Complement activation in atypical hemolytic uremic syndrome and scleroderma renal crisis: a critical analysis of pathophysiology

Abstract

Scleroderma is an autoimmune disease that affects multiple systems. While pathophysiologic mechanisms governing the development of scleroderma are relatively poorly understood, advances in our understanding of the complement system are clarifying the role of complement pathways in the development of atypical hemolytic uremic syndrome and scleroderma renal crisis. The abundant similarities in their presentation as well as the clinical course are raising the possibility of a common underlying pathogenesis. Recent reports are emphasizing that complement pathways appear to be the unifying link. This article reviews the role of complement system in the development of atypical hemolytic uremic syndrome and scleroderma renal crisis, and calls for heightened awareness to the development of thrombotic angiopathy in patients with scleroderma.

Atypical hemolytic uremic syndrome in the Colombian Caribbean: its particular characteristics

“…There is an established correlation between aHUS and membranoproliferative glomerulonephritis (C3 glomerulopathy) whose physiopathology involves genetic alterations in the regulatory proteins of the alternative complement pathway. Based on this finding, it has been hypothesized that both conditions could be the same entity with different phenotypes, varying from aHUS to C3 glomerulopathy (DDD or C3 glomerulonephritis) [ 4 , 14 , 23 , 25 ]. Hypocomplementemia was seen in 60% of the cases; however, this finding is not very sensitive or specific, being reported in only 30–50% of cases [ 25 ].…”

“…Based on this finding, it has been hypothesized that both conditions could be the same entity with different phenotypes, varying from aHUS to C3 glomerulopathy (DDD or C3 glomerulonephritis) [ 4 , 14 , 23 , 25 ]. Hypocomplementemia was seen in 60% of the cases; however, this finding is not very sensitive or specific, being reported in only 30–50% of cases [ 25 ]. Fakhouri et al reported 85% of cases with disorders in the complement regulatory proteins, being CFI mutation frequently documented [ 18 ].…”

Refractory scleroderma renal crisis precipitated after high-dose oral corticosteroids and concurrent intravitreal injection of bevacizumab

“…Table 1 details the cases of SRC treated with eculizumab and the corresponding clinical response data. [18][19][20][21][22][23][24] In addition, this patient's genetic testing led to some equivocal findings of alleles not generally thought to be pathogenic. We cannot exclude a yet undescribed role for these genetic variants which affect susceptibility to complement amplifying and endothelium disruptive insults.…”

“…Table 1 details the cases of SRC treated with eculizumab and the corresponding clinical response data. 18 – 24 …”

“…The patient was made aware of the favorable response of eculizumab in 66.7% of SRC cases. [18][19][20][21][22][23][24] The patient ultimately declined use of complement blockade despite the copious explanation of benefits, given the risks reported for meningitis despite existence of vaccines and prophylactic antibiotics. The patient's renal function continued to worsen with serum creatinine rising to 1.9 mg/dL, to 2.7 mg/dL, and then to 7 mg/dL over the course of 5 months.…”