Abstract: TH-PO0548
Who's in the Driver's Seat? IgAN vs. FSGS as Competing Drivers of Progressive CKD in the Setting of a Variant of Uncertain Significance
Session Information
- Glomerular Diseases: IgAN, IgA Vasculitis, and More
October 22, 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
- Senthil Kumar, Prasiddha, Saint Vincent Hospital, Worcester, Massachusetts, United States
- Martin, Suzanne Gwen, Saint Vincent Hospital, Worcester, Massachusetts, United States
Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis. Treatment of FSGS varies depending on pathophysiology, with immunosuppression generally being ineffective in genetic forms. Widespread use of genetic testing can reveal variants of uncertain significance (VUS), which may fit the clinical scenario but are not proven to be pathogenic. Competing reasons for proteinuria, with two lesions on renal biopsy, can complicate therapeutic decision making.
Case Description
40M presented with hematuria, proteinuria (0.5-1g/gCr), and a GFR of 84ml/min. Over the next decade, his GFR fell to 51ml/min, and proteinuria rose to 2.5-3 g/gCr, without nephrotic syndrome. Blood pressure was controlled and workup for autoimmune disease was unremarkable. Biopsy revealed IgAN (M1E0S2T2 C0), along with FSGS with features of collapsing glomerulopathy, chronic interstitial nephritis, and significant glomerulosclerosis. HIV was negative and he was not taking bisphosphonates. His father had CKD and his sister had proteinuria. Genetic testing showed a heterozygous CD2AP VUS, a gene whose known mutations cause childhood onset FSGS with nephrotic syndrome.
Discussion
If IgAN is driving increasing proteinuria and progression of CKD, new therapies should be considered, including sparsentan for CKD attenuation, and upstream agents, including iptacopan, sibeprenlimab, atacicept or targeted release budesonide, to reduce proteinuria to the new goal of < 0.3-0.5g/day. He has had persistent microscopic hematuria, suggesting ongoing inflammation. If the collapsing FSGS is the dominant process driving proteinuria and CKD progression, he is unlikely to benefit from, and may be harmed by, immunosuppression. The CD2AP mutation was a VUS, so its pathogenicity is uncertain. VUS reclassification ultimately occurs in about 5% of cases. Shared decision-making should be employed in cases with two pathologic diagnoses on renal biopsy, with a possible time-limited trial of treatment for IgAN to assess response. The appropriate use of new disease-altering therapies for IgAN, a relatively common second, and sometimes incidental, finding on biopsy, should be investigated further to better predict who should receive these medications.