Rare CFI mutation affects risk, severity of various forms of HUS: Study

CFI mutation is 'facilitating genetic factor' for the disease following triggers

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A rare mutation in the CFI gene affects the risk and clinical severity of various forms of hemolytic uremic syndrome (HUS), including atypical HUS (aHUS), according to a recent study.

The study, “Hot Spot of Complement Factor I Rare Variant p.Ile357Met in Patients With Hemolytic Uremic Syndrome,” was published in the American Journal of Kidney Diseases.

HUS is marked by inflammation and damage to blood vessels, causing injury to the kidneys. The typical form of the disease is caused by a bacterial infection, whereas aHUS is usually associated with mutations in genes that regulate the complement system, a part of the immune system that’s overactive in people with the disease.

More than 100 mutations in the CFI gene, which encodes a protein involved in complement regulation, have been observed in a small fraction (5% to 15%) of aHUS patients.

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Report includes 10 unrelated people with HUS linked to rare CFI mutation

In this report, clinicians in France and Switzerland described the cases of 10 unrelated patients with HUS that was associated with a rare CFI mutation.

Patients were identified following a retrospective analysis of data from the French HUS Registry collected from January 2007 to January 2022.

All HUS patients shared a rare missense mutation, called p.Ile357Met (c.1071T>G), in the CFI gene. No mutations were present in other complement-related genes, including the CFH, MCP, C3, or FB genes. Of note, missense mutations are those that lead to a switch in an amino-acid — the building blocks of proteins — in the resulting protein.

The p.Ile357Met mutation was identified in 2.5% of all HUS cases in the French HUS registry and in 9.2% of all cases of CFI-associated HUS.

Seven of the 10 aHUS patients had a first episode of the disease affecting their kidneys, while the three remaining patients had new-onset HUS after undergoing a kidney transplant.

In two of the seven aHUS patients whose kidneys were affected, both women, the disease manifested in the period around childbirth. High blood pressure was detected in five patients, four of whom required hemodialysis for severe acute kidney injury. Four of these cases occurred before Soliris (eculizumab) was approved in France. Two patients recovered rapidly.

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5 patients developed kidney failure following aHUS onset

Five patients developed kidney failure in less than one month following the onset of aHUS and required replacement therapy. Four underwent a kidney transplant, and no cases of disease recurrence were reported.

Two patients were treated with Soliris following the transplant, but one of them eventually lost the transplanted kidney four years later.

In two of the three patients with new-onset HUS following kidney transplant, the reason for kidney failure remained unknown. The third patient was believed to have kidney disease due to diabetes.

In these patients, HUS episodes were associated with different types of triggers, including bacterial and viral infections, and acute antibody-mediated rejection.

Two patients underwent plasma exchange, a blood-cleaning procedure, and two received Soliris.

One patient showed signs of chronic thrombotic microangiopathy in a kidney biopsy, and another lost the transplant and had to restart hemodialysis. Of note, thrombotic microangiopathy encompasses a group of disorders like aHUS that are characterized by the formation of blood clots in small blood vessels leading to organ damage.

Overall, this report suggests the p.Ile357Met CFI mutation is a “facilitating genetic factor for the occurrence of HUS following various triggers. Further data are needed to determine whether these findings may have direct implications for the management of carriers,” the researchers wrote.