Why did dose trials fail?

The search for the optimal intensity in renal replacement therapy of the critically ill has resulted in several well-designed randomized controlled trials over the last decade. The findings, however, have been somewhat disappointing. Whereas earlier trials indicated a survival benefit using higher doses ( > 35 ml/kg/h) or daily dialysis, more recent and much larger trials have shown that intensities in the range of 20-25 ml/kg/h or alternate day dialysis may be sufficient. This review attempts to explain these discrepant findings by critically reappraising several issues including the concept of dose, comparability of doses, importance of middle molecule clearance, indication and timing of treatment as well as patient heterogeneity between the published studies.