Describing and Explaining ADPKD Variability Within Families

Differences in the experience of kidney disease and other complications of Autosomal Dominant Polycystic Kidney Disease (ADPKD) within families has long been a clinical conundrum1Persu A. Duyme M. Pirson Y. et al.Comparison between siblings and twins supports a role for modifier genes in ADPKD.Kidney Int. 2004; 66: 2132-2136Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar. Where large cohort studies have previously identified key associations between genetic aetiology and ADPKD phenotype2Cornec-Le Gall E. Audrezet M.P. Chen J.M. et al.Type of PKD1 Mutation Influences Renal Outcome in ADPKD.J Am Soc Nephrol. 2013; 24: 1006-1013Crossref PubMed Scopus (366) Google Scholar,3Hwang Y.H. Conklin J. Chan W. et al.Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease.J Am Soc Nephrol. 2016; 27: 1861-1868Crossref PubMed Google Scholar, there has been a persistent observed and reported phenomena of unexpectedly mild disease in close to one in five patients4Lanktree M.B. Guiard E. Akbari P. et al.Patients with Protein-Truncating PKD1 Mutations and Mild ADPKD.Clin J Am Soc Nephrol. 2021; 16: 374-383Crossref PubMed Scopus (0) Google Scholar. These unexpectedly divergent cases have challenged the traditionally deterministic dogma of genotype-phenotype correlations in monogenic disease. Multiple different lines of evidence have emerged to help explain such phenotypic discordance, including polygenic contributions to phenotype5Khan A. Shang N. Nestor J.G. et al.Polygenic risk alters the penetrance of monogenic kidney disease.Nat Commun. 2023; 14: 8318Crossref Scopus (0) Google Scholar, incomplete penetrance6Rossetti S. Kubly V.J. Consugar M.B. et al.Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease.Kidney Int. 2009; 75: 848-855Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, sex or environmental exposures7Heyer C.M. Sundsbak J.L. Abebe K.Z. et al.Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.J Am Soc Nephrol. 2016; 27: 2872-2884Crossref PubMed Scopus (122) Google Scholar, and an overarching theory of a polycystin signalling cystogenic threshold which relates to ADPKD phenotype8Antignac C. Calvet J.P. Germino G.G. et al.The Future of Polycystic Kidney Disease Research--As Seen By the 12 Kaplan Awardees.J Am Soc Nephrol. 2015; 26: 2081-2095Crossref PubMed Scopus (0) Google Scholar (Figure 1). The practical application of which has emerged in the form of the PROPKD Score9Cornec-Le Gall E. Audrezet M.P. Rousseau A. et al.The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease.J Am Soc Nephrol. 2016; 27: 942-951Crossref PubMed Scopus (217) Google Scholar which combines many of these factors to practically prognosticate kidney phenotype in ADPKD in a more individualised way. Further causative genes which help to explain phenotypic variability and the broader spectrum of ADPKD have also been identifiedS1-S3. Despite these efforts approximately one in ten families affected by ADPKD experience substantial and otherwise unexpected kidney disease discordanceS4 which continues to pose challenges for individual clinical management, prognostication and broader genetic counselling. Recently Elhassan et al (in press)S5 have replicated and expanded upon the previous findings around such intrafamily variability of ADPKD severity in an Irish family cohort. Similarly to Lanktree et alS4, they have identified that approximately 13% of families experience marked or extreme intrafamily variability. This is important in several key ways discussed below. Firstly, this studyS5 reconfirms these findings in a genetically distinct population which further aids in the translation of its findings. Whilst contemporary Canadian and Irish populations are diverse, it is likely that they remain overrepresented by those of White or Caucasian ancestry. As such further replication in additional diverse communities and jurisdictions is likely still required, especially in Asia, Africa and Oceania. Secondly, these findings of Elhassan et alS5 critically confirms the establishment of key definitions of ADPKD phenotype severity and variability:•Severe disease: Defined as patients who reached kidney failure (KF) before the age of 55 years, or with eGFR annual decline >5 ml/min/annum, or with PROPKD score >6, or with Mayo Clinic Imaging Classification (MCIC) class 1D or 1E, or with a kidney length on US >16.5 cm at age <45 years.•Mild disease: Defined as patients who developed KF later than the age of 70 years, or with PROPKD score #3 at an age later than 35 years, or with MCIC risk class 1A or 1B.•Intermediate Disease: Failed to meet the criteria for either mild or severe disease.•Marked/Discordant Intrafamily Variability: A family with at least 1 severe and 1 mild case. The confirmed assertion of these definitions is critical to future application of such findings in practice given that this now enables an accepted ontology to be applied. It must however be noted that the application of the definition of intrafamily variability is dependent upon a family having at least two known and well characterized family members. For de novo cases or those without known or well characterized affected family members, alternate approaches to individualized prognostication and counselling remain indicated such as PROPKD Score or Mayo Clinic Imaging Classification (MCIC)S6. Thirdly, this analysis was able to compare different criteria of disease severity for both interfamily variability as well as intrafamily variability of ADPKD phenotype. Whilst this identified that interfamily phenotypic variability was most discordant according to PROPKD score (63.7%), however this variability between different families was similar by age at kidney failure and MCIC (28.8% and 24% respectively). By contrast, intrafamily variability was most discordant according to MCIC (24%) with both age at kidney failure and PROPKD score representing much more modest phenotypic discordance within individual families (7.7% and 8.4% respectively). This suggests that a broad approach with multiple forms of severity assessment is indicated for individual and family characterization and prognostication. For a patient who might be encountered in clinic, appraisal of personal phenotype (kidney imaging; medical history), genetic information, and family history may all be required in addition to understanding of current kidney function in order to provide meaningful ADPKD prognostication for them. Lastly, this study gives further practical insights into a more nuanced experience of being affected by a monogenic disease such as ADPKD. The potential disease-associated changes in our genome do not necessarily define the whole story of what might happen next. Rather a broad combination of intrinsic and extrinsic factors is likely to together influence phenotypes and disease trajectories, and ADPKD is certainly illuminating this. Where this multilayered reality may be less binary or linear, the future challenge remains in applying it to the clinical care of affected or at-risk patients and families. Similar or larger high quality cohort studies across different populations and jurisdictions will assist with both confirming these findings but also to enable globalized approaches to ADPDK research in partnership with patients. Areas for priority action might include longitudinal characterization for more granular prognostication evidence, novel gene and polygenic characterization, platform trial designs, research/clinical data reuse to minimize research waste, and dynamic consent approaches to patient-centric participation. This studyS5 in concert with previous research and astute clinical investigation is enabling the delivery of a more personalized approach to ADPKD clinical care. It indicates that roughly one in ten families experience marked/discordant intrafamily variability of ADPKD phenotype, with a well defined approach to ADPKD phenotype ontology, and the indicated need to concurrently apply multiple approaches to disease severity assessment. Most importantly, it also highlights future avenues for clinical study and research to further refine the evidence base that underpins the patient-centric and increasingly personalized care paradigm in contemporary ADPKD practice. SA and AM drafted the manuscript with all co-authors providing input, review and edits. All coauthors do not have any disclosures. The authors would like to gratefully acknowledge the patients who participated in the studies referenced. Download .pdf (.08 MB) Help with pdf files Familial Variability of Disease Severity in Adult Patients With ADPKDKidney International ReportsPreviewAutosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity. Full-Text PDF Open Access

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