Claire Rigothier 1 , Yahsou Delmas 2 , Lubka T Roumenina 3 , Cécile Contin-Bordes 4 , Sébastien Lepreux 5 , Frank Bridoux 6 , Jean Michel Goujon 7 , Thomas Bachelet 2 , Guy Touchard 6 , Véronique Frémeaux-Bacchi 8 , Christian Combe 9
Gammopathy, alternative complement pathway, atypical hemolytic uremic syndrome (aHUS), autoantibody, complement activation, complement factor H (CFH), distal angiopathy, factor H antibody, macroangiopathy, microvascular injury
Abnormal regulation of the alternative pathway of the complement system is a well-described trigger of microangiopathy leading to atypical hemolytic uremic syndrome (aHUS). However, the involvement of complement dysregulation in distal angiopathy has not been reported in adults. We describe the clinical course of a patient with severe distal angiopathy (amputation of all fingers and toes) followed 3 years later by aHUS with end-stage renal disease. This course was attributed to a circulating monoclonal immunoglobulin A λ light chain (IgAλ) with unusual properties: it bound complement factor H (CFH) and impaired CFH-glycosaminoglycan interaction and cell-surface protection. Local complement activation with distal angiopathy and microvascular injury was suggested by deposition of IgA, C4d, and C5b-9 in limb and preglomerular arteries. We therefore postulated that the monoclonal IgAλ inhibited activity of endothelial cell-bound CFH, which led to local activation of complement, vasoconstriction (distal angiopathy), and aHUS. While the patient was dependent on dialysis and plasma exchange, treatment with the anti-C5 antibody eculizumab induced remission of distal angiopathy and aHUS. During eculizumab treatment, kidney transplantation was performed. The patient had normal kidney function at the 3-year follow-up. We suggest that the association of distal angiopathy and aHUS in this patient is clearly linked to anti-CFH properties of the monoclonal IgAλ.