Preservation of Kidneys by Machine Perfusion Influences Gene Expression and May Limit Ischemia/Reperfusion Injury

Wszoła, Michał; Kwiatkowski, A.; Domagała, Piotr; Wirkowska, Agnieszka; Bieniasz, M.; Diuwe, Piotr; Kieszek, R.; Durlik, M.; Chmura, A.

doi:10.7182/pit2014384

Cited by 18 publications

(13 citation statements)

References 34 publications

(36 reference statements)

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“…45). Furthermore, its protective effects have been extensively described in diverse forms of extra-renal tissue damage (e.g., brain, liver, heart, organ transplantation) (46–52). However, less certain than the existence of HO’s protective actions is the exact mechanism by which that protection is effected.…”

Section: Discussionmentioning

confidence: 99%

Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Zager

2015

Translational Research

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The phenomenon of so called renal “ischemic preconditioning”, whereby an initial ischemic insult induces resistance against subsequent kidney damage, has been well established in the experimental literature. However, a clinically applicable way to safely recapitulate this state has not been defined. We hypothesized that a unique combination of agents (nitrited myoglobin + Sn protoporphyrin) can achieve these ends by safely, and synergistically, increasing cytoprotective proteins (e.g., HO-1, IL-10, haptoglobin) in kidney cells. To test this hypothesis, CD-1 mice received 1 mg N-Mgb and 1 µmole SnPP, either alone or in combination. Renal cortical HO-1, haptoglobin, and IL-10 gene expression (mRNA, protein levels) were determined 4 and 18 hrs later. Cytoresistance to three forms of AKI were assessed (glycerol- induced rhabdomyolysis; maleate nephrotoxicity; post-ischemic AKI progression to CKD). To ascertain whether cytoresistance might emerge in extra-renal organs, hepatic HO-1, IL-10, and haptoglobin levels were also measured, and resistance to 25 min of hepatic ischemia-reperfusion injury and hepatotoxicity (intraperitoneal glycerol injection) was sought. N-Mgb + SnPP induced additive or synergistic increases in renal HO-1, haptoglobin, and IL-10 mRNA/protein levels (up to 20 fold) without inducing any apparent renal or extra-renal damage. By 18 hrs post treatment, marked, or complete, protection against glycerol-induced AKI, maleate- induced AKI, and post ischemic AKI progression to CKD had emerged. Combined N-Mgb+SnPP was more protective than was either agent alone (assessed in glycerol model). N-Mgb+SnPP also up-regulated cytoprotective pathways in liver, and induced marked protection against both hepatic ischemia-reperfusion and toxic liver damage. In sum, we posit that “preconditioning” with combined N-Mgb+SnPP administration represents a promising approach for protecting against diverse forms of renal and non renal (hepatic) forms of tissue damage.

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Section: Discussionmentioning

confidence: 99%

Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Zager

2015

Translational Research

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“…1 The donor organ undergoes a number of injurious insults prior to, and during the early post-operative phase that are thought to contribute to the later development of chronic rejection. 2, 3 One such insult is ischemia reperfusion injury (IRI). 4 IRI is an unavoidable complication in the process of cardiac transplantation, with the donor heart rendered ischemic for prolonged periods prior to implantation into the recipient and subsequent reperfusion.…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity

et al. 2015

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In this study, we developed a stable, nontoxic novel micelle nanoparticle to attenuate responses of endothelial cell (EC) inflammation when subjected to oxidative stress, such as observed in organ transplantation. Targeted Rapamycin Micelles (TRaM) were synthesized using PEG-PE-amine and N-palmitoyl homocysteine (PHC) with further tailoring of the micelle using targeting peptides (cRGD) and labeling with far-red fluorescent dye for tracking during cellular uptake studies. Our results revealed that the TRaM was approximately 10 nm in diameter and underwent successful internalization in Human Umbilical Vein EC (HUVEC) lines. Uptake efficiency of TRaM nanoparticles was improved with the addition of a targeting moiety. In addition, our TRaM therapy was able to downregulate both mouse cardiac endothelial cell (MCEC) and HUVEC production and release of the pro-inflammatory cytokines, IL-6 and IL-8 in normal oxygen tension and hypoxic conditions. We were also able to demonstrate a dose-dependent uptake of TRaM therapy into biologic tissues ex vivo. Taken together, these data demonstrate the feasibility of targeted drug delivery in transplantation, which has the potential for conferring local immunosuppressive effects without systemic consequences while also dampening endothelial cell injury responses.

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“…Extracellular oxygen carriers may logistically, rheologically, and immunologically be superior to packed red blood cells, but need further investigation. Studies on human DCD and ECD kidneys supported the superiority of HMP over SCS (32,43,45,46). Reznik et al (43) found a considerably lower number of complications and negative effects, like acute rejection, correlated with HMP kidneys retrieved from DCD donors.…”

Section: Hypothermic Machine Perfusion Techniquesmentioning

confidence: 96%

Machine Perfusion of Extended Criteria Donor Organs: Immunological Aspects

et al. 2020

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Due to higher vulnerability and immunogenicity of extended criteria donor (ECD) organs used for organ transplantation (Tx), the discovery of new treatment strategies, involving tissue allorecognition pathways, is important. The implementation of machine perfusion (MP) led to improved estimation of the organ quality and introduced the possibility to achieve graft reconditioning prior to Tx. A significant number of experimental and clinical trials demonstrated increasing support for MP as a promising method of ECD organ preservation compared to classical static cold storage. MP reduced ischemia-reperfusion injury resulting in the protection from inadequate activation of innate immunity. However, there are no general agreements on MP protocols, and clinical application is limited. The objective of this comprehensive review is to summarize literature on immunological effects of MP of ECD organs based on experimental studies and clinical trials.

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Preservation of Kidneys by Machine Perfusion Influences Gene Expression and May Limit Ischemia/Reperfusion Injury

Cited by 18 publications

References 34 publications

Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity

Machine Perfusion of Extended Criteria Donor Organs: Immunological Aspects

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