Functional state of the nephron and diuretic dose-response--rationale for low-dose combination therapy

The functions of the different nephron segments follow changes in the effective arterial blood volume and the extracellular fluid volume. In syndromes with reduced effective arterial blood volume, for example congestive heart failure, decompensated hepatic cirrhosis and nephrotic syndrome, hyperreabsorption of sodium in the proximal tubule reduces the sodium load in the more distal segments of the nephron. As this is a major site of sodium excretion, reduction in the response to a diuretic may be predicted by a reduced fractional excretion of sodium (< 0.2%). Such diuretic resistance may be overcome with acetazolamide, which increases delivery of sodium to the distal tubule. In syndromes with increased extracellular fluid volume, such as chronic renal failure, distal tubular rejection of sodium leads to a progressive increase in its fractional excretion as the glomerular filtration rate is reduced. The remaining intact nephrons exhibit a relatively increased response to diuretics. The efficacy of loop diuretics in renal failure can be optimized by combination with thiazides. The latter prevent early distal tubular hyperreabsorption following diuretic-induced blockade of sodium transport in the loop of Henle. For these reasons, low-dose combinations of different diuretics induce 'segmental nephron blockade' and are, therefore, potentially more clinically effective and safer than high doses of single compounds.