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Monogenic causes of chronic kidney disease in adults.

ABSTRACT: Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.

SUBMITTER: Connaughton DM

PROVIDER: S-EPMC6431580 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Monogenic causes of chronic kidney disease in adults.

Connaughton Dervla M DM Kennedy Claire C Shril Shirlee S Mann Nina N Murray Susan L SL Williams Patrick A PA Conlon Eoin E Nakayama Makiko M van der Ven Amelie T AT Ityel Hadas H Kause Franziska F Kolvenbach Caroline M CM Dai Rufeng R Vivante Asaf A Braun Daniela A DA Schneider Ronen R Kitzler Thomas M TM Moloney Brona B Moran Conor P CP Smyth John S JS Kennedy Alan A Benson Katherine K Stapleton Caragh C Denton Mark M Magee Colm C O'Seaghdha Conall M CM Plant William D WD Griffin Matthew D MD Awan Atif A Sweeney Clodagh C Mane Shrikant M SM Lifton Richard P RP Griffin Brenda B Leavey Sean S Casserly Liam L de Freitas Declan G DG Holian John J Dorman Anthony A Doyle Brendan B Lavin Peter J PJ Little Mark A MA Conlon Peter J PJ Hildebrandt Friedhelm F

Kidney international 20190214 4

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 ...[more]

PMID: 30773290

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Project description:INTRODUCTION:Chronic kidney disease (CKD) risk staging is based on estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR). However, the relationship between all-cause hospitalization risk and the current CKD staging system has not been well studied among older adults, despite a high prevalence of CKD and a high risk of hospitalization in old age. METHODS:Among 4,766 participants of the Atherosclerosis Risk in Communities study, CKD was staged according to Kidney Disease Improving Global Outcomes (KDIGO) criteria, using creatinine-based eGFR (eGFRcr) and ACR. Incidence rates of all-cause hospitalization associated with each CKD risk group were analyzed using negative binomial regression. Additionally, cause-specific hospitalization risks for cardiovascular, infectious, kidney, and other diseases were estimated. The impacts of using cystatin C-based eGFR (eGFRcys) to estimate the prevalence of CKD and risks of hospitalization were also quantified. RESULTS:Participants experienced 5,548 hospitalizations and 29% had CKD. Hospitalization rates per 1,000 person-years according to KDIGO risk categories were 208-223 ("low risk"), 288-376 ("moderately increased risk"), 363-548 ("high risk"), and 499-1083 ("very high risk"). The increased risk associated with low eGFR and high ACR persisted in adjusted analyses, examinations of cause-specific hospitalizations, and when CKD was staged by eGFRcys or eGFRcr-cys, a combined equation based on both creatinine and cystatin C. In comparison to eGFRcr, staging by eGFRcys increased the prevalence of CKD to 50%, but hospitalization risks remained similarly high. DISCUSSION/CONCLUSION:In older adults, decreased eGFR, increased ACR, and KDIGO risk stages based on a combination of these measures, were strong risk factors for hospitalization. These relationships were consistent, regardless of the marker used to estimate GFR, but the use of cystatin C resulted in a substantially higher prevalence of CKD than the use of creatinine. Older adults in the population with very high risk stages of CKD have hospitalization rates exceeding 500 per 1,000 person-years.

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Monogenic causes of chronic kidney disease in adults.

Publications

Monogenic causes of chronic kidney disease in adults.

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