Acute renal failure: directions for the next decade.

In their landmark paper published in 1941, Bywaters and Beall described the causative association between crush injury and an abrupt decline in renal function (acute renal failure). Subsequently, acute renal failure (ARF) has been documented in more diverse clinical settings and currently represents one of the most common entities that nephrologists are asked to diagnose and treat. The availability of dialysis reduced the mortality rate for patients with ARF from about 90% to 50%. However, despite advances in renal replacement therapy and nutritional support for patients with ARF, there has been little improvement in this unacceptably high mortality rate. This high mortality rate is undoubtedly related to several factors, including more elderly patients, multi-organ system failure, and the complex nature of contemporary medicine. In patients with a mild renal insult, usually contrast media–associated, data are conflicting on prevention or treatment. However, in patients with more substantial forms of ARF, clinical trials have been based on compelling animal data but have had no evident success. Consequently, there is currently no single or sequence of clinical interventions that will significantly improve renal function once a patient has acute tubular necrosis. The failure of these clinical trials has often been attributed to the fact that animal models of ARF do not unequivocally reproduce the clinical circumstances encountered by patients. Additionally, interventions that have been found to be effective in animal models may not be pertinent or relevant in the clinical circumstance in which the nephrologist encounters the patient with acute renal failure, often after a multifactorial insult has occurred. However, a careful scrutiny of previous clinical trials combined with knowledge of the appropriate design of clinical studies would suggest that our basic understanding of the clinical circumstances of ARF requires a very careful, scientifically based rediscovery and return to basic principles. The articles included in this installment of Frontiers in Nephrology have been selected to initiate such a discussion and stimulate basic and clinical studies in ARF. The starting point for a renewed and rediscovered understanding of ARF must be based on an in-depth scientific understanding of the pathogenic mechanisms and the intrinsic processes that result in renal cell injury, including vascular and tubule components. To this end, Drs. Bonventre and Weinberg provide a contemporary update of our knowledge of the multiple factors that lead to ARF and the issues involved in the interpretation of experimental manipulations that may modify the course of disease. In the clinical setting, the definition of ARF is highly variable and may vary greatly from one study to another and from one medical center to another. Consequently, the detection of early ARF does not commonly occur, and it is well known that the timing of interventions is critical to the potential success and outcome of a trial. It could be easily argued that in the current circumstances the disease process has progressed beyond a point at which therapeutic interventions are likely to be effective. This problem could be addressed, partially, by the identification of biomarkers that could reliably and sensitively predict the development of a significant renal insult. Such markers would aid not only in the early detection of ARF, but they would also serve to substantiate the diagnosis and provide an assessment of the severity of injury. Drs. Molitoris and Dagher provide an elegant overview of two-photo admission microscopy, which can be used to quantify cellular damage and irreversible cell injury. Drs. Herget-Rosenthal and Ruehm describe state-of-art magnetic resCorrespondence to Dr. Sudhir V. Shah, University of Arkansas for Medical Sciences, Division of Nephrology, 4301 West Markham, Slot 501, Little Rock, AR 72205. Phone: 501-257-5832; Fax: 501-257-5827; E-mail: shahsudhirv@ uams.edu