Uncertainty-aware prediction of 48-month eGFR decline in type 2 diabetes mellitus: a secondary analysis of ACCORD

Long-horizon kidney trajectory prediction in type 2 diabetes mellitus (T2DM) is usually reported as a point estimate or event risk, although clinical decision-making also depends on whether an individual prediction is reliable. We developed an uncertainty-aware model for 48-month estimated glomerular filtration rate (eGFR) decline and tested whether conformal interval width provides a clinically structured, patient-level signal of prediction reliability.

We performed a secondary prognostic modeling analysis of Action to Control Cardiovascular Risk in Diabetes (ACCORD) participants with baseline and 48-month eGFR (n= 6,853). The outcome was annualized eGFR change, calculated as 48-month minus baseline eGFR divided by four years. The primary baseline feature set excluded serum creatinine since eGFR is creatinine-derived, and also excluded urine biomarkers. Random forest, gradient boosting, penalized linear models, and XGBoost were compared using fixed training, calibration, and test partitions. Split and locally adaptive conformal intervals were evaluated by empirical coverage and interval width. Interval-width analyses were repeated after conditioning on baseline eGFR.

The best primary model was random forest (R ² =0.382, MAE=3.271 mL/min/1.73m ² ). Split 90% conformal intervals achieved empirical coverage of 0.917. Locally adaptive 90% intervals achieved empirical coverage of 0.909 with mean width 13.759 mL/min/1.73m ² . In unadjusted analyses, wider intervals were associated with larger errors and more rapid decline. After interval-width quintiles were assigned within baseline-eGFR strata, wider intervals remained associated with realized prediction error (annual adjusted increase, 0.151 mL/min/1.73m ² per quintile). Beyond baseline eGFR, wider intervals were associated with younger age, female sex, higher HbA1c, higher triglycerides, and higher systolic blood pressure.

Baseline clinical variables predicted 48-month eGFR decline with good long-horizon performance in ACCORD, even after excluding serum creatinine and urine biomarkers from the primary model. Conformal prediction provided calibrated patient-specific intervals, and interval width behaved as an informative reliability phenotype rather than a random modeling artifact. These findings support a novel uncertainty-aware framing of kidney trajectory prediction in which rapid and uncertain decline can be identified from baseline clinical data.