Glycemia affects glomerular filtration rate in people with type 2 diabetes.

BACKGROUND: In type 2 diabetes (T2DM), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimated glomerular filtration rate (eGFR) systematically underestimates the measured adjusted glomerular filtration rate (aGFR) when aGFR is high. We studied the extent to which glycemic variables associate with kidney function, and developed equations including these variables that estimate aGFR in people with T2DM. METHODS: Diabetic Pima people had aGFR measured from iothalamate clearance divided by body surface area. eGFRs < 60 ml/min/1.73m2 were excluded. Multivariate linear regression identified variables correlated with kidney function. We constructed equations for approximating aGFR. Correlation analysis and 10-fold cross-validation were used to compare the CKD-EPI equation and the new approximating equations to the measured aGFR. Ability to detect hyperfiltration, defined as aGFR > 120 ml/min/1.73m2, was compared by analysis of receiver-operating (ROC) curves. RESULTS: aGFR was measured 2798 times in 269 individuals. HbA1c, fasting plasma glucose (FPG), age, and serum creatinine (SCR) were significantly associated with aGFR. The best equations for approximating aGFR used HbA1c and FPG in addition to age and SCR. They approximate aGFR in this cohort of obese people with T2DM more precisely than the CKD-EPI equation. Analysis of ROC curves show that these equations detect hyperfiltration better than does the CKD-EPI equation. CONCLUSIONS: HbA1c, FPG, age, and SCR yielded the best equations for estimating aGFR in these subjects. The new equations identify hyperfiltration better than the CKD-EPI equation in this cohort and may inform clinical decisions regarding hyperfiltration in individuals with T2DM.

Association of CREBRF variants with obesity and diabetes in Pacific Islanders from Guam and Saipan.

AIMS/HYPOTHESIS: Variants in CREBRF (rs12513649 and rs373863828) have been strongly associated with increased BMI and decreased risk of type 2 diabetes in Polynesian populations; the A allele at rs373863828 is common in Polynesians but rare in most other global populations. The aim of the present study was to assess the association of CREBRF variants with obesity and diabetes in Pacific Islander (largely Marianas and Micronesian) populations from Guam and Saipan. METHODS: CREBRF rs12513649 and rs373863828 were genotyped in 2022 participants in a community-based cross-sectional study designed to identify determinants of diabetes and end-stage renal disease (ESRD). Associations were analysed with adjustment for age, sex, ESRD and the first four genetic principal components from a genome-wide association study (to account for population stratification); a genomic control procedure was used to account for residual stratification. RESULTS: The G allele at rs12513649 had an overall frequency of 7.7%, which varied from 2.2% to 20.7% across different Marianas and Micronesian populations; overall frequency of the A allele at rs373863828 was 4.2% (range: 1.1-5.4%). The G allele at rs12513649 was associated with higher BMI (ß = 1.55 kg/m2 per copy; p = 0.0026) as was the A allele at rs373863828 (ß = 1.48 kg/m2, p = 0.033). The same alleles were associated with lower risk of diabetes (OR per copy: 0.63 [p = 0.0063] and 0.49 [p = 0.0022], respectively). Meta-analyses combining the current results with previous results in Polynesians showed a strong association between the A allele at rs373863828 and BMI (ß = 1.38 kg/m2; p = 2.5 × 10-29) and diabetes (OR 0.65, p = 1.5 × 10-13). CONCLUSIONS/INTERPRETATION: These results confirm the associations of CREBRF variants with higher BMI and lower risk of diabetes and, importantly, they suggest that these variants contribute to the risk of obesity and diabetes in Oceanic populations.

Effect of losartan on prevention and progression of early diabetic nephropathy in American Indians with type 2 diabetes.

Angiotensin receptor blockers are renoprotective in hypertensive azotemic patients with type 2 diabetes, but their efficacy in early diabetic kidney disease is uncertain. We performed a 6-year randomized clinical trial in 169 American Indians with type 2 diabetes and normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g; n = 91) or microalbuminuria (ACR 30-299 mg/g; n = 78) at baseline. The primary outcome was decline in glomerular filtration rate (GFR) to ≤60 mL/min or to half the baseline value in subjects who entered with GFR <120 mL/min. Another outcome was differences in glomerular structure at end of treatment. Subjects received 100 mg losartan or placebo daily. GFR was measured annually; 111 subjects underwent kidney biopsies. Only nine subjects reached the GFR outcome, and the unadjusted hazard ratio (losartan vs. placebo) was 0.50 (95% CI, 0.12-1.99). Differences in mesangial fractional volume were not estimated in the combined albuminuria groups because of an interaction with treatment assignment. In separate analyses, mesangial fractional volume was lower in subjects treated with losartan in the microalbuminuria group (18.8 vs. 25.6%; P = 0.02), but not in the normoalbuminuria group (19.6 vs. 17.8%; P = 0.86). Treatment with losartan may preserve some features of kidney structure in American Indians with type 2 diabetes and microalbuminuria.

Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy.

Podocyte detachment and reduced endothelial cell fenestration and relationships between these features and the classic structural changes of diabetic nephropathy have not been described in patients with type 2 diabetes. Here we studied these relationships in 37 Pima Indians with type 2 diabetes of whom 11 had normal albuminuria, 16 had microalbuminuria, and 10 had macroalbuminuria. Biopsies from 10 kidney donors (not American Indians) showed almost undetectable (0.03%) podocyte detachment and 43.5% endothelial cell fenestration. In patients with type 2 diabetes, by comparison, the mean percentage of podocyte detachment was significantly higher in macroalbuminuria (1.48%) than in normal albuminuria (0.41%) or microalbuminuria (0.37%). Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria. The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal albuminuria (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance). Podocyte detachment and diminished endothelial cell fenestration were not correlated, but were related to classic lesions of diabetic nephropathy. Thus, our findings confirm the important role these injuries play in the development and progression of kidney disease in type 2 diabetes, just as they do in type 1 diabetes. Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study.

Modeling GFR trajectories in diabetic nephropathy.

In an 8-year longitudinal study of Pima Indians with type 2 diabetes and nephropathy, we used statistical techniques that are novel and depend on minimal assumptions to compare longitudinal measurements of glomerular filtration rate (GFR). Individuals enrolled with new-onset microalbuminuria either progressed to macroalbuminuria (progressors, n = 13) or did not progress (nonprogressors, n = 13) during follow-up. Subjects with new-onset macroalbuminuria at screening were also followed (n = 22). Patients had their GFR determined serially by urinary iothalamate clearances (average 11 clearances; range 6-19). GFR courses of individuals were modeled using an adaptation of smoothing and regression cubic B-splines. Group comparisons were based on five-component vectors of fitted GFR values using a permutation approach to a Hotelling's T(2) statistic. GFR profiles of initially microalbuminuric progressors differed significantly from those of nonprogressors (P = 0.003). There were no significant baseline differences between progressors and nonprogressors with respect to any measured clinical parameters. The course of GFR in the first 4 yr following progression to macroalbuminuria in initially microalbuminuric subjects did not differ from that in newly screened macroalbuinuric subjects (P = 0.27). Without imposing simplifying models on the data, the statistical techniques used demonstrate that the courses of decline of GFR in definable subgroups of initially microalbuminuric diabetic Pima Indians, although generally progressive, follow distinct trajectories that are related to the extent of glomerular barrier dysfunction, as reflected by the evolution from microalbuminuria to macroalbuminuria.