INTRODUCTION: Although 10% of adults with chronic kidney disease (CKD) have a monogenic cause, the characteristics of monogenic CKD in older adults (aged ≥ 60 years) are less characterized. We aimed to assess the clinical and genetic spectrum of older adults with CKD and the clinical utility of genetic findings. METHODS: The diagnostic yield of clinically validated disease-causing variants and their type ("typical" vs. "later-onset" phenotypes) were analyzed in older patients with suspected monogenic CKD who were referred to an Irish registry according to predetermined criteria. Independent genetic diagnosis and kidney survival time predictors were analyzed using marginal logistic and Cox regression analyses. RESULTS: Two hundred sixty-five adults (from 202 families) were aged ≥ 60 years at the time of genetic testing, of which 74.3% (197/265) progressed to kidney failure. Diagnostic variants were found in 60.4% (122/202) families, including 39% of noncystic kidney disease families. Variants causing "later-onset" phenotypes were more prevalent in patients with disease-onset ≥ 60 years (56% vs. 8.3%; P ≤ 0.001), which include genetic variants in: IFT140, ALG5, ALG9, DNAJB11, COL4A5 in females, monoallelic COL4A3, and the UMOD p.Thr62Pro variant, associated with delayed onset of kidney failure compared with "typical" variants (hazard ratio: 0.52; 95% confidence interval: 0.27-0.98; P = 0.043). A family history of CKD and a priori cystic kidney disease diagnosis independently predicted genetic diagnosis (P ≤ 0.05). In 24% of older adults with positive results, the treatment plan was modified. CONCLUSION: In older patients with CKD, genetic testing revealed enriched variants associated with less-penetrant phenotypes, often with a family history of CKD, which affects clinical management.

Department of Medicine Royal College of Surgeons in Ireland Dublin Ireland

Department of Nephrology and Transplantation Beaumont Hospital Dublin Ireland

Department of Renal Medicine University Hospital Limerick Limerick Ireland

FutureNeuro SFI Research Center Royal College of Surgeons Dublin Ireland

Nephrology Department Galway University Hospitals Saolta University Healthcare Group Galway Ireland

Regenerative Medicine Institute at CÚRAM Research Center for Medical Devices School of Medicine University of Galway Ireland

Research Unit for Rare Diseases Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague Czech Republic

School of Pharmacy and Biomolecular Sciences Royal College of Surgeons Dublin Ireland

Section on Nephrology Wake Forest School of Medicine Winston Salem North Carolina

The Department of Clinical Genetics Children's Health Ireland at Crumlin Dublin Ireland

Kidney Int Rep. 2025 Jun 30;10(8):2548-2550. doi: 10.1016/j.ekir.2025.06.050. PubMed

See more in PubMed

Carney E.F. The impact of chronic kidney disease on global health. Nat Rev Nephrol. 2020;16:251. doi: 10.1038/s41581-020-0268-7. PubMed DOI

Stack A.G., Casserly L.F., Cronin C.J., et al. Prevalence and variation of chronic kidney disease in the Irish health system: initial findings from the National Kidney Disease Surveillance Programme. BMC Nephrol. 2014;15:185. doi: 10.1186/1471-2369-15-185. PubMed DOI PMC

Sundström J., Bodegard J., Bollmann A., et al. Prevalence, outcomes, and cost of chronic kidney disease in a contemporary population of 2.4 million patients from 11 countries: the CaReMe CKD study. Lancet Reg Health Eur. 2022;20 doi: 10.1016/j.lanepe.2022.100438. PubMed DOI PMC

Nguyen N.T.Q., Cockwell P., Maxwell A.P., Griffin M., O’Brien T., O’Neill C. Chronic kidney disease, health-related quality of life and their associated economic burden among a nationally representative sample of community dwelling adults in England. PLoS One. 2018;13 doi: 10.1371/journal.pone.0207960. PubMed DOI PMC

GBD Chronic Kidney Disease Collaboration Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395:709–733. doi: 10.1016/S0140-6736(20)30045-3. PubMed DOI PMC

Connaughton D.M., Bukhari S., Conlon P., et al. The Irish kidney gene project--prevalence of family history in patients with kidney disease in Ireland. Nephron. 2015;130:293–301. doi: 10.1159/000436983. PubMed DOI

Jefferis J., Hudson R., Lacaze P., et al. Monogenic and polygenic concepts in chronic kidney disease (CKD) J Nephrol. 2023;37:7–21. doi: 10.1007/s40620-023-01804-8. PubMed DOI PMC

Rasouly H.M., Groopman E.E., Heyman-Kantor R., et al. The burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing. Ann Intern Med. 2019;170:11–21. doi: 10.7326/M18-1241. PubMed DOI

Stokman M.F., Renkema K.Y., Giles R.H., Schaefer F., Knoers N.V., van Eerde A.M. The expanding phenotypic spectra of kidney diseases: insights from genetic studies. Nat Rev Nephrol. 2016;12:472–483. doi: 10.1038/nrneph.2016.87. PubMed DOI

Connaughton D.M., Kennedy C., Shril S., et al. Monogenic causes of chronic kidney disease in adults. Kidney Int. 2019;95:914–928. doi: 10.1016/j.kint.2018.10.031. PubMed DOI PMC

Groopman E.E., Marasa M., Cameron-Christie S., et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2019;380:142–151. doi: 10.1056/NEJMoa1806891. PubMed DOI PMC

World Health Organization . World Health Organization; Published 2012. Good health adds life to years: global brief for world health day 2012.https://www.who.int/publications/i/item/WHO-DCO-WHD-2012.2

Zhang J., Thio C.H.L., Gansevoort R.T., Snieder H. Familial aggregation of CKD and heritability of kidney biomarkers in the general population: the lifelines cohort study. Am J Kidney Dis. 2021;77:869–878. doi: 10.1053/j.ajkd.2020.11.012. PubMed DOI

Knoers N., Antignac C., Bergmann C., et al. Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice. Nephrol Dial Transplant. 2022;37:239–254. doi: 10.1093/ndt/gfab218. PubMed DOI PMC

Mrug M., Bloom M.S., Seto C., et al. Genetic testing for chronic kidney diseases: clinical utility and barriers perceived by nephrologists. Kidney Med. 2021;3:1050–1056. doi: 10.1016/j.xkme.2021.08.006. PubMed DOI PMC

Devuyst O., Knoers N.V., Remuzzi G., Schaefer F. Board of the Working Group for Inherited Kidney Diseases of the European Renal Association and European Dialysis and Transplant Association. Rare inherited kidney diseases: challenges, opportunities, and perspectives. Lancet. 2014;383:1844–1859. doi: 10.1016/S0140-6736(14)60659-0. PubMed DOI PMC

Domingo-Gallego A., Pybus M., Bullich G., et al. Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. Nephrol Dial Transplant. 2022;37:687–696. doi: 10.1093/ndt/gfab019. PubMed DOI

Hateboer N., v Dijk M.A., Bogdanova N., et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet. 1999;353:103–107. doi: 10.1016/s0140-6736(98)03495-3. PubMed DOI

Eckardt K.U., Alper S.L., Antignac C., et al. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management-a KDIGO consensus report. Kidney Int. 2015;88:676–683. doi: 10.1038/ki.2015.28. PubMed DOI

Cormican S., Connaughton D.M., Kennedy C., et al. Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland. Ren Fail. 2019;41:832–841. doi: 10.1080/0886022X.2019.1655452. PubMed DOI PMC

Connaughton D.M., Hildebrandt F. Personalized medicine in chronic kidney disease by detection of monogenic mutations. Nephrol Dial Transplant. 2019;35:390–397. doi: 10.1093/ndt/gfz028. PubMed DOI PMC

Brück K., Stel V.S., Gambaro G., et al. CKD prevalence varies across the European general population. J Am Soc Nephrol. 2016;27:2135–2147. doi: 10.1681/ASN.2015050542. PubMed DOI PMC

Lindeman R.D., Tobin J.D., Shock N.W. Association between blood pressure and the rate of decline in renal function with age. Kidney Int. 1984;26:861–868. doi: 10.1038/ki.1984.229. PubMed DOI

Mallappallil M., Friedman E.A., Delano B.G., McFarlane S.I., Salifu M.O. Chronic kidney disease in the elderly: evaluation and management. Clin Pract (Lond) 2014;11:525–535. doi: 10.2217/cpr.14.46. PubMed DOI PMC

Vendemia F., Gesualdo L., Schena F.P., D’Amico G., Renal Immunopathology Study Group of the Italian Society of Nephrology Epidemiology of primary glomerulonephritis in the elderly. Report from the Italian registry of renal biopsy. J Nephrol. 2001;14:340–352. PubMed

Tonelli M., Riella M.C. Chronic kidney disease and the aging population. Kidney Int. 2014;85:487–491. doi: 10.1038/ki.2013.467. PubMed DOI

van Oevelen M., Abrahams A.C., Bos W.J.W., et al. DIALysis or not: outcomes in older kidney patients with GerIatriC Assessment (DIALOGICA): rationale and design. BMC Nephrol. 2021;22:39. doi: 10.1186/s12882-021-02235-y. PubMed DOI PMC

Brown C.M., Scheven L., O’Kelly P., Dorman A.M., Walshe J.J. Renal histology in the elderly: indications and outcomes. J Nephrol. 2012;25:240–244. doi: 10.5301/JN.2011.8447. PubMed DOI

Grünfeld J.P., Jungers P., Fumeron C., Richard S. Genetic kidney diseases in the elderly. Nephrol Dial Transplant. 1998;13(suppl 7):48–50. doi: 10.1093/ndt/13.suppl_7.48. PubMed DOI

Levin A., Stevens P.E. Summary of KDIGO 2012 CKD Guideline: behind the scenes, need for guidance, and a framework for moving forward. Kidney Int. 2014;85:49–61. doi: 10.1038/ki.2013.444. PubMed DOI

Benson K.A., Murray S.L., Senum S.R., et al. The genetic landscape of polycystic kidney disease in Ireland. Eur J Hum Genet. 2021;29:827–838. doi: 10.1038/s41431-020-00806-5. PubMed DOI PMC

Elhassan E.A.E., Murray S.L., Connaughton D.M., et al. The utility of a genetic kidney disease clinic employing a broad range of genomic testing platforms: experience of the Irish Kidney Gene Project. J Nephrol. 2022;35:1655–1665. doi: 10.1007/s40620-021-01236-2. PubMed DOI PMC

Blumenstiel B., DeFelice M., Birsoy O., et al. Development and validation of a mass spectrometry-based assay for the molecular diagnosis of Mucin-1 kidney disease. J Mol Diagn. 2016;18:566–571. doi: 10.1016/j.jmoldx.2016.03.003. PubMed DOI

Živná M., Kidd K., Přistoupilová A., et al. Noninvasive immunohistochemical diagnosis and novel MUC1 mutations causing autosomal dominant tubulointerstitial kidney disease. J Am Soc Nephrol. 2018;29:2418–2431. doi: 10.1681/ASN.2018020180. PubMed DOI PMC

Poplin R., Ruano-Rubio V., DePristo M.A., et al. Scaling accurate genetic variant discovery to tens of thousands of samples. Preprint. Posted online July 24, 2018 bioRxiv.

Richards S., Aziz N., Bale S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–423. doi: 10.1038/gim.2015.30. PubMed DOI PMC

Köttgen A., Cornec-Le Gall E., Halbritter J. Genetics in chronic kidney disease: conclusions from a Kidney Disease: improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2022;101:1126–1141. doi: 10.1016/j.kint.2022.03.019. PubMed DOI PMC

Tonelli M., Riella M. Chronic kidney disease and the aging population. Am J Physiol Ren Physiol. 2014;306:F469–F472. doi: 10.1152/ajprenal.00063.2014. PubMed DOI

Bleyer A.J., Westemeyer M., Xie J., et al. Genetic etiologies for chronic kidney disease revealed through next-generation renal gene panel. Am J Nephrol. 2022;53:297–306. doi: 10.1159/000522226. PubMed DOI PMC

Dahl N.K., Bloom M.S., Chebib F.T., et al. The clinical utility of genetic testing in the diagnosis and management of adults with chronic kidney disease. J Am Soc Nephrol. 2023;34:2039–2050. doi: 10.1681/ASN.0000000000000249. PubMed DOI PMC

Elliott M.D., Vena N., Marasa M., et al. Increased risk of kidney failure in patients with genetic kidney disorders. J Clin Invest. 2024;134 doi: 10.1172/JCI178573. PubMed DOI PMC

Olinger E., Schaeffer C., Kidd K., et al. An intermediate-effect size variant in UMOD confers risk for chronic kidney disease. Proc Natl Acad Sci U S A. 2022;119 doi: 10.1073/pnas.2114734119. PubMed DOI PMC

Becherucci F., Landini S., Palazzo V., et al. A clinical workflow for cost-saving high-rate diagnosis of genetic kidney diseases. J Am Soc Nephrol. 2023;34:706–720. doi: 10.1681/ASN.0000000000000076. PubMed DOI PMC

Wojcik M.H., Lemire G., Berger E., et al. Genome sequencing for diagnosing rare diseases. N Engl J Med. 2024;390:1985–1997. doi: 10.1056/NEJMoa2314761. PubMed DOI PMC