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Context Hypothyroidism is associated with reversible decline in kidney function as measured by estimated glomerular filtration rate (eGFR). eGFR and proteinuria are the most important markers for clinical assessment of kidney function. Though hypothyroidism is associated with proteinuria in cross-sectional data, the impact of treatment on proteinuria is unknown. Objective This study explores the effect of thyroid hormone replacement therapy on eGFR and 24-hour urine protein excretion in patients with severe primary hypothyroidism. Design and Participants This study was a prospective, observational cohort study in adults with severe primary hypothyroidism (serum thyrotropin [TSH] > 50 µIU/mL). Individuals with preexisting or past kidney disease, kidney or urinary tract abnormalities, calculi or surgery, diabetes mellitus, or hypertension were excluded. The participants received thyroid hormone replacement therapy. Thyroid functions, eGFR, 24-hour urine protein excretion, and biochemical parameters were measured at baseline and 3 months. Setting This study took place at a single center, a tertiary care referral and teaching hospital. Results Of 44 enrolled participants, 43 completed 3 months of follow-up. At 3 months, serum TSH levels decreased and thyroxine levels increased (P Conclusions Thyroid hormone replacement therapy in patients with severe primary hypothyroidism improves eGFR and decreases 24-hour urine protein excretion, thereby suggesting reversible alterations.