Autosomal Dominant Polycystic Kidney Disease Progression by Variant Type and Molecular Domain Among HALT-PKD Participants

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage kidney disease. Disease severity depends on the causative gene ( PKD1 versus PKD2 ) and whether its pathogenic variant is truncating or non-truncating. 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), estimated glomerular filtration rate (eGFR), and Mayo Imaging Class (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 non-truncating 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 non-truncating status and the protein domain location of PKD1 variants. Results: PKD1 truncating variants demonstrated similar disease progression to PKD1 non-truncating variants overall, and disease severity did not differ by domain location for truncating variants. However, patients with PKD1 non-truncating variants in the REJ (8.6% per year; 95% CI [6.9–10.2]) and PLAT (8.5% per year [5.9–11.2]) domains demonstrated significantly greater htTKV growth compared to PKD1 non-truncating variants in the C-type lectin (3.6% per year [1.1–6.1]) and PKD repeat (4.4% per year [2.3–6.5]) 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/year; p=0.09). Conclusion: Our findings demonstrate that the domain locations of non-truncating variants in PKD1 should be explored as potential prognostic markers of early-stage ADPKD progression.