Deficiencies in the regulation of the complement system are rather common in atypical HUS, and such deficiencies could be inherited or acquired in nature. In aHUS, patients may be identified as familial or sporadic cases. In inherited cases, genetic mutations in CFH, CFI, C3 convertases, C3 and factor B, thrombomodulin, CD46 and MCP can lead to complement-related HUS. In addition, factors such as deficiency in activity of metalloprotease that cleaves von Willebrand factor (VWF-CP or ADAMTS-13), CFI deficiency, and autoantibodies against CFH may also cause aHUS . This study reports retrospectively scanned results of a family who presented to our center. In six of 13 family members, p.S1191L mutation in the CFH gene was heterozygous. Clinical and laboratory findings detected heterozygous p.S1191L mutation in the CFH gene, while the other three members showed normal clinical and laboratory results. There was no gene mutation or aHUS finding in the other seven family members.
Mutations in the complement genes cause over-activation of the complement alternative route, which results in an excessive increase in C3 and C5 and the formation of the C5b-9 complex. This complex leads to activation of platelets, endothelial damage, inflammation and the formation of systemic microangiopathic lesions . In this study, the presence of aHUS-related progressive decline in renal function, microangiopathic hemolytic anemia, and thrombocytopenia in one person in the family was attributed to the heterozygous p.S1191L mutation in the CFH gene. The history of CKD and renal transplantation resulting in rejection in two patients was also associated with aHUS that might have occurred as a result of a mutation in this gene. No pathologies were detected in the other three family members with gene mutation, including the mother and a 2-year-old child. Hence, the question arises as to whether factors like female gender, not having experienced a triggering event and young age could serve as protective features in the disease. The absence of any pathological findings in the third family member may have resulted from a mechanism that we cannot explain. There exist studies describing this phenomenon in the literature. Despite heterozygous pathogenic variants in complement genes often identified in diseased and healthy parents, the disease is often sporadic, which indicates that genetic mutations give rise to sensitivity, but they do not cause disease . The disease occurs in approximately 50% of the family members affected by the gene mutation by the time they reach the age of 45 . This well-established feature of the disease has also been confirmed by our study. In the present study, 3 (50%) of 6 patients with heterozygous gene mutation developed the disease.
In addition to our index patient, CFH p.S1191L mutation was heterozygous in his two siblings with CKD. These two patients had a history of a deceased-donor kidney transplant, but both developed acute rejection shortly after their transplant surgeries. Both of these patients still receive regular hemodialysis treatment 3 days a week. The fact that other laboratory findings are normal in these patients indicates that no triggering events of aHUS have so far occurred in their life. The diagnosis of aHUS in their siblings and mutations in the CFH gene in the same gene with their siblings suggests that the presence of CKD and rejection after renal transplant in these patients might be associated with their aHUS, but they are not yet in the period of aHUS episodes.
In the treatment of atypical HUS, Eculizumab, a monoclonal antibody that inhibits complement protein C5, has been demonstrated to be an effective treatment option. In recent years, multicentre studies have shown that Eculizumab (Soliris) therapy rapidly improves the platelet count and renal functions in most patients after the first dose, eliminating the need for dialysis and plasma treatment. Eculizumab has been reported to be a fast, effective, and life-saving option in the treatment of aHUS [15, 16, 17, 18]. Accordingly, we administered Eculizumab therapy to our index patient following plasmapheresis after the first admission. The patient’s blood creatinine was reduced from 7.8 mg/dL to 1.2 mg/dL through Eculizumab therapy.