Linking To And Excerpting From “Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure”

Today, I link to and excerpt from Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Hypertension. 2020 Oct; 76(4): 1045–1054. Published online 2020 Aug 24. doi: 10.1161/HYPERTENSIONAHA.120.15205

All that follows is from the above resource.

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.
We review the pathophysiology of diuretic resistance and its implications for improving the management of patients with chronic heart failure (CHF). Diuretic resistance is a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema or congestion despite a full dose of a loop diuretic. More quantitative definitions include a failure of oral furosemide (160 mg twice daily or equivalent) to increase Na+ excretion by at least 90 mmol over 3 days.1 Alternatively, a spot urine sample obtained 1 to 2 hours after a loop diuretic can be used to predicts Na+ output. A Na+ output <50 mmol is generally insufficient to induce a negative Na+ balance with loop diuretics and therefore predicts diuretic resistance. This was validated prospectively in 50 patients2:
Na+ output (mmol)=estimated glomerular filtration rate (eGFR) (body surface area/1.73) (SCr/UCr)×60 min×3.25h×(UNa/1000 mL) where Cr is urine or serum creatinine and UNa is urine sodium concentration.2
A poor diuretic response predicts subsequent death, readmission, or renal complications from CHF.3 Recognition of diuretic resistance is hampered by imprecise metrics. Intravenous diuretics for patients hospitalized with decompensated HF can reduce body weight by 11 kg yet signs of hypervolemia and congestion persist in >50% and blood volume, that predicts mortality,4 remains ≈30% expanded.5 Thus, interstitial fluid, including peripheral and pulmonary edema, is depleted selectively but blood volume is well defended. Indeed, >85% of fluid removed by diuretics is from extravascular sites that include peripheral and pulmonary edema. Steady-state measurements of daily Na+ excretion can indicate daily Na+ intake but cannot diagnose diuretic resistance (Figure 1). Presently, a practical and quantitative definition of diuretic resistance remains elusive.

Loop Diuretics and Dosage

Furosemide diuresis normally lasts about 4 hours. Bumetanide is somewhat shorter and torsemide somewhat longer. An approximate dose conversion ratio is 1:20:40:50 for bumetanide: torsemide: furosemide: ethacrynic acid. The normal ceiling daily dose of furosemide above which little further natriuresis occurs is 80 mg once or twice daily, increasing to 160 and 240 mg in patients with chronic kidney disease (CKD) stages 3 and 4 or nephrotic syndrome or 80 to 160 mg in patients with cirrhosis or HF with preserved GFR. Very high doses of circa 500 mg of furosemide may be required in patients with end-stage renal disease.6 The higher furosemide doses required for patients with CKD are a consequence of many factors including a decreased diuretic delivery to the kidney because of decreased renal blood flow (RBF), an increased volume of distribution of the protein-bound diuretic because of hypoalbuminemia, a decreased proximal tubule (PT) secretion of the diuretic by the organic anion transporters because of competition by urate and other organic anions that are retained in the plasma in patients with CKD, and a decreased filtered load of Na+ because of a decreased GFR.7 However, the response to the diuretic delivered to the loop of Henle (LH) is well maintained in CKD. In practice, the dose of loop diuretics should generally be increased in proportion to the reduction in eGFR. Patients with CHF may have an impaired absorption of loop diuretics and an impaired tubular response mandating higher doses often given twice daily.8
Special problems with furosemide include a low and variable bioavailability of 10 −80% that is impaired further in the elderly and those with HF or CKD.9 In theory, this should be addressed by intravenous dosing or by substituting torsemide or bumetanide that have higher and more consistent bioavailabilities.10 However, intravenous infusions are not strikingly superior to oral or bolus intravenous dosing (see later below) and variations in the gene expressions for the organic anion transporters and other genes adds to torsemide variability.11,12

Individual Diuretic Responsiveness

The natriuretic response depends on salt intake,13 diuretic dose, renal function, and right atrial pressure.14 Whereas a low eGFR in patients with HF predicts a poor outcome, a worsening eGFR during hospitalization for acute HF in the Diuretic Optimization Strategies in Acute Heart Failure (DOSE) study paradoxically predicted a better outcome.15 This may reflect a successful hemodynamic response to renin-angiotensin-aldosterone system (RAAS) blockade that itself reduces the GFR but is beneficial for long term renal function.2

Perspectives

Resistance to diuretics is a frequent, but a sometimes preventable or reversible, cause of hospitalization for congestion, and worsening symptoms. Unfortunately, clinical signs and symptoms are often unreliable to detect diuretic resistance. The development of new diuretics, strategies, or combinations is important to overcome diuretic resistance. Many factors can contribute to diuretic resistance that provide rationales for the use of specific interventions. As recently presented,6 these strategies are shown in Figure 7. However, they have not been rigorously tested in clinical trials. Therefore, this should be used as a guide for consideration of appropriate treatment rather than a rigorous algorithm.
This entry was posted in Diuretic Resistance, Diuretics, Heart Failure. Bookmark the permalink.