Role of Levothyroxine on the progression of Chronic Kidney Disease in subclinical hypothyroid populations - A multicenter randomized controlled trial

Chronic kidney disease (CKD) is a progressive condition marked by gradual loss of kidney function, affecting 3–18% of the global population. Subclinical hypothyroidism (SCH), defined by elevated TSH with normal free T4, is common in CKD and may accelerate disease progression. Hypothyroidism prevalence rises with CKD severity, with SCH affecting up to 18% of non-dialysis patients. The thyroid–kidney interaction is bidirectional—thyroid hormones influence renal function, while kidneys regulate their metabolism. Elevated TSH in SCH is linked to reduced GFR, proteinuria, and increased cardiovascular risk. Although levothyroxine (LT4) is standard therapy for hypothyroidism, its role in SCH with CKD remains uncertain, with conflicting evidence on renal and cardiovascular benefits. This multicenter randomized controlled trial aims to evaluate whether LT4 therapy can slow CKD progression, reduce proteinuria, and improve cardiovascular outcomes and quality of life in patients with CKD and SCH.

This multicenter, double-blind, randomized, placebo-controlled trial was conducted at five Indian centers. Adults aged 18–65 years with CKD stages 2–4 (eGFR 15–59 ml/min/1.73 m²) and subclinical hypothyroidism (TSH 4–10 µIU/mL, normal fT4) were enrolled. Patients with unstable renal function, acute illness, cardiovascular, hepatic, or neurological disease, malignancy, pregnancy, or thyroid therapy were excluded. Participants were randomized 1:1 to receive levothyroxine (25 µg/day, titrated to normalize TSH) or placebo. Standard CKD care was continued. The primary endpoint was ≥50% eGFR decline, ESKD, or all-cause mortality; secondary endpoints included cardiovascular events and arrhythmias. Adverse effects were monitored. Follow-up included history, labs, and compliance checks. Patients developing overt hypothyroidism (TSH > 10 mIU/L) were withdrawn. Target enrollment: 500 (250/group) to achieve 90% power and 99% CI

Of 1,224 screened CKD stage 2–4 patients, 503 were randomized: 253 to levothyroxine and 250 to placebo. Baseline characteristics were comparable (mean age 48.5 ± 11.9 years; 57.1% male; median eGFR 34 ml/min/1.73 m²; mean TSH 8.22 ± 1.45 µIU/mL). CKD etiologies included diabetic kidney disease (31.3%) and chronic glomerulonephritis (29%). During follow-up, 39 participants (10.5%) met the composite endpoint (≥50% eGFR decline, ESKD, or death): 9.2% in the levothyroxine group vs 11.7% in placebo (p = 0.45). ESKD occurred in 4 vs 9, deaths in 7 vs 6, and ≥50% eGFR decline in 6 vs 7 patients, respectively. Mean eGFR improved in both groups over 12 months (48 vs 44 ml/min/1.73 m², p 0.05). Adverse events were mild; headache (4.9%) and palpitations (2.7%) were more frequent with levothyroxine. No deaths were attributed to study medication.

This multicenter RCT found that the composite primary outcome (≥50% eGFR decline, ESKD, or death) was not significantly different between levothyroxine and placebo groups (9.2% vs. 11.7%). However, the levothyroxine group showed a modest eGFR improvement (+4 ml/min/1.73 m² at 12 months). While the composite endpoint was not met, the rise in eGFR suggests a possible renoprotective trend, warranting longer-term studies to confirm potential benefit.