Kidney Week

Abstract: TH-PO576

New Pathogenic Mutations of Complement Factor H Causing Early Recurrence of C3 Glomerulonephritis After Kidney Transplantation

Session Information

• Trainee Case Reports - II
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Trainee Case Reports

• 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

• Huidobro, Juan Pablo, Pontificia Universidad Católica de Chile, Santiago, Chile

Juan Pablo Huidobro,

• Sepúlveda, Rodrigo, Pontificia Universidad Católica de Chile, Santiago, Chile

Rodrigo Sepúlveda,

• Mendez, Gonzalo P., Pontificia Universidad Catolica de Chile., Santiago, Chile

Gonzalo P. Mendez,

• Tagle, Rodrigo, Pontificia Universidad Católica de Chile, Santiago, Chile

Rodrigo Tagle,

• Bresin, Elena, Mario Negri Institute for Pharmacological Research, Ranica, BG, Italy

Elena Bresin,

• Jara, Aquiles, Pontificia Universidad Católica de Chile, Santiago, Chile

Aquiles Jara,

Introduction

C3 glomerulonephritis (C3GN) is a rare group of kidney disorders caused by over-activation of the alternative complement pathway. C3GN usually recurs between 3 to 6 months post-transplant. Here we report two likely pathogenic heterozygous variants in complement factor H (CFH), not previously described, involved in early recurrence of C3GN.

Case Description

A 24 year old female with history of left nephrectomy (vesicoureteral reflux) and ESRD with a kidney biopsy showing C3GN (MPGN with C3 deposition and microangiopathy (TMA)) received a deceased donor kidney transplant (KDPI 54%). She was on hemodialysis for 3 years with 2 vascular access thrombotic events. Her cPRA was 0% and received steroids-basiliximab for induction.
She developed early post-transplant renal vein thrombosis (day 1) with no urinary flow. A thrombectomy was performed and heparin was started. Thymoglobulin was initiated. The patient evolved with delayed graft function, with scintigraphy (MAG3) compatible with acute tubular necrosis (ATN), and was discharged on dialysis with tacrolimus, mycophenolate and prednisone. Three weeks later her creatinine clearance was 11 ml/min/1.73m². A kidney graft biopsy was performed showing signs of ATN but also arteriolar acute TMA and extensive C3 deposition, with negative C4d. Anti-HLA antibodies were negative.
The patient developed recurrent allograft infections and loss of kidney function. Therefore, a transplant nephrectomy was performed 3 months after transplantation.
A genetic study was performed by NGS for CFH, CFI, CFB, C3, MCP, THBD, DGKE, and MLPA for CFH-CFHR1 hybrid gene and CFHR1-CFHR3 deletion. Levels of CFH were slightly low 111.8 mg/L (NV 156-572). We found two variants in the N-terminal end of CFH: a new one in SCR1 domain (p.G60R) and a rare one in SCR4 domain (p.P260S) not previously reported.

Discussion

Several modeling software predicted that both mutations are probably pathogenic. In both cases the substitution induces the change of a hydrophobic amino-acid for an hydrophilic one, potentially affecting structure and function of CFH.
We report these two new CFH mutations as a potential cause for both fluid phase and cell-surface complement activation, accounting for the original disease and the early recurrence after transplant.