Iohexol clearance, but not estimated GFR, reveals a steeper GFR decline in patients with prediabetes

Prediabetes, an intermediate state between normoglycemia and type 2 diabetes affecting 720 million individuals worldwide, is associated with hyperfiltration, an early stage of diabetic kidney disease. It remains unclear whether prediabetes is an independent risk factor for glomerular filtration rate (GFR) decline, potentially due to previously inaccurate GFR estimates.

In a prospective study of middle-aged Europeans without diabetes, cardiovascular disease, or kidney disease, we measured the GFR (mGFR) using iohexol clearance at baseline (1594 individuals), after a median of 5.2-6.0 years (1299 individuals), and 11.0 years (1151 individuals). A linear mixed model was used to estimate the mGFR slope. Accelerated mGFR decline was defined as the participants with the 10% steepest mGFR decline. We also estimated GFR (eGFR) from creatinine (eGFR_crea) and cystatin C (eGFR_cys). Prediabetes was defined as fasting glucose of 6.1-6.9 mmol/l (prediabetes World Health Organization (_WHO)) or 5.6-6.9 mmol/l and/or HbA1c 5.7-6.4% (39-47 mmol/mol) (prediabetes American Diabetes Association (_ADA)).

In adjusted linear mixed models, those with prediabetes_WHO and those with prediabetes_ADA had steeper mean mGFR decline rates of 0.30 (95% confidence interval: 0.04 to 0.57) and 0.14 (0.00 to 0.28) mL/min per year, respectively. The odds ratios of accelerated GFR decline were 2.6 (2.0-5.1) for prediabetes_WHO and 2.0 (1.3-3.0) for prediabetes_ADA. Significantly, prediabetes was not associated with eGFR_crea or eGFR_cys decline.

In a representative sample of Caucasians without diabetes, prediabetes was associated with an accelerated mGFR decline but not with eGFR decline. Prediabetes represents a window of opportunity to prevent hyperfiltration and early mGFR loss before diabetic kidney disease.