Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application

Qi, Ruochen; Qin, Weijun

doi:10.3389/fimmu.2022.811696

Cited by 8 publications

(3 citation statements)

References 173 publications

(234 reference statements)

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“…The rationale behind this lies in the detrimental roles that ROS plays in transplant organs where it collectively contributes to the oxidative damage of critical biomolecules, including proteins, lipids, and nucleic acids (DNA), and are implicated in triggering inflammatory responses, including complement activation. 41, 42 Injury to transplant grafts during ischemia, particularly at the point of reperfusion, is predominantly driven by aberrant formation of ROS. 43 It is well-established that an imbalance characterized by excessive ROS production and diminished antioxidant defenses precipitates cell membrane damage, apoptosis, necrosis, and, consequently, DGF or even failure.…”

Section: Resultsmentioning

confidence: 99%

Antioxidant Polysulfide Nanoparticles Ameliorate Ischemia-Reperfusion Injury and Improve Porcine Kidney Function Post-Transplantation

Stone

d’Arcy

Geraghty³

et al. 2023

Preprint

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Introduction: Ischaemia-reperfusion injury (IRI) results in the pathophysiological generation of reactive oxygen species (ROS) with concurrent activation of the complement cascade. This manifests as delayed graft function, which has a significant impact on the longevity of the graft. We aimed to evaluate if ROS scavenging nanoparticles can be used to mitigate IRI related injury during normothermic machine perfusion (NMP). Methods: A randomised, two-stage, preclinical trial was used to assess the impact of poly(propylene sulfide) (polysulfide) nanoparticles (PPS-NPs) on parameters associated with IRI in a renal NMP system (experiment 1, n=6 vs 6). Paired porcine kidneys were randomised to receive either an NP-preservation flush followed by 6 hours of NMP with NP-perfusate, or control preservation flush and standard NMP. Following this, an allogeneic transplant- reperfusion model was used to evaluate if treatment with PPS-NPs improved renal haemodynamics post-transplantation (experiment 2, n=6 vs 6). Kidneys were perfused for 3 hours with or without NP, before being reperfused on a circuit primed with matched blood from genetically different donor pigs for 6 hours, without immunosuppression. Results: In experiment 1, all kidneys perfused well for 6 hours with physiological renal haemodynamics and biochemistry. Kidneys perfused with PPS-NPs had improved regional tissue perfusion on infra-red imaging. In experiment 2, renal haemodynamics were significantly improved during allogeneic reperfusion (post-transplant) after treatment with NP. Complement activation remained significantly lower in treated kidneys with a diminished TNF-a response. This translated into an improvement in tissue integrity. Conclusion: IRI was ameliorated following treatment with NPs during preservation and NMP. This was evidenced by an improvement in renal haemodynamics and diminished inflammatory markers upon reperfusion with allogeneic blood.

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Section: Resultsmentioning

confidence: 99%

Antioxidant Polysulfide Nanoparticles Ameliorate Ischemia-Reperfusion Injury and Improve Porcine Kidney Function Post-Transplantation

Stone

d’Arcy

Geraghty³

et al. 2023

Preprint

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“…Different events occur during IRI: transcriptional reprogramming, activation of apoptosis, necrosis and necroptosis, endothelial dysfunction, and activation of innate and adaptive immune responses [104,105]. The rationale for the creation of an immune microenvironment is for the clearance of injured cells and for subsequent tissue repair [106][107][108]. Locally generated component proteins seem to be more predominant during IRI than circulating ones.…”

Section: Complement and Kidney Transplantationmentioning

confidence: 99%

Complement System and the Kidney: Its Role in Renal Diseases, Kidney Transplantation and Renal Cell Carcinoma

Lasorsa,

Rutigliano,

Milella

et al. 2023

IJMS

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The crosstalk among the complement system, immune cells, and mediators of inflammation provides an efficient mechanism to protect the organism against infections and support the repair of damaged tissues. Alterations in this complex machinery play a role in the pathogenesis of different diseases. Core complement proteins C3 and C5, their activation fragments, their receptors, and their regulators have been shown to be active intracellularly as the complosome. The kidney is particularly vulnerable to complement-induced damage, and emerging findings have revealed the role of complement system dysregulation in a wide range of kidney disorders, including glomerulopathies and ischemia-reperfusion injury during kidney transplantation. Different studies have shown that activation of the complement system is an important component of tumorigenesis and its elements have been proved to be present in the TME of various human malignancies. The role of the complement system in renal cell carcinoma (RCC) has been recently explored. Clear cell and papillary RCC upregulate most of the complement genes relative to normal kidney tissue. The aim of this narrative review is to provide novel insights into the role of complement in kidney disorders.

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“…Given the kidney's unique susceptibility to complement attack, considerable research is being undertaken to elucidate the potential efficacy of complement inhibitors in the setting of various kidney pathologies, including renal transplant [145][146][147][148], lupus nephritis [149,150], IgA nephropathy [141,151], immune complex-mediated membranoproliferative glomerulonephritis [152,153], and C3 glomerulopathies [139,140,154,155]. The potential therapeutic benefit of targeting complement in chronic kidney pathologies, such as DKD, remains to be further explored.…”

Section: Dysregulated C5ar2 Is Associated With Impaired Immunometabolismmentioning

confidence: 99%

Therapeutic Potential of Targeting Complement C5a Receptors in Diabetic Kidney Disease

Trambas,

Coughlan,

Tan

2023

IJMS

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Diabetic kidney disease (DKD) affects 30–40% of patients with diabetes and is currently the leading cause of end-stage renal disease (ESRD). The activation of the complement cascade, a highly conserved element of the innate immune system, has been implicated in the pathogenesis of diabetes and its complications. The potent anaphylatoxin C5a is a critical effector of complement-mediated inflammation. Excessive activation of the C5a-signalling axis promotes a potent inflammatory environment and is associated with mitochondrial dysfunction, inflammasome activation, and the production of reactive oxygen species. Conventional renoprotective agents used in the treatment of diabetes do not target the complement system. Mounting preclinical evidence indicates that inhibition of the complement system may prove protective in DKD by reducing inflammation and fibrosis. Targeting the C5a-receptor signaling axis is of particular interest, as inhibition at this level attenuates inflammation while preserving the critical immunological defense functions of the complement system. In this review, the important role of the C5a/C5a-receptor axis in the pathogenesis of diabetes and kidney injuries will be discussed, and an overview of the status and mechanisms of action of current complement therapeutics in development will be provided.

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Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application

Cited by 8 publications

References 173 publications

Antioxidant Polysulfide Nanoparticles Ameliorate Ischemia-Reperfusion Injury and Improve Porcine Kidney Function Post-Transplantation

Antioxidant Polysulfide Nanoparticles Ameliorate Ischemia-Reperfusion Injury and Improve Porcine Kidney Function Post-Transplantation

Complement System and the Kidney: Its Role in Renal Diseases, Kidney Transplantation and Renal Cell Carcinoma

Therapeutic Potential of Targeting Complement C5a Receptors in Diabetic Kidney Disease

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