Acute But Transient Release of Terminal Complement Complex After Reperfusion in Clinical Kidney Transplantation

Vries, Dorottya K. de; Pol, Pieter van der; Anken, Gerritje E. van; Gijlswijk, D.J. van; Damman, Jeffrey; Lindeman, J.; Reinders, Marlies E.J.; Schaapherder, Alexander F.; Kooten, Cees van

doi:10.1097/tp.0b013e31827e31c9

Cited by 69 publications

(51 citation statements)

References 28 publications

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“…A role for complement activation in human IR injury was evaluated by de Vries et al (28). These investigators detected soluble C5b-9 following reperfusion of deceased donor but not living donor kidneys.…”

Section: Figurementioning

confidence: 99%

Complement as a multifaceted modulator of kidney transplant injury

Cravedi¹,

Heeger²

2014

J. Clin. Invest.

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Section: Figurementioning

confidence: 99%

Complement as a multifaceted modulator of kidney transplant injury

Cravedi¹,

Heeger²

2014

J. Clin. Invest.

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“…Experimental studies in humans, C3 and C4 knockout mice, and mice treated with C5a receptor antagonists show that complement activation is involved in ischemia-reperfusion injury in the context of transplantation or stroke. [27][28][29][30] In TMA, ischemia-reperfusion injury could lead to complement activation, possibly amplifying complement-mediated injury.…”

Section: Discussionmentioning

confidence: 99%

Complement Factor C4d Is a Common Denominator in Thrombotic Microangiopathy

Chua¹,

Baelde²,

Zandbergen³

et al. 2015

Journal of the American Society of Nephrology

102

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Complement activation has a major role in thrombotic microangiopathy (TMA), a disorder that can occur in a variety of clinical conditions. Promising results of recent trials with terminal complement-inhibiting drugs call for biomarkers identifying patients who might benefit from this treatment. The primary aim of this study was to determine the prevalence and localization of complement factor C4d in kidneys of patients with TMA. The secondary aims were to determine which complement pathways lead to C4d deposition and to determine whether complement activation results in deposition of the terminal complement complex. We examined 42 renal sections with histologically confirmed TMA obtained from a heterogeneous patient group. Deposits of C4d, mannose-binding lectin, C1q, IgM, and C5b-9 were scored in the glomeruli, peritubular capillaries, and arterioles. Notably, C4d deposits were present in 88.1% of TMA cases, and the various clinical conditions had distinct staining patterns within the various compartments of the renal vasculature. Classical pathway activation was observed in 90.5% of TMA cases. C5b-9 deposits were present in 78.6% of TMA cases and in 39.6% of controls (n=53), but the staining pattern differed between cases and controls. In conclusion, C4d is a common finding in TMA, regardless of the underlying clinical condition. Moreover, C5b-9 was present in .75% of the TMA samples, suggesting that terminal complement inhibitors may have a beneficial effect in these patients. C4d and C5b-9 should be investigated as possible diagnostic biomarkers in the clinical work-up of patients suspected of having complement-mediated TMA.

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“…Local activation through the alternative pathway yields C3a/C5a, which amplifies local inflammation through autocrine/paracrine ligations with their kidney cell-expressed receptors (102). Confirmatory evidence in humans includes detection of soluble C5b-9 after reperfusion of deceased donor but not living donor kidneys (103) and higher expression of complement genes in deceased versus living donor kidneys on reperfusion (104).…”

Section: Kidney-derived Complement and Diseasementioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

242

192

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The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

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Acute But Transient Release of Terminal Complement Complex After Reperfusion in Clinical Kidney Transplantation

Cited by 69 publications

References 28 publications

Complement as a multifaceted modulator of kidney transplant injury

Complement as a multifaceted modulator of kidney transplant injury

Complement Factor C4d Is a Common Denominator in Thrombotic Microangiopathy

Molecules Great and Small

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