Brenner and Rector's The Kidney, 8th ed.

CHAPTER 29. Acute Kidney Injury

Michael R. Clarkson   John J. Friedewald   Joseph A. Eustace   Hamid Rabb



Definition and Classification, 943



Incidence, 944



Etiology of Acute Kidney Injury, 945



Prerenal Acute Kidney Injury, 945



Intrinsic Acute Kidney Injury, 946



Postrenal Acute Kidney Injury, 950



The Pathology and Pathophysiology of Acute Tubule Necrosis, 951



Morphology of Acute Tubular Necrosis, 951



Pathophysiology of Kidney Dysfunction in Acute Kidney Injury, 951



New Experimental Models, 956



Novel Biomarkers, 956



Course of Acute Tubule Necrosis, 957



Differentiation of Acute Tubule Necrosis from Other Causes of Acute Kidney Injury, 958



Clinical Features, Urinary Findings, and Confirmatory Tests, 958



Renal Failure Indices for Differentiation of Prerenal Acute Kidney Injury and Ischemic Acute Tubule Necrosis, 962



Differential Diagnosis of Acute Kidney Injury in Specific Clinical Settings, 963



Complications of Acute Kidney Injury, 966



Management of Acute Kidney Injury, 968



Prerenal Acute Kidney Injury, 968



Intrinsic Acute Kidney Injury, 969



Postrenal Acute Kidney Injury, 975



Outcome, 975


Acute kidney injury (AKI) is a protean syndrome of varied severity. It is characterized by a rapid (hours to weeks) decline in the glomerular filtration rate (GFR) and retention of nitrogenous waste products such as blood urea nitrogen (BUN) and creatinine. [1] [2] In recent years, it has been recognized that the time-honored term acute renal failure (ARF) fails to adequately describe what is a dynamic process extending across initiation, maintenance, and recovery phases, each of which may be of variable duration and severity. The term acute renal failure suggests that the syndrome is dichotomous and places an undue emphasis on whether or not renal function has overtly failed. This belies the now well-established fact that even mild decrements in glomerular filtration may be associated with adverse clinical outcomes. [3] [4] [5] [6] [7] The alternative proposed term acute kidney injury has much to recommend it, perhaps better captures the diverse nature of this syndrome, and has entered into widespread clinical use. In this chapter, the two terms are used interchangeably. In clinical practice, acute tubular necrosis (ATN) has come to be used almost synonymously with AKI, although preferably, its use should be limited to a histologic context.

Historically, patients with AKI have been classified as being nonoliguric (urine output >400 mL/day), oliguric (urinary out-put <400 mL/day), or anuric (urinary output <100 mL/day).[8] Lower levels of urinary output typically reflect a more severe initial injury, have implications for volume overload and electrolyte disturbances, and are of prognostic importance. However, the therapeutic manipulation of the urine output does not ameliorate this prognostic association (vide infra).

For purposes of diagnosis and management, AKI has been divided into three categories ( Table 29-1 ):



Diseases characterized by renal hypoperfusion in which the integrity of renal parenchymal tissue is preserved (prerenal states),



Diseases involving renal parenchymal tissue (intrarenal AKI or intrinsic AKI), and



Diseases associated with acute obstruction of the urinary tract (postrenal or obstructive AKI).

TABLE 29-1   -- Classification and Major Disease Categories Causing Acute Kidney Injury

Disease Category

Percentage of Patients with Acute Kidney Injury

Prerenal azotemia caused by acute renal hypoperfusion




Intrinsic renal azotemia caused by acute diseases of renal parenchyma



Diseases involving large renal vessels



Diseases of small renal vessels and glomeruli



Acute injury to renal tubules mediated by ischemia or toxins[*]



Acute diseases of the tubulointerstitium


Postrenal azotemia caused by acute obstruction of urinary collecting system




Accounts for more than 90% of cases in the intrinsic renal azotemia category in most series.


Most acute intrinsic AKI is caused by ischemia or nephrotoxins and is classically associated with ATN.

AKI may occur in someone either with previously normal renal function or as an acute and unanticipated deterioration in function in the setting of previously established chronic kidney disease. The etiology and outcome of AKI is heavily influenced by the circumstances in which it occurs, such as whether it develops in the community or in the hospital. It is similarly important to distinguish whether the kidney injury occurs as an isolated process, which is more common in community-acquired AKI, or if it occurs as part as a more extensive multiorgan syndrome. In the former context, management is often, at least initially, conservative and follows an expectant approach—deferring renal replacement therapy when possible while awaiting the spontaneous recovery of renal function. In the case of a critically ill patient with multiorgan failure, dialysis may be commenced much earlier, because the goal is not simply control of azotemia but rather one of renal support in an attempt to optimize the subject's physiologic parameters.[9]

More than 35 different definitions of AKI have been used in the recent literature.[10] These are typically based on either a fixed or relative increment in the serum creatinine level or reductions in urinary output. Most of these definitions are arbitrary and have not been validated with regard to their prognostic importance. Not surprisingly, this has limited the comparability of different studies and has hampered the translation of bench research into clinical practice.[11] Recently, a consensus conference sponsored by the Acute Dialysis Quality Improvement Initiative (ADQI) has proposed a new definition of ARF, that has been widely endorsed and is increasingly being used.[12] In keeping with the spectrum of changes seen in AKI, a diagnostic classification scheme was developed. This scheme is referred to by the acronym RIFLE, and includes three levels of renal dysfunction of increasing severity, namely, Risk of renal dysfunction, Injury to the kidney and Failure of kidney function, and two outcome categories: Loss of function, and End stage kidney disease ( Fig. 29-1 ) . Renal dysfunction is defined in terms of either a rise in creatinine or a reduction in urine output, the more severe of the two criteria being selected. RIFLE-F (Failure) is present even if the rise in serum creatinine is less than threefold above baseline, provided that the new serum creatinine is greater than 4 mg/dL and has risen by at least 0.5 mg/dL. When the achieved designation results from urine output criteria a subscript “o” is added e.g. RIFLE-Fo. Similarly, a subscript “c” is used to denote the presence of preexisting chronic kidney disease. An inevitable limitation of any definition that uses relative changes in renal function is the problem of when the patient's baseline function is unknown and, therefore, can only be estimated. A worse RIFLE criteria score is associated with a progressively worse APACHE II score and higher mortality at both 1 and 6 months. [5] [13] A more extensive classification system based on an multidimensional approach, as used in several other area of medicine such as with cirrhosis, has also recently been proposed for AKI.[14] This includes 4 separate axis, namely (1) susceptibility—the prior level of renal function, (2) the nature and timing of the applied insult, (3) the response to this injury as measured by the RIFLE criteria and (4) the associated number of failed organs. This more complicated schema has the advantage of including not only the renal response but also of quantifying the clinical circumstances in which the injury occurs, factors that influence the clinical outcome and which therefore should equally be considered in estimating clinical risks and determining the optimal management.



FIGURE 29-1  RIFLE classification scheme for acute renal failure. The classification system includes separate criteria for creatinine and urine output. A patient can fulfill the criteria through changes in serum creatinine (SCreat) or changes in urinary output, or both. The criteria that lead to the worst possible classification should be used. The shape of the figure denotes the fact that more patients (high sensitivity) will be included in the mild category, including some without actually having renal failure (less specificity). In contrast, at the bottom of the figure, the criteria are strict and therefore specific, but some patients will be missed.  (From Bellomo R, Ronco C, Kellum JA, et al: Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204–R212, 2004.)




A major challenge in the investigation and management of AKI is the timely recognition of the syndrome. It remains difficult to easily and reliably measure rapid changes in the GFR. Although the severity in decline in GFR correlates with the onset of oliguria, the latter is insensitive marker of the syndrome because many subjects with severe renal failure remain nonoliguric. In AKI, there is poor agreement between serum creatinine and GFR, at least until a serum creatinine steady state is reached, and even then, the absolute rise in serum creatinine must take into account differences in creatinine generation rates.[15] As a result, definitions of AKI that are based on a fixed increment in serum creatinine would be expected to be biased toward making an early diagnosis in well-muscled as compared with malnourished subjects or in men as compared with women. Creatinine clearances, especially when measured over a short time frame such as 2 to 4 hours, has some utility but may substantially overestimate GFR at low levels of renal function owing to a relatively high proportion of tubular secretion. Even the use of markers such as iothalamate to estimate GFR may be less precise in the acute as compared with the chronic setting owing to alterations in their volume of distribution as well as issues relating to tubular obstruction and backleak. The use of cystatin C or of other alternative makers of early AKI is an area of ongoing research.[16]


The incidence of in hospital AKI is difficult to estimate because no registry of its occurrence exists and because up until recently there was no standardized definition. From a variety of predominantly single center studies it is estimated that 3% to 7% of hospitalized patients develop AKI. [17] [18] [19] More detailed information is available regarding its development in the intensive care unit (ICU) environment, where approximately 25% to 30% of unselected patients develop some degree of AKI, although again estimates vary considerable depending on the definition used and the population casemix. Renal replacement therapy is typically required in 5% to 6% of the general ICU population or 8.8 to 13.4 cases per 100,000 population/year. [5] [20] [21] [22] [23] [24] However, with the increasing prevalence of older subjects, higher degrees of comorbidity and preexisting chronic kidney disease in some centers, the proportion of patients requiring dialysis is substantially higher, two thirds of patients with AKI in one large multicenter study.[25] The occurrence of AKI and the need for renal replacement therapy may also be much higher in specific high-risk populations, such as those with haematologic malignancies, in whom in one study the requirement for renal replacement therapy was 22.5% as compared with 5.8% in those without haematological malignancies.[26]

A recent analysis of a random 5% sample of Medicare beneficiaries based on inpatient claims data from between 1992 and 2001 found an overall AKI incidence of 23.8 cases per 1000 hospital discharges. The rate per 1000 discharges progressively increased—by approximately 11% per year—over the decade from 14.6 in 1992 to 36.4 in 2001 and was consistently higher in older subjects, men, and blacks.[27] A similar incidence rate—9.2 cases per 1000 hospitalizations, equivalent to 1.9% of all hospital discharges—and similar demographic associations were observed using the 2001 National Hospital Discharge Survey, a national collected database based on a representative sample of nonfederal acute care hospitals.[28]


Prerenal Acute Kidney Injury

Prerenal AKI is the most common cause of AKI and is an appropriate physiologic response to renal hypoperfusion. [2] [22] [29] By definition, the integrity of renal parenchymal tissue is maintained and GFR is corrected rapidly with restoration of renal perfusion. Severe renal hypoperfusion may cause ischemic ATN. Thus, prerenal AKI and ischemic ATN are part of a spectrum of manifestations of renal hypoperfusion, and the clinical and biochemical features of prerenal ARF and ischemic ATN coexist in many patients.

Prerenal AKI can complicate any disease characterized by hypovolemia, low cardiac output, systemic vasodilatation, or intrarenal vasoconstriction ( Table 29-2 ). True or “effective” hypovolemia leads to a fall in mean systemic arterial pressure, which, in turn, activates arterial (e.g., carotid sinus) and cardiac baroreceptors and initiates a series of neural and humoral responses that include activation of the sympathetic nervous system and renin-angiotensin-aldosterone system and release of antidiuretic hormone (see Fig. 29-1 ). [30] [31] [32] Norepinephrine, angiotensin II, and antidiuretic hormone act in concert in an attempt to maintain blood pressure and preserve cardiac and cerebral perfusion by stimulating vasoconstriction in relatively “less important” vascular beds such as the musculocutaneous and splanchnic circulations, by inhibiting salt loss through sweat glands, by stimulating thirst and salt appetite, and by promoting renal salt and water retention. Glomerular perfusion, ultrafiltration pressure, and filtration rate are preserved during mild hypoperfusion through several compensatory mechanisms. Stretch receptors in the walls of afferent arterioles detect a reduction in perfusion pressure, triggering relaxation of afferent arteriolar smooth muscle cells and vasodilatation (autoregulation). Intrarenal biosynthesis of vasodilator prostaglandins (e.g., prostacyclin, prostaglandin E2), kallikrein and kinins, and possibly nitric oxide (NO) is enhanced. Angiotensin II may induce preferential constriction of efferent arterioles, probably because most angiotensin II receptors are found at this location.[33] As a result, intraglomerular pressure is preserved, the fraction of renal plasma that is filtered by glomeruli (filtration fraction) is increased, and GFR is maintained.

TABLE 29-2   -- Major Causes of Prerenal Azotemia



Intravascular volume depletion



Hemorrhage: traumatic, surgical, gastrointestinal, postpartum



Gastrointestinal losses: vomiting, nasogastric suction, diarrhea



Renal losses: drug-induced or osmotic diuresis, diabetes insipidus, adrenal insufficiency



Skin and mucous membrane losses: burns, hyperthermia, and other causes of increased insensible losses



“Third-space” losses: pancreatitis, crush syndrome, hypoalbuminemia



Decreased cardiac output



Diseases of myocardium, valves, pericardium, or conducting system



Pulmonary hypertension, pulmonary embolism, positive-pressure mechanical ventilation



Systemic vasodilatation



Drugs: antihypertensives, afterload reduction, anesthetics, drug overdoses



Sepsis, liver failure, anaphylaxis



Renal vasoconstriction



Norepinephrine, ergotamine, liver disease, sepsis, hypercalcemia



Pharmacologic agents that acutely impair autoregulation and glomerular filtration rate in specific settings



Angiotensin-converting enzyme inhibitors in renal artery stenosis or severe renal hypoperfusion



Inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs during renal hypoperfusion




These compensatory renal responses are overwhelmed during states of moderate to severe hypoperfusion, and ARF ensues. Autoregulatory dilatation of afferent arterioles is maximal at a mean systemic arterial blood pressure of about 70 to 80 mm Hg, and hypotension below this level is associated with a precipitous decline in glomerular ultrafiltration pressure and GFR. [34] [35] Lesser degrees of hypotension may provoke prerenal AKI in the elderly, in patients with renovascular disease, and in patients with diseases affecting the integrity of afferent arterioles (e.g., hypertensive nephrosclerosis, diabetic nephropathy).[36] In addition, very high levels of angiotensin II, as are found in patients with marked circulatory failure, provoke constriction of both afferent and efferent arterioles, thus negating the relatively selective effect of low levels of this peptide on efferent arteriolar resistance.

Several classes of commonly used drugs impair renal adaptive responses and can convert compensated renal hypoperfusion to overt prerenal AKI or trigger progression of prerenal AKI to ischemic ATN.[37] Nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase II (COX-II) inhibitors, inhibit renal prostaglandin biosynthesis. They do not compromise GFR in normal individuals but may precipitate prerenal AKI in subjects with true hypovolemia or decreased effective arterial blood volume, or in patients with chronic renal insufficiency in whom GFR is maintained in part by prostaglandin-mediated hyperfiltration through remnant nephrons. [38] [39] [40] [41]Similarly, inhibitors of angiotensin-converting enzyme (ACE) and angiotensin II receptor blockers (ARBs) may trigger prerenal AKI in individuals in whom intraglomerular pressure and GFR are dependent on angiotensin II. This complication is classically seen in patients with bilateral renal artery stenosis or unilateral stenosis in a solitary functioning kidney. [42] [43] [44] [45] [46] [47] Here, angiotensin II preserves glomerular filtration pressure distal to renal arterial stenosis by increasing systemic arterial pressure and by triggering selective constriction of efferent arterioles. ACE inhibitors and ARBs blunt these compensatory responses and can precipitate reversible AKI in such patients. ACE inhibitors or ARBs, like NSAIDs, may also precipitate prerenal AKI in patients with compensated renal hypoperfusion of other causes, mandating close monitoring of the serum creatinine level when these drugs are administered to high-risk individuals.

The classic urinary and biochemical sequelae of prerenal AKI can be predicted from the stimulatory actions of norepinephrine, angiotensin II, antidiuretic hormone, and low urine flow rate on salt and water reabsorption from urine and include concentrated urine (specific gravity >1.018, osmolality >500 mOsm/kg H2O, low urinary Na+ concentration, and benign urine sediment. Nonoliguric prerenal ARF may be seen in patients with renal concentrating deficits (e.g., diabetes insipidus) and in the setting of large endogenous (glucose/urea) or exogenous (mannitol) solute loads. [48] [49] Hypernatremia due to increased free water losses is a clue to the presence of a polyuric prerenal state.

Some vasoactive mediators, drugs, and diagnostic agents stimulate intense intrarenal vasoconstriction and induce glomerular hypoperfusion and AKI with many of the functional, clinical, and biochemical features of prerenal AKI. Examples include hypercalcemia, endotoxin, radiocontrast agents, calcineurin inhibitors (cyclosporin, FK506/tacrolimus), amphotericin B, cocaine, and norepinephrine (e.g., therapeutic administration, pheochromocytoma, brain damage). [50] [51] [52] Cyclosporine and tacrolimus precipitate ARF by inducing intrarenal vasoconstriction and hypoperfusion, and by stimulating mesangial cell contraction and a fall in glomerular filtration surface area. [53] [54]Frank tubule necrosis is rare in this setting, although long-term calcineurin inhibition may lead to irreversible renal impairment, probably as a consequence of obliterative arteriopathy and chronic medullary ischemia.

Intrinsic Acute Kidney Injury

Ischemic ATN and toxic ATN account for about 80% to 90% of intrinsic AKI. [22] [55] [56] From a clinicopathologic viewpoint, it is helpful to categorize the causes of intrinsic ARF into the following categories ( Table 29-3 )



Diseases involving large renal vessels,



Diseases of the renal microvasculature and glomeruli,



Ischemic and nephrotoxic ATN, and



Other acute processes involving the tubulointerstitium.

TABLE 29-3   -- Major Causes of Acute Intrinsic Renal Azotemia



Diseases involving large renal vessels



Renal arteries[*]: thrombosis, atheroembolism, thromboembolism, dissection, vasculitis (e.g., Takayasu)



Renal veins[*]: thrombosis, compression



Diseases of glomeruli and the renal microvasculature (see Table 29-4 )



Inflammatory: acute or rapidly progressive glomerulonephritis, vasculitis, allograft rejection, radiation



Vasospastic: malignant hypertension, toxemia of pregnancy, scleroderma, hypercalcemia, drugs, radiocontrast agents



Hematologic: hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, hyperviscosity syndromes



Diseases characterized by prominent injury to renal tubules often with ATN[†][‡]



Ischemia caused by renal hypoperfusion (see Table 29-2 )



Exogenous toxins (e.g., antibiotics, anticancer agents, radiocontrast agents, poisons; see Table 29-6 )



Endogenous toxins (e.g., myoglobin, hemoglobin, myeloma light chains, uric acid, tumor lysis; see Table 29-7 )



Acute diseases of the tubulointerstitium (see Table 29-5 )



Allergic interstitial nephritis (e.g., antibiotics, nonsteroidal anti-inflammatory drugs)



Infectious (viral, bacterial, fungal)



Acute cellular allograft rejection



Infiltration[§] (e.g., lymphoma, leukemia, sarcoid)



Acute renal failure (ARF) in this context usually implies bilateral disease or unilateral disease in a solitary functioning kidney.

The majority of cases of acute intrinsic renal azotemia fall into this category.

Although frank necrosis of renal tubules is not invariably present, the term acute tubule necrosis (ATN) is used by convention to denote ARF related to tubule injury by either ischemia or nephrotoxins (see section on pathophysiology of ischemic ATN).


Although infiltration of renal parenchyma is common, renal failure rarely occurs.


Diseases of Large Renal Vessels, Microvasculature, and Tubulointerstitium

Occlusion of large renal vessels, either arteries or veins, is an uncommon cause of AKI. To affect BUN and serum creatinine, occlusion must be either bilateral or unilateral in patients with underlying chronic renal insufficiency or a solitary functioning kidney. Renal arteries may be occluded acutely by atheroemboli, thromboemboli, thrombosis, dissection of an aortic aneurysm, or, rarely, vasculitis. Atheroemboli are the most common culprits and are usually dislodged from an atheromatous aorta during arteriography, angioplasty, or aortic surgery.[57] Cholesterol emboli lodge in medium or small renal arteries, where they incite an inflammatory reaction characterized classically by intimal proliferation, infiltration of vessel wall by macrophages and giant cells, fibrosis, and irreversible occlusion of the vessel lumen. Thromboemboli may originate in the heart in patients with atrial arrhythmias or mural thrombi and trigger acute infarction of renal tissue. [58] [59] This may present with sudden flank pain and signs of a systemic inflammatory response. Renal artery thrombosis is usually superimposed on an atheromatous plaque but may also complicate traumatic intimal tears or the site of surgical anastomosis after renal transplantation. Outside of the immediate post-transplantation period, renal vein thrombosis is an exceedingly rare cause of AKI and is usually encountered as a complication of the nephrotic syndrome in adults or of severe dehydration in children. [60] [61]

Virtually all diseases that compromise blood flow within the renal microvasculature may induce AKI. [62] [63] [64] These include inflammatory (e.g., glomerulonephritis or vasculitis) and noninflammatory (e.g., malignant hypertension) diseases of the vessel wall, thrombotic microangiopathies, and hyperviscosity syndromes ( Table 29-4 ). Indeed, the decrement in renal perfusion in these settings may be severe enough to trigger superimposed ischemic ATN.[65] In general, these disorders can be distinguished from prerenal AKI and ischemic or nephrotoxic ATN by clinical or laboratory criteria; how-ever, a renal biopsy may be required for definitive diagnosis (see later section on differential diagnosis). Disorders of the tubulointerstitium that induce AKI, other than ischemia or tubule cell toxins, include allergic interstitial nephritis, severe infections, allograft rejection, and, rarely, infiltrative disorders such as sarcoid, lymphoma, or leukemia ( Table 29-5 ). A comprehensive discussion of these diseases is beyond the scope of this chapter and is presented elsewhere in this book.

TABLE 29-4   -- Some Diseases of Glomeruli and the Renal Microvasculature Associated with Acute Intrinsic Renal Azotemia



Glomerulonephritis or vasculitis



Associated with antiglomerular basement membrane antibody (anti-GBM Ab)



(Goodpasture syndrome if associated with lung hemorrhage)



Associated with antineutrophil cytoplasmic antibodies (ANCA)



Wegener granulomatosis



Microscopic or Churg-Strauss variant of polyarteritis nodosa



Renal-limited crescentic glomerulonephritis



Associated with glomerular immune complexes and hypocomplementemia



Acute diffuse proliferative glomerulonephritis (postinfectious)



Membranoproliferative glomerulonephritis



Subacute bacterial endocarditis






Systemic lupus erythematosus (SLE)



Associated with absence of hypocomplementemia, ANCA, and anti-GBM Ab



Immunoglobulin A nephropathy



Schönlein-Henoch purpura



Classic polyarteritis nodosa



Radiation injury



Associated with collapsing glomerulopathy



Infection (HIV)






Hyperviscosity syndromes



Multiple myeloma



Waldenström macroglobulinemia






Hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura






Viral (e.g., enterovirus, coxsackievirus, influenza virus, hepatitis A virus, HIV)



Bacterial (e.g., Escherichia coli O157:H7, Shigella dysenteriae, Salmonella, Yersinia, Campylobacter)






Disseminated malignancy (e.g., gastric adenocarcinoma)



Chemotherapeutic agents (mitomycin C, cisplatin, bleomycin, gemcytabine)



Calcineurin inhibitors, oral contraceptives, ticoldipine, clopidrogrel



Immunologic Diseases



SLE, rheumatoid arthritis, Sjögren, ankylosing spondylitis






Idiopathic, familial, pregnancy and puerperium









Accelerated hypertension



Scleroderma crisis



Toxemia of pregnancy






Calcineurin inhibitors



Amphotericin B






Radiocontrast agents




TABLE 29-5   -- Diseases of the Tubulointerstitium Associated with Acute Intrinsic Renal Azotemia

Drug-Induced Allergic Interstitial Nephritis




Other Antibiotics


























Penecillin G

























































Mefenamic acid































































Acute pyelonephritis[†]






Scarlet fever



Typhoid Fever



Legionaires Disease


















Rocky Mountain spotted fever






Candidiasis, other fungi[‡]






Systemic disease






Sjögren syndrome




















NSAIDS, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus; TINU, tubulointerstitial nephritis and uveitis syndrome.


Rare to get AKI unless bilateral disease in diabetic patients.

May cause AKI by obstruction of tubules (fungus balls), in addition to causing acute interstitial nephritis.


Acute Tubule Necrosis

As discussed earlier, the pathologic term ATN and the clinical term ARF/AKI are often used interchangeably when referring to ischemic and nephrotoxic renal injury, evidence of frank necrosis of renal tubules is sparse or absent in most cases (vide infra).[66] Prerenal AKI and ischemic ATN are part of a spectrum of manifestations of renal hypoperfusion-prerenal AKI being a response to mild or moderate hypoperfusion and ischemic ATN being the result of more severe or prolonged hypoperfusion, often coexistent with other renal insults.[25] It is notable that extracellular fluid losses or transient renal hypoperfusion (e.g., cardiac arrest or aortic cross clamping) generally do not cause ATN in the absence of either preexisting renal impairment or the coincidence of another nephrotoxic insult (e.g., vasoactive drugs, sepsis, or rhabdomyolysis).[67] Prerenal AKI differs from ischemic ATN in that it is associated with injury to renal parenchyma and does not resolve immediately on restoration of renal perfusion. In its more extreme form, renal hypoperfusion may result in bilateral renal cortical necrosis and irreversible renal failure.

Ischemic ATN is observed most frequently in patients who have major surgery, trauma, severe hypovolemia, overwhelming sepsis, and burns. [55] [68] [69] [70] [71] [72] The risk of ischemic ATN after cardiac surgery correlates directly with the duration of cardiopulmonary bypass and the degree of preoperative and postoperative cardiac impairment. [73] [74] [75] [76] ATN most commonly complicates aortic surgery in patients undergoing emergency repair of ruptured abdominal aneurysms or after complicated elective procedures requiring prolonged (>60 minutes) clamping of the aorta above the origin of the renal arteries. [77] [78] However, 50% of cases of postsurgical ATN occur in the absence of documented hypotension. ATN complicating trauma is frequently multifactorial in origin and due to the combined effects of hypovolemia and myoglobin or other toxins released by damaged tissue. ATN occurs in 20% to 40% of patients who suffer burns involving more than 15% of their surface area and, again is frequently multifactorial and due to the combined effects of hypovolemia, rhabdomyolysis, sepsis, and nephrotoxic antibiotics.[79] Sepsis induces renal hypoperfusion by provoking a combination of systemic vasodilatation and intrarenal vasoconstriction. [17] [69] [71] [80] [81] [82] [83] [84] [85] In addition, endotoxin sensitizes renal tissue to the deleterious effects of ischemia. [85] [86] [87] The pathophysiology, pathology, management, and clinical course of ischemic ATN are discussed in detail later in this chapter.

Nephrotoxic ATN complicates the administration of many structurally diverse pharmacologic agents and poisons. [38] [52] [88] [89] [90] [91] [92] The proliferation in recent years of novel antimicrobial and anticancer agents has broadened the range of known therapeutic agents that cause nephrotoxic renal injury and has re-enforced the need for vigilance amongst clinicians ( Table 29-6 ). [93] [94] [95] [96] [97] In addition, some endogenous compounds provoke AKI when present in the circulation at high concentrations. [70] [98] In general, nephrotoxins cause renal injury by inducing a varying combination of intrarenal vasoconstriction, direct tubule toxicity, and intratubular obstruction.[88]The kidney is particularly vulnerable to nephrotoxic renal injury by virtue of its rich blood supply (25% of cardiac output) and its ability to concentrate toxins to high levels within the medullary interstitium (via the renal countercurrent mechanisms) and renal epithelial cells (via specific transporters). In addition, the kidney is an important site for xenobiotic metabolism and may transform relatively harmless parent compounds into toxic metabolites. The nephrotoxic potential of most agents is dramatically increased in the presence of borderline or overt renal ischemia, sepsis, or other renal insults. A detailed description of the pathophysiology and clinical features of drug-induced toxic nephropathies is presented in Chapter 63 and only a brief review of some common nephrotoxic syndromes is included here.

TABLE 29-6   -- Some Exogenous Nephrotoxins That Are Common Causes of Acute Intrinsic Renal Azotemia with Acute Tubule Necrosis


Chemotherapeutic agents






Anti-inflammatory and immunosuppressive agents







 Amphotericin B

NSAIDs (including COX-II inhibitors)

Organic solvents


 Ethylene glycol

Intravenous immune globulin


Radiocontrast agents


Bacterial toxins



 Snake bites





Tables 29-6 and 29-7 [6] [7] list the toxins that are most frequently associated with ATN. Acute intrarenal vasoconstriction is an important pathophysiologic event in AKI associated with radiocontrast agents (contrast nephropathy) and calcineurin inhibitors. [54] [90] [99] [100] [101] [102] Contrast nephropathy typically presents as an acute decline in GFR within 24 to 48 hours of administration, a peak in serum creatinine value after 3 to 5 days, and return of the serum creatinine value to the “normal” range within 1 week. [99] [100] The diagnosis is usually straightforward given the temporal correlation with contrast administration; however, consideration must be given to other potential diagnoses including atheroembolic renal disease, renal ischemia (e.g., aortic dissection) and other nephrotoxins. Individuals with chronic renal insufficiency (serum creatinine >2.0 mg/dL) are at the greatest risk of contrast-induced renal injury. [99] [103] [104] Other risk factors include diabetic nephropathy, congestive heart failure, jaundice, volume depletion, multiple myeloma, the volume of contrast used, and the coincident use of ACE inhibitors or NSAIDs. Patients usually present with benign urine sediment, concentrated urine, and low fractional excretion of Na+ and, thus, have many features of prerenal AKI; however, in more severe cases, tubule cell injury may be evident.[105]

TABLE 29-7   -- Some Sources of Endogenous Nephrotoxins That Cause Acute Intrinsic Renal Azotemia with Acute Tubule Necrosis[*]

Rhabdomyolysis with myoglobinuria[†]


Muscle injury

Trauma,[‡] electric shock, hypothermia, hyperthermia (e.g., malignant hyperpyrexia)

Extreme muscular exertion

Seizures,[‡] delirium tremens,[‡] physical exercise

Muscle ischemia

Prolonged compression[‡] (e.g., coma), compromise of major vessels (e.g., thromboembolism, dissection)

Metabolic disorders

Hypokalemia, hypophosphatemia, hypo- and hypernatremia, diabetic ketoacidosis, hyperosmolar states


Influenza, infectious mononucleosis, legionnaires' disease, tetanus


Ethanol,[‡] isopropyl alcohol, ethylene glycol, toluene, snake and insect bites


Cocaine, HMG CoA reductase inhibitors, amphetamines, phencyclidine, lysergic acid diethylamide, heroin, methadone, salicylate overdose, succinylcholine

Immunologic diseases

Polymyositis, dermatomyositis

Inherited diseases

Myophosphorylase, phosphofructokinase, carnitine palmityltransferase, or myoadenylate deaminase deficiency

Hemolysis with hemoglobinuria[†]


Transfusion reactions[‡]

Infections and venoms

Malaria,[‡] clostridia, spider bite (e.g., tarantula, brown recluse), snake bite[‡] (e.g., rattlesnake, copperhead)

Drugs and chemicals

Aniline, arsine, benzene, cresol, fava beans, glycerol, hydralazine, phenol, quinidine, methydopa

Genetic diseases

Glucose 6-phosphate deficiency, paroxysmal nocturnal hemoglobinuria, march hemoglobinuria


Valvular prosthesis, extracorporeal circulation, microangiopathic hemolytic anemias, distilled water (intravenous dialysis, transurethral prostatectomy)

Increased uric acid production with hyperuricosuria

Primary increase in uric acid production

Hypoxanthine-guanine phosphoribosyltransferase



Secondary increase in uric acid production

Treatment of malignancies[‡] (especially lymphoproliferative or myeloproliferative)


Myeloma light chains,[‡] oxalate[‡] (e.g., ethylene glycol toxicity), products of tumor lysis other than uric acid



All of these diseases are sources of potential nephrotoxins, but not all have been definitively associated with acute renal failure (ARF).

Hemoglobin and myoglobin cause little compromise of glomerular filtration when administered to experimental animals. Thus, it remains to be determined whether ARF in these settings is due to hemoglobin or myoglobin, metabolites of these compounds, or other toxic species released from red blood cells or muscle, or requires the coexistence of other renal insults (e.g., hypoperfusion).

Denotes most common causes of ARF. Renal failure is rare in other circumstances.


Postulated mechanisms of contrast agent-induced renal injury favor a combination of medullary ischemia and direct contrast-mediated tubular toxicity due to reactive oxygen species generation. [101] [106] [107] [108] Contrast induces a biphasic hemodynamic response within the kidney; an initial transient vasodilation is followed by a period of sustained vasoconstriction. With regard to the latter, changes in the synthesis and release of NO, endothelin, and adenosine from endothelial cells combine to shunt blood flow away from the renal medulla, which has a high oxygen demand, to the renal cortex. [109] [110] [111] Although most patients recover renal function and the need for dialysis is unusual, contrast nephropathy is associated with a significant prolongation of hospital stay and increased patient mortality.[7]

Intrarenal vasoconstriction is also a central component of AKI complicating hypercalcemia and, in addition, contributes to the nephrotoxicity of myoglobin and hemoglobin. [51] [70] [112] [113] [114] [115] Interestingly, hemoglobin and myoglobin may promote vasoconstriction, at least in part by scavenging the vasodilator NO and thereby disrupting the balance between vasodilators and vasoconstrictors that is critical for maintenance of normal renal perfusion. [116] [117] [118]

Therapeutic agents that are directly toxic to renal tubule epithelium include antimicrobials such as aminoglycosides, amphotericin B, acyclovir, indinavir, cidofovir, pentamidine, and foscarnet, and chemotherapeutic agents such as cisplatin and ifosfamide (see Table 29-6 ). Nonoliguric ATN complicates 10% to 30% of courses of aminoglycoside antibiotics, even when blood levels are in the therapeutic range. [89] [119] [120] [121] [122] Aminoglycosides are polycations and are freely filtered across the glomerular filtration barrier and accumulated by proximal tubule cells by absorbtive endocytosis after interaction with negatively charged phospholipid residues on brush border membranes. Important risk factors for aminoglycoside nephrotoxicity include use of high or repeated doses or prolonged therapy, preexisting renal insufficiency, advanced age, volume depletion, and the coexistence of renal ischemia or other nephrotoxins. [120] [121] [123] [124] [125] [126] Although the precise subcellular mechanisms by which aminoglycosides perturb renal function has not yet been fully elucidated, gentamicin has been demonstrated to bind to megalin, an endocytic receptor in the clathrin-coated pits of the apical cell membrane. When endocytosed, this complex may induce cellular injury by inhibiting endosomal fusion events.[127] Hypomagnesemia is a relatively common additional finding in patients with aminoglycoside-induced ATN and suggests coexistent injury to the thick ascending limb of the loop of Henle, the major site of Mg2+ reabsorption. AKI is usually detected during the second week of therapy, probably reflecting a requirement for accumulation within epithelial cells, but may be manifest earlier in the presence of ischemia or other nephrotoxins. ARF is almost invariable in patients receiving cumulative doses of amphotericin B of more than 1 g and is a common complication even with lower doses. [52] [97] [128] Amphotericin B induces direct renal vasoconstriction and exerts direct toxicity on a variety of tubular segments. The tubular dysfunction is manifested by an increase in tubuloglomerular feedback with resultant suppression of GFR, ATN, hypomagnesemia, hypophosphatemia, hypocalcemia, and a renal tubular acidosis due to backleakage of secreted H+ in the distal cortical nephron. ATN due to amphotericin B is typically reversible, but chronic use can lead to nephrocalcinosis. High-dose intravenous acyclovir causes AKI within 24 to 48 hours in 10% to 30% of patients, particularly if they are volume depleted or if the drug is administered as a bolus. [129] [130] ARF is usually nonoliguric; frequently associated with colic, nausea, and vomiting; and appears to be induced by intratubular precipitation of acyclovir crystals. A similar syndrome in now recognized in patients receiving the oral antiretroviral drug indinavir.[131] Asymptomatic crystaluria in seen in up to 10% of patients, with half this number presenting with loin pain and hematuria. A Fanconi-like syndrome is seen in up to 40% of patients receiving adefovir, a nucleoside reverse transcriptase inhibitor due to a direct toxic effect on tubular cell mitochondrial function.[132]A similar syndrome has also been decribed with tenofovir.[133] Cidofovir, a nucleotide analog used to treat cytomegaolvirus infections is also nephrotoxic.[134] Pentamidine induces AKI in 25% to 95% of patients, usually during the second week of therapy and frequently in association with hypomagnesemia, hypo- or hyperkalemia, and a distal renal tubular acidosis. [135] [136] [137] The mechanism of injury is unclear but may involve an immune process, because AKI does not appear to be dose dependent and is often associated with pyuria, hematuria, proteinuria, and casts. Foscarnet causes a distinct pattern of renal injury characterized by nonoliguric, often polyuric, ARF within 7 days, hyperphosphatemia, ATN, interstitial fibrosis, and a slow recovery that may take months. [138] [139] [140] ATN complicates up to 70% of courses of cisplatin and ifosfamide, two commonly used chemotherapeutic agents. [94] [95] [141] [142] [143] Cisplatin is accumulated by proximal tubule cells and induces mitochondrial injury, inhibition of ATPase activity and solute transport, and free radical-mediated injury to cell membranes. [2] [95] [142] [143] [144] [145] [146] [147]In addition, cisplatin may cause severe hypomagnesemia, even in the absence of AKI, which may persist long after therapy has been stopped. Ifosfamide-induced ATN is being recognized increasingly and is often associated with the Fanconi syndrome, an unusual complication of proximal tubule injury by other agents. [141] [148] [149] The mechanism of proximal tubule injury in this setting is unknown. Methotrexate is primarily excreted unchanged in the urine. With the advent of high-dose intravenous methotrexate administration, typically in the setting of autologous bone marrow transplantation, AKI due to intratubular deposition of methotrexte is increasingly recognized. [94] [150]Recently, there have been increasing reports of ATN associated with sucrose-containing intravenous immunoglobulin preparations. [151] [152] [153] The pathogenesis is believed to involve osmotic injury to the renal tubular epithelial cells by filtered sucrose.

Myoglobin, hemoglobin, uric acid, and myeloma light chains are the endogenous toxins that are most commonly associated with ATN. Renal dysfunction complicates approximately 30% of cases of rhabdomyolysis, the most common causes of which are listed in Table 29-7 . [70] [114] [154] [155] [156] [157] [158] [159] Hemoglobin-induced ATN is rare and is most commonly encountered after blood transfusion reactions (see Table 29-7 ). [117] [160] The precise mechanisms by which rhabdomyolysis and hemolysis impair GFR are unclear, but intrarenal vasoconstriction, intratubular obstruction, and tubule injury have been well documented as contributory pathophysiologic events in experimental animals. Neither myoglobin nor hemoglobin is markedly nephrotoxic when injected in vivo. Both pigments induce intrarenal vasoconstriction, probably by scavenging the vasodilator NO in the renal microcirculation. At acid pH, myoglobin and hemoglobin are also sources of ferrihemate, a substance that is a potent inhibitor of tubule transport. In this regard, it is noteworthy that hypovolemia and acidosis predispose experimental animals and humans to pigment-induced ATN. Finally, both pigments, being ferrous iron compounds, may potentially induce tubule injury by stimulating local production of OH-. [114] [157] [161] [162] [163] [164]

Intratubular obstruction has been implicated as a central event in the pathophysiology of ATN induced by some other endogenous (e.g., myeloma light chains, uric acid) and exogenous (ethylene glycol) nephrotoxins. Casts, composed of filtered immunoglobulin light chains and other urinary proteins such as Tamm-Horsfall protein (THP), induce AKI in patients with multiple myeloma (myeloma-cast nephropathy). [98] [112] [165] [166] [167] [168] [169] High urinary salt concentrations and low urine pH promote this process. The correlation between cast formation and renal insufficiency is relatively weak, how-ever, suggesting that light chains may be directly toxic to tubule epithelial cells. Acute uric acid nephropathy typically complicates treatment of lymphoproliferative or myeloproliferative disorders and is usually associated with other biochemical evidence of tumor lysis such as hyperkalemia, hyperphosphatemia, and hypocalcemia. [170] [171] [172] [173] Acute uric acid nephropathy is rare when plasma concentrations are less than 15 to 20 mg/dL but may be precipitated at relatively low levels by volume depletion or low urine pH. Both myeloma cast nephropathy and acute urate nephropathy are usually encountered in the setting of widespread malignancy and massive tumor destruction, and other potential contributory toxins in these clinical settings include hypercalcemia, hyperphosphatemia, and other products of tumor lysis (see later discussion of AKI in the cancer patient). Oxalate-induced AKI is usually encountered as a complication of ethylene glycol toxicity but occasionally complicates pri-mary defects in oxalate metabolism (primary hyperoxaluria) or other secondary forms of hyperoxaluria (e.g., malabsorption, massive vitamin C ingestion, methoxyflurane anesthesia). [174] [175] [176] [177] [178] [179]

Postrenal Acute Kidney Injury

Urinary tract obstruction accounts for less than 5% of cases of AKI. Because one kidney has sufficient clearance capacity to excrete the nitrogenous waste products generated daily, AKI resulting from obstruction requires either obstruction of urine flow between the external urethral meatus and bladder neck, bilateral ureteric obstruction, or unilateral ureteric obstruction in a patient with one functioning kidney or underlying chronic renal insufficiency (Table 29-8 ). Obstruction of the bladder neck is the most common cause of postrenal AKI and may complicate prostatic disease (e.g., hypertrophy, neoplasia, or infection), neurogenic bladder, or therapy with anticholinergic drugs. Less common causes of acute lower urinary tract obstruction include blood clots, calculi, and urethritis with spasm. Ureteric obstruction may result from intraluminal obstruction (e.g., calculi, blood clots, sloughed renal papillae), infiltration of the ureteric wall (e.g., neoplasia) or external compression (e.g., retroperitoneal fibrosis, neoplasia or abscess, inadvertent surgical ligature). During the early stages of obstruction (hours to days), continued glomerular filtration leads to increased intraluminal pressure upstream of the site of obstruction. This results in gradual distention of proximal ureter, renal pelvis, and calyces, and a fall in GFR. Although acute obstruction may lead to an initial modest increase in renal blood flow, arterial vasoconstriction soon supervenes, leading to a further decline in glomerular filtration. The pathophysiology and treat-ment of obstructive uropathy are discussed extensively in Chapter 36 .

TABLE 29-8   -- Causes of Acute Postrenal Azotemia



Ureteric obstruction



Intraluminal: stones, blood clot, sloughed renal papillae, uric acid or sulfonamide crystals, fungus balls



Intramural: postoperative edema after ureteric surgery, BK virus-induced ureteric fibrosis in renal allograft



Extraureteric: iatrogenic (ligation during pelvic surgery)



Periureteric: hemorrhage, tumor, or fibrosis



Bladder neck obstruction



Intraluminal: stones, blood clots, sloughed papillae



Intramural: bladder carcinoma, bladder infection with mural edema, neurogenic, drugs (e.g., tricyclic antidepressants, ganglion blockers)



Extramural: prostatic hypertrophy, prostatic carcinoma



Urethral obstruction



Phimosis, congenital valves, stricture, tumor





Morphology of Acute Tubule Necrosis

Tubular injury is the hallmark of ATN and is most severe in the outer medulla of the kidney during injury from reduced blood flow with ischemia.[180] This damage involves the pars recta (S3 segments) of the proximal tubule and the medullary thick ascending limb (mTAL) of the distal nephron. Other areas of injury can be seen within the renal cortex, involving both proximal and distal segments of the nephron. [181] [182] [183] [184] Although the term ATN is often used, synonymous with ARF/AKI, in fact, actual necrosis of tubular epithelial cells is a less common finding in ATN than cellular injury and dysfunction. [181] [185] These forms of cell injury can include apoptosis, loss of cells forming gaps in the tubular architecture and denuded basement membrane, and cells sloughing into tubular lumens ( Fig. 29-2 ). [181] [185]



FIGURE 29-2  Cellular cast formation (arrows) in renal tubules of a human renal biopsy with acute tubular necrosis.  (Courtesy of Dr. Yashpal Kanwar.)


Damage to the brush border of the proximal tubules in the cortex is a common feature seen in ATN. The microvilli that make up the brush border are shortened or completely absent and can be found collecting in the tubular lumen.[66] [181] [185] [186] Also frequently seen in ATN is the accumulation of tubular casts containing THP along with exfoliated tubular cells, remnants of shed brush border, and other cellular debris. [66] [181] [186] [187]

Pathophysiology of Kidney Dysfunction in Acute Kidney Injury

The effect of renal injury, whether from ischemia or from other causes, is a profound decrease in the GFR. This large decrease in filtration capacity of the kidney often occurs in the absence overwhelmingly evident damage to the kidney as seen on light microscopy. There are at least three major classic proposed mechanisms for the fall in GFR, as determined by micropuncture studies on animals and indirect methods in humans. The first mechanism is a drop in the filtration pressure in the glomerulus. This drop in pressure is caused by afferent arteriolar vasoconstriction and proximal tubular obstruction. [188] [189] [190] [191] [192] This first mechanism leads to a direct fall in the GFR. Afferent arteriolar vasoconstriction is thought to be a result of endothelial cell injury.[193] This leads to an imbalance in vasoactive substances, with a predominance of vasoconstrictive activity. The second mechanism, tubular back-leakage, leads to a fall in the effective GFR. Glomerular filtrate that enters the tubular/urinary space is allowed to leak back into the renal interstitium and consequently be reabsorbed into the systemic circulation. Back-leakage of glomerular filtrate occurs in the setting of damage and loss of epithelial cells (denuded basement membranes) ( Fig. 29-3 ) and loss of tight junctions between those cells that are critical to maintaining separation of tubular filtrate and the surrounding interstitium (see the section entitled The Epithelial Cell).[194] The role of tight junctions in normal solute trafficking is discussed later. Tight junctions are disrupted in the setting of adenosine triphosphate (ATP) depletion, allowing back-leakage of sodium and other solutes into the renal interstitium. [195] [196] The third mechanism, tubular obstruction, is a result of cast formation from sloughed tubular epithelial cells as well as THP. THP tends to polymerize and form a gel that can further trap cells and tubular cell debris following AKI. The concentration of various molecules in the renal tubules in evolving ATN further promotes THP gel formation.[187]



FIGURE 29-3  Cellular debris and cast formation in renal tubules of a human renal biopsy with acute tubular necrosis.  (Courtesy of Dr. Yashpal Kanwar.)


Besides a fall in GFR, there is also a decreased ability of the kidney to concentrate urine following AKI. This is due in part to the loss of aquaporin water channel expression in different parts of the nephron including the collecting duct and the proximal tubules, as has been shown in animal models.[197] Blocking inflammation with alpha-melanocyte-stimulating hormone (a-MSH) infusion can partially normalize aquaporin expression and allow the kidney to retain concentrating ability. Moreover, the addition of erythropoietin (EPO) can either on its own, or in combination with α-MSH, be protective by maintaining aquaporin expression and concentrating ability.[198] Sodium and acid-base transporters are also dysregulated by kidney injury.[199]


Inflammation plays a central role in AKI. From initiation to extension through repair, inflammatory cells and soluble mediators are likely major determinants of the outcome from ARF. A number of different inflammatory cells and soluble mediators have been shown to be necessary for full renal damage and loss of glomerular filtration to occur.[200] Inflammatory pathways are attractive targets for therapy, and there has been great success with interventions in experimental models of AKI. The limitation of this approach seems to be that blocking inflammation after the renal insult has occurred affords much less protection to the kidney.

Microvascular Inflammation

The proximal events leading to damage of renal tubular epithelial cells likely start in the microvasculature. The kidney receives 20% to 25% of cardiac output, and most of that blood flow is directed to the renal cortex. [201] [202] [203]Postglomerular vessels, branching from efferent arterioles, eventually become the vessels of the vasa recta. The low-flow state in the vasa recta is a critical aspect of the countercurrent multiplier, allowing for appropriate trafficking of water and solutes.[202] However, the low-flow state leaves the medulla relatively hypoxic when compared with other regions of the kidney. Unlike the renal cortex with a partial pressure of oxygen of about 50 mm Hg, the outer medulla has a partial pressure of oxygen in the 10 to 20 mm Hg range ( Fig. 29-4 ).[204] Consequently, very slight decreases in the blood flow and oxygen delivery can lead to anoxic damage. Anoxic injury to local cells, including vascular smooth muscle cells and endothelial cells, leads to depletion of cellular energy stores and resultant disruption of their actin cytoskeleton.[205] The cellular deformities and hypoxia in and around the microvasculature leads to endothelial-erythrocyte interactions and promotes sludging of erythrocytes (RBCs) in a way that is analogous to a sickle cell vaso-occlusive crisis. Vascular congestion with RBC sludging has been described on renal biopsies. [206] [207] Elegant video-microscopy has shed light on the kinetics of RBC sludging and blood flow.[208] These studies have demonstrated that peritubular capillaries had cessation of blood flow following an ischemic event as compared with glomerular capillaries that had diminished but never absent flow. Peritubular capillaries also took longer to recover normal blood flow when compared with other intrarenal vessels. The combination of hypoxic injury, changes in endothelial cell morphology, and heightened interactions between RBC and endothelium leads to the extension of the initial renal injury and contributes to our understanding of the regionalization of injury within the kidney. Hypoxia in the renal medulla can also predispose to other forms of renal injury, such as damage from aminoglycoside antibiotics.[209]



FIGURE 29-4  Anatomic and physiologic features of the renal cortex and medulla. The cortex, whose ample blood supply optimizes glomerular filtration, is generally well oxygenated, except for the medullary-ray areas devoid of glomeruli, which are supplied by venous blood ascending from the medulla. The medulla, whose meager blood supply optimizes the concentration of the urine, is poorly oxygenated. Medullary hypoxia results both from countercurrent exchange of oxygen within the vasa recta and from the consumption of oxygen by the mdedullary thick ascending limbs. Renal medullary hypoxia is an obligatory part of the process of urinary concentration. PO2 denotes partial pressure of oxygen.  (From Brezis M, Rosen S: Hypoxia of the renal medulla—its implications for disease. N Engl J Med 332:647–655, 1995.)





Neutrophils have been extensively studied in ischemic reperfusion injury (IRI) models of AKI. Infiltrating neutrophils are infrequently seen on biopsies of human ATN but are known to infiltrate the kidney following an acute experimental ischemic insult.[210] Nonetheless, some experimental studies have demonstrated that decreased renal injury occurs when neutrophil migration and activity are blocked (see later), whereas others have not found a protective effect of neutrophil blockade or depletion on the course of ARF. [211] [212]

Early inflammation is classically characterized by margination of neutrophils to vascular endothelium. Tethering interactions between selectins and their ligands initially slows neutrophils, allowing firmer adhesion and transmigration by integrins and their ligands. Platelet P-selectin was shown to be the main determinant of the P-selectin mediated renal injury.[213] Blockade of the shared ligand to all three selectins (E-, P-, and L-selectin) significantly protected rats from both renal IRI and associated mortality.[214] A key fucosyl sugar on the selectin ligands appears to be the critical determinant of the renal injury after ischemia. Both in rats and mice, selectin ligand blockade, initially targeted to abrogate neutrophil infiltration, resulted in renal protection while neutrophils continued to infiltrate the post ischemic kidney.[215] Thus, it appears that modulation of the selectin pathway can alter outcome of ARF through neutrophil-independent ways. Owing to the promising nature of these experimental studies, a multicenter clinical trial is under way blocking selectin ligands to reduce ischemic kidney injury in deceased donor transplants.

After the slowing of leukocytes at the site of injury by selectins, firm adhesion occurs by the interactions of integrins with intercellular adhesion molecule-1 (ICAM-1). Blockade of the integrin CD11/CD18 protects from experimental IRI-induced ARF in rats; mice deficient in ICAM-1 were also found to have relative protection from renal ischemic injury. [212] [216] Interestingly, neutrophil depletion in the rat model did not lead to protection, whereas it was protective in the mouse. [216] [217] The importance of ICAM-1 interactions has also been studied in human renal transplant models. An initial study showed treatment with anti-ICAM-1 (or CD54) monoclonal antibodies protected human patients receiving a “high-risk” deceased donor renal allograft. Their rates of delayed graft function were lower than patients who received the sister organ but were not treated with the antibody.[218] However, a randomized controlled trial (RCT) of anti-ICAM-1 monoclonal antibody in recipients of deceased donor renal transplants showed that short-term induction with anti-ICAM-1 did not reduce the rate of delayed graft function or acute rejection.[219] A major logistic challenge for clinical use is that experimental studies demonstrate a dramatic protection by adhesion molecule blockade when given preischemia, whereas human studies had administered adhesion blockade after ischemia.

Mice and rats were treated with α-MSH, a known inhibitor of interleukin-8 (IL-8, a murine neutrophil chemokine) and ICAM-1 induction.[220] Significantly less renal damage was seen following IRI, both by measurements of serum creatinine and by renal histology. In a follow-up study, it was demonstrated that α-MSH inhibited renal injury in a neutrophil-depleted model, suggesting a more complex role for α-MSH, possibly by acting directly on renal tubular cells.[221] Other possible effects of α-MSH suggest a role in limiting apoptosis and down-regulating fas and fas ligand expression, as seen in animal models of AKI.[222] Other studies demonstrating a renal protection by an anti-inflammatory intervention have attributed the mechanism of protection to neutrophil blockade, only to later find the neutrophil was less important: A2A adenosine receptor blockade lead to renoprotective effects in IRI models; however, recent data demonstrates that this is working primarily through CD4 T cells rather than neutrophils. [223] [224] Blockage of platelet-activating factor (PAF), which is thought to play a mediating role in neutrophil adherence to endothelium, was protective in a rat cold ischemia reperfusion model.[225] Cumulative results suggest a real but only modest role for the neutrophil in ischemic AKI.

Although classic models of immunology or acute tissue injury do not predict a role for T cells in ischemic ARF, studies on human ARF had identified predominately mononuclear leukocytes, not neutrophils, in the vasa recta.[184]The production of T cell associated cytokines occurs in experimental IRI.[226] In addition, the same leukocyte adhesion molecules targeted for neutrophil blockade in renal IRI (e.g., selectins, CD11/CD18, and ICAM-1) also mediate T cell adhesion. Using special stains, T cells have been identified in the kidneys of rats and mice following IRI. [227] [228] This led to studies that have now identified a modulatory role for T cells in experimental ARF. Double CD4/CD8 knockout mice had renal protection from IRI.[228] When T cell deficient (nu/nu) knockout mice were subjected to renal IRI, they also had less depression of kidney function following IRI when compared with wild-type mice, primarily mediated by CD4 T cells. Adoptive transfer of T cells from wild type animals into the (nu/nu) mice restored ischemic injury, proving the role of the T cell in ischemic injury.[229] The CD4+ T cell effect was found to require interferon-γ (IFN-γ) and the B7-CD28 pathway. Wild-type mice depleted of T cells to very low levels, particularly of CD4+ cells, had significant protection from renal IRI, but simple CD4 depletion was not protective. [230] [231] Alternative approaches using CTLA4Ig to block the B7-CD28 interaction significantly attenuated renal dysfunction in a rat renal IRI model.[232] It appears that B7-1 and not the B7-2 pathway is the important T cell co-stimulatory pathway in ARF.[233] An early, transient increase in T cells, a so-called hit-and-run hypothesis, might explain how T cells could play a role in the initiation of ARF. Recently, T cells have been shown to infiltrate postischemic kidney within 3 hours of reperfusion, which supports the hit-and-run model.[234]

The role for T cells in ARF is becoming increasingly complex, with the surprising finding that specific T cells can serve a protective function in ARF, which could be dependent one whether one examines early injury, extension, or repair. It appears that the Th1 phenotype of T cells is deleterious, and the Th2 phenotype is protective. These data, elicited with STAT6- and STAT4-deficient mice that have impaired Th2 and Th1 responses, respectively, is opposite to the asthma model of T cell engagement.[231] In addition, mice deficient in both T and B cells, are not protected from renal IRI.[235] This may be in part due to enhanced innate immunity in these mice, possibly from up-regulation of natural killer cells. Identification of the role of the T cell in renal IRI opens up the opportunity to evaluate well-characterized T cell reagents to prevent and treat ARF. Another mononuclear leukocyte that could be playing an important role in ARF is the macrophage.[224]

There are many other key inflammatory pathways that mediate the pathogenesis of AKI. Toll receptors (TLRs) likely play an important role. TLR2 has been shown to mediate experimental ischemic ARF, and TLR4 mediates ARF in a mouse endotoxemia (LPS) model. [236] [237] TLR4 and MyD88 have been implicated in a mouse sepsis model.[238] Many of the cytokines and chemokines play a role in ARF, which is a rapidly advancing and promising area of investigation.


Apoptosis, or programmed cell death, plays an important role in the pathophysiology of ARF. Apoptosis differs from cellular necrosis. Cellular necrosis is characterized by swelling of cells, loss of plasma membrane integrity, and eventually cell rupture with spillage of cellular contents into the extracellular space.[239] In apoptosis, the cell nucleus and cytoplasm condense and then split off into smaller apoptotic bodies.[239] Cytoplasmic organelles, including the mitochondria, are often intact and are phagocytized by macrophages or other cells, which leads to less spillage of cellular contents to cause inflammation.[239]

The effects of apoptosis on the host may change during the course of AKI, ranging from harmful to beneficial, depending on the phase of AKI. Initially, apoptosis may be deleterious to the kidney and overall renal function, whereas during the recovery phase, apoptosis may be an important mechanism to regulate cell number and morphology.[240] The signs of apoptosis in the kidney, initially heralded by DNA fragmentation in the cells of the thick ascending limb, can be seen within 15 minutes of a hypoxic insult in the rat kidney.[241] The same findings were seen following a radiocontrast nephropathy injury model in rats. These early findings of apoptosis often precede any discernable deterioration in renal function.[240] A second peak in the amount of apoptosis in renal tissue occurs days to weeks after the initial insult.[240] This peak often follows removal of necrotic tubular cells from the area, and may be a way to help regulate the number of newly generated cells.

Why some cells are destined for apoptosis and others for necrosis may have to do with the duration of ischemia as a surrogate for the extent of intracellular ATP depletion. Studies of cell culture found that the initial hypoxic injury triggers apoptotic pathways in some cells, but if the hypoxia is prolonged, then cells switch to primarily a necrosis pathway. [242] [243] When human kidneys were examined at autopsy using 3’ end labeling (TUNEL stain) to identify apoptotic cells following a hypoxic insult, apoptosis was found in most cases. Interestingly, findings of apoptosis did not correlate with renal function (as compared with a classic histologic finding such as fibrosis).[244]

Renal transplantation induces ischemic renal injury in the donor kidney. The duration and severity of that injury often correlates with the type of donor, deceased or living, and the cold ischemic time. Deceased donor kidneys were compared with living donor kidneys to determine if there were differences in rates of apoptosis.[245] Very little apoptosis was found in the kidneys of live donors. Apoptosis was seen in all deceased donor kidneys, with a direct correlation between the duration of cold ischemic time and the amount of apoptosis. [245] [246] Also noted in the study of apoptosis in human renal allografts was the consistent activation of several proapoptotic factors from the mitochondrial pathway, mainly Bax and Bak. These are proapoptotic members of the Bcl-2 family can translocate from their normal cytosolic location to the mitochondria in response to ischemic stimuli. Once in the mitochondria, they cause release of cytochrome c and active caspase 9. [245] [247] [248]

Blocking apoptosis, using the active caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2F (ZVAD-fmk) attenuated reperfusion-induced inflammation in a murine model of renal IRI.[249] Animals treated with the caspase inhibitor before renal IRI had significant protection from renal damage and loss of renal function, but that protection was lost if animals were treated following the onset of apoptosis. The expression of caspases in the cascade of events leading to apoptosis was found to be a critical step in the release of proinflammatory mediators, such as endothelial monocyte-activating polypeptide-II, which can further induce P- and E-selectins.[250]

Blocking caspase activity and apoptosis has been the target of other interventions, often successfully limiting renal damage in models of ischemic injury. Minocycline, the tetracycline antibiotic, was shown to block renal damage through reduction of apoptosis in a rat model of IRI.[251] Other studies have targeted different pathways of apoptosis. Death-associated protein kinase (DAPK) modulates cell death induced by IFN-g, tumor necrosis factor-α (TNF-α), Fas, and detachment from the extracellular matrix. [252] [253] DAPK has been also implicated in TGF-β–induced apoptosis in several cultured cell lines in which Smad proteins mediate transcriptional activation of DAPK.[254]DAPK-mutant mice had less apoptosis, and were protected from renal IRI when compared with wild-type mice.[253]

EPO administration can protect the kidney from the effects of IRI in experimental models. Many investigators have shown that EPO can decrease the number of apoptotic cells following an ischemic insult. [198] [255] [256] [257] [258]There have been several purported mechanisms, but an exact pathway has not been elucidated. Down-regulation of the proapoptotic intracellular molecule Bax, as well as down-regulation of NF-kb and caspase-3, -8, and -9 has been shown. [256] [257] Treatment with α-MSH, which was protective in animal models of ARF, was shown to decrease apoptosis in the rat kidney in an IRI model.[259]

Apoptosis has been shown to be an important pathway of injury in the kidney in other models as well. The use of cell cycle inhibitors that also effectively blocked caspase-3 were found to protect cultured renal tubular epithelial cells from an otherwise lethal dose of cisplatin. [260] [261] Cisplatin is a highly nephrotoxic chemotherapeutic agent that damages cells in the S3 segment of the proximal tubule.[262]

The Endothelial Cell

The endothelial cell plays an important role in the development of ARF. When an initial insult damages the endothelium of the renal vessels, the result is an endothelial bed that is ineffective in regulating local blood flow and cell migration into tissues, and preventing coagulation. [263] [264] This vascular dysregulation, as perpetuated by dysfunctional endothelial cells, leads to continued ischemic injury following the initial insult, the extension phase of AKI. The structural alterations that occur in the endothelial cell following an ischemic injury have been partially elucidated and help explain the functional changes that occur during this injury process. The baseline structure of the endothelial cell is maintained by a network of protein filaments that make up the cytoskeleton. Actin filament bundles, which have been shown to shrink in the setting of ATP depletion, form a supportive ring around the periphery of the endothelial cell.[265] The assembly and disassembly of actin filaments is regulated by a family of actin binding proteins. The actin depolymerizing factor/cofilin (ADF) family of proteins is known to regulate actin dynamics and play a role in the changes to the actin cytoskeleton during ischemia.[266] ADF/cofilin has a concentration-dependent effect on changes to the actin cytoskeleton under ATP-depleted conditions (such as ischemia).[267] Modulation of the ADF/cofilin-mediated changes to the actin cytoskeleton in ischemic endothelial cells has potentially important therapeutic implications for ischemic AKI, and may have applications in other organ systems as well.

Many of the endothelial changes in ARF are more functional rather than structural in origin. It was found that tubuloglomerular feedback is preserved in prolonged ischemic AKI, and that excessive NO as well as endothelium-derived hyperpolarizing factor antagonize autoregulation and cause endothelial dysfunction and a drop in GFR.[268] Further evidence for the role of endothelial cells in ARF comes from animal models of transplanted endothelial cells or surrogate cells expressing endothelial NO synthase. Animals subjected to renal ischemia had functional protection by the transplanted endothelial cells.[269] Interactions between endothelial cells and inflammatory cells also changes with an ischemic insult. Both P- and E-selectin are up-regulated on endothelial cells in the setting of ischemic damage as is ICAM-1. [200] [270] [271] [272] Understanding the damage and dysfunction of renal endothelium in AKI opens the door to several potential therapeutic targets, some of which have been demonstrated in animal models of AKI.

The Renal Tubular Epithelial Cell

The renal tubular epithelial cells, which are visible on routine light microscopy as well as urine analysis, are the most obvious cell type injured in ARF. Injury and loss of epithelial cells, through necrosis or apoptosis can lead to loss of kidney function and apparent drop in GFR through processes of back-leakage of glomerular filtrate and tubular obstruction. The renal tubular cell has a remarkable ability to recover from an ischemic injury.[273] The tubular epithelial cell progresses through a series of morphologic changes that finally leads to restoration of normal structure and function. These steps include an initial loss of cell polarity and brush border, which contributes to altered solute trafficking.[274] Some cells die and are sloughed into the tubular lumen, and the remaining viable cells dedifferentiate and proliferate leading to final restoration of normal epithelium. The initial insult to the tubular epithelial cell depletes cellular ATP, which, in turn, leads to disruption of the apical actin cytoskeleton in a fashion that mirrors the changes in vascular endothelial cells in the kidney (see the section on endothelial cells earlier).[275] This structural change in the cell leads to the formation of membrane-bound vesicles or blebs that can either be internalized or shed into the tubular lumen as part of the cellular debris leading to cast formation and tubular obstruction.[276]Another important consequence of disruption of the apical cytoskeleton is the loss of tight junctions and adherens junctions.[194] The loss of these junctions contributes to the back-leakage of glomerular filtrate as a result of tubular obstruction.

Some elements of the basolateral cytoskeleton in epithelial cells are disrupted during AKI. The Na,K-ATPase that is found in the basolateral membrane as well as integrins that help tether cells to the basement membrane are both affected during IRI. The loss of the Na,K-ATPase decreases proximal tubular sodium reabsorption and increases the fractional excretion of sodium (FENa) contributing to tubuloglomerular feedback and drop in GFR. [276] [277] The elevated FENa is a hallmark of intrinsic AKI (see previous section of this chapter). Loss of integrin polarity, particularly the b1 integrins, away from the basolateral membrane to the apical domain can lead to detachment of viable cells from the basement membrane and sloughing of cells into the tubular lumen.[276]

Stem Cells

A better understanding of the repair process and renal recovery holds great therapeutic promise for AKI. Whereas it is well known that renal tubular epithelial and other resident kidney cells repair and repopulate following AKI, the source of these cells has been unclear. If stem cells did play a role in renal recovery, are the cells found in the kidney? Do they migrate to the kidney from the bone marrow or other organs? Recently, some of these questions surrounding the role of stem cells in the repair of ARF have been answered.

Stem cells have been shown to have the ability to differentiate into a limited number of cell types. Hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) located in the adult bone marrow can differentiate into all types of blood cells, in the former case, or into adipocyte, chondrocyte or osteocyte lineages in the latter case. [278] [279] [280] Initial reports suggested that HSCs play a role in the recovery of ARF. An ischemic insult to the kidneys can mobilize bone marrow-derived HSCs, which can then differentiate into renal tubular cells. HSCs derived from the bone marrow were stained and shown to migrate to the postischemic kidney to repopulate and repair intrinsic kidney cells that were damaged. [281] [282] In animal models, tracking transplanted exogenous HSCs showed their migration into the damaged kidney, particularly segments of the kidney that are known to be susceptible to ischemic damage such as the proximal tubule.[282] Ablation of the bone marrow in animal models led to increased renal damage and dysfunction following an ischemic renal injury, wherease reinfusion of HSCs conferred protection from renal IRI.[281] The evidence against HSCs as the major source of cells for renal recovery includes the absence of significant detection of these cells in the kidney during the recovery phase.

Other studies using animal models of IRI have demonstrated renoprotection by infusions of MSCs. [283] [284] Infusions of MSCs at the time of, or up to 24 hours following an ischemic insult to the kidney, provided significant renal protection. Contrary to the initial thoughts, the renoprotective effects of MSCs are due more likely due to paracrine effects than to their differentiation into target kidney cells. [279] [283] In fact, MSCs were not identified in the kidney, but local expression of inflammatory mediators had shifted to a predominantly anti-inflammatory milieu. [283] [285] These anti-inflammatory substances include hepatocyte growth factor, vascular endothelial growth factor, and insulin-like growth factor 1 (IGF-1), which have all been shown to improve the course of experimental AKI. [276] [286] MSC infusions can also lead to improvement of AKI by providing endothelial progenitor cells to repair injured microvasculature. [287] [288]

The most recent thinking about the role of stem cells in renal recovery favors the dedifferentiation of intrarenal cells and their eventual transformation to replace the loss of neighboring cells.[273] There is also new evidence of a resident pool of stem cells located within the renal papillae. [289] [290]

Distant Organ Pathophysiology

ARF is a systemic disease, and with the availability of dialysis, most deaths during ARF are due to hypotension, cardiorespiratory failure, sepsis, and gastrointestinal bleeding. Organ cross-talk during ARF is being increasingly studied, and may help explain the excess morbidity and mortality associated with even mild degrees of acute kidney impairment ( Fig. 29-5 ). There is a strong association between ARF and acute lung injury, and the mortality rate during ARF rises from 50% to 80% when both lung and kidney are involved. [291] [292] Evidence for direct AKI-induced distant organ dysfunction was demonstrated when clamping of the renal artery in rats increased pulmonary vascular permeability with microvascular inflammation and both leukocyte and RBC sludging.[293] This effect occurred as early as 24 hours following IRI and peaks around 48 hours, with return to baseline near 96 hours. When rats were randomly treated with CNI-1493, which blocks the release of macrophage derived inflammatory products, the lung injury was blunted but the course of ARF was unchanged. In the same rat model, AKI led to pulmonary edema that was associated with a down regulation of pulmonary epithelial sodium channels, sodium/potassium ATP-ase (Na/K ATPase), and aquaporin-5 following IRI and ARF.[294] These changes likely impaired lung clearance of salt and water during ARF. In mice prone to sickle cell anemia, small amounts of kidney injury markedly increased lung and distant organ inflammation.[295]



FIGURE 29-5  Organ cross-talk: Distant organ effects following ischemic acute kidney injury. Organ cross-talk can include the liver, heart, lungs, bone marrow, and gastrointestinal tract.



Acute ischemic kidney injury can also produce cross-talk between the kidney and bone marrow, perhaps supporting or enhancing the inflammation that is seen during ARF. Mice that were subjected to renal ischemia through a clamp model were found to have increased levels of serum granulocyte colony-stimulating factor (G-CSF).[296] Increased levels of G-CSF mRNA and G-CSF protein were found in the kidneys of these animals. This production was localized to the epithelial cells of the mTAL. It was also demonstrated that cultured mTAL cells produce G-CSF mRNA and protein in response to stimulation with reactive oxygen species in vitro.

Cross-talk between the kidney and liver has also been demonstrated in the setting of AKI. The injured kidney produces IL-6, which exerts local proinflammatory and distant anti-inflammatory effects. [297] [298] IL-6 is produced by several different cells in the body following injury (brain, muscle, gut). IL-6 can stimulate hepatic Kupffer cells to produce IL-10, which has been shown to be protective in animal models of AKI.[298] It was also recognized that ischemic renal injury leads to up-regulation of IL-10 receptors in the kidney. AKI in mice can also lead to cardiac apoptosis, which in part is cytokine mediated.[299] Cross-talk between kidney and heart has also been demonstrated, potentially involving apoptotic mechanisms and TNF. Studies to dissect mechanisms of kidney influence on distant organ dysfunction could elucidate key therapeutic targets that will reduce mortality during AKI.

New Experimental Models

Several new experimental models of ATN have been developed to allow better understanding of its underlying pathophysiology as well as to enable discovery of new therapeutics. Although there are several new models of AKI arising from a variety of causes, only a few new models are highlighted.[300] One of the most widely used classic small animal models involves a clamp applied to one or both kidneys. The length of injury as well as the site of injury (clamping one or both kidneys) can be controlled. Cold ischemia with warm reperfusion can also be achieved by removing a kidney, placing it on ice, and then re-implanting the kidney. This model mimics the situation commonly seen in renal transplantation.[300] However, the more an experimental model is distilled from what happens to humans in vivo, the less likely it is to encompass the complexity of the actual process. It is very rare in human native kidney that an isolated ischemic insult to the kidneys alone leads to AKI. In reality, a host of factors (concomitant medication use—NSAIDS, ACE-Inhibitors; sepsis; shock; congestive heart failure or hepatic failure) all set the stage for the ischemic insult. One cause of human renal IRI is sudden shock from hemorrhage or cardiac arrest. AKI develops in nearly a third of patients that survive an in-hospital cardiac arrest.[301] Whole-body IRI followed by resuscitation is also highly pertinent to the non-heart-beating deceased donor kidney, in which there is an opportunity to use more transplantable kidneys. To mimic this injury, a mouse cardiac arrest model was developed.[302]Cardiac arrest was induced by an infusion of potassium chloride and was allowed to persist for 10 minutes. Following this time, resuscitation was achieved by cardiac compressions, epinephrine, ventilation, and fluids, as is commonly done in cases of human cardiac arrest. This mouse model produced very similar findings to isolated renal artery clamp models. One significant difference was that only 10 minutes of ischemia was required with whole body ischemia, whereas with isolated clamp models, usually at least 30 minutes of warm ischemia is necessary to lead to significant renal injury. The reason for this difference was posited to be the effects of ischemia on distant organs and the release of inflammatory mediators. The implication of this finding to human IRI is that only brief episodes of systemic arterial hypotension may be sufficient to induce AKI.

A new model of AKI in sepsis has been developed in the mouse. [238] [303] This model sought to expand upon a commonly used lipopolysaccharide (LPS) model that was in use. In the LPS model, the animal was injected with LPS to mimic the vascular collapse seen in septic shock. A newer model was developed and compared with the LPS model. The new model used a cecal ligation puncture (CLP) to induce polymicrobial sepsis, to more closely echo the events in humans leading to sepsis-related AKI. Mice were given a period of fluid resuscitation as well as antimicrobial therapy, which differentiates this model from the LPS model, and more closely mimics the events surrounding human sepsis and resultant ARF. The CLP model was applied to both young and old mice. It was noticed that the best fit of the model to human disease was found in the CLP model in older mice when compared with the LPS model. In the mouse CLP model, it was discovered that a single dose of ethyl pyruvate, which is known to scavenge free radicals and down-regulate inflammatory cytokines (IL-6 and TNF-α), provided significant protection from ARF.[303]The benefits of ethyl pyruvate therapy were found even when the drug was given up to 12 hours after the initiation of sepsis.

Another model of ATN has been developed in the zebrafish.[304] The advantage of the larval zebrafish model is the relative simplicity and visual accessibility of the kidney. With a primarily nephrotoxic model using the aminoglycoside gentamicin and the chemotherapeutic agent cisplatin, similar histologic changes in the zebrafish where found compared with changes caused by known nephrotoxic medications frequently implicated in human ARF. The possibility exists for genetic manipulation in the zebrafish to allow for knockout models to probe specific pathways in AKI.

Novel Biomarkers

New biomarkers hold the promise of allowing clinicians to detect kidney injury earlier, to guide future therapy, and to better prognosticate. The currently employed, traditional markers of AKI in the blood (creatinine and urea nitrogen) are insensitive, lagging indicators that are not specific for any given disease process.[305] The urinary sediment is made up of byproducts of cellular injury (i.e., casts) that are also lagging indicators of a previous and sometimes ongoing injury. There are several biomarkers currently under investigation, as detailed later ( Table 29-9 ). Using known models of human ATN, such as deceased donor renal transplantation with delayed graft function, as well as animal models of IRI, investigators have found blood and urine proteins that may be effective biomarkers of AKI.

TABLE 29-9   -- Novel Biomarkers in Acute Renal Failure







Zahedi et al[323]


Rat kidney—RT-PCR and Northern blot

SSAT was able to distinguish ARF with tubular injury from ARF without ATN

Rat & Mouse

Muramatsu et al[319]


Kidney and urine—Western blot

CYR61 is upregulated in kidneys with IRI—able to distinguish prerenal from intrarenal ARF


Parikh et al[313]



IL-18 elevated in human kidney ATN (native and transplanted kidneys)


du Cheyron et al[312]


Urine—semiquantitative immunoblotting

NHE3 differentiated prerenal from intrarenal ischemic ATN from other intrarenal causes of ARF


Nguyen et al[322]

Urine Proteome pattern

Urine—mass spectroscopy

Humans following cardiopulmonary bypass surgery—markers at 2 and 6 hours postoperative highly sensitive and highly predictive of AKI


Han et al[310]


Urine, kidney—multiple methods

Specific for ischemic ARF/ATN when compared with other forms of kidney disease

Human, Mouse

Molls et al[306]

Gro-α, KC

Urine, blood—ELISA

Gro-α correlates well with renal recovery from AKI/DGF in transplant, early increase in urine and blood well before rise in serum creatinine in ARF models


Mishra et al [307] [308]


Blood, urine—western blot and ELISA

NGAL sensitive, specific and predictive marker of ARF in blood and urine of patients after cardiopulmonary bypass


Kwon et al[316]

Actin, IL-6 and IL-8

Urine—dot immunoblot and ELISA

All three markers predicted prolonged ARF following renal transplantation in humans


AKI, acute kidney injury; CYR61, cysteine-rich protein 61; DGF, delayed graft function; Gro-α, human growth-related oncogene-α; IL-6, interleukin-6; IL-8, interleukin-8; IL-18, interleukin-18; KC, keratinocyte-derived chemokine; KIM-1, kidney injury molecule 1; NGAL, neutrophil gelatinase- associated lipocalin; NHE3, Na+/H+ exchanger isoform 3; SSAT, spermidine/spermine N1-acetyltransferase.




Keratinocyte-derived chemokine (KC) was shown to be up-regulated very early in the course of IRI in a mouse model in the urine, blood and kidney. It was subsequently shown that the human analog of KC, Gro-α, is abundant in the urine of human deceased donor renal allograft recipients who have delayed graft function. The early elevation of urine Gro-α distinguished kidney transplants that had immediate function or a live donor kidney transplant from those with worse outcomes.[306] Elevations in KC/Gro-α in serum and urine were evident as early as 3 hours postischemia, well before the onset of histologic changes or rise in serum creatinine.

Neutrophil gelatinase-associated lipocalin (NGAL) is a promising early biomarker of AKI. NGAL is highly up-regulated in the postischemic kidney of the human, mouse, and the rat, as well as in animal models of cisplatin nephrotoxicity. [307] [308] [309] NGAL is rapidly excreted in the urine to allow detection. Interestingly, NGAL is highly expressed in proliferating renal tubular cells, and NGAL has been used as a therapeutic agent in experimental models of AKI.[276]

Kidney injury molecule-1 (KIM-1) is a transmembrane protein that is expressed in high levels on dedifferentiated renal tubular epithelial cells in humans and rodents following ischemic or toxic injury. [305] [310] Human KIM-1 ectodomain can be found in the urine, and elevations occur as early as 12 hours following IRI and persist until repair of the epithelium. KIM-1 is expressed at low levels in the noninjured kidney and so potentially represents a useful marker for AKI.

The sodium/hydrogen exchanged isoform 3 (NHE3) protein is an apical sodium transporter widely expressed in renal tubules and found primarily in the proximal tubule and thick ascending limb cells. [305] [311] NHE3 is not detected in the urine of normal control subjects but is found in cases of prerenal AKI, postrenal AKI, and ATN. It was not detected in subjects with intrinsic causes of AKI such as glomerulonephritis, transplant rejection, or interstitial nephritis.[312] Levels of NHE3 in ATN and prerenal AKI were different, suggesting NHE3 as a possible marker to differentiate the two conditions.

Several urinary cytokines have been suggested as markers of AKI. IL-18 is a mediator of inflammation and ischemic tissue injury in a variety of organs. Quantification of urinary IL-18 levels in a series of patients showed different levels between normal controls, patients with ATN, prerenal ARF, urinary tract infection, and nephrotic syndrome. Importantly, levels were highest in patients with ATN, including recipients of deceased donor renal allografts with delayed graft function.[313] For this reason, IL-18 may be a good potential marker of ischemic AKI.[314] Other markers of inflammation, such as the macrophage chemoattractant protein-1, have been found in increased amounts in the urine of rats in experimental models of IRI.[315]

In studies of human renal transplantation, the urinary cytokines IL-6, IL-8, and the cytoskeletal protein actin were found to be markers of sustained AKI following transplant. These molecules were found in abundance in the urine samples of patients with prolonged delayed graft function when compared with those that had early recovery or immediate graft function.[316] In critically ill patients with ARF, plasma cytokine levels, particularly IL-6, IL-8, and IL-10, were associated with mortality.[317] Patients with high plasma levels of these three cytokines had a higher risk of death when compared with patients with lower levels. In another study of critically ill patients, plasma IL-6, IL-8, and IL-10 were up-regulated in patients with AKI, but the levels were not predictive of mortality in that cohort.[318]

Certain genomic markers, such as urinary mRNA, have been studied as early markers of AKI. mRNA for cyr61, a secreted growth factor-inducible immediate early gene in the proximal straight tubules, was up-regulated in the kidney 2 hours following an ischemic injury.[319] The cyr61 protein levels peaked 6 to 9 hours postischemia, and they were not elevated in the setting of volume depletion, helping to differentiate intrinsic AKI from prerenal AKI. Another genomic biomarker for ischemic AKI is Zf9, a Kruppel-like transcription factor involved in the regulation of a number of downstream targets, such as transforming growth factor-β1 (TGF-β1).[320] Zf9 is expressed in stable kidneys at low levels in both proximal and distal tubular cells in a diffuse cytoplasmic distribution. Zf9 is highly up-regulated in the postischemic renal tubular cells in animal models as well as in cultured cells. Zf9 is also expressed in the developing kidney. Gene silencing of Zf9 abrogated TGF-β1 overexpression and mitigated the apoptotic response to ATP in vitro. [276] [320] TGF-β has been shown in other models to be up-regulated following ischemic renal damage, and it undoubtedly plays an important role in either injury, repair, or both.[321] New techniques such as microarrays and advanced proteomic technology have generated many other new possible biomarkers for AKI.[322]Stathmin, spermidine acetyl transferase, and thrombospondin-1 are among the promising biomarkers for ARF that were discovered using microarray analysis in a rodent model of ARF. [323] [324] [325] As the fields of biomarker discovery and genomics advance, they will undoubtedly change the way we diagnose and treat AKI.


As discussed earlier, the clinical course of ATN can be divided into three phases: the initiation, maintenance phase, and recovery phases. The initiation phase is the period when patients are exposed to the ischemia or toxins and parenchymal renal injury is evolving but not yet established. ATN is potentially preventable during this period, which may last hours to days. The initiation phase is followed by a maintenance phase, during which parenchymal injury is established and GFR stabilizes at a value of 5 to 10 mL/min. [326] [327] [328] Urine output is usually lowest during this period. The maintenance phase typically lasts 1 to 2 weeks but may be prolonged for 1 to 11 months before recovery. The recovery phase is the period, during which patients recover renal function through repair and regeneration of renal tissue. Its onset is typically heralded by a gradual increase in urine output and a fall in serum creatinine, although the latter may lag behind the onset of diuresis by several days. This post-ATN diuresis may reflect appropriate excretion of salt and water accumulated during the maintenance phase, osmotic diuresis induced by filtered urea and other retained solutes, and the actions of diuretics administered to hasten salt and water excretion. [329] [330] [331] Occasionally, diuresis may be inappropriate and excessive if recovery of tubule reabsorptive processes lags behind glomerular filtration, although this phenomenon is more common after relief of urinary tract obstruction. [332] [333] [334] [335]


Clinical Features, Urinary Findings, and Confirmatory Tests

The assessment of patients with AKI requires a meticulous history, physical examination and urinalysis, in-depth review of previous records and recent drug history, judicious utilization of laboratory tests, renal imaging, assessment of response to fluid repletion, and occasionally renal biopsy ( Table 29-10 ). [1] [2] [29] [336] A graph of remote and recent serum creatinine levels versus time, incorporating drug therapy and interventions, is invaluable for differentiation of acute and chronic renal failure and the identification of the cause of AKI. An acute process is easily established if review of laboratory records reveals a recent rise in BUN and serum creatinine levels. Spurious causes of increased BUN or serum creatinine values should be excluded (see Fig. 29-1 ). When previous measurements are not available, anemia, hyperparathyroidism, neuropathy, band keratopathy, and radiologic evidence of renal osteodystrophy or small scarred kidneys are useful indicators of a chronic process. However, it should be noted that anemia may also complicate AKI, particularly if prolonged, and renal size can be normal or increased in a variety of chronic renal diseases (e.g., diabetic nephropathy, amyloid, polycystic kidney disease). Once a diagnosis of AKI is established, attention should focus on the differentiation between prerenal, intrinsic renal, and postrenal AKI, and the identification of the specific causative disease. Table 29-11 summarizes some clinical features, urinary findings, and confirmatory tests that are useful for diagnosis of the most common causes of AKI.

TABLE 29-10   -- Clinical Approach to the Diagnosis of Acute Kidney Injury

History, physical examination (including fundoscopy and weight), detailed review of hospital chart, previous records, and drug history

Urinalysis including specific gravity, dipstick, sulfosalicylic acid, microscopy, and staining for eosinophils

Flowchart of serial blood pressures, weights, BUN, serum creatinine, major clinical events, interventions, and therapies

Routine blood chemistry assays (BUN, creatinine, Na+, K+, Ca2+, HCO3-, Cl-, PO43-,) and hematologic tests (complete blood count and differential white blood cell count)



Selected special investigations:



Urine chemistry, eosinophils, and/or immunoelectrophoresis



Serologic tests: antiglomerular basement membrane antibodies, antineutrophil cytoplasmic antibodies, complement, antinuclear antibodies, cryoglobulins, serum protein electrophoresis, anti-streptolysin O or anti-DNase titers



Radiologic evaluation: plain abdominal film, renal ultrasonography, intravenous pyelography, renal angiography, magnetic resonance angiography.

Renal biopsy


BUN, blood urea nitrogen.




TABLE 29-11   -- Useful Clinical Features, Urinary Findings, and Confirmatory Tests in the Differential Diagnosis of Major Causes of Acute Azotemia

Cause of Acute Kidney Injury

Some Suggestive Clinical Features

Typical Urinalysis

Some Confirmatory Tests

Prerenal azotemia

Evidence of true volume depletion (thirst, postural or absolute hypotension and tachycardia, low jugular vein pressure, dry mucous membranes and axillae, weight loss, fluid output > input) or decreased effective circulatory volume (e.g., heart failure, liver failure), treatment with NSAIDs or ACE inhibitor

Hyaline casts

Occasionally requires invasive hemodynamic monitoring; rapid resolution of AKI on restoration of renal perfusion

FENa < 1%

UNa < 10 mEq/L

SG > 1.018

Intrinsic renal azotemia




 Diseases involving large renal vessels




  Renal artery thrombosis

History of atrial fibrillation or recent myocardial infarct, nausea, vomiting, flank or abdominal pain

Mild proteinuria

Elevated LDH with normal transaminases, renal arteriogram, MAG-3 renal scan, MRA

Occasionally red cells


Usually > 50 y, recent manipulation of aorta, retinal plaques, subcutaneous nodules, palpable purpura, livedo reticularis, vasculopathy, hypertension

Often normal, eosinophiliuria
Rarely casts.

Eosinophilia, hypocomplentemia, skin biopsy, renal biopsy

 Renal vein thrombosis

Evidence of nephrotic syndrome or pulmonary embolism, flank pain

Proteinuria, hematuria

Inferior venocavogram, Doppler flow studies, MRV

Disease of the small vessels and glomeruli




Glomerulonephritis or vasculitis

Compatible clinical history (e.g., recent infection) sinusitis, lung hemorrhage, rash or skin ulcers, arthralgias, hypertension, edema

Red blood cell or granular casts, red blood cells, white blood cells, proteinuria

Low C3, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies. Anti-streptolysin O antibodies, anti-DNase, cryoglobilins, renal biopsy


Compatible clinical history (e.g., recent gastrointestinal infection, cyclosporine, anovulants), pallor, ecchymoses, neurologic abnormalities

May be normal, red blood cells, mild proteinuria, rarely red blood cell or granular casts

Anemia, thrombocytopenia, schistocytes on peripheral blood smear, low haptoglobin, increased LDH, renal biopsy

Malignant hypertension

Severe hypertension with headaches, cardiac failure retinopathy, neurological dysfunction papilledema

May be normal, red blood cells, mild proteinuria, rarely red blood cell casts

LVH by echocardiography or EKG

Resolution of ARF with BP control

ARF mediated by ischemia or toxins (ATN)





Recent hemorrhage, hypotension (e.g. cardiac arrest), surgery often in combination with vasoactive medication (e.g. ACE-inhibitor or NSAID) or chronic renal insufficiency

Muddy brown granular or tubule epithelial cell casts, FENa > 1%, UNa > 20 mEq/L, SG = 1.010

Clinical assessment and urinalysis usually sufficient for diagnosis

 Exogenous toxin

Recent radiocontrast study, nephrotoxic antibiotic or chemotherapy often with coexistent volume depletion, sepsis or chronic renal insufficiency

Muddy brown granular or tubule epithelial cell casts, FENa > 1%, UNa > 20 mEq/L, SG = .010

Clinical assessment and urinalysis usually sufficient for diagnosis.

Endogenous toxin

History suggestive of rhabdomyolysis (coma, seizures, drug abuse, trauma)

Urine supernatant tests positive for heme in absence of red cells

Hyperkalemia, hyperphosphatemia, hypocalcemia, increased CK, MM, and myoglobin

History suggestive of hemolysis (recent blood transfusion)

Urine supernatant pink and tests positive for hee in absence of red cells

Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia and free circulating hemoglobin

History suggestive of tumor lysis (recent chemotherapy), myeloma (bone pain), or ethylene glycol ingestion

Urate crystals, dipstick negative proteiuria, oxalate crystals respectively

Hyperuricemia, hyperkalemia, hyperphosphatemia (for tumor lysis); circulating or urinary monoclonal spike (for myeloma); toxicology screen, acidosis, osmolal gap (forethylene glycol)

Acute diseases of the tubulointerstitium




Allergic interstitial nephritis

Recent ingestion of drug and fever, rash, loin pain or arthralgia

White blood cellcasts, white blood cells (frequently eosinophiluria), red blood cells, rarely red blood cell casts, proteinuria (occasionally nephrotic)

Systemic eosinophilia, skin biopsy of rash area (leukocytoclastic vasculitis), renal biopsy

Acute bilateral pyelonephritis

Fever, flank pain and tenderness, toxic state

Leukocytes, occasionally white cell casts, red blood cells, bacteria

Urine and blood cultures

Post renal azotemia

Abdominal and flank pain, palpable bladder

Frequently normal, hematuria if stones, hemmorhage, prostatic hypertrophy

Plain film, renal ultrasonography, intravenous pyelography, computed tomography, retrograde or antegade pyelography


ACE, angiotensin-converting enzyme; ATN, acute tubular necrosis; ARF, acute renal failure; BP, blood pressure; CK, creatinine kinase; EKG, electrocardiogram; FENa, fractional excretion of sodium; HUS, hemolytic-uremic syndrome; LDH, lactate dehydropgenase; LVH, left ventricular hypertrophy; MM, multiple myeloma; MRA, magnetic resonance angioraphy; MRV, magnetic resonance venography; NSAID, nonsteroidal anti-inflammatory drug; SG, specific gravity; TTP, thrombotic thrombocytopenic purpura; UNa, urine Na+ concentration.




Clinical Assessment

Prerenal AKI should be suspected when the serum creatinine value rises after hemorrhage; excessive gastrointestinal, urinary, or insensible fluid losses; or extensive burns, particularly if access to fluids is restricted (e.g., comatose, sedated, or obtunded patients). Supportive findings on clinical assessment include symptoms of thirst or orthostatic dizziness and objective evidence of orthostatic hypotension (postural fall in diastolic pressure greater than 10 mm Hg) and tachycardia (postural increase of more than 10 beats/min), reduced jugular venous pressure, decreased skin turgor, dry mucous membranes, and reduced axillary sweating. However, florid symptoms or signs of hypovolemia are usually not manifest until extracellular fluid volume has fallen by 10% to 20%. Nursing and pharmacy records should be reviewed for evidence of a progressive fall in urine output and body weight and recent use of NSAIDs, ACE inhibitors or ARBs. Consideration should be given to the misuse of illicit drugs such as cocaine. Careful clinical examination may reveal stigmata of chronic liver disease and portal hypertension (e.g., palmar erythema, jaundice, telangiectasia, caput medusae, splenomegaly, ascites), advanced cardiac failure (e.g., peripheral edema, hepatic congestion, ascites, elevated jugular venous pressure, bibasilar lung crackles, pleural effusion, cardiomegaly, gallop rhythm, cold extremities), or other causes of reduced effective critical blood volume. Although clinical assessment provides a satisfactory index of cardiac output and tissue perfusion in most patients, invasive hemodynamic monitoring (central venous and Swan-Ganz catheterization) is often necessary in critically ill patients in whom edema can obscure the clinical examination and complicate the assessment of body weight and fluid balance.

Definitive diagnosis of prerenal AKI hinges on prompt resolution of AKI after restoration of renal perfusion. There is a high likelihood of ischemic ATN if AKI follows a period of severe renal hypoperfusion and persists despite restoration of renal perfusion. [34] [37] [71] [337] It should be noted, however, that significant hypotension is recorded in the case notes of less than 50% of patients with postsurgical ATN. The diagnosis of nephrotoxic ATN requires scouring of clinical, pharmacy, nursing, and radiology records for evidence of recent administration of nephrotoxic medications or radiocontrast agents. [52] [88] [90] [119] [132] [338] [339] AKI after cancer chemotherapy suggests a diagnosis of tumor lysis syndrome and acute urate nephropathy, although other diagnoses must be considered (see later section on differential diagnosis in specific settings). [340] [341] [342] [343] Pigment-induced ATN may be suspected if the clinical assessment reveals clues to rhabdomyolysis (e.g., seizures, excessive exercise, alcohol or drug abuse, muscle tenderness, limb ischemia) or hemolysis (e.g., recent transfusion). [68] [70] [114] [344]

Although most AKI is either prerenal or due to ischemic and nephrotoxic ATN, patients should be assessed carefully for evidence of other renal parenchymal diseases, because many of the latter are treatable and their diagnosis alters management and prognosis. Flank pain may be a prominent symptom of acute renal artery or vein occlusion, acute pyelonephritis, and occasionally necrotizing glomerulonephritis. [345] [346] [347] [348] [349] [350] [351] [352] Interstitial edema leading to distention of the renal capsule and flank pain is seen in up to one third of patients with acute interstitial nephritis.[353] Close examination of the skin may reveal the subcutaneous nodules, livedo reticularis, digital ischemia, and palpable purpura of atheroembolism or vasculitis, the butterfly rash of systemic lupus erythematosus (SLE), impetigo in patients with postinfectious glomerulonephritis, a maculopapular rash suggestive of allergic interstitial nephritis, the yellow hue of liver disease or phenazopyridine (Pyridium) toxicity, telltale puncture marks of intravenous drug abuse, or the scarlatiniform eruption of staphylococcal toxic shock syndrome. [354] [355] [356] [357] The eyes should be assessed for evidence of atheroembolism; hypertensive or diabetic retinopathy; the keratitis, scleritis, uveitis, and iritis of autoimmune vasculitides; icterus; and the rare but nevertheless pathognomonic band keratopathy of hypercalcemia and flecked retina of hyperoxalemia. Uveitis may also be an indicator of coexistent allergic interstitial nephritis, the tubulointerstitial nephritis and uveitis syndrome. [353] [358] [359] Examination of the ears, nose, and throat may reveal conductive deafness and mucosal inflammation or ulceration suggestive of Wegener granulomatosis or the neural deafness caused by aminoglycoside toxicity. Respiratory difficulty or the stigmata of chronic liver disease should immediately suggest a pulmonary-renal or hepatorenal syndrome (HRS), respectively. Cardiovascular assessment may be notable for marked elevation in systemic blood pressure and suggest malignant hypertension or scleroderma, or it may reveal a new arrhythmia or murmur that is a potential source of thromboemboli or subacute bacterial endocarditis (acute glomerulonephritis), respectively. Chest or abdominal pain and reduced pulses in the lower limbs should suggest aortic dissection or rarely Takayasu arteritis, and widespread atheromatous disease increases the likelihood of atheroembolic disease. Abdominal pain and nausea are frequent clinical correlates of atherombolic disease in a patient who has recently undergone an angiographic examination. Pallor and recent bruising are important clues to the thrombotic microangiopathies, and the combination of bleeding and fever should raise the possibility of AKI in association with viral hemorrhagic fevers. A recent jejunoileal bypass may be a vital clue to a rare but reversible cause of AKI in obese patients. [178] [360] Hyperreflexia and asterixis often portends the development of uremic encephalopathy, or may, in the presence of focal neurological signs, suggest a diagnosis of thrombotic thrombocytopenic purpura.

Postrenal AKI may be asymptomatic if obstruction develops relatively slowly. Alternatively, patients may present with suprapubic or flank pain if there is acute distention of the bladder or renal collecting system and capsule, respectively. Colicky flank pain radiating to the groin suggests acute ureteric obstruction. Prostatic disease should be suspected in patients with a history of nocturia, frequency, and hesitancy and an enlarged or indurated prostate gland on rectal examination. Similarly, a rectal or pelvic examination may reveal obstructing tumors in female patients. Neurogenic bladder is a likely diagnosis in patients receiving anticholinergic medications (e.g., tricyclic antidepressants) or with physical evidence of neurologic disease and autonomic insufficiency (e.g., paralysis, abnormal rectal sphincter tone, postvoid urine volume more than 200 to 300 mL). Bladder distention may be evident on abdominal percussion and palpation in patients with bladder neck or urethral obstruction. Definitive diagnosis of postrenal ARF usually relies on judicious use of radiologic investigations and rapid improvement in renal function after relief of obstruction.


Assessment of the urine is a mandatory and inexpensive tool in the evaluation of AKI. [361] [362] [363] [364] Urine volume is a relatively unhelpful parameter in differential diagnosis. Anuria suggests complete urinary tract obstruction but may be a complication of severe prerenal or intrinsic ARF (e.g., renal artery occlusion, severe proliferative glomerulonephritis or vasculitis, bilateral cortical necrosis). Wide fluctuations in urine output suggest intermittent obstruction. Patients with partial urinary tract obstruction may present with polyuria caused by secondary impairment of urine concentrating mechanisms. In contrast, analysis of the sediment and supernatant of a centrifuged urine specimen is valuable for distinguishing between prerenal, intrinsic renal, and postrenal AKI and elucidating the precise etiology of intrinsic renal AKI ( Table 29-12 ). Urine sediment should be inspected for the presence of cells, casts, and crystals. The sediment is typically acellular in prerenal AKI and may contain transparent hyaline casts (“bland,” “benign,” “inactive” urine sediment). Hyaline casts are formed in concentrated urine from normal constituents of urine, principally THP secreted by epithelial cells of the loop of Henle. Postrenal ARF may also present with a benign sediment, although hematuria and pyuria are common in patients with intraluminal obstruction (e.g., stones, sloughed papilla, blood clot) or prostatic disease. Pigmented “muddy brown” granular casts and tubule epithelial cell casts are characteristic of ischemic or nephrotoxic ATN. They are usually found in association with microscopic hematuria and mild “tubular” proteinuria (<1 g/d). Casts may be absent, however, in approximately 20% to 30% of patients with ischemic or nephrotoxic ATN and are not a requisite for diagnosis. [362] [363] Indeed, there is generally a poor correlation between the severity of renal failure and the amount of debris in the urine sediment in these conditions (see section on pathology and pathophysiology of ischemic ATN). Red blood cell (RBC) casts almost always indicate acute glomerular injury but may also be observed, albeit rarely, in acute interstitial nephritis. Dysmorphic RBCs are a more common urinary finding in patients with glomerular injury but are a significantly less specific finding than RBC casts. Urine sediment abnormalities vary in diseases involving preglomerular blood vessels, such as hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), atheroembolic disease, and vasculitis involving medium-sized or large vessels, and range from benign to frankly nephritic. White blood cell casts and nonpigmented granular casts suggest interstitial nephritis, and broad granular casts are characteristic of chronic renal disease and probably reflect interstitial fibrosis and dilatation of tubules. Eosinophiluria (between 1% and 50% of urine leukocytes) is a common finding (90%) in drug-induced allergic interstitial nephritis. [365] [366] However, eosinophiluria is only 85% specific for allergic interstitial nephritis, and eosinophiluria of 1% to 5% can occur in a variety of other diseases including atheroembolization, ischemic and nephrotoxic ARF, proliferative glomerulonephritis, pyelonephritis, cystitis, and prostatitis. Uric acid crystals (pleomorphic) may be seen in urine in prerenal AKI but should raise the possibility of acute urate nephropathy if seen in abundance. Oxalate (envelope-shaped) and hippurate (needle-shaped) crystals suggest a diagnosis of ethylene glycol toxicity. [367] [368]

TABLE 29-12   -- Urine Sediment in the Differential Diagnosis of Acute Kidney Injury



Normal or few red blood cells or white blood cells



Prerenal azotemia



Arterial thrombosis or embolism



Preglomerular vasculitis






Scleroderma crisis



Postrenal azotemia



Granular casts



ATN (muddy brown)



Glomerulonephritis or vasculitis



Interstitial nephritis



Red blood cell casts



Glomerulonephritis or vasculitis



Malignant hypertension



Rarely interstitial nephritis



White blood cell casts



Acute interstitial nephritis or exudative glomerulonephritis



Severe pyelonephritis



Marked leukemic or lymphomatous infiltration



Eosinophiluria (>5%)



Allergic interstitial nephritis (antibiotics > NSAIDs)



Atheroembolic disease






Acute urate nephropathy



Calcium oxalate (ethylene glycol toxicity)












Radiocontrast agents


ATN, acute tubular necrosis; HUS, hemolytic-uremic syndrome; NSAIDS, nonsteroidal anti-inflammatory drugs; TTP, thrombotic thrombocytopenic purpura.




Increased urinary protein excretion, characteristically less than 1 g/d, is a common finding in ischemic or nephrotoxic ARF and reflects both failure of injured proximal tubule cells to reabsorb normally filtered protein and excretion of cellular debris (tubule proteinuria). Proteinuria greater than 1 g/d suggests injury to the glomerular ultrafiltration barrier (glomerular proteinuria) or excretion of myeloma light chains. [98] [112] [369] [370] The latter are not detected by conventional dipsticks (which detect albumin) and must be sought by other means (e.g., sulfosalicylic acid test, immunoelectrophoresis). Heavy proteinuria is also a frequent finding (80%) in patients with allergic interstitial nephritis triggered by NSAIDs. These patients have a glomerular lesion that is almost identical to minimal-change glomerulonephritis, in addition to acute interstitial inflammation. [371] [372] [373] A similar syndrome has been reported in patients receiving other agents such as ampicillin, rifampin, and interferon alfa. [374] [375] Hemoglobinuria or myoglobinuria should be suspected if urine is strongly positive for hemoglobin by dipstick but contains few RBCs and if the supernatant of centrifuged urine is pink and also positive for free hemoglobin. Hemolysis and rhabdomyolysis can usually be differentiated by inspection of plasma. The latter is usually pink in hemolysis, but not in rhabdomyolysis, because free hemoglobin (65,000 daltons) is a larger molecule than myoglobin (17,000 daltons) that is heavily protein bound and filtered slowly by the kidney.

Confirmatory Tests

The pattern of change in serum creatinine value often provides clues to the cause of AKI. Prerenal AKI is typified by rapid fluctuations in creatinine that parallel changes in hemodynamic function and renal perfusion. The serum creatinine level begins to rise within 24 to 48 hours in patients with ARF after renal ischemia, atheroembolization, and radiocontrast exposure, three major diagnostic possibilities in patients undergoing emergency cardiac or aortic angiography and surgery. Creatinine levels, as already discussed, usually peak after 3 to 5 days in contrast nephropathy and return to the normal range within 5 to 7 days. In contrast, creatinine levels typically peak later (7 to 10 days) in ischemic ATN and atheroembolic disease. AKI usually resolves in the next 7 to 14 days in ischemic AKI, whereas AKI is frequently irreversible in atheroembolic disease. These rapid changes are in marked contrast to the delayed elevation in serum creatinine levels (7 to 10 days) that is characteristic of many tubule epithelial cell toxins (e.g., aminoglycosides, cisplatin).

Additional diagnostic clues can be gleaned from routine biochemical and hematologic tests. Hyperkalemia, hyperphosphatemia, hypocalcemia, and elevated serum uric acid and creatine kinase levels suggest a diagnosis of rhabdomyolysis. [114] [155] [157] A similar biochemical profile in association with AKI after cancer chemotherapy, but with higher levels of uric acid, a urine uric acid to creatinine ratio greater than 1.0 , and normal or marginally elevated creatine kinase, is typical of acute urate nephropathy and tumor lysis syndrome. [340] [343] [376] Severe hypercalcemia of any cause can induce AKI. Widening of the serum anion (Na+ - [HCO3- + Cl-]) and osmolal (measured serum osmolality minus calculated osmolality) gaps is a clue to the diagnosis of ethylene glycol toxicity and should prompt a search for urine oxalate crystals. [367] [377] Severe anemia in the absence of hemorrhage may reflect the presence of hemolysis, multiple myeloma, or thrombotic microangiopathy (e.g., HUS, TTP, toxemia, disseminated intravascular coagulation, accelerated hypertension, SLE, scleroderma, radiation injury). Other laboratory findings suggestive of thrombotic microangiopathy include thrombocytopenia, dysmorphic RBCs on a peripheral blood smear, a low circulating haptoglobin level, and elevated circulating levels of lactate dehydrogenase. Systemic eosinophilia suggests allergic interstitial nephritis but may also be a prominent feature in other diseases such as atheroembolic disease and polyarteritis nodosa, particularly the Churg-Strauss variant. Depressed complement levels and high titers of antiglomerular basement membrane antibodies, antineutrophil cytoplasmic antibodies, antinuclear antibodies, circulating immune complexes, or cryoglobulins are useful diagnostic tools in patients with suspected glomerulonephritis or vasculitis (see Table 29-4 ).

Imaging of the urinary tract by plain film of the abdomen, ultrasonography, computed tomography (CT), or magnetic resonance is recommended for most patients with ARF to distinguish between acute and chronic renal failure and exclude acute obstructive uropathy. [378] [379] [380] The plain film of the abdomen, with tomography if necessary, usually provides a reliable index of kidney size and may detect Ca2+-containing kidney stones. However, the capacity of ultrasonography to determine cortical thickness, differences in cortical and medullary density, and the integrity of the collecting system, in addition to kidney size, makes it the screening modality of choice in most cases of AKI.[378] [379] [381] [382] [383] Although pelvicalyceal dilatation is usual in cases of urinary tract obstruction (98% sensitivity), dilatation may not be observed in the volume-depleted patient during the initial 1 to 3 days after obstruction when the collecting system is relatively noncompliant or in patients with obstruction caused by ureteric encasement or infiltration (e.g., retroperitoneal fibrosis, neoplasia).[384] CT scanning has largely replaced retrograde pyelography through cystography or percutaneous anterograde pyelography for definitive diagnosis when obstruction without dilatation is considered likely. The latter procedures remain useful for precise localization of the site of obstruction in selected cases and facilitate decompression of the urinary tract. Intravenous pyelography should be avoided in patients with AKI to avoid adding contrast nephropathy to already compromised renal function. Radionuclide scans have been touted as useful for assessing renal blood flow, glomerular filtration, tubule function, and infiltration by inflammatory cells in AKI; however, these tests generally lack specificity or yield conflicting or poor results in controlled studies and their use is largely restricted to the immediate postrenal transplantation period. [378] [379] [385] Magnetic resonance angiography (MRA) of the kidneys is extremely useful for detecting renal artery stenosis, and its role has been extended to the evaluation of acute renovascular crises. [378] [380] [386] [387] MRA is a time-efficient and safe test when compared with conventional arteriography. Doppler ultrasonography and spiral CT are also useful in patients with suspected vascular obstruction; however, contrast angiography remains the gold standard for definitive diagnosis.

Renal biopsy is usually reserved for patients in whom prerenal and postrenal failure have been excluded and the cause of intrinsic AKI is unclear.[186] Renal biopsy is particularly useful when clinical assessment, urinalysis, and laboratory investigation suggest diagnoses other than ischemic or nephrotoxic injury that may respond to specific therapy. Examples include antiglomerular basement membrane disease and other forms of necrotizing glomerulonephritis, vasculitis, HUS and TTP, allergic interstitial nephritis, myeloma cast nephropathy, and acute allograft rejection.

Renal Failure Indices for Differentiation of Prerenal Acute Kidney Injury and Ischemic Acute Tubule Necrosis

Analysis of urine and blood biochemistry is useful for discriminating between the major categories of oliguric ARF, namely prerenal ARF and intrinsic ARF caused by ischemia or nephrotoxins ( Table 29-13 ). The fractional excretion of Na+ (FENa) is the most sensitive index for this purpose. [388] [389] [390] [391] The FENa relates Na+ clearance to creatinine clearance. Na+ is reabsorbed avidly from glomerular filtrate in patients with prerenal AKI as a consequence of suppression of atrial natriuretic peptide (ANP) secretion, activation of renal nerves and the renin-angiotensin-aldosterone axis, and local changes in peritubular hemodynamics. In contrast, Na+ reabsorption is inhibited in ATN as a result of tubule cell injury. Creatinine is reabsorbed to a much smaller extent than Na+ in both conditions. Consequently, oliguric patients with prerenal ARF typically have a FENa of less than 1.0% (frequently <0.01%), whereas the FENa is usually greater than 2.0% in patients with ischemic or nephrotoxic AKI. The renal failure index (see Table 29-13 ) provides comparable information, because clinical variations in serum Na+concentration are relatively small. Urinary Na+ concentration is a less sensitive index for distinguishing prerenal AKI from ATN. Similarly, indices of urinary concentrating ability such as urine specific gravity, urine osmolality, urine/plasma creatinine or urea ratios, and serum urea nitrogen/creatinine ratio are of limited value in differential diagnosis. This is particularly true for elderly subjects, in whom urine concentrating mechanisms are frequently impaired while mechanisms for Na+ reabsorption are preserved.

TABLE 29-13   -- Urine Indices Used in the Differential Diagnosis of Prerenal and Ischemic Intrinsic Renal Azotemia

Diagnostic Index

Prerenal Azotemia

Ischemic Intrinsic Azotemia

Fractional excretion of Na+ (%),[*]






Urinary Na+ concentration (mEq/L)



Urinary creatinine/plasma creatinine ratio



Urinary urea nitrogen/plasma urea nitrogen ratio



Urine specific gravity



Urine osmolality (mOsm/kg H2O)



Plasma BUN/creatinine ratio



Renal failure index,[*] UNa/Ucr/Pcr



Urine sediment

Hyaline casts

Muddy brown granular casts


BUN, blood urea nitrogen.



Most sensitive indices. UNa, urine Na+ concentration; Ucr, urine creatinine concentration; PNa, plasma Na+ concentration; Pcr, plasma creatinine concentration.


Although beloved by textbooks and clinical teachers, the FENa is only of limited discriminatory value. The FENa is frequently greater than 1.0% in prerenal AKI in patients receiving diuretics or with bicarbonaturia (when HCO3- is excreted with Na+ to maintain electroneutrality), underlying chronic renal failure complicated by salt wasting, or adrenal insufficiency. [337] [388] [389] [392] [393] [394] On the other hand, approximately 15% of patients with nonoliguric ischemic or nephrotoxic AKI have a FENa less than 1.0%, which probably reflects a milder form of renal injury (sometimes termed the intermediate syndrome). The latter has been described in patients with ATN of a variety of causes, including ischemia, radiocontrast agents, burns, sepsis, and HRS. Under these circumstances, epithelial cell damage is probably localized to the corticomedullary junction and outer medulla with relative preservation of function in other Na+-transporting segments. The apparent increase in frequency of the intermediate syndrome may reflect increasing attention by physicians to volume status and drug therapy in high-risk patients. It should be noted that the FENa is often less than 1.0% in AKI caused by urinary tract obstruction, glomerulonephritis, and diseases of the renal vasculature, and other parameters must be employed to distinguish these conditions from prerenal AKI.

Differential Diagnosis of Acute Kidney Injury in Specific Clinical Settings

The differential diagnosis of ARF in several common clinical situations warrants special mention ( Table 29-14 ).

TABLE 29-14   -- Major Causes of Acute Kidney Injury (AKI) in Specific Clinical Settings



AKI in the cancer patient



Prerenal azotemia



Hypovolemia (e.g., poor intake, vomiting, diarrhea)



Intrinsic renal azotemia



Exogenous nephrotoxins: chemotherapy, antibiotics, radiocontrast agents



Endogenous toxins: hyperuricemia, hypercalcemia, tumor lysis, light chains



Other: radiation, HUS, TTP, glomerulonephritis, amyloid, infiltration



Postrenal azotemia



Ureteric or bladder neck obstruction



AKI after cardiac surgery



Prerenal azotemia



Hypovolemia (surgical losses, diuretics), cardiac failure, vasodilators



Intrinsic renal azotemia



Ischemic renal failure with ATN (even in absence of documented hypotension)



Atheroembolic renal disease after aortic manipulation/intra-aortic balloon pump



Pre- or perioperative administration of radiocontrast agent



Allergic interstitial nephritis induced by perioperative antibiotics



Postrenal azotemia



Blocked urinary catheter



AKI in pregnancy



Intrinsic renal azotemia



Pre-eclampsia or eclampsia



Ischemia: postpartum hemorrhage, abruptio placentae, amniotic fluid embolus



Direct toxicity of illegal abortifacients



Postpartum HUS or TTP



Acute fatty liver of pregnancy






Obstruction with pyelonephritis



AKI after solid organ or bone marrow transplantation (BMT)



Prerenal azotemia



Intravascular volume depletion (e.g., diuretic therapy)



Vasoactive drugs (e.g., calcineurin inhibibitors, amphotericin B)



Hepatorenal syndrome, veno-occlusive disease of liver (BMT)



Intrinsic renal azotemia



Post operative ischemic renal failure with ATN (even in absence of documented hypotension)






Exogenous nephrotoxins: aminoglycosides, amphoterincin B, radiocontrast



Endogenous toxins: light chains



HUS, TTP (e.g., cyclosporine or myeloablative radiotherapy-related)



Allergic tubulointerstitial nephritis



Postrenal azotemia



Blocked urinary catheter



AKI and pulmonary disease (pulmonary-renal syndrome)



Vasculitis: Goodpasture syndrome, Wegener syndrome, SLE, Churg-Strauss syndrome, or classic polyarteritis nodosa; cryoglobulinemia; right-sided endocarditis; lymphomatoid granulomatosis; sarcoidosis; scleroderma



Toxins: ingestion of paraquat or diquat



Infections: Legionnaire disease, Mycoplasma infection, tuberculosis, disseminated viral or fungal infection



Acute renal azotemia from any cause with hypervolemia and pulmonary edema



Prerenal azotemia caused by diminished cardiac output complicating pulmonary embolism, severe pulmonary hypertension, or positive- pressure mechanical ventilation



Lung cancer with hypercalcemia, tumor lysis, or glomerulonephritis



AKI and liver disease



Prerenal azotemia



Primary liver disease with secondary renal failure caused by reduced effective (hypoalbuminemia, splanchnic vasodilatation) or true (gastrointestinal hemorrhage, diuretics) circulatory volume



Right-sided heart failure with liver and renal failure



Intrinsic renal azotemia



Ischemia (severe hypoperfusion—see above) or direct nephrotoxicity and hepatotoxicity of drugs or toxins (e.g., carbon tetrachloride, acetaminophen, tetracyclines, methoxyflurane)



Tubulointerstitial nephritis + hepatitis caused by drugs (e.g., sulfonamides, rifampin, phenytoin, allopurinol, phenindione), infections (leptospirosis, brucellosis, Epstein-Barr virus infection, cytomegalovirus infection), malignant infiltration (lymphoma, leukemia), or sarcoidosis



Glomerulonephritis or vasculitis (e.g., polyarteritis nodosa, Wegener syndrome, cryoglobulinemia, SLE, postinfections hepatitis or liver abscess)



Occlusion of renal veins: tense ascites



AKI and nephrotic syndrome



Prerenal azotemia



Intravascular volume depletion (diuretic therapy, hypoalbuminemia)



Intrinsic renal azotemia



Manifestation of primary glomerular disease



Collapsing glomerulopathy (e.g., HIV, pamidronate)



Associated ATN (elderly hypertensive males)



Associated interstitial nephritis (NSAIDs, rifampin, interferon alfa)



Myeloma cast nephropathy or light chain deposition disease



Renal vein thrombosis



Severe interstitial edema


ATN, acute tubular necrosis; HUS, hemolytic-uremic syndrome; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura.




Acute Kidney Injury in a Patient with Cancer

Most AKI in patients with cancer is due to either prerenal AKI—often induced by vomiting and diarrhea in the presence of NSAIDs use—or hypercalcemia. [170] [340] [395] [396] [397] [398] [399] [400] Intrinsic AKI can be triggered by chemotherapeutic agents or by the products of tumor lysis. Renal parenchymal invasion by solid and hematologic cancers occurs in 5% to 10% of autopsy studies but is rarely of clinical significance. [341] [401] AKI consequent to leukemic infiltration of the kidney parenchyma typically presents with hematuria, proteinuria, and enlarged kidneys on ultrasound imaging. The diagnosis is an important one because the AKI may respond to chemotherpeutic intervention.

The tumor lysis syndrome is characterized by AKI associated with hyperuricemia, hyperphosphatemia and hypocalcemia. [402] [403] It occurs most often following initiation of chemotherapy in patients with poorly differentiated lymphoproliferative malignancies, particularly the acute leukemias. [342] [343] [402] [403] [404] It occasionally occurs spontaneously, or in patients with solid organ tumors. AKI is triggered by direct tubular injury/obstruction by uric acid and calcium phosphate crystals. Less common causes of AKI include tumor-associated glomerulonephritis or a thrombotic microangiopathy (TMA) induced by drugs or irradiation. [96] [405] [406] In regard to the latter, chemotherapy-associated TMA is a well-recognized complication of several chemotherapeutic agents of which mitomycin C and gemcytabine are pre-eminent. [406] [407] [408]

AKI in association with multiple myeloma carries a wide differential diagnosis that includes in decreasing order of frequency hypovolemia, myeloma cast nephropathy, sepsis, hypercalcemia, ATN induced by drugs or tumor lysis during therapy, light chain deposition disease, cryoglobulinemia, hyperviscosity syndrome, plasma cell infiltration and vascular amyloidosis. [98] [112] [165] [166] [169] [370] [409] [410]

Acute Kidney Injury in Pregnancy

The incidence of AKI requiring dialysis complicating pregnancy in industrialized countries is approximately 1 in 20,000 births. [411] [412] [413] [414] [415] [416] [417] [418] The marked decline over the past 50 years is a result of improved prenatal care and obstetric practice. In early pregnancy, ATN induced by nephrotoxic abortifacients is still a relatively common cause of AKI in developing countries but is rarely seen in the developed world. Ischemic ATN, severe toxemia of pregnancy, and postpartum HUS and TTP are the most common causes later in pregnancy (see Table 29-14 ). [412] [414] [415] [419] Ischemic ATN is usually provoked by postpartum hemorrhage or abruptio placentae and less commonly by amniotic fluid embolism or sepsis. [413] [415] [418] Glomerular filtration is usually normal in mild or moderate pre-eclampsia; however, AKI may complicate severe disease. [414] [417] [418] [420] In this setting, AKI is typically transient and found in association with intrarenal vasospasm, marked hypertension and neurologic abnormalities. A variant of pre-eclampsia, the HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets), is characterized by an initial benign course that can rapidly deteriorate with the development of a thrombotic microangiopathy characterized by hemolysis and derangement of coagulation, and hepatic and renal function. [416] [420] [421]Immediate delivery of the fetus is indicated in such cases. This presentation contrasts with that of postpartum thrombotic microangiopathy, which typically occurs against a background of normal pregnancy; is characterized by postpartum thrombocytopenia, microangiopathic anemia, and normal prothrombin and partial thromboplastin times; and frequently causes long-term impairment of renal function. [422] [423] [424] Acute fatty liver of pregnancy (AFLP) occurs in approximately 1 in 7000 pregnancies and induces acute renal impairment probably by triggering intrarenal vasoconstriction, as in other HRSs. Although the exact origin of AFLP is not known, the incidence is increased in women who carry a fetus with a defect in fatty acid oxidation, and who are themselves carriers of a genetic mutation that compromises intramitochondrial fatty acid oxidation.[421] Acute bilateral pyelonephritis may also precipitate AKI in pregnancy and should be obvious from clinical assessment (fever, flank pain) and routine urinalysis (bacteria, leukocytes) and laboratory tests (leukocytosis, increase in serum creatinine from basal levels). [414] [416] [425] [426] The diagnosis of postrenal AKI is complicated in pregnancy by the fact that the collecting system undergoes a physiologic dilatation in the second and third trimesters, thus complicating the interpretation of ultrasonographic imaging.[427]

Acute Kidney Injury after Cardiovascular Surgery

AKI requiring dialytic support is seen in 1% to 5% of patients undergoing coronary bypass grafting procedures. [4] [74] [428] [429] [430] Patients undergoing cardiac surgery are frequently predisposed to the development of postoperative AKI owing to the presence of preoperative hypertensive nephrosclerosis, diabetic nephropathy, and silent renal ischemia. [4] [74] AKI in this setting can usually be attributed to prerenal AKI, ischemic ATN, atheroembolic disease, or the effects of radiocontrast material administered perioperatively (see Table 29-14 ). [57] [74] [431] [432] The pattern of rise in serum creatinine may be extremely helpful in the differential diagnosis of ARF in this setting. As noted earlier, prerenal AKI is typified by rapid fluctuations in serum creatinine values that usually precede surgery and mirror changes in systemic hemodynamics and renal perfusion. Overzealous use of diuretics or afterload-reducing agents is a frequent cause of prerenal AKI postoperatively, particularly in elderly patients in whom renal autoregulation is frequently reduced secondary to hypertensive atherosclerotic or diabetic vasculopathy. The serum creatinine value characteristically rises for 3 to 4 days after the administration of contrast agent and returns rapidly to the normal range within 1 week. This pattern contrasts with those observed with ischemic ATN and atheroembolic disease, in which the serum creatinine value also rises progressively after surgery but typically takes 7 to 14 days before recovery begins (ATN) or fails to resolve (atheroemboli). [17] [99] [100] Rarer but nevertheless important causes include allergic tubulointerstitial nephritis induced by antibiotics administered perioperatively and obstruction of urine drainage. Independent preoperative risk factors for the development of AKI following cardiovascular surgery include advanced age, creatinine clearance less than 60 mL/min, peripheral vascular disease, cardiomegaly, and a left ventricular ejection fraction of less than 35%. Intraoperative risk factors include emergent surgery, bypass time greater than 100 minutes, intra-aortic balloon pump insertion, and combined valvular and coronary revascularization procedures. [74] [431] Off-pump coronary artery bypass grafting surgery has been suggested to lessen the risk of postoperative renal failure in some but not all prospective studies. [433] [434] [435]

Acute Kidney Injury after a Solid Organ or Bone Marrow Transplant

Nonrenal solid organ transplant recipients have a notably high risk of developing AKI from cardiopulmonary, hepatic failure, sepsis, and the nephrotoxic effects of antimicrobials and immunosuppressive agents. The differential diagnosis of renal impairment following renal transplantation is discussed in detail in Chapter 36 . In a large retrospective multicenter study, 25% of all nonrenal solid organ transplant recipients developed AKI, with 8% requiring renal replacement therapy. The development of dialysis-requiring AKI was associated with a 9- to 12-fold increase in patient mortality in this study.[436] AKI occurred in 35% of heart transplants and 15% of lung transplant recipients. Approximately 20% to 30% of liver transplantation patients will develop AKI, with a significant proportion of these having had, preoperative renal dysfunction. [437] [438] There is conflicting evidence as to whether pretransplant renal dysfunction predicts outcome in patients undergoing orthotopic liver transplantation; however, patients with preoperative renal failure have significantly longer hospital and intensive care unit stays and an increased need for dialysis compared with patients with normal preoperative renal function. [439] [440] [441]

AKI is a recognized complication of myeloablative allogenic and, to a lesser extent, autologous hematopoetic cell transplantation (HCT). [400] [442] [443] [444] The incidence of AKI following myeloablative HCT is as high as 50%, with 20% to 31% of patients requiring hemodialysis. The prognosis is grave, particularly for patients requiring dialysis (>80% mortality rate). [445] [446] [447] [448] The incidence of AKI following autologous HCT is considerably lower.[448] A study of 232 patients following autologous HCT found reported an incidence of moderate to severe ARF of 21%, with an associated mortality of 18% in affected cases. Causes of AKI in this setting include hypovolemia, sepsis, tumor lysis syndrome, direct tubular toxicity from cytoreductive therapy, antibiotics, and calcineurin inhibitors. The most common cause of severe AKI complicating myeloablative HCT is the HRS complicating the development of veno-occulsive disease (VOD) of the liver. [448] [449] VOD is most common in conditioning regimens that include total body irradiation and cyclophosphamide and or busulphan. The syndrome is characterized clinically by profound jaundice and avid salt retention with edema and ascites within the first month after engraftment. Oliguric AKI is common in moderate disease and certain in severe cases. The mortality rate approaches 100% for severe VOD.

Acute Kidney Injury in Association with Pulmonary Disease

The coexistence of AKI and pulmonary disease (pulmonary-renal syndrome) classically suggests a diagnosis of Goodpasture syndrome, Wegener granulomatosis, or other vasculitides. [450] [451] [452] [453] [454] [455] The detection of circulating antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies, or hypocomplementemia can be useful in the differentiation of these diseases (see Tables 29-4 and 29-14 [4] [14]), although the urgent need for definitive diagnosis and treatment may mandate a lung or renal biopsy. Several toxic ingestions and infections may also cause simultaneous pulmonary and renal injury that mimics a vasculitic process (see Table 29-14 ). Furthermore, intrinsic renal or postrenal AKI of any cause may be complicated by secondary hypervolemia and pulmonary edema, and severe lung diseases may compromise cardiac output and induce prerenal AKI (see Table 29-14 ).

Acute Kidney Injury in Association with Chronic Liver Disease

The differential diagnosis for AKI in association with liver disease is similarly large. In chronic liver disease, causes of AKI include volume depletion, gastrointestinal hemorrhage, sepsis, nephrotoxins (antibiotic radiocontrast), and the HRS. The term HRS is usually reserved for a syndrome of irreversible AKI that usually complicates advanced cirrhosis; however, this syndrome has been described in association with fulminant viral and alcoholic hepatitis. [456] [457] [458] [459] [460] [461] [462] The syndrome is characterized by renal failure and disturbed regulation of circulatory function. The latter is characterized by intense intrarenal vasoconstriction, whereas in the extrarenal circulation, arteriolar vasodilation triggers a reduction in total peripheral vascular resistance and a decrease in effective systemic circulatory volume despite an expanded total extracellular fluid volume. [456] [459] [460] [463] [464] [465] [466] Most patients have clinical evidence of advanced cirrhosis. HRS almost certainly represents the terminal stage of a hypoperfusion state that begins early in the course of chronic liver disease. The pathogenic mechanisms for the dramatic hemodynamic alterations are incompletely understood. In the early stages of HRS, arterial underfilling is thought to trigger activation of the renin-angiotensin and sympathetic nervous systems. [456] [463] [466] [467] Renal perfusion is initially preserved by the local release of renal vasodilatory factors; however these compensatory mechanisms are eventually overwhelmed and progressive renal hypoperfusion ensues. The splanchnic circulation is protected from the effects of the vasoconstrictors such as angiotensin II owing to the local production of mediators such as NO, prostaglandins, and vasoactive peptides; a process that likely accentuates arterial underfilling in other vascular beds including the kidney. Mean arterial blood pressure is typically low, reflecting the reduction in peripheral vascular resistance.

Two subtypes of HRS have been described; type 1 is characterized by a rapid onset of renal failure with a doubling of serum creatinine to greater than 2.5 mg/dL or a 50% reduction in GFR to less than 20 mL/min over a 2-week period. [460] [461] [468] This subtype is characterized by a fulminant course with oliguria, encephalopathy, marked hyperbilirubinemia, and death usually within 1 month of presentation. Type II HRS is typified by a more indolent course with a stable reduction in GFR accompanying diuretic resistant ascites and avid sodium retention. The diagnosis of HRS is one of exclusion. Other diagnoses that must be entertained in the patient with AKI and liver disease include prerenal AKI due to gastrointestinal losses, drug toxicity, combined hepatitis and tubulointerstitial nephritis induced by drugs or infectious agents, and multiorgan involvement in vasculitides (e.g., hepatitis C-induced cryoglobulinemia; see Table 29-14 ). The BUN and serum creatinine values are characteristically deceptively low, despite marked impairment of GFR, because of impaired urea generation and coexisting muscle wasting.[469] The urinary findings include a benign sediment and a low FENa.[337] The most common precipitant of the HRS in patients with compensated cirrhosis is spontaneous bacterial peritonitis. [459] [470] Other postulated trigger factors include vigorous diuresis or paracentesis, gastrointestinal bleeding, infections, minor surgery, or the use of NSAIDs and other drugs. However, caution must be exerted in these cases to exclude reversible causes of AKI. Adverse prognostic features include type I variant and the severity of the liver failure (Child-Pugh Class). [457] [459] [465] [471] In the past, type I HRS was associated with a very bleak prognosis, with a median survival of less than a month. However, advances in the management of HRS discussed later suggest that in those patients who respond to therapy, there may be a trend toward better survival.

Acute Kidney Injury and the Nephrotic Syndrome

AKI in the context of the nephrotic syndrome presents a unique array of potential diagnoses. Epithelial cell injury, if severe, can trigger both nephrotic range proteinuria and acute or subacute renal failure. [472] [473] This typically occurs as a manifestation of a primary glomerular disease such as collapsing glomerulopathy or crescentic membranous nephropathy. Less dramatic visceral epithelial cell injury, in combination with proximal tubular injury (e.g., panepithelial cell injury induced by NSAIDs or possibly undiagnosed viral illness) or interstitial nephritis (e.g., rifampicin induced) can also present as AKI complicating the nephrotic syndrome. [474] [475] [476] Massive excretion of light chain protein in patients with myeloma may present in a similar fashion. [98] [477] [478] ATN in association with the nephrotic syndrome is seen in a subpopulation of older patients with minimal change disease. These patients are more hypertensive and have heavier proteinuria than patients without AKI.[472] The higher incidence of arteriosclerosis in biopsy samples from these patients may point to preexisting hypertensive nephrosclerosis as a risk factor in the development of this complication. Renal vein thrombosis must always be considered in the differential diagnosis, particularly in the pediatric population; however, the commonest cause for ARF in the patient with the nephrotic syndrome is prerenal ARF complicating diuretic therapy for mobilization of edema. [60] [61]


AKI impairs renal excretion of Na+, K+, and water; divalent cation homeostasis; and urinary acidification mechanisms. As a result, AKI is frequently complicated by intravascular volume overload, hyperkalemia, hyponatremia, hyperphosphatemia, hypocalcemia, hypermagnesemia, and metabolic acidosis ( Table 29-15 ). In addition, patients are unable to excrete nitrogenous waste products and may develop the uremic syndrome. In general, the severity of these complications mirrors the severity of renal injury and the catabolic state of the patient. [29] [326] [479] For example, the average daily increases in BUN and serum creatinine values in patients with nonoliguric, noncatabolic renal failure range from 10 to 20 mg/dL and 0.5 to 1.0 mg/dL, respectively. Comparable increments in BUN and creatinine levels in oliguric, catabolic patients typically range from 20 to 100 mg/dL and 2 to 3 mg/dL, respectively. Not surprisingly, therefore, the latter group is at significantly higher risk for life-threatening metabolic complications and has a worse prognosis[8] (see later).

TABLE 29-15   -- Common Complications of Acute Kidney Injury













Metabolic Acidosis


















Pulmonary edema









Pericardial effusion



Pulmonary Embolism






Myocardial Infarction












GI hemorrhage



Neuromuscular irritability









Mental status changes















Urinary tract infection






Elevated parathroid hormone



Low total triiodothyronine and throxine



Normal free throxine


GI, gastrointestinal.




Intravascular volume overload is an almost inevitable consequence of diminished salt and water excretion in AKI and may present clinically as mild hypertension, increased jugular venous pressure, bibasilar lung crackles, pleural effusions or ascites, peripheral edema, increased body weight, and life-threatening pulmonary edema. Hypervolemia may be particularly troublesome in patients receiving multiple intravenous medications, sodium bicarbonate for correction of acidosis, or enteral or parenteral nutrition. Moderate or severe hypertension is unusual in ATN and should suggest other diagnoses such as hypertensive nephrosclerosis, glomerulonephritis, renal artery stenosis, and other diseases of the renal vasculature. [62] [414] [452] [480] [481] [482] Excessive water ingestion or administration of hypotonic saline or isotonic dextrose solutions can trigger hyponatremia, which, if severe, may cause cerebral edema, seizures, and other neurologic abnormalities.[483]

Hyperkalemia is a common and potentially life-threatening complication of AKI. [13] [484] [485] [486] [487] Serum K+ typically rises by 0.5 mEq/L/day in oligoanuric patients and reflects impaired excretion of K+ derived from diet, K+-containing solutions, drugs administered as potassium salts (e.g., penicillin V), and K+ released from injured tubule epithelium. Hyperkalemia may be compounded by coexistent metabolic acidosis that promotes K+ efflux from cells. Severe hyperkalemia or hyperkalemia present at the time of diagnosis of AKI suggests massive tissue destruction such as rhabdomyolysis, hemolysis, or tumor lysis. [68] [155] [404] [488] Mild hyperkalemia (<6.0 mEq/L) is usually asymptomatic. Higher levels are frequently associated with electrocardiographic abnormalities, typically peaked T waves, prolongation of the PR interval, flattening of P waves, widening of the QRS complex, and left axis deviation. [489] [490] [491] [492] [493] These changes may antecede the onset of life-threatening cardiac arrhythmias such as bradycardia, heart block, ventricular tachycardia or fibrillation, and asystole. In addition, hyperkalemia may induce neuromuscular abnormalities such as paresthesias, hyporeflexia, weakness, ascending flaccid paralysis, and respiratory failure. Hypokalemia is unusual in AKI but may complicate nonoliguric ATN caused by aminoglycosides, cisplatin, or amphotericin B, presumably by causing epithelial cell injury in the thick ascending limb of the loop of Henle, the last major site of K+ reabsorption. [5] [494] [495] [496]

Normal metabolism of dietary protein yields between 50 and 100 mmol/day of fixed nonvolatile acids (principally sulfuric and phosphoric acid), which must be excreted by the kidneys for preservation of acid-base homeostasis. Predictably, AKI is commonly complicated by metabolic acidosis, typically with a widening of the serum anion gap.[497] Acidosis may be severe (daily fall in plasma HCO3- >2 mEq/L) when the generation of H+ is increased by additional mechanisms (e.g., diabetic or fasting ketoacidosis; lactic acidosis complicating generalized tissue hypoperfusion, liver disease, or sepsis; metabolism of ethylene glycol). [176] [368] [459] In contrast, metabolic alkalosis is an infrequent finding but may complicate overzealous correction of acidosis with HCO3- or loss of gastric acid by vomiting or nasogastric aspiration.

Uric acid is cleared from blood by glomerular filtration and secretion by proximal tubule cells, and mild asymptomatic hyperuricemia (12 to 15 mg/dL) is typical in established AKI. Higher levels suggest increased production of uric acid and should suggest a diagnosis of acute urate nephropathy. [170] [498] [499] In borderline cases, measurement of the urinary urate/creatinine ratio on a random specimen may help distinguish between hyperuricemia caused by overproduction and impaired excretion. This ratio is typically greater than 1.0 when uric acid production is increased and less than 0.75 in normal individuals and patients with renal failure.[173]

Mild hyperphosphatemia (5 to 10 mg/dL) is a common consequence of AKI, and hyperphosphatemia may be severe (10 to 20 mg/dL) in highly catabolic patients or when AKI is associated with rapid cell death as in rhabdomyolysis, hemolysis, or tumor lysis. [398] [500] [501] [502] Metastatic deposition of calcium phosphate can lead to hypocalcemia, particularly when the product of serum Ca2+ (mg/dL) and PO43- (mg/dL) concentrations exceeds 70. [484] [503]Other factors that potentially contribute to hypocalcemia include skeletal resistance to the actions of parathyroid hormone, reduced levels of 1,25-dihydroxyvitamin D, and Ca2+ sequestration in injured tissues. [484] [504] [505]Hypocalcemia is usually asymptomatic, possibly because of the counterbalancing effects of acidosis on neuromuscular excitability. However, symptomatic hypocalcemia can occur in patients with rhabdomyolysis or acute pancreatitis or after treatment of acidosis with HCO3-.[484] Clinical manifestations of hypocalcemia include perioral paresthesias, muscle cramps, seizures, hallucinations and confusion, and prolongation of the QT interval, and nonspecific T-wave changes on an electrocardiogram. The Chvostek sign (contraction of facial muscles on tapping of the jaw over the facial nerve) and the Trousseau sign (carpopedal spasm after occlusion of arterial blood supply to the arm for 3 minutes with a blood pressure cuff) are useful indicators of latent tetany in high-risk patients. Mild asymptomatic hypermagnesemia is usual in oliguric AKI and reflects impaired excretion of ingested magnesium (dietary magnesium, magnesium-containing laxatives, or antacids). [506] [507] [508] Hypomagnesemia occasionally complicates nonoliguric ATN associated with cisplatin or amphotericin B and, as with hypokalemia, probably reflects injury to the thick ascending limb of loop of Henle, the principal site for Mg2+ reabsorption. [495] [509] [510] Hypomagnesemia is usually asymptomatic but may occasionally be manifest as neuromuscular instability, cramps, seizures, cardiac arrhythmias, or resistant hypokalemia or hypocalcemia. [506] [508]

Anemia develops rapidly in AKI and is usually mild and multifactorial in origin. Contributing factors include inhibition of erythropoiesis, hemolysis, bleeding, hemodilution, and reduced RBC survival time. [511] [512] Prolongation of the bleeding time and leukocytosis are also common. [513] [514] Prolongation of the bleeding time may result from mild thrombocytopenia, platelet dysfunction, and clotting factor abnormalities (e.g., factor VIII dysfunction), and the complementary actions of administered drugs (e.g., penicillins), and leukocytosis usually reflects sepsis, stress response, and other concurrent illness. [513] [515] [516] [517] Infection is the most common and serious complication of AKI, occurring in 50% to 90% of cases and accounting for up to 75% of deaths. [13] [17] [18] [19] [20] [29] [428] [485] [518] It is unclear whether this high incidence of infection is due to a defect in host immune responses or repeated breaches of mucocutaneous barriers (e.g., intravenous cannulae, mechanical ventilation, bladder catheterization).

Cardiac complications include arrhythmias, myocardial infarction, and pulmonary embolism. Although these events may reflect primary cardiac disease, abnormalities in myocardial contractility and excitability may be triggered or compounded by hypervolemia, acidosis, hyperkalemia, and other metabolic sequelae of AKI. The increased incidence of pulmonary embolism probably reflects protracted periods of immobilization. Mild gastrointestinal bleeding is common (10% to 30%) and is usually due to stress ulceration of gastric or small intestinal mucosa. [519] [520] Alterations in neurologic function may reflect the onset of the uremic syndrome, metabolic complications of AKI, impaired excretion of prescribed neuropsychiatric medications, or primary neurologic disease including TTP. [521] [522] [523] [524]

Malnutrition remains one of the most frustrating and troublesome complications of AKI. The majority of patients have net protein breakdown, which may exceed 200 g/day in catabolic subjects. [525] [526] Malnutrition is usually multifactorial in origin and may reflect (1) inability to eat or loss of appetite; (2) the catabolic nature of the underlying medical disorder (e.g., sepsis, rhabdomyolysis, trauma); (3) nutrient losses in drainage fluids or dialysate; (4) increased breakdown and reduced synthesis of muscle protein and increased hepatic gluconeogenesis, probably through the actions of toxins, hormones (e.g., glucagon, parathyroid hormone), or other substances (e.g., proteases) that are accumulated in AKI; and (5) inadequate nutritional support. [527] [528] [529] [530] [531] Nutrition may also be compromised by the high incidence of acute gastrointestinal hemorrhage, which complicates up to 15% of cases of AKI.

Protracted periods of severe ARF or short periods of catabolic, anuric AKI often lead to the development of the uremic syndrome. Clinical manifestations of the uremic syndrome, in addition to those already listed, include pericarditis, pericardial effusion, and cardiac tamponade; gastrointestinal complications such as anorexia, nausea, vomiting, and ileus; and neuropsychiatric disturbances including lethargy, confusion, stupor, coma, agitation, psychosis, asterixis, myoclonus, hyperreflexia, restless leg syndrome, focal neurologic deficit, or seizures (see Table 29-15 ). The uremic toxin (or toxins) responsible for this syndrome has yet to be defined. Candidate molecules include (1) urea and its breakdown products, (2) other products of nitrogen metabolism such as guanidino compounds, (3) products of bacterial metabolism such as aromatic amines and skatoles, and (4) other compounds that are inappropriately retained in the circulation in AKI, or are underproduced, such as NO.[479]

A vigorous diuresis may complicate the recovery phase of AKI and precipitate intravascular volume depletion and a delay in recovery of renal function. This diuretic response probably reflects the combined effects of an osmotic diuresis induced by retained urea and other waste products and delayed recovery of tubule function relative to glomerular filtration. [330] [331] [333] [334] Hypernatremia may also complicate this recovery phase if free water losses are not replenished or are inappropriately replaced by relatively hypertonic saline solutions. Hypokalemia, hypomagnesemia, hypophosphatemia, and hypocalcemia are rarer metabolic complications during recovery from AKI. Mild transient hypercalcemia is relatively frequent during recovery and appears to be a consequence of hyperparathyroidism. In addition, hypercalcemia may complicate recovery from rhabdomyolysis because of mobilization of sequestered Ca2+ from injured muscle.


The goals of management of AKI encompass the need to prevent death, ameliorate metabolic and extracellular volume complications, and preserve renal function so as to prevent the development of chronic kidney disease.

Prerenal Acute Kidney Injury

By definition, prerenal AKI is rapidly reversible on restoration of renal perfusion.[48] The composition of replacement fluids for treatment of hypovolemia varies depending on the source of fluid loss. Hypovolemia caused by hemorrhage is ideally corrected with packed RBCs if the patient is hemodynamically unstable or if the hematocrit is dangerously low. In the absence of active bleeding or hemodynamic instability, isotonic saline may suffice. The choice of replacement for nonhemorrhagic renal, extrarenal, or third-space losses is controversial. Recent critical reviews of RCTs comparing crystalloid with colloid replacement for resuscitation in critically ill patients conclude that the routine use of colloids may be associated with an adverse outcome and is not justified. [532] [533] [534] [535] [536] [537] [538] A study comparing the use of hydroxyethylstarch or gelatin as a volume expander in patients with sepsis found that the use of hydroxyethylstarch was an independent risk factor for the development of AKI, and its routine use should be discouraged in the management of prerenal AKI and sepsis.[539] Thus, isotonic saline is the appropriate replacement fluid for plasma losses (e.g., burns, pancreatitis). The SAFE trial compared the use of either 4% albumin or normal saline for fluid resuscitation in ICU patients.[540] At 28 days, there was no significant difference noted between the two groups with respect to the primary outcome of death or secondary outcomes of organ failure, need for renal replacement therapy, or duration of hospitalisation. Colloid solutions should be used only sparingly, with regular monitoring of renal function and the risk of hyperoncotic renal failure minimized by the concomitant use of appropriate crystalloid solutions.[532] Urinary or gastrointestinal fluids vary greatly in composition but are usually hypotonic. Accordingly, initial replacement is best achieved with hypotonic solutions (e.g., 0.45% saline), and subsequent therapy should be based on measurements of the volume and ionic content of excreted or drained fluids. Serum K+ and acid-base status should be monitored in all subjects. K+ supplementation of replacement fluids is rarely required unless sodium bicarbonate induces hypokalemia during treatment of metabolic acidosis. Cardiac failure may require aggressive management with loop diuretics, antiarrhythmic drugs, positive inotropes, preload- and afterload-reducing agents, and mechanical aids such as an intra-aortic balloon pump. Invasive hemodynamic monitoring of the central venous pressure can be an important aid for guiding therapy in complicated patients in whom clinical assessment of cardiovascular function and intravascular volume may be difficult and unreliable. The routine use of pulmonary artery catheters is discouraged based on recent trial data.[541]

Fluid management may be particularly challenging in patients with AKI and cirrhosis. [457] [458] [462] [463] Although these subjects typically have intense intrarenal vasoconstriction and expanded total plasma volume because of pooling of blood in the splanchnic circulation, true hypovolemia or reduced effective systemic arterial blood volume may be an important contributory factor to AKI. The relative contribution of hypovolemia to AKI in this setting can be determined only by administration of a fluid challenge. Fluids should be administered slowly, because nonresponders may suffer an increase in ascites formation and pulmonary edema. Spontaneous bacterial peritonitis is a common trigger factor for HRS in patients with advanced cirrhosis and ascites. The administration of albumin (1.5 g/kg on diagnosis and 1 g/kg on day 3) in combination with standard antibiotic therapy in this setting has been demonstrated to reduce the incidence of HRS and improve patient survival.[470] Paracentesis can be employed to remove large volumes of ascitic fluid. Albeit controversial, simultaneous administration of albumin intravenously is touted by some investigators to minimize the risk of prerenal AKI and full-blown HRS during large-volume paracentesis. [458] [462] [542] Indeed, large-volume paracentesis may occasionally improve GFR, possibly by lowering intra-abdominal pressure and promoting blood flow in renal veins. Shunting of ascitic fluid from the peritoneum to a central vein (transjugular portosystemic shunt, peritoneojugular shunt, LeVeen or Denver shunt) is an alternative approach in refractory cases. [457] [543] [544] [545] [546] These maneuvers can cause an improvement in GFR and Na+ excretion, probably because the increase in central blood volume stimulates the release of ANP and inhibits aldosterone and norepinephrine secretion; however, definitive data on whether the improvement in renal function is associated with improved survival are lacking. Given that these procedures carry significant morbidity (e.g., hepatic encephalopathy); thus, their role needs to be determined by prospective controlled studies.

Vaospressin (V1) receptor agonists have shown promise in the reversal of established HRS. [547] [548] [549] The use of vasocontrictors in patients with HRS is based on the premise that reversal of splanchnic vasodilatation will augment peripheral vascular resistance, suppress the generation of endogenous vasoconstrictors, and thus improve renal perfusion. In most studies, albumin is administered concomitantly to further aid renal perfusion. Several studies have suggested that intravenous terlipressin improves renal function in patients with HRS, especially when combined with intravenous albumin. [548] [549] [550] In a small randomized trial, terlipressin (1 mg IV twice daily) combined with albumin resuscitation (goal CVP 10-12 mm Hg) resulted in 5 of 12 patients surviving 15 days as opposed to none of the placebo group.[550] Predictors of nonresponse include older age and more severe liver failure (Child-Pugh score >13). Further large-scale RCTs are awaited with interest.

Intrinsic Acute Kidney Injury


Optimization of cardiovascular function and intravascular volume is the single most important maneuver in the management of intrinsic AKI. There is compelling evidence that aggressive restoration of intravascular volume dramatically reduces the incidence of ATN after major surgery or trauma, burns, and cholera. [344] [534] [551] [552] [553] [554] [555] Sepsis-related AKI is a common clinical presentation and is associated with mortality rates as high as 80%. [17] [20] [556] [557] Recent studies have emphasized two salient features of successful management of sepsis that may be of importance in the prevention of AKI. Early goal-directed resuscitation to defined hemodymanic targets (MAP >65 mm Hg, CVP 10-12, urine output >0.5 mL/kg per hour, ScvO2 >70%) using a combination of crystalloid solutions, red cell transfusion, and vasopressors results in a significant reduction in organ dysfunction and mortality in patients with the sepsis syndrome.[558] Although the therapeutic goals chosen in this study were to a degree arbitrary, this study emphasizes the imperative for early and aggressive volume resuscitation in the management of patients with the sepsis syndrome. In another study of critically ill patients, intensive insulin therapy to maintain a glucose level of 180 to 220 mg/dL resulted in a 41% decrease in AKI requiring renal replacement therapy.[559]

Volume depletion has been identified as a risk factor for nephrotoxic ATN induced by radiocontrast material, acyclovir, aminoglycosides, amphotericin B, cisplatin, acute urate nephropathy, rhabdomyolysis, hemolysis, multiple myeloma, hypercalcemia, and numerous other nephrotoxins. [98] [112] [402] [404] [499] [555] [560] [561] [562] [563] [564] Restoration of volume prevents the development of experimental and human ATN in many of these settings. The importance of maintaining euvolemia in high-risk clinical situations has been demonstrated most convincingly with contrast nephropathy, in which close attention to intravascular volume status ensures a low frequency of AKI. [565] [566] Multiple studies have addressed this issue in an attempt to identify the optimal preventive strategy. Prophylactic infusion of half-normal saline (1 mL/kg for 12 hours before and after procedure) is more effective in preventing AKI than either mannitol and furosemide, both of which should be avoided in this setting.[567] In another large randomized trial, isotonic saline significantly reduced the incidence of contrast nephropathy following coronary angiography compared with half-normal saline with a particular benefit noted in diabetic patients and those receiving large contrast loads.[568] In a smaller single trial, hydration with sodium bicarbonate before contrast exposure was more effective than hydration with isotonic saline for the prevention of contrast nephropathy.[569] In aggregate, the key message from these studies is that the avoidance of hypovolaemia is the key intervention in preventing contrast nephropathy. Definitive data regarding the optimal hydration regimen require additional confirmatory studies. In the interim, a hydration regimen of isotonic saline (≈1 mL/kg per hour) starting the morning of the procedure and continuing for several hours afterward would appear most appropriate. The rate of administration must take into consideration the patient's cardiopulmonary status and may require adjustment in this regard.

N-acetylcysteine has been suggested as an ideal agent to prevent the nephrotoxicity of contrast mediums through antioxidant and vasodilatory effects.[570] Prophylactic oral administration of oral acetylcysteine (600 mg twice a day pre- and postprocedure), in combination with hydration, reduces the incidence of contrast nephropathy in patients with moderate renal insufficiency in several new trials. [570] [571] [572] [573] [574] [575] [576] The regimen is inexpensive and safe, and although definitive data are lacking, the use of prophylactic oral N-acetylcysteine should be considered in all patients with impaired renal function before receiving intravenous or intra-arterial iodinated contrast material. The use of low- or iso-osmolar contrast media has been suggested to reduce the incidence of contrast-induced AKI.[577] In a large randomized trial of patients undergoing coronary angiography, use of the low-osmolar contrast agent iohexol was associated with a reduction in the incidence of contrast nephropathy in patients with CKD and diabetes mellitus when compared with the standard high-osmolar diatrizoate.[578] In a second smaller study comparing the iso-osmolar agent iodixanol (≈290 mOsm) with iohexol, the former reduced the risk of contrast nephropathy among diabetics with renal insufficiency when given with standard hydration regimens, albeit that the incidence of renal dysfunction in the iohexol group was remarkably high.[579] On balance, it would appear appropriate to use low-osmolar agents in patients with known diabetic nephropathy. However, definitive trial data is awaited regarding the generalizabilty of these findings to all patients with CKD. Other important interventions include spacing the timing of repeated contrast interventions as allowed by the patient's clinical need and considering alternate imaging techniques. The use of less nephrotoxic contrast agents (e.g., gadolinium or carbon dioxide) in combination with enhanced digital subtraction technology as an alternative to standard iodinated contrast administration is an evolving area of interest that offers the possibility of adequate imaging with significantly less renal injury.[580] Recent years have seen the wider application of MRA. [380] [386] [581] Its safety and accuracy make it a useful diagnostic tool for screening and diagnostic angiography of the abdominal aorta, renal, and visceral arteries in patients with renal impairment; however, interventional procedures (i.e., angioplasty and stenting) still require conventional digital subtraction angiography.

Diuretics, NSAIDs (including COX-II inhibitors), ACE inhibitors, and other vasodilators should be used with caution in patients with suspected true or effective hypovolemia or renovascular disease, because they may convert prerenal ARF to ischemic ATN and sensitize such patients to the actions of nephrotoxins. Careful monitoring of circulating drug levels appears to reduce the incidence of ARF associated with aminoglycoside antibiotics or calcineurin inhibitors. [89] [121] [582] Interestingly, the antimicrobial efficacy of aminoglycosides appears to persist in tissues even after the drug has been cleared from the circulation. Also, there is convincing evidence that once-daily dosing with these agents affords equal antimicrobial activity and less nephrotoxicity than conventional regimens. [123] [125] [582] [583] The use of lipid-encapsulated formulations of amphotericin B may offer some protection against renal injury. [52] [128] Several other agents are commonly employed to prevent AKI in specific clinical settings. Allopurinol (10 mg/kg/day in 3 divided doses, max 800 mg) is useful for limiting uric acid generation in patients at high risk for acute urate nephropathy; however, occasional patients receiving allopurinol still develop AKI, probably through the toxic actions of hypoxanthine crystals on tubule function. [170] [395] [402] [404] [499] [584] In this setting, the use of recombinant urate oxidase (raburicase, 0.05–0.2 mg/kg) should be considered. Raburicase promotes the degradation of uric acid to allantoin and has been proven efficacy both as prophylaxis and treatment for acute uric acid-mediated tumor lysis syndrome. [404] [584] [585] [586] [587] In oligoanuric patients, prophylactic hemodialysis to remove excess uric acid may be of value.

Amifostine, an organic thiophosphate, has been demonstrated to ameliorate cisplatin nephrotoxicity in patients with solid organ or hematologic malignancies. [93] [588] [589] [590] N-Acetylcysteine limits acetaminophen-induced renal injury if given within 24 hours of ingestion, and dimercaprol, a chelating agent, may prevent heavy metal nephrotoxicity. [591] [592] Ethanol inhibits ethylene glycol metabolism to oxalic acid and other toxic metabolites but has been superceded by the introduction of fomepizole, an effective alcohol dehydrogenase inhibitor that decreases production of ethylene glycol metabolites and thence prevents the development of renal injury. [593] [594] [595] [596]

Specific Therapies

During the past 2 decade there has been extensive investigation into the pathogenesis of AKI using experimental animal models and cultured cells. These studies have led to substantial advances in our understanding of the mechanisms that could potentially play a role in ATN in humans. This information has led to an exciting array of potentially novel targets for the treatment of this common and serious disease. However, a number of interventions shown to be effective in ameliorating AKI in animals have failed to be effective in humans with ATN. There are many possible reasons for lack of success in translating therapeutic successes for AKI from “bench to bedside.” We lack adequate information regarding the pathology of ATN in humans in the current era, because there has been a lack of systematic studies in this area for many years. It is possible that human tissue, subjected to conventional histologic stains as well as more “state-of-the-art” approaches (such as gene array and proteomics) would facilitate the identification of those patients most likely to response to treatment.


Renal dose dopamine (1 to 3 mg/kg/min) has been widely advocated for the management of oliguric AKI. [597] [598] [599] In experimental animals and healthy human volunteers, renal dose dopamine increases renal blood flow and, albeit to a lesser extent, GFR. Renal dose dopamine has not been demonstrated to prevent or alter the course of ischemic or nephrotoxic ATN in prospective controlled clinical trials. [600] [601] [602] [603] Indeed, the available evidence would suggest lack of efficacy. Furthermore, dopamine, even at low doses, is potentially toxic in critically ill patients and can induce tachyarrhythmias, myocardial ischemia, extravasation necrosis among other complications.[604]Thus, the routine administration of dopamine to patients with oliguric AKI is not justified based on the balance of experimental and clinical evidence. [605] [606]


Fenoldopam is a selective postsynaptic dopamine agonist (D1-receptors) that mediates more potent renal vasodilatation and natriuresis than dopamine.[607] However, it also promotes hypotension by decreasing peripheral vasculature resistance. Early positive results from small studies suggested a possible benefit renoprotective effect of fenoldopam in high-risk clinical situations. [608] [609] However, a subsequent larger randomized trial comparing fenoldopam to standard hydration in patients undergoing invasive angiographic procedures found no benefit.[610] Moreover, in a large RCT, fenoldopam administration did not reduce mortality or the need for renal replacement therapy in ICU patients with early ATN.[611]

Natriuretic Peptides

ANP is a 28-amino acid polypeptide synthesized in cardiac atrial muscle. [598] [612] [613] [614] ANP augments GFR by triggering afferent arteriolar vasodilatation and increasing Kf. In addition, ANP inhibits sodium transport and lowers oxygen requirements in several nephron segments. Synthetic analogs of ANP have shown promise in the management of ATN in the laboratory setting. To date, this promise has failed to translate into clinically apparent benefit and a large multicenter, prospective, randomized placebo controlled trial of anaritide, a synthetic analog of ANP, failed to show clinically significant improvement in dialysis-free survival or overall mortality in ATN.[615]Subgroup analysis suggested an improvement in dialysis-free survival in treated patients, but this was not confirmed in a subsequent prospective trial of patients with oliguric AKI. Ularitide (urodilantin) is a natriuretic pro-ANP fragment produced within the kidney. In a small randomized trial, ularitide did not reduce the need for dialysis in patients with AKI.[616]

Loop Diuretics

The administration of high-dose intravenous diuretics to individuals with oliguric AKI is commonly practiced.[617] Although this strategy may minimize fluid overload, there is no evidence that it alters mortality or dialysis-free survival. Some retrospective analyses have reported an increased risk of death and nonrecovery of renal function in patients treated in this manner.[618] In a recent large RCT, high-dose intravenous furosemide augmented urine output but did not alter the outcome of established AKI.[619] Given the risks of loop diuretics in AKI, including irreversible ototoxicity and exacerbation of prerenal AKI, their use should be restricted to the conservative management of volume overload (vide infra). [620] [621]


No adequate data exist to support the routine administration of mannitol to oliguric patients. Moreover, when administered to severely oliguric or anuric patients, mannitol may trigger expansion of intravascular volume and pulmonary edema, and severe hyponatremia owing to an osmotic shift of water from the intracellular to the intravascular space. [555] [567] [617] [622] [623] [624] [625] [626]

AKI caused by other intrinsic renal diseases such as acute glomerulonephritis or vasculitis may respond to corticosteroids, alkylating agents, and plasmapheresis, depending on the primary disease. Corticosteroids appear to hasten remission in some cases of allergic interstitial nephritis. [353] [359] [627] [628] Plasma exchange is useful in treatment of sporadic TTP and possibly sporadic HUS in adults. [629] [630] The role of plasmapheresis in the drug-induced thrombotic microangiopathies is less clear, and removal of the offending agent is the most important initial therapeutic maneuvre. [400] [405] [406] Post-diarrheal HUS in children is usually managed conservatively and evidence exists suggesting that early antibiotic therapy may actually promote the development of HUS.[631] Early studies suggested that plasmapheresis may be of benefit in ARF due to myeloma cast nephropathy. [167] [564] Clearance of circulating light chains with concomitant chemotherapy to decrease the rate of production had been postulated to reverse renal injury in patients with circulating light chains, heavy Bence Jones proteinuria, and AKI. A recent relatively large RCT compared plasma exchange and standard chemotherapy with chemotherapy alone. The study did not demonstrate improvement with plasma exchange with regard to the composite variable of death, dialysis dependence, or GFR less than 30 mL/min at 6 months, and its routine use in this setting can no longer be justified.[632]

Aggressive control of systemic arterial pressure is of paramount importance in limiting renal injury in malignant hypertensive nephrosclerosis, toxemia of pregnancy, and other vascular diseases. Hypertension and AKI associated with scleroderma may be exquisitely sensitive to treatment with ACE inhibitors. [633] [634] [635] The specifics of treatment strategies for these disorders are discussed in other chapters.

Management of Complications

Metabolic complications such as intravascular volume overload, hyperkalemia, hyperphosphatemia, and metabolic acidosis are almost invariable in oliguric AKI, and preventive measures should be taken from the time of diagnosis (Table 29-16 ). Prescription of nutrition should be designed to meet caloric requirements and minimize catabolism. In addition, doses of drugs excreted through the kidney must be adjusted for the degree of renal impairment.

TABLE 29-16   -- Supportive Management of Intrinsic Acute Kidney Injury



Intravascular Volume Overload

Restriction of salt (<1–1.5 g/day) and water (<1 L/day)


Consider diuretics (usually loops +/- thiazide)




Restriction of oral and intravenous free water


Restriction of dietary potassium


Discontinue K+ supplements or K+-sparing diuretics


K+-binding resin


Loop diuretic


Glucose (50 mls of 50%) + insulin (10–15 U regular) IV


Sodium bicarbonate (50–100 meq IV)


Calcium gluconate (10 mLs of 10% solution over 5 min)



Metabolic Acidosis

Restriction of dietary protein


Sodium bicarbonate (if HCO3- <15 mEq/L)




Restriction of dietary phosphate intake


Phosphate binding agents (calcium carbonate, calcium acetate, sevalemer)


Calcium carbonate (if symptomatic or sodium bicarbonate to be administered)


Discontinue magnesium containing antacids


Restriction of dietary protein (<0.8 g/kg/day up to 1.5 g/kg/day on CVVHD) 25–30 kcal/day


Enteral route of nutrition preferred

Drug Dosage

Adjust all doses for GFR and renal replacement modality

Absolute Indications for RRT

Clinical evidence of uremia


Intractable volume overload


Hyperkalemia or severe acidosis resistant to conservative management


CVVHD, continuous venovenous hemodialysis; GFR, glomerular filtration rate; IV, intravenous; RRT, renal replacement therapy.




After correction of intravascular volume deficits, salt and water intake should be adjusted to match losses (urinary, gastrointestinal, drainage sites, insensible losses). Intravascular volume overload can usually be managed by restriction of salt and water intake and by use of diuretics. Indeed, there is as yet no proven rationale for routine administration of diuretics to patients with AKI other than to treat this complication. In the volume-overloaded patient, high doses of loop diuretics such as furosemide (bolus doses of up to 200 mg or up to 20 mg/hr as an IV infusion) or sequential thiazide and loop diuretic may be required if they fail to respond to conventional doses. Diuretic therapy should be discontinued in resistant patients to avoid complications such as ototoxicity. Caution should be exerted in the use of pharmacologic agents that require an obligate sodium and fluid load. Ultrafiltration or dialysis may be required for removal of volume when conservative measures fail. Hyponatremia associated with a fall in effective serum osmolality can usually be corrected by restriction of water intake. Conversely, hypernatremia is treated by administration of water, hypotonic saline solutions, or hypotonic dextrose-containing solutions (the latter are effectively hypotonic because dextrose is rapidly metabolized).

Mild hyperkalemia (<5.5 mEq/L) should be managed initially by restriction of dietary potassium intake and elimination of potassium supplements and potassium-sparing diuretics. Moderate hyperkalemia (5.5 to 6.5 mEq/L) in patients without clinical or electrocardiographic evidence of hyperkalemia can usually be controlled by administration of K+-binding ion exchange resins such as sodium polystyrene sulfonate (15 to 30 g every 3 or 4 hours) with sorbitol (50 to 100 mL of 20% solution) by mouth or as a retention enema. Loop diuretics also increase K+ excretion in diuretic-responsive patients. Emergency measures should be employed for patients with serum K+ values greater than 6.5 mEq/L and all patients with electrocardiographic abnormalities or clinical features of hyperkalemia. Intravenous insulin (5–10U of regular insulin) and glucose (50 mL of 50% dextrose) promote K+ shift into cells within 30 to 60 minutes, a benefit that lasts for several hours. Sodium bicarbonate (1 ampule, 44.6 mEq intravenously over 5 minutes) also promotes rapid (onset less than 15 minutes, duration 1 to 2 hours) shift of K+ into the intracellular space as does nebulized (5–10 mg) albuterol. Sodium polysterene sulfonate and sodium bicarbonate have an obligatory sodium load; these compounds should be used judiciously for oliguric patients to avoid intravascular volume overload and life-threatening pulmonary edema. Calcium solutions such as calcium gluconate (10 mL of 10% solution intravenously over 5 minutes) antagonize the cardiac and neuromuscular effects of hyperkalemia and is a valuable emergency temporizing measure, whereas other agents reduce serum K+ concentration. Dialysis is indicated if hyperkalemia is resistant to these measures.

Metabolic acidosis does not require treatment unless the serum HCO3- concentration falls below 15 mEq/L. More severe acidosis can be corrected by either oral or intravenous bicarbonate administration. Initial rates of replacement should be based on estimates of HCO3- deficit and adjusted thereafter according to serum levels. Patients should be monitored for complications of bicarbonate administration including metabolic alkalosis, hypocalcemia, hypokalemia, volume overload, and pulmonary edema. Hyperphosphatemia can usually be controlled by restriction of dietary phosphate intake and oral administration of agents (e.g., aluminum hydroxide, calcium carbonate or sevelamer) that reduce absorption of PO43- from the gastrointestinal tract. Hypocalcemia does not usually require treatment unless it is severe, as may occur in patients with rhabdomyolysis or pancreatitis or after administration of bicarbonate. Hyperuricemia is usually mild in ARF (<15 mg/dL) and does not require specific intervention.

Nutritional management in patients with AKI requires close collaboration among physicians, nurses, and dietitians. Patients with ARF represent a heterogenous group and individualized nutritional management is required, especially in critically ill patients on renal replacement therapy in whom protein catabolic rates can exceed 1.5 g/kg body weight/day. [9] [526] [527] [528] [529] [636] The objective of dietary modification in ARF is to provide sufficient calories to preserve lean body mass, avoid starvation ketoacidosis, and promote healing and tissue repair while minimizing production of nitrogenous waste. If the duration of renal insufficiency is likely to be short and the patient is not catabolic, then dietary protein should be restricted to <0.8 g/kg body weight/day. Catabolic patients, including those on continuous renal replacement therapy, may receive up to 1.4 mg/kg body weight/day. Total caloric intake should not exceed 35kcal/kg body weight/day and will typically be in the range of 25 to 30kcal/kg body weight/day. [526] [528] The enteral route of nutrition is preferred, because it avoids the morbidity associated with parenteral nutrition while providing support to intestinal function. Management of nutrition is easier in nonoliguric patients and after institution of dialysis. Vigorous parenteral hyperalimentation has been claimed to improve prognosis in AKI; however, a consistent benefit has yet to be demonstrated in this regard. Water-soluble vitamin supplementation is advised with the exception of vitamin C, which can, in high doses (>200 mg/day), promote urinary oxalate excretion and stone formation.

Anemia may necessitate blood transfusion or administration of recombinant human erythropoietin if severe or if recovery is delayed. Uremic bleeding usually responds to desmopressin, correction of anemia, estrogens, or dialysis. Doses of drugs that are excreted by the kidney must be adjusted for the degree of renal impairment.[513] Gastric stress ulcer prophylaxis is not indicated unless the patient is intubated or has a concurrent coagulopathy. Febrile patients must be investigated aggressively for infection and may require treatment with broad-spectrum antibiotics while awaiting identification of specific organisms. Meticulous care of intravenous cannulas, Foley catheters, and other invasive devices is mandatory. Unfortunately, prophylactic antibiotics have not been shown to reduce the incidence of infection in these high-risk patients.

Indications and Modalities of Dialysis

General Comments

Dialysis does not hasten recovery from AKI. Initial studies suggesting that early dialysis therapy improved prognosis for patients with AKI have not been confirmed. [637] [638] [639] Similarly, there is no consensus on the optimal renal replacement therapy in AKI. The preferred mode of renal replacement therapy is an area of active research. [640] [641] The claimed superiority of the continuous renal replacement techniques remains unproven. Neither are there evidenced-based guidelines on the initiation of dialysis in AKI. [12] [642] Absolute indications for the commencement of renal replacement therapy include symptomatic uremia (asterixis, pericardial rub, encephalopathy) and acidosis, hyperkalemia, or volume overload that proves refractory to medical management. However, in clinical practice, most nephrologists initiate renal replacement therapy (RRT) before the onset of overt metabolic disarray when the need for renal support appears inevitable. The choice of dialysis modality (peritoneal dialysis, hemodialysis, or hemofiltration) is often guided by the resources of the health care institution, the technical expertise of the physician and the clinical status of the patient.

Peritoneal Dialysis

Peritoneal dialysis in AKI is effected through a temporary intraperitoneal catheter. With the development of intermittent hemodialysis, and more recently, the slow continuous blood purification therapies, there has been a decline in the use of peritoneal dialysis in the acute setting. [643] [644] [645] [646] [647] It is still used in the treatment of AKI in regions where access to acute intermittent or slow continuous hemodialysis is not possible. Peritoneal dialysis has the advantage of being relatively “low-tech” and portable, thus facilitating its use in remote or resource-constrained areas.[646] Systemic hypotension is typically avoided, and other benefits include the avoidance of systemic anticoagulation and need for angioaccess. Solute clearance and control of metabolic disarray in critically ill patients may be inferior to continuous veno-veno hemofiltration, and this has been associated with an adverse outcome in infection-associated AKI.[643] Other drawbacks include the risk of visceral injury during catheter placement and peritonitis subsequently.

Acute Intermittent Hemodialysis

Acute intermittent hemodialysis has been the mainstay of renal replacement therapy in AKI over the past 40 years.[638] Typically, patients undergo dialysis for 3 to 4 hours daily or on alternate days depending on their catabolic state. Vascular access for short-term hemodialysis or hemofiltration is usually achieved using a double-lumen catheter inserted into the internal jugular vein. Subclavian canulation offers an alternative but is associated with high rates of venous stenosis and is best avoided.[648] Femoral vein catheterization is technically easy and relatively free of complications. It is useful in patients who cannot tolerate the Trendelenburg position or who require only an abbreviated treatment course (e.g., removal of an exogenous toxin). Jugular lines are preferred for more prolonged treatment courses, but with careful nursing management, it is possible to maintain a femoral line in situ in the bedbound patient without incurring a significant excess infection risk.[649] The choice of membrane used during dialysis may have an effect on outcome. [650] [651] Several, although not all, RCTs indicate that the maintenance phase of ATN is significantly shorter with use of more biocompatible synthetic dialysis membranes (e.g., polysulphone, polyacrylonitrile) than with cuprophane membranes. However, systematic reviews of the literature have failed to convincingly demonstrate a benefit of synthetic over more modern substituted cellulose membranes. [652] [653] [654] [655] [656] [657]

Anticoagulation with heparin is the standard method for preventing thrombosis of the extracorporeal circuit during acute intermittent dialysis.[658] Routine bedside measurement of the activated clotting time (ACT) allows heparin dosage adjustment as required to maintain a target ACT of baseline value plus 80%. Heparin-free dialysis can be performed in patients at high risk of hemorrhagic complications. This involves prerinsing the dialyzer with a heparinized solution (3000U/L) and setting the blood flow rate at least 250 to 300 mL/min. A periodic saline rinse is then administered every 30 minutes to prevent the clotting in the extracorporeal circuit. If heparin-induced thrombocytopenia (HIT) is a concern then the heparin prerinse should be avoided. Other anticoagulation techniques include the administration of a single bolus of low-molecular-weight heparin at the start of dialysis. [659] [660] Less used anticoagulant strategies include (1) regional heparinization with protamine infusion in the venous return line, (2) regional citrate anticoagulation, (3) continuous prostacyclin infusion, and (4) use of direct thrombin inhibitors: hirudin, argatroban, and lepirudin. [661] [662] [663] [664] [665]

The major complications of acute intermittent hemo-dialysis relate to rapid shifts in plasma volume and solute composition, the angioaccess procedure, and the necessity for anticoagulation. [486] [524] [645] [666] Intradialytic hypotension is common in patients undergoing acute intermittent hemodialysis. Hypotension impairs solute clearance and the efficiency of dialysis. In addition, hypotension can further compromise renal perfusion and exacerbate tubular necrosis (see earlier). Intradialytic hypotension is typically triggered by excessive fluid removal during ultrafiltration. [667] [668] [669] [670] [671] The latter, in turn, may occur if the degree of hypervolemia is overestimated, if the fluid removed is not matched by flux of fluid into the intravascular space from interstitial and cellular compartments, if the volume of fluid removed is excessive, or if the patient's compensatory responses are impaired as a result of microvascular disease or vasodilatatory medications (e.g., nitrates, antihypertensive medication). Hypotension may be particularly problematic in critically ill patients with ATN and concurrent sepsis, hypoalbuminemia, malnutrition, or large third-space losses. Management of intradialytic hypotension requires careful assessment of intravascular volume, by invasive hemodynamic monitoring, if necessary; prescription of realistic ultrafiltration targets; and close observation for tachycardia or hypotension during dialysis. The immediate management of hypotension involves the discontinuation of hemofiltration, placing the patient in the Trendelenburg position, and the rapid infusion of 250 to 500 mL of normal saline.

The dialysis disequilibrium syndrome is a self-limited condition characterized by nausea, vomiting, headache, altered consciousness, and rarely, seizures or coma. It typically occurs after a first dialysis in patients with long-standing severe uremia. [524] [638] The syndrome is triggered by rapid movement of water into brain cells following the development of transient plasma hypo-osmolality as solutes are rapidly cleared from the bloodstream during dialysis. The incidence of this complication has fallen in recent years, with the more gradual institution of dialysis, and the target reduction in BUN levels following the first dialysis treatment should not exceed 40%.The precise prescription of dialysis to achieve this outcome includes such variables as membrane size, blood flow rate, and duration of treatment. Typically, this will involve an initial treatment time of approximately 2 hours with a blood flow rate of 200 to 250 mL/min. Isolated ultrafiltration can continue for a longer period if volume removal is the critical management issue.[672]

Once the patient is established on dialysis, the optimal dose of dialysis is controversial. The standards for dialysis adequacy using intermittent hemodialysis in ARF are not defined. Of note, the catabolic state observed in critically ill patients may justify large dialysis dose delivery. [12] [642] In patients with AKI, the discrepancy between delivered versus prescribed hemodialysis dialysis dose may be significant owing to hemodynamic instability, filter clotting and inadequate vascular access, among other reasons. A randomized prospective trial of daily versus alternate-day hemodialysis suggested a significant mortality benefit in patients receiving daily dialysis.[486] In this study, daily hemodialysis afforded better uremic control while facilitating more intensive nutritional support without additional hemodynamic compromise and is now considered the standard of care.

The potential importance of dialysis membrane bio-incompatibility as a determinant of outcome in ATN has been discussed earlier. Occasionally robust complement and leukocyte activation by cellulosic membranes is followed by leukocyte sequestration in the lungs, hypoxemia, dyspnea, and back pain; this is also called the first use syndrome.[654] More dramatic anaphylactoid reactions were occasionally seen in the past as a result of hypersensitivity to ethylene oxide used to sterilize the dialysis circuitry. These reactions are now uncommon as a result of changes in commercial sterilization techniques and the routine prerinsing of the dialysis circuit. Rarely, anaphylactoid reactions are observed in patients dialyzed on AN60 synthetic membranes who receive concomitant ACE inhibition. AN69 activates the kallikrein system and promotes bradykinin generation. The breakdown of bradykinin is inhibited by ACE inhibition so that in combination, ACE inhibitors and an AN69 membrane can dramatically augment circulating bradykinin levels.

Continuous Renal Replacement Therapy

Many patient with ATN are critically ill, hypercatabolic, and hemodynamically unstable. They frequently have large obligate fluid requirements, being on intravenous medication and parenteral alimentation. In this setting, ultrafiltration of large volumes of plasma over a relatively short period by acute intermittent hemodialysis may induce circulatory compromise. Even if tolerated hemodynamically, acute intermittent hemodialysis may not achieve adequate ultrafiltration or solute clearance to avoid life-threatening pulmonary edema or uremia, and continuous renal replacement therapy (CRRT) may be more appropriate. Hemofiltration was first described in 1977 for the management of refractory edema. Technical advances over the past 2 decades have yielded a variety of slow continuous dialytic therapies ( Table 29-17 ) that are now well established in the management of AKI. [673] [674] Whereas the various techniques differ slightly in their technical detail, they share several attractive features such as relative simplicity of operation, the ability to remove large volumes of fluid over a prolonged period with minimal hemodynamic compromise, and the capacity to control uremia and electrolyte and acid-base abnormalities with minimal perturbation of plasma osmolality.

TABLE 29-17   -- Dialytic Modalities in Acute Kidney Injury



Physical Principle

Urea Clearance (mL/min)

Middle Molecule Clearance








Intermittant diffusive clearance and ultrafiltration (UF) concurrently



Sustained low efficiency dialysis (SLED)


Intermittent, but prolonged diffusive clearance and ultrafiltration (UF) concurrently



Sequential ultrafiltration and clearance


Intermittent (UF), followed by diffusive clearance



Continuous arteriovenous hemodialysis (CAVHD)


Slow diffusive clearance and UF concurrently without a blood pump



Continuous venovenous hemodialysis (CVVHD)


Slow diffusive clearance and UF concurrently with a blood pump








Continuous arteriovenous hemofiltration (CAVHF)


Continuous convective clearance without a blood pump



Continuous venovenous hemofitration (CVVHF)


Continuous convective clearance with a blood pump



Continuous venovenous hemodialysis plus hemofitration (CVVHDF)


Continuous convective clearance plus diffusive clearance with a blood pump



Ultrafiltration (UF)





Isolated UF


Intermittent UF alone



Slow continuous UF (SCUF)


Continuous arteriovenous or venovenous hemofiltration UF alone without convective or diffusive clearance



Peritoneal dialysis







Continuous clearance and UF via exchanges performed at varying intervals





Intermittent clearance and UF via exchanges performed at varying intervals



Adapted from Owen WF, Lazarus JM: Dialytic management of acute renal failure. In Lazarus JM, Brenner BM (eds): Acute Renal Failure, 3rd ed. New York, Churchill Livingstone, 1993.




Continuous venovenous hemodialysis (CVVHD), continuous venovenous hemofiltration (CVVH), or a combination thereof, called continuous venovenous hemodiafiltration (CVVHDF) are the techniques favored by most centers.[675] Angioaccess is achieved through a double-lumen venous catheter as described earlier. A roller pump ensures constant blood flow and generates hydraulic pressure for ultrafiltration. A variety of dialysates and filtrates are available and range from standard solutions used for peritoneal dialysis to solutions specifically tailored for CRRT. Importantly, all are isotonic and contain potassium well below the serum concentration. Standard solutions use lactate as their bicarbonate equivalent; however, tailored solutions may use bicarbonate or citrate as the base. Systemic heparinization is usually instituted; however, heparin requirements may be relatively low in patients with coagulopathy or thrombocytopenia, or in patients receiving replacement fluids into the dialysis circuitry before the dialysis filter (predilution fluid replacement). Regional citrate anticoagulation is an alternative anticoagulant strategy with several advantages in the critically ill patient. [676] [677] Anticoagulation is achieved by infusion of trisodium citrate into the arterial blood inflow line, thus lowering the ionized calcium level and impairing the activity of calcium-dependent clotting factors. The process is reversed by a calcium infusion into the venous return line. This method provides highly effective local anticoagulation with prolonged filter life and is particularly useful in patients with HIT or in those at high risk of bleeding in whom systemic anticoagulation is contraindicated. Other anticoagulant options include prostacyclin or argatroban and lepirudin both direct thrombin inhibitors that have been used successfully for anticoagulant therapy in patients with HIT. [661] [663] [678]

Most modern units contain an air trap, air detector, venous pressure monitor, and automated control of the ultrafiltration rate. Clearance of low-molecular-weight solutes can be enhanced by an increase in the blood flow and dialysate rates, or by increasing the rate of hemofiltration if this technique is being used. On a milliliter-for-milliliter basis, increasing the ultrafiltration rate is the most efficient way of improving clearance using the combined technique of CVVHDF. Some authorities have advocated prophylactic high-volume hemofiltration (>50L/day) as an adjunctive therapy in sepsis with a view to removing septic mediators from the circulation. [679] [680] No compelling prospective data exist at this time to recommend such an approach unless there is coexistent ARF requiring renal replacement therapy. As with hemodialysis, the optimal clearance targets in the slow continuous therapies is a matter of active debate. In patients undergoing continuous hemofiltration, an RCT has demonstrated that an ultrafiltration rate of 35/mL/kg/hr or above is associated with improved outcomes when compared to 20 mL/kg/hr suggesting a dose-response relationship in AKI.[681] However, further improvements in outcome from even higher ultrafiltration volumes have not been observed in randomized studies.[682]

The venovenous forms of CRRT have supplanted continuous arteriovenous techniques such as continuous arteriovenous hemodialysis and continuous arteriovenous hemodialysis plus hemofiltration (see Table 29-17 ) in the management of AKI. The latter techniques use arterial and venous cannulas, and rely on the patient's own blood pressure to provide the driving force for blood flow and ultrafiltration. [683] [684] In the critically ill and often hemodynamically unstable patient, such methods afford less reliable blood flow rates, and the necessity for arterial cannulation incurs a risk of distal atheroembolic or artery-occlusive complications. Slow continuous ultrafiltration is a similar technique to the other slow continuous therapies described earlier except that the dialysis flow rate is set at zero and no replacement solution is administered.[685] This technique yields “pure” ultrafiltration and is typically used in the patient with marked volume overload as a result of obligate fluid intake and heart failure or capillary leak syndrome in the absence of overt uremic or metabolic indications for renal replacement.

The disadvantages of CRRT include its high cost and the need for specialized training of large numbers of nursing staff. Miscalculations in flow sheet computation can lead to significant errors in ultrafiltration rates and the continuous nature of the procedure restricts patient access to investigative procedures. Occasionally, lactate or citrate accumulation is a concern, especially in patients with severe hepatic dysfunction. [686] [687] [688] [689] This usually manifests as a rise in total serum calcium combined with a fall in the ionized calcium level in the case of citrate accumulation. Hypophosphatemia can occur due to the higher clearance of phosphate as compared with conventional hemodialysis.

The persistent high mortality among patients with AKI requiring dialysis begs the question as to whether the continuous forms of renal replacement therapy offer any survival advantage over acute intermittent hemodialysis. [5] [17] [26] [27] [556] Several retrospective studies suggest an improvement in outcome in critically ill patients treated with CRRT; however, randomized prospective trials have failed to show a survival benefit and a more recent systematic review found no significant difference between continuous techniques and intermittent hemodialysis with regard to overall mortality. [9] [690] [691] However, the observed trend toward increasing use of slow continuous therapies will likely continue, especially in the hemodynamically unstable and catabolic patient.

An emerging alternative approach in the hemodynamically unstable patient is the use of slow, low-efficiency daily dialysis for prolonged periods of up to 12 hours a day. [670] [692] The development of slow, low-efficiency daily dialysis is an attempt to harness the most attractive features of both intermittent hemodialysis (high efficiency, relative inexpensiveness, no requirement for presterilized fluids) and CRRT (hemodynamic stability, smooth metabolic control). This hybrid technique typically requires blood flows of less than 175 mL/min and dialsylate flows less than 330 mL/min can achieve adequate solute and volume control in the critically ill patients with comparable hemodynamic stability to CRRT with less anticoagulation.[693]

Given the deficiencies of current renal replacement therapies several investigators have been investigating the potential of so-called bioartificial kidneys. These employ bioartificial tubule device using hollow fiber membranes lined with proximal tubular epithelial cells. [694] [695] [696] A small pilot study has been completed in human subjects with AKI and multiorgan failure. The renal assist device was demonstrated to possess metabolic activity with systemic effects and a randomized, controlled phase II clinical trial is under way to further assess the clinical safety and efficacy of this new therapeutic approach.[697]

Postrenal Acute Kidney Injury

Management of postrenal AKI usually involves a multidisciplinary approach and requires close collaboration among nephrologist, urologist, and radiologist. This topic is reviewed extensively in Chapter 36 . Urethral or bladder neck obstruction is usually relieved temporarily by transurethral or suprapubic placement of a bladder catheter, thereby providing a window for identification and treatment of the obstructing lesion. Similarly, ureteric obstruction may be treated initially by percutaneous catheterization of the dilated ureteric pelvis or ureter. Indeed, obstructing lesions can often be removed percutaneously (e.g., calculus, sloughed papilla) or bypassed by insertion of a ureteric stent (e.g., carcinoma). Most patients experience an appropriate diuresis for several days after relief of obstruction; however, approximately 5% develop a transient salt-wasting syndrome, because of delayed recovery of tubule function relative to GFR, that may require intravenous fluid replacement to maintain blood pressure. [332] [334]


The crude mortality rate among patients with intrinsic AKI approximates 50% and has changed little over the past 3 decades. [13] [17] [19] [20] [21] [23] [25] [26] [485] [486] [518] [556] [557] [691] [698] [699] [700] [701] This lack of improvement in outcome, despite significant advances in supportive care, may be more apparent than real and reflect a reduction in the percentage of isolated AKI combined with an increase in AKI complicating the multiple-organ dysfunction syndrome. [25] [556] [702] [703] When allied with the current trend for more aggressive surgical and medical intervention in the aging population, these factors probably mask an improvement in outcome. Mortality rates differ markedly depending on the cause of AKI: being approximately 15% in obstetric patients, 30% in toxin-related AKI, and 60% to 90% in patients with sepsis. [17] [20] [80] [414] [702] [704] Although it was once widely held that the provision of effective renal replacement therapy largely corrected the prognostic import of an episode of AKI, more recent observations clearly demonstrate that this is not and probably never was the case, and that all too often, the development of AKI directly contributes to poor patient outcomes.[487] Factors associated with a poor prognosis include male sex, advanced age, oliguria (<400 mL/day), and a rise in the serum creatinine value of greater than 3 mg/dL, factors reflecting more severe renal injury and failure of other organ systems.

Even mild decreases in renal function are now recognized as being associated with worse patient outcomes. In a study of contrast nephropathy subjects whose serum creatinine rose by at least 25% to 2 mg/dL or over was associated with a greater than fivefold increase in mortality even after adjustment for potential confounders.[7] Although it is unclear with the use of dichotomized levels of renal function, to what extent the relationship is driven by the subjects with more extreme deteriorations in function. A study of 6000 general ICU patients found significant association between early degrees of AKI as assessed by RIFLE score and mortality.[705] Even with the use of renal replacement therapy, mortality remains elevated as compared with those with maintained independent renal function. [6] [23] [705]

In addition to its clinical consequences, ARF prolongs hospital stays and is associated with substantially increased medical expenditure. [5] [485] [706] [707] [708] The U.S. cost of treated AKI per Quality Adjusted Life Year (QALY) was estimated in 1999 to be $50,000 per QALY, a level that often raises concerns regarding the cost effectiveness of an intervention.[709] In a more recent analysis of long-term outcomes of ICU survivors who had recovered from renal failure quality adjusted survival was poor—15 QALYs per 100 patient-years in the first year postdischarge. However the subject's self-perceived health satisfaction was not significantly different from that of the general population.[710]

There are many problems with the design of most of the clinical studies that have examined the efficacy of several novel therapeutic interventions on the outcome of AKI. Measurement of the effect of treatment interventions in AKI is complicated by our inability to accurately define the onset and resolution of ARF. In addition, most clinical trials of AKI in humans have been limited because of an imbalance in the randomization of risk factors among control and experimental patients. This problem could be dealt with either by stratifying patients before randomization (using a score of severity of illness), or ideally, by studying numbers of patients large enough to ensure adequate randomization. Accurate scoring systems are needed to stratify patients enrolled in clinical trials and also to allow physicians to make informed treatment decisions including the withdrawal of medical care when the patient's condition make further intervention futile. The three most widely used general outcome mathematical models for critically ill patients are version II of the Acute Physiology and Chronic Health Evaluation (APACHE II), version II of the Acute Physiology Score and version II of the Mortality Probability Model at 24 hours. [13] [525] [711] [712] [713] These models were developed for critically ill patients with and without ARF, and although APACHE II may be superior in patients requiring renal replacement therapy, none are reliably predictive of outcome in the subgroup of patients with ARF. More recently, several ARF specific indices have been developed, but their generalizability outside the environment in which they were developed is uncertain.[714] In general, although several of these scoring systems are of interest from an epidemiology and research context, they remain poor discriminators of outcome in the individual patient. Finally, many human studies of AKI suffer from a lack of well-defined “end points.”[12] Although the need for dialysis has been used as an end point in many trials of AKI, uniform criteria for the initiation and discontinuation of dialysis has have often not been set before the study. The necessary duration of follow-up to fully capture the sequelae of an episode of AKI is uncertain. Follow-up clearly needs to extend beyond ICU discharge and equally beyond hospital discharge, because there is some evidence that mortality rates start to stabilize after 2 months following hospital discharge.[715]

Most patients who survive an episode of AKI regain independent renal function. However, 50% have subclinical functional defects in glomerular filtration, tubule solute transport, H+ secretion, and urinary concentrating mechanisms, and glomerular or tubulointerstitial scarring on renal biopsy ( Table 29-18 ). AKI is irreversible in approximately 5% of patients, usually as a consequence of complete cortical necrosis, and requires long-term renal replacement therapy with dialysis or transplantation. An additional 5% of patients suffer progressive deterioration in renal function after an initial recovery phase, probably because of hyperfiltration and subsequent sclerosis of remnant glomeruli. Experimental animals and humans who experience one episode of AKI are at increased risk of additional episodes of AKI on subsequent exposure to ischemia or nephrotoxins. It is possible that the latter predisposition to acute and chronic renal failure may become increasingly relevant as human life expectancy increases.

TABLE 29-18   -- Residual Defects in Renal Structure and Function after Acute Kidney Injury (AKI)

Glomerular abnormalities

Thickening and/or splitting of the glomerular basement membrane

Glomerular hyalinosis

Decrease in GFR

Hyperfiltration in remnant nephrons

Increase in filtration fraction

Tubular abnormalities

Tubule atrophy

Interstitial fibrosis

Decrease in phenolsulfonphthalein excretion

Concentrating defects



Decrease in renal size

Predisposition to further episodes of ARF

Occasional progression to end-stage renal disease

Adapted from Finn WF. Recovery from acute renal failure. In Lazarus JM, Brenner BM (eds): Acute Renal Failure, 3rd ed. New York: Churchill Livingstone, 1993.

GFR, glomerular filtration rate.






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