Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure

Abstract

Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean±SD prediuretic FELi was 16.2%±9.5%, similar to that in a control cohort without HF not receiving diuretics (=52; 16.6%±9.2%; =0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%±10.8% (<0.001) but increased FENa by only 4.8%±3.3%. Thus, only 34% (interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodium release did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.

Outcomes Associated With a Strategy of Adjuvant Metolazone or High‐Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis

“…However, compensatory sodium reabsorption that occurs in the distal convoluted tubule, the site of action of thiazide diuretics, is an important cause for diuretic resistance 25. The addition of a thiazide or thiazide‐like diuretic (ie, metolazone) to loop diuretics, often referred to as sequential nephron blockade, inhibits compensatory distal tubular sodium reabsorption, thereby enhancing natriuresis 26.…”

The use of diuretics in heart failure with congestion — a position statement from the Heart Failure Association of the European Society of Cardiology

“…This potassium losing effect is especially pronounced in high aldosterone states, such as heart failure . The rationale for using thiazides in acute heart failure is based on the finding of increased distal nephron sodium avidity in the case of (prolonged) loop diuretic administration . Indeed, animal data indicate that distal nephron hypertrophy occurs following chronic loop diuretic administration, which might explain loop diuretic resistance to an extent .…”

“…99 The rationale for using thiazides in acute heart failure is based on the finding of increased distal nephron sodium avidity in the case of (prolonged) loop diuretic administration. 100 Indeed, animal data indicate that distal nephron hypertrophy occurs following chronic loop diuretic administration, which might explain loop diuretic resistance to an extent. 101 In contrast to conventional teaching, more recent evidence does support the effectiveness of thiazides in patients with a reduced glomerular filtration rate (< 30 mL/min).…”

Clinical Pharmacology in Diuretic Use

“…Although the braking phenomenon is adaptive once ECF volume has been reduced successfully, it is maladaptive, when it occurs in the setting of persistent ECF volume expansion. Many factors resulting primarily from changes in ECF volume, such as stimulation of nerves innervating the kidney and activation of the renin-angiotensin system, likely contribute to braking (59,60), but it is now recognized that adaptive changes in segments other than the thick ascending limb also play an important role (61,62). Remodeling of the distal nephron occurs (63), leading to hypertrophy and hyperplasia, especially of distal segments.…”