Acute Renal Failure Definitions and Classification: Time for Change?

Abstract

Epidemiology of Acute Renal Failure The development of acute renal failure (ARF) in the hospital setting continues to be associated with poor outcomes (1–7). Over the last three decades, several experimental models have identified pathophysiologic mechanisms associated with ARF and have enhanced our understanding of the disease (8–10). It is evident that ARF can result from alterations in renal perfusion, changes in glomerular filtration, and tubular dysfunction, and that correction of these factors can ameliorate the effects of ARF (11,12). On the basis of the identification of the underlying mechanisms, several new potential interventions have been developed that have been shown to alter the course of incipient and established ARF in experimental models (13–15). Application of these findings has resulted in improvements in the prevention of ARF due to radiocontrast agents, aminoglycoside antibiotics, and rhabdomyolysis (16,17). Several other agents are now in advanced stages of development or initial phases of clinical trials (18,19). In concert, advances in dialysis have occurred with the availability of continuous renal replacement therapies in addition to intermittent hemodialysis and acute peritoneal dialysis (20–22). It is well recognized that uncomplicated ARF can usually be managed outside the intensive care unit (ICU) setting and carries a good prognosis, with mortality rates less than 5% to 10% (23,24). In contrast, ARF complicating nonrenal organ system failure in the ICU setting is associated with mortality rates of 50% to 70%, which has not changed for several decades (6,25–30). These figures are in sharp contrast to the experience with acute myocardial infarction (AMI), where in-hospital mortality rates have declined from the range of 50% to approximately 6% over the past 25 to 30 yr. Much of the credit for improved AMI outcomes has been attributed to the use of coronary care units, cardiac catheterization, aspirin, β-adrenergic antagonists, thrombolytic therapy, and, more recently, specialized percutaneous coronary interventions and glycoprotein IIb–IIIa inhibitors (31–34). In spite of improved dialytic technology, including the development and refinement of continuous renal replacement therapies for the most critically ill patients, we have seen no material change in the high mortality rates associated with ARF. Indeed, we have not demonstrated any pharmacologic or other intervention effective in the early management of ARF. Interventions that have been deemed ineffective (or potentially harmful) include the following: loop and osmotic diuretic agents (35,36), “renal dose” dopamine (37,38), atrial natriuretic peptide (39,40), insulin-like growth factor-1 (41), and endothelin receptor antagonists (42). Although ARF may develop in 5% or more of hospitalized patients, the heterogeneity of ARF and associated comorbidity make its study more difficult than AMI and other, more discrete conditions. Among the impediments to progress in ARF research is the lack of a uniform definition of ARF that might be used to compare and contrast observational studies, and to allow for rational design of clinical trials. Relatively few studies have examined the incidence of hospital-acquired ARF. The oft-cited study by Hou et al. (23) reported an ARF incidence estimate of 4.9%. Shusterman et al. (24) conducted a similar study identifying ARF in 1.9% of hospitalized patients. A follow-up study recently published by Hou and colleagues (43) showed an increase in incidence (7%), but a similar spectrum of risk factors. ARF in the ICU setting has also been characterized in the last two decades. Lian[Combining Tilde]o et al. (6) found ICU patients with ARF to have associated organ failure, sepsis, and other complications. It is well recognized that the development of ARF is associated with an increase in mortality (22,25,26,44,45). It is also known that patients with ARF as part of multiorgan failure have the highest mortality rates. In several studies, sepsis-related ARF had a significantly worse prognosis than ARF in the absence of sepsis (46,47). It is also recognized that untreated ARF may contribute to a higher incidence of new-onset sepsis (48). Definition of ARF The spectrum of definitions in published studies of ARF is striking, ranging from severe (e.g., ARF requiring dialysis) to relatively modest observable increases in serum creatinine concentration (e.g., increase in serum creatinine of 0.3 to 0.5 mg/dl above baseline). Solomon et al. (36) used the definition of an increase in serum creatinine of 0.5 mg/dl within 48 h of radiocontrast exposure in a widely cited study that showed a borderline significant difference in ARF among individuals given saline infusion versus furosemide or mannitol before radiocontrast exposure. However, neither the Solomon et al. study nor others that use this ARF definition (including the Tepel et al. (49) and Kay et al. (50) publications on N-acetyl cysteine) have shown an associ