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Kidney Week

Abstract: TH-PO471

A New BMP-4 Gene Mutation Associated with Adult Focal Segmental Glomerulosclerosis (FSGS)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Szendrey, John Alexander, UMass Chan Med School-Baystate, Springfield, Massachusetts, United States
  • Landry, Daniel L., UMass Chan Med School-Baystate, Springfield, Massachusetts, United States
  • Hodgins, Spencer, UMass Chan Med School-Baystate, Springfield, Massachusetts, United States
  • Mulhern, Jeffrey, UMass Chan Med School-Baystate, Springfield, Massachusetts, United States
  • Fatima, Sana, UMass Chan Med School-Baystate, Springfield, Massachusetts, United States
  • Braden, Gregory Lee, UMass Chan Med School-Baystate, Springfield, Massachusetts, United States

Group or Team Name

  • Kidney Care & Transplant service of New England.
Introduction

FSGS has been associated with numerous gene defects in children, adolescents & adults. We describe a new BMP-4 gene mutation associated with adult onset FSGS treated successfully with combined supratherapeutic ACE inhibitors with an ARB.

Case Description

In 1994 a 40 year(yr) old non-smoking obese man developed nephrotic syndrome & hypertension. His daily urine protein excretion was 3.6 gms, iothalamate gfr 81 ml/min, s creatinine 1.2 mg/dl, s albumin 3.0 gm/dl & cholesterol 400 mg/dl. He had no signs of systemic diseases. C3 & C4 complements, ANA, ANCA, immunofixation, hepatitis A,B & C were normal. A renal biopsy showed: Light: 3/16 glomeruli with focal glomerular sclerosis & moderate tubular & interstitial sclerosis. IF: completely negative. EM: increased measangial matrix with focal foot process fusion, thickened basement membranes & no immune deposits. A Dx of FSGS.NOS possibly due to obeisty was made. He was treated with supratherapeutic lisinopril 40 mg bid and valsartan 160 mg a day for 30 years despite retraction of the Lancet COOPERATE trial in 2012. His decrease in gfr over 29 yrs was only 1.8 ml/mim/yr. His urine protein decreased to 1 gm after 6 yrs & was only 1 gm/d until 2015 when it increased to 1.5 gm/d,& then to 2.2 gm in 2022. His gfr gradually declined to 65 ml /min in 2000, 50 ml/min in 2010, 36 ml/min in 2015 & 29 ml/min in 2023.
A Renasight gene panel (Natera, Austin,TX) showed: a c 124G>C (pAla 42 Pro) mutation, codon 42 missense on exon 3 guanine for cytosine.

Discussion

Loss of function mutations in BMP-4 are associated with CAKUT. A BMP-4 gain of function mutation in animal studies shows increased SMAD which inhibits podocyte VEGF leading to shrinkage & immature glomeruli (H.Euda, JASN 19:685, 2008). In addition Iv and intravitreal VEGF inhibitors in humans can cause FSGS (CC Estrada JASN 30:187, 2019).We conclude that the BMP-4 mutation in our pt could lead to inhibition of intraglomerular VEGF inducing FSGS. Supratherapeutic ACE inhibitors with an ARB may slow the loss of gfr in FSGS & could be used as a control for a study against sparsentan for FSGS.