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The Patient with Acute Kidney Injury

Patricia Khalil, MDa, Preethi Murty, MDa,Paul M. Palevsky, MDa,b,*

aRenal-Electrolyte Division, University of Pittsburgh School of Medicine,

A-919 Sciafe Hall, 3550 Terrace Street, Pittsburgh, PA 15213, USAbRenal Section, VA Pittsburgh Healthcare System, Room 7E123 (111F-U),

University Drive Division, Pittsburgh, PA 15240, USA

During the past half decade there has been a paradigm shift in the view of

acute kidney disease that has resulted in a change in the nosology for these

conditions. Acute renal failure (ARF) is generally defined as a sudden loss of

kidney function, occurring over a period of hours to days, manifested by

accumulation of creatinine, urea, and other metabolic waste products

(azotemia) and often accompanied by reductions in urine volume (oliguria)with associated salt and water retention. It has been increasingly recognized,

however, that even small decrements in renal function, changes that are in-

sufficient to be categorized as organ failure, are associated with increased

morbidity and mortality [1–3]. For this reason the term ‘‘acute kidney in-

jury’’ (AKI) has been adopted to recognize the importance of the broader

spectrum of acute kidney disease. In this article the term ‘‘acute kidney

injury’’ (AKI) is used to refer to the entire spectrum of acute kidney disease,

irrespective of etiology; the term ‘‘acute renal failure’’ (ARF) is reserved for

severe organ failure requiring specific supportive care.

Definition and staging

The reported incidence of AKI varies widely, depending on the definition

used and specific clinical setting. The definitions used in clinical trials and

epidemiologic studies have varied widely, ranging from small changes in

serum creatinine levels to severe azotemia, oliguria, or the need for renal

* Corresponding author. Renal Section, VA Pittsburgh Healthcare System, Room 7E123

(111F-U), University Drive Division, Pittsburgh, PA 15240.

E-mail address: [email protected] (P.M. Palevsky).

0095-4543/08/$ - see front matter. Published by Elsevier Inc.

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replacement therapy (RRT) [1,4]. This lack of a universally recognized

definition of AKI has significantly limited progress in understanding its ep-

idemiology and treatment. The adoption of a uniform definition and classi-fication system that can be readily implemented across multiple clinical

settings has been recognized as a necessary prerequisite for clinical advances

[5]. Such a definition would facilitate patient selection and the standardiza-

tion of end points in clinical trials and epidemiologic studies.

In 2002, the Acute Dialysis Quality Initiative group proposed the RIFLE

criteria as interim consensus criteria for the definition and staging of AKI

(Table 1). The acronym RIFLE defines three grades of increasing severity

of acute renal dysfunction (risk, injury, and failure; R, I and F, respectively)

on the basis of graded changes in serum creatinine or urine output and twooutcome variables (loss and end-stage kidney disease; L and E, respectively)

based on the duration of loss of kidney function [6]. Risk, injury, and failure

are defined as increases in serum creatinine levels of 50%, 100%, or 200%,

respectively, or oliguria for 6, 12, or 24 hours, respectively (see Table 1).

Loss is defined as ARF persisting for more than 4 weeks, and end-stage kid-

ney disease is defined as renal failure persisting for more than 3 months.

These criteria have been shown to correlate with clinical outcomes across

multiple clinical settings [7–13].

More recently, the Acute Kidney Injury Network (AKIN), an interna-tional consortium of renal and critical care societies, endorsed the concept

of the RIFLE criteria with minor modifications [5]. In a consensus

Table 1

RIFLEa and Acute Kidney Injury Network (AKIN) staging criteria for acute kidney injury

RIFLE stage

AKIN

stage Serum creatinine criteria Urine output criteria

Risk 1 Increase in serum creatinine of

1.5- to two-fold from baseline

(RIFLE and AKIN)) or increase

in serum creatinine of R 0.3 mg/

dL (AKIN)

! 0.5 mL/kg/h for 6 h

Injury 2 Increase in serum creatinine of

two- to threefold from baseline


Failure 3 Increase in serum creatinine

of more than threefold from

baseline or a serum creatinine

of O 4 mg/dL with an acute rise

of R 0.5 mg/dL


or anuria for 12 h

Loss Persistent renal failure for O 4 wk

End-stage

renal disease

Persistent renal failure for O 3 mo

a RIFLE defines three grades of increasing severity of acute renal dysfunction (risk, injury,

and failure; respectively R, I, and F) on the basis of graded changes in serum creatinine or urine

output and two outcomes variables (loss and end-stage kidney disease, L and E, respectively)

based on the duration of loss of kidney function.

240 KHALIL et al



conference held in 2005, a workgroup convened by AKIN proposed the

term ‘‘acute kidney injury’’ in place of ‘‘acute renal failure’’ to encompass

the entire spectrum of acute kidney dysfunction. The use of this terminologyacknowledges that, despite disparate causative factors, most acute declines

in kidney function are secondary to injury that leads to functional or struc-

tural changes in the kidney. They further argued that the word ‘‘failure’’

reflects only one end of the spectrum of clinical conditions that comprise

AKI [5].

The AKIN workgroup defined AKI as a reduction in kidney function

occurring over no more than 48 hours manifest by an absolute increase

in serum creatinine level of 0.3 mg/dL (25 mmol/L) or more or a relative in-

crease in serum creatinine level of 50% or more; or documented oliguria of less than 0.5 mL/kg/h for more than 6 hours despite adequate fluid resus-

citation [5]. The major changes in this definition over the original RIFLE

criteria are the addition of an absolute change in serum creatinine of

0.3 mg/dL (25 mmol/L) or more and the specification that the decline in kid-

ney function must occur over no more than 48 hours. The workgroup also

proposed staging criteria (see Table 1) based on the RIFLE criteria with the

following modifications: AKI stage 1 is defined using the same criteria as

RIFLE-R, with the addition of the absolute change in serum creatinine

level of 0.3 mg/dL (25 mmol/L) or more; AKI stages 2 and 3 are identicalto RIFLE-I and -F, respectively; and the RIFLE-L and -E categories

were removed from the staging system but were retained as outcomes.

In addition, all patients requiring RRT for AKI are included in AKI

stage 3.

Although the RIFLE and AKIN criteria provide a standardized nomen-

clature for the definition of AKI, their dependence on serum creatinine level

and urine output are significant weaknesses. Changes in serum creatinine

level lag behind the development of renal injury and associated changes

in renal function [14,15]. For example, despite an abrupt fall in glomerularfiltration rate (GFR) from normal to nearly zero, the serum creatinine con-

centration may not rise significantly for 1 to 2 days. The serum creatinine

concentration also may be aff ected by changes in volume status, with acute

increases blunted by hemodilution [3]. Although decreases in urine output

may represent AKI, oliguria may reflect transient hemodynamic changes

rather than true renal injury. In addition, not all AKI is oliguric, and the

actual volume of urine output may vary with diuretic administration

[16,17].

In the future the diagnosis of AKI probably will be based on changes inbiomarkers of cellular injury rather than on purely functional criteria. Sev-

eral candidate biomarkers are under evaluation for the diagnosis of AKI,

including neutrophil gelatinase–associated lipocalin [18–21], kidney injury

molecule-1 [22–26], and interleukin-18 [27,28]. Although these molecules

seem promising, further validation is required before they can be applied

in clinical practice.

241THE PATIENT WITH ACUTE KIDNEY INJURY



Epidemiology

Although AKI is a common clinical problem, its epidemiology is poorly

characterized. Its reported incidence depends on both the precise population

studied and the definition of AKI used. Several studies have used large ad-

ministrative databases to explore the epidemiology and outcomes of AKI in

hospitalized populations [29–31]. In each of these studies, AKI was defined

based on International Classification of Disease (ICD)-9 coding. Using the

2001 National Hospital Discharge Survey, AKI was diagnosed in 1.9% of

hospitalizations, with ARF requiring RRT present in 7.5% of these cases

[29]. Hospital mortality was 21.3% in patients who had AKI, compared

with only 2.3% in patients not identified as having AKI. In a similar anal-

ysis using the Medicare 5% Beneficiary Sample, AKI was coded in 2.4% of

hospital discharges between 1992 and 2001 with a progressive increase in the

incidence of AKI during of approximately 11% per year over the 10 years

studied, from 14.6 cases per 1000 discharges in 1992 to 36.4 cases per

1000 discharges in 2001 [30]. The hospital mortality rate associated with a di-

agnosis of AKI was 32.9%, compared with 4.6% in patients without a diag-

nosis of AKI. Similar trends also were observed in an analysis of the

National Inpatient Sample for years 1988 to 2002 [31]. The rates of AKI in-

creased from 0.4% of hospital discharges in 1988 to 2.1% in 2002 with the

rates of AKI requiring RRT increasing from 0.03% of hospital discharges in

1998 to 0.2% in 2002. During the same years the mortality associated with

AKI fell from 40.4% to 20.3%, a reduction of almost 50%.

Although these three studies provide important insights into the epidemi-

ology of AKI, they must be interpreted with considerable caution. Valida-

tion studies have demonstrated specificity rates for ICD-9 coding for AKI

of 97% to 99%, but reported sensitivity rates are between 17% and 29%,

with an upward drift over time [29,32]. Thus, these studies may underesti-

mate the true incidence of AKI by a factor of four- to sixfold. In addition,

it is possible that a portion of the observed increase in incidence over time

reflects changes in coding rather than a true increase in the incidence of

AKI.

Despite these caveats, qualitatively similar results were observed in an ep-

idemiologic assessment of AKI in the Kaiser Permanente of Northern Cal-

ifornia Health System [33]. In this study, AKI was identified using electronic

searching of laboratory data to identify patients who had increases in serum

creatinine concentration. Between 1996 and 2003, the incidence of AKI not

requiring dialysis increased from 323 to 522 cases per 100,000 person-years,

whereas cases of ARF requiring dialysis increased from 19.5 to 29.5 cases

per 100,000 person-years.

The incidence of AKI is significantly greater in critically ill patients than

in the general hospitalized population. In a multinational, prospective, ob-

servational study of 29,269 critically ill patients in 54 hospitals in 23 coun-

tries, the period prevalence of AKI was 5.7%, with 72.5% of these patients

242 KHALIL et al



requiring RRT [34]. ICU mortality was 52%, with an additional 8% mor-

tality in the hospital after ICU discharge for an overall hospital mortality

of 60.3%. Among surviving patients, 13.8% continued to require RRT atthe time of hospital discharge [34].

Etiologic classification of acute kidney injury

AKI can be divided broadly into three categories: prerenal, intrinsic, and

postrenal (Fig. 1). Diff erentiation into these three categories is clinically use-

ful, because they diff er in their pathophysiology and management.

Prerenal acute kidney injury

Prerenal AKI (also called ‘‘prerenal azotemia’’) represents a functional

response to renal hypoperfusion that is not associated with structural renal

injury. The defining feature of prerenal azotemia is that restoration of nor-

mal renal perfusion results in a prompt recovery of renal function. It is crit-

ical, however, to recognize that prerenal azotemia increases the risk of, and

may be a precursor to, the development of intrinsic AKI and that sustained

renal hypoperfusion that is initially manifest as prerenal AKI may result in

irreversible renal injury.The pathophysiology of prerenal azotemia represents an extension of the

normal renal response to volume depletion [35]. Decreased renal perfusion

or eff ective arterial volume depletion is characterized by activation of the

sympathetic nervous system and the renin-angiotensin system. Increased

angiotensin II levels vasoconstrict the postglomerular (eff erent) arteriole;

although angiotensin II also acts on the preglomerular (aff erent) arteriole,

its vasoconstrictive eff ects are opposed by vasodilatory prostaglandins. The

predominance of postglomerular vasoconstriction maintains intraglomeru-

lar capillary pressure close to normal, sustaining a nearly normal GFR.Hemodynamic factors, increased levels of angiotensin II, and activation of

the sympathetic nervous system increase proximal tubular sodium and water

reabsorption. Aldosterone and vasopressin (antidiuretic hormone) secretion

Fig. 1. Classification of the causes of acute kidney injury (AKI).




also are stimulated, resulting in increased sodium, urea, and water reab-

sorption in distal nephron segments. Thus, the physiologic response to

modest degrees of renal hypoperfusion is maintenance of GFR with theelaboration of concentrated urine with a low sodium concentration.

In patients who have prerenal AKI, these regulatory mechanisms are

unable to compensate fully for more severe degrees of hypoperfusion. As

a result, the GFR declines. The classic urinary features of prerenal azotemia,

including a low urine sodium concentration (!20 mmol/L), a low fractional

excretion of sodium (!1%), a low fractional excretion of urea (!35%), and

a high urine osmolality follow directly from the physiologic processes

described (Fig. 2).

Although classically associated with true volume depletion, prerenal AKIdevelops in any state associated with eff ective renal hypoperfusion (Box 1).

In addition to classic volume-depleted states, prerenal azotemia may occur

in the setting of total body volume overload but decreased eff ective arterial

blood volume, as may occur in congestive heart failure, cirrhosis of the liver,

and early sepsis. The treatment of prerenal azotemia is correction of the

underlying cause of renal hypoperfusion. In patients who have true volume

depletion, volume resuscitation with isotonic crystalloid is of primary im-

portance. In patients who have decreased eff ective arterial blood volume de-

spite total body volume overload, treatment of the primary organ failure(eg, heart failure) is paramount.

Fig. 2. Pathophysiology of prerenal acute kidney injury. In response to decreased renal perfu-

sion, the renal-angiotensin system is activated, leading to increased angiotensin II (AII) levels.Angiotensin II causes vasoconstriction of both the preglomerular (aff erent) and postglomerular

(eff erent) arterioles; however the preglomerular vasoconstriction is countered by vasodilatory

prostaglandins (PG). The net eff ect is a decrease in renal plasma flow (RPF) but a proportionally

smaller decrease in glomerular capillary pressure (PGC). The decrease in glomerular capillary

pressure results in a fall in glomerular filtration rate (GFR), but because the magnitude of

the decline in GFR is smaller than the decrement in RPF, filtration fraction (FF) increases.

Tubular reabsorption of sodium (Na), water, and urea are all increased.

244 KHALIL et al



Postrenal acute kidney injury

Postrenal AKI results from obstruction of the urinary collecting system.

Obstruction may occur at the level of the bladder or urethra (lower tract ob-

struction) or at the level of the ureters or renal pelvis (upper tract obstruc-tion). To cause AKI, however, upper tract obstruction must be bilateral or

aff ect a solitary functioning kidney. Although unilateral obstruction may

present with renal colic or hydronephrosis, it usually is not associated

with a significant decrement in kidney function because of the preservation

of function in the contralateral kidney.

The conditions associated with obstructive uropathy vary by age and

gender (Box 2).

Common causes of obstruction in children include congenital ureteral

strictures and urethral strictures or valves. In adults, retroperitoneal andpelvic malignancies predominate in women, whereas prostate cancer and

prostatic hypertrophy are most common in men. Postrenal AKI can present

as either complete or partial obstruction. Complete obstruction usually is

associated with anuria, whereas partial obstruction may be asymptomatic

or manifest with symptoms of voiding dysfunction such as frequency, hesi-

tancy, intermittency, nocturia, and incomplete emptying. Although urine

Box 1. Causes of prerenal acute kidney injury

True hypovolemia Hemorrhage

Cutaneous losses

Burns

Sweat

Gastrointestinal losses

Diarrhea

Vomiting

Drainage from intestinal, pancreatic, or biliary fistulas

Renal losses Osmotic diuresis

Diuretics

Decreased effective blood volume

Heart failure

Cirrhosis

Nephrotic syndrome

Intrarenal vasoconstriction

HypercalcemiaHepatorenal syndrome

Nonsteroidal anti-inflammatory drugs




volume often is preserved, partial obstruction may manifest as oliguria,

polyuria, or fluctuating urine output with periods of oliguria alternating

with polyuria. Associated symptoms may include hematuria; abdominal,

back or flank pain; renal colic; or pelvic fullness.

The diagnosis of postrenal obstruction should be suspected in patients

who have prostatic hypertrophy or symptoms of bladder outlet obstruction,

diabetes mellitus, nephrolithiasis, opiate use, prior abdominal or pelvicsurgery, a history of radiation therapy, pelvic neoplasms, or neoplastic pro-

cesses associated with retroperitoneal adenopathy. Lower tract obstruction

usually is diagnosed based on the presence of urinary retention. An elevated

postvoid residual bladder volume (O100 mL) can be measured by ultra-

sound or by measuring urine volume after placement of a bladder catheter.

Historically, intravenous pyelography was the diagnostic test of choice for

Box 2. Causes of postrenal acute kidney injury

Upper tract obstruction (bilateral obstruction or unilateral obstruction of a single functioning kidney)

Intrinsic

Nephrolithiasis

Papillary necrosis

Blood clots

Transitional cell carcinoma

Extrinsic

Retroperitoneal or pelvic malignancy

Retroperitoneal adenopathy Retroperitoneal fibrosis

Endometriosis

Abdominal aortic aneurysm

Surgical injury

Lower tract obstruction

Bladder

Neurogenic bladder

Transitional cell carcinoma of the bladder Blood clot

Bladder calculus

Prostate

Prostate cancer

Benign prostatic hypertrophy

Urethra

Stricture

Phimosis

Urethral valves

246 KHALIL et al



evaluation of obstructive uropathy, but now it has been supplanted by ultra-

sound and high-resolution CT. Ultrasound is very sensitive and specific in

diagnosing upper tract obstruction, although it may not detect early stagesof hydronephrosis and may not detect obstruction in the setting of retroper-

itoneal fibrosis or other retroperitoneal disease causing encasement of the

ureters and kidneys. Combined plain film radiographs, ultrasonography,

and high-resolution CT scans of the abdomen and pelvis are diagnostic in

more than 90% of cases [36–38]. Isotopic renography may be useful as

a functional test to diff erentiate obstructive from nonobstructive urinary

tract dilatation. Antegrade and retrograde pyelography are invasive proce-

dures but provide definitive diagnosis and the opportunity for therapeutic

intervention.

Intrinsic acute kidney injury

Intrinsic processes that result in AKI are categorized according to the

structural component of the kidney that is the primary site of histologic in-

jury (see Fig. 1). Classically, intrinsic AKI is divided into acute glomerular,

interstitial, and tubular injury. Several forms of intrinsic AKI do not fit log-

ically into this triadic division, so the authors have included two additional

categoriesd

acute vascular disease and AKI secondary to intratubular ob-struction. The important distinction between intrinsic AKI and pre- and

postrenal AKI is the presence of structural injury to the kidney in intrinsic

AKI. Hence, unlike pre- and postrenal disease, correction of the off ending

cause in intrinsic AKI does not necessarily result in prompt recovery of re-

nal function.

Acute tubular necrosis

Acute tubular necrosis (ATN) is the most common cause of intrinsic

AKI. Precipitating insults usually are divided into ischemic and nephrotoxicprocesses, but ATN frequently is multifactorial, developing in the setting of

acute illness with sepsis, hypotension, and nephrotoxic medications all con-

tributing to its development.

The clinical course of ATN can be highly variable. Typically there is an

initial oliguric phase, beginning within 24 hours of the inciting event and

lasting 1 to 3 weeks, followed by a diuretic phase, characterized by a progres-

sive increase in urine volume that usually is indicative of renal recovery.

Many patients, however, may be nonoliguric throughout their course. Mor-

tality associated with ATN is high, with reported mortality rates as high as50% to 70% in some series [39]. Although this mortality may, in part, reflect

comorbid illness, multiple studies have suggested that ATN is an indepen-

dent risk factor for mortality [3,40,41]. The majority of surviving patients

recover renal function, although complete recovery may not occur.

The urine sediment in ATN commonly demonstrates many tubular epi-

thelial cells and coarse granular casts, often described as ‘‘muddy brown’’




casts. Tubular sodium reabsorption is commonly, although not always, im-

paired. The urinary sodium usually is greater than 40 mmol/L with a frac-

tional excretion of sodium in excess of 3%.

Ischemic acute tubular necrosis. Ischemic injury and prerenal azotemia rep-

resent two ends of the spectrum of the renal response to hypoperfusion. In

prerenal azotemia, hypoperfusion results in functional disturbances that re-

verse promptly when normal renal perfusion is restored. When the hypoper-

fusion is more intense or prolonged, tubular cell injury ensues, and renal

dysfunction persists even after the hemodynamic insult resolves [42,43].

As the name implies, the most evident site of injury following renal ischemia

is the tubular epithelial cells, with evidence of both epithelial cell death(necrosis) and apoptosis [42] It now is understood, however, that ischemia

reperfusion injury involves not only the tubular epithelium but also injury

to the vascular endothelium and activation inflammatory cells and humoral

mediators (Fig. 3) [43–48].

The pathogenesis of ischemic ATN can be divided into several phases

[43,47]. There usually is a preceding prerenal phase. More profound or pro-

longed hypotension and renal ischemia triggers an initiation phase charac-

terized by epithelial and endothelial cell injury. The initiation phase is

followed by an extension phase, independent of the initial ischemic insult,mediated by microvascular endothelial injury [43,47] and activation of in-

flammatory pathways [44–46,48]. This phase is followed by a maintenance

Fig. 3. Pathogenesis of ischemic acute tubular necrosis. Ischemia-reperfusion injury leads to

direct injury to both tubular epithelial cells and endothelial cells. Endothelial cell injury leads

to capillary obstruction and continued ischemia, increasing tubular injury. In addition, both en-

dothelial and tubular injury lead to activation of inflammatory mediators that serve to amplify

the cellular injury, leading to extension of the ischemia-reperfusion injury after normal renal

perfusion is restored.

248 KHALIL et al



phase, during which the epithelial and endothelial cells undergo repair and

rediff erentiation, followed by recovery of renal function.

The major histologic changes associated with ATN include eff acementand loss of the brush border of proximal tubular cells, patchy loss of tubular

cells with denudement of the basement membrane, dilatation of the proxi-

mal tubules, formation of casts of cellular debris in the distal tubule, and

areas of cellular regeneration that appear during the recovery phase [49].

Several mechanisms are thought to underlie the reduction in GFR during

ATN [42]. There is profound vasoconstriction, mediated directly by endo-

thelial injury and indirectly through tubuloglomerular feedback, resulting

in a direct reduction in glomerular filtration. In addition, sloughing of cells

from the tubular epithelium denudes the tubular basement membrane andleads to formation of intratubular casts. These casts cause tubular obstruc-

tion, and the denuded basement membrane permits backleak of glomerular

filtrate.

Risk factors for the development of ischemic ATN include pre-existing

chronic kidney disease, atherosclerosis, diabetes mellitus, and poor nutri-

tional status [50]. Three surgical procedures are associated particularly

with an increased risk for the development of ischemic ATN: surgical repair

of an abdominal aortic aneurysm [51], surgery to correct obstructive jaun-

dice [52], and cardiac surgery [53,54].Ischemic ATN may occur in the absence of overt hypotension if renal au-

toregulation is impaired [55]. This phenomenon is well described in elderly

patients and in patients who have atherosclerosis, hypertension and reno-

vascular disease, or pre-existing chronic kidney disease. In contrast, it has

been suggested that patients who have chronic heart failure may be at de-

creased risk of developing ATN despite significant systemic hypotension

as the result of a cardio-renal reflex that reduces renal sympathetic tone

and increases the secretion of atrial natriuretic peptide, leading to preserva-

tion of renal perfusion despite systemic hypotension [56].

Nephrotoxic acute tubular necrosis. Nephrotoxic ATN may result from ei-

ther endogenous or exogenous toxins. The endogenous heme pigments

hemoglobin and myoglobin cause ATN in the settings of massive intravas-

cular hemolysis or rhabdomyolysis, respectively. The spectrum of exogenous

agents associated with nephrotoxic ATN has changed dramatically during

the past 30 to 40 years. In the past, heavy metals and organic solvents

were the most common causative agents; ATN from these agents now is

rare, and most cases of nephrotoxic ATN are associated with antimicrobialagents such as aminoglycosides and amphotericin B, radiocontrast media,

chemotherapeutic agents including cisplatinum and ifosfamide, and acet-

aminophen (Box 3).

Sepsis-associated acute tubular necrosis. Sepsis-associated ATN generally

has been classified as a form of ischemic ATN, but more recent data suggest




Box 3. Causes of intrinsic acute kidney injury

Acute tubular necrosis Ischemic

Hypotension

Hypovolemic shock

Cardiopulmonary arrest

Cardiopulmonary bypass

Nephrotoxic

Drug-induced

Aminoglycosides

Radiocontrast mediaAmphotericin

Cisplatinum

Ifosfamide

Acetaminophen

Pigment nephropathy

Intravascular hemolysis

Rhabdomyolysis

Sepsis

Acute interstitial nephritis

Drug-induced

Penicillins

Cephalosporins

Sulfonamides

Rifampin

Phenytoin

Furosemide

Proton-pump inhibitors Nonsteroidal anti-inflammatory drugs

Infection-related causes

Systemic diseases

Systemic lupus erythematosus

Sarcoidosis

Sjogren’s syndrome

Tubulointerstitial nephritis and uveitis syndrome

Malignancy

Idiopathic causesAcute glomerulonephritis

Poststreptococcal glomerulonephritis

Postinfectious glomerulonephritis

Endocarditis-associated glomerulonephritis

250 KHALIL et al



that endotoxemia may play an important independent role in its pathogen-

esis [56]. It has been shown that mild renal ischemia, which alone is notsufficient to cause renal injury, can lead to AKI in the presence of primed

neutrophils [57]. Recent studies also have suggested preservation of renal

perfusion in experimental models of sepsis [58,59]. Thus, it seems that, al-

though systemic and renal perfusion play an important role in the pathogen-

esis of septic ATN, it is likely that endotoxin, activation of inflammatory

mediators and microvascular endothelial damage play an independent path-

ogenic role.

Acute interstitial nephritisAcute interstitial nephritis (AIN) is AKI resulting from lymphocytic in-

filtration of the interstitium. Although classically described as presenting

with fever, rash, eosinophilia, and eosinophiluria, the classic triad of fever,

rash, and eosinophilia is seen in only 10% to 30% of patients who have AIN

[60]. Antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs)

Systemic vasculitis

Systemic lupus erythematosus Microscopic polyangiitis

Granulomatous vasculitis

Cryoglobulinemia

Thrombotic microangiopathy

Hemolytic-uremic syndrome

Thrombotic thrombocytopenic purpura

Rapidly progressive glomerulonephritis

Acute vascular syndromes

Macrovascular Renal artery thromboembolism

Renal artery dissection

Renal vein thrombosis

Microvascular

Atheroembolic disease

Intratubular obstruction

Paraprotein

Multiple myelomaCrystalline

Ethylene glycol ingestion

Tumor lysis syndrome

Acyclovir

Indinavir

Methotrexate




currently are the most common causative agents, although AIN can occur

with almost any medication. AIN also can develop in the setting of infec-

tion, malignancy, or systemic disease or as an idiopathic condition (seeBox 3).

The urine findings in AIN include sterile pyuria, white blood cell casts,

non–nephrotic-range proteinuria, hematuria, and eosinophiluria. Although

eosinophiluria is not specific for AIN, it is associated with a high negative

predictive value [61]. The reference standard for diagnosis of AIN is renal

biopsy; in the majority of patients, however, a presumptive diagnosis is

made based on clinical presentation alone.

The clinical course of NSAID-associated AIN diff ers from other forms of

drug-induced AIN. The onset often occurs months rather than days afterthe initiation of therapy. Features of hypersensitivity such as fever, rash,

and eosinophilia usually are not present, whereas severe proteinuria, often

in the nephrotic range, may be the prominent feature [62]. On biopsy, histo-

logic findings of minimal change disease often are present [62].

Acute glomerulonephritis

Acute glomerulonephritis (GN) and rapidly progressive GN comprise

a spectrum of glomerular diseases that present as AKI, with progressive

decline in renal function over days to weeks. Prompt recognition of these en-tities is critical because prompt initiation of therapy is essential to preserve

kidney function and prevent irreversible renal damage. The prototypic form

of acute GN is poststreptococcal GN, although acute and rapidly progres-

sive GN also may develop in the setting of endocarditis and other infections,

as a manifestation of systemic autoimmune disease or systemic vasculitis, or

as an idiopathic renal-limited disease (see Box 3).

The hallmark findings of GN-associated AKI are related to damage to the

glomerular basement membrane and glomerular bleeding. The presence of

dysmorphic red blood cells and red blood cell casts on microscopic examina-tion of the urine sediment are pathognomonic for an acute glomerular pro-

cess. Serologic studies, including serum complement levels, markers for

hepatitis B and C viruses, anti-streptococcal antibodies, antinuclear anti-

bodies, anti-neutrophil cytoplasmic antibodies, and anti-glomerular base-

ment membrane antibodies may be helpful in making a diagnosis; however,

renal biopsy usually is necessary for definitive diagnosis. The specific findings

on kidney biopsy depend on the underlying glomerular process; proliferative

lesions in the glomerulus, often associated with crescentic changes, are

characteristic.

Acute vascular syndromes

Acute vascular syndromes associated with AKI can be broadly divided

into large-vessel and small-vessel disease. The large-vessel diseases include

renal thromboembolism, renal artery dissection, and renal vein thrombosis

(see Box 3). The common feature of the large-vessel vascular syndromes is

252 KHALIL et al



renal infarction, usually presenting with flank pain, hematuria, and elevated

levels of serum lactate dehydrogenase. As with upper tract obstructive dis-

ease, renal involvement must be bilateral; unilateral disease will not causeAKI unless it involves a solitary functional kidney. Diagnosis may be

made using contrast-enhanced CT, radioisotope renography, or angiogra-

phy. Thrombolytic therapy or revascularization usually is not feasible; treat-

ment usually consists of anticoagulation and supportive care.

More common is small-vessel disease resulting from atheroembolization

into the distal renal vasculature. Atheroembolic disease, resulting from em-

bolization of cholesterol crystals from atheromatous plaques, is a multisys-

tem disorder that can involve the skin, muscle, gastrointestinal tract, liver,

and central nervous system in addition to the kidneys. In the kidneys, theatheroemboli lodge in small arteries and arterioles where they usually are

nonobstructing but incite an inflammatory reaction that ultimately leads

to narrowing or obliteration of the vascular lumen. Although the clinical

course of renal atheroembolic disease can be highly variable, ranging

from severe AKI to the gradual progression of chronic kidney disease, the

typical clinical course is one of subacute kidney injury, with a stuttering de-

cline in kidney function occurring over days to weeks [63,64]. Although

atheroembolization may occur spontaneously, it is most common after sur-

gical or angiographic manipulation of the aorta, often with a delayed onsetof several days to weeks. AKI secondary to atheroembolic disease after an-

giographic procedures can be confused with radiocontrast-induced nephrop-

athy (RCN). Typically, however, RCN occurs 24 to 36 hours following

contrast administration, resolves within 3 to 5 days, and is not associated

with systemic manifestations [64]. In atheroembolic disease, in contrast,

the onset often is delayed, the time course is slower, and it is associated

with cutaneous and systemic involvement. The diagnosis is made most read-

ily when cutaneous manifestations, including livedo reticularis and digital

ischemia, are present. Laboratory findings are variable, depending on theorgan systems involved, but may include low serum complement levels,

eosinophilia, and eosinophiluria. Proteinuria, sometimes in the nephrotic

range, may be present [65]. There is no specific therapy for atheroembolic

disease. Anticoagulation generally should be avoided, because it may accel-

erate embolization from atheromatous plaques.

Intratubular obstruction

Intratubular obstruction from precipitation of either protein or crystals

within the tubular lumen also can cause AKI (see Box 3). Tubular obstruc-tion from precipitated monoclonal light chains underlies the development of

cast nephropathy in multiple myeloma. AKI from intratubular precipitation

of crystals occurs in several clinical settings. Ethylene glycol ingestion is as-

sociated with the intratubular precipitation of calcium oxalate crystals and

should be suspected when AKI develops in the setting of acute intoxication

and a high anion gap metabolic acidosis. Abundant calcium oxalate crystals




usually are present on urinary microscopy. In the tumor lysis syndrome,

marked hyperuricemia leads to intratubular precipitation of uric acid crys-

tals. The urine sediment usually demonstrates abundant uric acid crystals,and the urine uric acid-to-creatinine ratio usually is greater than 1, com-

pared with values of less than 0.6 to 0.75 in AKI of other etiologies

[66,67]. Prevention and treatment include forced saline diuresis, urinary

alkalinization, and treatment with either allopurinol to inhibit urate synthe-

sis or rasburicase for urate degradation [67]. Intratubular precipitation of

acyclovir, indinavir, and methotrexate is the major mechanism of AKI asso-

ciated with the use of these drugs.

Clinical evaluation of the patient who has acute kidney injury

The clinical evaluation of the patient who has AKI begins with assessing

whether the patient has prerenal, postrenal, or intrinsic disease. Postrenal or

obstructive disease is suggested by clinical symptoms of voiding dysfunction

or a clinical history suggesting pelvic or retroperitoneal disease. Bladder

outlet obstruction should be assessed by measuring a postvoid residual blad-

der volume using an ultrasonic bladder scanner or by placement of a bladder

catheter after the patient attempts to void. A postvoid bladder volume of

more than 100 mL is highly suggestive of bladder outlet obstruction. Uppertract obstruction should be assessed using renal ultrasound or CT.

In a patient who has true volume depletion, the diagnosis of prerenal azo-

temia is not difficult. Intravascular volume depletion may be manifest by

hypotension, orthostatic hypotension, flat neck veins, poor skin turgor,

and dry oral mucosa. The urine sediment usually is without casts or cellular

elements, and the urine usually is concentrated (specific gravity O 1.015;

urine osmolality O 350 mOsm/kg) with a low urine sodium concentration

(!20 mmol/L) (Table 2). The fractional excretion of sodium, calculated

as the ratio of urine (UNa) to plasma sodium concentration (PNa) dividedby the ratio of urine (UCr) to plasma creatinine (PCr) [(UNa/PNa) O (UCr/

PCr)] on a random urine sample, is usually less than 1%. In patients who

have heart failure or liver disease, the diagnosis may be more difficult, be-

cause total body volume overload with edema may coexist with decreased

eff ective arterial blood volume. The use of urine diagnostic indices may be

useful; but the concomitant use of diuretics may decrease the utility of urine

sodium measurements. In the setting of diuretic use, the fractional excretion

of urea [(UUrea/PUrea)O (UCr/PCr)], where UUrea and PUrea are the urine and

plasma urea nitrogen concentrations, respectively, may be a useful adjunct.In patients who have prerenal azotemia, the fractional excretion of urea is

usually less than 35%, compared with normal values of more than 60%

[68,69]. The ultimate determination of whether a patient has prerenal or in-

trinsic AKI may require a diagnostic trial of intravenous fluids.

The diff erentiation between the causes of intrinsic AKI requires a careful

clinical history and physical examination. Urine microscopy also may

254 KHALIL et al



provide useful clues to the diagnosis (see Table 2). The presence of dysmor-

phic red blood cells and red blood cell casts is strongly suggestive of an acuteglomerular process. The presence of white blood cells, white blood cell casts,

and eosinophiluria suggests the diagnosis of AIN. Tubular epithelial cells

and muddy brown granular casts suggest the diagnosis of ATN. Heavy ox-

alate or uric acid crystalluria or the presence of drug crystals suggests intra-

tubular crystal deposition, and the presence of non-albumin proteinuria

suggests a diagnosis of myeloma kidney. When the diagnosis remains

Table 2

Diagnostic findings in acute kidney injury

Condition

Blood ureanitrogen/

creatinine

ratio

Urine

sodium

(mmol/L)

Fractionalexcretion

of sodium

(%) Urinalysis Other findings

Prerenal acute

kidney injury

O20:1 !20 !1 Specific gravity

O 1.015 Normal

or hyaline casts

Fractional

excretion of

urea ! 35%


Acute tubular

necrosis

10:1 O40 O3a Specific gravity

w 1.010

Muddy brown

casts and

tubular

epithelial cells

Fractional

excretion of

urea ! 60%

Acute interstitial

nephritis

O20 O1 Hematuria,

white blood

cells, white

blood cell

casts,

eosinophiluria

Eosinophilia

Acute

glomerulonephritis

!20 !1 Dysmorphic

red blood cells

and red blood

cell casts

Serum serologic

studies

Intratubular

obstruction

Variable Variable Crystalluriabor

nonalbumin

proteinuria

(Bence-Jones

proteinuria)

Monoclonal

paraprotein on

electrophoresis

Acute vascular

syndromes

O20 Variable Hematuria Elevated lactate

dehydrogenase

with renal

infarctionPostrenal acute

kidney injury

O20:1 O20 Variable Variable

a Fractional excretion of sodium can be low in radiocontrast nephropathy and pigment

nephropathy.b Calcium oxalate crystals with ethylene glycol ingestion; uric acid crystals in tumor lysis

syndrome; drug crystals with acyclovir and indinavir toxicity.




uncertain, especially if there is suspicion of acute GN or AIN, a kidney bi-

opsy may be indicated.

Prevention and treatment of a cute kidney injury

Prerenal acute kidney injury

The goal of treatment of prerenal azotemia is restoration of normal renal

perfusion. With true hypovolemia, correction of volume deficits with intra-

venous isotonic fluids is the primary therapy. Treatment also should

be directed at the cause of volume loss, such as diarrhea or vomiting.

Most patients who have heart failure or cirrhosis who develop prerenal azo-temia do so in the setting of aggressive diuresis. In these patients diuretics

should be discontinued and judicious intravenous volume expansion should

be provided. In patients who have severely decompensated heart failure in-

travenous inotropic agents may be used to optimize renal perfusion, al-

though usually this treatment is only a temporizing measure.

Postrenal acute kidney injury

The treatment of postrenal AKI is relief of the obstruction. Placement of

a bladder catheter, either as a urethral or a suprapubic catheter, will relieve

obstruction at the level of the bladder outlet or urethra. Upper tract obstruc-

tion requires either ureteral stenting or placement of percutaneous nephros-

tomies; the approach used often depends on the resources of the individual

institution. Prompt relief of obstruction is necessary to prevent irreversible

renal injury. Relief of obstruction may be associated with the development

of a postobstructive diuresis; therefore careful monitoring of urine output is

required. If excessive diuresis develops, replacement of urinary losses may be

necessary to prevent intravascular volume depletion.


Acute tubular necrosis

The development of ATN is an often unpredictable complication of acute

illness. With the exception of a few specific situations discussed later, pre-

ventive measures are limited to broad recommendations for avoidance of

hypotension, hypovolemia, and nephrotoxic. When drugs with nephrotoxic

potential (such as aminoglycosides) are required, they should be dosed cau-

tiously, especially in elderly patients and in patients who have underlyingchronic kidney or liver disease, who may have decreased drug clearance

and are therefore at increased risk for toxicity. Whenever possible, pharma-

cokinetic monitoring of these agents should be used. Caution also should be

used when prescribing medications that alter renal hemodynamics and

therefore may predispose the user to the development of ischemic ATN, par-

ticularly in patients who have underlying chronic kidney disease. Classes of

256 KHALIL et al



drugs in which the alteration of renal hemodynamics is of concern are the

nonselective and cyclo-oxygenase 2–selective NSAIDs and medications

that alter the activity of the renin-angiotensin system.No specific pharmacologic therapy is eff ective in established ATN. Al-

though multiple agents including diuretics, renal vasodilators, and growth

factors have shown promise in animal models, none has demonstrated effi-

cacy in clinical trials. The role of loop diuretics in the management of ATN

has been the subject of controversy. Although it was hypothesized that in-

hibition of sodium transport would reduce metabolic demand and minimize

the extent of ischemic renal injury, this benefit has not been substantiated in

clinical trials. A second role for diuretics has been the ‘‘conversion’’ of oli-

guric to nonoliguric ATN. Although it is well recognized that nonoliguricATN is associated with a better prognosis than oliguric disease, there is

no evidence that pharmacologic conversion from an oliguric to a nonoligu-

ric state alters prognosis. Rather, the response to diuretics seems merely to

identify a subset of patients who have less severe renal injury. More re-

cently, it even has been suggested that diuretic therapy may be associated

with an increased mortality risk [17,70], but after accounting for diuretic

responsiveness, the impact on mortality risk seems minimal. Although

diuretic therapy clearly provides benefit in volume management, there is

reasonable concern that excessive reliance on diuretics might delay initia-tion of renal support. The authors therefore recommend a trial of high-

dose furosemide (160–200 mg) or an equivalent dose of other loop diuretics

in oliguric patients who are modestly volume overloaded intravascularly,

but the authors do not believe that diuretic therapy should be used to delay

initiation of RRT if otherwise indicated. Repeated dosing of diuretics in

patients who do not respond to the initial dose is not warranted.

Dopamine is another agent that has been used widely for the prevention

and treatment of ATN. The rationale for its use is the belief that at low

doses (!2 mg/kg/min) it is a renal vasodilator and increases renal perfusion.Clinical trials have not supported any clinical benefit with this agent, how-

ever [71,72]. Given the absence of proven benefit and the risk of complica-

tions, especially cardiac tachyarrhythmias, there is no role for the use of

low-dose dopamine for the prevention or treatment of ATN.

Thus, short of support with RRT, the management of ATN remains pre-

dominantly supportive. Fluid administration should be managed carefully

to assure that any volume deficits are corrected, but excessive volume ad-

ministration should be avoided to prevent severe iatrogenic volume over-

load. Electrolytes that accumulate in renal failure, including potassium,magnesium, and phosphate, should be restricted; phosphate binders may

be required to prevent severe hyperphosphatemia. Supplemental bicarbon-

ate can be used to correct the metabolic acidosis of renal failure. Nutrition

should be managed carefully to assure adequate caloric and protein intake.

Protein intake should not be restricted and generally should range from

1.2 to 1.6 g/kg/d, and caloric intake should be at least 30 kcal/kg/d [73,74].




Medication dosing needs to be adjusted for reduced renal clearance. In pa-

tients receiving RRT, supplemental dosing may be necessary to compensate

for extracorporeal drug removal.In the absence of eff ective pharmacologic therapy, RRT remains the pri-

mary treatment for severe AKI. The term ‘‘RRT’’ encompasses all the mo-

dalities of renal support that currently are available, including intermittent

hemodialysis, the various modalities of continuous RRTs, the newer

‘‘hybrid’’ modalities such as sustained low-efficiency dialysis, and peritoneal

dialysis. Indications for RRT include hyperkalemia, metabolic acidosis, vol-

ume overload, and overt uremic symptoms. In many patients who have

AKI, however, RRT is initiated prophylactically, before the development

of specific indications, because of progressive asymptomatic azotemia.The optimal timing for initiation of RRT in AKI has not been well defined,

and there is debate as to whether earlier initiation of therapy is associated

with improved outcomes [75,76]. Increased intensity of renal support seems

to be associated with improved survival [77–79]; but more definitive studies

are ongoing [76,80]. The impact of modality of therapy on outcomes also is

controversial [81,82], although a series of recent randomized, controlled tri-

als has failed to demonstrate improved outcomes with continuous RRT

than with intermittent hemodialysis [83–86]. No studies have reported on

outcomes of the ‘‘hybrid’’ therapies compared with other modalities.Thus, recommendations for the use of a specific RRT modality in AKI can-

not be based on outcomes. The authors recommend that each hospital use

the modality or modalities that can be provided most safely and efficiently,

based on local resources.

Radiocontrast-induced nephropathy

RCN is one of the most common causes of nephrotoxic ATN, and be-

cause most imaging studies requiring radiocontrast administration are elec-

tive or semi-elective, it is one of the few causes of ATN amenable to specificpreventative interventions. Most patients are at minimal risk for the devel-

opment of RCN, but patients who have chronic kidney disease, particularly

if associated with diabetes mellitus, have a markedly increased risk for de-

velopment of RCN [87]. Three strategies have been shown conclusively to

minimize the risk of contrast nephropathy in high-risk patients: intravenous

volume expansion with isotonic crystalloid [88–90], use of low- or iso-osmo-

lar contrast media [91–94], and minimization of the total dose of contrast

media used [92,94].

The optimal regimen for administration of pre- and postprocedure fluidsis uncertain. Most studies have used a regimen of isotonic saline adminis-

tered at a rate of 1 mL/kg/h for 12 hours pre- and postprocedure. Whether

shorter regimens are equally efficacious has not been evaluated. Recent stud-

ies also have compared the use of isotonic bicarbonate with that of isotonic

saline and have suggested that when administered at 3 mL/kg for 1 hour pre-

procedure and 1 mL/kg/h for 6 hours postprocedure, bicarbonate is superior

258 KHALIL et al



to saline [89,95]. These studies have had relatively small sample sizes, and

larger studies will be required to demonstrate the superiority of bicarbonate

definitively.A number of pharmacologic agents have been evaluated for prevention of

RCN, the majority showing little or no demonstrable benefit [92,94,96–99].

A large number of studies have evaluated the role of N-acetylcysteine (Mu-

comyst, Bristol-Myers Squibb S.r.l., Anagni, Italy) in preventing RCN, with

highly variable results [100–106]. At present, it is not possible to make

a strong recommendation for the use of this agent [92,94]; however, given

its low risk and minimal cost, its use as an adjunctive agent for the preven-

tion of RCN is not inappropriate.

Acute interstitial nephritis

Discontinuation of the off ending agent or treatment of underlying disease

is the mainstay of treatment of AIN. In most patients, renal function re-

covers over a period of days to weeks. The role of steroid therapy is contro-

versial. Although several case series have suggested potential benefit from

steroid therapy, no randomized, controlled trials have been reported [61].

Acute glomerulonephritis

The treatment of GN-associated AKI depends on the specific cause. Post-streptococcal GN requires general supportive care without specific therapy.

The treatment of infection-associated acute GN is treatment of the underly-

ing infection. Patients who have renal involvement from vasculitis or rapidly

progressive GN require urgent initiation of therapy with steroids and cyto-

toxic or immunosuppressive therapy. In patients who have anti-glomerular

basement membrane disease, plasmapheresis often is required in addition to

high-dose glucocorticoids and cytotoxic therapy. There may also be a role

for plasmapheresis in patients who have acute cryoglobulinemia, and

prompt initiation of plasma exchange is indicated in patients who have he-molytic uremic syndrome and thrombotic thrombocytopenic purpura.

Given the risk of irreversible renal injury, rapid initiation of treatment is

necessary in many patients who have acute or rapidly progressive GN.

Therefore it often is necessary to initiate therapy based on a presumptive

diagnosis while awaiting the definitive results of a kidney biopsy.

Summary

AKI is a common complication with an incidence that has been increas-

ing over time. The increasing understanding of this syndrome has led to re-

vised criteria for its definition and staging. A disparate range of conditions

can cause AKI, including functional prerenal states, obstructive (postrenal)

conditions, and a wide spectrum of intrinsic renal diseases including ATN,

AIN, acute GN, acute large- and small-vessel vascular syndromes, and




intratubular obstruction. The diagnosis of specific etiology usually is based

on careful assessment of history and physical examination aided by urinary

diagnostic indices and urine microscopy. Unfortunately, the treatment of most causes of intrinsic AKI remains supportive care, without specific pre-

ventive or pharmacologic therapies.

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