2 new genetic mutations identified as cause of severe aHUS in humans, 24 |...

2 new genetic mutations identified as cause of severe aHUS in humans, 24 |…

Two new mutations in the FHR2 were first identified as the cause of severe atypical hemolytic uremic syndrome (aHUS) in a 24-year-old patient.

After two years of dialysis, the man underwent a kidney transplant which was preceded by preventive treatment with Soliris (eculizumab) and plasma exchange therapy. Soliris was discontinued two months after surgery, and the patient continues to do well in a five-year follow-up, the researchers said.

“This unique patient provides an example of the application of a translational medicine framework that could be useful in the management of patients with aHUS carrying new genetic variants of unknown significance, with the aim of defining the best therapeutic strategy. in people undergoing kidney transplantation,” the team wrote.

Entitled “Case study: Novel FHR2 variants in atypical hemolytic uremic syndrome: case study of a translational medicine approach in renal transplantation“, the study was published in the journal Frontiers in immunology.

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Gene mutations, a key cause of aHUS

aHUS is characterized by the progressive destruction of red blood cells (haemolytic anemia) due to dysregulation of the complement system, a set of more than 30 blood proteins that are part of the body’s immune defenses. The disease can be associated with different types of mutations in genes encoding complement regulatory proteins.

An overactive complement system contributes to endothelial cell dysfunction, promoting the formation of blood clots. Endothelial cells are those that line the inside of blood vessels.

These 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 can hamper the efficiency of a transplant.

Now, a team of researchers in Italy and Germany have described the first case of an aHUS patient carrying two new mutations in the FHR2 embarrassed. These gene mutations resulted in a marked decrease in blood levels of the FHR2 protein, which is involved in complement regulation.

The patient attended for a pre-kidney transplant assessment. He had been diagnosed with aHUS two years earlier, after being hospitalized with sudden swelling in his face and legs, as well as nosebleeds, chest pain and high blood pressure, among other symptoms. In the two weeks prior to his hospitalization, he had flu-like symptoms without a fever.

Blood tests revealed that he had hemolytic anemia, low platelet count (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 of these signs suggested 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 disease and was negative for infection with Escherichia coli. The diagnosis of aHUS was finally made following a kidney biopsy which showed signs of damage typically seen in patients with TMA.

He received blood transfusions and underwent hemodialysis, as well as steroid treatment and two doses of Soliris one month after his hospitalization. Despite this aggressive therapeutic regimen, he quickly progressed to end-stage renal failure. Due to signs of kidney damage in the biopsy, Soliris was discontinued and the patient was kept on dialysis.

He underwent genetic testing which showed that he carried two new mutations in a gene associated with complement, called FHR2, which caused abnormally low levels of the FHR2 protein in his blood. One of the mutations was inherited from his father.

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Preparing for a Kidney Transplant

Because he was being considered for a kidney transplant, follow-up lab work was done to assess how FHR2 mutations affected the complement pathway. This would also inform the best therapeutic approach to follow.

As expected, complement protein levels increased in the patient’s blood. To assess the hemolytic potential of the patient’s blood compared to blood from a healthy donor, the researchers mixed each blood sample with guinea pig blood.

Increased destruction of guinea pig red blood cells was observed when they were mixed with the patient’s blood at different concentrations.

The 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 reduction in concentration-dependent red blood cell destruction from 34% to 12%.

In addition, they found that endothelial cells exposed to 30% of the patient’s blood, along with increased amounts of FHR2 protein, showed reduced complement activation.

Additionally, the results confirmed that Soliris and FHR2 were able to reduce complement pathway activation on endothelial cells in a similar manner.

Based on these results, the patient underwent a kidney transplant after being on hemodialysis for 23 months.

Prior to the surgery, he received a tailored treatment regimen that included a single plasma exchange session, which involves replacing a person’s plasma – the non-cellular parts of blood. The man also received a thymoglobulin infusion, steroids and a dose of Soliris. This was done to reduce the risk of transplant rejection.

After the transplant, the steroids were gradually reduced. He also stopped plasma exchange and instead received a thymoglobulin infusion for six days. This was followed by a therapeutic diet to attenuate endothelial damage.

Blood analysis of complement levels performed 10 days after surgery showed low levels of complement activation, “confirming the Direct effectiveness of this therapeutic approach.

Soliris was given weekly for three weeks, then every two weeks for two months. Although there is no clear evidence on the best time to stop Soliris, especially after a kidney transplant, in this case, in the absence of 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, renal graft dysfunction or proteinuria [high protein levels in the urine] were detected,” the researchers wrote.

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