Nephrolithiasis and nephrocalcinosis

Nephrolithiasis and nephrocalcinosis present clinically with renal colic, haematuria, recurrent urinary tract infections, or incidental imaging findings of calcified deposits in the calyceal system or renal parenchyma. Adult kidney stone disease is common in Europe and largely multifactorial, but a clinically meaningful subset of affected individuals harbour a monogenic tubular disorder. Age of onset across the genetic spectrum spans paediatric to adult presentations. Recurrent stone formation, bilateral disease, a positive family history, early onset, and coexisting nephrocalcinosis raise the index of suspicion for an underlying monogenic cause; in such individuals genetic confirmation alters surveillance, family counselling, and disease-specific therapy.

Kidney stones are highly prevalent and represent a major global health burden, affecting approximately 10% of adults worldwide. Epidemiological data shows the incidence is steadily rising across all demographics. Population-level data for nephrocalcinosis are lacking, but it is much rarer in the general population.

A monogenic cause is identified in 15-30% of cases in pediatric cohorts and roughly 10% of cases in adult cohorts, respectively. Many genes have been associated with nephrolithiasis and nephrocalcinosis. The genetic forms can be grouped into cystinuria and dibasic amino acid transport defects, hypercalciuric and calcium-handling tubular disorders, and hyperoxaluric disorders. In an adult European single-center cohort, cystinuria, vitamin D-24-hydroxylase deficiency and primary hyperoxaluria were the most frequently identified monogenic causes; X-linked Dent disease was a further recognised cause.

The genetic conditions associated with nephrolithiasis and nephrocalcinosis follow heterogeneous inheritance patterns. Autosomal recessive transmission predominates among the most frequently identified monogenic causes (cystinuria, vitamin D-24-hydroxylase deficiency, primary hyperoxaluria), while autosomal dominant and X-linked forms (e.g., Dent disease) are also represented across the spectrum.

• Where nephrolithiasis or nephrocalcinosis is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• While empirical management often fails or falls short in monogenic stone diseases, genetic analysis makes it possible to determine the precise molecular aetiology, enabling pathway-specific targeted therapies.
• Early genetic diagnosis enables aggressive intervention before significant nephron loss occurs, potentially preventing progression to end-stage renal disease and maximising renal longevity.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Anderegg MA, Olinger EG, Bargagli M, Geraghty R, Taylor L, Nater A, et al. Prevalence and characteristics of genetic disease in adult kidney stone formers. Nephrol Dial Transplant. 2024;39(9):1426-41. doi:10.1093/ndt/gfae074. PMID:; PMCID:PMC11483609.
• Geraghty R, Lovegrove C, Howles S, Sayer JA. Role of genetic testing in kidney stone disease: a narrative review. Curr Urol Rep. 2024;25(12):311-23. doi:10.1007/s11934-024-01225-5. PMID:; PMCID:PMC11374836.
• Singh P, Harris PC, Sas DJ, Lieske JC. The genetics of kidney stone disease and nephrocalcinosis. Nat Rev Nephrol. 2022;18(4):224-40. doi:10.1038/s41581-021-00513-4. PMID:.
• Gefen AM, Zaritsky JJ. Review of childhood genetic nephrolithiasis and nephrocalcinosis. Front Genet. 2024;15:1381174. doi:10.3389/fgene.2024.1381174. PMID:; PMCID:PMC11007102.