How Is the Family of a Person With Adpkd Affected

Introduction

Discordance in kidney disease severity between affected relatives is a recognized characteristic of autosomal dominant polycystic kidney illness (ADPKD). Here, we report a systematic report 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 Illness (eTGESP) cohort includes 1390 patients from 612 unrelated families with ADPKD ascertained in a regional polycystic kidney affliction heart. All probands underwent comprehensive PKD1 and PKD2 mutation screening. Total kidney book past magnetic resonance imaging (MRI) was bachelor in 500 study patients.

Results

Based on (i) rate of estimated glomerular filtration rate (eGFR) refuse, (ii) age at onset of end-phase renal disease (ESRD), and (iii) Mayo Dispensary Imaging Classification (MCIC), twenty% of patients were classified as having balmy disease, and 33% as having severe affliction. Intrafamilial ADPKD discordance with at least 1 mild and 1 astringent 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 blazon (protein-truncating versus nontruncating). Intrafamilial discordance was more mutual in larger families and was present in xxx% of families with more than five affected members. The heritability of age at onset of ESRD was similar betwixt different mutation types.

Conclusion

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

Graphical abstruse

Keywords

• polycystic kidney disease
• ADPKD
• genetics

ADPKD is the nigh mutual hereditary kidney disease worldwide, characterized by bilateral kidney enlargement with numerous cysts and a variable rate of chronic kidney disease (CKD) progression. A large proportion of patients affected with ADPKD also endure from hypertension, kidney stones, and urinary tract infections, as well every bit other extrarenal complications, including polycystic liver illness and intracranial avenue aneuryms.

Up to 70% of patients with ADPKD develop ESRD by the age of 70 years.

²

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• Crossref
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However, some patients die at an elderly historic period with intact renal function whereas others develop ESRD in early on or centre adulthood, illustrating the wide spectrum of kidney disease severity in ADPKD.

²

• Spithoven E.M.
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Renal replacement therapy for autosomal dominant polycystic kidney illness (ADPKD) in Europe: prevalence and survival─an assay of data from the ERA-EDTA Registry.

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Assessing the risk of progression in ADPKD has become of peachy clinical importance since the approval of tolvaptan, the starting time machinery-based drug treatment approved for patients with high gamble for progression.

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In this regard, a family history of an older affected relative who adult ESRD at or before age 55 years is thought to exist predictive of severe disease in the family.

By contrast, a positive history of an affected relative who remained renal sufficient at historic period lxx is idea to be predictive of balmy affliction in the family.

Even so, intrafamilial renal affliction variability is a well-documented feature of ADPKD, making risk prediction at the level of the private patient challenging, even among affected relatives. Comparing of 56 sibships with ADPKD showed a 6.9-year hateful divergence in the age at onset of ESRD, and nine sets of monozygotic twins had a 2.one-yr mean departure.

In add-on, a meaning heritability for both creatinine clearance and historic period at onset of ESRD was found in 406 affected relatives from 66 PKD1-linked families.

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Progressive loss of renal function is an historic period-dependent heritable trait in blazon 1 autosomal dominant polycystic kidney disease.

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Taken together, these findings suggest that genetic and environmental modifiers may affect within-family renal disease variability in ADPKD.

In clinically ascertained samples, mutations in PKD1 and PKD2 are responsible for threescore%–78% and 15%–26% of ADPKD, respectively.

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⁹

• Heyer C.Chiliad.
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About 10%–xv% of patients with apparent ADPKD take no identifiable PKD1 or PKD2 mutation,

and whole-exome sequencing studies accept identified boosted genes (i.e., GANAB, DNAJB11) mutated in a small proportion of patients (<i%).

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Both genic and allelic heterogeneity contribute to phenotype severity in ADPKD. Mutations in PKD1 lead to more-severe affliction with larger kidneys and earlier development of ESRD compared to mutations in PKD2.

^,

^ix

• Heyer C.M.
• Sundsbak J.L.
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Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney affliction.

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Protein-truncating mutations, acquired past nonsense, frameshift, and canonical splice-site mutations, and large insertions/deletions in general, lead to more-astringent illness than practise nontruncating mutations, including inframe insertion/deletions (Indels), missense mutations, and atypical splicing mutations.

^,

^nine

• Heyer C.M.
• Sundsbak J.L.
• Abebe K.Z.
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Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney disease.

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In addition to family history of renal disease severity and ADPKD mutation class for prognostication, the MCIC employs age-adjusted total kidney volume (TKV) to provide take chances cess of kidney disease progression in ADPKD and identification of loftier-take chances patients for enrollment into clinical trials.

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¹⁴

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The MCIC approach is based on the findings of the Consortium for Radiological Imaging Studies of Polycystic Kidney Illness (CRISP), which documented that TKV on average increases at approximately 5% per year during adulthood in patients with ADPKD and predicts future CKD progression.

¹⁵

• Irazabal Grand.V.
• Rangel L.J.
• Bergstralh E.J.
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Imaging classification of autosomal dominant polycystic kidney illness: a simple model for selecting patients for clinical trials.

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^,

A TKV-based prognostic biomarker is particularly useful for identifying patients at loftier risk for CKD progression before the onset of kidney failure, which typically occurs tardily in the clinical course.

^xv

• Irazabal Grand.5.
• Rangel L.J.
• Bergstralh E.J.
• et al.

Imaging nomenclature of autosomal dominant polycystic kidney affliction: a simple model for selecting patients for clinical trials.

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Although intrafamilial renal disease discordance amid affected relatives is a recognized characteristic of ADPKD, defining its prevalence is challenging, in part due to a lack of big, family-based cohort studies and robust risk assessment tools to identify patients with astringent affliction earlier the onset of CKD. In the current report, we used the following measures: (i) the rate of eGFR refuse, (ii) age at onset of ESRD, and/or (three) MCIC to assess ADPKD kidney disease severity in 1390 patients from 612 unrelated families ascertained through the eTGESP. We identified all families with 2 or more affected relatives with available clinical data on kidney illness severity, and determined the prevalence and clinical features of intrafamilial kidney disease discordance.

Methods

Written report Population

The eTGESP cohort comprised consecutive patients seen at a regional PKD center at the Toronto Full general Hospital from December 1, 2006 to December thirty, 2017. Patients were referred from more than 100 academic and community nephrologists at the Greater Toronto Area and from St. Joseph'southward Healthcare in Hamilton, Ontario, Canada. Patients were referred for early gamble stratification and genetic assessment, not at the point of ESRD for transplant assessment. All except 2% of patients seen participated in the current study and provided consent according to a prespecified protocol approved by the institutional review board at the Academy Health Network in Toronto, Ontario, Canada.

Measurement of Exposures and Outcomes

Date of birth, age at recruitment, and terminal follow-up was available for all patients. Age of death and development of ESRD was obtained from patient history or medical chart when available. Using age, sex, race, and serum creatinine measurements, eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

Rate of decline of kidney function was determined using linear regression of available CKD-EPI eGFR values in all patients with more than than 3 measurements over more ane year. Ultrasound- or MRI-based criteria confirmed the ADPKD diagnosis in all probands.

All MR images were reviewed and classified equally typical (grade 1) or singular (course 2).

^xv

• Irazabal M.V.
• Rangel L.J.
• Bergstralh E.J.
• et al.

Imaging classification of autosomal dominant polycystic kidney disease: a unproblematic model for selecting patients for clinical trials.

• Crossref
• PubMed
• Scopus (265)
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MRI-derived TKV was estimated by an experienced radiologist using the ellipsoid method and coupled with historic period at MRI to generate the MCIC adventure grade.

^xv

• Irazabal Thou.V.
• Rangel L.J.
• Bergstralh E.J.
• et al.

Imaging classification of autosomal ascendant polycystic kidney disease: a simple model for selecting patients for clinical trials.

• Crossref
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• Scopus (265)
• Google Scholar

All cases with singular PKD on renal imaging (i.e., MCIC class 2) were excluded from the current study. Genetic testing was performed in a single research laboratory in Toronto using a validated long-range polymerase chain reaction protocol and bidirectional sequencing of coding region and splice junctions of PKD1 and PKD2.

^,

^nine

• Heyer C.Chiliad.
• Sundsbak J.50.
• Abebe K.Z.
• et al.

Predicted mutation forcefulness of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney affliction.

• Crossref
• PubMed
• Scopus (93)
• Google Scholar

Every bit previously reported, all nonsense, frameshift, and canonical splice-site mutations were grouped every bit protein-truncating mutations, and nonsynonymous missense or atypical splice-site mutations were grouped equally not-truncating mutations. All nontruncating mutations and inframe insertions/deletions were evaluated for their potential pathogenicity using prediction algorithms (Marshal GVGD, PolyPhen-2, SIFT, PROVEAN, and Man Splicing Finder), review of the PKD mutation database (http://pkdb.mayo.edu), and segregation analysis with additional affected family members when possible.

^,

^ix

• Heyer C.Thou.
• Sundsbak J.L.
• Abebe Thou.Z.
• et al.

Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal ascendant polycystic kidney illness.

• Crossref
• PubMed
• Scopus (93)
• Google Scholar

All mutation-negative patients were re-screened by multiplex ligation–dependent probe distension for detection of large gene rearrangements.

Cess of ADPKD Severity

In guild to identify families with discordant affliction severity, we showtime evaluated all patients individually to score their affliction severity using stringent criteria. Mild disease was divers as (i) ESRD or renal sufficiency at the age of 70 or more than years, or (2) an MCIC risk class of 1A or 1B. Severe disease was defined as presence of at least i of the following criteria: (i) development of ESRD before the age of 55 years; (2) an MCIC gamble grade of 1D or 1E; and (iii) >5 ml/min per 1.73 m² per-year loss in eGFR with at least 3 measurements over at to the lowest degree 1 year. Patients who did not satisfy any of the in a higher place criteria had intermediate or indeterminate disease severity.

Statistical Assay

We compared the prevalence of intrafamilial discordance between mutation types using Pearson'southward χ², and trends by family size were determined using the Cochrane-Armitage test for trend. The 95% confidence intervals (95% CIs) for binomial proportions were calculated using the normal approximation (Wald) interval

$\hat{p}\pm z\sqrt{\frac{\hat{p}\left(1-\hat{p}\right)}{\mathrm{northward}}}$

. We compared historic period of ESRD onset or age at censoring between mutation classes (PKD1 protein-truncating, PKD1 nonprotein-truncating, PKD1 in frame insertion/deletion, PKD2, and no mutation detected) past Kaplan-Meyer survival analysis. To account for the familial relationship and biological sex in the analysis, we used a mixed-furnishings Cox proportional take a chance model, every bit implemented in the R bundle "coxme" (https://cran.r-project.org/web/packages/coxme/index.html). Each sample was assumed to have an individual random effect/adventure of reaching ESRD, but those risks were correlated between family unit members according to the distance of the familial human relationship.

Heritability was defined as the proportion of trait variability attributable to additive genetic effects. We estimated heritability using SOLAR-Eclipse (v.viii.1.1, http://world wide web.solar-eclipse-genetics.org/), which implements the variance components method. All familial ADPKD patients were connected by cosmos of common ancestors with phenotypes coded equally unknown. We first fitted an intercept-only Cox proportional hazard model, with historic period at ESRD or censoring as the survival outcome variable, and biological sex as a covariate. The deviance residuals were used as the quantitative trait variable in SOLAR-Eclipse. Mutation-specific heritability was compared using 2-sided ii-sample t-tests.

Results

Assessing Kidney Illness Severity in the eTGESP Cohort

In full, in this study we examined 1390 patients from 612 unrelated families from the eTGESP accomplice (Figure one). The probands of all study families were screened for PKD1 and PKD2 mutations. V-hundred patients had MRI-derived TKV and MCIC risk assessment; 529 patients had reached ESRD; and 89 patients died without development of ESRD. A total of 237 (17%) patients were excluded due to: (i) positive family history of ADPKD but no available clinical data in any of the affected relatives (78 cases [six%]); (ii) no credible family history of ADPKD (115 cases [8%]); or (iii) unknown and unavailable family history (44 cases [iii%]). Of the remaining 375 unrelated families containing at least two affected relatives, 241 (64%) had a PKD1 mutation (protein-truncating: 160 of 375 [43%]; inframe Indel: 11 of 375 [3%]; nontruncating: seventy of 375 [19%]), 98 (26%) had a PKD2 mutation, and 36 (ten%) had no detected mutation (Supplementary Figure S1). Two families had evidence of biallelic inheritance: one with both a PKD1 missense mutation (c.6395T>G; p.F2132C) and frameshift insertion (c.11359_11360delAG; p.P3788fs), and a second with a PKD2 truncating mutation (c.2159_2160InsA; p.N720fs) and a PKD1 missense variant (c.8299C>T; p.R2767C). Families with more than afflicted members were not enriched for severe mutations (P = 0.84; Supplementary Figure S2).

Effigy 1 Study flow diagram of the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Affliction cohort. ADPKD, autosomal dominant polycystic kidney disease; Cr, creatinine; ESRD, terminate-stage renal disease; MCIC, Mayo Clinic Imaging Classification; MRI, magnetic resonance imaging.

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Overall, 231 of 1153 (xx%) patients were classified as having mild disease; 375 of 1153 (33%) patients had severe disease; and 542 of 1153 (47%) did not have prove of either mild or severe illness and were classified as intermediate or indeterminate (Figure two). A total of 302 of 1153 (26%) patients had intermediate disease, including 220 who reached ESRD between the ages of 55 and 70 years, and 84 who had an MCIC of 1C; 2 patients had both an MCIC 1C and reached ESRD between historic period 55 and 70 years. A total of 240 of 1153 (21%) patients had indeterminate disease, including: 63 who died earlier historic period 70 years without renal hazard stratification but without ESRD, 30 of whom were above age 55 years; and 177 patients between the ages of xviii and 70 years with renal sufficiency and no imaging available, 53 of whom were above age 55 years. The mean historic period at last follow-up, and gender, for those with severe, intermediate or indeterminate, and mild disease were, respectively, 45.vii years (SD = 9.nine), 54% male; 53.half dozen years (SD = 14.0), 45% male; and 61.four years (SD = xix.8), 39% male (Supplementary Effigy S3).

Figure ii Kidney disease severity in the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Illness accomplice. Proportion of patients with balmy, intermediate or indeterminate, or severe kidney disease (a). 5 patients had alien assessment of kidney disease severity (i.east., prove of both mild and severe disease; see Supplementary Table S1). Venn diagrams showing criteria used for defining the severe (b) and balmy (c) cases. eGFR, estimated glomerular filtration rate; ESRD, end-phase renal disease; Mayo, Mayo Clinic Imaging Classification.

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Five patients (0.iv%) showed alien evidence of both balmy and severe affliction (Supplementary Table S1). All 5 were young women (mean age: 29.6 years) with small-scale kidneys (1A or 1B) and eGFR >90 ml/min per ane.23 m², but with an boilerplate eGFR decline >five ml/min per 1.73 yard^two per twelvemonth over one.4–3.v years of follow-up. Three had PKD1 protein-truncating mutations, one had a PKD1 nontruncating mutation (p.G3651S), and i had a PKD2 mutation. All had a family history of intermediate-to-severe ADPKD. Due to the conflict in rating their renal illness severity, they were excluded from farther assay. Four of the excluded patients were in families with 2 affected members, thus reducing the total number of families with at least 2 affected members from 375 to 371. Xv patients had both MCIC and age at ESRD available, and none had discrepant risk classifications.

In keeping with previous observations, patients with severe disease were more probable to have a PKD1 mutation (275 of 375 [73%]) than those with intermediate/indeterminate disease severity (218 of 542 [40%]) or mild disease (27 of 231 [12%]; P < 1 x x^–5; Supplementary Effigy S4).

Those with mild illness were more probable to have a PKD2 mutation (114 of 231 [49%]) than those with intermediate/indeterminate disease severity (156 of 542 [29%]) or those with severe disease (29 of 375 [8%]). Patients with severe affliction were also more likely to have a protein-truncating mutation, whereas those with mild disease were more likely to have a nontruncating mutation (P < 1 x ten^–5; Supplementary Figure S4). Like to our previous study, survival analysis showed that mutation type was a meaning predictor of the age at onset of ESRD (likelihood ratio examination P < ii.2 x x^–xvi; Supplementary Figure S5).

Moderate heritability (35%–70%) was observed for age at ESRD onset beyond major mutation classes but did not significantly differ between the classes (P > 0.05; Table i).

Table i Heritability of age at onset of stop-stage renal disease is similar regardless of gene or mutation type

Mutation type	h2 (SE)	P comparison versus not heritable	P comparison versus PKD1-PT	P comparison versus PKD1-NT
PKD1-PT	0.45 (0.12)	0.00001	—	0.28
PKD1-NT	0.70 (0.nineteen)	0.00009	0.28	—
PKD2	0.35 (0.xx)	0.03	0.65	0.23

h², heritability; NT, nontruncating; PT, protein-truncating.

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Intrafamilial Kidney Disease Variability

Next, we adamant the minimal prevalence and associated clinical features of intrafamilial renal illness discordance in our study cohort. Of 371 families with data on at least two afflicted family members, 43 (12%, 95% CI: eight%–15%) had prove of intrafamilial discordance of their kidney disease severity, defined as having at least i afflicted relative with mild disease and 1 affected relative with severe disease. If indeterminate patients were excluded from the analysis, we observed intrafamilial discordance in 43 of 292 (fifteen%, 95% CI: 11%–19%) families. Only 45 families had at least 2 affected relatives with MCIC risk assessment, and vii of these 45 (xvi%, 95% CI: 5%–26%) displayed discordant renal affliction severity (1 family unit member with MCIC A or B, and some other family member with MCIC D or E). Equally expected, the prevalence of intrafamilial renal disease discordance increased with family size: 14 of 190 (7%, 95% CI: iv%–eleven%) families with 2 affected relatives, increasing to 8 of 27 (30%, 95% CI: 12%–47%) of families with more than 5 affected relatives displayed disease discordance (Figure three). There was no significant difference in the prevalence of discordant families by the gene mutated (i.e., PKD1 vs. PKD2) or past mutation blazon (i.e., PKD1 PT mutations, PKD1 inframe indels, PKD1 NT mutations, PKD2 mutations, and no mutation detected, P > 0.five; Figure iv).

Figure 3 Big families are more likely to display discordance in kidney illness severity. Families were divers every bit discordant if they had at to the lowest degree 1 affected fellow member with mild kidney illness and 1 member with severe kidney disease. Cochrane-Armitage examination for trend: Z = 2.82; P = 0.005.

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Figure iv 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 illness severity. IF, inframe insertion/deletion; NT, nontruncating; PT, protein-truncating.

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Families with PKD1 PT mutations on average have the most-astringent renal disease compared to all the other mutation classes (Supplementary Figure S5). In these families with severe mutations, the use of MCIC (1A and 1B) identified 88% (fourteen of 16) of the mildly affected relatives, and a history of "renal sufficiency at the age of 70 years or older" identified the remaining 2 (Figure v). Conversely, families with PKD2 mutations on boilerplate take the mildest renal affliction compared to all the other mutation classes (Supplementary Figure S5). In these families, the use of MCIC (1D and 1E) identified 62% (8 of xiii) of the severely affected relatives, and a history of "ESRD before the age of 55 years" identified the remaining 5 (Effigy 5).

Figure v 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 historic period at end-phase renal disease (ESRD), and empty circles are age of censor (death or final follow-up with renal sufficiency). IF, in-frame insertion/deletion; NT, nontruncating; PT, protein-truncating.

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Discussion

In this big prospective report of clinically ascertained families with ADPKD recruited from a unmarried geographic region, we found a minimal prevalence estimate of intrafamilial kidney disease discordance of 12%, defined by the presence of at to the lowest degree ane mildly affected relative and one severely affected relative, using stringent criteria. Among the report patients, twenty% had mild disease, 33% had severe disease, and 47% had intermediate or indeterminate disease severity. In keeping with previous observations, those with severe disease were more likely to have PKD1 truncating mutations, whereas those with balmy disease were more likely to have PKD2 mutations and nontruncating PKD1 mutations. Heritability estimates of the historic period at ESRD onset were like regardless of ADPKD mutation type, indicating that boosted genetic and environmental factors contribute to and modify the kidney disease severity, regardless of the main ADPKD mutation blazon. Families with kidney disease discordance between affected relatives were equally probable to have PKD1 or PKD2 mutations, and equally probable to have protein-truncating or nontruncating mutations.

The use of multiple criteria (i.e., age at ESRD, MCIC risk grade, and slope of eGFR decline) to define disease severity allowed us to increase the number of informative families for evaluation and include patients from multiple generations. For younger patients, the TKV-based MCIC risk class provides a robust measure of affliction severity, as eGFR often remains inside the normal range for the first 3 to iv decades of life. In contrast, belatedly-onset ESRD or continued renal sufficiency despite sometime age (in a higher place 70 years) provides a uncomplicated means to place patients with mild disease, whereas early-onset ESRD (before age 55 years) is indicative of astringent disease. Including all iii measures produces an effective method to examine intergenerational discordance in kidney illness severity over a wide range of CKD stages. Every bit would be expected, larger families, by providing additional affected relatives for comparison, yielded a higher prevalence of intrafamilial kidney disease discordance than did small families. Complete evaluation of all afflicted relatives and deep phenotyping, such as TKV in all participants, may uncover additional families with intrafamilial kidney disease discordance. We put bully endeavour into obtaining clinical records for family members of probands, just complete records were unavailable at times. Thus, our estimate of intrafamilial kidney disease discordance should be viewed every bit a lower-bound estimate.

Report of intrafamilial kidney disease discordance provides an opportunity to delineate genetic and environmental modifiers and improve our ability to predict the rate of kidney disease progression in ADPKD. One potential explanation for intrafamilial disease discordance is compound heterozygosity or digenic inheritance of an additional mutation in a cystogenic cistron, including PKD1 and PKD2. Our previous work described a family with bilineal PKD1 inframe indel and PKD1 missense mutations, resulting in intrafamilial discordance like to that described here.

Overall, bilineal mutations in PKD1 and PKD2 appear uncommon, bookkeeping for only two families identified here. Mosaicism, in which 2 populations of cells with dissimilar genotypes exist in the same person, can lead to intrafamilial kidney disease discordance. We previously described a family in eTGESP with somatic mosaicism, including an afflicted mother with germline transmission of a PKD1 frameshift deletion to her daughter.

All the daughter's cells carried the heterozygous PKD1 frameshift mutation, leading to a 1:1 ratio of wild type to mutant alleles and a severe phenotype, whereas her mother had a ten:1 ratio of wild type to mutant alleles in claret and a mild phenotype. Mosaicism is hard to find with Sanger (capillary) sequencing, owing to a low point-to-dissonance ratio, and the prevalence of mosaicism in ADPKD remains poorly defined. All the same, the recognition of somatic mosaicism will improve with the advance of next-generation sequencing and likely accounts for a proportion of cases displaying intrafamilial kidney disease discordance in ADPKD.

²⁰

Lanktree MB, Iliuta I-A, Haghighi A, et al. Evolving role of genetic testing for the clinical management of autosomal ascendant polycystic kidney disease [e-pub ahead of print]. Nephro Dial Transplant. doi: x.1093/ndt/gfy261. Accessed May 27, 2019.

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Mutations in additional affliction modifiers, including COL4A1 and HNF1B,

^,

have been described and could create intrafamilial variation if 1 member carries the additional mutation and the other does non. Mutations in genes responsible for other cystic disease, such as autosomal dominant polycystic liver disease and tuberous sclerosis circuitous, are also possible candidates. In our recent analyses of whole genome and exome sequencing of the general population, 1% of the population was establish to carry a truncation mutation, and 23% of the population was establish to carry rare missense mutations in genes with potential to change the kidney affliction phenotype in ADPKD.

Mutual genetic variants may too change the kidney disease severity of ADPKD, as exemplified by the variant clan observed with DKK3,

and a polygenic component with numerous genetic variants with small effects cumulatively contributing to affliction progression is possible.

On the other mitt, concomitant clinical weather, including obesity, diabetes, vascular affliction, and astute kidney injury, and environmental factors such as cigarette smoking, nutrition, and water intake could potentially alter the rate of progression and contribute to intrafamilial kidney illness discordance in ADPKD. Changes in intervention rates (i.eastward., prescription of angiotensin-converting enzyme inhibitors) or secular changes, such as increasing prevalence of obesity, could also lead to differences in affliction severity between generations of affected relatives from the same family.

In conclusion, by using multiple stringent criteria to define ADPKD severity, we establish a minimal prevalence of kidney disease discordance in 11% of our study families regardless of their underlying mutated cistron or mutation class. Potential causes for the observed variability include bilineal ADPKD and somatic mosaicism for some families, but much of the intrafamilial kidney disease discordance remains unexplained. Future studies of families with intrafamilial kidney illness discordance by next-generation sequencing targeting a panel of potential cystic or CKD modifier genes have the potential to uncover genetic contributors to kidney illness progression in ADPKD.

Disclosure

MBL and YP received compensation for participating in advisory and consultancy boards with Otsuka pharmaceuticals. All the other authors declared no competing interests.

Acknowledgments

MBL received a Ben Lipps Post-Doctoral Fellowship from the American Society of Nephrology and is a fellow of the Krescent Program, a national kidney inquiry training partnership of the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institutes of Health Research. The Canadian Institutes of Health Inquiry Strategy for Patient Oriented Research in Chronic Kidney Disease program grant to YP supported this work.

MBL, EG, and YP designed the study; MBL and EG analyzed the data, produced the figures, and drafted the paper; WL and AP provided statistical support; the remaining authors contributed data collection and validation, and edited and approved the terminal version of the manuscript. The authors thank the patients and their families, besides as the administrative and research staff of the Center for Innovative Direction of PKD at Toronto General Hospital and St. Joseph's Healthcare, Hamilton, Toronto, Canada.

Supplementary Material

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Article Info

Publication History

Published online: May 07, 2019

Accepted: April 22, 2019

Received in revised form: March 27, 2019

Received: January 16, 2019

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DOI: https://doi.org/ten.1016/j.ekir.2019.04.018

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© 2019 International Society of Nephrology. Published by Elsevier Inc.

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