injury. At least five

prospective randomized trials have been undertaken to test this

hypothesis (outlined in reference 1 ). Improved survival and

decreased frequency of ARF have been seen in some, but not

all, studies. Compelling data that this strategy will have a major

impact on prevention of hospital-acquired ARF remain to be

established.

Treatment of Hospital-Acquired ARFTreatment of hospital-acquired ARF starts with the provi-

sion of excellent general supportive care. The key aspects of

supportive care include careful, sequential clinical and bio-

chemical monitoring to detect complications; frequent surveil-

lance of the medication lists to eliminate unnecessary drugs

and to adjust, when appropriate, the dosage of drugs excreted

by the kidneys to reduce drug-associated morbidity; minimi-

zation of the use of invasive lines to avoid nosocomial infec-

tions; and provision of adequate nutrition to optimize general

health and recovery. These aspects of ARF care have been

reviewed in detail elsewhere and will not be discussed in this

review. Recent advances in two other areas of ARF therapy,

i.e. , pharmacologic manipulations to attenuate ARF and the use

of renal replacement therapy, have drawn some controversy

and thus merit further discussion.

Pharmacologic manipulation to either attenuate the severity

of ARF on to hasten recovery have centered on mannitol, loop

diuretics, dopamine, and atrial natriuretic peptide. To date,

randomized trials have failed to establish that mannitol pre-

vents postoperative ARF (32). On the basis of clinical experi-

Hospital-Acquired ARF 715

enee and retrospective studies, however, many experienced

nephrologists continue to use mannitol in an effort to attenuate

ARF, especially pigment-associated ARF (I). With regard to

loop diuretics, prospective randomized trials, undertaken in

patients with advanced, well established ARF, fail to demon-

strate a beneficial effect on duration of azotemia, dialysis

requirement, or mortality (32,33). Although some of these

studies demonstrate that loop diuretics increase urine output, it

is not clear whether oligurie ARF patients with a loop diuretic-

induced increase in urine flow have the same, more favorable

prognosis than do ARF patients that are spontaneously nono-

liguric. Nonetheless, because of the generally low complication

rate associated with loop diuretics, many clinicians administer

loop diuretics to patients with ARF who continue to be oliguric

despite optimization of renal perfusion and exclusion of post-

renal factors.

Low-dose (<3 to 5 p.g/kg per mm) dopamine is widely used

in ARF, especially in oligurie patients. A large study, using

each patient as his or her own control, has clearly established

that low-dose dopamine can render many oligurie patients

nonoliguric (34). This nonoligurie state, however, does not

necessarily appear to reflect a rise in GFR. In a recent analysis

of 256 patients with ARF in which dopamine was administered

nonrandomly at the discretion of the treating physician, the

relative risk of death or dialysis associated with low-dose

dopamine administration, after adjustment for several van-

ables, was 0.95 (95% confidence interval, 0.58 to 1.58; refer-

ence 35). Because there was no statistically significant differ-

ence in outcome in patients treated with low-dose dopamine,

the authors concluded that the routine use of low-dose dopa-

mine in ARF should be discouraged until a prospective, ran-

domized, placebo-controlled trial establishes its safety and

efficacy. Other researchers, however, believe that the docu-

mented potential diuretic effect and nonthreatening side-effect

profile of low-dose dopamine mandate its continued use, es-

pecially in oligurie ARF.

Atnial natriuretic peptide is known to increase GFR by

dilation of afferent arterioles and constriction of efferent arte-

rioles. Several experimental and uncontrolled clinical trials

suggest clinical benefit from both intranenal and intravenous

atrial natriuretic peptides in established ARF. In a recent mul-

ticenter, randomized, double-blind, placebo-controlled clinical

trial of anaritide in 504 critically ill patients with acute tubular

necrosis, patients received a 24-h infusion of either anaritide

(0.2 �tg/kg per mm) on placebo (36). The primary end point

was dialysis-free survival for 2 1 d after treatment. The rate of

dialysis-free survival was not significantly different between

the two groups (47% in the placebo group and 43% in the

ananitide group, P = 0.35). However, in a subgroup of 120

patients with oliguria, dialysis-free survival was 8% in the

placebo group (five of 60 patients) and 27% in the anaritide

group ( 16 of 60 patients, P = 0.008). Anaritide-treated patients

who became nonoliguric after treatment seemed to benefit the

most. A subsequent, similarly designed study that enrolled only

patients with oligunic acute tubular necrosis failed to demon-

strate a benefit of anaritide administration. Drug company

development of ananitide, however, has been suspended. The

suspension was prompted by a low probability that a positive

outcome could be obtained with respect to the primary clinical

end point of dialysis-free survival (Robin Allgnen, personal

communication).

There are several arguable issues regarding renal replace-

ment therapy (RRT) for ARF. These issues include: when to

begin, what membrane and modality to use, and what level of

intensity is sufficient? With regard to commencement of RRT,

there has been a general trend in recent years toward earlier

initiation. This aggressive approach does not necessarily

equate with an improvement in therapy. To our knowledge, no

study in the modern era has adequately addressed timing of

initiation of RRT. One study of 132 critically ill ARF patients

found an inverse relationship between serum eneatinine con-

centration at initiation of hemodialysis and mortality (37).

Although these data are subject to at least two interpretations

(early dialysis is deleterious versus patients dialyzed earlier are

sicker with more fluid overload and electrolyte disturbances),

they do raise concerns. Moreover, intermittent hemodialysis

may be associated with hemodynamie instability, which, with

potential impairment of renal autoregulatory responses that can

occur in ARF, may lead to enhanced isehemie injury (38). Few

would argue that volume overload and hypenkalemia refractory

to medical therapy, as well as uremie symptoms and compli-

eations, merit RRT. As far as the level of azotemia is eon-

cerned, little data support prophylactic RRT for blood urea

nitrogen (BUN) levels <200 mg/dl (37).

The choice of RRT modality is also a subject of debate. One

issue involves the type of membrane. It has recently become

apparent that biocompatibility of dialysis membranes may be

an important determinant of survival and recovery of renal

function in patients with ARF (39,40). The polysacchanide

structure of cellulosie (bioincompatible) membranes provides a

trigger for complement activation via the alternative pathway,

which leads to the liberation of anaphylotoxins and activation

of leukocytes. The potential induction of a systemic inflamma-

tory reaction during each dialysis treatment with bioincompat-

ible dialysis membranes could conceivably cause further is-

ehemia or inflammatory changes within the previously injured

renal microcireulation.

In a recent study of 72 patients with ARF, patients were

randomized to intermittent dialysis treatment with either bioin-

compatible Cuprophane dialysis membranes, which activate

the complement system and leukocytes, on to dialysis with a

biocompatible membrane composed of polymethyl methacry-

late, which has a less marked effect on complement and leu-

kocytes (39). The two dialysis membranes chosen for the study

had similar clearance and ultrafiltration characteristics and the

patient groups were similar. Fifty-seven percent of patients on

dialysis with biocompatible membranes survived, compared

with 37% of those dialyzed with Cuprophane membranes (P =

0. 1 1 ). Recovery of renal function occurred in 62% of those

dialyzed with a biocompatible membrane, compared with 37%

of those who underwent dialysis with Cuprophane membranes

(P = 0.04). The time to recovery of renal function after

initiation of dialysis was also significantly shorter in the bio-

compatible membrane group compared with the Cuprophane

716 Journal of the American Society of Nephrology

group: five dialysis treatments over I 1 d versus 17 dialysis

treatments over 33 d, respectively. Subgroup analysis revealed

that the benefits of biocompatible membrane dialysis were

evident only in patients who were nonoligunic before the mi-

tiation of dialysis. These results suggest that use of the bio-

compatible dialysis membrane increases the likelihood of me-

covery of renal function and survival of patients with ARF.

Other studies have confirmed and extended these observations

to include other biocompatible dialysis membranes, including

polysulfone and polyacrylonitnile membranes (40). However,

this issue may not be quite as clear-cut as these two studies

suggest. For example, in the most recent prospective random-

ized study (ii = 1 33) of patients with severe ARF who were

concomitantly undergoing mechanical ventilation and contin-

uous, high-flux dialysis, the type of membrane did not influ-

ence survival in those patients undergoing continuous high-

flux dialysis (41).

The modality of RRT for ARF is also debatable, with

proponents of both intermittent hemodialysis (IHD) and con-

tinuous modes of RRT (CRRT) (42,43). Surveys of nephrolo-

gists in the United States reveal that IHD is the most common

modality used for treating ARF, followed by CRRT and then

penitoneal dialysis (43). The IHD modality has been in wide-

spread use for the past four decades for the treatment of ARF.

In recent years, the development of bicarbonate-based dialy-

sate and volumetrically controlled machines for precise control

of ultrafiltration has made IHD a safer procedure in the h�mo-

dynamically unstable ICU patient with multiorgan failuk. In

most centers in the United States, the standard approach to IHD

for ARF uses moderate blood flow rates (200 to 250 ml/min)

and dialysate flow rates of 500 mllmin. In contrast to the

situation for treatment of chronic renal failure, there are no

well established guidelines for defining IHD adequacy in ARF.

Dialysis frequency and intensity are usually determined em-

pinically based on the patient’s volume status, associated elm-

ical events, BUN levels, and other blood chemistries.

The most common reasons cited for preferential choice of

IHD are efficacy, ease of use, and familiarity of the dialysis

and ICU nursing personnel with the procedure. CRRT tends to

be reserved for patients who are hemodynamically unstable or

hypereatabolie. or for those with large fluid burdens due to

aggressive nutritional support (42). The minority of nephrobo-

gists who administer peritoneal dialysis cite the absence of a

need for anticoagulation and better hemodynamie stability as

the main reasons for using this technique. For rapid correction

of life-threatening electrolyte or acid-base disorders, IHD is

probably the best choice, given both the efficacy and rapidity

of response. On the other hand, if fluid removal is the primary

objective, hemodynamic instability may limit aggressive ultra-

filtration during a 3- to 4-h IHD treatment. Thus, for hyper-

catabolic patients receiving nutritional support with a high

nitrogen content, even daily hemodialysis may provide made-

quate urea clearance. CRRT modalities, especially hemofiltra-

tion techniques that combine dialysis with significant ultrafil-

trate volumes to enhance solute clearances, may provide the

more intensive treatment necessary to control azotemia in

catabolic ICU patients receiving high protein content nutrition

(42). The major disadvantage of CRRT is the need for well

trained ICU nursing personnel to perform the procedure. A

lack of detailed understanding of the CRRT flow sheets and the

computations necessary to determine replacement fluid vol-

umes can lead to disaster due to significant volume depletion.

Occasionally, lactate-based replacement fluid may result in

lactate accumulation and worsening acid-base status if the

patient has liver disease and is unable to metabolize lactate as

a source of base. On-site formulation of custom bicarbonate-

containing replacement fluid is costly and time consuming.

Ambulation and physical therapy may be difficult while the

patient is receiving CRRT.

The issue of dialysis intensity in ARF also remains contro-

versial. In one study, patients with ARF were matched by

etiology and randomly assigned to either an intensive treatment

group (dialysis to maintain BUN <60 mg/dl and ereatinine <5

mg/dl) or to a nonintensive group (dialysis to maintain BUN

< 100 mg/dl and creatinine <9 mg/dl; reviewed in reference

37). Seven of 17 (41 %) patients in the intensive group survived

compared with nine of 17 (53%) in the nonintensive group.

Complications such as hemorrhage (24% versus 59%) and

septicemia (47% versus 65%) were less common in the inten-

sive treatment group. Although none of the differences be-

tween groups reached statistical significance, this study has

been criticized because of insufficient power to detect a dif-

ference in survival (37). It has been postulated that a random-

ized clinical trial capable of identifying an absolute risk redue-

tion of 10% would require a sample size in excess of 750

matched patients (37). In general, once RRT is initiated, most

nephrologists aim to keep BUN and serum creatinine at levels

<80 to 100 and 8 to 10 mg/dl, respectively.

Outcome of Hospital-Acquired ARFThe outcome of hospital-acquired ARF depends on the site

(ward or ICU), comonbidity, cause, and severity of the renal

failure. As a general estimate, contemporary survival of hos-

pital-aequired ARF severe enough to be dialyzed averages 10

to 50% ( I ). The development of even mild hospital-acquired

ARF sufficient to cause a 25% increase in serum creatinine to

at least 2 mg/dl increased mortality fivefold in a recent case

control cohort analysis of contrast-associated ARF (4).

New developments have been reported in three areas with

regard to ARF outcome. First, some analyses suggest that the

outcome of severe hospital-acquired ARF, although generally

dismal, may be improving. An excellent retrospective study

found that ICU-associated ARF is associated with significantly

lower mortality in the more modern era versus two decades ago

despite comparable or more severe comorbidity (44). In the

Mayo Clinic study, there was a 20% increase in hospital

survival and a 9% increase in 1-yr survival when ICU patients

with ARF who required dialysis from the period 1977 to 1979

were compared with comparable patients from the period 1991

to 1992 (44). Second, substantial effort is being placed on the

application of existing severity of illness and outcome predie-

tion models, as well as the development of new models, to

patients with ARF (reviewed in references I and 45). These

prediction models are useful to stratify and assign patients for

Hospital-Acquired ARF 717

prospective studies, as well as to compare risk-adjusted out-

comes across several sites. However, to date, they remain

insufficiently predictive to be routinely used in clinical deci-

sion-making with regard to level of care in many cases.

Finally, reasonable cost-effectiveness analyses are being

done regarding RRT in critically ill patients with hospital-

acquired ARF (46). A recent prospective cohort study from

five geographically diverse teaching hospitals included 490

patients with ARF requiring dialysis (46). Median survival was

32 d, and 27% survived 6 mo. Survivors were dependent for at

least one activity of daily life (bathing, moving, toileting,

feeding, or dressing), but 62% rated their quality of life as

good. The estimated cost per quality-adjusted life-year saved

by initiating dialysis was $274, 100 for the 103 patients in the

worst prognostic category and $61 ,900 for the 94 patients in

the best prognostic category. These costs somewhat exceed

$50,000 per quality-adjusted life-year, which has been arbi-

trarily defined as the threshold for cost-effective care.

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