Combining genotype with height-adjusted kidney length predicts rapid progression of ADPKD.

Abstract

Our main objective was to identify baseline prognostic factors predictive of rapid disease progression in a large unselected clinical ADPKD cohort. A cross-sectional analysis was performed in 618 consecutive ADPKD patients assessed and followed-up for over a decade. 123 patients (19.9%) had reached kidney failure by the study date. Data was available for the following: baseline eGFR (n= 501), genotype (n=549), baseline ultrasound mean kidney length (MKL, n=424), height adjusted baseline MKL (htMKL, n=377). Rapid disease progression was defined as an annualised eGFR decline (∆eGFR) of >2.5ml/min/year by linear regression over 5 years (n=158). Patients were further divided into slow, rapid and very rapid ∆eGFR classes for analysis. Genotyped patients were classified into several categories: PKD1 (T, truncating or NT, non-truncating), PKD2, other genes (non-PKD1 or PKD2), NMD (no mutation detected) or variants of uncertain significance (VUS). A PKD1-T genotype had the strongest influence on the probability of reduced baseline kidney function by age. A multivariate logistic regression model identified PKD1-T genotype and htMKL (>9.5 cm/m) as independent predictors for rapid disease progression. The combination of both factors increased the positive predictive value (PPV) for rapid disease progression over age 40 years and of reaching kidney failure by age 60 years to 100%. Exploratory analysis in a subgroup with available total kidney volumes (TKV) showed higher PPV (100% v 80%) and NPV (42% v 33%) in predicting rapid disease progression compared to the Mayo Imaging Classification (1C-E). Real-world longitudinal data confirms the importance of genotype and kidney length as independent variables determining ∆eGFR. Individuals with the highest risk of rapid disease progression can be positively selected for treatment based on this combination.