Loop diuretics for patients with acute renal failure: helpful or harmful?

INTRINSIC ACUTE RENAL FAILURE (ARF) THAT DOES NOT result from primary vascular, glomerular, or interstitial disorders has been ascribed to acute tubular necrosis and accounts for approximately 45% of cases of hospital-acquired ARF. While acute tubular necrosis usually is caused by ischemic (50%) or nephrotoxic (35%) injury to the kidney, the cause is often multifactorial. Unfortunately, neither the occurrence of acute tubular necrosis nor the morbidity and mortality associated with it have declined despite ongoing improvement in the supportive care of patients with renal failure and the advent and availability of intermittent and continuous dialysis. One reason for this lack of improvement is a change in the severity of the underlying diseases causing ARF. The incidence of acute tubular necrosis is particularly high in patients admitted to an intensive care unit (ICU). The spectrum of acute tubular necrosis in the ICU, compared with other settings, is indeed different. Critically ill patients develop acute tubular necrosis predominantly as part of a multiple organ dysfunction syndrome, whereas isolated ARF is the usual presentation for patients outside the ICU. The mortality rate among critically ill patients with acute tubular necrosis has been estimated to be as high as 80% to 85% in some series. Acute renal failure also complicates the medical management of hospitalized patients and contributes to their morbidity and mortality. Hence, a treatment that would prevent ARF or accelerate the recovery of renal function in patients with established ARF might be expected to reduce morbidity and possibly mortality and could substantially reduce the cost of medical care. Acute tubular necrosis has traditionally been characterized as either oliguric (urine output 400 mL/d) or nonoliguric (urine output 400 mL/d); this distinction is important because of several clinically relevant associations and implications. In comparison with oliguric acute tubular necrosis, nonoliguric acute tubular necrosis is more often reported to have a nephrotoxic cause; is associated with shorter hospital stay; has fewer septic, neurologic, hemorrhagic, and acidemic complications; requires less dialysis; and has a lower mortality rate. However, the distinction between oliguric and nonoliguric acute tubular necrosis is somewhat arbitrary, because urine flow rates in patients with acute tubular necrosis represent a continuum from very low to high values without an obvious biphasic distribution. Most probably, the residual level of glomerular filtration rate is the primary determinant of variations in urine flow rate in patients with ARF. Several theoretical arguments support the use of mannitol and loop diuretics for prevention or treatment of ARF. Both mannitol and loop diuretics can induce a diuresis, potentially “washing out” obstructing cellular debris and casts. Mannitol may preserve mitochondrial function by osmotically minimizing the degree of postischemic swelling and by scavenging free radicals. Loop diuretics have been reported to improve medullary oxygenation, presumably because they selectively decrease oxygen use in this portion of the tubule by blocking active transport. The ensuing decrease in energy requirements may protect the renal cell in ischemic conditions. In addition, loop diuretics may act as renal vasodilators. But how theory relates to actual pathophysiology in individual patients is often unclear. In this issue of THE JOURNAL, Mehta and colleagues retrospectively analyzed the outcome of all ICU patients with ARF who received nephrology consultation in 4 teaching hospitals over a 6-year period. Patients who received loop diuretics or a combination of thiazide and loop diuretics at the time of nephrology consultation were compared with a group of similar patients who did not receive diuretics. After adjustment for relevant covariates and propensity scores, diuretic use was associated with a 68% increase in in-hospital mortality, and a 77% increase in the odds of death or nonrecovery of renal function. The increased risk was mainly observed in patients who were relatively unresponsive to diuretics. Moreover, the risk associated with a high ratio of diuretic dose to urine output, an index of diuretic resistance, was magnified over time. The authors suggest that the use of loop diuretics must be harmful to patients, although it also seems possible that these diuretics are used more frequently in patients who would have done worse anyway.