Multidisciplinary Approach Needed to Evaluate Patients Suspected of Having aHUS, Case Report Says

A multidisciplinary approach is needed to evaluate patients suspected of having atypical hemolytic uremic syndrome (aHUS) and to select the best course of treatment in each instance, a case report says.

The report, “A Multimodality Approach to Assessing Factor I Genetic Variants in Atypical Hemolytic Uremic Syndrome,” was published in Kidney International Reports.

aHUS is caused by the progressive destruction of red blood cells 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. Damaged red blood cells can aggregate and form clots that clog the kidney’s small blood vessels (thrombotic microangiopathy, or TMA), potentially leading to kidney failure.

Most often, patients with aHUS carry genetic mutations that lower the activity of complement system regulators, including factor H, factor I, and membrane cofactor protein.

“Genetic variants in factor I (FI) have been reported in 5%–15% of patients with aHUS. The likely clinical outcome of patients with an FI mutation is dismal, and the risk of recurrence after kidney transplantation is high,” the authors wrote.

In this case report study, authors described the clinical cases of five patients carrying different genetic mutations in FI who had been referred to the Washington University School of Medicine in St. Louis due to suspicions of aHUS.

“These patients were referred to us for assistance in clinical decision-making relative to therapeutic options for renal transplant and/or targeted therapy using a humanized monoclonal antibody that blocks C5 activity (eculizumab, brand name Soliris]. In order to obtain a more comprehensive assessment of each patient’s risk, we wanted to evaluate their clinical history and genetic data in relation to a functional assessment of each variant,” they explained.

The first patients was a 22-year-old Caucasian man who developed end-stage kidney disease at the age of 3 and underwent a kidney transplant at age 11. Unfortunately, one year later his body started to reject the transplant and he had to undergo dialysis and a second transplant a few years later, which he also started to reject two years later.

Genetic and biochemical analyses revealed he carried a missence mutation (p.R406H) in FI, which was considered “functionally impaired.” (A missence mutation is a single nucleotide mutation that alters protein composition; nucleotides are the building blocks of DNA.)

“Although future studies will affect the decision on how long to continue treatment, we would recommend that he receive eculizumab at the time of his third transplant and remain on it indefinitely. Additionally, we would advise that his family members undergo genetic testing,” the authors wrote.

The second patient was a 17-year-old African American woman who complained of pain and swelling in her extremities, shortness of breath, and heart palpitations. Lab tests revealed she had a a series of blood abnormalities, and a kidney biopsy performed one year later showed she had TMA.

Genetic and biochemical analyses showed she also carried a missence mutation (p.I306V) in FI, which did not affect its normal activity. Based on these findings, the authors argued her TMA most likely was related to lupus or infection and not associated with aHUS.

The third patient was a 20-year-old Caucasian woman who developed preeclampsia (high blood pressure) during her second pregnancy and had to undergo a cesarean section. Lab tests revealed a series of blood abnormalities and the presence of end-stage kidney disease.

As did the previous patient, she also carried a missence mutation (p.P553S) in FI that did not compromise its normal activity. That led the authors to decide her kidney disease most likely was unrelated to this missence mutation.

The fourth patient was a 57-year-old Caucasian man who complained of prolonged fatigue and weakness. Analyses revealed he was in septic shock due to a liver abscess. A few days later his health deteriorated rapidly after he developed anemia and kidney failure.

Genetic and biochemical analyses showed he carried a rare genetic mutation in FI (p.D403N) that did not compromise its normal activity. Nevertheless, he was diagnosed with aHUS and recommended to begin treatment with Soliris.

The last patient was a 24-year-old Caucasian man who had to undergo a heart transplant at age 9. At age 19, he started showing signs of kidney failure and blood abnormalities suggestive of aHUS.

Genetic and biochemical analyses revealed he had a missence mutation (p.I370N) in FI that had never been reported in the literature. Further analysis revealed that even though FI was produced, it failed to be secreted (released) normally, which had a negative effect on its function.

Based on these findings, the authors predicted he was at risk of having recurrent episodes of aHUS and recommended treatment with Soliris. Unfortunately the patient was lost to follow-up.

“[G]iven the current challenges to the clinician of reconciling genetic data with clinical management of aHUS, we believe our [multidisciplinary] strategy (…) is informative. The ability to more comprehensively define the functional repertoire of the variant protein provides critical guidance relative to the appropriate therapeutic regimen and thereby will ultimately pave the way for precision medicine in complement-mediated renal disease,” they wrote.