2 Novel FHR2 Gene Mutations ID’d as Cause of Severe aHUS in Man, 24
No symptoms for patient 5 years after kidney transplant, Soliris
Two new mutations in the FHR2 gene were identified for the first time as the cause of severe atypical hemolytic uremic syndrome (aHUS) in a 24-year-old patient.
After two years on dialysis, the man underwent a kidney transplant that was preceded by preventive treatment with Soliris (eculizumab) and plasma exchange therapy. Soliris was discontinued two months after the surgery, and the patient continues to fare well in a five-year follow-up, according to researchers.
“This unique patient provides an example of the application of a translational medicine framework that could be useful in managing patients with aHUS carrying novel genetic variants of unknown significance, with the aim of defining the best therapeutic strategy in those undergoing kidney transplantation,” the team wrote.
Titled “Case report: Novel FHR2 variants in atypical Hemolytic Uremic Syndrome: A case study of a translational medicine approach in renal transplantation,” the study was published in the journal Frontiers in Immunology.
Gene mutations a key cause of aHUS
aHUS is characterized by the progressive destruction of red blood cells (hemolytic anemia) due to the dysregulation of the complement system — a set of more than 30 blood proteins that form part of the body’s immune defenses. The disease can be associated with different types of mutations in genes coding for complement regulator proteins.
A hyperactive complement system contributes to endothelial cell dysfunction, favoring blood clot formation. Endothelial cells are those lining the inside of blood vessels.
Such blood clots damage internal organs, especially the kidneys, with patients often requiring a transplant. However, the existence of genetic mutations coupled with excessive complement activation may hinder a transplant’s efficacy.
Now, a team of researchers in Italy and Germany described the first case of a patient with aHUS carrying two novel mutations in the FHR2 gene. These gene mutations led to a marked reduction in the levels in the blood of the FHR2 protein, which is involved in complement regulation.
The patient went to a consultation for a pre-transplant kidney evaluation. He had been diagnosed with aHUS two years earlier, after being hospitalized due to sudden swelling of the face and legs, along with nosebleed, chest pain, and high blood pressure, among other symptoms. In the two-weeks prior to hospitalization, he experienced flu-like symptoms without fever.
Blood testing revealed he had hemolytic anemia, low platelet counts (thrombocytopenia), and higher-than-normal levels of creatinine, a waste product normally eliminated by the kidneys, and indicating acute kidney injury. He also had low levels of complement 3 (C3).
All these signs were indicative of thrombotic microangiopathy (TMA). TMAs comprise a group of disorders that also include aHUS and are characterized by the destruction of red blood cells and platelets.
The man had no family history of TMA or other kidney diseases, and was negative for infection with Escherichia coli. The aHUS diagnosis was ultimately reached following a kidney biopsy that showed signs of damage typically seen in TMA patients.
He received blood transfusions and underwent hemodialysis, along with steroid treatment and two doses of Soliris one month after being hospitalized. Despite this aggressive therapeutic regimen, he rapidly progressed to end-stage kidney disease. Due to signs of kidney damage in the biopsy, Soliris was discontinued and the patient was kept on dialysis.
He underwent genetic testing that showed he carried two novel mutations in a complement-associated gene, called FHR2, which caused the levels of the FHR2 protein to be abnormally low in his bloodstream. One of the mutations was inherited from his father.
Preparing for kidney transplant
Because he was being considered for a kidney transplant, follow-up lab work was conducted to assess how FHR2 mutations affected the complement pathway. This also would inform the best therapeutic approach to follow.
As expected, the levels of complement proteins were increased in the patient’s blood. To assess the hemolytic potential of the patient’s blood as compared with blood from a healthy donor, researchers mixed each blood sample with blood from a guinea pig.
An enhanced destruction of the guinea pig’s red blood cells was seen when they were mixed with the patient’s blood at different concentrations.
Researchers repeated the experiment using 5% of the patient’s blood, but this time adding increasing amounts of a lab-made version of FHR2 to the mix. This resulted in a significant concentration-dependent reduction of red blood cells’ destruction, which dropped from 34% to 12%.
Also, they found that endothelial cells exposed to 30% of the patient’s blood, along with increased amounts of FHR2 protein, showed a reduction in complement activation.
Moreover, the results confirmed that both Soliris and FHR2 were able to reduce the activation of the complement pathway on endothelial cells in a similar manner.
Based on these findings, the patient underwent a kidney transplant after being on hemodialysis for 23 months.
Before surgery, he received a tailor-made therapeutic regimen that included a single plasma exchange session, which involves replacing a person’s plasma — the non-cellular parts of blood. The man also was given thymoglobulin infusion, steroids, and one dose of Soliris. This was done to lower the risk of transplant rejection.
Following the transplant, steroids were gradually reduced. He also stopped plasma exchange and received instead an infusion of thymoglobulin for six days. This was followed by a therapeutic regimen to lessen endothelial damage.
Blood analysis for complement levels conducted 10 days after surgery showed low levels of complement activation, “confirming the in vivo efficacy of this therapeutic approach.”
Soliris was administered weekly for three weeks, and then every two weeks for two months. While there is no clear evidence on the best timing for stopping Soliris, especially following a kidney transplant, in this case, given no signs of transplant rejection, Soliris was suspended two months after the procedure.
The patient was closely monitored with regular follow-up visits. After five years of “follow-up, no signs of hemolysis, kidney graft dysfunction, or proteinuria [high protein levels in the urine] were detected,” the researchers wrote.
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