Thyroid Hormone Indices and Histopathological Severity of Diabetic Nephropathy in Euthyroid Patients with Type 2 Diabetes: A Biopsy-Based Cross-Sectional Study

Purpose: Thyroid hormones (THs) influence glucose homeostasis, vascular tone, and renal hemodynamics. Whether subtle variations in TH indices within the euthyroid range are associated with histopathological severity of diabetic nephropathy (DN) is unclear. We examined the association between TH indices and renal pathological severity in euthyroid patients with type 2 diabetes mellitus (T 2 DM) and biopsy-proven DN. Methods: In this single-center cross-sectional study, 362 euthyroid adults with T 2 DM and biopsy-confirmed DN were included. DN lesions were classified according to the Renal Pathology Society classification as early (class I–II) or advanced (class III–IV). Serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and the FT3/FT4 ratio were measured. Multivariable logistic regression and restricted cubic splines (RCS) were used to evaluate associations with advanced DN. Results: Of 362 patients, 143 had early DN and 219 had advanced DN. Compared with the early DN group, patients with advanced DN had lower FT3 levels (4.46 ± 0.66 vs 4.82 ± 0.73 pmol/L, P < 0.001) and a lower FT3/FT4 ratio (median 0.31 vs 0.33, P = 0.013). In fully adjusted models, lower FT3 levels were independently associated with higher odds of advanced DN (OR = 0.442, 95% CI 0.293– 0.666, P < 0.001). In sensitivity analyses with further adjustment for estimated glomerular filtration rate (eGFR) and diabetic retinopathy, the inverse association between the FT3/FT4 ratio and advanced DN was attenuated and became borderline significant, whereas the association for FT3 remained robust. Moreover, higher FT3 quartiles were associated with progressively lower odds of advanced DN (Q4 vs Q1: OR = 0.160, 95% CI 0.070– 0.365; P for trend < 0.001). RCS and quartile analyses suggested a predominantly linear inverse association between FT3 and the probability of advanced DN, with a similar but weaker pattern observed for the FT3/FT4 ratio. Conclusion: Our findings extend prior studies based on eGFR or albuminuria by providing biopsy-confirmed histopathological evidence linking low-normal THs to the structural severity of DN. These results suggest that subtle reductions in peripheral T3 activity may be associated with underlying renal injury and could have potential value in identifying patients at higher risk. Plain Language Summary: Diabetic nephropathy is a common kidney complication of type 2 diabetes and a major cause of kidney failure. Thyroid hormones, especially triiodothyronine (T3), not only regulate metabolism but also affect blood vessels and kidney cells. Even when routine thyroid tests are “normal”, small differences in thyroid hormone levels may still be related to kidney damage. In this study, we included 362 patients with type 2 diabetes whose kidney biopsies confirmed diabetic nephropathy. All participants had normal thyroid function tests. Based on their kidney biopsy results, we divided patients into early-stage and advanced-stage disease. We measured levels of free T3 (FT3), free T4 (FT4), and thyroid-stimulating hormone (TSH) in the blood. We also calculated the FT3/FT4 ratio, which reflects how efficiently the body converts FT4 into the active hormone FT3. We found that patients with more advanced kidney damage tended to have lower FT3 levels and a lower FT3/FT4 ratio. After we accounted for other risk factors such as age, blood pressure, blood sugar control, kidney function, and the amount of protein in urine, higher FT3 levels and a higher FT3/FT4 ratio were still linked to a lower likelihood of advanced kidney damage. These results suggest that small differences in thyroid hormone levels, even within the normal range, may provide additional information about kidney disease severity in people with type 2 diabetes. Because these tests are already routinely available, they may help doctors better assess kidney health and potentially support decisions about further evaluation, including the need for kidney biopsy. More research is needed to determine whether tracking these hormone levels over time could improve patient care. Keywords: diabetic kidney disease, free triiodothyronine, FT3/FT4 ratio, renal histopathology, euthyroid status