The GFR may be abruptly reduced in acute glomerulonephritis. In poststreptococcal glomerulonephritis, the prototypic nephritic disorder, patients often present with AKI and oliguria.

Hypertension and edema result from their inability to excrete salt and water normally. The constellation of hypertension, edema, azotemia, and hematuria is known as the acute nephritic syndrome. Although the history of a previous sore throat or streptococcal infection may provide diagnostic clues, the urinalysis is particularly valuable. The urine may be grossly bloody or tea colored. The urinary sediment contains red blood cells (RBCs) and often RBC casts (Fig. 73.2). Similar findings are frequent in patients with other primary nephritic disorders as well as in secondary nephritides, such as those seen in systemic lupus, and bacterial endocarditis. The crescentic glomerulonephritides (rapidly progressive glomerulonephritis) can evoke the acute nephritic syndrome.

Diseases affecting either the main renal arteries or their branches may precipitate AKI. Renal artery occlusion by acute thrombosis or thromboembolism typically only causes AKI if it is bilateral or involves a solitary functioning kidney. These processes may be silent or may produce flank pain and hematuria, particularly if abrupt enough to cause renal infarction. Fever, moderate leukocytosis, and an elevated serum level of
lactate dehydrogenase should raise the suspicion of infarction. With rare exceptions, renal arterial thromboembolism occurs only in the settings of acute myocardial infarction, atrial fibrillation, bacterial endocarditis, hypercoagulable disorders, or other cardiac valvular disease.

Acute renal vein thrombosis seldom causes renal failure unless both kidneys are simultaneously occluded. Acute flank pain and hematuria are the clinical hallmarks. Renal venous obstruction may occur as a complication of nephrotic syndrome and renal cell carcinoma. Microscopic occlusion of smaller vessels occurs in a variety of disorders, including atheroembolic renal disease, thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome, scleroderma, postpartum kidney injury, and malignant hypertension. Scleroderma or malignant hypertension may appear as AKI, with severe blood pressure elevation due to activation of the renin–angiotensin system. These vascular disorders produce renal injury by reducing glomerular blood flow. Because the lesion is proximal to the glomerulus, the urine sediment is usually acellular and bland. Vasculitis produces AKI either through direct involvement of the renal arterial system or by inducing glomerulonephritis. Often, microscopic polyarteritis or Wegener’s granulomatosis may present with evident renal parenchymal disease, as suggested by urinary abnormalities such as microscopic hematuria, RBC casts, and proteinuria. These patients may present to the ICU when there is multiorgan involvement, such as the pulmonary disease that occurs in Wegener’s granulomatosis. Fulminant presentations with severe hypoxemia and pulmonary hemorrhage may be accompanied by rapidly progressive renal dysfunction. In these cases, glomerular involvement may range from focal and segmental necrotizing glomerulitis to severe crescentic glomerulonephritis.

Two syndromes are responsible for most cases of parenchymal AKI in hospitalized populations: ATN and acute interstitial nephritis (AIN).

Extracellular volume depletion accounted for approximately 17% of cases of AKI in a prospective study of AKI in a major hospital [14]. In most instances, urinary losses are the cause of hypovolemia. Injudicious use of diuretics and the osmotic diuresis that accompanies diabetic hyperglycemia are the most common etiologies. Cessation of diuretic therapy and volume repletion lead to rapid recovery; consequently, the mortality is quite low [14].

In rare instances, gastrointestinal losses of substantial magnitude may lead to AKI. (In the developing world, however, this is one of the most common causes of AKI and the major cause of morbidity and mortality in epidemic cholera.) In such cases, the source of the gastrointestinal losses, either gastric or intestinal, may lead to distinctive electrolyte abnormalities. In the former, metabolic alkalosis mandates repletion with
chloride-rich replacement solutions (normal saline, usually with potassium chloride, as most patients are also hypokalemic). With intestinal losses of fluid, metabolic acidosis often ensues, and appropriate replacement may consist of a buffer solution of either isotonic bicarbonate or lactate-containing (Ringer’s) solution in combination with saline. (This is more fully discussed in Chapter 71.)

Transdermal fluid losses usually occur in the setting of major burns, with the degree of hypovolemia and the severity of AKI corresponding to the extent of thermal injury (body surface-area involvement). Significant burns can lead to severe hypovolemia as a result of massive evaporative and exudative fluid loss across the damaged epidermis as well from redistribution of fluid due to edema in the injured tissues. This hypovolemia can stimulate a sympathetic nerve-mediated response with resultant renal vasoconstriction. In some instances, the severity of renal vasoconstriction, superimposed on hypovolemia, culminates in ATN. In addition, deeper thermal injury with skeletal muscle involvement may induce myoglobinuric AKI (see following discussion). Dermal losses of fluid are also seen in the setting of hyperthermia and heat stroke. The evaporative loss of sweat, which is hypotonic, leads to a hypertonic dehydration in these cases. Replacement with half-normal saline corrects free water and sodium deficits.

Postoperative AKI has long been recognized as a common complication of major vascular, abdominal, and open-heart surgery. The pathogenesis of postoperative renal dysfunction varies with the type of the surgery and the preoperative condition of the patient. AKI following abdominal surgery is often the result of translocation of fluid into the peritoneal cavity. In this phenomenon, third spacing causes intravascular hypovolemia and subsequent renal hypoperfusion. AKI is uncommon in patients undergoing routine abdominal surgery, but the risk is substantial in surgery for obstructive jaundice; this complication may develop in approximately 10% of patients [22]. Major vascular surgery, particularly aortic repairs, is also frequently complicated by AKI, especially in the setting of a ruptured aortic aneurysm [23]. Elective repair of an aortic aneurysm is seldom associated with AKI unless cross clamping is placed above the renal arteries. Although the definition of AKI and its incidence varies among studies, cardiac surgery appears to generate most of the cases in the acute care hospital. In a prospective study, cardiac surgery accounted for nearly two thirds of the postoperative AKI with an overall incidence of 15% [14]. Repeated episodes of AKI and sepsis complicating AKI are associated with substantially higher mortality (85%) after surgery.

Myers and Moran [10] have described three distinct clinical patterns of AKI following open-heart surgery. The abbreviated pattern, observed in 80% to 90% of patients, usually has an abrupt onset after surgery, followed by a brief and mild rise in the serum creatinine, peaking by 3 to 4 days, after which recovery is rapid. This form of AKI is frequently associated with the use of vasoconstrictors, such as norepinephrine and epinephrine, in the immediate postoperative period. The overt form is associated with a more severe reduction in GFR and rise in serum creatinine, which peaks 1 to 2 weeks after surgery. This is generally associated with poor cardiac performance following surgery, whereas recovery is associated with improved ventricular function. The protracted form of AKI generally follows a second insult after surgery, such as sepsis or pericardial tamponade, and is associated with prolonged AKI and a poor prognosis.

Several predisposing factors for the development of postoperative AKI have been identified, which can be used to stratify risk (Table 73.7). These include emergent surgery, an elevated preoperative serum creatinine, the use of an intra-aortic balloon pump, and combined coronary artery bypass graft and valvular surgery [24]. Still, it is often difficult to prospectively identify those patients at heightened risk for perioperative AKI, especially since 40% of patients who develop AKI do not have frank perioperative hypotension or evidence of shock. Other factors appear to be important in the development of AKI. For example, aprotinin, an antifibrinolytic agent used until recently to decrease perioperative blood loss in cardiac surgery patients, tends to increase AKI and postoperative mortality [25]. Prolonged cardiopulmonary bypass appears to induce oxidative stress, embolism, and systemic inflammation, thus contributing to AKI [26]. An improved mortality and reduced incidence of AKI is observed with the use of “off-pump” technology in one large observational study [27]. Prospective, randomized trials are underway to study the effects of the off pump cardiac surgery.

A number of methods have been used to try to protect kidney function in patients undergoing surgery. Administration of “low-dose” dopamine has long been advocated for the prevention of AKI but has fallen out of favor due to the lack of efficacy [28]. A meta-analysis of fenoldopam, a selective dopamine receptor agonist, demonstrated a reduction in mortality and the need for dialysis in cardiac surgery patients [29]. A large, randomized, prospective trial of preventive role of fenoldopam is underway. Nesiritide, a recombinant human B-type natriuretic peptide, which increases diuresis, natriuresis, and afterload reduction, was studied in a double-blind, randomized trial of 300 patients with mostly preserved renal function undergoing coronary artery bypass graft surgery [30]. The use of nesiritide was associated with improved postoperative serum creatinine and reduced length of hospital stay as compared with the placebo. Nevertheless, significant concerns remain regarding the safety of nesiritide, especially in patients with acute decompensated heart failure (ADHF) and reduced renal function (discussed later in the chapter). Several other strategies, including perioperative N-acetylcysteine and mannitol administration, have not been shown to be effective for the prevention of postoperative AKI [31,32]. The use of calcium channel blockers, ACE
inhibitors, or diuretics has been disappointing in this context as well [33]. In fact, perioperative furosemide use has been associated with detrimental effect on renal function after cardiac surgery [34]. Furosemide should be used only in patients with definite volume overload.

Prevention of postoperative renal failure still hinges on withdrawal of vasopressors as early as safely possible and maintenance of adequate perioperative intravascular volume. Identification of modifiable risk factors for the prevention of postoperative AKI is paramount. A retrospective study of 3,500 patients identified three potentially modifiable risk factors associated with AKI after cardiac surgery, such as preoperative anemia, perioperative RBC transfusions, and the need for surgical reexploration [35].

Our understanding of “cardiorenal syndrome” is evolving beyond the concept of low cardiac output causing renal dysfunction. We know that approximately half of patients with ADHF have preserved left ventricular function [36]. In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), optimization of hemodynamics did not prevent AKI, further suggesting that reduction in cardiac output does not fully explain the development of impaired renal function [36].

A complex bidirectional relationship emerges, whereby heart failure and associated renal dysfunction affect each other. In addition to the traditional hemodynamically mediated AKI due to low cardiac output, the heart and the kidney are simultaneously affected by activation of the sympathetic nervous and renin–angiotensin–aldosterone systems. Such activation results in systemic vasoconstriction, salt and water retention, and volume overload, further exacerbating kidney dysfunction and heart failure. In addition, the immune system affects renal and cardiac function through monocyte-mediated endothelial activation, cytokine release, and apoptosis induction [16,17,37]. Furthermore, CKD, a risk factor for coronary artery disease [38], contributes to volume overload, diuretic resistance, and poor prognosis in CHF [39] and ADHF [36]. Here, we will focus on acute ADHF with AKI as a common clinical problem in the ICU setting.

ADHF is frequently complicated by AKI. The Acute Decompensated Heart Failure Registry (ADHERE) of more than 30,000 patients with ADHF suggests that AKI has poor prognostic implications and predicts mortality in this patient group [40]. In one study, more than a quarter of patients with ADHF developed AKI as defined by a rise in serum creatinine of 0.3 mg per dL. However, even this relatively small rise was associated with 7.5-fold increase in hospital mortality [41].

Traditional treatment strategies of ADHF include diuresis, afterload reduction, and administration of inotropic agents. However, these patients are frequently diuretic resistant and hypotensive. The use of ACE inhibitors is often limited by AKI and hyperkalemia. Recently, nesiritide, a recombinant B-type natriuretic peptide, was approved for management of symptomatic ADHF [42]. However, a meta-analysis of five randomized clinical trials in more than 1,200 patients with ADHF suggested nesiritide was associated with worsening of renal function [43]. New trials are ongoing to further investigate the risk and benefit of nesiritide. Tolvaptan, a vasopressin antagonist, has been studied in a large international randomized trial of more than 4,000 heart failure patients [44]. Tolvaptan was statistically better then placebo at improving dyspnea, edema, and weight loss but did not significantly improve the rate of death and rehospitalization for heart failure.

Inotropic agents such as dobutamine and milrinone are used in the treatment of ADHF. Dobutamine acts primarily on β₁-adrenergic receptors, with minimal effects on β₂ and α₁ receptors. Dobutamine increases cardiac output and stroke volume and decreases systemic vascular resistance and pulmonary capillary wedge pressure. The 2004 ACC/AHA STEMI guidelines suggest using dobutamine in patients with hypotension who do not have clinical evidence of shock [45]. Milrinone is a phosphodiesterase inhibitor that increases myocardial contractility, reduces systemic vascular resistance, and improves left ventricular diastolic relaxation. However, inotropes increase myocardial oxygen consumption and can worsen myocardial ischemia, and their use has been limited by arrhythmia development and adverse outcomes. In a large prospective, randomized trial, milrinone infusion was associated with increased hypotension and atrial arrhythmias as well as a trend toward increased mortality [46]. The use of inotropes is limited to patients with ADHF and low cardiac output who fail or cannot tolerate diuretic and vasodilator therapy. Additional information on the use of inotropes can be found in Chapter 33 of the “Cardiovascular Problems and Coronary Care” section.

Other strategies for diuretic-resistant patients with ADHF include mechanical fluid removal with ultrafiltration or paracentesis. The use of ultrafiltration in the ICU setting is discussed in “Renal Replacement Therapies” section of the text. Mullens et al. suggested that elevated intra-abdominal pressures in ADHF may play a role in the pathogenesis of renal dysfunction [47]. The reduction of intra-abdominal pressure from approximately 13 to 7 mm Hg by paracentesis was associated with a reduction in serum creatinine from 3.4 to 2.4 mg per dL in diuretic-resistant patients.

Sepsis is among the most common causes of AKI. In one large series of patients with ATN, sepsis was believed to be the cause in 15%, with a mortality rate of 40% [48]. The association between septicemia and AKI is confounded by the experience that renal dysfunction due to other causes is often complicated by infection. Although the incidence of sepsis in patients with AKI has been reported as high as 75% [49], only one third of patients have clinically apparent septicemia at the outset of renal dysfunction [50].

AKI may develop in a setting of sepsis through multiple mechanisms. As discussed previously, inflammation appears to play a significant role. In animal models, sepsis can cause renal impairment even in the absence of hypotension [51]. Clinically, it is likely that endotoxin causes a reduction in GFR through hemodynamic mechanisms, including vascular pooling and renal vasoconstriction, which are mediated by local vasoconstrictors such as thromboxane and endothelin. Although cardiac output is often elevated in patients with sepsis, systemic vasodilation coupled with renal vasoconstriction can shunt perfusion away from the kidneys. Vascular pooling and third spacing generally necessitate volume expansion with isotonic saline. Because myocardial suppression, oliguria, and capillary leakage may accompany sepsis, it is essential to monitor the administration of fluids closely.

Pancreatitis may occur in association with various causes of AKI but can itself induce ATN. This is a rare phenomenon and is generally seen in patients with severe or hemorrhagic pancreatitis with serum amylase values of more than 1,000 U per L. Mortality may approach 70% to 80% in this setting, especially in those with multiorgan failure.

AKI associated with severe trauma generally reflects the combination of acute volume depletion, hemorrhage, and
myoglobinuria (see following discussion). Survival after trauma is markedly reduced when complicated by AKI.

Rhabdomyolysis is often associated with leakage of myocyte contents, particularly the pigment protein myoglobin, into the plasma. Myoglobin, with a molecular weight of approximately 17,000 daltons, is freely filtered by the glomerulus. In the distal nephron, myoglobin forms proteinaceous casts that obstruct urine flow. Myoglobin may also exert direct cytotoxic effects on tubular epithelium through the generation of reactive oxygen species.

Myoglobinuric AKI is a consequence of massive skeletal muscle injury of diverse causes. Traumatic rhabdomyolysis occurs in the setting of direct mechanical injury (crush syndrome), burns, or prolonged pressure. Myoglobinuric renal failure is an important cause of morbidity in virtually all wide-scale human catastrophes. Indeed, much of what is known about the syndrome derives from experiences with victims of wars and natural disasters. Crush injuries during the Armenian earthquake of 1988 necessitated emergent mobilization of dialysis resources on a massive scale [56].

Nontraumatic rhabdomyolysis can occur with toxic, metabolic, and inflammatory myopathies, vigorous exercise, severe potassium and phosphate depletion, and hyperthermic states such as the neuroleptic malignant syndrome and malignant hyperthermia. Lipid-lowering drugs currently represent one of the most common causes of rhabdomyolysis. The use of heroin and amphetamines [57,58] has been reported in association with rhabdomyolysis.

As with other forms of AKI, the prognosis depends largely on the gravity of the predisposing condition; AKI following massive trauma can be expected to run a longer course than that associated with nontraumatic causes, such as drugs. In particularly severe cases, oliguria and dialysis dependence may persist for weeks.

Clinical signs and symptoms of muscle injury, such as muscle tenderness, are absent in at least half of cases of significant nontraumatic rhabdomyolysis. The diagnosis is suggested by markedly elevated serum levels of muscle enzymes with serum creatine kinase levels usually higher than 5,000. The serum levels of phosphate and potassium are also typically elevated in rhabdomyolysis because lysis of muscle cells causes release of intracellular contents into the blood. A fall in the serum calcium is quite common. Rebound hypercalcemia often occurs during the recovery phase.

The therapy of myoglobinuria is similar to that of other forms of AKI, but there are several particular considerations. The tubular toxicity of myoglobin is enhanced when urine flow rates are low, urine is concentrated, and urinary acidification is maximal. It is therefore important in the early phases of the illness to ensure that the patient is in a volume-replete state and maintaining a rapid diuresis (i.e., urine output of at least 150 mL per hour). To this end, isotonic fluids may be administered. Most experts recommend the administration of bicarbonate-rich fluids to alkalinize the urine above a pH of 6.5 so as to improve the solubility of myoglobin. Diuresis may be enhanced with concurrent administration of loop diuretics. Some have argued that loop diuretics may introduce the potentially adverse effect of increasing urinary acid excretion and have advocated the use of osmotic diuretic agents such as mannitol [59]. Mannitol, however, has the potential drawback of causing intravascular volume overload in patients whose kidneys may already have impaired urine output.

Hemoglobinuria can also result in AKI. The pathophysiologic mechanisms are similar to those involved in myoglobinuric AKI. Hemoglobinuric renal failure is relatively rare. Hemoglobin, with a molecular weight almost four times that of myoglobin, is less readily filtered. Furthermore, when hemoglobin is released into the plasma, it binds to haptoglobin, forming a bulky, nonfilterable molecular complex. Only when the haptoglobin binding capacity is saturated (at plasma hemoglobin concentrations > 100 mg per dL) does hemoglobin appear in the tubular fluid. Thus, only massive intravascular hemolysis, as may occur with fulminant transfusion reactions, autoimmune hemolytic crises, and mechanical hemolysis [60] from a dysfunctional prosthetic heart valve (Waring blender syndrome), can induce AKI.

The administration of intravascular radiocontrast agents leads to a syndrome of rapidly developing AKI. Contrast-induced nephropathy (CIN) is commonly defined as an absolute increase in serum creatinine of 0.5 mg per dL or a relative increase of 25% from the baseline within 48 to 72 hours of contrast exposure. The serum creatinine level begins to rise 12 to 24 hours and peaks approximately 4 days after the procedure [61]. Some patients develop a transient increase in urine output as a result of contrast-induced osmotic diuresis, followed by oliguria. The majority of patients are nonoliguric and do not require dialysis. Some, but not all, studies identified an increased mortality risk in patients with CIN [62,63,64]. In patients who have undergone endovascular procedures, CIN must be differentiated from atheroembolic disease, which has a significantly worse prognosis (discussed below).

Prospective studies report that the incidence of radiocontrast-induced kidney injury ranges from 1% to more than 50%. Some of this variance in frequency can be attributed to the disparity in the definitions of AKI, the number of associated risk factors, and the type of procedure performed [65]. The incidence appears to be low in patients with normal renal function, even in the presence of diabetes. Preexisting CKD, however, particularly in patients with diabetes, confers a 6- to 10-fold increased likelihood of radiocontrast-induced AKI [66,67]. Contrast-enhanced CT is associated with a lower risk of CIN as compared with coronary angiography. Noncoronary angiography had the highest incidence of CIN in a study of 660 military veterans, reaching 15% in patients with GFR less than 60 mL per minute per 1.73 m² [68]. Other risk factors are listed in Table 73.8.

There are several mechanisms by which radiocontrast-induced renal injury may develop. Hemodynamic factors are believed important, as contrast exposure causes initial vasodilation followed by prolonged vasoconstriction of the renal circulation. The finding of a low FE_Na in some patients with contrast-induced AKI and the tendency toward rapid recovery suggest a role for reversible vasoconstriction. The intensity and duration of the vasoconstriction may be influenced by the underlying characteristics of the renal microcirculation. Endothelial factors that promote vasoconstriction of preglomerular vessels, such as endothelin, may participate in the pathogenesis of radiocontrast-induced nephropathy [11,69]. Tubular adenosine receptors appear to be stimulated by radiocontrast agents in animal models [70,71]. Adenosine induces afferent glomerular vasoconstriction and reduction in GFR. However, the protective effect of theophylline, an antagonist of adenosine receptors, was not statistically significant in the meta-analysis of available trials of CIN prevention [65]. Other postulated mechanisms of radiocontrast-induced nephropathy include the generation of reactive oxygen species and the direct cytotoxic effect of the contrast media, especially with highly osmolar agents [72].

Because there is no specific treatment for radiocontrast-induced nephropathy other than supportive measures, attention has focused on methods of prevention. The best preventive measure is avoidance of radiocontrast and use of an alternative noncontrast imaging procedure if at all possible.

A number of prophylactic measures (listed in Table 73.9) have been promoted. Experimental data and retrospective clinical studies suggest that radiocontrast injury is augmented by preexisting hypovolemia, particularly in the presence of prostaglandin inhibitors [73,74,75,76]. Therefore, modest hydration before the procedure and avoidance of diuretics and NSAIDs are justifiable.

Reports suggest that pharmacoprophylaxis of radiocontrast nephropathy may be possible. In a German study, N-acetylcysteine (NAC) was given to patients with CKD once before and once after they underwent angiography. The incidence of radiocontrast nephropathy in these patients was 2%, compared with 9% in an untreated control group. Both groups received concomitant hydration, and low-osmolality contrast medium was used [77]. Some, but not all, subsequent studies have confirmed these results [78,79]. Maranzi et al. [80] compared two different regimen of NAC in patient undergoing emergent angioplasty for STEMI. Patients receiving a high dose of NAC (1,200 mg IV prior to procedure, followed by 1,200 mg orally for four more doses) had a significantly lower incidence of CIN. The benefit of NAC remains controversial as conflicting results continue to emerge from other studies [65,81]. However, NAC appears to be a low risk intervention and is frequently used. We typically give NAC 1,200 mg orally for two doses before and two doses after the contrast exposure.