Effect of Melatonin on 24‐Hour Urinary Protein Excretion and Sleep Quality in Patients With Stage 3–4 Chronic Kidney Disease: A Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial

ABSTRACT Background and Aims Proteinuria is an established marker of renal injury and is closely associated with adverse outcomes in chronic kidney disease (CKD). Melatonin has attracted interest as a potential renoprotective agent because of its antioxidant, anti‐inflammatory, and regulatory effects on several pathways implicated in kidney injury. However, clinical data regarding its effects on proteinuria in patients with non‐dialysis CKD are limited. This trial investigated whether melatonin supplementation alters 24‐h urinary protein excretion in adults with stage 3–4 CKD. Methods We conducted a 12‐week, randomized, double‐blind, placebo‐controlled clinical trial in adults with stage 3–4 CKD and persistent proteinuria. Seventy‐three participants were allocated in a 1:1 ratio to receive either oral melatonin (3 mg at bedtime) or a matching placebo. The prespecified primary endpoint was the change in 24‐h urinary protein excretion between baseline and week 12. Secondary assessments included renal function, blood pressure, sleep quality, metabolic and laboratory parameters, and treatment safety. Results A reduction in 24‐h urinary protein excretion was observed in both treatment groups. The mean reduction was 52.45 ± 128.19 mg/day with melatonin and 28.69 ± 82.59 mg/day with placebo, yielding a between‐group difference of −23.76 mg/day (95% CI, −74.08 to 26.56; p = 0.92). Serum creatinine and estimated glomerular filtration rate remained largely stable during follow‐up. Compared with placebo, melatonin was associated with a significant reduction in total cholesterol. Sleep quality also showed a statistically significant difference in the change in PSQI score between groups, with mean changes of −0.18 ± 0.84 and −0.69 ± 1.06 in the melatonin and placebo groups, respectively ( p = 0.047). No treatment‐related serious adverse events were observed. Conclusion In adults with stage 3–4 CKD, 12 weeks of melatonin supplementation at 3 mg nightly did not demonstrate a clinically meaningful reduction in 24‐h urinary protein excretion compared with placebo. Although the point estimate favored melatonin, the confidence interval was compatible with both a modest benefit and no treatment effect. Melatonin was generally well tolerated and was associated with modest changes in selected metabolic and sleep‐related outcomes. Larger, multicenter trials with longer follow‐up and adequate statistical power are needed to determine whether melatonin has clinically relevant renal effects in specific CKD populations. Trial Registration: This clinical trial was registered in the Iranian Registry of Clinical Trials (IRCT No. IRCT20160412027346N12)