Definition

Acute kidney injury (AKI) is a common problem in the contemporary practice of medicine and urology. Prospective studies have demonstrated that 2% to 5% of all patients admitted to a general medical/surgical hospital unit will develop AKI (Nolan and Anderson, 1998). In selected patients in the intensive care unit following cardiovascular or abdominal vascular surgery, the incidence may exceed 20%. Epidemiologic studies continue to indicate that despite advances in the overall medical care of patients, the development of AKI is associated with significant increases in morbidity (which prolongs hospitalization and increases costs) and mortality (Dimick et al, 2003). The high occurrence and substantial morbidity and mortality of AKI demand a logical approach to its early recognition and prevention, as well as prompt diagnosis and management of its complications.

AKI is defined as a rapid reduction in renal function characterized by progressive azotemia (best measured clinically by serum creatinine [SCr]), which may or may not be accompanied by oliguria. This abrupt decline in renal function occurs over the course of hours to days and results in the failure to excrete nitrogenous wastes from the plasma or to maintain normal volume and electrolyte homeostasis. AKI can be diagnosed with certainty when the patient’s prior renal function is known and the reduction in renal function is documented.

The cardinal feature of AKI is a decline in glomerular filtration rate (GFR). Although ideally determined by inulin or radio-isotopic clearance techniques, it is usually identified in routine clinical practice by a rise in serum blood urea nitrogen (BUN) or creatinine. It is important to understand the limitations of these common clinical chemistries in order for them to be properly interpreted. The correlation among BUN, creatinine, and GFR assumes they are delivered into the serum at a constant rate. Therefore conditions such as hypercatabolic state and massive trauma, which may be seen in surgical patients, can affect renal function assessment. BUN may be disproportionately elevated in states of marked volume contraction, hypercatabolic states, and with marked increases in protein loads seen with gastrointestinal bleeding or total parenteral nutrition (TPN). SCr is produced at a constant rate by muscle and more accurately reflects GFR. When renal function deteriorates, tubular secretion represents an increasing proportion of creatinine excretion. Therefore creatinine clearance may overestimate GFR as renal function slowly declines when measured in the “steady state.” Both the creatinine clearance and the Cockcroft Gault calculation may be useful tools to estimate GFR because they take into account the patient’s body size, age, and SCr. For example, the Cockcroft Gault formula states that creatinine clearance = (140 − age) × weight × (0.85, female) divided by 72 × plasma creatinine (Cockcroft and Gault, 1976). Both methodologies have their disadvantages. The urinary creatinine clearance method is cumbersome, and the Cockcroft Gault method may have a margin of error up to approximately 30% compared with GFR measured by formal I¹²⁵ iothalamate techniques. Recently the Modification of Diet in Renal Disease (MDRD) calculations have been used as a way to estimate GFR. This equation has then been reformulated to account for various creatinine assay calibration biases across different laboratories (Levey et al, 2007). However, none of these techniques are suitable for estimating GFR in the AKI patient because such a “steady state” does not exist (Hoste et al, 2005). Use of “real-time” estimates of GFR using infused radio-isotopic plasma disappearance techniques in the ICU patient with AKI has been advocated by some but has not achieved wide clinical acceptance. In clinical practice the experienced clinician infers from a rapidly rising SCr and clinical picture that the patient’s true GFR is approaching zero.

Epidemiology and Classification of Acute Kidney Injury

Clinically, it is useful to separate the causes of AKI into three major categories: prerenal, intrarenal, and postrenal. Distinguishing among the three basic categories of AKI is a challenging clinical exercise. Assigning a patient to one of the three categories usually requires a combination of clinical and laboratory evaluations and may require invasive monitoring of central hemodynamics or imaging studies of the genitourinary tract. The importance of differentiating the major causes of AKI must be stressed because the initial evaluation and management are tailored to the particular cause. Because the greatest proportion of hospital-acquired AKI is secondary to acute tubular necrosis (ATN), this chapter places special emphasis on the diagnosis, pathophysiology, and management of ATN. For example, a report from Madrid evaluated 748 cases of AKI at 13 tertiary care hospital centers (Di Tullio et al, 1996). The causes of AKI were: 45% ATN, 21% prerenal, 13% acute or chronic renal failure, 10% urinary tract obstruction, 4% glomerulonephritis/vasculitis, 2% acute interstitial nephritis (AIN), and 1% atheroembolic renal disease. Earlier reports had documented that AKI occurs more commonly in the surgical/trauma ICU, medical ICU, and postoperative units. A recent study of the American College of Surgeons National Surgical Quality Improvement Program has identified 11 independent preoperative predictors for the development of AKI including age 56 years or older, male sex, emergency surgery, intraperitoneal surgery, diabetes mellitus necessitating oral therapy, diabetes mellitus necessitating insulin therapy, active congestive heart failure, ascites, hypertension, mild preoperative renal insufficiency, and moderate preoperative renal insufficiency (Kheterpal et al, 2009).

Intrinsic Renal Disease

The major causes of AKI due to intrinsic renal disease include acute glomerulonephritis (AGN), AIN, and ATN. Because ATN is the most common cause of AKI in the hospitalized patient, special emphasis will be given to ATN.

Incidence and Etiology

Overall, AKI may affect 2% to 7% of patients in a tertiary care hospital, and the incidence of AKI in the surgical or medical ICU may exceed 25% to 35% (Palevsky et al, 2008). The majority of all hospital-acquired AKI is secondary to ATN (Myers and Moran, 1986; Uchino et al, 2005). Renal hypoperfusion and renal ischemia are the most common causes of ATN, although nephrotoxic insults from various agents are being recognized with increasing frequency. A detailed listing of both exogenous and endogenous nephrotoxic compounds is summarized in Tables 43–4 and 43–5.

Table 43–4 Causes of Exogenous Toxic Acute Kidney Injury

* Direct toxicity or indirect systemic effects (shock, intravascular hemolysis, or coagulation).

† Slow onset of renal failure unless associated with rhabdomyolysis.

Table 43–5 Acute Kidney Injury Related to Endogenous Nephrotoxic Products

* Questionable direct nephrotoxic effect.

Pigment nephropathy may be suspected in the appropriate clinical situation (post-traumatic or atraumatic after intoxications) where there is discrepancy between the finding of hematuria by dipstick and the absence of red blood cells on urinary microscopy. In urology, two clinical circumstances have been identified in association with rhabdomyolysis. This includes protracted extended lithotomy positioning (as seen in urethral stricture cases) (Anema et al, 2000) and after laparoscopic donor nephrectomy (Kuang et al, 2002; Troppmann and Perez, 2003; Reisiger et al, 2005). The combination of renal hypoperfusion and the nephrotoxic insult of myoglobin or hemoglobin within the proximal tubule can result in ATN. Early recognition of this disorder is crucial because a forced alkaline diuresis is indicated to minimize nephrotoxicity. Similarly, the tumor lysis syndrome may be suspected in the appropriate clinical setting, when marked hyperuricemia/hyperuricosuria and crystalluria are recognized. A forced alkaline diuresis may limit nephrotoxicity and is usually recommended prophylactically before an aggressive chemotherapy regimen.

The list of potential exogenous nephrotoxic agents is exhaustive (see Table 43–4). Simply stated, a patient who develops ATN while receiving medications should have each medication reviewed for the possibility of nephrotoxicity. The most commonly seen nephrotoxins in the hospitalized patient include radiographic contrast material, antibiotics (especially aminoglycosides and amphotericin B), chemotherapeutic agents, NSAIDs, and ACE-inhibitor drugs.

In the contemporary practice of hospital-based medicine, recognition of AKI in HIV patients deserves special comments. Patients with HIV-infection may develop AKI due to the same causes as uninfected patients (Cohen et al, 2008), but protease inhibitors have been associated with the development of AKI. Ritonavir and indinavir (as well as acyclovir, foscarnet, and sulfadiazine) have been associated with reversible AKI thought secondary to crystalluria and intrarenal obstruction (Olyaei et al, 2000). In addition, patients treated with indinavir may present with renal colic because indinavir renal stones can be associated with urinary tract obstruction (Kohan et al, 1999). Newer antiretroviral agents may be toxic to the kidney, and newer forms of AKI related to AIN have recently been described (Cohen et al, 2008).

Natural History

The oliguric phase usually begins less than 24 hours after the inciting incident and may last for 1 to 3 weeks. Urine volume averages 150 to 300 mL/day. The oliguric phase may be prolonged in the elderly. During this phase, the clinician must be alert for the expected complications, with special emphasis on metabolic consequences, gastrointestinal bleeding, and infection.

The diuretic phase is characterized by a progressive increase in urine volume, a harbinger of renal recovery. However, the SCr may continue to rise for another 24 to 48 hours before it reaches a plateau and falls. Severe polyuria during this phase is seen less frequently now. Careful management during this phase is crucial because up to 25% of deaths with AKI may occur in this phase, usually related to fluid and electrolyte abnormalities, as well as infection. Finally, the recovery phase ensues. Renal function returns to near baseline, but abnormalities of urinary concentration and dilution may persist for weeks or months.

Pathophysiology

Knowledge of the basic processes involved in the development of ATN is a prerequisite to understanding contemporary therapies directed at limiting renal damage and promoting more rapid renal recovery (Fig. 43–1). In hospital practice, ischemic ATN is the most commonly encountered form of the disease. Therefore the following discussion focuses on ischemic renal injury.

Figure 43–1 Pathophysiology of ischemic acute renal failure. The profound reduction in glomerular filtration rate associated with renal ischemia is due to a combination of intrarenal hemodynamic alterations and tubular epithelial injury leading to tubular obstruction and back-leakage of glomerular ultrafiltrate filtrate.

(From Brady HR, Brenner BM, Lieberthal W. Acute renal failure. In: Brenner BM, editor. Brenner & Rector’s the kidney. Philadelphia: WB Saunders; 1996. p. 1200–52.)

A variety of biochemical changes occur during ischemia and reperfusion that are responsible for the cell dysfunction observed in ATN (Myers et al, 1984; Myers and Moran, 1986). The sentinel biochemical event in renal ischemia is the depletion of adenosine triphosphate (ATP), which is the major energy currency for cellular work. ATP is metabolized to adenosine monophosphate (AMP). During prolonged oxygen deprivation, AMP is further metabolized to the nucleosides adenosine, inosine, and hypoxanthine. These compounds diffuse from the cell, resulting in the loss of the substrate reservoir for ATP synthesis after reperfusion (Brady et al, 1996). Furthermore, hypoxanthine becomes an important substrate in the development of oxygen free radicals during the reperfusion period. Provision of exogenous adenine and inosine decreases cellular injury in experimental renal ischemia (Siegel et al, 1980).

ATP depletion results in impaired function of the plasma membrane and intracellular ATPases that are vital to normal cell function. As a consequence of impairment of the Na⁺/K⁺ ATPase, cytosolic concentrations of Na⁺ and K⁺ are altered and cell swelling results (Alejandro et al, 1995). Dysfunction of the plasma membrane Na⁺/Ca²⁺-ATPase and intracellular Ca²⁺-ATPase leads to high intracellular levels of Ca²⁺. The increase in intracellular Ca²⁺ has been associated with multiple aspects of renal cell injury including disruption of the cytoskeleton, activation of Ca²⁺-dependent phospholipases, acceleration of the conversion of xanthine dehydrogenase to xanthine oxidase (potentiating reperfusion injury), and uncoupling oxidative phosphorylation (Brady et al, 1996). The activation of phospholipases results in damage to the lipid bilayer, which is critical to the normal function of the plasma membrane and intracellular organelles such as mitochondria. Phospholipase activation leads to an accumulation of free fatty acids and lysophospholipids, which are detrimental to vital cellular function, although the mechanism of such action is not clear.

Oxidative stress during reperfusion after ischemia is associated with cellular damage (Fig. 43–2). Recall that ATP is metabolized to hypoxanthine. High levels of intracellular Ca²⁺ activate a calmodulin-dependent protease that converts xanthine dehydrogenase to xanthine oxidase (Brady et al, 1996). The conversion of hypoxanthine to xanthine during reperfusion is the major source of superoxide. This is ultimately metabolized to OH⁻, which causes cell damage. Finally, the protease calpain is activated and contributes to ischemic renal injury (Edelstein et al, 1997). Calpain regulates membrane channels, kinase activation, and interactions between cytoskeletal proteins.

Figure 43–2 The pathophysiology of reperfusion injury. The generation of reactive oxygen species. See text for details.

(From Brady HR, Brenner BM, Lieberthal W. Acute renal failure. In: Brenner BM, editor. Brenner & Rector’s the kidney. Philadelphia: WB Saunders; 1996. p. 1200–52.)

As the name suggests, ischemic ATN is characterized by renal tubular cell injury. This may be sublethal or lethal. Because obvious necrosis is not a cardinal histopathologic finding in ATN (Racusen et al, 1991), sublethal injury is important. During normal function of the kidney, the medulla operates at the brink of hypoxia due to the countercurrent diffusion of oxygen from the descending to ascending vasa rectae. During prolonged ischemia, medullary hypoxia intensifies and the high metabolic requirement of the nephron structures located in the outer medulla is most sensitive to injury. The S3 portion of the proximal tubule sustains the most severe injury (Witzgall et al, 1994). Other structures that sustain injury in this region include the medullary thick ascending limb (mTAL), which is metabolically active and rich in the energy requiring Na⁺/K⁺-ATPase.

Sublethal injury to tubular cells leads to aberrations in the cytoskeletal organization of the tubule cells (Molitoris, 1991) (Fig. 43–3). This is manifest as a loss in the cell polarity. The brush border disappears, and there is redistribution of the basolateral Na⁺/K⁺-ATPase and integrins (Lieberthal, 1997). As a result, the normal unidirectional transport of salt and water across tubular cells is disrupted and the ability of the renal epithelium to act as a barrier to the free movement of solute and water is lost. The loss of the tight junctions permits backleak of glomerular filtrate, which has been one of the well-established pathophysiologic features of ATN (see Fig. 43–1). In addition to the loss of tight junctions, there is a loss in cell-matrix adhesion (Gailit and Clark, 1993). The redistribution of the integrins disrupts the normal cell adherence to the tubular basement membrane. As a result, abnormal cell–cell adherence develops and contributes to tubular obstruction. The validation of this concept is provided by research demonstrating that an excess of a matrix protein sequence (RGD peptides), which is a critical ligand for the β1 integrin, can ameliorate the reduction in GFR in experimental ATN (Noiri et al, 1994). Conceptually this works because the integrin receptors are saturated by the supplemented matrix protein sequence ligand, making them unavailable for abnormal cell–cell adhesion. This can reduce tubular obstruction and backleak of glomerular filtrate.

Figure 43–3 Tubular-cell injury and repair in ischemic acute kidney injury. After ischemia and reperfusion, morphologic changes occur in the proximal tubules. This includes loss of the brush border, loss of cell polarity, and redistribution of integrins and Na⁺/K⁺-ATPase to the apical surface. There is sloughing of viable and nonviable cells into the tubular lumen, resulting in the formation of casts and luminal obstruction. The damaged kidney can restore its structure and function. Spreading and dedifferentiation of viable cells occurs during recovery, which duplicates aspects of normal renal development. A variety of growth factors contribute to the restoration of normal renal architecture.

(From Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996;334:1448–60. Copyright 1996, Massachusetts Medical Society. All rights reserved.)

Following sublethal injury, the kidney has a remarkable capacity for repair of normal structure and function. The study of renal recovery from ATN is a relatively new concept with great potential for clinical application. Increased mitotic activity and epithelial regeneration are notable features of ATN (Thadhani et al, 1996). Certain aspects of renal recovery duplicate events in renal development (Witzgall et al, 1994). A number of growth factors play a role in recovery. Epidermal growth factor, insulin growth factor 1, and hepatocyte growth factor have been demonstrated to limit renal injury and accelerate renal recovery in experimental ischemic ATN (Thadhani et al, 1996).

RBF is reduced by 50% or more in ischemic ATN, and the perfusion defect is most marked in the outer medulla. The two predominant reasons for this include vasoconstriction and congestion of the medullary vasculature by leukocytes, red cells, and platelets. Ischemic renal injury is marked by intrarenal vasoconstriction as a result of endothelial cell injury. Vasoconstriction results from the imbalance between endothelin (ET) and endothelial-derived nitric oxide (EDNO) (Lieberthal, 1997). Endothelin receptor blockers have been shown to ameliorate ischemic renal damage and improve renal function (Lieberthal, 1997). The endothelial injury sustained in ATN also leads to decreased production of EDNO by constitutive nitric oxide synthase. The decreased EDNO leads directly to vasoconstriction but also permits increased ET production (Lieberthal, 1998).

The persistent hemodynamic abnormalities in ATN are also maintained by congestion of the medullary vasculature. Current evidence suggests that ischemic injury results in the release of inflammatory mediators that activate adhesion molecules on leukocytes and upregulates their receptors on the endothelium (Kinsey et al, 2008). Antibodies directed at leukocyte adhesion molecules or their endothelial ligands (i.e., ICAM-1) ameliorate ischemic renal injury (Kelly et al, 1996; Dragun and Haller, 1999). Neutrophils play an important part in the injury cascade. In models where the effects of neutrophils are eliminated by delivering antibodies to certain chemokines, injury is ameliorated (Miura et al, 2001). Interestingly, the tubular epithelium plays an active role in this inflammatory response by generating chemokines that potentiate recruitment of inflammatory cells (Bonventre and Zuk, 2004). These include monocyte chemoattractant protein-1 (MCP-1), interleukin 8 (IL-8), regulated-on activation, normal T cells expressed and secreted (RANTES), and epithelial neutrophil-activating protein 78 (ENA-78). In addition to the role of neutrophils there is evolving evidence that lymphocytes are important in the ischemia/reperfusion injury paradigm. Knockout mice lacking CD4+/CD8+ cell adhesion receptors on T lymphocytes are protected from ischemic injury (Rabb et al, 2000). Also, costimulatory blockade can ameliorate ischemic injury (Takada et al, 1997). Newer agents are being developed to deal with the early inflammatory events in renal ischemia, which may bear practical application, particularly in the setting of renal transplantation.

General

Distinguishing among prerenal, intrinsic renal, and postrenal causes of AKI may prove to be a challenging clinical exercise (Fig. 43–4). A thorough history and physical examination to assess volume status, cardiovascular hemodynamics, potential nephrotoxic insults, and evidence of systemic disease should be undertaken in AKI patients. All interventions and drug therapies surrounding an AKI event should be outlined against the timeline of changes in renal function. Therefore it is critical to know the level of preexisting renal function. One should identify the presence of risk factors known to be associated with AKI such as advanced age; comorbid conditions (heart failure, liver failure, renal insufficiency, diabetes); radiocontrast exposure; therapy with aminoglycoside antibiotics, NSAIDs, or ACE inhibitors; and atheroembolism. In perioperative AKI, critical intraoperative issues to identify include the nature and magnitude of the procedure (open vs. endoscopic), blood loss, hemodynamic stability, integrity of the urinary tract, and intraoperative drug treatment.

Figure 43–4 Algorithm for the differential diagnosis of acute renal failure. See text for details. AKI, acute kidney injury; ATN, acute tubular necrosis; BUN, blood urea nitrogen; CVP, central venous pressure; PCWP, pulmonary capillary wedge pressure; R/O, rule out; U/S, ultrasound.

(Modified from Goldfarb DA, O’Hara JF. Etiology, pathogenesis, and management of peri-operative acute renal failure. American Urological Association Update Series, Lesson 4, vol XX, 2001.)

On examination, the vital signs and hemodynamic parameters should be critically assessed. Hypotension, particularly orthostatic hypotension, suggests volume depletion and prerenal AKI. Hypertension with advanced renal insufficiency can be an indicator of volume overload, suggesting the need for diuretics or dialysis. A patient’s weight is helpful information, and its daily measurement is important in the diagnosis and management of AKI. An acute decrease in weight over days may indicate volume depletion and prerenal AKI. In contrast, increasing weight in association with a rising creatinine level occurs in ATN with volume overload. After major urologic procedures (e.g., cystectomy, nephrectomy, transplantation), measurement of the central venous pressure or pulmonary artery wedge pressure is the most accurate method to assess volume status. Other clinical parameters that correlate with volume status include neck vein distention, lung rales, and peripheral edema (pretibial or presacral).

The urine output may be a clue to the diagnosis of AKI. The presence of marked oligoanuria suggests urinary tract obstruction, renovascular occlusion, or cortical necrosis. In contrast, nonoliguric AKI is being recognized with increased frequency, and careful monitoring of SCr levels in patients at risk is of paramount importance.

Examination of the urinalysis results is fundamental to the evaluation of the patient with AKI (Perazella and Parikh, 2009). The simple urinalysis may distinguish the cause of AKI among the various possibilities. Table 43–6 highlights the various urinary abnormalities associated with the clinical diagnoses. For example, proteinuria, hematuria, and red blood cell casts are pathognomonic of glomerulonephritis. The classic sediment of ATN includes pigmented (muddy brown) granular casts and renal tubular epithelial cells, which may be seen in nearly 80% of cases of oliguric AKI.

Table 43–6 Urine Sediment in Acute Kidney Injury

Determination of urinary chemistry may be helpful in determining the cause of the AKI. The urine sodium, creatinine, and osmolality should be measured. The fractional excretion of sodium or the renal failure index should be calculated (Fig. 43–5). Note that a low fractional excretion of sodium (or renal failure index) may be associated with either prerenal azotemia or AGN (Table 43–7). These entities can be separated clinically by examination of the urinalysis results. Conditions associated with prerenal azotemia have bland urinalysis results, whereas proteinuria, red blood cells, and red blood cell casts are seen with AGN. Other causes of AKI associated with a low fractional excretion of sodium include hepatorenal syndrome and selected types of ATN such as that due to iodinated contrast material, rhabdomyolysis, sepsis, and multisystem organ failure. Both ATN and obstruction may have an increased fractional excretion of sodium or renal failure index. Here again, the urinalysis is crucial in sorting out the differential diagnosis. ATN has a classic sediment with pigmented coarsely granular casts, but the urinalysis results seen in obstruction are often bland with and without microhematuria.

Figure 43–5 Urinary indices.

Table 43–7 Patterns of Urinary Indices in Acute Kidney Injury

The urine output may be a clue to the diagnosis of AKI. The presence of marked oligoanuria suggests urinary tract obstruction, renovascular occlusion, or cortical necrosis. In contrast, nonoliguric AKI is being recognized with increased frequency, and careful monitoring of SCr in patients at risk is of paramount importance.

Imaging

A variety of imaging modalities have clinical utility in the evaluation of AKI. The most widely used is renal ultrasonography. This noninvasive and readily available study is fairly sensitive for the identification of hydronephrosis, as discussed earlier in the section Postrenal Azotemia. Duplex ultrasonography of the renal artery is useful for the identification of renal artery stenosis (RAS) or thrombosis (Carman et al, 2001). The absence of a Doppler signal from the artery is a noninvasive sign to confirm renal artery thrombosis.

Another common imaging study in AKI is the abdominal plain radiograph to identify the presence or location of renal calculi or both. Additionally, the abdominal plain radiograph is particularly helpful to discern the proper position of the stents and drains. The radionuclide renal scan is a useful imaging study in selected clinical circumstances. Tc⁹⁹-MAG³ is a more useful imaging agent in renal insufficiency than Tc⁹⁹-DTPA and is able to evaluate both renal flow and function (Taylor, 1999). The renal scan is a simple way to evaluate for renal flow in situations where renal artery thrombosis is a serious consideration such as after partial nephrectomy or renal transplantation. It is especially useful when there is renal insufficiency that prohibits the use of iodinated contrast (Jafri et al, 1988). Urinary extravasation can also be assessed by isotope renography.

Radiocontrast studies (IVP, CT, angiography) are of limited value during AKI because of their ability to worsen renal insufficiency. Angiography is used to confirm renal artery thrombosis, stenosis, or dissection. Studies such as an IVP yield poor-quality images in azotemic patients because of the inability to adequately excrete contrast. Notwithstanding, radiocontrast studies are frequently performed just proximal to surgery and may contribute in this manner to perioperative AKI.

Pharmacologic Intervention

Pharmacologic intervention to convert oliguric ATN to nonoliguric ATN is a salutary goal for the reasons noted earlier (Townsend and Bagshaw, 2008). Experimental studies on the use of diuretics, dopamine, atrial natriuretic peptide (ANP), and calcium channel blockers (CCBs) that attempt to convert oliguria to nonoliguric AKI have been performed. The applicability of these experimental studies to patients with AKI remains unproved. Uncontrolled studies suggest that patients who respond to mannitol, furosemide, or dopamine with an increased urine output have better outcomes than nonresponders (Cosentino, 1995). The responders may simply have had less severe disease from the outset. Although de novo nonoliguric AKI has been associated with a lower mortality rate, there is little evidence that conversion from an oliguric to a nonoliguric state decreased mortality rate. For the patients with established ATN, therapy with loop diuretics may increase urine output but has little effect on the severity or duration of the AKI (Cosentino et al, 1994). Results of clinical trials involving diuretics, dopamine, ANP, and CCBs for established ATN are reviewed here.

Both loop diuretics and mannitol administration have been proved to minimize the degree of renal injury if given at the time of the ischemic insult (Hanley and Davidson, 1981; Schrier et al, 1984; Cosentino, 1995). Both diuretics are capable of inducing a diuresis to wash out obstructive debris and casts. Loop diuretics (e.g., ethacrynic acid, furosemide, and bumetanide) exert their pharmacologic effect in the loop of Henle, causing a large solute diuresis. Additionally, they decrease active NaCl transport in the thick ascending limb of Henle and thereby limit energy requirements in the metabolically active segment, which often bears significant ischemic insult. There are several theoretical reasons why loop diuretics may be of benefit in AKI. Loop diuretics may protect cells of the ascending limb of Henle from hypoxic damage, increase tubular flow to prevent intratubular obstruction, inhibit tubuloglomerular feedback to maintain a favorable GFR, and increase RBF by decreasing renal vascular resistance. The available clinical data do not support an improved outcome in patients who respond to loop diuretics (Shilliday and Allison, 1994). A prospective, randomized placebo-controlled study examining the effect of loop diuretics on renal recovery, dialysis, and death in patients with AKI found no effect (Shilliday et al, 1997). Observational data suggested that diuretic use in critically ill patients with AKI is associated with an increased mortality rate using multivariate analysis and propensity scores (Mehta et al, 2002). A more recent prospective, multicenter, epidemiologic study found that the use of loop diuretics was not associated with higher mortality (Uchino et al, 2004). Therefore it is reasonable to give a trial of a loop diuretic in escalating doses, and if the patient does not respond, the drug should not be readministered because large doses of loop diuretics may be ototoxic and the large infusion volume may cause pulmonary edema.

Mannitol, an osmotic diuretic, theoretically ameliorates AKI by flushing intratubular casts, increasing RBF, increasing urine flow, reducing hypoxic cell swelling, protecting mitochondrial function, and scavenging free radicals. Mannitol use continues to be promoted prophylactically in certain high-risk patient groups because of its demonstrated benefit in animal models of AKI (Burke et al, 1983; Shilliday and Allison, 1994). Mannitol has shown some benefit in the clinical setting of AKI (Novick et al, 1983; Weimar et al, 1983; Simmons et al, 2008), particularly when administered prophylactically or within a short time after an ischemic or nephrotoxic insult. The best clinical example of this is its administration before renal artery clamping during partial nephrectomy. However, other studies in humans failed to demonstrate the effectiveness of mannitol in prevention or treatment of ischemic or toxic AKI (Shilliday and Allison, 1994; Baker and Pusey, 2004).

Dopamine has selective renal vasodilator properties that cause natriuresis and increased urine output. Low-dose “renal-dose” dopamine (0.4 to 2.0 µg/kg/min) activates dopamine-1 receptors, which induce renal vasodilation and increased RBF. Objective review of controlled studies demonstrates that these benefits remain speculative (Denton et al, 1996; Lassnigg et al, 2000). Bellomo and colleagues (2000) reported on 328 critically ill patients with AKI who were randomly assigned to continuous infusion of placebo or low-dose dopamine (2 µg/kg/min). Peak SCr concentration, requirement for dialysis, length of hospital stay, and mortality rate did not differ between the two groups. Also, prophylactic use of low-dose dopamine in patients undergoing coronary artery bypass surgery has not been shown to be effective in preventing the development of renal impairment in these patients (Woo et al, 2002). Lauschke and colleagues (2006) recently reported on the effects of renal-dose dopamine on renal perfusion as measured by resistive indices obtained by ultrasonography. Although renal perfusion indeed increased in subjects with no AKI, renal vascular resistance actually increased in those with AKI, a finding that was more marked in older patients (Lauschke et al, 2006). It is also important to note that the use of dopamine has been associated with serious cardiac, vascular, and metabolic complications in the critically ill and therefore should be used with caution (Polascik et al, 1999). Other than dopamine, the literature provides little guidance on the effects of other vasoactive agents on the kidney and thus a need for large randomized, controlled studies to clarify this issue (Baker and Pusey, 2004).

Fenoldopam is a selective dopamine receptor-1 agonist (DA-1) that causes DA-1 receptor-mediated vasodilation and does not stimulate DA-2 or α- or β-adrenergic receptors (Baker and Pusey, 2004). Fenoldopam reduces renal vascular resistance and increases RBF and fractional excretion of sodium and free water clearance in studies in normal volunteers and hypertensive patients (Mathur et al, 1999). A few studies in animal models (Singer and Epstein, 1998; Halpenny et al, 2001) are consistent with the notion that DA-1 agonists may be useful in preventing or treating AKI. Some clinical studies have been encouraging in the treatment (Stone et al, 2003) and prevention (Kini et al, 2002) of contrast-induced nephropathy and when used perioperatively in cardiovascular surgery (Halpenny et al, 2001). A recent multicenter trial, however, did not find any protective benefit of the selective dopamine-1 agonist (fenoldopam mesylate) in the prevention of contrast-induced renal dysfunction in an at-risk population (Landoni, 2007). One study showed when fenoldopam was used prophylactically in patients undergoing aortic surgery, its use was associated with improvement in renal function, reductions in dialysis requirements, length of hospital stay, and mortality (Gilbert et al, 2001). A meta-analysis of all randomized controlled trials using fenoldopam to prevent AKI, which included 1290 patients from 16 different studies, suggests that the use of this drug may be beneficial in reducing the need for renal replacement therapy, shortening ICU stay, and perhaps improving mortality (Landoni et al, 2007); however, because these studies were small, defining fenoldopam’s role in clinical situations is difficult without a large-scale randomized controlled trial.

In some animal studies the effects of ischemic AKI could be reversed with the use of an intrarenal arterial infusion of ANP (Nakamoto et al, 1987; Shaw et al, 1987), but other experimental studies have been contradictory. The proposed mechanism by which this occurs is the vasodilatory action of ANP. In experimental models of established ATN, the combination of ANP with dopamine to prevent systemic hypotension resulted in a rise in GFR induced by arteriolar vasodilatation. The treated animals also exhibited less tubular necrosis and fewer casts, suggesting tubular recovery was promoted. The efficacy of ANP in established ATN in humans has been evaluated in two trials (Rahman et al, 1994). First was a small, randomized trial suggesting a benefit of ANP therapy. More recently, a prospective, multicenter, randomized study with ANP in patients with ATN (oliguric and nonoliguric) has been reported. Overall, there was no established benefit on morbidity and mortality with ANP. However, in a subset of patients with oliguric ATN, clinical improvement was seen with ANP infusion. Further studies in such a select population did not demonstrate benefit (Lewis et al, 2000). ANP is still considered an investigational drug, and its role in the management of patients with ATN remains uncertain.

Experimental studies suggest the possibility of accelerating the rate of tubular regeneration in ATN by administration of growth factors such as insulin-like growth factor-1 (IGF-1) (Miller et al, 1992) and epidermal growth factor (EGF) (Hammerman, 1999). The recovery process involves both tubular cell regeneration and differentiation into mature functioning cells. The applicability of these observations to human disease remains to be determined. A report of a randomized trial of AKI patients of less than 7 days’ duration found no benefit in patients treated with IGF-1 (Hirschberg et al, 1999). In a large, randomized, double-blind, placebo-controlled trial in intensive care units in 20 teaching hospitals involving 72 patients, it was shown that IGF-1 does not accelerate the recovery of renal function in AKI patients with substantial comorbidities (Hirschberg et al, 1999). Similarly, there is no role for thyroxine in modifying the course and outcome in AKI; in fact, it could have a negative effect on outcome through prolonged suppression of TSH (Acker et al, 2000). Therefore on the basis of current evidence, there is no role for the use of growth factors to treat AKI.

Calcium channel blockers inhibit voltage-gated calcium entry into cells and are reported to reverse vascular constriction, increase GFR, and improve renal plasma flow (Epstein, 1993). A few limited animal studies in experimental AKI generally support a protective benefit of calcium channel blockers. The clinical benefit of calcium channel blockers most widely studied has been the effect on graft function in renal transplant recipients (Alkhunaizi and Schrier, 1996).

In summary, review of the data regarding pharmacologic intervention for established ATN supports a trial of isotonic fluid repletion. Judicious use of intravenous loop diuretics may increase urine output, but their ability to have an impact on improved patient survival in AKI is still unproven. Similarly, the clinical data on “renal-dose” dopamine are scant and do not support its widespread use in established ATN. If a trial of dopamine is considered, it should be limited to a 24- to 48-hour infusion. Additional studies on the use of fenoldopam, ANP, dopamine, calcium channel blockers, and growth factors are warranted to examine their impact on the course of ischemic or nephrotoxic ATN.

Conservative Management

Once the clinical diagnosis of ATN is made, conservative medical management is in order (Table 43–9). This would include attempts to minimize further renal parenchymal injury, ensure provision of nutrition, maintain the metabolic balance, and promote recovery of renal function.

Table 43–9 Conservative Medical Management of Acute Kidney Injury

Optimizing the patient’s volume status is imperative, particularly in patients with oliguric AKI (DiBona, 1994). If such patients are administered large volumes of IV fluid or allowed free access to oral fluids, they are at risk for developing fluid overload. In the oliguric patient, fluids should be restricted to total output plus insensible losses. If required, pharmacologic intervention with loop diuretics may promote increases in urinary volume.

Providing adequate nutrition is important for the recovery of the critically ill patient with AKI (Fiaccadori et al, 2008). Preexisting or hospital-acquired malnutrition is an important factor contributing to high mortality seen in patients with AKI (Druml, 1998; Kriz et al, 1998). AKI not only affects water, electrolyte, and acid-base metabolism but induces specific alterations in protein and amino acid, carbohydrate, and lipid metabolism (Druml, 1992). The metabolic alterations in AKI patients are determined not only by acute loss of renal function but also by the underlying disease process (i.e., sepsis, trauma, or multiple organ failure) and by the type and intensity of renal replacement therapy (RRT) (Druml, 1992, 2005).

The hallmark of metabolic alterations in AKI is activation of protein catabolism with excessive release of amino acids from skeletal muscle and sustained negative nitrogen balance (Druml, 1998; Price et al, 1998). Hepatic extraction of amino acids from the circulation, gluconeogenesis, and ureagenesis are all increased. Several additional catabolic factors (secretion of catabolic hormones, hyperparathyroidism, suppression and decreased sensitivities to growth factors, and release of inflammatory mediators) are operative in AKI. All of these factors mediate protein breakdown (Cianciaruso et al, 1991).

Frequently, AKI is associated with hyperglycemia caused by insulin resistance (Klouche and Beraud, 1998). When plasma insulin concentration is elevated, maximal insulin-stimulating glucose uptake by skeletal muscle is decreased by 50%. AKI is also associated with accelerated hepatic gluconeogenesis, mainly from conversion of amino acids released during protein catabolism, which cannot be suppressed by exogenous glucose infusions (Druml, 1992).

The triglyceride content of plasma lipoprotein is increased in AKI, whereas total cholesterol and high-density lipoprotein (HDL) cholesterol are decreased (Schneeweiss et al, 1990). The major cause of lipid abnormalities in AKI is impairment of lipolysis. RRTs themselves may have significant metabolic and nutritional consequences.

Appropriate nutritional therapy in patients with AKI may be beneficial in promoting recovery (Fiaccadori et al, 2008). Caloric intake should be maintained, and carbohydrate intake should be at least 100 g/day to minimize ketosis and endogenous protein catabolism. A moderate protein intake of about 1 to 1.8 g/kg by weight per day may be required to maintain positive nitrogen balance. Higher protein intakes of up to 2.5 g/kg/day have been necessary to improve nitrogen balance in critically ill AKI patients on continuous dialysis, although no survival advantage was noted. Hence it should be stressed that a low-protein intake (<0.5 g/kg/day) may be unnecessary and protein intake should not be severely restricted in AKI to limit the need for dialysis. In terms of types of amino acids used, diet or solutions including both essential and nonessential amino acids in standard proportions are recommended. Dietary phosphorus, potassium, and sodium chloride may be restricted. In the critically ill patient, nutritional support via TPN or enteral feedings should be considered. Prior studies demonstrate that provision of adequate nutrition to the AKI population may improve survival (Chertow et al, 2000). Patients with AKI are candidates to develop significant electrolyte abnormalities such as hyperkalemia, metabolic acidosis, hyperphosphatemia, and hypocalcemia. These problems may be minimized by the prophylactic institution of a low-potassium diet accompanied by fluid restriction and oral phosphate binders.

Hyperkalemia is the most common and most dangerous electrolyte abnormality in the AKI setting. If serum potassium exceeds 6 mEq/L, an electrocardiogram (ECG) should be performed with subsequent therapy based on the ECG findings. With hyperkalemia, the earliest changes demonstrate peaked T waves with subsequent broadening of the PR interval and eventual QRS broadening, which may mature into a sine wave form. The stages of therapy for acute hyperkalemia with ECG changes include (1) stabilizing the electrical membrane of the cardiac conduction system, (2) shifting potassium back intracellularly, and (3) eventual elimination of potassium from the body. Stabilizing the membrane of the cardiac conduction system may be accomplished with IV calcium salts, which have an immediate effect and a rather short duration of action. Shifting potassium into cells may be accomplished by a combination of IV glucose and insulin or IV sodium bicarbonate. Elimination of potassium from the body in a patient with AKI may be accomplished via the gastrointestinal tract with a cationic binding resin (Kayexalate). If severe hyperkalemia exists, dialysis may be required.

Dialytic Interventions

General

Despite adequate medical therapy, dialysis may be required for patients with severe AKI. The indications for the initiation of dialysis include volume overload, severe hyperkalemia, severe metabolic acidosis, pericarditis, selected poisonings, and uremic symptomatology.

The initiation of dialysis for patients with AKI is usually precipitated by one or more of the specific indications. There is still debate on whether patient morbidity and mortality might be improved by early, more intensive dialysis to keep the BUN less than 80 to 100 mg/dL. A recent study from a multicenter trial suggested that in those patients who developed AKI requiring dialysis, patients with BUN levels lower than 76 mg/dL had a better prognosis than those with higher levels, suggesting that initiation of treatment at earlier time points may be beneficial (Liu et al, 2006

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