Acute Renal Failure Definitions and Classification (2003)

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 association between a transient change in serum creatinine and morbidity, or the likelihood of long-term recovery of renal function. Many other definitions of ARF have been applied; some are outlined in Table 1. The most liberal of definitions have been used in intervention studies aimed at ARF prevention, usually in the context of radiocontrast exposure, one of the few instances in which ARF can be anticipated.Table 1: Alternative ARF definitions from several published studiesSeveral of the definitions are extremely complex (see Lian[Combining Tilde]o et al. (6) and others) and could allow excessive subjectivity in ARF determination. These would likely be impractical for prospective, multicenter investigations. Moreover, none of the definitions used to date take into account the modifying effects of age, gender, and race on creatinine generation (and thereby serum creatinine concentration in ARF). It is noteworthy that creatinine generation is typically higher among individuals who are younger, male, and African American (51). Therefore, at the same decrement in GFR, persons with different demographic characteristics may be more likely to “qualify” with ARF diagnoses, particularly those definitions that require a minimum peak creatinine (e.g., 50% increase, to at least 2.0 mg/dl). By use of this definition, we found a twofold increase in the incidence of amphotericin B–associated ARF among men (52). Whether male gender is a true risk for ARF or simply a risk for being diagnosed with ARF is unclear. Regardless, the association of ARF with male gender highlights one of the limitations of the use of a definition of ARF that is creatinine based and not age, gender, and race adjusted. Changes in serum creatinine are not specific and do not discriminate the nature and type of renal insult (e.g., ischemic, nephrotoxic) or the site and extent of glomerular or tubular injury, and levels are relatively insensitive to small changes in GFR (53). Moreover, changes in serum creatinine may lag behind changes (decline or recovery) in GFR by several days. Finally, because serum creatinine is influenced by one of the potential interventions for ARF (e.g., creatinine is removed by dialysis), its specificity for renal recovery is even more problematic. Empiric Evidence of the Focus on Creatinine and Urine Output We recently completed an analysis focusing on correlates of timing of nephrology consultation for ARF in the ICU (54). To avoid the complexities of comparing individuals whose ARF developed during a complicated ICU stay, we restricted our analysis to those patients with evidence of ARF at ICU admission and excluded individuals designated as “do not resuscitate.” We considered a wide array of demographic, clinical, laboratory, and physiologic variables (including pulmonary artery catheter data in some patients). The serum creatinine concentration and urine output (either as a continuous variable or the dichotomous “oliguria”) (<400 ml/d) were associated with the timing of consultation. There was no relation between the timing of consultation and hospital service, medical history, physiologic parameters, other laboratory studies, or the presence or absence of organ system failure, despite the fact that many of these factors have been shown to predict mortality in ARF in other studies. In other words, empiric evidence demonstrates that the definitions used in published reports are operative in practice, with little attention to risk profiles or associated nonrenal organ system failure. Analogous Definitions in Other Conditions Conceptual Framework for Disease Definitions. Disease definitions may be used to ascertain the presence of a disease in an individual or a population, guide the nature and timing of diagnostic and therapeutic interventions, and, in individual patients, help determine prognosis. The presence of any disease is inferred from a combination of clinical symptoms and signs, and alterations in biologic markers that can be reproducibly measured. Measures defining a disease should be responsive to change, track the natural history of the disease, and provide an assessment of the severity of injury. Consequences of the untreated disease and its response to specific interventions are additional criteria that might be considered when evaluating the choice of variables to define and classify a disease. Most disease definitions rely on the presence of specific markers that are measurably altered in response to an injury, and the sensitivity and specificity of any definition depends on the criteria used. These “response variables” may appear at varying time points in the disease and help define the course of the disease. Ideally, the magnitude and pattern of change of the response variable correlate with disease outcomes. For instance, AMI can be diagnosed with the combination of chest pain and elevated cardiac troponins or creatine phosphokinase. Gradations in the severity of signs (including electrocardiography) and symptoms and the levels of troponin and creatine phosphokinase profile allow further classification of the disease spectrum (e.g., angina, unstable angina, demand ischemia, silent ischemia, myocardial infarction). A key feature for AMI is that the clinical presentation is directly related to an underlying event (i.e., coronary thrombosis). Moreover, the markers are sensitive, specific, and correlate with the severity of injury, even in the absence of typical clinical features. In contrast, sepsis is heterogeneous in its presentation and affects multiple organs, so no single marker can be used to define the presence or absence of disease. Recognizing this limitation, a functional definition for sepsis has been based on events in the natural history of the sepsis syndrome: systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock (55). In the absence of specific markers, effective definitions for a disease rely on multiple parameters, some of which represent the specific response to the disease, whereas others reflect nonspecific consequences of the disease. Disease severity is graded on the basis of the presence of specific parameters. For instance, the transition from sepsis to severe sepsis requires the presence of sepsis-related organ dysfunction. These graded definitions are more readily applied to classify populations, although they have also been used to guide interventions in individual patients and research subjects (56,57). The multidimensional definition and classification construct has been applied to several diseases where a single specific diagnostic criterion is not available or is otherwise unsuitable. For example, the Ranson criteria enable early classification of severe acute pancreatitis (58). These criteria rely on the presence of three or more of the 11 criteria evident within 48 h of admission. Criteria include age and a series of laboratory parameters that reflect consequences of disordered pancreatic function (i.e., hyperglycemia in absence of diabetes, hypocalcemia, azotemia, anemia, hypoalbuminemia, leukocytosis, elevations of the hepatic enzymes lactate dehydrogenase and aspartate aminotransferase) and physiologic variables (i.e., metabolic acidosis, hypoxia) to grade the response. Interestingly, serum amylase and lipase, enzymes directly related to pancreatic injury (and analogous to creatinine in ARF), are not included in the scoring system. The number of positive criteria are associated with mortality ranging from <5% for zero to two criteria to 100% for seven to eight criteria (58). Similarly, the Child-Pugh classification is a means of assessing the severity of hepatic cirrhosis (59). It assigns scores for each of three laboratory parameters (bilirubin, albumin, and prothrombin time) and two clinical criteria representing the consequences of liver failure (encephalopathy and ascites). The individual scores are summed and then grouped as <7 (A), 7 to 9 (B), and >9 (C). A Child-Pugh “C” classification forecasts survival of less than 12 mo. Cancer staging similarly uses the tumor node metastasis grading system to classify malignant disease. 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