Functional State of the Nephron and Diuretic Dose-Response - Rationale for Low-Dose Combination Therapy

Abstract

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.

Refractory Edema with Congestive Heart Failure Stepwise Approaches Nephrology Perspectives

“…Sequential nephron blockade means a parallel use of different diuretics acting at different segments of the nephron; therefore producing an additive or synergistic diuretic response. 25 As mentioned above, long term administration of a loop diuretic will increase the distal sodium delivery, a flow-dependent hypertrophy in distal convoluted tubule can, which increases sodium reabsorption secondary to the increased activity of the sodium chloride cotransporter in the luminal membrane of the distal tubule cells and its hypertrophy. 7,8 Therefore adding thiazide diuretic (in patient with known long term use of loop diuretics) will block the distal reabsorption of sodium, leading to a better diuretic effect.…”

Management of the Cardiorenal Syndrome in Decompensated Heart Failure

“…Thiazidetype diuretics inhibit sodium reabsorption in the distal nephron and primarily benefit patients who have distal nephron hypertrophy and hyperfunction due to chronic treatment with loop diuretics [65] . In addition, they markedly increase the fractional sodium excretion, which is needed to achieve a neutral or negative sodium balance if GFR is depressed [66] . Another important cause of diuretic resistance in decompensated HF is poor renal perfusion with an increased filtration fraction and, due to glomerulotubular balance, increased proximal sodium reabsorption [4] .…”

“…As the problem in this case is insufficient tubular flow through Henle's loop and the distal nephron, thiazide-type diuretics are of little value to increase diuresis. In contrast, increasing the effective circulatory volume through arteriolar vasodilators or inotropes should be considered, while proximal sodium reabsorption might also be directly inhibited by acetazolamide [4,33,66] . Indeed, it has been reassuring that in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), stepwise pharmacological care including thiazide-type diuretics, vasodilator therapy and inotropes was as effective as ultrafiltration in relieving congestion, although the study specifically included patients with CRS [67] .…”

Mechanisms, Risks, and New Treatment Options for Hyponatremia

“…Hyponatremia also contributes to diuretic resistance, a state in which sodium intake and excretion are equalized without adequate elimination of fluid [46]. The effectiveness of loop diuretics is related to the amount of sodium present in the loops of Henle, and diminished sodium delivery in advanced HF results in diminished diuresis [46, 47]. The incidence of diuretic resistance increases in advanced disease as cardiac output and renal function decline.…”