Kidney Week

Abstract: SA-PO0699

A Familial Case Highlights the Necessity of Biomarker Determination Alongside Genetic Testing in C3 Glomerulopathy, Age-Related Macular Degeneration, and Neuromyelitis Optica Spectrum Disorder

Session Information

• Glomerular Diseases: Complement-Mediated Glomerulopathies and Infection-Related GN
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics

Authors

• Martin Merinero, Hector, University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States

Hector Martin Merinero, PhD

• Taylor, Amanda O., University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States

Amanda O. Taylor

• Kruger, Kameron J., University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States

Kameron J. Kruger

• Roberts, Sarah M., University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States

Sarah M. Roberts

• Mandelbrot, Didier A., University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States

Didier A. Mandelbrot, MD

• Nester, Carla M., University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States

Carla M. Nester, MD, MS, FASN

• Smith, Richard J., University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States

Richard J. Smith, MD

• Garg, Neetika, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States

Neetika Garg, MD

• Zhang, Yuzhou, University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States

Yuzhou Zhang, PhD

Introduction

Dysregulation of the complement system is the main driver of the ultra-rare kidney disease C3 glomerulopathy (C3G), but it is also associated with non-renal pathologies, such as age-related macular degeneration (AMD) and neuromyelitis optica spectrum disorder (NMOSD). Effective use of complement genetic information is restricted by the incomplete penetrance of genetic variants, the rarity of C3G, the late onset of AMD/NMOSD, and the limited availability of family clinical records. Here, we present a familial case that exemplifies this variability and highlights the importance of measuring biomarkers, in addition to genetic testing, to optimize the use of genetic information.

Case Description

A 35-year-old male with lifelong biopsy-proven C3G presented for kidney transplant evaluation. Genetic and molecular testing revealed two novel CFH variants (c.546C>A and c.1288A>C) and undetectable levels of factor H (FH), consistent with null alleles. Segregation analysis confirmed compound heterozygosity and that five relatives (sister, father, mother, paternal aunt and maternal uncle) carried one null allele. They had AMD and/or NMOSD, while a healthy cousin carried no variants and was approved as living donor. Notably, FH levels varied significantly in carriers, with the development of AMD and NMOSD seen only with the lowest FH levels. The patient began treatment with complement inhibitors before transplantation and post-transplant remains stable with normal renal function and complement biomarkers.

Discussion

The patient’s genetics and biomarkers recapitulate findings in the well-established pig and mouse models^(1,2) of C3G, confirming the diagnosis, defining the disease driver and guiding clinical decisions. FH level variability amongst relatives reflects the impact of expression quantitative trait loci and illustrates the value of complement biomarkers to make optimal use of genetic information. In this regard, the sister has inherited the low expression wild type allele and is at risk for NMOSD.

Acknowledgment

This work was supported in part by the R01 DK110023; we thank those patients who have made this research possible.
References: ⁽¹⁾ PMID 9461093; ⁽²⁾ PMID 12091909