Optimizing diuretic treatment of patients with edema and nephrotic syndrome

In the current issue of Acta Physiologica,¹ Schork et al. address a significant unresolved issue that puzzles researchers and challenges clinical decision-making, namely how to treat best edema associated with nephrotic syndrome (NS). NS is a kidney disorder with primary or secondary injury to the glomerular filtration barrier. NS is characterized by protein loss in urine above 3.5 g/d and generalized edema. Treatment of NS edema constitutes a therapeutic challenge. There is an unmet clinical need to evaluate the efficacy of diuretics and a need for better understanding of the pathogenesis as stated in Kidney Disease/Improving Global Outcome (KDIGO) 2021 guidelines on glomerular disease.² By a gold-standard randomized approach, Schork et al. compared the efficacy of the epithelial sodium channel (ENaC) blocker amiloride with the loop diuretic furosemide in adult patients with edema and NS. The primary endpoint was “overhydration” (OH) determined by non-invasive bioimpedance. Amiloride monotherapy was comparable to furosemide with similar reduction achieved in OH after 8 days. By testing these diuretic treatments, the authors provide further insight into the pathophysiological mechanism of salt retention known to reside in the tubular system.¹

The rationale for investigating amiloride, a theoretically weak diuretic compared to the more potent loop diuretic-class of drugs, is based on human studies demonstrating limited efficacy of volume correction with albumin infusion, renin-angiotensin system blockers and with furosemide. Preclinical studies in mice and rats with induced NS show that ENaC inhibitors mitigate sodium retention³ although hormonal stimulators of ENaC, aldosterone, and angiotensin II, are unchanged or suppressed in plasma. The concept that ENaC may be activated by alternative pathways including proteolytic cleavage through soluble, extracellular, proteases present in tubular fluid in proteinuria has gained support. Not least the group of Schork et al. has contributed significantly to this concept and published in Acta Physiologica that the protease inhibitor aprotinin leads to natriuresis in mice with NS.⁴

Intervention studies in patients with NS edema are limited. In pediatric patients, amiloride was as effective as furosemide and additive.⁵ In adult patients with NS, amiloride (or its analogue triamterene) has been administered as a rational add-on for sequential blockade of Na⁺ transporters along the nephron^{6, 7} or as add-on in single patients with NS and resistant edema with remarkable, but casuistic, effect.⁸

Schork et al. show in adult patients with NS¹ that amiloride significantly reduced OH on Day 8, and both drugs did at Day 16 compared to baseline. The ratio between extra- versus intracellular water decreased significantly with no change in blood volume supported by an increase in plasma renin activity despite similar blood pressures. Surprisingly, body weight and 24 h absolute Na⁺ excretions were not changed from baseline, only fractional sodium excretion increased. In general, both treatments were well tolerated. Plasma potassium increased modestly in the amiloride-treated group and plasma aldosterone increased significantly only in patients treated with amiloride. The study was terminated prematurely with inclusion of a reduced number of participants. This underscores the considerable challenge associated with conducting trials with patients with NS. It may seem straightforward to test two diuretics; however, as the authors openly discuss, there are several complicating factors. Patients presenting with severe edema caused by NS as an isolated clinical problem are rare. Typically, NS manifests as a complication to other primary diseases. Patients are therefore treated with multiple classes of drugs at inclusion, which can significantly confound findings. Moreover, collection of several 24 h urine samples is a major obstacle for compliance and participation.

What insights have we gained despite the low numbers of participants? (1) Randomized clinical trials in patients with nephrotic syndrome edema are challenging yet indispensable, (2) amiloride monotherapy may be employed in NS to manage edema and sodium retention, (3) careful monitoring of plasma potassium is needed when using amiloride especially in patients with low eGFR, and (4) ENaC contributes to sodium retention also in adult patients with NS.

In perspective, when clinicians need to treat patients with resistant edema and extracellular fluid “overfill” in NS, they must consider that the choice of pharmacological treatment is not foremost between amiloride monotherapy and other diuretics. Rather, they should recognize that ENaC represents a pathophysiologically relevant yet often underestimated target for achieving edema control in patients with NS and proteasuria. Considering this, using first-line sequential nephron blockade including amiloride could be the best approach to treat edema in NS.

Research in author's lab is supported by Independent Research Fund-Denmark; by Novo Nordisk Foundation, by Augustinus Foundation.

The author declares no conflicts of interest.