Kidney Week

Abstract: FR-PO0133

Shared Genetic Mechanisms Between Congenital Anomalies of the Kidney and Urinary Tract and FSGS Revealed by Whole-Exome Sequencing

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Ke, Juntao, Columbia University, New York, New York, United States

Juntao Ke, PhD

• Martinelli, Elena, Columbia University, New York, New York, United States

Elena Martinelli, MD

• Lim, Tze Yin, Columbia University, New York, New York, United States

Tze Yin Lim, PhD

• Shril, Shirlee, Boston Children Hospital, Boston, Massachusetts, United States

Shirlee Shril

• Gupta, Yask, Columbia University, New York, New York, United States

Yask Gupta, PhD

• Mitrotti, Adele, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy

Adele Mitrotti, MD, PhD

• Westland, Rik, Amsterdam UMC Locatie AMC, Amsterdam, NH, Netherlands

Rik Westland, MD, PhD

• Pisani, Isabella, University of Parma, Parma, Italy

Isabella Pisani, MD

• Montini, Giovanni, Universita degli Studi di Milano, Milan, Lombardy, Italy

Giovanni Montini, MD

• Maggiore, Umberto, University of Parma, Parma, Italy

Umberto Maggiore, MD

• Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy

Loreto Gesualdo, DrMed

• Ghiggeri, Gian Marco, Istituto Giannina Gaslini, Genoa, Liguria, Italy

Gian Marco Ghiggeri, MD

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk, MD

• Ko, Vincent, KidneyFuture (formerly CAKUT Foundation), Rockville, Maryland, United States

Vincent Ko

• Saleem, Moin A., University of Bristol, Bristol, England, United Kingdom

Moin A. Saleem, MD, MBBS, MBChB, PhD

• Gbadegesin, Rasheed A., Duke University, Durham, North Carolina, United States

Rasheed A. Gbadegesin, MD, MBBS, FASN

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi, MD

• Sampson, Matt G., Boston Children Hospital, Boston, Massachusetts, United States

Matt G. Sampson, MD

• D'Agati, Vivette D., Columbia University, New York, New York, United States

Vivette D. D'Agati, MD

• Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Martin Pollak, MD

• Hildebrandt, Friedhelm, Boston Children Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

• Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Simone Sanna-Cherchi, MD

Background

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are linked to reduced nephron endowment, glomerular hyperfiltration and glomerulomegaly, potentially predisposing to Focal Segmental Glomerulosclerosis (FSGS). Case reports and small series have identified mutations in CAKUT-associate genes in patients with biopsy-proven FSGS, suggesting shared genetic mechanisms between these two diseases. Whether CAKUT and secondary FSGS are mechanistically related remains to be elucidated.

Methods

To understand the role of the developmental genes in the pathobiology of FSGS, we analyzed whole exome sequencing (WES) data from 5,259 cases with idiopathic nephrotic syndrome (INS) caused by FSGS or minimal change disease. A comprehensive screening was performed to identify cases harboring Mendelian variants in 114 known FSGS genes including 12 CAKUT genes previously reported in cases with FSGS. We next conducted clinical-pathological correlations in 15 CAKUT mutation carriers with available kidney biopsy data.

Results

Pathogenic variants in the 12 top-priority CAKUT genes were identified in 1.1% (N=56) of INS cases, accounting for 8.1% of 694 genetically solved NS cases. This yield was similar to the one of tubulointerstitial kidney disease (TKD) genes (7.4%, N=51). Pathogenic variants were highly enriched in individuals with steroid-resistant nephrotic syndrome (SRNS) or FSGS, accounting for 51/3,248 cases (1.6%). 38/1,869 (2.0%) were children and 13/1,379 (0.9%) were adults. Overall, two-third (66.9%) of adult monogenic FSGS was attributable to genotypes in non-podocytopathy genes, including COL4A3-5, CAKUT and TKD. FSGS patients with CAKUT mutations showed clinical and biopsy hallmarks of secondary/adaptive FSGS, including obesity (40%), hypertension (40%), subnephrotic proteinuria (60%), glomerulomegaly (60%), and variable (0 to 100%) podocyte foot process effacement.

Conclusion

This study supports shared genetic architecture between CAKUT and FSGS. CAKUT genes’ mutations accounted for 8-10% of monogenic FSGS and displayed clinical and biopsy characteristics of secondary FSGS. These data motivate extension of these analyses to all genes involved in monogenic CAKUT. Genetics offers the causal framework to support CAKUT as part of the spectrum of FSGS and proteinuric kidney diseases that are commonly observed in the clinic.