Kidney Week

Abstract: SA-PO0639

SLC34A3 Variants Associated with Urinary Stone Disease and Hypercalciuria in the Mayo Clinic Biobank

Session Information

• Monogenic Kidney Diseases: Tubular and Other
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Ahmed, Omar Ahmed Saad, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

Omar Ahmed Saad Ahmed, MD

• Cogal, Andrea G., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

Andrea G. Cogal

• McDonnell, Shannon K., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

Shannon K. McDonnell, MS

• Larson, Nicholas B., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

Nicholas B. Larson, PhD

• Harris, Peter C., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

Peter C. Harris, PhD

• Lieske, John C., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

John C. Lieske, MD, FASN

Group or Team Name

• Division of Nephrology and Hypertension - Mayo Clinic.

Background

Urinary stone disease (USD) is a multifactorial condition with both environmental and genetic risk factors. Genome-wide studies have shown that variants in monogenic USD genes account for some of the genetic risk for USD. Among these, SLC34A3, encoding the sodium-phosphate cotransporter NPT2c, which plays a key role in proximal tubular phosphorus reabsorption, is emerging as a risk gene. This study aimed to characterize the association of SLC34A3 rare variants with USD and assess the role of SLC34A3 variants and USD hypercalciuria in a population cohort, the Mayo Clinic Biobank (MCBB).

Methods

Participants were categorized as stone formers (SF) or non-stone formers (non-SF) using ICD-9/10 and procedure codes. Hypercalciuria was defined as >250 mg/day for males and >200 mg/day for females in available 24-hour urine data. Exome sequencing data were employed for genome-wide gene-based rare variant association testing with the USD phenotype.

Results

Among the 43,743 participants in MCBB, 5,998 were classified as USD cases (SF), while 37,745 served as controls (non-SF). Gene-based rare variant testing identified SLC34A3 as the only gene significantly associated with SF (P=6.1E-07). Rare SLC34A3 variants were also tested against 1809 phenotypes (PheWAS) and the only significant associations were with urinary calculus (p=9.24e-07) and calculus of the kidney (p=3.20e-06). Within MCBB SF, 20 carriers of the four most strongly associated recurrent (>5x) SLC34A3 variants (p.Leu526del, c.448+1G>A, p.Ser138Phe, c.304+2T>C) were identified. Hypercalciuria was present in 5 of 6 (83.3%) in this SF group (where 24-hour urine data were available). Additionally, 16 carriers of the p.Ser192Leu variant were identified in the SF group, and both patients with urinary data were hypercalciuric (median 441 mg/day while on chlorthalidone). Chart review showed that these SF SLC34A3 variant carriers often had recurring stone events (72.7%), and most of these cases required urological intervention.

Conclusion

Rare variants in SLC34A3 are enriched in SF, suggesting a significant genetic contribution to USD risk. Among these, hypercalciuria is common, but further research is needed to determine the clinical implications of these findings.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025c7gb6tcm