Disease Progression and Variability of ADPKD

The most common monogenic nephropathy is autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with variability in severity of kidney disease among affected relatives and families. Researchers in Ireland, led by Elhussein A. E. Elhassan, MD, conducted an analysis to examine variation in phenotype between families of adult Irish patients affected by ADPKD and assess the impact of kinship on disease progression.

Results were reported during a poster session at the American Society of Nephrology Kidney Week 2022 in a poster titled Effects of Kinship on Disease Progression and Variability in Families With Autosomal Dominant Polycystic Kidney Disease.

The researchers collected data on phenotype (age, sex, kinship with index patient, age at initial presentation, hypertension and urological events, and Predicting Renal Outcomes in Polycystic Kidney Disease score), as well as renal survival (time to end-stage renal disease [ESRD] and decline in estimated glomerular filtration rate [eGFR]). Patients with disease-causing PKD1 and PKD2 variants were included in the analysis. ADPKD was diagnosed using a combination of molecular methods, including targeted next-generation sequencing.

Variability between families was assessed based on the age at onset of ESRD. A frailty model using detailed phenotypic features of patients with available genetic diagnosis was used to account for the impact of kinship on disease progression.

The analysis included data on 103 unrelated families (369 patients). A majority (63.1%, n=65) had a diagnostic variant at PKD1 gene. Average age was 55.2 years, and 55.3% were female. Mean age at initial presentation was 30.2 years. At last follow-up, 71% of the patients (n=262) developed ESRD. The remaining patients had chronic kidney disease, with average creatinine 133.2 mg/dL and average eGFR 51.2 mL/min/1.73 m2. Mean annual eGFR decline was 3.1 mL/min/1.73 m2 per year.

Median variance in age at time of ESRD between families was 7 years. Among families with at least two ESRD patients, 33% (n=34) of families had wide delta difference in age at ESRD (eg, >10 years difference).

In the univariate frailty model, there was a significant association between kinship and time to renal failure (P<.001), taking into account phenotypic and genetic factors that are associated with disease severity. In multivariate analyses, there was no statistical impact of kinship in age at ESRD, with the exception of those with earlier initial presentation (hazard ratio, 0.96; 95% CI, 0.94-0.98; P<.001).

“Wide variability in age of ESRD 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,” the researchers said.

Source: Elhassan EAE, Collins KE, Gilbert EH, Cavalleri G, Benson KA, Conlon PJ. Effects of kinship on disease progression and variability in families with autosomal dominant polycystic kidney disease. TH-PO364. Abstract of a poster presented at the American Society of Nephrology Kidney Week 2022; November 3, 2022; Orlando, Florida.