Combination therapy with furosemide and metolazone as compared to furosemide alone for treatment of edema in children with nephrotic syndrome: a randomized controlled trial.

Nephrotic syndrome (NS) in children often presents with debilitating edema and optimal use of diuretics in presence of hypoalbuminemia is uncertain. Early initiation of a combination diuretic therapy can be efficacious in greater. The primary objective was to compare cumulative urine output over 48 h between children receiving furosemide plus metolazone and those receiving furosemide alone. Children aged 1-14 years with NS presenting with moderate to severe edema were enrolled and randomized into two groups, furosemide plus metolazone and furosemide-alone group. The urine volumes and weight were monitored twice daily for 48 h. Serum urea, creatinine, electrolytes, hematocrit, and hospital stay were recorded as secondary outcomes. Fifty children were randomized (25 per group) with comparable baseline characteristics and urine output. Mean urine output over 48 h was 3.13 (± 1.5) ml/kg/h in furosemide plus metolazone group and 2.96 (± 1.32) ml/kg/h in furosemide alone which did not significantly differ between the groups (p > 0.05). The change in urine output from baseline was significantly higher in combination group (2.15 ± 1.31 vs 1.44 ± 1.28 ml/kg/h; p = 0.03) in the unadjusted comparison, but it was not statistically significant after adjustment for baseline urine output by ANCOVA. Dyselectrolytemia, percentage of weight loss, and hospital stay were similar in both groups. Sixteen percent of children in the combination group had significant weight loss requiring discontinuation of therapy.

conclusionThere was no difference in urine output or weight loss with combination therapy. Given the neutral primary outcome and the need to discontinue therapy in a subset of patients, upfront combination therapy is not recommended based on these findings. However, it should be considered hypothesis-generating for further studies in selected group of children.

trial registrationCTRI/2023/05/052552 dated 12th May 2023. WHAT IS KNOWN: • Combination diuretic therapy has been used in children with refractory edema due to nephrotic syndrome. • Similar combination approaches are employed in other edematous conditions, often resulting in improved diuresis. WHAT IS NEW: • In this randomized controlled trial, combination therapy did not significantly improve urine output compared to controls. There was significantly greater increase in urine output from baseline in the unadjusted comparison. However, when adjusted for baseline urine output, it was no longer statistically significant. • The regimen was not free of adverse events even though no hemodynamically safety issues were observed under strict monitoring; however, findings do not support routine upfront use in unselected children with nephrotic syndrome.