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Abstract: TH-PO364

Effects of Kinship on Disease Progression and Variability in Families With Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Elhassan, Elhussein Aamir Elzein, Beaumont Hospital, Dublin, Ireland
  • Collins, Kane Edmund, Royal College of Surgeons in Ireland, Dublin, Ireland
  • Gilbert, Edmund H., Royal College of Surgeons in Ireland, Dublin, Ireland
  • Cavalleri, Gianpiero, Royal College of Surgeons in Ireland, Dublin, Ireland
  • Benson, Katherine A., Royal College of Surgeons in Ireland, Dublin, Ireland
  • Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy in humans that recognised with striking variability in kidney disease severity among affected relatives and families. Here, we evaluate variation in phenotype between families of adult Irish patients affected by ADPKD and the impact of kinship on disease progression.

Methods

Phenotypic details (age, sex, kinship with index patient, age at initial presentation, hypertension and urological events, and PROPKD score) and renal survival (time to end-stage kidney disease (ESKD) and eGFR decline) were collected. A combination of molecular methods, including targeted NGS, were used for diagnosis of ADPKD, patients with disease-causing PKD1 and PKD2 variants were included for analysis. We assessed variability between families based on the age of onset of ESKD. To account for the impact of kinship on disease progression, we used a frailty model using detailed phenotypic features of patients with available genetic diagnosis.

Results

In total, we studied 103 unrelated families (369 patients), a majority (65/103;63.1%) of whom had a diagnostic variant at PKD1 gene, with average age of 55.2±14.5 years; 55.3% females. Mean age at initial presentation was 30.2±13.8 years. At last follow up, 262 (71%) patients developed ESKD at 49.3±11 years. The remaining individuals had CKD with average creatinine and eGFR 133.2±114.7 and 51.2±25, respectively, and median annual eGFR decline 3.1 (IQR 1.3 – 5.25) ml/yr. Median variance in age at ESKD between families was 7 years, and among families with at least two ESKD patients, 34 (33%) families had wide delta difference in age of ESKD (i.e. >10 years difference).

In the univariate frailty model, kinship has significantly associated with time to renal failure (P= <0.001) taking into account each phenotypic and genetic factors of interest which are associated with disease severity. However, using a multivariate frailty model, we observed no statistical impact of kinship in age at ESKD among ADPKD families, except those with earlier initial presentation (HR: 0.96; 95% CI 0.94 – 0.98; P= <0.001).

Conclusion

Wide variability in age of ESKD among families with ADPKD is present in at least 33% of families and the impact of family effects was evident on factors related with disease progression.