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Kidney Week

Abstract: TH-PO663

PKD1 Truncating Mutations with Mild Kidney Disease Is Underrecognized

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Guiard, Elsa, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Lanktree, Matthew B., University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Iliuta, Ioan-Andrei, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Shi, Beili, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Pourafkari, Marina, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Song, Xuewen, University of Toronto, Toronto, Ontario, Canada
  • Khalili, Korosh, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Pei, York P., University Health Network and University of Toronto, Toronto, Ontario, Canada
Background

Renal disease is highly variable in autosomal dominant polycystic kidney disease (ADPKD). Multiple studies have shown that PKD1 protein truncating (PT) mutations are associated with the most severe disease with larger TKV and earlier onset of renal failure among all mutation classes. In the Extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP), we sought to determine whether PKD1 PT mutations were uniformly associated with severe kidney disease.

Methods

The study cohort comprised 1279 patients from 555 families recruited in Toronto between 2006 and 2017. All recruited families were comprehensively screened for PKD1 and PKD2 mutations; Mayo Clinic Imaging Classification (MCIC) was performed in 430 patients with TKV by MRI. Kidney function and MCIC were used to assess disease severity.

Results

We studied 430 patients with TKV and mutation results for their renal disease severity. Among 146 patients with PKD1 PT mutations and TKV, 31 (21%) from 28 families were found to have mild renal disease (MCIC 1A or 1B; most with normal eGFR) which is comparaible to patients with PKD2 mutations (Table 1). Three families displayed concordance with mild renal disease among affected family members; 13 families displayed discordance with both mild and severe disease among affected family members. Their PKD1 PT mutations were distributed across all exons and included 16 frameshift, 10 nonsense, and 2 canonical splice site mutations. No patients had atypical kidney imaging patterns.

Conclusion

We found mild kidney disease comparable to that associated with PKD2 mutations in 21% of patients with PKD1 PT mutations. The presence of a positive familiy history of ADPKD in many of these patients makes somatic mosaicism an unlikely explanation. Rather, our data suggest a favorable modifier effect due to as yet unidentified genetic and/or environmental factors. Future research to identify factors underpinning this modifier effect can provide insight into disease mechanism and improve patient care.

 PKD1 PT
Mayo 1A-1B
n=31
PKD1 PT
Mayo 1C-1D-1E
n=115
PKD2

n=107
Age at MRI (years)
mean (SD)
35.7 (11.6)37.1 (10.7)44 (12.3)*
Gender (M/F)11/2050/6543/64
ht-TKV (ml/m)
median [IQR]
342 [270-383]902 [662-1319]*707 [335-1133]*
eGFR (ml/min/1.73m2- CKD-EPI)
median [IQR]
96 [85.5-107]79.7 [50-107]*85.2 [62.2-99.6]
CKD stages (n, %) Stage 1-2
Stage 3
Stage 4-5
27 (87)
4 (13)
0
77 (67)
27 (25.5)
11 (9.5)
76 (81)
16 (17)
2 (2)

* p<0.05