Study Background

Acute renal failure (ARF) is a family of syndromes that are characterized by a loss of kidney function over a period of hours to days. ARF may be caused by a large variety of processes and is generally divided into three broad categories - decreased renal function resulting from decreased renal perfusion in the absence of injury to the kidney itself (pre-renal ARF), decreased renal function from blockages to the drainage of urine (obstructive ARF), and decreased renal function as the result of injury to the kidney itself (intrinsic ARF). This latter form of ARF also has several subcategories, the most common of which is called acute tubular necrosis (ATN).

ATN is caused by ischemic or toxic injury to the kidney that results in damage to the kidney. The kidney is made up of millions of filtering units called nephrons. Blood is filtered in vascular structures called glomeruli. Normally, approximately 180 liters of filtrate is made each day. The filtrate is then processed during passage through the specialized tubular structures of the nephrons. As the glomerular filtrate passes through these tubules approximately 99% of the filtered salt and water are reabsorbed, while waste products that are concentrated in the remaining fluid which is ultimately excreted by the kidney as urine. In ATN, the renal tubules are injured, causing the kidney to stop functioning. This injury may be caused by ischemic injury, usually associated with episodes of low blood pressure; by exposure to chemicals that are toxic to the kidney, such as some antibiotics, contrast media used in X-ray studies or chemicals released when muscle cells or red blood cells are injured; or in the setting of severe infections. Fortunately, the kidney is able to repair itself from this form of injury and the majority of patients who survive an episode of ATN will recover kidney function. Unfortunately, however, the development of ATN is associated with very high mortality rates. This is particularly true of patients who develop ARF while in the intensive care unit, in whom mortality rates exceed fifty percent.

There are no drugs that are effective in the treatment of ARF due to ATN. Treatment is therefore primarily supportive, with hemodialysis and other forms of renal replacement therapy providing the cornerstone of therapy. Several recent studies have suggested that increased frequency of hemodialysis or intensity of therapy using continuous renal replacement therapy may improve survival in patients with ATN. In one study, Claudio Ronco and colleagues found that increasing the intensity of therapy of one form of CRRT, continuous venovenous hemofiltration, decreased mortality from nearly 60% to less than 45% . In a second study, Helmut Schiffl showed that providing intermittent hemodialysis on a daily basis rather than every other day reduced mortality from more than 45% to less than 30%.

Both of these studies were single-center studies and used only a single modality of renal replacement therapy. As a result, the general applicability of their results has been questioned. The ATN Study was therefore designed to provide a more definitive answer to the question: does an increased dose of renal replacement therapy improve survival in critically ill patients with ARF.

Ronco C, et al. Effects of different doses of continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomized trial. Lancet 2000; 356:26-30.
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Schiffl H, et al. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002; 346:305-310.
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