Dataset Information

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

ABSTRACT:

Purpose

Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder.

Methods

In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders.

Results

In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected.

Conclusion

Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.

SUBMITTER: Schrezenmeier E

PROVIDER: S-EPMC8257480 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

Schrezenmeier Eva E Kremerskothen Elisa E Halleck Fabian F Staeck Oliver O Liefeldt Lutz L Choi Mira M Schüler Markus M Weber Ulrike U Bachmann Nadine N Grohmann Maik M Wagner Timo T Budde Klemens K Bergmann Carsten C

Genetics in medicine : official journal of the American College of Medical Genetics 20210312 7

<h4>Purpose</h4>Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder.<h4>Methods</h4>In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders.<h4>Results</h4>In total, 635 patient ...[more]

PMID: 33712733

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Project description:BackgroundChronic kidney disease (CKD) is a genetically complex disease determined by an interplay of monogenic, polygenic, and environmental risks. Most forms of monogenic kidney diseases have incomplete penetrance and variable expressivity. It is presently unknown if some of the variability in penetrance can be attributed to polygenic factors.MethodsUsing the UK Biobank (N=469,835 participants) and the All of Us (N=98,622 participants) datasets, we examined two most common forms of monogenic kidney disorders, autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious variants in the PKD1 or PKD2 genes, and COL4A-associated nephropathy (COL4A-AN caused by deleterious variants in COL4A3 , COL4A4 , or COL4A5 genes). We used the eMERGE-III electronic CKD phenotype to define cases (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or kidney failure) and controls (eGFR >90 mL/min/1.73m2 in the absence of kidney disease diagnoses). The effects of the genome-wide polygenic score (GPS) for CKD were tested in monogenic variant carriers and non-carriers using logistic regression controlling for age, sex, diabetes, and genetic ancestry.ResultsAs expected, the carriers of known pathogenic and rare predicted loss-of-function variants in PKD1 or PKD2 had a high risk of CKD (OR meta= 17.1, 95% CI: 11.1-26.4, P=1.8E-37). The GPS was comparably predictive of CKD in both ADPKD variant carriers (OR meta= 2.28 per SD, 95%CI: 1.55-3.37, P=2.6E-05) and non-carriers (OR meta= 1.72 per SD, 95% CI=1.69-1.76, P< E-300) independent of age, sex, diabetes, and genetic ancestry. Compared to the middle tertile of the GPS distribution for non-carriers, ADPKD variant carriers in the top tertile had a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile had only a 3-fold increased risk of CKD. Similarly, the GPS was predictive of CKD in both COL4-AN variant carriers (OR meta= 1.78, 95% CI=1.22-2.58, P=2.38E-03) and non-carriers (OR =1.70, 95%CI: 1.68-1.73 P<E-300). The carriers in the top tertile of the GPS had a 2.5-fold higher risk of CKD while the risk for carriers in the bottom tertile was similar to the middle tertile of non-carriers.ConclusionsVariable penetrance of kidney disease in ADPKD and COL4-AN is partially explained by differences in polygenic risk profiles. Accounting for polygenic factors has the potential to improve risk stratification in monogenic kidney disease and may have implications for genetic counseling.

Project description:BackgroundCardiovascular diseases are one of the major limitations in the evaluation of potential kidney transplantation. The study aimed to assess cardiovascular status, including cardiovascular risk factors in waitlisted hemodialyzed patients.Material and methodsFrom the population of 5,068 hemodialyzed patients (60% men), we included 449 waitlisted and 4,619 not considered for potential kidney transplantation. We assessed demographic data, basal biochemical data, and cardiovascular disease prevalence.ResultsWaitlisted patients (262 males) were significantly younger when compared to non-listed patients (2,718 males); 53.2 ± 14.2 vs. 67.2 ± 3.3 years (p < 0.001), had lower Charlson comorbidity score (3.33 ± 1.52 vs. 4.42 ± 1.93, p < 0.001), lower BMI (26.3±.5.07 vs. 27.7 ± 6.15 kg/m2, p < 0.001), with lower prevalence of cardiovascular disease (46.5% vs. 66.8%, p < 0.001), diabetes (20.5% vs. 37,8%, p < 0.001). The prevalence of hypertension was similar in both groups (94.7% vs. 92.7%, NS). Blood pressure was significantly higher in waitlisted patients relative to non-waitlisted (143 ± 16 mmHg vs. 140 ± 17 mm Hg, p < 0.001 for systolic blood pressure and 80 ± 9 mmHg vs. 75 ± 9 mmHg, p < 0.001 for diastolic blood pressure). Ultrafiltration was also higher in waitlisted population over non-waitlisted (31.3 ± 12.7 mL/kg per HD session vs. 28.4 ± 12.6 mL/kg per HD session, p < 0.001). Mean dialysis vintage, the mean number of hypotensive medications (mean 2.5), the prevalence of apparent treatment-resistant hypertension, and eKt/V were similar, as well as sex distribution.ConclusionWaitlisted patients are a much healthier population, with fewer comorbidities but blood pressure control not meeting target ranges for the present guidelines. The low number of hypotensive medications should be reassessed and the treatment of hypertension may require further attention.

Dataset Information

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

Purpose

Methods

Results

Conclusion

Publications

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

Similar Datasets

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