MO043: Role of the I416L variant of complement factor I in the occurrence of thrombotic microangiopathy among patients of African ancestry
Authors: Nobile Giulio , Doreille Alice , Raymond Laure , Robert Thomas , Villie Patricia , Mesnard Laurent , Rafat Cédric 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Complement dependent hemolytic and uremic syndrome (c-HUS) predisposes to hypertensive crisis and chronic hypertension. Reciprocally, hypertensive crisis may precipitate thrombotic microangiopathy (TMA) via endothelial shear stress. Patients of African ancestry have long been recognized for their predisposition to both chronic hypertension and chronic kidney disease (CKD). Yet, despite growing evidence meant to bridge the divide between the complement alternative pathway and hypertensive crisis [1] (i) c-HUS is only known to account for a small fraction of the cases of malignant HTA (5%) [2] or TMA (4%) [3] (ii) complement genetic investigations in the population of African ancestry are sparse. Recently, the I416L CFI variant, which is specific to patients of African ancestry, has been classified as likely pathogenic (https://databases.lovd.nl/shared/variants/0000521158#00005040). By running a query through the BIOMNIS genetic databank, we sought to identify and provide a phenotypic description of the patients carrying the I416L CFI variant.

METHOD
All samples were sequenced at the BIOMNIS center (Lyon, France) using the Illumina platform and subsequently processed via the in-center bioinformatics pipeline. The BIOMNIS genetic databank compiles a total of 2886 whole exome sequencing (WES) nationwide (single unrelated patients) for renal (n = 1200) and non-renal indications (n = 1686). Once patients were recognized to carry the I416 variant, deidentified clinical data was provided by the attending nephrologist.

RESULTS
Among 1686 WES performed for non-renal indications, three unrelated patients harbored the I416L variant. Out of the 1200 WES performed for renal indications, we identified eight unrelated patients carrying the I416L CFI variant. All patients were of African Ancestry and were heterozygous for the variant, including five males with median age of 38.5 years. They all shared a common history remarkable for hypertension of early onset at median of 33 years [21–38]. None of these patients were acknowledged to have c-HUS prior to WES. In six cases, the kidney disease was undetermined. Four patients experienced TMA: three during bouts of malignant hypertension with concurrent biological TMA. One of them exhibited signs of TMA on biopsy with superimposed signs of malignant nephrosclerosis and another on a kidney transplant. Three patients disclosed genetic risk factor for kidney disease including Apol1 pathogenic variants (G1 and/or G2) (n = 2) and URAT1-related pathogenic variant (n = 1). Five patients had at least one additional risk factor for renal disease. All but one patient progressed to CKD including end-stage CKD on four instances with a median follow-up of 6.5 years. One patient presented with TMA following kidney transplantation. Only one patient whose hypertensive crisis manifested as preeclampsia and HELLP was free of CKD on last follow-up.

CONCLUSION
C-HUS may go unrecognized or mimic vascular nephropathy. These results make a case for a streamlined genotyping of patients, especially patients of African ancestry with a history of hypertension of early onset. Additional triggers acting as second ‘hits’ such as hypertension, pregnancy or genetic and non-genetic renal risk factors may aggravate the course of kidney disease. Yet, further investigations are warranted to appreciate the true clinical significance of this variant as it entails momentous therapeutic and medico-economic implications, most notably the use of anti-C5 therapy.