Acute renal failure (ARF) is an abrupt loss of renal function resulting in the failure of the kidneys to excrete urea and other nitrogenous waste products. Despite substantial advances in our understanding of the pathogenesis of ARF, clinical advances in treatment have been limited, and morbidity and mortality remain high. Although multiple pharmacologic interventions have shown promise in animal models, no agents have proven to be effective in clinical practice [1
]. As a result, the management of ARF is primarily supportive, with renal replacement therapy (RRT) serving as the mainstay of treatment in patients with severe renal failure. Despite more than a half-century of experience, many fundamental issues regarding the management of RRT in ARF remain to be resolved, including the indications for and timing of initiation of therapy, the selection of modality of RRT, and the optimal dosing of therapy [3
In patients with ARF, RRT is commonly initiated either to treat overt manifestations of renal failure (i.e., uremic symptoms, volume overload, hyperkalemia and metabolic acidosis) or, in the absence of overt symptoms, in response to progressive azotemia [5
]. An increasing number of modalities of RRT are used in clinical practice. Intermittent hemodialysis is the most commonly prescribed form of renal support, usually provided on a three to four times per week schedule. Other modalities, such as the continuous renal replacement therapies (CRRT) and sustained low efficiency dialysis (SLED) have gained increasing acceptance in the management of hemodynamically unstable patients. Although several recent clinical studies have suggested that more intensive renal support may improve survival [6
], these data have not been widely accepted in clinical practice in the USA [4
]. In addition, these studies evaluated individual modalities of therapy in isolation rather than evaluating strategies of care that parallel clinical practice.
In light of the lack of consensus regarding best practice of renal support in ARF, the VA/NIH Acute Renal Failure Trial Network Study (ATN Study) was conceived to address the question of whether there is a benefit to delivering more intensive RRT in critically ill patients. The ATN Study is a prospective, randomized trial involving protocol-driven treatment strategies of titrated therapies. It compares a strategy of intensive renal support to more conventionally utilized (conventional) management of RRT, utilizing multiple modalities of RRT within each treatment arm. The primary study hypothesis is that intensive renal support will decrease mortality in critically ill patients with ARF as compared to more conventional management of RRT. Secondary hypotheses are that intensive renal support will shorten the duration of ARF, will decrease the incidence and duration of nonrenal complications, and will be cost-effective. The study is jointly funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development and by the National Institute of Diabetes, Digestive and Kidney Diseases. Subject enrollment initiated in November 2003, with a planned close of enrollment in November 2006.
In this report we describe the design, interventions and analysis plan of the ATN Study. In addition, strategies to address concerns raised by the Office of Human Research Protections (OHRP) regarding other studies comparing protocol-driven treatment strategies conducted in the setting of uncertainty regarding prevailing standards of practice [10
] are discussed, including the use of practitioner surveys prior to study initiation and the inclusion of an observational cohort to assess processes of care outside of the research setting.