Why Diuretics Fail Failing Hearts

Loop diuretics represent a key component of the therapeutic armamentarium used to reduce extracellular fluid volume in heart failure. Unfortunately, resistance to loop diuretics commonly occurs, complicating clinical management. In general, diuretic resistance refers to the inability to reduce extracellular fluid volume, despite maximal therapeutic doses of diuretics. There are several proposed mechanisms through which diuretic resistance in heart failure occurs.1 First, activation of the sympathetic nervous system and release of volume regulatory hormones increase the reabsorption of filtered Na+ in the proximal tubule, resulting in reduced Na+ delivery to more distal segments.2,3 Second, enhanced Na+ reabsorption may occur at sites distal to the thick ascending limb of the loop of Henle, dampening potential urinary Na+ losses that occur with administration of a loop diuretic. This may reflect activation of distal convoluted tubule (DCT) Na+/Cl− cotransporters by diuretic-induced hypokalemia as well as hypertrophy of cells in the DCT.4,5 Recent studies suggest that low serum K+ levels, which can occur with administration of a loop diuretic, lead to activation of kinases that eventually result in phosphorylation and activation of the Na+/Cl− cotransporter in the DCT.6 Furthermore, distal nephron Na+ transporters, including the Na+/Cl− cotransporter, the epithelial Na+ channel, the Na+-dependent Cl−/HCO3− exchanger, and pendrin, a Na+-independent Cl−/HCO3− exchanger, are activated by volume regulatory hormones (angiotensin II and/or aldosterone) in the context of reduced effective arterial volume.7–11 Third, reduced glomerular filtration diminishes the filtered load of Na+.12 Fourth, impaired gastrointestinal absorption or reduced proximal tubular secretion of a loop diuretic can result in reduced delivery of the diuretic to the tubular lumen.12,13 Understanding key mechanisms of diuretic resistance in the human heart failure population is important in determining approaches to overcome resistance. The work published in this issue of the Journal of the American Society of Nephrology by Rao et al.14 addresses mechanisms of diuretic resistance in an outpatient heart failure population managed at the Yale Transitional Care Center. In these subjects, diuretic-induced changes in fractional excretion of endogenous Li+ (FELi) and fractional excretion of endogenous Na+ (FENa) were compared with those in controls who did not have heart failure and were not receiving diuretics. Because filtered Li+ is primarily reabsorbed in the more proximal aspects of the nephron (proximal tubule and loop of Henle), a loop diuretic should substantially increase both FELi and FENa by blocking absorption of Li+ and Na+ in the loop of Henle. Measurements of FELi and FENa in response to a loop diuretic provide a tool to assess whether diuretic resistance in this population reflects increased proximal tubular Na+ reabsorption, with reduced delivery to more distal segments. In this situation, both FELi and FENa would exhibit only modest increases, at best, in response to a loop diuretic. In contrast, a selective increase in FELi suggests that diuretic resistance reflects enhanced Na+ absorption in more distal nephron segments. The authors observed heterogeneity in individual responses to a loop diuretic in their study population. The majority of individuals with diuretic resistance exhibited findings consistent with increased Na+ absorption in nephron segments distal to the thick ascending limb of the loop of Henle, suggesting that these subjects might benefit from adding a thiazide or K+-sparing diuretic targeting distal segments.14 A minority of individuals had findings consistent with enhanced proximal tubular reabsorption of Na+ with reduced distal delivery. These individuals are likely to be more challenging to manage and might benefit from carbonic anhydrase or sodium-glucose cotransporter inhibitors to reduce proximal tubule Na+ absorption. These medications are often underused in patients with heart failure, and the sodium-glucose cotransporter-2 inhibitors have recently been shown to reduce that rate of heart failure admissions by 35%.15 Finally, a small percentage of individuals had low urinary levels of the loop diuretic, a setting where increasing the dose of diuretic could prove beneficial. The study suggests that concentrations of a loop diuretic in individuals receiving an equivalent of at least 40 mg furosemide are likely to reach therapeutic levels in the loop of Henle in the absence of acute kidney injury or CKD.14 This study’s findings suggest that enhanced distal Na+ reabsorption is an important factor contributing to diuretic-resistant heart failure in the majority of the study subjects. Given these findings, adding a thiazide diuretic to block the Na+/Cl− cotransporter in the setting of loop diuretic–resistant heart failure makes sense, as does maintaining serum K+ in the mid- to high-normal range. In the setting of diuretic-resistant heart failure that does not respond to a combination of loop and thiazide diuretics, increasing the dose of the loop diuretic and/or adding drugs that inhibit proximal tubule Na+ absorption may be beneficial. Disclosures None.