Kidney Outcomes in Patients with ADPKD with or Without a Family History

Background: ~20% of ADPKD families are linked to a likely de novo mutation but it is unclear if the phenotype in these individuals differs from those with a positive family history. Here we analyzed groups with a positive and negative family history to provide insight into genetic mechanisms and expected outcomes. Methods: A retrospective review of family history in ADPKD patients that were positive for PKD1 and PKD2 pathogenic variants or were unresolved following genetic testing. Used a keyword search with an AI search engine of electronic health record and pedigree analysis to determine family history status. After manually reviewing we included in the negative family history cohort if: both parents had negative genetic testing, both parents had negative abdominal imaging, or a reported negative family history was supported by clinical observations. We determined kidney function and height adjusted total kidney volumes (htTKVs), where possible. A control, positive family history group was matched by sex and approximately by age. Results: The negative family history of ADPKD group (n=62) included 32/1291 PKD1 patients, 7/303 PKD2, and 23/389 unresolved genetically. A control group of 62 patients with a positive family history was selected for comparison. htTKV was significantly lower in the negative family history group, (median 594 mL/m) compared to positive group (891mL/m) (0.0212, Mann-Whitney test; Figure). Kaplan Meier kidney failure analysis did not show a significant difference, but the median age at kidney failure was higher in the negative (72 years) compared to the positive family history group (69 years). Conclusion: ADPKD patients with a negative family history had significantly lower htTKV, suggesting a milder phenotype. This could be partly explained by mosaicism in this group. Initial analysis of kidney failure has not shown a difference associated with family history status, but studies are ongoing. Other parameters, such as cyst count may allow other differences between these groups to be detected. Funding: NIDDK Support