Kidney Week

Abstract: FR-PO0153

Natural History of NPHS2 Nephropathy

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

• Ding, Wen Yi, University of Bristol, Bristol, England, United Kingdom

Wen Yi Ding, MBBS, PhD

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

Elena Martinelli, MD

• Hayward, Samantha JL, University of Bristol, Bristol, England, United Kingdom

Samantha JL Hayward, MBChB

• Marchuk, Daniel, Boston Children's Hospital, Boston, Massachusetts, United States

Daniel Marchuk, MD

• Knob, Andrea, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Andrea Knob

• Angeletti, Andrea, Istituto Giannina Gaslini, Genoa, Liguria, Italy

Andrea Angeletti, MD, PhD

• Morello, William, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

William Morello, MD, PhD

• Varner, Jennifer Drucker, Duke University School of Medicine, Durham, North Carolina, United States

Jennifer Drucker Varner, MD, MS

• Oto, Ozgur Akin, Istanbul Universitesi, Fatih, Istanbul, Turkey

Ozgur Akin Oto, MD

• Rampino, Teresa, Fondazione IRCCS Policlinico San Matteo, Pavia, Lombardia, Italy

Teresa Rampino, MD

• Pisani, Isabella, Universita degli Studi di Parma, Parma, Emilia-Romagna, Italy

Isabella Pisani, MD

• Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)

Velibor Tasic

• Zaza, Gianluigi, Universita degli Studi di Foggia, Foggia, Apulia, Italy

Gianluigi Zaza, MD, PhD

• Esposito, Pasquale, IRCCS Ospedale Policlinico San Martino, Genoa, Liguria, Italy

Pasquale Esposito, MD, PhD

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

Adele Mitrotti, MD, PhD

• Montini, Giovanni, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Giovanni Montini, MD

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

Rasheed A. Gbadegesin, MD, MBBS, FASN

• Caliskan, Yasar, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Yasar Caliskan, MD

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

Gian Marco Ghiggeri, MD

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

Martin Pollak, MD

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

Friedhelm Hildebrandt, MD

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

Simone Sanna-Cherchi, MD

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

Moin A. Saleem, MD, MBBS, MBChB, PhD

Background

In childhood nephrotic syndrome (NS), NPHS2 is the commonest gene implicated in Europe (EU). NPHS2 nephropathy is autosomal recessive, with R138Q being the most common childhood variant in EU, while R229Q is late onset and conditionally pathogenic and only pathogenic in trans with specific variants. Here, we aimed to describe the genetic, clinical and pathological features of NPHS2 nephropathy.

Methods

Cases were identified from 5,259 individuals with NS from centres or studies in the US and EU. Variants were curated according to ACMG guidelines. Written informed consent was collected from all participants and in compliance with local ethic committees.

Results

81 cases with NPHS2 pathogenic variants were identified (32 EU, 49 US). We classified genotypes into homozygous (47%), other compound heterozygous (excluding R229Q) (14%) and R229Q compound heterozygous (39%). Age of onset was significantly higher for R229Q compound heterozygous (17 (range 1-71) years) compared to homozygous cases (5 (range 0.3-22) years). The most common variant was R229Q (mostly US, 25/32), followed by R138Q (mostly EU, 14/22), followed by A284V (mostly US, 13/15). Presentation with proteinuria without NS accounted for 27.8% of cases. Light microscopy demonstrated mostly focal segmental glomerulosclerosis (41/55, 74.5%), while electron microscopy (EM) (n=14) consistently showed diffuse foot process effacement (FPE). Complete remission was not achieved with steroids, while one patient on Tacrolimus achieved complete remission. End stage renal disease (ESRD) progression was slower in V180M homozygous, V290M compound heterozygous and R229Q compound heterozygous cases compared to other genotypes.

Conclusion

We report here an international NPHS2 nephropathy cohort, confirming the high frequency of R138Q associated with fast ESRD progression. We show that EM appearances are consistently of diffuse FPE. We demonstrate a high frequency of R229Q compound heterozygous cases, particularly in the US. These cases, in addition to V180M homozygous and V290M compound heterozygous, show slower ESRD progression, emphasising that NPHS2 nephropathy is not limited to a fast-progressing childhood phenotype. Genetic screening for NPHS2 should not be limited by age of presentation nor by speed of progression, while minimal immunosuppression response (with diffuse FPE) should increase the index of suspicion for NPHS2 nephropathy.