Perfusion Techniques in Kidney Allograft Preservation to Reduce Ischemic Reperfusion Injury: A Systematic Review and Meta-Analysis
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SUBMITTER: Hasjim B
PROVIDER: S-EPMC11200710 | biostudies-literature | 2024 May
REPOSITORIES: biostudies-literature
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Project description:BackgroundDuring transplantation, a kidney graft undergoes a cascade of pathological changes, referred to as ischemia-reperfusion injury (IRI), as it is incorporated into the bloodstream. Various studies have reported that retrograde reperfusion (RRP) leads to improved myocardial recovery and could reduce IRI in liver transplantation. This study investigated the effect of RRP in renal transplantation with a focus on reduction of kidney IRI.MethodsBetween December 2019 and July 2022, 15 consecutive kidney transplants were performed with retrograde venous reperfusion. To conduct a comparative study and to recruit a control group, 15 kidney transplants that had been performed in the same center by the same two surgeons were retrospectively analyzed. Differences between the two groups were considered statistically significant at P<0.05.ResultsThe baseline characteristics of the two groups were statistically comparable (P>0.05). The surgical technique for kidney transplantation was the same in both groups. On the first postoperative day, polyuria was less pronounced in the RRP group (P<0.01). Serum creatinine and urea levels and estimated glomerular filtration rates on postoperative days 1, 4, 7, and 30 were lower in the RRP group (P<0.05).ConclusionsRetrograde venous reperfusion of a kidney transplant, preceding antegrade arterial reperfusion, reduced the effects of renal parenchyma IRI. To validate the results of this study, it is necessary to conduct further studies on a larger cohort of patients with a longer follow-up period.
| S-EPMC9832596 | biostudies-literature
Project description:Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.
| S-EPMC8160749 | biostudies-literature
Project description:Metformin may act renoprotective prior to kidney transplantation by reducing ischemia-reperfusion injury (IRI). This study examined whether metformin preconditioning and postconditioning during ex vivo normothermic machine perfusion (NMP) of rat and porcine kidneys affect IRI. In the rat study, saline or 300 mg/kg metformin was administered orally twice on the day before nephrectomy. After 15 minutes of warm ischemia, kidneys were preserved with static cold storage for 24 hours. Thereafter, 90 minutes of NMP was performed with the addition of saline or metformin (30 or 300 mg/L). In the porcine study, after 30 minutes of warm ischemia, kidneys were preserved for 3 hours with oxygenated hypothermic machine perfusion. Subsequently, increasing doses of metformin were added during 4 hours of NMP. Metformin preconditioning of rat kidneys led to decreased injury perfusate biomarkers and reduced proteinuria. Postconditioning of rat kidneys resulted, dose-dependently, in less tubular cell necrosis and vacuolation. Heat shock protein 70 expression was increased in metformin-treated porcine kidneys. In all studies, creatinine clearance was not affected. In conclusion, both metformin preconditioning and postconditioning can be done safely and improved rat and porcine kidney quality. Because the effects are minor, it is unknown which strategy might result in improved organ quality after transplantation.
| S-EPMC7877823 | biostudies-literature
Project description:Remote ischemic conditioning (RIC) is a noninvasive therapeutic strategy that uses brief cycles of blood pressure cuff inflation and deflation to protect the myocardium against ischemia-reperfusion injury. The objective of this systematic review was to determine the impact of RIC on myocardial salvage index, infarct size, and major adverse cardiovascular events when initiated before catheterization. Electronic searches of Medline, Embase, and Cochrane Central Register of Controlled Trials were conducted and reference lists were hand searched. Randomized controlled trials comparing percutaneous coronary intervention (PCI) with and without RIC for patients with ST-segment-elevation myocardial infarction were included. Two reviewers independently screened abstracts, assessed quality of the studies, and extracted data. Data were pooled using random-effects models and reported as mean differences and relative risk with 95% confidence intervals. Eleven articles (9 randomized controlled trials) were included with a total of 1220 patients (RIC+PCI=643, PCI=577). Studies with no events were excluded from meta-analysis. The myocardial salvage index was higher in the RIC+PCI group compared with the PCI group (mean difference: 0.08; 95% confidence interval, 0.02-0.14). Infarct size was reduced in the RIC+PCI group compared with the PCI group (mean difference: -2.46; 95% confidence interval, -4.66 to -0.26). Major adverse cardiovascular events were lower in the RIC+PCI group (9.5%) compared with the PCI group (17.0%; relative risk: 0.57; 95% confidence interval, 0.40-0.82). RIC appears to be a promising adjunctive treatment to PCI for the prevention of reperfusion injury in patients with ST-segment-elevation myocardial infarction; however, additional high-quality research is required before a change in practice can be considered.
| S-EPMC5524098 | biostudies-literature
Project description:Deteriorating kidney function is frequently observed in the elderly population, as well as vulnerability to acute kidney failure, such as ischemic/reperfusion injury (IRI), and inadequate recovery from IRI is one of the mechanisms of kidney dysfunction in the elderly. The potential mediators in the progression of kidney dysfunction in the aging kidney have not yet been clearly revealed. In this study, we investigated the role of nuclear factor erythroid 2-related factor 2 (NRF2), which is an essential regulator of cellular redox homeostasis, in restoring kidney function after IRI in the aging kidney. NRF2 expression decreased significantly in the kidneys of old mice, as well as histologic and functional renal recovery after IRI; 45-min renal pedicle clamping was retarded in old compared with young mice. Persistent renal injury during the recovery phase after IRI was aggravated in NRF2 knockout (KO) mice compared to wild-type mice. Oxidative stress occurred in NRF2 KO old mice during the IRI recovery phase along with decreased expression of mitochondrial OXPHOS-related proteins and a reduction in mitochondrial ATP content. In vitro, hypoxia/reoxygenation (H/R) injury was aggravated in senescent human proximal tubuloepithelial cells after NRF2 restriction using NRF2 siRNA, which also increased the level of oxidative stress and deteriorated mitochondrial dysfunction. Treating the mice with an NRF2 activator, CDDO-Me, alleviated the injury. These results suggest that NRF2 may be a therapeutic target for the aging kidney.
| S-EPMC10376352 | biostudies-literature
Project description:Dendritic cells (DCs) are central in regulating immune responses of kidney ischemia-reperfusion injury (IRI), and strategies to alter DC function may provide new therapeutic opportunities. Sphingosine 1-phosphate (S1P) modulates immunity through binding to its receptors (S1P1-5), and protection from kidney IRI occurs in mice treated with S1PR agonist, FTY720 (FTY). We tested if ex vivo propagation of DCs with FTY could be used as cellular therapy to limit the off-target effects associated with systemic FTY administration in kidney IRI. DCs have the ability of regulate innate and adaptive responses and we posited that treatment of DC with FTY may underlie improvements in kidney IRI. Herein, it was observed that treatment of bone marrow derived dendritic cells (BMDCs) with FTY induced mitochondrial biogenesis, FTY-treated BMDCs (FTY-DCs) showed significantly higher oxygen consumption rate and ATP production compared to vehicle treated BMDCs (Veh-DCs). Adoptive transfer of FTY-DCs to mice 24 h before or 4 h after IRI significantly protected the kidneys from injury compared to mice treated with Veh-DCs. Additionally, allogeneic adoptive transfer of C57BL/6J FTY-DCs into BALB/c mice equally protected the kidneys from IRI. FTY-DCs propagated from S1pr1-deficient DCs derived from CD11cCreS1pr1 fl/fl mice as well as blunting mitochondrial oxidation in wildtype (WT) FTY-DCs prior to transfer abrogated the protection observed by FTY-DCs. We queried if DC mitochondrial content alters kidney responses after IRI, a novel but little studied phenomenon shown to be integral to regulation of the immune response. Transfer of mitochondria rich FTY-DCs protects kidneys from IRI as transferred FTY-DCs donated their mitochondria to recipient splenocytes (i.e., macrophages) and prior splenectomy abrogated this protection. Adoptive transfer of FTY-DCs either prior to or after ischemic injury protects kidneys from IRI demonstrating a potent role for donor DC-mitochondria in FTY's efficacy. This is the first evidence, to our knowledge, that DCs have the potential to protect against kidney injury by donating mitochondria to splenic macrophages to alter their bioenergetics thus making them anti-inflammatory. In conclusion, the results support that ex vivo FTY720-induction of the regulatory DC phenotype could have therapeutic relevance that can be preventively infused to reduce acute kidney injury.
| S-EPMC7328774 | biostudies-literature
Project description:Acute kidney injury (AKI) is associated with an abrupt loss of kidney function that results in significant morbidity and mortality. Considerable effort has focused around the identification of diagnostic biomarkers and the analysis of molecular events. Most studies have adopted organ-wide approaches that do not fully capture the interplay among different cell types in the pathophysiology of AKI. To extend our understanding of molecular and cellular events in AKI, we developed a mouse line that enables the identification of translational profiles in specific cell types by CRE recombinase-dependent activation of an eGFP-tagged L10a ribosomal protein subunit, and consequently, translating ribosome affinity purification (TRAP) of mRNA populations. By utilizing cell-type specific CRE-driver lines, in this study we identify distinct cellular responses in an ischemia reperfusion injury (IRI) model of AKI. Cell-specific translational expression profiles were uncovered 24 hours after IRI from four populations enriched for distinct anatomical and cellular subgroups: nephron, interstitial cell populations, vascular endothelium, and macrophages/monocytes by Affymetrix microarray. A construct containing the CAGGS promoter driving eGFP-L10a, with a loxP-site flanked triple SV40 polyA cassette between promoter and eGFP-L10a cassette was targeted into the ubiquitously active Rosa26 locus. The upstream polyA cassette is designed to block activity of the downstream eGFP-L10a cassette. CRE-dependent removal of this transcriptional block activates eGFP::L10a production within the CRE-producing cell, and all of its descendants. Mice carrying the conditional eGFP-L10a allele, referred to as L10a, were maintained in a homozygous state. L10a mice were crossed to four CRE strains to activate eGFP::L10a expression in four predominantly non-overlapping cellular compartments in the kidney. A Six2-Tet-GFP::CRE allele is active exclusively within nephron progenitors; consequently, historical labeling results in eGFP::L10a expression throughout the main body of the nephron. A Foxd1-GFP::CRE allele is active in the progenitors of many of the interstitial cell lineages including those generating mesangial and non-glomerular pericytes. In addition, Foxd1 is normally expressed in podocytes. Cdh5-CRE is reported to be active throughout the vascular endothelium, and finally, Lyz2-CRE specifically labels cells of the myeloid lineage, notably macrophages, monocytes and dendritic cells. Mice carrying any CRE allele and the L10a allele are designated generically CRE-L10a. six2-L10a, foxd1-L10a, cdh5-L10a and lyz2-L10a denote specifically mice that are compound heterozygotes for the indicated CRE driver and L10a. CRE-L10a, L10a heterozygous littermates without CRE allele, C57BL/6 wild type mice were subjected to renal bilateral warm ischemia 28 minutes followed by 24-hour reperfusion when the kidney TRAP RNA and total RNA were isolated and subjected to Affymetrix microarray. Biological triplicates for each CRE-L10a line underwent no Surgery; sham Surgery and IRI treatment.
2014-03-06 | E-GEOD-52004 | biostudies-arrayexpress
Project description:BackgroundKidney ischemia-reperfusion injury is inevitable in kidney transplantation, and is essential for primary graft dysfunction and delayed graft function. Our previous study has proved that miR-92a could ameliorate kidney ischemia-reperfusion injury, but the mechanism has not been studied.MethodsThis study conducted further research on the role of miR-92a in kidney ischemia-reperfusion injury and organ preservation. In vivo, mice models of bilateral kidney ischemia (30 min), cold preservation after ischemia (cold preservation time of 6, 12, and 24 h), and ischemia-reperfusion (reperfusion time of 24, 48, and 72 h) were established. Before or after modeling, the model mice were injected with miR-92a-agomir through the caudal vein. In vitro, the hypoxia-reoxygenation of HK-2 cells was used to simulate ischemia-reperfusion injury.ResultsKidney ischemia and ischemia-reperfusion significantly damaged kidney function, decreased the expression of miR-92a, and increased apoptosis and autophagy in kidneys. miR-92a agomir tail vein injection significantly increased the expression of miR-92a in kidneys, improved kidney function, and alleviated kidney injury, and the intervention before modeling achieved a better effect than after. Moreover, miR-92a agomir significantly reduced the apoptosis and autophagy in HK-2 cells induced by hypoxia, hypoxia-reoxygenation, and rapamycin, while miR-92a antagomir had opposite effects. Furthermore, mitogen-activated protein kinase, c-Jun NH (2) terminal kinase, caspase 3, Beclin 1, and microtubule-associated protein 1 light chain 3B were inhibited by overexpression of miR-92a both in vivo and in vitro, which in turn reduced apoptosis and autophagy.ConclusionsOur results prove that overexpression of miR-92a attenuated kidney ischemia-reperfusion injury and improved kidney preservation, and intervention before ischemia-reperfusion provides better protection than after.
| S-EPMC9997008 | biostudies-literature
Project description:Oxidative stress is a key element of ischemia-reperfusion injury, occurring during kidney preservation and transplantation. Current options for kidney graft preservation prior to transplantation are static cold storage (CS) and hypothermic machine perfusion (HMP), the latter demonstrating clear improvement of preservation quality, particularly for marginal donors, such as extended criteria donors (ECDs) and donation after circulatory death (DCDs). Nevertheless, complications still exist, fostering the need to improve kidney preservation. This review highlights the most promising avenues of in kidney perfusion improvement on two critical aspects: ex vivo and in vitro evaluation.
| S-EPMC7662866 | biostudies-literature
Project description:Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.
| S-EPMC4305280 | biostudies-literature