Chronic renal failure is accompanied by endothelial activation and a large increase in microparticle numbers with reduced procoagulant capacity

Trappenburg, Marijke C.; Schilfgaarde, Muriel van; Frerichs, Fenneke C.P.; Spronk, Henri M. H.; Cate, Hugo Ten; Fijter, C. W. H. De; Terpstra, Wim; Leyte, Anja

doi:10.1093/ndt/gfr474

Cited by 40 publications

(47 citation statements)

References 35 publications

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“…Renal disease, [25][26][27] hypertension, 28 thrombotic thrombocytopenic purpura, 29 and pregnancy 30 promote the release of endothelial microparticles. A wide range of diseases and insults are also associated with the generation of platelet and leukocyte microparticles.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Renner¹,

Klawitter²,

Goldberg³

et al. 2013

Journal of the American Society of Nephrology

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Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases.

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Section: Discussionmentioning

confidence: 99%

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Renner¹,

Klawitter²,

Goldberg³

et al. 2013

Journal of the American Society of Nephrology

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“…75 Endothelial activation, as indicated by an elevated VWFpp level has been implicated in chronic renal failure, aortic stenosis, ischemic stroke, sepsis, meningococcal disease, dengue, systemic sclerosis, sickle cell disease, HELLP syndrome, and asthma. [78][79][80][81][82][83][84][85][86] In addition to utility in identifying endothelial activation, VWFpp and VWF may also be used in a similar manner to identify platelet activation. 87 In some clinical circumstances, an elevated VWFpp level may indicate activation of both platelets and endothelial cells.…”

Section: Assay Of Plasma Vwfpp: Clinical Utility Vascular Disorders Amentioning

confidence: 99%

von Willebrand factor propeptide: biology and clinical utility

Haberichter

2015

Blood

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von Willebrand factor (VWF) is a large multimeric glycoprotein that mediates the attachment of platelets to damaged endothelium and also serves as the carrier protein for coagulation factor VIII (FVIII), protecting it from proteolytic degradation. Quantitative or qualitative defects in VWF result in von Willebrand disease (VWD), a common inherited bleeding disorder. VWF is synthesized with a very large propeptide (VWFpp) that is critical for intracellular processing of VWF. VWFpp actively participates in the process of VWF multimerization and is essential for trafficking of VWF to the regulated storage pathway. Mutations identified within VWFpp in VWD patients are associated with altered VWF structure and function. The assay of plasma VWFpp has clinical utility in assessing acute and chronic vascular perturbation associated with diseases such as thrombotic thrombocytopenic purpura, sepsis, and diabetes among others. VWFpp assay also has clear utility in the diagnosis of VWD subtypes, particularly in discriminating true type 3 subjects from type 1C (reduced plasma survival of VWF), which is clinically important and has implications for therapeutic treatment.

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“…A number of recent studies have shown that diseases of the vasculature and kidneys, including CKD, are associated with increased numbers of circulating endothelial microparticles 17, 18, 19, 20, 21, 22. We have previously reported that the microparticles released from endothelial cells can, under some conditions, activate the complement system, and that generation of complement‐activating microparticles is associated with vascular and renal injury in mice 23.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease

Jalal

Renner

Laskowski

et al. 2018

JAHA

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BackgroundEndothelial microparticles are associated with chronic kidney disease (CKD) and complement activation. We hypothesized that the complement pathway is activated in patients with CKD via endothelial microparticles and that complement activation correlates with endothelial dysfunction in CKD.Methods and ResultsWe analyzed complement data of 30 healthy subjects, 30 patients with stage III/IV CKD, and 30 renal transplant recipients with stage III/IV CKD, evaluating the potential correlation of complement fragments with brachial artery flow–mediated dilation, Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and urinary albumin/creatinine ratio. Endothelial microparticles were characterized via proteomic analysis and compared between study groups. Complement fragment Ba was significantly increased in CKD and post–kidney transplant CKD. Plasma Ba levels correlated significantly with lower brachial artery flow–mediated dilation, lower Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and higher urinary albumin/creatinine ratio. Factor D levels were significantly higher in the plasma microparticles of patients with CKD versus healthy controls. Plasma microparticles isolated from patients with CKD and containing factor D activated the alternative pathway in vitro.ConclusionThe alternative complement pathway is activated in CKD and correlates with endothelial dysfunction and markers of CKD. Future studies are needed to evaluate whether endothelial microparticles with increased factor D play a pathologic role in CKD‐associated vascular disease.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02230202.

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Chronic renal failure is accompanied by endothelial activation and a large increase in microparticle numbers with reduced procoagulant capacity

Cited by 40 publications

References 35 publications

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

von Willebrand factor propeptide: biology and clinical utility

Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease

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