Differential contribution of C5aR and C5b-9 pathways to renal thrombic microangiopathy and macrovascular thrombosis in mice carrying an atypical hemolytic syndrome–related factor H mutation

Ueda, Yoshiyasu; Miwa, Takashi; Ito, Daisuke; Kim, Hangsoo; Sato, Sayaka; Gullipalli, Damodar; Zhou, Lin; Golla, Madhu; Song, Delu; Dunaief, Joshua L.; Palmer, Matthew; Song, Wen‐Chao

doi:10.1016/j.kint.2019.01.009

Cited by 28 publications

(34 citation statements)

References 43 publications

(45 reference statements)

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“…Crossing FH R/R mice with C5aR1-deficient mice prevented macrovessel thrombosis but did not improve survival rates or reduce renal TMA. 4 This finding differs from data published earlier and regarding a different mouse model of TMA induced by antiphospholipid antibodies, in which C5aR1-deficient mice were protected from glomerular injury. 6 Conversely, crossing FH R/R mice with either C6-or C9-deficient mice to block C5b-9 formation improved survival and diminished renal TMA but did not prevent macrovessel thrombosis.…”

Section: See Basic Research On Page 67contrasting

confidence: 92%

“…5 It is noteworthy that these mice also experienced strokes, retinopathy, and thrombosis involving large blood vessels-mostly veins-in several organs, including the liver, brain, lung, spleen, and kidney. 5 Ueda 4 found that both genetic C5 deficiency and treatment with an anti-C5 monoclonal antibody prevented all disease manifestations in FH R/R mice, supporting the possibility that C5 plays a central pathogenetic role in this model, like in human aHUS. Crossing FH R/R mice with C5aR1-deficient mice prevented macrovessel thrombosis but did not improve survival rates or reduce renal TMA.…”

Section: See Basic Research On Page 67mentioning

confidence: 85%

“…In this issue of Kidney International, Ueda and colleagues 4 investigated the pathogenetic role of C5a/C5aR1 and C5b-9 in a murine model that they previously generated by introducing a single amino acid mutation (p.W1206R) to mouse FH through gene targeting (FH R/R mice). 5 The p.W1206R mutation is the mouse orthologue of the p.W1183R mutation identified in patients with aHUS and is located in the C-terminal surface recognition domain.…”

Section: See Basic Research On Page 67mentioning

confidence: 99%

“…6 Conversely, crossing FH R/R mice with either C6-or C9-deficient mice to block C5b-9 formation improved survival and diminished renal TMA but did not prevent macrovessel thrombosis. 4 These data have been interpreted as indicating that in mice carrying a genetic background causing loss of FH complement regulatory activity on the cell surface, C5aR1 drives macrovascular thrombosis while C5b-9 is responsible for renal TMA (Figure 1). 4 It is also worth highlighting that renal TMA was prevented completely in FH R/R C6 À/À mice while FH R/R C9 À/À mice were only protected partially.…”

Section: See Basic Research On Page 67mentioning

confidence: 99%

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Terminal complement effectors in atypical hemolytic uremic syndrome: C5a, C5b-9, or a bit of both?

Noris

Remuzzi

2019

Kidney International

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Section: See Basic Research On Page 67contrasting

confidence: 92%

Section: See Basic Research On Page 67mentioning

confidence: 85%

Section: See Basic Research On Page 67mentioning

confidence: 99%

Section: See Basic Research On Page 67mentioning

confidence: 99%

See 2 more Smart Citations

Terminal complement effectors in atypical hemolytic uremic syndrome: C5a, C5b-9, or a bit of both?

Noris

Remuzzi

2019

Kidney International

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“…Eculizumab is a humanised monoclonal antibody that binds to complement component C5, blocking its cleavage into C5a and C5b and preventing the formation of the terminal complement complex C5b-9, thought to be responsible for the endothelial damage and platelet activation underlying the pathology of aHUS [5]. A recent in vivo study in complement factor H mice implicated specific involvement of C5b-9 in driving the development of renal TMA [6]. At the time of this analysis, eculizumab was the only pharmacological treatment approved by the US FDA and the European Medicines Agency (EMA) for aHUS (recently, the FDA approved ravulizumab, a long-acting C5 inhibitor engineered from eculizumab, for aHUS).…”

Section: Introductionmentioning

confidence: 99%

Economic Impact of Early-in-Hospital Diagnosis and Initiation of Eculizumab in Atypical Haemolytic Uraemic Syndrome

et al. 2019

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Background Atypical haemolytic uraemic syndrome (aHUS) is a rare, potentially life-threatening condition caused by dysregulation of the complement pathway. Eculizumab is currently the only approved treatment for this disorder. Objective Our objective was to investigate the impact of early administration of eculizumab on inpatient resource use and hospitalisation costs in 222 patients with aHUS. Methods We conducted a retrospective analysis of the Premier Perspective ® Hospital Database, including patients with a diagnosis of aHUS and evidence of eculizumab use for aHUS. Early initiation was defined as having received eculizumab within 7 days of admission, with late initiation defined as starting eculizumab on day 8 or later. This date represents the average time required to obtain a specific diagnostic test to discriminate aHUS from a similar haemolytic syndrome that requires a different treatment. Outcome measures were time from first eculizumab initiation to discharge, discharge status or death, days spent in the intensive care unit (ICU), readmission indicators, dialysis indicators, and total hospital costs. Time from first eculizumab initiation to discharge was analysed using a generalised linear model with a log link and an assumed underlying negative binomial distribution. Logistic regression models were used to test the statistical significance of early versus late initiation as a predictor of the occurrence of readmissions, dialysis, and death. Total hospital costs were analysed using a generalised linear model with a log link and an assumed underlying gamma distribution. Results Before modelling, total length of stay and ICU duration were significantly longer for late initiators than for early initiators, and significantly more late initiators were readmitted within 90 days. Late initiation was associated with significantly higher hospital costs than early initiation. After multivariable analysis, late initiators were 3.2 times more likely to require dialysis. However, there was no significant association between early initiation and time to discharge, readmission, or death for any definition or early initiation after multivariable analysis. Estimated total hospital costs (year 2017 values) were $US103,557 in late initiators and $US85,776 in early initiators (p = 0.0024). Conclusion Initiation of eculizumab within 7 days of hospitalisation is associated with lower dialysis rates, less time in ICU, less plasmapheresis, and lower hospitalisation costs compared with late initiation.

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Complement cascade in severe forms of COVID‐19: Recent advances in therapy

2021

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The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS‐CoV‐2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID‐19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID‐19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a‐C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.

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Differential contribution of C5aR and C5b-9 pathways to renal thrombic microangiopathy and macrovascular thrombosis in mice carrying an atypical hemolytic syndrome–related factor H mutation

Cited by 28 publications

References 43 publications

Terminal complement effectors in atypical hemolytic uremic syndrome: C5a, C5b-9, or a bit of both?

Terminal complement effectors in atypical hemolytic uremic syndrome: C5a, C5b-9, or a bit of both?

Economic Impact of Early-in-Hospital Diagnosis and Initiation of Eculizumab in Atypical Haemolytic Uraemic Syndrome

Complement cascade in severe forms of COVID‐19: Recent advances in therapy

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