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International Journal of Clinical and... 2019This study was conducted to investigate the effect of warm ischemia duration on hepatocyte mitochondrial damage after liver transplantation, and confirm the role of...
This study was conducted to investigate the effect of warm ischemia duration on hepatocyte mitochondrial damage after liver transplantation, and confirm the role of CaMKIIγ in this process. Rat donation after cardiac death (DCD) liver transplantation model was established by exposing donor liver to 0 (W group), 15 (W group), and 30 (W group) min warm ischemia. Some rats in W group were transfected with CaMKIIγ and CaMKIIγ-shRNA lentivirus. On day 1, 3, and 7 post-transplantation, a series of experiments, including HE staining, TEM observation, ALT and AST measurement, flow cytometry analysis, qRT-PCR, and Western blotting were performed to evaluate the extent of hepatic and mitochondria damage. Within 7 days post-transplantation, prolonged ischemia led to an obvious deterioration of hepatic and mitochondria damage, presenting with a marked increase of apoptotic hepatocytes, ALT and AST levels, cells with low MMP, and AIF and Cyt C expression. CaMKIIγ overexpression caused the significant ultrastructural damage of hepatic cells, increase of cells with low MMP, enhancement of AIF and Cyt C expression, and augmented Ca/CaM/CaMKIIγ, while blocking CaMKIIγ showed an opposite result. In conclusion, ischemia duration is proportional to the extent of hepatic mitochondria damage, and CaMKIIγ plays a negative regulatory role in this process by regulating the Ca/CaM/CaMKII signaling pathway.
PubMed: 31933737
DOI: No ID Found -
Kidney International Mar 2016Warm ischemia time is a potentially modifiable insult to transplanted kidneys, but little is known about its effect on long-term outcomes. Here we conducted a study of... (Comparative Study)
Comparative Study
Warm ischemia time is a potentially modifiable insult to transplanted kidneys, but little is known about its effect on long-term outcomes. Here we conducted a study of United States kidney transplant recipients (years 2000-2013) to determine the association between warm ischemia time (the time from organ removal from cold storage to reperfusion with warm blood) and death/graft failure. Times under 10 minutes were potentially attributed to coding error. Therefore, the 10-to-under-20-minute interval was chosen as the reference group. The primary outcome was mortality and graft failure (return to chronic dialysis or preemptive retransplantation) adjusted for recipient, donor, immunologic, and surgical factors. The study included 131,677 patients with 35,901 events. Relative to the reference patients, times of 10 to under 20, 20 to under 30, 30 to under 40, 40 to under 50, 50 to under 60, and 60 and more minutes were associated with hazard ratios of 1.07 (95% confidence interval, 0.99-1.15), 1.13 (1.06-1.22), 1.17 (1.09-1.26), 1.20 (1.12-1.30), and 1.23 (1.15-1.33) for the composite event, respectively. Association between prolonged warm ischemia time and death/graft failure persisted after stratification by donor type (living vs. deceased donor) and delayed graft function status. Thus, warm ischemia time is associated with adverse long-term patient and graft survival after kidney transplantation. Identifying strategies to reduce warm ischemia time is an important consideration for future study.
Topics: Adult; Delayed Graft Function; Female; Graft Survival; Humans; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Registries; Renal Dialysis; Reoperation; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; United States; Warm Ischemia; Young Adult
PubMed: 26880458
DOI: 10.1016/j.kint.2015.09.002 -
Minerva Urology and Nephrology Apr 2022The impact of warm ischemia time (WIT) on renal functional recovery remains controversial. We examined the length of WIT>30 min on the long-term renal function following...
BACKGROUND
The impact of warm ischemia time (WIT) on renal functional recovery remains controversial. We examined the length of WIT>30 min on the long-term renal function following on-clamp partial nephrectomy (PN).
METHODS
Data from 23 centers for patients undergoing on-clamp PN between 2000 and 2018 were analyzed. We included patients with two kidneys, single tumor, cT1, minimum 1-year follow-up, and preoperative eGFR≥60 mL/min/1.73m. Patients were divided into two groups according to WIT length: group I "WIT≤30 min" and group II "WIT>30 min." A propensity-score matched analysis (1:1 match) was performed to eliminate potential confounding factors between groups. We compared eGFR values, eGFR (%) preservation, eGFR decline, events of chronic kidney disease (CKD) upgrading, and CKD-free progression rates between both groups. Cox regression analysis evaluated WIT impact on upgrading of CKD stages.
RESULTS
The primary cohort consisted of 3526 patients: group I (N.=2868) and group II (N.=658). After matching the final cohort consisted of 344 patients in each group. At last follow-up, there were no significant differences in median eGFR values at 1, 3, 5, and 10 years (P>0.05) between the matched groups. In addition, the median eGFR (%) preservation and absolute eGFR change were similar (89% in group I vs. 87% in group II, P=0.638) and (-10 in group I vs. -11 in group II, P=0.577), respectively. The 5 years new-onset CKD-free progression rates were comparable in the non-matched groups (79% in group I vs. 81% in group II, log-rank, P=0.763) and the matched groups (78.8% in group I vs. 76.3% in group II, log-rank, P=0.905). Univariable Cox regression analysis showed that WIT>30 min was not a predictor of overall CKD upgrading (HR:0.953, 95%CI 0.829-1.094, P=0.764) nor upgrading into CKD stage ≥III (HR:0.972, 95%CI 0.805-1.173, P=0.764). Retrospective design is a limitation of our study.
CONCLUSIONS
Our analysis based on a large multicenter international cohort study suggests that WIT length during PN has no effect on the long-term renal function outcomes in patients having two kidneys and preoperative eGFR≥60 mL/min/1.73m.
Topics: Cohort Studies; Glomerular Filtration Rate; Humans; Kidney Neoplasms; Nephrectomy; Retrospective Studies; Warm Ischemia
PubMed: 34308610
DOI: 10.23736/S2724-6051.21.04466-9 -
British Journal of Anaesthesia Jan 2012Donation after circulatory death (DCD) describes the retrieval of organs for the purposes of transplantation that follows death confirmed using circulatory criteria. The... (Review)
Review
Donation after circulatory death (DCD) describes the retrieval of organs for the purposes of transplantation that follows death confirmed using circulatory criteria. The persisting shortfall in the availability of organs for transplantation has prompted many countries to re-introduce DCD schemes not only for kidney retrieval but increasingly for other organs with a lower tolerance for warm ischaemia such as the liver, pancreas, and lungs. DCD contrasts in many important respects to the current standard model for deceased donation, namely donation after brain death. The challenge in the practice of DCD includes how to identify patients as suitable potential DCD donors, how to support and maintain the trust of bereaved families, and how to manage the consequences of warm ischaemia in a fashion that is professionally, ethically, and legally acceptable. Many of the concerns about the practice of both controlled and uncontrolled DCD are being addressed by increasing professional consensus on the ethical and legal justification for many of the interventions necessary to facilitate DCD. In some countries, DCD after the withdrawal of active treatment accounts for a substantial proportion of deceased organ donors overall. Where this occurs, there is an increased acceptance that organ and tissue donation should be considered a routine part of end-of-life care in both intensive care unit and emergency department.
Topics: Critical Pathways; Euthanasia, Passive; Heart Arrest; Humans; Terminal Care; Tissue Donors; Tissue and Organ Harvesting; Tissue and Organ Procurement; Warm Ischemia
PubMed: 22194426
DOI: 10.1093/bja/aer357 -
Sulforaphane Is Protective against Warm Ischemia/Reperfusion Injury and Partial Hepatectomy in Rats.International Journal of Molecular... Jan 2024Sulforaphane (SFN) has various beneficial effects on organ metabolism. However, whether SFN affects inflammatory mediators induced by warm hepatic ischemia/reperfusion...
Sulforaphane (SFN) has various beneficial effects on organ metabolism. However, whether SFN affects inflammatory mediators induced by warm hepatic ischemia/reperfusion injury (HIRI) is unclear. To investigate the hepatoprotective effects of SFN using an in vivo model of HIRI and partial hepatectomy (HIRI + PH), rats were subjected to 15 min of hepatic ischemia with blood inflow occlusion, followed by 70% hepatectomy and release of the inflow occlusion. SFN (5 mg/kg) or saline was randomly injected intraperitoneally 1 and 24 h before ischemia. Alternatively, ischemia was prolonged for 30 min to evaluate the effect on mortality. The influence of SFN on the associated signaling pathways was analyzed using the interleukin 1β (IL-1β)-treated primary cultured rat hepatocytes. In the HIRI + PH-treated rats, SFN reduced serum liver enzyme activities and the frequency of pathological liver injury, such as apoptosis and neutrophil infiltration. SFN suppressed tumor necrosis factor-alpha (TNF-α) mRNA expression and inhibited nuclear factor-kappa B (NF-κB) activation by HIRI + PH. Mortality was significantly reduced by SFN. In IL-1β-treated hepatocytes, SFN suppressed the expression of inflammatory cytokines and NF-κB activation. Taken together, SFN may have hepatoprotective effects in HIRI + PH in part by inhibiting the induction of inflammatory mediators, such as TNF-α, via the suppression of NF-κB in hepatocytes.
Topics: Animals; Rats; Hepatectomy; NF-kappa B; Tumor Necrosis Factor-alpha; Warm Ischemia; Reperfusion Injury; Inflammation Mediators; Interleukin-1beta; Ischemia; Sulfoxides; Isothiocyanates
PubMed: 38203749
DOI: 10.3390/ijms25010579 -
Experimental Biology and Medicine... May 2019Over the past several decades, ex vivo perfusion has emerged as a promising technology for the assessment, preservation, and recovery of donor organs. Many exciting... (Review)
Review
Over the past several decades, ex vivo perfusion has emerged as a promising technology for the assessment, preservation, and recovery of donor organs. Many exciting pre-clinical findings have now been translated to clinical use, and successful transplantation following ex vivo perfusion has been achieved for heart, lung, and liver. While machine perfusion provides distinct advantages over traditional cold preservation, many challenges remain, including that of long-term (multi-day) ex vivo support. Here, we provide an overview of the current status of ex vivo machine perfusion in the pre-clinical and clinical setting and share our perspective on the future direction of the field.
Topics: Bioengineering; Cadaver; Cold Ischemia; Forecasting; Heart; Heart Transplantation; Humans; Liver; Liver Transplantation; Lung; Lung Transplantation; Organ Preservation; Perfusion; Reperfusion Injury; Tissue and Organ Harvesting; Transplants; Warm Ischemia
PubMed: 30889963
DOI: 10.1177/1535370219834498 -
Scientific Reports Feb 2016Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized...
Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR, and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion. Hepatic and systemic hemodynamics, liver injury (AST, ALT, LDH), endothelial function (vasodilatation in response to acetylcholine), KLF2 and nitric oxide pathways, oxidative stress, inflammation (neutrophil and macrophage infiltration) and cell death were evaluated. Profound microcirculatory dysfunction occurred rapidly following WIR. This was evidenced by down-regulation of the KLF2 vasoprotective pathway, impaired vasodilatory capability and endothelial activation, altogether leading to increased hepatic vascular resistance and liver inflammation, with significant leukocyte infiltration, oxidative stress and cell death. Simvastatin preserved the hepatic endothelial phenotype, and blunted the detrimental effects of WIR on liver hemodynamics and organ integrity. In conclusion, WIR-induced injury to liver sinusoidal endothelial cells is mitigated by pre-treatment with Simvastatin probably through a KLF2-dependent mechanism.
Topics: Animals; Cells, Cultured; Drug Evaluation, Preclinical; Hepatocytes; Kruppel-Like Transcription Factors; Kupffer Cells; Liver; Male; Microcirculation; Neutrophil Infiltration; Nitric Oxide; Nitric Oxide Synthase Type III; Rats, Wistar; Reperfusion Injury; Simvastatin; Warm Ischemia
PubMed: 26905693
DOI: 10.1038/srep22107 -
Canadian Journal of Gastroenterology &... 2019Decreased organ function following liver resection is a major clinical issue. The practical method of ischemic postconditioning (IPostC) has been studied in heart...
BACKGROUND
Decreased organ function following liver resection is a major clinical issue. The practical method of ischemic postconditioning (IPostC) has been studied in heart diseases, but no data exist regarding fibrotic livers.
AIMS
We aimed to determine whether IPostC could protect healthy, fibrotic, and cirrhotic livers from ischemia reperfusion injury (IRI).
METHODS
Fibrosis was induced in male SD rats using bile duct ligation (BDL, 4 weeks), and cirrhosis was induced using thioacetamide (TAA, 18 weeks). Fibrosis and cirrhosis were histologically confirmed using HE and EvG staining. For healthy, fibrotic, and cirrhotic livers, isolated liver perfusion with 90 min of warm ischemia was performed in three groups (each with n=8): control, IPostC 8x20 sec, and IPostC 4x60 sec. additionally, healthy livers were investigated during a follow-up study. Lactate dehydrogenase (LDH) and thromboxane B (TXB) in the perfusate, as well as bile flow (healthy/TAA) and portal perfusion pressure, were measured.
RESULTS
LDH and TXB were reduced, and bile flow was increased by IPostC, mainly in total and in the late phase of reperfusion. The follow-up study showed that the perfusate derived from a postconditioned group had much less damaging potential than perfusate derived from the nonpostconditioned group.
CONCLUSION
IPostC following warm ischemia protects healthy, fibrotic, and cirrhotic livers against IRI. Reduced efflux of TXB is one possible mechanism for this effect of IPostC and increases sinusoidal microcirculation. These findings may help to improve organ function and recovery of patients after liver resection.
Topics: Animals; Disease Models, Animal; Ischemic Postconditioning; Liver; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Warm Ischemia
PubMed: 31281804
DOI: 10.1155/2019/5683479 -
Annals of Transplantation Jul 2019BACKGROUND Prolonged cold ischemia is an established risk factor for poor early graft function (EGF). However, warm ischemia incurring during graft implantation has...
BACKGROUND Prolonged cold ischemia is an established risk factor for poor early graft function (EGF). However, warm ischemia incurring during graft implantation has received little attention regarding its possible detrimental effect on EGF. The aim of our study was to examine the impact of recipient warm ischemia time on EGF. MATERIAL AND METHODS The data of 102 consecutive kidney transplants were analyzed to determine the association between duration of graft implantation time (IT) and EGF. Recipient IT groups were (GI) up to 45 min, (GII) 45-60 min, and (GIII) >60 min. EGF was categorized as immediate (IGF), slow (SGF), or delayed graft function (DGF). In recipients with IGF, graft function was further assessed by time needed for reduction in serum creatinine by 50% (SC50) of pre-transplant value, and serum creatinine on day 7 (SCD7). RESULTS Of a total of 102 recipients, 55 (55%) were in GI, 33 (32%) were in GII, and 14 (13%) were in GIII. Factors prolonging IT were recipient body mass index (BMI) (p=0.02) and multiple arteries in donor kidneys (p<0.01). No recipients in GI had DGF or SGF, while 2 in GII had DGF, and 5 patients in GIII had poor EGF. SC50 was significantly longer in GIII and GII versus GI (40.8±42.4 and 32.8±20.4 vs. 22.2±17.2 [p=.02, p≤.01]), respectively. Mean SCD7 was also significantly higher in GIII and GII versus GI. The mean last serum creatinine was comparable among all groups. CONCLUSIONS IT of more than 45 min was a risk factor for poor EGF, but achieved statistical significance only when it exceeded 60 min. Longer IT also significantly slowed the fall in SC50, and led to a higher SCD7. However, poor EGF and suboptimal early SC trends had little long-term effect on serum creatinine.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Delayed Graft Function; Female; Graft Rejection; Graft Survival; Humans; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Transplant Recipients; Treatment Outcome; Warm Ischemia; Young Adult
PubMed: 31332156
DOI: 10.12659/AOT.916012 -
Mediators of Inflammation 2017Liver ischemia and reperfusion (I/R) induce local and distant tissue injuries, contributing to morbidity and mortality in a wider range of pathologies. This is...
Liver ischemia and reperfusion (I/R) induce local and distant tissue injuries, contributing to morbidity and mortality in a wider range of pathologies. This is especially seen under uncontrolled aseptic inflammatory conditions, leading to injury of remote organs, such as lung injury, and even failure. Saquinavir (SQV) is a kind of HIV protease inhibitor that possesses an anti-inflammatory property. In this study, we investigated whether SQV suppresses Toll-like receptor 4- (TLR4-) dependent signaling pathways of high-mobility group box 1 (HMGB1) and P38/JNK, conferring protection against murine liver I/R-induced lung injury. To investigate our hypothesis, C57BL/6 mice and TLR4 knockout mice (TLR4) were used to perform the study. SQV administration markedly attenuated remote lung tissue injury after 1-hour ischemia and 6-hour reperfusion of the liver. To our expectation, SQV attenuated I/R-induced lung edema, hyperpermeability, and pathological injury. The beneficial effects of SQV were associated with decreased levels of circulating and lung tissue inflammatory cytokines, such as IL-6, IL-1, TNF-, and iNOS. The protective effect of SQV was also associated with decreased lung tissue expression of HMGB1, TLR-4, and p-P38/JNK, but not p-ERK in wild-type liver I/R mice. Overall, this study demonstrated a new role of SQV, facilitating negative regulation of HMGB1- and P38/JNK-mediated TLR-4-dependent signaling pathways, conferring protection against liver I/R-induced lung injury.
Topics: Animals; Cytokines; HMGB1 Protein; JNK Mitogen-Activated Protein Kinases; Liver; Lung Injury; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury; Saquinavir; Signal Transduction; Toll-Like Receptor 4; Warm Ischemia; p38 Mitogen-Activated Protein Kinases
PubMed: 29440779
DOI: 10.1155/2017/7083528