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Kidney Week

Abstract: TH-PO465

RAAS Inhibition Delays Onset of Nephrotic Syndrome due to TRPC6-Mediated FSGS: A Case Report of a Sibling Pair

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Carver, Ashley W., The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Glenn, Dorey A., The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Westreich, Katherine D., The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
Introduction

Transient receptor potential channel (TRPC6) is a slit diaphragm protein located on the podocyte, and a known genetic cause of focal segmental glomerulosclerosis (FSGS). Upregulation of TRPC6 channel activity is proposed to disturb podocyte structure, leading to proteinuria. ACE inhibitors (ACEi) demonstrate reno-protective benefits, reduction in proteinuria, and are commonly used to reduce proteinuria in FSGS. Here we describe progression to symptomatic nephrotic syndrome in a sibling pair with TRPC6 mediated steroid resistant FSGS as a function of early vs. late initiation of ACEi.

Case Description

Sibling A, the older of the two affected siblings, presented to care at 3 years of age with generalized edema, hypoalbuminemia (1.6g/dL), and nephrotic range proteinuria (UPCR 35mg/mg). Family history revealed that the child's father had end stage kidney disease of unclear etiology at the age of 3 years. Genetic testing of the child and parents demonstrated an autosomal dominant mutation in TRPC6 ((c.523C>T)[p.R175W]). Sibling A was unresponsive to steroids and cyclosporine and progressed to dialysis dependence due to fluid overload and pulmonary edema. Sibling A underwent kidney transplantation without recurrence of proteinuria. Sibling B, whose genetic diagnosis was made shortly after birth, was immediately started on RAAS inhibition, which was then maximally up-titrated (0.6mg/kg) as tolerated by blood pressure. He eventually underwent unilateral nephrectomy at age 4 to aid with proteinuria reduction. At age 5, nephrectomy of the remaining kidney was pursued with transition to peritoneal dialysis and preparation for kidney transplant. The age at dialysis dependence was 3 years in Sibling A and 5.5 years in Sibling B.

Discussion

In summary, this report describes delay in progression to symptomatic nephrotic syndrome in a child with TRPC6 mutation due to early exposure to ACEi. The reno-protective mechanisms of ACEi are not fully understood and include proteinuria reduction and anti-fibrotic effects. Angiotensin II has been described to cause upregulation of TRPC6, thus aggressive blockade of this pathway may be a unique benefit to patients with TRPC6 mutations. A comparison of the siblings reported here would suggest that ACEi may significantly delay symptomatic nephrotic syndrome when started early and dosed maximally.