Insights From the Use in Clinical Practice of Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome Affecting the Native Kidneys: An Analysis of 19 Cases

Fakhouri, Fádi; Delmas, Yahsou; François, Patrice; Barbet, Christelle; Karras, Alexandre; Makdassi, R; Courivaud, Cécile; Rifard, Khair; Servais, Aude; Allard, Catherine; Besson, Virginie; Cousin, Maud; Châtelet, Valérie; Goujon, Jean-Michel; Coindre, Jean‐Philippe; Laurent, Guillaume; Loirat, Chantal; Frémeaux‐Bacchi, Véronique

doi:10.1053/j.ajkd.2013.07.011

Cited by 78 publications

(77 citation statements)

References 18 publications

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“…The propensity for aHUS relapses in association with infection/ inflammation (35,36) led us to evaluate complement parameters in both GMVECs and HUVECs during cytokine stimulation using TNF and IL-1b. Whereas IL-1b affected AP production and regulation by GMVECs and HUVECs only mildly, TNF caused FIGURE 6.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that GMVECs have differences in AP regulation, compared with HUVECs, thereby explaining their susceptibility to injury in aHUS. Because infectious/inflammatory conditions may lead to initial or recurrent episodes of aHUS (35,36), we also studied the effects of two proinflammatory cytokines, TNF and IL-1b, on complement parameters in both EC types. We further hypothesized that these inflammatory cytokines affect AP regulation in HUVECs and GMVECS by altering gene expression or surface presence of the AP components/regulators, thereby explaining the recurrences of aHUS during inflammatory or infectious events.…”

mentioning

confidence: 99%

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TNF Regulates Essential Alternative Complement Pathway Components and Impairs Activation of Protein C in Human Glomerular Endothelial Cells

Sartain

Turner

Moake

2016

The Journal of Immunology

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Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe renal injury secondary to an overactive alternative complement pathway (AP). aHUS episodes are often initiated or recur during inflammation. We investigated gene expression of the surface complement regulatory proteins (CD55, CD59, CD46, and CD141 [thrombomodulin]) and AP components in human glomerular microvascular endothelial cells (GMVECs) and in HUVECs, a frequently used investigational model of endothelial cells. Surface complement regulatory proteins were also quantified by flow cytometry. All experiments were done with and without exposure to IL-1β or TNF. Without cytokine stimulation, we found that GMVECs had greater AP activation than did HUVECs. With TNF stimulation, THBD gene expression and corresponding CD141 surface presence in HUVECs and GMVECs were reduced, and gene expression of complement components C3 (C3) and factor B (CFB) was increased. Consequently, AP activation, measured by Ba production, was increased, and conversion of protein C (PC) to activated PC by CD141-bound thrombin was decreased, in GMVECs and HUVECs exposed to TNF. IL-1β had similar, albeit lesser, effects on HUVEC gene expression, and it only slightly affected GMVEC gene expression. To our knowledge, this is the first detailed study of the expression/display of AP components and surface regulatory proteins in GMVECs with and without cytokine stimulation. In aHUS patients with an underlying overactive AP, additional stimulation of the AP and inhibition of activated PC–mediated anticoagulation in GMVECs by the inflammatory cytokine TNF are likely to provoke episodes of renal failure.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

TNF Regulates Essential Alternative Complement Pathway Components and Impairs Activation of Protein C in Human Glomerular Endothelial Cells

Sartain

Turner

Moake

2016

The Journal of Immunology

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“…105 A query sent to all nephrology centers in France retrospectively identified 19 adults with aHUS that received eculizumab as first-line or rescue therapy. 106 The risk of reaching ESRD was reduced by one half compared with recent historical controls. 106 Finally, in a prospective phase II trial in 37 patients (31 adults and 6 adolescents) with aHUS, eculizumab was associated with substantial renal recovery.…”

Section: Inhibit Complement Activationmentioning

confidence: 95%

“…106 The risk of reaching ESRD was reduced by one half compared with recent historical controls. 106 Finally, in a prospective phase II trial in 37 patients (31 adults and 6 adolescents) with aHUS, eculizumab was associated with substantial renal recovery. 107 The response to eculizumab was similar in patients with and without identified complement mutation or anti-CFH autoantibodies.…”

Section: Inhibit Complement Activationmentioning

confidence: 95%

“…107 Earlier intervention was associated with improved renal function. 106,107 These data have led to the recommendation [105][106][107] that eculizumab should be the first-line therapy when the diagnosis of aHUS is unequivocal (i.e., in children, familial forms, relapses, and recurrences posttransplantation), regardless of the results of the complement investigations. Screening of anti-CFH autoantibodies, however, is indicated, because positive results may dictate the need for additional immunosuppression.…”

Section: Inhibit Complement Activationmentioning

confidence: 99%

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Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway

Vriese

Sethi²,

Praet

et al. 2015

Journal of the American Society of Nephrology

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Kidney diseases caused by genetic or acquired dysregulation of the complement alternative pathway (AP) are traditionally classified on the basis of clinical presentation (atypical hemolytic uremic syndrome as thrombotic microangiopathy), biopsy appearance (dense deposit disease and C3 GN), or clinical course (atypical postinfectious GN). Each is characterized by an inappropriate activation of the AP, eventuating in renal damage. The clinical diversity of these disorders highlights important differences in the triggers, the sites and intensity of involvement, and the outcome of the AP dysregulation. Nevertheless, we contend that these diseases should be grouped as disorders of the AP and classified on an etiologic basis. In this review, we define different pathophysiologic categories of AP dysfunction. The precise identification of the underlying abnormality is the key to predict the response to immune suppression, plasma infusion, and complement-inhibitory drugs and the outcome after transplantation. In a patient with presumed dysregulation of the AP, the collaboration of the clinician, the renal pathologist, and the biochemical and genetic laboratory is very much encouraged, because this enables the elucidation of both the underlying pathogenesis and the optimal therapeutic approach.

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