FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3130604475> ?p ?o ?g. }

• W3130604475 endingPage "880" @default.
• W3130604475 startingPage "878" @default.
• W3130604475 abstract "C5 inhibitor, eculizumab, has revolutionized the management of the primary, complement-dependent, atypical hemolytic uremic syndrome (aHUS) by dramatically decreasing the rate of end-stage renal disease (ESRD) from approximately 50% in historical cohorts to 6% to 15% after treatment.1Fakhouri F. Zuber J. Frémeaux-Bacchi V. et al.Haemolytic uraemic syndrome.Lancet. 2017 Aug 12; 390: 681-696Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar This benefit on kidney function clearly counterbalances the risk of meningococcal infection under eculizumab therapy and its huge cost. Unlike aHUS, secondary thrombotic microangiopathies (TMAs) represent a large and heterogenous group of diseases including connective tissue disorders. In scleroderma renal crisis (SRC) and idiopathic inflammatory myopathies (IIMs), vascular lesions are found predominantly in kidney biopsy specimens2Woodworth T.G. Suliman Y.A. Li W. et al.Scleroderma renal crisis and renal involvement in systemic sclerosis.Nat Rev Nephrol. 2018; 14: 137Crossref PubMed Scopus (8) Google Scholar,3Couvrat-Desvergnes G. Masseau A. Benveniste O. et al.The spectrum of renal involvement in patients with inflammatory myopathies.Medicine (Baltimore). 2014; 93: 33-41Crossref PubMed Scopus (26) Google Scholar and may trigger TMAs, which, in contrast to aHUS, may not be the consequences of complement dysregulation. However, in the absence of any other specific treatment, the use of C5 inhibitors is tempting in order to improve the patient prognosis. Potential efficacy of eculizumab in secondary TMAs has been reported by some research groups through case reports and case series.4Caravaca-Fontan F. Praga M. Complement inhibitors are useful in secondary hemolytic uremic syndromes.Kidney Int. 2019; 96: 826-829Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar In this issue, the study from Gouin et al.5Gouin A. Ribes D. Colombat M. et al.Role of C5 inhibition in idiopathic inflammatory myopathies and scleroderma renal crisis-induced thrombotic microangiopathies.Kidney Int Rep. 2021; 6: 1015-1021Abstract Full Text Full Text PDF Scopus (5) Google Scholar presents a real interest by describing the effects of eculizumab in a large retrospective series of 18 patients suffering from secondary TMA associated with SRC and IIM, an uncommon complication of these rare diseases. Importantly, despite adequate treatment with converting enzyme inhibitors, renal prognosis of TMA-SRC seems to be very poor. Indeed, early need of dialysis was found in 7 of 11 patients (64%) and persisted until the end of the study. These results are consistent with the rate of dialysis requirement previously reported in the literature (52% to 100%), but many patients could also be weaned from dialysis within 6 months after SRC (23% to 29%).2Woodworth T.G. Suliman Y.A. Li W. et al.Scleroderma renal crisis and renal involvement in systemic sclerosis.Nat Rev Nephrol. 2018; 14: 137Crossref PubMed Scopus (8) Google Scholar This worse renal outcome without reversibility in the current cohort can be explained by the shorter follow-up time (median: 58 days [interquartile range 31 to 127 days]). In addition, 3 of 4 deceased patients had been given eculizumab in TMA-SRC, and no improvement in overall survival rate was observed (52%), compared to a survival rate of 64% to 81% in previous publications about SRC.2Woodworth T.G. Suliman Y.A. Li W. et al.Scleroderma renal crisis and renal involvement in systemic sclerosis.Nat Rev Nephrol. 2018; 14: 137Crossref PubMed Scopus (8) Google Scholar Interestingly, the hematological features of TMA seemed to improve under eculizumab with a rapid increase in platelet count. However, this treatment was not associated with a better renal prognosis compared to the untreated patients in SRC, and compared to previous cohorts.2Woodworth T.G. Suliman Y.A. Li W. et al.Scleroderma renal crisis and renal involvement in systemic sclerosis.Nat Rev Nephrol. 2018; 14: 137Crossref PubMed Scopus (8) Google Scholar Furthermore, the investigators failed to show evidence of efficacy in SRC despite treatment being initiated at an early stage of the disease, with a median time (admission to treatment) of 6 days. This cohort showed a better survival rate in the seven patients with IIM (72% compared to 19% in a historical cohort). However, the historical cohort was a publication of a case series with a review of the literature about 16 patients with TMA-IIM, 9 of them having been published in 2000 or earlier. These historical controls received less rituximab, methrotrexate or intravenous immunoglobulins than the actual series, so the impact of eculizumab, administered in all but one patient, should be interpreted cautiously. As discussed by Gouin et al.,5Gouin A. Ribes D. Colombat M. et al.Role of C5 inhibition in idiopathic inflammatory myopathies and scleroderma renal crisis-induced thrombotic microangiopathies.Kidney Int Rep. 2021; 6: 1015-1021Abstract Full Text Full Text PDF Scopus (5) Google Scholar the complement system could be implicated in the pathogenesis of these diseases, as described in dermatomyositis but also in antisynthetase syndrome.6Dalakas M.C. Inflammatory muscle diseases.N Engl J Med. 2015; 372: 1734-1747Crossref PubMed Scopus (334) Google Scholar By blocking the formation of C5b9, it is possible that muscle inflammation can also be reduced in cardiomyocytes. Further investigations are necessary to evaluate the exact role of the complement in lesions induced by IIM. Kidney histological features, obtained in 15 patients, showed patterns of glomerular TMA in half of the patients and arteriolar TMA in all but one. Interestingly, C5b9 staining was shown in arterioles in seven of nine patients, which likely indicates an activation of the complement pathway. Whether, this activation is pathogenic and plays a role in the TMA lesions or is a secondary event with no relation with TMA remains unknown. In summary, this publication by Gouin et al.5Gouin A. Ribes D. Colombat M. et al.Role of C5 inhibition in idiopathic inflammatory myopathies and scleroderma renal crisis-induced thrombotic microangiopathies.Kidney Int Rep. 2021; 6: 1015-1021Abstract Full Text Full Text PDF Scopus (5) Google Scholar highlights a potential benefit of C5 inhibition on hematological TMA and on survival rate in TMA-IIM. It seems that there is no benefit to kidney function despite the presence of C5b9 in kidney biopsy specimens. Dysregulation of the complement system is well described in aHUS with the presence in 60% of the patients of a genetic predisposition — rare variants encoding proteins regulating the alternative pathway — or acquired antibodies against factor H.1Fakhouri F. Zuber J. Frémeaux-Bacchi V. et al.Haemolytic uraemic syndrome.Lancet. 2017 Aug 12; 390: 681-696Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar In this disease, the efficacy of C5 inhibition is clear with a major improvement in renal prognosis. In secondary TMAs, implication of the complement system is less obvious, with a completely different genetic background. As shown in a recent study, the prevalence of rare variants in genes regulating the alternative pathway is similar to unaffected controls.7Le Clech A. Simon-Tillaux N. Provôt F. et al.Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors.Kidney Int. 2019; 95: 1443-1452Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar As discussed by Duineveld and Wetzels,8Duineveld C. Wetzels J.F.M. Complement inhibitors are not useful in secondary hemolytic uremic syndromes.Kidney Int. 2019; 96: 829-833Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar complement activation is well-described in secondary TMAs, but activation differs from dysregulation. Whereas endothelial lesions in aHUS are the consequence of dysregulation of the complement system, specifically the alternate pathway at the endothelial cell surface,1Fakhouri F. Zuber J. Frémeaux-Bacchi V. et al.Haemolytic uraemic syndrome.Lancet. 2017 Aug 12; 390: 681-696Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar in IIM and SRC the complement system is probably secondarily activated, possibly through the classical pathway in fluid phase, and C5 inhibition fails to solve the initial cause. This is also the case for typical HUS, which is caused by infection with bacteria producing shiga toxins. These shiga toxins lead to endothelial lesions and secondary activation of the complement system in a limited way. In this setting, C5 inhibition failed to show any benefits in retrospective studies with large population (outbreak of typical HUS occurring in Germany, 2011) including a well-designed case control study.8Duineveld C. Wetzels J.F.M. Complement inhibitors are not useful in secondary hemolytic uremic syndromes.Kidney Int. 2019; 96: 829-833Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar The question about the efficacy of C5 inhibition in secondary TMAs will not be answered until well-designed prospective randomized controlled trials are performed, even if such trials will be difficult to complete due to the low number of cases. At the present time, short, uncontrolled, retrospective case series may provide encouraging results but not definitive proof. In addition, the absence of preselection of patients susceptible to respond to C5 inhibition could lead to negative studies. Some research teams developed an ex vivo test evaluating potential dysregulation of complement pathway, first shown in aHUS, then studied in some secondary TMAs such as malignant hypertension.9Timmermans S.A.M.E.G. Werion A. Damoiseaux J.G.M.C. et al.Diagnostic and risk factors for complement defects in hypertensive emergency and thrombotic microangiopathy.Hypertension. 2020; 75: 422-430Crossref PubMed Scopus (23) Google Scholar This test involves incubating immortalized human dermal microvascular endothelial cells (HMEC-1) with the patient’s serum ex vivo and quantifying C5b9 deposits through immunofluorescence. In malignant hypertension, patients with massive ex vivo C5b9 formation on the endothelium showed more prevalent pathogenic variants in complement genes and may benefit from eculizumab treatment.9Timmermans S.A.M.E.G. Werion A. Damoiseaux J.G.M.C. et al.Diagnostic and risk factors for complement defects in hypertensive emergency and thrombotic microangiopathy.Hypertension. 2020; 75: 422-430Crossref PubMed Scopus (23) Google Scholar More in-depth characterization must be performed in secondary TMAs as it could allow us to identify patients likely to be susceptible to the potential efficacy of C5 inhibition. In conclusion, this study provides further knowledge regarding the use of C5 inhibitors in the field of secondary TMAs. However, the evidence seems insufficient to consistently implement this treatment considering its potential side effects, its cost, and the lack of definitive proof of its efficacy. Randomized control trials are required to solve this challenging question. AW has nothing to declare. ER declares grants, and fees from Alexion Pharmaceuticals. Role of C5 inhibition in Idiopathic Inflammatory Myopathies and Scleroderma Renal Crisis–Induced Thrombotic MicroangiopathiesKidney International ReportsVol. 6Issue 4PreviewConnective tissue diseases, including systemic sclerosis and idiopathic inflammatory myopathies (IIMs), are a very rare cause of thrombotic microangiopathies (TMAs). Whether dysregulation of the complement pathways underlies these secondary forms of TMA and may be targeted by complement blocking agents remains elusive. Full-Text PDF Open Access" @default.
• W3130604475 created "2021-03-01" @default.
• W3130604475 creator A5008683655 @default.
• W3130604475 creator A5010002554 @default.
• W3130604475 date "2021-04-01" @default.
• W3130604475 modified "2023-09-30" @default.
• W3130604475 title "C5 Inhibition in Secondary Thrombotic Microangiopathies: A Yet Unresolved Question" @default.
• W3130604475 cites W2081031295 @default.
• W3130604475 cites W2159985097 @default.
• W3130604475 cites W2523740842 @default.
• W3130604475 cites W2590258299 @default.
• W3130604475 cites W2921983598 @default.
• W3130604475 cites W2947426741 @default.
• W3130604475 cites W2973413843 @default.
• W3130604475 cites W2973827443 @default.
• W3130604475 cites W2998353501 @default.
• W3130604475 cites W3128728471 @default.
• W3130604475 doi "https://doi.org/10.1016/j.ekir.2021.02.012" @default.
• W3130604475 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8071650" @default.
• W3130604475 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33939775" @default.
• W3130604475 hasPublicationYear "2021" @default.
• W3130604475 type Work @default.
• W3130604475 sameAs 3130604475 @default.
• W3130604475 citedByCount "2" @default.
• W3130604475 countsByYear W31306044752023 @default.
• W3130604475 crossrefType "journal-article" @default.
• W3130604475 hasAuthorship W3130604475A5008683655 @default.
• W3130604475 hasAuthorship W3130604475A5010002554 @default.
• W3130604475 hasBestOaLocation W31306044751 @default.
• W3130604475 hasConcept C177713679 @default.
• W3130604475 hasConcept C71924100 @default.
• W3130604475 hasConceptScore W3130604475C177713679 @default.
• W3130604475 hasConceptScore W3130604475C71924100 @default.
• W3130604475 hasIssue "4" @default.
• W3130604475 hasLocation W31306044751 @default.
• W3130604475 hasLocation W31306044752 @default.
• W3130604475 hasLocation W31306044753 @default.
• W3130604475 hasLocation W31306044754 @default.
• W3130604475 hasLocation W31306044755 @default.
• W3130604475 hasOpenAccess W3130604475 @default.
• W3130604475 hasPrimaryLocation W31306044751 @default.
• W3130604475 hasRelatedWork W1506200166 @default.
• W3130604475 hasRelatedWork W1995515455 @default.
• W3130604475 hasRelatedWork W2048182022 @default.
• W3130604475 hasRelatedWork W2080531066 @default.
• W3130604475 hasRelatedWork W2604872355 @default.
• W3130604475 hasRelatedWork W2748952813 @default.
• W3130604475 hasRelatedWork W2899084033 @default.
• W3130604475 hasRelatedWork W3031052312 @default.
• W3130604475 hasRelatedWork W3032375762 @default.
• W3130604475 hasRelatedWork W3108674512 @default.
• W3130604475 hasVolume "6" @default.
• W3130604475 isParatext "false" @default.
• W3130604475 isRetracted "false" @default.
• W3130604475 magId "3130604475" @default.
• W3130604475 workType "article" @default.