Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure

Abstract

Diuretic resistance implies a failure to increase fluid and sodium (Na⁺) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na⁺ losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na⁺ reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and aquaretics combined in severely diuretic-resistant patients with heart failure.

Keywords: diuretics; edema; furosemide; heart failure; torsemide.

Figure 1.. Diuretic braking phenomenon and diuretic resistance:

Schematic representation of a diuretic responsive (grey lines and grey boxes) or resistant subject (dark lines and solid boxes), showing body weight (Panel A) and daily sodium excretion (Panel B) during loop diuretic administration.

Figure 2.. The effects of salt intake on the responses of volunteers to furosemide:

Mean (± sem) changes over 6 hours (Panel A) or over 24 hours (Panels B to E) after 40 mg of furosemide over three days during a daily sodium intake of 280 mmol (open boxes) or 20 mmol (closed boxes) depicting changes in fractional excretion of sodium for 6 hours after the first dose of furosemide (Panel A), daily sodium balance (Panel B), changes in daily body weight over three days (Panel C) and the patterns of 6 hourly sodium excretion (Panels D and E).

Figure 3.. Apparent Dose-Response, diuretic plasma or urine levels and natriuretic pattern after a loop diuretic:

The apparent dose-response relationship at time points after a single dose (Panel A), the profile of diuretics with the most efficient levels corresponding to the middle 50% of the rising phase (Panel B) and the natriuretic pattern of brief sodium loss (negative balance) followed by Na⁺ retention (positive balance) (Panel C).

Figure 4.. Hypothesis for activation of renal reflex vasoconstriction by loop diuretics:

Diuretics reduce the reabsorption of sodium chloride in the loop of Henle (LH R_NaCl), distend the distal tubules and increase the renal interstitial pressure (Pi) that activates renal afferent baroreceptor nerves but also increase the pelvic urine sodium chloride concentration that activates renal afferent chemoreceptor nerves. The increased afferent nerve discharge activates a central nervous system (CNS) reno-renal reflex that increases the renal efferent nerve activity and the afferent arteriolar tone that reduces the renal blood flow and glomerular filtration rate.

Figure 5.. Strategies for the use of additional diuretics to counteract loop diuretic resistance in patients with heart failure:

Schematic representation of nephron sites contributing to loop diuretic resistance and the major classes of diuretic drug to correct these. CAIs, carbonic anhydrase inhibitors; CA, carbonic anhydrase; SGLT2i’s, sodium glucose linked transport 2 inhibitors; torsemide ER, torsemide extended release; NKCC2, sodium, potassium, 2 chloride transporter; NCC, sodium, chloride cotransporter; E_NaC, epithelial sodium channel; V2 vasopressin type 2 receptor; MRA’s, mineralocorticosteroid receptor antagonists; R_NaCl, reabsorption of sodium chloride; PT, proximal tubule; LH, Loop of Henle; DT, distal tubule; CD, collecting duct. Also shown is a summary from studies of patients with diuretic resistant heart failure that apportioned the contribution to diuretic resistance between proximal effects that limited diuretic and sodium delivery to the LH and distal effects of increased R_NaCl in the DT and CD. After Rao, V et al, J Am Soc Nephrol 28:3414–3424, 2017, with permission.

Figure 6.. Response of a patient with furosemide-resistant edema from the nephrotic syndrome to treatment with diuretics and potassium chloride.

Figure 7.. Diagrammatic representation of an approach to the management of diuretic resistance in patients with heart failure:

DCT, distal convoluted tubule diuretic; NSAIDs, non-steroidal anti-inflammatory agents; PT, proximal tubule; MRA, mineralocorticosteroid antagonist *, experimental therapy.