Prim Care Clin Office Pract

35 (2008) 239264

The Patient with Acute Kidney Injury

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

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

A-919 Sciafe Hall, 3550 Terrace Street, Pittsburgh, PA 15213, USA
b
Renal 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 insucient to be categorized as organ failure, are associated with increased
morbidity and mortality [13]. For this reason the term acute kidney injury (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: palevsky@pitt.edu (P.M. Palevsky).
0095-4543/08/$ - see front matter. Published by Elsevier Inc.
doi:10.1016/j.pop.2008.01.003

primarycare.theclinics.com

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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 epidemiology and treatment. The adoption of a uniform definition and classification 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 standardization 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 two
outcome 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 kidney 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 [713].
More recently, the Acute Kidney Injury Network (AKIN), an international 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

Risk

Injury

Failure

Loss
End-stage
renal disease

Serum creatinine criteria

Urine output criteria

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)
Increase in serum creatinine of
two- to threefold from baseline
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
Persistent renal failure for O 4 wk
Persistent renal failure for O 3 mo

! 0.5 mL/kg/h for 6 h

! 0.5 mL/kg/h for 12 h

! 0.3 mL/kg/h for 24 h
or anuria for 12 h

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.

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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 terminology
acknowledges that, despite disparate causative factors, most acute declines
in kidney function are secondary to injury that leads to functional or structural 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 increase 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 resuscitation [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 kidney 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 identical
to 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 nomenclature 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 glomerular
filtration rate (GFR) from normal to nearly zero, the serum creatinine concentration may not rise significantly for 1 to 2 days. The serum creatinine
concentration also may be aected 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 in
biomarkers of cellular injury rather than on purely functional criteria. Several candidate biomarkers are under evaluation for the diagnosis of AKI,
including neutrophil gelatinaseassociated lipocalin [1821], kidney injury
molecule-1 [2226], and interleukin-18 [27,28]. Although these molecules
seem promising, further validation is required before they can be applied
in clinical practice.

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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 administrative databases to explore the epidemiology and outcomes of AKI in
hospitalized populations [2931]. 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 analysis 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 diagnosis of AKI was 32.9%, compared with 4.6% in patients without a diagnosis 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 increased 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 epidemiology of AKI, they must be interpreted with considerable caution. Validation 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 underestimate 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 epidemiologic assessment of AKI in the Kaiser Permanente of Northern California 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, observational study of 29,269 critically ill patients in 54 hospitals in 23 countries, the period prevalence of AKI was 5.7%, with 72.5% of these patients

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requiring RRT [34]. ICU mortality was 52%, with an additional 8% mortality in the hospital after ICU discharge for an overall hospital mortality
of 60.3%. Among surviving patients, 13.8% continued to require RRT at
the 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). Dierentiation into these three categories is clinically useful, because they dier 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 normal renal perfusion results in a prompt recovery of renal function. It is critical, 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 eective arterial volume depletion is characterized by activation of the
sympathetic nervous system and the renin-angiotensin system. Increased
angiotensin II levels vasoconstrict the postglomerular (eerent) arteriole;
although angiotensin II also acts on the preglomerular (aerent) arteriole,
its vasoconstrictive eects are opposed by vasodilatory prostaglandins. The
predominance of postglomerular vasoconstriction maintains intraglomerular 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).

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also are stimulated, resulting in increased sodium, urea, and water reabsorption in distal nephron segments. Thus, the physiologic response to
modest degrees of renal hypoperfusion is maintenance of GFR with the
elaboration 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 AKI
develops in any state associated with eective 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 eective 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 importance. In patients who have decreased eective arterial blood volume despite 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 perfusion, the renal-angiotensin system is activated, leading to increased angiotensin II (AII) levels.
Angiotensin II causes vasoconstriction of both the preglomerular (aerent) and postglomerular
(eerent) arterioles; however the preglomerular vasoconstriction is countered by vasodilatory
prostaglandins (PG). The net eect 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.

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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
Hypercalcemia
Hepatorenal syndrome
Nonsteroidal anti-inflammatory drugs

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 obstruction) or at the level of the ureters or renal pelvis (upper tract obstruction). To cause AKI, however, upper tract obstruction must be bilateral or
aect 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 and
pelvic 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, hesitancy, intermittency, nocturia, and incomplete emptying. Although urine

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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
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 pelvic
surgery, a history of radiation therapy, pelvic neoplasms, or neoplastic processes 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 ultrasound or by measuring urine volume after placement of a bladder catheter.
Historically, intravenous pyelography was the diagnostic test of choice for

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evaluation of obstructive uropathy, but now it has been supplanted by ultrasound and high-resolution CT. Ultrasound is very sensitive and specific in
diagnosing upper tract obstruction, although it may not detect early stages
of hydronephrosis and may not detect obstruction in the setting of retroperitoneal 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 [3638]. Isotopic renography may be useful as
a functional test to dierentiate obstructive from nonobstructive urinary
tract dilatation. Antegrade and retrograde pyelography are invasive procedures 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 injury (see Fig. 1). Classically, intrinsic AKI is divided into acute glomerular,
interstitial, and tubular injury. Several forms of intrinsic AKI do not fit logically into this triadic division, so the authors have included two additional
categoriesdacute vascular disease and AKI secondary to intratubular obstruction. 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 oending
cause in intrinsic AKI does not necessarily result in prompt recovery of renal function.
Acute tubular necrosis
Acute tubular necrosis (ATN) is the most common cause of intrinsic
AKI. Precipitating insults usually are divided into ischemic and nephrotoxic
processes, but ATN frequently is multifactorial, developing in the setting of
acute illness with sepsis, hypotension, and nephrotoxic medications all contributing 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 progressive increase in urine volume that usually is indicative of renal recovery.
Many patients, however, may be nonoliguric throughout their course. Mortality associated with ATN is high, with reported mortality rates as high as
50% to 70% in some series [39]. Although this mortality may, in part, reflect
comorbid illness, multiple studies have suggested that ATN is an independent 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 epithelial cells and coarse granular casts, often described as muddy brown

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casts. Tubular sodium reabsorption is commonly, although not always, impaired. The urinary sodium usually is greater than 40 mmol/L with a fractional excretion of sodium in excess of 3%.
Ischemic acute tubular necrosis. Ischemic injury and prerenal azotemia represent two ends of the spectrum of the renal response to hypoperfusion. In
prerenal azotemia, hypoperfusion results in functional disturbances that reverse promptly when normal renal perfusion is restored. When the hypoperfusion 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) [4348].
The pathogenesis of ischemic ATN can be divided into several phases
[43,47]. There usually is a preceding prerenal phase. More profound or prolonged hypotension and renal ischemia triggers an initiation phase characterized 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 inflammatory pathways [4446,48]. 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 endothelial 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.

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phase, during which the epithelial and endothelial cells undergo repair and
redierentiation, followed by recovery of renal function.
The major histologic changes associated with ATN include eacement
and loss of the brush border of proximal tubular cells, patchy loss of tubular
cells with denudement of the basement membrane, dilatation of the proximal 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 endothelial 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 and
leads to formation of intratubular casts. These casts cause tubular obstruction, 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 nutritional 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 jaundice [52], and cardiac surgery [53,54].
Ischemic ATN may occur in the absence of overt hypotension if renal autoregulation is impaired [55]. This phenomenon is well described in elderly
patients and in patients who have atherosclerosis, hypertension and renovascular disease, or pre-existing chronic kidney disease. In contrast, it has
been suggested that patients who have chronic heart failure may be at decreased 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 preservation of renal perfusion despite systemic hypotension [56].
Nephrotoxic acute tubular necrosis. Nephrotoxic ATN may result from either endogenous or exogenous toxins. The endogenous heme pigments
hemoglobin and myoglobin cause ATN in the settings of massive intravascular 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 antimicrobial
agents such as aminoglycosides and amphotericin B, radiocontrast media,
chemotherapeutic agents including cisplatinum and ifosfamide, and acetaminophen (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

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Box 3. Causes of intrinsic acute kidney injury

Acute tubular necrosis
Ischemic
! Hypotension
! Hypovolemic shock
! Cardiopulmonary arrest
! Cardiopulmonary bypass
Nephrotoxic
! Drug-induced
Aminoglycosides
Radiocontrast media
Amphotericin
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
! Sjogrens syndrome
! Tubulointerstitial nephritis and uveitis syndrome
Malignancy
Idiopathic causes
Acute glomerulonephritis
Poststreptococcal glomerulonephritis
Postinfectious glomerulonephritis
Endocarditis-associated glomerulonephritis

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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 myeloma
Crystalline
! Ethylene glycol ingestion
! Tumor lysis syndrome
! Acyclovir
! Indinavir
! Methotrexate
that endotoxemia may play an important independent role in its pathogenesis [56]. It has been shown that mild renal ischemia, which alone is not
sucient 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, although systemic and renal perfusion play an important role in the pathogenesis of septic ATN, it is likely that endotoxin, activation of inflammatory
mediators and microvascular endothelial damage play an independent pathogenic role.
Acute interstitial nephritis
Acute interstitial nephritis (AIN) is AKI resulting from lymphocytic infiltration 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)

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currently are the most common causative agents, although AIN can occur
with almost any medication. AIN also can develop in the setting of infection, malignancy, or systemic disease or as an idiopathic condition (see
Box 3).
The urine findings in AIN include sterile pyuria, white blood cell casts,
nonnephrotic-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 diers from other forms of
drug-induced AIN. The onset often occurs months rather than days after
the 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, histologic 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 entities 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 progressive 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 examination of the urine sediment are pathognomonic for an acute glomerular process. Serologic studies, including serum complement levels, markers for
hepatitis B and C viruses, anti-streptococcal antibodies, antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, and anti-glomerular basement 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

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renal infarction, usually presenting with flank pain, hematuria, and elevated
levels of serum lactate dehydrogenase. As with upper tract obstructive disease, renal involvement must be bilateral; unilateral disease will not cause
AKI unless it involves a solitary functional kidney. Diagnosis may be
made using contrast-enhanced CT, radioisotope renography, or angiography. Thrombolytic therapy or revascularization usually is not feasible; treatment 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 embolization of cholesterol crystals from atheromatous plaques, is a multisystem disorder that can involve the skin, muscle, gastrointestinal tract, liver,
and central nervous system in addition to the kidneys. In the kidneys, the
atheroemboli 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 decline in kidney function occurring over days to weeks [63,64]. Although
atheroembolization may occur spontaneously, it is most common after surgical or angiographic manipulation of the aorta, often with a delayed onset
of several days to weeks. AKI secondary to atheroembolic disease after angiographic procedures can be confused with radiocontrast-induced nephropathy (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 readily when cutaneous manifestations, including livedo reticularis and digital
ischemia, are present. Laboratory findings are variable, depending on the
organ 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 accelerate 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 obstruction 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 associated 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

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

marked hyperuricemia leads to intratubular precipitation of uric acid crystals. The urine sediment usually demonstrates abundant uric acid crystals,
and the urine uric acid-to-creatinine ratio usually is greater than 1, compared 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 synthesis or rasburicase for urate degradation [67]. Intratubular precipitation of
acyclovir, indinavir, and methotrexate is the major mechanism of AKI associated 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 bladder 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. Upper
tract obstruction should be assessed using renal ultrasound or CT.
In a patient who has true volume depletion, the diagnosis of prerenal azotemia is not dicult. 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) divided
by 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 dicult, because total body volume overload with edema may coexist with decreased
eective 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 intrinsic AKI may require a diagnostic trial of intravenous fluids.
The dierentiation between the causes of intrinsic AKI requires a careful
clinical history and physical examination. Urine microscopy also may

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THE PATIENT WITH ACUTE KIDNEY INJURY

Table 2
Diagnostic findings in acute kidney injury
Blood urea
nitrogen/ Urine
creatinine sodium
ratio
(mmol/L)

Fractional
excretion
of sodium
(%)
Urinalysis

O20:1

!20

!1

Specific gravity
Fractional
O 1.015 Normal excretion of
or hyaline casts
urea ! 35%

Intrinsic acute kidney injury

Acute tubular
10:1
necrosis

O40

O3a

Acute interstitial
nephritis

O20

O1

Acute
glomerulonephritis

!20

!1

Intratubular
obstruction

Variable Variable

Acute vascular
syndromes

O20

Variable

Specific gravity
w 1.010
Muddy brown
casts and
tubular
epithelial cells
Hematuria,
white blood
cells, white
blood cell
casts,
eosinophiluria
Dysmorphic
red blood cells
and red blood
cell casts
Crystalluriabor
nonalbumin
proteinuria
(Bence-Jones
proteinuria)
Hematuria

O20

Variable

Variable

Condition
Prerenal acute
kidney injury

Postrenal acute
kidney injury

O20:1

Other findings

Fractional
excretion of
urea ! 60%

Eosinophilia

Serum serologic
studies

Monoclonal
paraprotein on
electrophoresis

Elevated lactate
dehydrogenase
with renal
infarction

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.

provide useful clues to the diagnosis (see Table 2). The presence of dysmorphic red blood cells and red blood cell casts is strongly suggestive of an acute
glomerular 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 oxalate or uric acid crystalluria or the presence of drug crystals suggests intratubular crystal deposition, and the presence of non-albumin proteinuria
suggests a diagnosis of myeloma kidney. When the diagnosis remains

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uncertain, especially if there is suspicion of acute GN or AIN, a kidney biopsy 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 intravenous 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 azotemia 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 intravenous inotropic agents may be used to optimize renal perfusion, although 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 obstruction requires either ureteral stenting or placement of percutaneous nephrostomies; 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.
Intrinsic acute kidney injury
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, preventive 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 cautiously, especially in elderly patients and in patients who have underlying
chronic kidney or liver disease, who may have decreased drug clearance
and are therefore at increased risk for toxicity. Whenever possible, pharmacokinetic 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, particularly in patients who have underlying chronic kidney disease. Classes of

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257

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

nonselective and cyclo-oxygenase 2selective NSAIDs and medications
that alter the activity of the renin-angiotensin system.
No specific pharmacologic therapy is eective in established ATN. Although multiple agents including diuretics, renal vasodilators, and growth
factors have shown promise in animal models, none has demonstrated ecacy in clinical trials. The role of loop diuretics in the management of ATN
has been the subject of controversy. Although it was hypothesized that inhibition 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 oliguric to nonoliguric ATN. Although it is well recognized that nonoliguric
ATN is associated with a better prognosis than oliguric disease, there is
no evidence that pharmacologic conversion from an oliguric to a nonoliguric state alters prognosis. Rather, the response to diuretics seems merely to
identify a subset of patients who have less severe renal injury. More recently, 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 initiation of renal support. The authors therefore recommend a trial of highdose furosemide (160200 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, however [71,72]. Given the absence of proven benefit and the risk of complications, 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 predominantly supportive. Fluid administration should be managed carefully
to assure that any volume deficits are corrected, but excessive volume administration should be avoided to prevent severe iatrogenic volume overload. Electrolytes that accumulate in renal failure, including potassium,
magnesium, and phosphate, should be restricted; phosphate binders may
be required to prevent severe hyperphosphatemia. Supplemental bicarbonate 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].

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Medication dosing needs to be adjusted for reduced renal clearance. In patients receiving RRT, supplemental dosing may be necessary to compensate
for extracorporeal drug removal.
In the absence of eective pharmacologic therapy, RRT remains the primary treatment for severe AKI. The term RRT encompasses all the modalities of renal support that currently are available, including intermittent
hemodialysis, the various modalities of continuous RRTs, the newer
hybrid modalities such as sustained low-eciency dialysis, and peritoneal
dialysis. Indications for RRT include hyperkalemia, metabolic acidosis, volume 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 [7779]; 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 trials has failed to demonstrate improved outcomes with continuous RRT
than with intermittent hemodialysis [8386]. 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 cannot be based on outcomes. The authors recommend that each hospital use
the modality or modalities that can be provided most safely and eciently,
based on local resources.
Radiocontrast-induced nephropathy
RCN is one of the most common causes of nephrotoxic ATN, and because most imaging studies requiring radiocontrast administration are elective or semi-elective, it is one of the few causes of ATN amenable to specific
preventative interventions. Most patients are at minimal risk for the development of RCN, but patients who have chronic kidney disease, particularly
if associated with diabetes mellitus, have a markedly increased risk for development 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 [8890], use of low- or iso-osmolar contrast media [9194], and minimization of the total dose of contrast
media used [92,94].
The optimal regimen for administration of pre- and postprocedure fluids
is uncertain. Most studies have used a regimen of isotonic saline administered at a rate of 1 mL/kg/h for 12 hours pre- and postprocedure. Whether
shorter regimens are equally ecacious has not been evaluated. Recent studies 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 preprocedure and 1 mL/kg/h for 6 hours postprocedure, bicarbonate is superior

THE PATIENT WITH ACUTE KIDNEY INJURY

259

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 [92,94,9699].
A large number of studies have evaluated the role of N-acetylcysteine (Mucomyst, Bristol-Myers Squibb S.r.l., Anagni, Italy) in preventing RCN, with
highly variable results [100106]. 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 prevention of RCN is not inappropriate.
Acute interstitial nephritis
Discontinuation of the oending agent or treatment of underlying disease
is the mainstay of treatment of AIN. In most patients, renal function recovers over a period of days to weeks. The role of steroid therapy is controversial. 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. Poststreptococcal GN requires general supportive care without specific therapy.
The treatment of infection-associated acute GN is treatment of the underlying infection. Patients who have renal involvement from vasculitis or rapidly
progressive GN require urgent initiation of therapy with steroids and cytotoxic 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 hemolytic 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 increasing over time. The increasing understanding of this syndrome has led to revised 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

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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 preventive or pharmacologic therapies.
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