Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes

Abstract

Objective: Type 2 diabetes (T2D) is a leading cause of end-stage kidney disease worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease in youth-onset compared with adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth onset was associated with greater early tissue injury.

Research design and methods: Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing, and participants were stratified as youth onset (age <25 years) or adult onset (age ≥25 years). Associations between clinical and morphometric parameters and age at onset were tested using linear models.

Results: At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1 ± 9.9 vs. 51.4 ± 10.2 years; P < 0.0001), but their diabetes duration was similar (19.3 ± 8.1 vs. 17.0 ± 7.8 years; P = 0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th-75th percentile 17-470] vs. 27 [13-73] mg/g; P = 0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552 ± 128 vs. 490 ± 114 nm; P = 0.002) and mesangial fractional volume (0.31 ± 0.10 vs. 0.27 ± 0.08; P = 0.001) than adult-onset participants. Glomerular sclerosis percentage, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age at diabetes onset as a continuous variable.

Conclusions: Younger age at T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.

Figure 1

Distribution of age at onset of diabetes.

Figure 2

Association of kidney structure with age at onset of diabetes. A: GBM width. B: Mesangial fractional volume. C: Glomerular filtration surface density. D: Podocyte number density per glomerulus. E: Glomerular sclerosis percentage. F: Mean glomerular volume. Left column shows association of structural measure in youth-onset and adult-onset T2D with P values from generalized linear models adjusted for age, sex, HbA_1c, BMI, and GFR. Right column shows correlation of residuals for each structural measure and age at onset of diabetes adjusted for age, sex, HbA_1c, BMI, and GFR. In panel E, models are based on cube root values because of positive skew of measure and are adjusted for embedding media in addition to other covariates.

Figure 2

Association of kidney structure with age at onset of diabetes. A: GBM width. B: Mesangial fractional volume. C: Glomerular filtration surface density. D: Podocyte number density per glomerulus. E: Glomerular sclerosis percentage. F: Mean glomerular volume. Left column shows association of structural measure in youth-onset and adult-onset T2D with P values from generalized linear models adjusted for age, sex, HbA_1c, BMI, and GFR. Right column shows correlation of residuals for each structural measure and age at onset of diabetes adjusted for age, sex, HbA_1c, BMI, and GFR. In panel E, models are based on cube root values because of positive skew of measure and are adjusted for embedding media in addition to other covariates.