Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 May 7;4(7):995-1003.
doi: 10.1016/j.ekir.2019.04.018. eCollection 2019 Jul.

Intrafamilial Variability of ADPKD

Matthew B Lanktree  1   2 , Elsa Guiard  1   2 , Weili Li  3 , Pedram Akbari  1   2 , Amirreza Haghighi  1   2 , Ioan-Andrei Iliuta  1   2 , Belili Shi  1   2 , Chen Chen  1   2 , Ning He  1   2 , Xuewen Song  1   2 , Peter J Margetts  4 , Alistair J Ingram  4 , Korosh Khalili  5   6 , Andrew D Paterson  7   8 , York Pei  1   2
Affiliations

Intrafamilial Variability of ADPKD

Matthew B Lanktree et al. Kidney Int Rep. .

Abstract

Introduction: Discordance in kidney disease severity between affected relatives is a recognized feature of autosomal dominant polycystic kidney disease (ADPKD). Here, we report a systematic study of a large cohort of families to define the prevalence and clinical features of intrafamilial discordance in ADPKD.

Methods: The extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP) cohort includes 1390 patients from 612 unrelated families with ADPKD ascertained in a regional polycystic kidney disease center. All probands underwent comprehensive PKD1 and PKD2 mutation screening. Total kidney volume by magnetic resonance imaging (MRI) was available in 500 study patients.

Results: Based on (i) rate of estimated glomerular filtration rate (eGFR) decline, (ii) age at onset of end-stage renal disease (ESRD), and (iii) Mayo Clinic Imaging Classification (MCIC), 20% of patients were classified as having mild disease, and 33% as having severe disease. Intrafamilial ADPKD discordance with at least 1 mild and 1 severe case was observed in 43 of 371 (12%) families, at a similar frequency regardless of the responsible gene (PKD1/PKD2/no mutation detected) or mutation type (protein-truncating versus nontruncating). Intrafamilial discordance was more common in larger families and was present in 30% of families with more than 5 affected members. The heritability of age at onset of ESRD was similar between different mutation types.

Conclusion: Extreme kidney disease discordance is present in at least 12% of families with ADPKD, regardless of the underlying mutated gene or mutation class. Delineating genetic and environmental modifiers underlying the observed intrafamilial ADPKD variability will provide novel insights into the mechanisms of progression in ADPKD.

Keywords: ADPKD; genetics; polycystic kidney disease.

PubMed Disclaimer

Figures

None
Graphical abstract
Figure 1
Figure 1
Study flow diagram of the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease cohort. ADPKD, autosomal dominant polycystic kidney disease; Cr, creatinine; ESRD, end-stage renal disease; MCIC, Mayo Clinic Imaging Classification; MRI, magnetic resonance imaging.
Figure 2
Figure 2
Kidney disease severity in the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease cohort. Proportion of patients with mild, intermediate or indeterminate, or severe kidney disease (a). Five patients had conflicting assessment of kidney disease severity (i.e., evidence of both mild and severe disease; see Supplementary Table S1). Venn diagrams showing criteria used for defining the severe (b) and mild (c) cases. eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; Mayo, Mayo Clinic Imaging Classification.
Figure 3
Figure 3
Large families are more likely to display discordance in kidney disease severity. Families were defined as discordant if they had at least 1 affected member with mild kidney disease and 1 member with severe kidney disease. Cochrane-Armitage test for trend: Z = 2.82; P = 0.005.
Figure 4
Figure 4
Presence of PKD1, PKD2, or no mutation detected (NMD) is not associated with intrafamilial discordance of kidney disease severity in autosomal dominant polycystic kidney disease (ADPKD). Comparison of gene (a) and mutation type (b) responsible for ADPKD in families with concordant and discordant intrafamilial kidney disease severity. IF, inframe insertion/deletion; NT, nontruncating; PT, protein-truncating.
Figure 5
Figure 5
Families display intrafamilial disease discordance regardless of responsible underlying mutation type. Each vertical line represents 1 family with intrafamilial discordance, and each dot represents a single patient. Filled dots represent age at end-stage renal disease (ESRD), and empty circles are age of censor (death or last follow-up with renal sufficiency). IF, in-frame insertion/deletion; NT, nontruncating; PT, protein-truncating.
See this image and copyright information in PMC

References

    1. Lanktree M.B., Chapman A.B. New treatment paradigms for ADPKD: moving towards precision medicine. Nat Rev Nephrol. 2017;13:750–768. - PubMed
    2. Lanktree MB, Chapman AB. New treatment paradigms for ADPKD: moving towards precision medicine. Nat Rev Nephrol. 2017;13:750-768. - PubMed
    1. Spithoven E.M., Kramer A., Meijer E. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival─an analysis of data from the ERA-EDTA Registry. Nephrol Dial Transplant. 2014;29(suppl 4):iv15–iv25. - PMC - PubMed
    2. Spithoven EM, Kramer A, Meijer E, et al. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival─an analysis of data from the ERA-EDTA Registry. Nephrol Dial Transplant. 2014;29(suppl 4):iv15-iv25. - PMC - PubMed
    1. Torres V.E., Chapman A.B., Devuyst O. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377:1930–1942. - PubMed
    2. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377:1930-1942. - PubMed
    1. Torres V.E., Chapman A.B., Devuyst O. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407–2418. - PMC - PubMed
    2. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407-2418. - PMC - PubMed
    1. Barua M., Cil O., Paterson A.D. Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol. 2009;20:1833–1838. - PMC - PubMed
    2. Barua M, Cil O, Paterson AD, et al. Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol. 2009;20:1833-1838. - PMC - PubMed