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,*
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
a

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 dened 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 specic supportive care.

Denition and staging The reported incidence of AKI varies widely, depending on the denition used and specic clinical setting. The denitions 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

240

KHALIL

et al

replacement therapy (RRT) [1,4]. This lack of a universally recognized denition of AKI has signicantly limited progress in understanding its epidemiology and treatment. The adoption of a uniform denition and classication system that can be readily implemented across multiple clinical settings has been recognized as a necessary prerequisite for clinical advances [5]. Such a denition 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 denition and staging of AKI (Table 1). The acronym RIFLE denes 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 dened 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 dened as ARF persisting for more than 4 weeks, and end-stage kidney disease is dened 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 modications [5]. In a consensus
Table 1 RIFLEa and Acute Kidney Injury Network (AKIN) staging criteria for acute kidney injury RIFLE stage Risk AKIN stage 1 Serum creatinine 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 Urine output criteria ! 0.5 mL/kg/h for 6 h

Injury Failure

2 3

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

Loss End-stage renal disease

a RIFLE denes 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.

THE PATIENT WITH ACUTE KIDNEY INJURY

241

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 reects only one end of the spectrum of clinical conditions that comprise AKI [5]. The AKIN workgroup dened 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 uid resuscitation [5]. The major changes in this denition 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 specication 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 modications: AKI stage 1 is dened 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 denition of AKI, their dependence on serum creatinine level and urine output are signicant 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 ltration rate (GFR) from normal to nearly zero, the serum creatinine concentration may not rise signicantly 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 reect 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.

242

KHALIL

et al

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 denition 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 dened based on International Classication 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 identied as having AKI. In a similar analysis using the Medicare 5% Beneciary 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 specicity 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 reects 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 identied 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 signicantly 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

THE PATIENT WITH ACUTE KIDNEY INJURY

243

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 classication 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 dening 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. Classication of the causes of acute kidney injury (AKI).

244

KHALIL

et al

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 ow (RPF) but a proportionally smaller decrease in glomerular capillary pressure (PGC). The decrease in glomerular capillary pressure results in a fall in glomerular ltration rate (GFR), but because the magnitude of the decline in GFR is smaller than the decrement in RPF, ltration fraction (FF) increases. Tubular reabsorption of sodium (Na), water, and urea are all increased.

THE PATIENT WITH ACUTE KIDNEY INJURY

245

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 stulas Renal losses  Osmotic diuresis  Diuretics Decreased effective blood volume Heart failure Cirrhosis Nephrotic syndrome Intrarenal vasoconstriction Hypercalcemia Hepatorenal syndrome Nonsteroidal anti-inammatory 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 signicant 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

246

KHALIL

et al

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 brosis  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 uctuating urine output with periods of oliguria alternating with polyuria. Associated symptoms may include hematuria; abdominal, back or ank 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

THE PATIENT WITH ACUTE KIDNEY INJURY

247

evaluation of obstructive uropathy, but now it has been supplanted by ultrasound and high-resolution CT. Ultrasound is very sensitive and specic in diagnosing upper tract obstruction, although it may not detect early stages of hydronephrosis and may not detect obstruction in the setting of retroperitoneal brosis or other retroperitoneal disease causing encasement of the ureters and kidneys. Combined plain lm 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 denitive 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 t 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, reect 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

248

KHALIL

et al

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 inammatory 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 inammatory 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 inammatory mediators that serve to amplify the cellular injury, leading to extension of the ischemia-reperfusion injury after normal renal perfusion is restored.

THE PATIENT WITH ACUTE KIDNEY INJURY

249

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 ltration. 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 ltrate. 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 signicant systemic hypotension as the result of a cardio-renal reex 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 classied as a form of ischemic ATN, but more recent data suggest

250

KHALIL

et al

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-inammatory drugs Infection-related causes Systemic diseases  Systemic lupus erythematosus  Sarcoidosis  Sjo grens syndrome  Tubulointerstitial nephritis and uveitis syndrome Malignancy Idiopathic causes Acute glomerulonephritis Poststreptococcal glomerulonephritis Postinfectious glomerulonephritis Endocarditis-associated glomerulonephritis

THE PATIENT WITH ACUTE KIDNEY INJURY

251

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 inammatory mediators and microvascular endothelial damage play an independent pathogenic role. Acute interstitial nephritis Acute interstitial nephritis (AIN) is AKI resulting from lymphocytic inltration 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-inammatory drugs (NSAIDs)

252

KHALIL

et al

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 ndings in AIN include sterile pyuria, white blood cell casts, nonnephrotic-range proteinuria, hematuria, and eosinophiluria. Although eosinophiluria is not specic 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 ndings 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 ndings 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 denitive diagnosis. The specic ndings 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

THE PATIENT WITH ACUTE KIDNEY INJURY

253

renal infarction, usually presenting with ank 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 inammatory 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 ndings 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 specic 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

254

KHALIL

et al

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, at 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 (specic 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 uids. The dierentiation between the causes of intrinsic AKI requires a careful clinical history and physical examination. Urine microscopy also may

THE PATIENT WITH ACUTE KIDNEY INJURY

255

Table 2 Diagnostic ndings in acute kidney injury Blood urea nitrogen/ Urine creatinine sodium ratio (mmol/L) O20:1 !20 Fractional excretion of sodium (%) Urinalysis !1

Condition Prerenal acute kidney injury

Other ndings

Specic gravity Fractional O 1.015 Normal excretion of or hyaline casts urea ! 35% Specic 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 Fractional excretion of urea ! 60%

Intrinsic acute kidney injury Acute tubular 10:1 necrosis

O40

O3a

Acute interstitial nephritis

O20

O1

Eosinophilia

Acute glomerulonephritis

!20

!1

Serum serologic studies

Intratubular obstruction

Variable Variable

Monoclonal paraprotein on electrophoresis

Acute vascular syndromes

O20

Variable

Elevated lactate dehydrogenase with renal infarction

Postrenal 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.

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

256

KHALIL

et al

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 decits with intravenous isotonic uids 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 specic 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

THE PATIENT WITH ACUTE KIDNEY INJURY

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 specic 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 benet 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 benet 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 benet with this agent, however [71,72]. Given the absence of proven benet 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 decits 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].

258

KHALIL

et al

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 specic indications, because of progressive asymptomatic azotemia. The optimal timing for initiation of RRT in AKI has not been well dened, 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 denitive 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 specic 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 specic 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 uids 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 denitively. A number of pharmacologic agents have been evaluated for prevention of RCN, the majority showing little or no demonstrable benet [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 benet from steroid therapy, no randomized, controlled trials have been reported [61]. Acute glomerulonephritis The treatment of GN-associated AKI depends on the specic cause. Poststreptococcal GN requires general supportive care without specic 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 denitive 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 denition 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

260

KHALIL

et al

intratubular obstruction. The diagnosis of specic 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 specic preventive or pharmacologic therapies. References
[1] Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:336570. [2] Praught ML, Shlipak MG. Are small changes in serum creatinine an important risk factor? Curr Opin Nephrol Hypertens 2005;14:26570. [3] Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 2004;15:1597605. [4] Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet 2005;365:41730. [5] Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. [6] Bellomo R, Ronco C, Kellum JA, et al. Acute renal failureddenition, outcome measures, animal models, uid therapy and information technology needs: the second international consensus conference of the Acute Dialysis Quality Initiative (ADQI) group. Crit Care 2004;8:R20412. [7] Uchino S, Bellomo R, Goldsmith D, et al. An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med 2006;34:19137. [8] Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10: R73. [9] Bell M, Liljestam E, Granath F, et al. Optimal follow-up time after continuous renal replacement therapy in actual renal failure patients stratied with the RIFLE criteria. Nephrol Dial Transplant 2005;20:35460. [10] Abosaif NY, Tolba YA, Heap M, et al. The outcome of acute renal failure in the intensive care unit according to RIFLE: model application, sensitivity, and predictability. Am J Kidney Dis 2005;46:103848. [11] Kuitunen A, Vento A, Suojaranta-Ylinen R, et al. Acute renal failure after cardiac surgery: evaluation of the RIFLE classication. Ann Thorac Surg 2006;81:5426. [12] Lopes JA, Jorge S, Silva S, et al. An assessment of the RIFLE criteria for acute renal failure following myeloablative autologous and allogeneic haematopoietic cell transplantation. Bone Marrow Transplant 2006;38:395. [13] Cruz DN, Bolgan I, Perazella MA, et al. North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury (NEiPHROS-AKI): targeting the problem with the RIFLE criteria. Clin J Am Soc Nephrol 2007;2:41825. [14] Moran SM, Myers BD. Course of acute renal failure studied by a model of creatinine kinetics. Kidney Int 1985;27:92837. [15] Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992;38:193353. [16] Lameire N, Vanholder R, Van Biesen W. Loop diuretics for patients with acute renal failure: helpful or harmful? JAMA 2002;288:2599601. [17] Mehta RL, Pascual MT, Soroko S, et al. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002;288:254753. [18] Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:12318.

THE PATIENT WITH ACUTE KIDNEY INJURY

261

[19] Mishra J, Ma Q, Prada A, et al. Identication of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003;14: 253443. [20] Parikh CR, Jani A, Mishra J, et al. Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant 2006;6: 163945. [21] Wagener G, Jan M, Kim M, et al. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006;105:48591. [22] Han WK, Bonventre JV. Biologic markers for the early detection of acute kidney injury. Curr Opin Crit Care 2004;10:47682. [23] Zhou Y, Vaidya VS, Brown RP, et al. Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium. Toxicol Sci 2008;101:15970. [24] Han WK, Bailly V, Abichandani R, et al. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 2002;62:23744. [25] Ichimura T, Hung CC, Yang SA, et al. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol 2004; 286:F55263. [26] Vaidya VS, Ramirez V, Ichimura T, et al. Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 2006;290:F51729. [27] Parikh CR, Abraham E, Ancukiewicz M, et al. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 2005;16:304652. [28] Parikh CR, Mishra J, Thiessen-Philbrook H, et al. Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006;70:199203. [29] Liangos O, Wald R, OBell JW, et al. Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol 2006;1:4351. [30] Xue JL, Daniels F, Star RA, et al. Incidence and mortality of acute renal failure in Medicare beneciaries, 1992 to 2001. J Am Soc Nephrol 2006;17:113542. [31] Waikar SS, Curhan GC, Wald R, et al. Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol 2006;17:114350. [32] Waikar SS, Wald R, Chertow GM, et al. Validity of international classication of diseases, ninth revision, clinical modication codes for acute renal failure. J Am Soc Nephrol 2006; 17:168894. [33] Hsu CY, McCulloch CE, Fan D, et al. Community-based incidence of acute renal failure. Kidney Int 2007;72:20812. [34] Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:8138. [35] Blantz RC. Pathophysiology of pre-renal azotemia. Kidney Int 1998;53:51223. [36] Webb JA. Ultrasonography in the diagnosis of renal obstruction. BMJ 1990;301:9446. [37] Webb JA, Reznek RH, White FE, et al. Can ultrasound and computed tomography replace high-dose urography in patients with impaired renal function? Q J Med 1984;53:41125. [38] Shokeir AA, Shoma AM, Mosbah A, et al. Noncontrast computed tomography in obstructive anuria: a prospective study. Urology 2002;59:8614. [39] Star RA. Treatment of acute renal failure. Kidney Int 1998;54:181731. [40] Levy EM, Viscoli CM, Horwitz RI. The eect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:148994. [41] Metnitz PG, Krenn CG, Steltzer H, et al. Eect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30:20518. [42] Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996;334: 144860.

262

KHALIL

et al

[43] Molitoris BA, Sutton TA. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 2004;66:4969. [44] Friedewald JJ, Rabb H. Inammatory cells in ischemic acute renal failure. Kidney Int 2004; 66:48691. [45] Rabb H. Immune modulation of acute kidney injury. J Am Soc Nephrol 2006;17:6046. [46] Rabb H, Daniels F, ODonnell M, et al. Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol 2000;279:F52531. [47] Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 2002;62:153949. [48] Bonventre JV, Zuk A. Ischemic acute renal failure: an inammatory disease? Kidney Int 2004;66:4805. [49] Solez K, Morel-Maroger L, Sraer JD. The morphology of acute tubular necrosis in man: analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine (Baltimore) 1979;58:36276. [50] Chawla LS, Abell L, Mazhari R, et al. Identifying critically ill patients at high risk for developing acute renal failure: a pilot study. Kidney Int 2005;68:227480. [51] Gornick CC Jr, Kjellstrand CM. Acute renal failure complicating aortic aneurysm surgery. Nephron 1983;35:14557. [52] Cahill CJ, Pain JA, Bailey ME. Bile salts, endotoxin and renal function in obstructive jaundice. Surg Gynecol Obstet 1987;165:51922. [53] Thakar CV, Arrigain S, Worley S, et al. A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 2005;16:1628. [54] Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 2006;1:1932. [55] Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med 2007;357:797805. [56] Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004;351:15969. [57] Linas SL, Whittenburg D, Parsons PE, et al. Mild renal ischemia activates primed neutrophils to cause acute renal failure. Kidney Int 1992;42:6106. [58] Langenberg C, Bellomo R, May CN, et al. Renal vascular resistance in sepsis. Nephron Physiol 2006;104:111. [59] Langenberg C, Wan L, Egi M, et al. Renal blood ow in experimental septic acute renal failure. Kidney Int 2006;69:19962002. [60] Baker RJ, Pusey CD. The changing prole of acute tubulointerstitial nephritis. Nephrol Dial Transplant 2004;19:811. [61] Rossert J. Drug-induced acute interstitial nephritis. Kidney Int 2001;60:804. [62] Clive DM, Sto JS. Renal syndromes associated with nonsteroidal antiinammatory drugs. N Engl J Med 1984;310:56372. [63] Scolari F, Tardanico R, Zani R, et al. Cholesterol crystal embolism: a recognizable cause of renal disease. Am J Kidney Dis 2000;36:1089109. [64] Modi KS, Rao VK. Atheroembolic renal disease. J Am Soc Nephrol 2001;12:17817. [65] Greenberg A, Bastacky SI, Iqbal A, et al. Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: clinicopathological correlations. Am J Kidney Dis 1997;29:33444. [66] Kelton J, Kelley WN, Holmes EW. A rapid method for the diagnosis of acute uric acid nephropathy. Arch Intern Med 1978;138:6125. [67] Davidson MB, Thakkar S, Hix JK, et al. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med 2004;116:54654. [68] Kaplan AA, Kohn OF. Fractional excretion of urea as a guide to renal dysfunction. Am J Nephrol 1992;12:4954. [69] Carvounis CP, Nisar S, Guro-Razuman S. Signicance of the fractional excretion of urea in the dierential diagnosis of acute renal failure. Kidney Int 2002;62:22239. [70] Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32:166977.

THE PATIENT WITH ACUTE KIDNEY INJURY

263

[71] Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000;356:213943. [72] Friedrich JO, Adhikari N, Herridge MS, et al. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005;142: 51024. [73] Druml W. Nutritional management of acute renal failure. J Ren Nutr 2005;15:6370. [74] Druml W. Nutritional management of acute renal failure. Am J Kidney Dis 2001;37:S8994. [75] Palevsky PM. Renal replacement therapy I: indications and timing. Crit Care Clin 2005;21: 34756. [76] Rondon-Berrios H, Palevsky PM. Treatment of acute kidney injury: an update on the management of renal replacement therapy. Curr Opin Nephrol Hypertens 2007;16:6470. [77] Schi H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002;346:30510. [78] Ronco C, Bellomo R, Homel P, et al. Eects of dierent doses in continuous veno-venous haemoltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000;356:2630. [79] Saudan P, Niederberger M, De Seigneux S, et al. Adding a dialysis dose to continuous hemoltration increases survival in patients with acute renal failure. Kidney Int 2006; 70:13127. [80] Palevsky PM, OConnor T, Zhang JH, et al. Design of the VA/NIH Acute Renal Failure Trial Network (ATN) study: intensive versus conventional renal support in acute renal failure. Clin Trials 2005;2:42335. [81] Ronco C. Continuous dialysis is superior to intermittent dialysis in acute kidney injury of the critically ill patient. Nat Clin Pract Nephrol 2007;3:1189. [82] Himmelfarb J. Continuous dialysis is not superior to intermittent dialysis in acute kidney injury of the critically ill patient. Nat Clin Pract Nephrol 2007;3:1201. [83] Mehta RL, McDonald B, Gabbai FB, et al. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001;60:115463. [84] Augustine JJ, Sandy D, Seifert TH, et al. A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis 2004;44:10007. [85] Uehlinger DE, Jakob SM, Ferrari P, et al. Comparison of continuous and intermittent renal replacement therapy for acute renal failure. Nephrol Dial Transplant 2005;20:16307. [86] Vinsonneau C, Camus C, Combes A, et al. Continuous venovenous haemodialtration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet 2006;368:37985. [87] Weisbord SD, Palevsky PM. Radiocontrast-induced acute renal failure. J Intensive Care Med 2005;20:6375. [88] Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002;162:32936. [89] Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004;291:232834. [90] Mueller C. Prevention of contrast-induced nephropathy with volume supplementation. Kidney Int 2006;69:S169. [91] McCullough PA, Bertrand ME, Brinker JA, et al. A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast media. J Am Coll Cardiol 2006;48: 6929. [92] McCullough PA, Stacul F, Becker CR, et al. Contrast-Induced Nephropathy (CIN) Consensus Working Panel: executive summary. Rev Cardiovasc Med 2006;7:17797. [93] Solomon R. The role of osmolality in the incidence of contrast-induced nephropathy: a systematic review of angiographic contrast media in high risk patients. Kidney Int 2005;68: 225663.

264

KHALIL

et al

[94] Solomon R, Deray G. How to prevent contrast-induced nephropathy and manage risk patients: practical recommendations. Kidney Int 2006;69:S513. [95] Briguori C, Airoldi F, DAndrea D, et al. Renal Insuciency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation 2007;115:12117. [96] Solomon R, Werner C, Mann D, et al. Eects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994; 331:141620. [97] Kurnik BR, Allgren RL, Genter FC, et al. Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 1998;31:67480. [98] Stone GW, McCullough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA 2003;290:228491. [99] Abizaid AS, Clark CE, Mintz GS, et al. Eects of dopamine and aminophylline on contrastinduced acute renal failure after coronary angioplasty in patients with preexisting renal insuciency. Am J Cardiol 1999;83:2603. [100] Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 2002; 40:13838. [101] Kay J, Chow WH, Chan TM, et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA 2003;289:5538. [102] Briguori C, Colombo A, Airoldi F, et al. N-acetylcysteine versus fenoldopam mesylate to prevent contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2004;44:7625. [103] Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agentinduced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:1804. [104] Nallamothu BK, Shojania KG, Saint S, et al. Is acetylcysteine eective in preventing contrast-related nephropathy? A meta-analysis. Am J Med 2004;117:938. [105] Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006;354:277382. [106] Bagshaw SM, McAlister FA, Manns BJ, et al. Acetylcysteine in the prevention of contrastinduced nephropathy: a case study of the pitfalls in the evolution of evidence. Arch Intern Med 2006;166:1616.