Diuretic Resistance

Abstract

Diuretic resistance is defined as a failure to achieve the therapeutically desired reduction in edema despite a full dose of diuretic. The causes of diuretic resistance include poor adherence to drug therapy or dietary sodium restriction, pharmacokinetic issues, and compensatory increases in sodium reabsorption in nephron sites that are not blocked by the diuretic. To illustrate the pathophysiology and management of diuretic resistance, we describe a patient with nephrotic syndrome. This patient presented with generalized pitting edema and weight gain despite the use of oral loop diuretics. Nephrotic syndrome may cause mucosal edema of the intestine, limiting the absorption of diuretics. In addition, the patient's kidney function had deteriorated, impairing the tubular secretion of diuretics. He was admitted for intravenous loop diuretic treatment. However, this was ineffective, likely due to compensatory sodium reabsorption by other tubular segments. The combination of loop diuretics with triamterene, a blocker of the epithelial sodium channel, effectively reduced body weight and edema. Recent data suggest that plasmin in nephrotic urine can activate the epithelial sodium channel, potentially contributing to the diuretic resistance in this patient. This case is used to illustrate and review the mechanisms of, and possible interventions for, diuretic resistance.

Keywords: Diuretic resistance; SCNN1B; cryoglobulinemic membranoproliferative glomerulonephritis; eNaC; edema; epithelial Na(+) channel; hepatitis C virus; kidney disease; nephrotic syndrome; oral loop diuretic; pathophysiology; proteinuria; triamterene.

Copyright © 2016 National Kidney Foundation, Inc. All rights reserved.

Figures

Figure 1

Patient’s course in terms of body weight and serum creatinine levels during admission. Treatment periods with diuretics are indicated. Abbreviation: i.v., intravenous. Conversion factor for creatinine in mg/dL to μmol/L, ×88.4.

Figure 2

Schematic of a nephron shows sites of action of diuretics along the various segments. Abbreviations: CNT, connecting tubule; DCT, distal convoluted tubule; G, glomerulus.

Figure 3

Schematic of proposed mechanism by which luminal plasmin in nephrotic patients activates the epithelial sodium channel (ENaC) in the collecting duct. eNaC comprises 3 subunits, α, β, and γ, each with extracellular loops, as shown. Plasmin, derived from filtered plasminogen in nephrotic patients, cleaves eNaC extracellular loops (γ subunit shown here). Plasmin may also activate prostasin, which can also cleave ENaC. Notches in plasmin and prostasin indicate active enzymatic activity. When cleaved, ENaC is activated, increasing sodium reabsorption. Epithelial cells are shown schematically, separating tubular fluid (lumen) from peritubular capillary.

Figure 4

Stepwise approach to assess and manage diuretic resistance. *Consider reducing the dose or frequency of distal convoluted tubule (DCT) diuretic when control of edema has been achieved. Abbreviations: CCD, cortical collecting duct; NSAIDs, nonsteroidal anti-inflammatory drugs; PT, proximal tubule. Adapted from Brady and Wilcox with permission of Elsevier.