Atypical hemolytic-uremic syndrome (aHUS) is a severe thrombotic microangiopathy in which kidney involvement is common. aHUS can be due to either genetic or acquired abnormalities, with most abnormalities affecting the alternative complement pathway. Several genetic factors/alterations can drive the clinical presentation, therapeutic response, and risk of recurrence, especially recurrence following kidney transplantation. We report here the case of a 22-year-old man who developed a severe form of aHUS. Renal biopsy revealed thrombotic microangiopathy and features of chronic renal damage. Despite two eculizumab infusions, the patient remained dialysis dependent. Two novel rare variants, c.109G>A (p.E37K) and c.159 C>A (p.Y53*), were identified in the factor H-related 2 (FHR2) gene, and western blot analysis revealed a significant reduction in the level of FHR2 protein in the patient's serum. Although FHR2 involvement in complement 3 glomerulopathy has been reported previously, a role for FRH2 as a complement modulator has not yet been definitively shown. In addition, no cases of aHUS in individuals with FHR2 variants have been reported. Given the role of FHRs in the complement system and the fact that this patient was a candidate for a kidney transplant, we studied the relevance of low FHR2 plasma levels through a set of functional in vitro assays. The aim of our work was to determine if low FHR2 plasma levels could influence complement control at the endothelial surface with a view to identifying a therapeutic approach tailored to this specific patient. Interestingly, we observed that low FHR2 levels in the patient's serum could induce complement activation, as well as C5b-9 deposition on human endothelial cells, and affected cell morphology. As C5b-9 deposition is a prerequisite for endothelial cell damage, these results suggest that extremely low FHR2 plasma levels increase the risk of aHUS. Given their ability to reduce C5b-9 deposition, recombinant FHR2 and eculizumab were tested in vitro and found to inhibit hemolysis and endothelial cell surface damage. Both molecules showed effective and comparable profiles. Based on these results, the patient underwent a kidney transplant, and received eculizumab as induction and maintenance therapy. Five years after transplantation, the patient remains in good general health, with stable graft function and no evidence of disease recurrence. To our knowledge, this is first reported case of an aHUS patient carrying FHR2 mutations and provides an example of a translational therapeutic approach in kidney transplantation.
Case report: Novel FHR2 variants in atypical Hemolytic Uremic Syndrome: A case study of a translational medicine approach in renal transplantation
Stea E. D.;Accetturo M.;Pesce F.;Pontrelli P.;Conserva F.;Gesualdo L.
2022-01-01
Abstract
Atypical hemolytic-uremic syndrome (aHUS) is a severe thrombotic microangiopathy in which kidney involvement is common. aHUS can be due to either genetic or acquired abnormalities, with most abnormalities affecting the alternative complement pathway. Several genetic factors/alterations can drive the clinical presentation, therapeutic response, and risk of recurrence, especially recurrence following kidney transplantation. We report here the case of a 22-year-old man who developed a severe form of aHUS. Renal biopsy revealed thrombotic microangiopathy and features of chronic renal damage. Despite two eculizumab infusions, the patient remained dialysis dependent. Two novel rare variants, c.109G>A (p.E37K) and c.159 C>A (p.Y53*), were identified in the factor H-related 2 (FHR2) gene, and western blot analysis revealed a significant reduction in the level of FHR2 protein in the patient's serum. Although FHR2 involvement in complement 3 glomerulopathy has been reported previously, a role for FRH2 as a complement modulator has not yet been definitively shown. In addition, no cases of aHUS in individuals with FHR2 variants have been reported. Given the role of FHRs in the complement system and the fact that this patient was a candidate for a kidney transplant, we studied the relevance of low FHR2 plasma levels through a set of functional in vitro assays. The aim of our work was to determine if low FHR2 plasma levels could influence complement control at the endothelial surface with a view to identifying a therapeutic approach tailored to this specific patient. Interestingly, we observed that low FHR2 levels in the patient's serum could induce complement activation, as well as C5b-9 deposition on human endothelial cells, and affected cell morphology. As C5b-9 deposition is a prerequisite for endothelial cell damage, these results suggest that extremely low FHR2 plasma levels increase the risk of aHUS. Given their ability to reduce C5b-9 deposition, recombinant FHR2 and eculizumab were tested in vitro and found to inhibit hemolysis and endothelial cell surface damage. Both molecules showed effective and comparable profiles. Based on these results, the patient underwent a kidney transplant, and received eculizumab as induction and maintenance therapy. Five years after transplantation, the patient remains in good general health, with stable graft function and no evidence of disease recurrence. To our knowledge, this is first reported case of an aHUS patient carrying FHR2 mutations and provides an example of a translational therapeutic approach in kidney transplantation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
