Blocking Complement Factor B Activation Reduces Renal Injury and Inflammation in a Rat Brain Death Model

Jager, Nynke A.; Zanden, Judith E. van; Subias, Marta; Leuvenink, Henri G. D.; Daha, Mohamed R.; Córdoba, Santiago Rodrı́guez de; Poppelaars, Felix; Seelen, Marc A.

doi:10.3389/fimmu.2019.02528

Cited by 9 publications

(8 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This might lead to an increased inflammatory response in kidneys retrieved from DBD donors during NMP ( 13 , 31 ). Kidneys retrieved from brain-dead donors might thus specifically benefit from treatment with a complement inhibitor during NMP ( 18 , 32 , 33 ). No differences in complement activation during NMP were seen between preservation with SCS or HMP.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Complement Is Activated During Normothermic Machine Perfusion of Porcine and Human Discarded Kidneys

et al. 2022

Self Cite

View full text Add to dashboard Cite

BackgroundThe gap between demand and supply of kidneys for transplantation necessitates the use of kidneys from extended criteria donors. Transplantation of these donor kidneys is associated with inferior results, reflected by an increased risk of delayed graft function. Inferior results might be explained by the higher immunogenicity of extended criteria donor kidneys. Normothermic machine perfusion (NMP) could be used as a platform to assess the quality and function of donor kidneys. In addition, it could be useful to evaluate and possibly alter the immunological response of donor kidneys. In this study, we first evaluated whether complement was activated during NMP of porcine and human discarded kidneys. Second, we examined the relationship between complement activation and pro-inflammatory cytokines during NMP. Third, we assessed the effect of complement activation on renal function and injury during NMP of porcine kidneys. Lastly, we examined local complement C3d deposition in human renal biopsies after NMP.MethodsNMP with a blood-based perfusion was performed with both porcine and discarded human kidneys for 4 and 6 h, respectively. Perfusate samples were taken every hour to assess complement activation, pro-inflammatory cytokines and renal function. Biopsies were taken to assess histological injury and complement deposition.ResultsComplement activation products C3a, C3d, and soluble C5b-9 (sC5b-9) were found in perfusate samples taken during NMP of both porcine and human kidneys. In addition, complement perfusate levels positively correlated with the cytokine perfusate levels of IL-6, IL-8, and TNF during NMP of porcine kidneys. Porcine kidneys with high sC5b-9 perfusate levels had significantly lower creatinine clearance after 4 h of NMP. In line with these findings, high complement perfusate levels were seen during NMP of human discarded kidneys. In addition, kidneys retrieved from brain-dead donors had significantly higher complement perfusate levels during NMP than kidneys retrieved from donors after circulatory death.ConclusionNormothermic kidney machine perfusion induces complement activation in porcine and human kidneys, which is associated with the release of pro-inflammatory cytokines and in porcine kidneys with lower creatinine clearance. Complement inhibition during NMP might be a promising strategy to reduce renal graft injury and improve graft function prior to transplantation.

show abstract

Section: Discussionmentioning

confidence: 99%

“…C3 and C3d were measured in perfusate samples after NMP of human discarded kidneys. C3d was measured as described previously ( 18 ). Briefly, samples were polyethylene glycol (PEG) precipitated.…”

Section: Methodsmentioning

confidence: 99%

Complement Is Activated During Normothermic Machine Perfusion of Porcine and Human Discarded Kidneys

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…[48] Targeting complement activation after the induction of brain death also reduced renal inflammation and improved renal function before transplantation in animal models. [49] Recently, a study by Jager et al [50] has shown that experimental donor rat pre-treatment with anti-FB preserved renal function reduced renal damage and inflammation prior to transplantation. Seemingly, high-dose C1-INH treatment of brain-dead rat donors resulted in significantly lower renal gene expression and serum levels of IL-6, which reflected with improved renal function and reduced renal injury.…”

Section: Inflammation Limiting Strategies In Organ Donorsmentioning

confidence: 99%

Pathophysiological Changes and Systemic Inflammation in Brain Dead Organ Donors: Effect on Graft Quality

Bezeljak¹,

Večerić-Haler²

2021

Organ Donation and Transplantation

View full text Add to dashboard Cite

Transplantation is the definitive treatment of end-stage organ disease. As the shortage of suitable organs poses its main limitation, the active management of potential organ donors becomes increasingly more important. The majority of solid organs are still obtained from donors after confirmed brain death. Brain death is the complete and irreversible cessation of all brain functions, and triggers a variety of severe pathophysiological changes in cardiovascular, hormonal and metabolic status that can result in organ damage. Moreover, brain death is associated with massive inflammatory response with a cytokine storm and complement activation that increases graft immunogenicity and adversely affects graft survival. Organs from brain-dead donors are more prone to graft dysfunction and rejection when compared to organs obtained from living donors. Brain death is thus believed to be an important risk factor influencing the quality of organs before procurement.

show abstract

“…The increasing number of studies of donor management research across the studied years shows that this is a rapidly evolving research area. The prevention of organ injury by in uencing the balance of pro-and anti-in ammatory mediators, targeting ischaemia-reperfusion and studying the role of the immune response to target recovery and repair has been studies in many pre-clinical settings (34)(35)(36)(37)(38)(39). However, there is limited translation of research of prevention of organ injury (and promotion of repair or recovery) into clinical practice during the period of donor management.…”

Section: Key Ndingsmentioning

confidence: 99%

Outcome measures in solid organ donor management research: a systematic review

Bera

Shah

English

et al. 2021

British Journal of Anaesthesia

View full text Add to dashboard Cite

BackgroundTo systematically review published outcome measures across randomised controlled trials (RCTs) of donor management interventions. MethodsThe systematic review was conducted in accordance with recommendations by the Cochrane Handbook and PRISMA statement. We searched MEDLINE, EMBASE, CENTRAL, Web of Science as well as trial databases from 1980 to December 2019 for RCTs of donor management interventions. ResultsTwenty-two RCTs (n = 3432 donors) were included in our analysis. Fourteen RCTs (63.6%) reported a primary outcome relating to a single organ only. Eight RCTs primarily focused on aspects of donor optimisation in critical care. Thyroid hormones and methylprednisolone were the most commonly evaluated interventions ( ve and four studies, respectively). Only two studies, focusing on single organs (e.g. kidney), evaluated outcomes relating to other organs. The majority of studies evaluated physiological or biomarker-related outcomes. No study evaluated recipient health-related quality of life.Only one study sought consent from potential organ recipients. ConclusionsThe majority of RCTs evaluating donor management interventions only assessed single organ outcomes or effects on donor stability in critical care. There is a need for an evaluation of patient-centred recipient outcomes, and standardisation and reporting of outcome measures for future donor management RCTs.

show abstract

Blocking Complement Factor B Activation Reduces Renal Injury and Inflammation in a Rat Brain Death Model

Cited by 9 publications

References 35 publications

Complement Is Activated During Normothermic Machine Perfusion of Porcine and Human Discarded Kidneys

Complement Is Activated During Normothermic Machine Perfusion of Porcine and Human Discarded Kidneys

Pathophysiological Changes and Systemic Inflammation in Brain Dead Organ Donors: Effect on Graft Quality

Outcome measures in solid organ donor management research: a systematic review

Contact Info

Product

Resources

About