ADPKD Progression by Variant Type and Molecular Domain Among Participants in the HALT PKD Trial

Key Points Patients with autosomal dominant polycystic kidney disease (ADPKD) experience substantial variation in disease progression. The location of pathogenic nontruncating variants in PKD1 significantly predicts disease progression in patients with early-stage ADPKD. Pathogenic variant location in PKD1 merits further exploration in determining prognosis in patients with ADPKD. Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of ESKD. Disease severity depends on the causative gene ( PKD1 versus PKD2 ) and whether its pathogenic variant is truncating or nontruncating. However, the association between ADPKD severity and the location of pathogenic variants is controversial. An emerging understanding of the functional domains of the PKD genes may enable further investigation of the impact of variant location on disease severity. Methods We studied longitudinal height-adjusted total kidney volume (htTKV), eGFR, and Mayo Imaging Classification (MIC) distributions among a cohort of 332 patients with early-stage ADPKD in the HALT A clinical trial dataset to examine the impact of PKD1 variant location on disease progression. HALT A provided Sanger sequencing confirmation for each patient's pathogenic variant. Truncating ( n =222) and nontruncating genetic variants ( n =110) were assigned by location to key polycystin-1 functional domains. We compared patients' longitudinal htTKV and eGFR trajectories and MIC distributions for truncating versus nontruncating status and the protein domain location of PKD1 variants. Results PKD1 truncating variants demonstrated similar disease progression to PKD1 nontruncating variants overall, and disease severity did not differ by domain location for truncating variants. However, patients with PKD1 nontruncating variants in the receptor egg jelly (8.6% per year; 95% confidence interval [6.9 to 10.2]) and polycystin-1, lipoxygenase, α -toxin domain (8.5% per year [5.9 to 11.2]) domains demonstrated significantly greater htTKV growth compared with PKD1 nontruncating variants in the C-type lectin (3.6% per year [1.1 to 6.1]) and polycystic kidney disease repeat (4.4% per year [2.3 to 6.5]) domains ( P < 0.001). Variants in these fast- and slow-progressing regions also showed clinically significant differences in MIC distribution ( P = 0.008) and eGFR rate of change (−3.51 versus −2.24 ml/min per year; P = 0.09). Conclusions Our findings demonstrate that the domain locations of nontruncating variants in PKD1 should be explored as potential prognostic markers of early-stage ADPKD progression. Clinical Trial registry name and registration number: NCT00283686.