Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Goodship, Timothy H.J.; Cook, H. Terence; Fakhouri, Fádi; Fervenza, Fernando C.; Frémeaux‐Bacchi, Véronique; Kavanagh, David; Nester, Carla; Noris, Marina; Pickering, Matthew C.; Córdoba, Santiago Rodrı́guez de; Roumenina, Lubka T.; Sethi, Sanjeev; Smith, Richard J.; Alpers, Charlie E.; Appel, Gerald B.; Ardissino, Gianluigi; Ariceta, Gema; Arıcı, Mustafa; Bagga, Arvind; Bajema, Ingeborg M.; Blasco, Miguel; Burke, Linda; Cairns, Thomas; Carratalá, M.C.; D’Agati, Vivette D.; Daha, Mohamed R.; Vriese, An S. De; Dragon-Durey, Marie-Agnès; Fogo, Agnes B.; Galbusera, Miriam; Gale, Daniel P.; Haller, Hermann; Johnson, Sally; Józsi, Mihály; Karpman, Diana; Lanning, Lynne D.; Quintrec, Moglie Le; Licht, Christoph; Loirat, Chantal; Monfort, Francisco; Morgan, B. Paul; Noël, Laure Hélène; O’Shaughnessy, Michelle M.; Rabant, Marion; Rondeau, Éric; Ruggenenti, Piero; Sheerin, Neil; Smith, Jenna; Spoleti, Fabrizio; Thurman, Joshua M.; Kar, Nicole C. A. J. van de; Vivarelli, Marina; Zipfel, Peter F.

doi:10.1016/j.kint.2016.10.005

Cited by 511 publications

(433 citation statements)

References 115 publications

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“…This interim analysis of the PMS included 17 patients with secondary TMA, which is referred to as secondary aHUS in other reports [12,13]. Median age (range) at baseline was 2 (0-17) years, and 5 (29.4%) patients were younger than 2 years.…”

Section: Patient Characteristics and Outcomes Of Tma Caused By Underlmentioning

confidence: 99%

Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

et al. 2018

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Background In 2013, eculizumab was approved for treatment of the atypical hemolytic-uremic syndrome (aHUS) in Japan, which was defined as a thrombotic microangiopathy (TMA) excluding Shiga toxin-producing Escherichia coli-HUS and thrombotic thrombocytopenic purpura. Simultaneously, post-marketing surveillance was started to assess its safety and effectiveness. In 2016, Japanese clinical guide redefined terms to limit the use of "aHUS" to complement-mediated HUS only. Accordingly, TMA with other causes was defined as secondary TMA. Here we report the interim analysis of post-marketing surveillance of pediatric patients with aHUS and secondary TMA. Methods Pediatric patients treated with eculizumab from approval to 15 March 2017 were included in this observational real-world study. Clinical endpoints of effectiveness were TMA event-free status, complete TMA response, platelet count normalization, and improvement of estimated glomerular filtration rate (eGFR). Adverse reactions to eculizumab were also analyzed. Results In 27 pediatric patients with aHUS, median age at diagnosis was 4 years. Complement genes' variants were detected in 14 of 21 patients (66.7%). Median time from diagnosis to eculizumab initiation was 2.0 days. TMA event-free status, complete TMA response, platelet normalization, and improvement in eGFR were achieved in 85.2, 36.4, 78.3, and 75.0% of patients, respectively. Three patients with aHUS died. Twenty-four and 10 adverse reactions were reported in 31 aHUS patients and 17 secondary TMA patients, respectively; however, no eculizumab-related death or meningococcal infection was reported. Conclusions This interim analysis confirmed that eculizumab is well-tolerated and effective for Japanese pediatric patients with aHUS in a real-world setting.

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Section: Patient Characteristics and Outcomes Of Tma Caused By Underlmentioning

confidence: 99%

Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

et al. 2018

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“…This interim analysis included 27 patients with TMA complicated by underlying diseases, which is classified as secondary TMA in Japanese clinical guides 2015 [2] and as secondary aHUS in other reports [8,14]. Median age (range) at first eculizumab administration was 50 (18-89) years, and median (range) total duration of eculizumab treatment was 2 (0-52) weeks.…”

Section: Characteristics Of Patients With Tma Complicated By Underlyimentioning

confidence: 99%

“…Accordingly, aHUS (complement-mediated HUS) was defined by TMAs caused by a congenital or acquired complement regulation abnormality or, in patients without a known relevant genetic mutation, a clinical TMA manifestation indicative of aHUS that cannot be classified as STEC-HUS, TTP, or secondary TMA. The narrow definition of aHUS is known as complement-mediated HUS [2,3] or primary aHUS [8], which we refer to as "aHUS" in this report [6,7].…”

Section: Introductionmentioning

confidence: 99%

Safety and effectiveness of eculizumab for adult patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

et al. 2018

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Background Eculizumab has been available for the treatment of atypical hemolytic-uremic syndrome (aHUS) in Japan since 2013. To assess safety and effectiveness of eculizumab in adult aHUS patients in the real-life setting, we performed interim analysis of a post-marketing surveillance mandated by Japanese regulations. Methods This study enrolled any patient who was diagnosed with TMA excluding Shiga toxin-producing Escherichia coli-HUS or thrombotic thrombocytopenic purpura based on Japanese clinical guide published in 2013 as inclusion criteria and treated with eculizumab. Although the term aHUS was redefined to denote only complement-mediated HUS in the guide revised in 2016, the patients with TMA caused by other causes (secondary TMA) were included. Patient outcomes and safety were evaluated at 6 months, 12 months, and annually thereafter. Results Thirty-three patients with aHUS and 27 patients with secondary TMA were enrolled. Median treatment duration of aHUS was 24weeks. Complement genes variants were detected in 11 of 18 patients with aHUS (61.1%). Among the 29 aHUS patients with available baseline data, platelet count (PLT), lactic dehydrogenase and serum creatinine (SCr) improved within 1-month after eculizumab initiation. TMA event-free status, complete TMA response, PLT normalization, and SCr decrease were achieved in 67.9% (19/28), 27.8% (5/18), 56.5% (13/23), and 57.1% (16/28) of patients, respectively. Thirty-three and 11 adverse reactions were observed in patients with aHUS (13/33 patients) and secondary TMA (6/27 patients), respectively. Conclusions This interim analysis confirmed the acceptable safety profile and effectiveness of eculizumab for Japanese adult aHUS patients in real-world settings.

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“…In line with this, the KDIGO 2017 consensus report suggests referring to aHUS as a 'microangiopathy,' with the term thrombotic being reserved for the cases with proven thrombosis. The KDIGO 2017 consensus underlines that the boundary between those diseases in some cases may be very subtle, and some patients may present with both entities [106]. The 'two-hit' model for endothelial activation in TMA has been proposed, in which the endothelium can change its properties from preferential synthesis of vasodilators and antithrombotic molecules to production of vasoconstrictors and prothrombotic mediators.…”

Section: C3g Versus Ahusmentioning

confidence: 99%

“…In most aHUS patients, an underlying complement abnormality is not enough to trigger the disease. The additional genetic and environmental or still unknown factors drive the patients toward one or another condition, or they remain disease-free despite the presence of gene abnormality [62,100,106,107]. The detailed role of the AP abnormalities in the pathogenesis of aHUS (due to its complexity) is currently prepared as a separate article.…”

Section: C3g Versus Ahusmentioning

confidence: 99%

The role of the alternative pathway of complement activation in glomerular diseases

2018

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The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.

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Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Cited by 511 publications

References 115 publications

Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

Safety and effectiveness of eculizumab for adult patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

The role of the alternative pathway of complement activation in glomerular diseases

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