135 results on '"Leuvenink HG"'
Search Results
2. ANGIOPOIETIN IN LIVING AND DECEASED BRAIN DEAD KIDNEY DONORS
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Westendorp, WH, Koudstaal, LG, Damman, J, Burgerhof, JG, Seelen, MA, Goor, HV, Ploeg, RJ, Leuvenink, HG, Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)
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- 2016
3. Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury (vol 11, pg 660, 2011)
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Damman, J, Daha, MR, van Son, WJ, Leuvenink, HG, Ploeg, RJ, and Seelen, MA
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- 2016
4. Heparin binding epidermal growth factor in renal ischaemia/reperfusion injury
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Mulder, GM, Nijboer, WN, Seelen, MA, Sandovici, M, Bos, EM, Melenhorst, WB, Trzpis, M, Kloosterhuis, NJ, Visser, L, Henning, RH, Leuvenink, HG, Ploeg, RJ, Sunnarborg, SW, van Goor, H, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Stem Cell Aging Leukemia and Lymphoma (SALL), Vascular Ageing Programme (VAP), and Translational Immunology Groningen (TRIGR)
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urogenital system ,proliferation ,fibrosis ,EARLY PHASE ,FACTOR-ALPHA ,human biopsies ,renal transplantation ,urologic and male genital diseases ,FACTOR MESSENGER-RNA ,ISCHEMIA/REPERFUSION INJURY ,MICE LACKING ,PKI-166 ,RAT-KIDNEY ,HB-EGF ,ANGIOTENSIN-II ,EGF receptor ,MESANGIAL CELLS ,cardiovascular diseases ,ischaemia/reperfusion injury ,FACTOR RECEPTOR INHIBITION ,hormones, hormone substitutes, and hormone antagonists - Abstract
The epidermal growth factor (EGF) receptor and its ligands are crucially involved in the renal response to ischaemia. We studied the heparin binding-epidermal growth factor (HB-EGF), a major ligand for the EGF receptor, in experimental and human ischaemia/reperfusion injury (IRI). HB-EGF mRNA and protein expression was studied in rat kidneys and cultured human tubular (HK-2) cells that were subjected to IRI and in human donor kidneys during transplantation. The effect of EGF receptor inhibition was investigated in vivo and in vitro. Furthermore, urinary HB-EGF protein excretion was studied after renal transplantation. Finally, HB-EGF KO and WT mice were subjected to IRI to study the role of HB-EGF in renal injury. HB-EGF mRNA was significantly up-regulated in the early phase of IRI in rats, cells, and human donor biopsies. Treatment with PKI-166 reduces macrophage accumulation and interstitial alpha-SMA in the early phase of IRI in rats. In vitro, PKI-166 causes a marked reduction in HB-EGF-induced cellular proliferation. Urinary HB-EGF is increased after transplantation compared with control urines from healthy subjects. HB-EGF KO mice subjected to IRI revealed significantly less morphological damage after IRI, compared with WT mice. We conclude that IRI results in early induction of HB-EGF mRNA and protein in vivo and in vitro. Absence of HB-EGF and inhibition of the EGF receptor in the early phase of IRI has protective effects, suggesting a modulating role for HB-EGF. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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- 2016
5. Erratum: Crosstalk between complement and toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury (American Journal of Transplantation (2011) 11 (660-669) DOI: 10.1111/j.1600-6143.2011. 03475.x)
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Damman, J, Daha, MR, Van Son, WJ, Leuvenink, HG, Ploeg, RJ, and Seelen, MA
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- 2016
6. The impact of donor pancreas extraction time on graft survival and postoperative complications in pancreas transplant recipients.
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Leemkuil M, Messner F, Benjamens S, Krendl FJ, Leuvenink HG, Margreiter C, and Pol RA
- Abstract
Background: Simultaneous pancreas kidney transplantation (SPK) is the best therapeutic option for patients with diabetes mellitus type 1 and end-stage renal disease. Recently, donor organ extraction time has been shown to affect kidney and liver graft survival. This study aimed to assess the effect of pancreas donor extraction time on graft survival and postoperative complications., Methods: We retrospectively analyzed all pancreas transplants performed in two Eurotransplant centers. The association of pancreas extraction time with pancreas graft survival was analyzed by a Cox proportional hazards regression analysis after 3 months, 1 and 5 year. Besides, the effect of pancreas extraction time on the incidence of severe postoperative complications was analyzed., Results: A total of 317 pancreas transplants were included in this study. Death-censored pancreas graft survival was 85.7% after one year and 76.7% after five years. Median pancreas donor extraction time was 64 min [IQR: 52-79 min]. After adjustment for potential confounders, death censored graft survival after 30 days (HR 1.01, 95% CI 0.9-1.03 (p = 0.23), 1 year (HR 1.01, 95% CI 0.99-1.03 (p = 0.22) and 5 years (HR 1.00, 95% CI 0.99-1.02 (p = 0.57) was not associated with pancreas donor extraction time. However, extraction time was significantly associated with a higher incidence of Clavien-Dindo ≥3 complications compared to Clavien-Dindo 1 + 2 complications: OR 1.012, 95% CI 1.00-1.02 (p = 0.039)., Conclusions: Our findings suggest that although no effect on graft survival was found, limiting pancreas extraction time can have a significant impact on lowering postoperative complications., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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7. Effects of Normothermic Machine Perfusion Conditions on Mesenchymal Stromal Cells.
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Sierra Parraga JM, Rozenberg K, Eijken M, Leuvenink HG, Hunter J, Merino A, Moers C, Møller BK, Ploeg RJ, Baan CC, Jespersen B, and Hoogduijn MJ
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- Animals, Cell Survival, Humans, Swine, Cryopreservation, Kidney Transplantation methods, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cells, Perfusion
- Abstract
Ex-situ normothermic machine perfusion (NMP) of transplant kidneys allows assessment of kidney quality and targeted intervention to initiate repair processes prior to transplantation. Mesenchymal stromal cells (MSC) have been shown to possess the capacity to stimulate kidney repair. Therefore, the combination of NMP and MSC therapy offers potential to repair transplant kidneys. It is however unknown how NMP conditions affect MSC. In this study the effect of NMP perfusion fluid on survival, metabolism and function of thawed cryopreserved human (h)MSC and porcine (p)MSC in suspension conditions was studied. Suspension conditions reduced the viability of pMSC by 40% in both perfusion fluid and culture medium. Viability of hMSC was reduced by suspension conditions by 15% in perfusion fluid, whilst no differences were found in survival in culture medium. Under adherent conditions, survival of the cells was not affected by perfusion fluid. The perfusion fluid did not affect survival of fresh MSC in suspension compared to the control culture medium. The freeze-thawing process impaired the survival of hMSC; 95% survival of fresh hMSC compared to 70% survival of thawed hMSC. Moreover, thawed MSC showed increased levels of reactive oxygen species, which indicates elevated levels of oxidative stress, and reduced mitochondrial activity, which implies reduced metabolism. The adherence of pMSC and hMSC to endothelial cells was reduced after the thawing process, effect which was particularly profound in in the perfusion fluid. To summarize, we observed that conditions required for machine perfusion are influencing the behavior of MSC. The freeze-thawing process reduces survival and metabolism and increases oxidative stress, and diminishes their ability to adhere to endothelial cells. In addition, we found that hMSC and pMSC behaved differently, which has to be taken into consideration when translating results from animal experiments to clinical studies.
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- 2019
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8. A steady decline in pancreas transplantation rates.
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Benjamens S, Leemkuil M, Margreiter C, Huurman VA, Leuvenink HG, and Pol RA
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- Diabetes Mellitus epidemiology, Diabetes Mellitus therapy, Europe epidemiology, Female, Humans, Male, Prevalence, Registries, United States epidemiology, Pancreas Transplantation statistics & numerical data
- Abstract
Background/objectives: After years of growth in many pancreas transplant programs, UNOS has reported declining transplant numbers in the USA. This precipitating trend urges for an evaluation of the transplant numbers and scientific productivity in the Eurotransplant region and the UK., Methods: We performed a trend analysis of pancreas transplantation rates, between 1997 and 2016, adjusting for changes in population size, and an analysis of scientific publications in this field. We used information from the UNOS, Eurotransplant, and UK transplant registry and bibliometric information from the Web of Science database., Results: Between 2004 and 2016 there was an average annual decline in pancreas transplantation rates per million inhabitants of 3.3% in the USA and 2.5% in the Eurotransplant region. In the UK, transplant numbers showed an average annual decline of 1.0% from 2009 to 2016. Publications in Q1 journals showed an annual change of -2.1% and +20.1%, before 2004, and a change of -3.8% and -5.5%, between 2004 and 2016, for USA and Eurotransplant publications, respectively., Conclusions: Adjusting pancreas transplantation rates for changes in population size showed a clear decline in transplant numbers in both the USA and Eurotransplant region, with first signs of decline in the UK. Following this trend, the number of scientific publications in this field have declined worldwide., (Copyright © 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.)
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- 2019
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9. Human alternative Klotho mRNA is a nonsense-mediated mRNA decay target inefficiently spliced in renal disease.
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Mencke R, Harms G, Moser J, van Meurs M, Diepstra A, Leuvenink HG, and Hillebrands JL
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- Cell Line, Codon, Nonsense, Cycloheximide antagonists & inhibitors, Gene Silencing, Glucuronidase genetics, Humans, In Situ Hybridization, Klotho Proteins, Nonsense Mediated mRNA Decay drug effects, RNA Helicases genetics, RNA Helicases metabolism, RNA, Messenger genetics, Trans-Activators genetics, Trans-Activators metabolism, Glucuronidase metabolism, Nonsense Mediated mRNA Decay physiology, RNA, Messenger metabolism, Renal Insufficiency, Chronic metabolism
- Abstract
Klotho is a renal protein involved in phosphate homeostasis, which is downregulated in renal disease. It has long been considered an antiaging factor. Two Klotho gene transcripts are thought to encode membrane-bound and secreted Klotho. Indeed, soluble Klotho is detectable in bodily fluids, but the relative contributions of Klotho secretion and of membrane-bound Klotho shedding are unknown. Recent advances in RNA surveillance reveal that premature termination codons, as present in alternative Klotho mRNA (for secreted Klotho), prime mRNAs for degradation by nonsense-mediated mRNA decay (NMD). Disruption of NMD led to accumulation of alternative Klotho mRNA, indicative of normally continuous degradation. RNA IP for NMD core factor UPF1 resulted in enrichment for alternative Klotho mRNA, which was also not associated with polysomes, indicating no active protein translation. Alternative Klotho mRNA transcripts colocalized with some P bodies, where NMD transcripts are degraded. Moreover, we could not detect secreted Klotho in vitro. These results suggest that soluble Klotho is likely cleaved membrane-bound Klotho only. Furthermore, we found that, especially in acute kidney injury, splicing of the 2 mRNA transcripts is dysregulated, which was recapitulated by various noxious stimuli in vitro. This likely constitutes a novel mechanism resulting in the downregulation of membrane-bound Klotho.
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- 2017
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10. Randomized clinical trial of biodegradeable intraluminal sheath to prevent anastomotic leak after stapled colorectal anastomosis.
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Bakker IS, Morks AN, Ten Cate Hoedemaker HO, Burgerhof JGM, Leuvenink HG, van Praagh JB, Ploeg RJ, and Havenga K
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- Aged, Anastomosis, Surgical adverse effects, Colorectal Neoplasms surgery, Diverticulum, Colon surgery, Female, Humans, Male, Middle Aged, Prosthesis Design, Surgical Stapling adverse effects, Absorbable Implants, Anastomotic Leak prevention & control, Colon surgery, Rectum surgery
- Abstract
Background: Anastomotic leakage is a potential major complication after colorectal surgery. The C-seal was developed to help reduce the clinical leakage rate. It is an intraluminal sheath that is stapled proximal to a colorectal anastomosis, covering it intraluminally and thus preventing intestinal leakage in case of anastomotic dehiscence. The C-seal trial was initiated to evaluate the efficacy of the C-seal in reducing anastomotic leakage in stapled colorectal anastomoses., Methods: This RCT was performed in 41 hospitals in the Netherlands, Germany, France, Hungary and Spain. Patients undergoing elective surgery with a stapled colorectal anastomosis less than 15 cm from the anal verge were eligible. Included patients were randomized to the C-seal and control groups, stratified for centre, anastomotic height and intention to create a defunctioning stoma. Primary outcome was anastomotic leakage requiring invasive treatment., Results: Between December 2011 and December 2013, 402 patients were included in the trial, 202 in the C-seal group and 200 in the control group. Anastomotic leakage was diagnosed in 31 patients (7·7 per cent), with a 10·4 per cent leak rate in the C-seal group and 5·0 per cent in the control group (P = 0·060). Male sex showed a trend towards a higher leak rate (P = 0·055). Construction of a defunctioning stoma led to a lower leakage rate, although this was not significant (P = 0·095)., Conclusion: C-seal application in stapled colorectal anastomoses does not reduce anastomotic leakage. Registration number: NTR3080 (http://www.trialregister.nl/trialreg/index.asp)., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)
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- 2017
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11. Liver ex situ machine perfusion preservation: A review of the methodology and results of large animal studies and clinical trials.
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Marecki H, Bozorgzadeh A, Porte RJ, Leuvenink HG, Uygun K, and Martins PN
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- Animals, Humans, Liver, Liver Transplantation, Organ Preservation methods, Perfusion methods
- Abstract
Ex vivo machine perfusion (MP) is a promising way to better preserve livers prior to transplantation. Currently, no methodology has a verified benefit over simple cold storage. Before becoming clinically feasible, MP requires validation in models that reliably predict human performance. Such a model has been found in porcine liver, whose physiological, anatomical, and immunological characteristics closely resemble the human liver. Since the 1930s, researchers have explored MP as preservation, but only recently have clinical trials been performed. Making this technology clinically available holds the promise of expanding the donor pool through more effective preservation of extended criteria donor (ECD) livers. MP promises to decrease delayed graft function, primary nonfunction, and biliary strictures, which are all common failure modes of transplanted ECD livers. Although hypothermic machine perfusion (HMP) has become the standard for kidney ex vivo preservation, the precise settings and clinical role for liver MP have not yet been established. In research, there are 2 schools of thought: normothermic machine perfusion, closely mimicking physiologic conditions, and HMP, to maximize preservation. Here, we review the literature for porcine ex vivo MP, with an aim to summarize perfusion settings and outcomes pertinent to the clinical establishment of MP. Liver Transplantation 23 679-695 2017 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)
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- 2017
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12. Inadequate Antioxidative Responses in Kidneys of Brain-Dead Rats.
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Hoeksma D, Rebolledo RA, Hottenrott M, Bodar YS, Wiersema-Buist JJ, Van Goor H, and Leuvenink HG
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- Animals, Biomarkers blood, Brain physiopathology, Brain Death blood, Brain Death physiopathology, Catalase metabolism, Creatinine blood, Disease Models, Animal, Glutathione blood, Glutathione Peroxidase metabolism, Glutathione Reductase metabolism, Heme Oxygenase (Decyclizing) genetics, Heme Oxygenase (Decyclizing) metabolism, Kidney enzymology, Male, Malondialdehyde metabolism, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type II metabolism, Oxidation-Reduction, Rats, Inbred F344, Superoxide Dismutase metabolism, Superoxides metabolism, Time Factors, Antioxidants metabolism, Brain metabolism, Brain Death metabolism, Lipid Peroxidation, Oxidative Stress
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Background: Brain death (BD)-related lipid peroxidation, measured as serum malondialdehyde (MDA) levels, correlates with delayed graft function in renal transplant recipients. How BD affects lipid peroxidation is not known. The extent of BD-induced organ damage is influenced by the speed at which intracranial pressure increases. To determine possible underlying causes of lipid peroxidation, we investigated the renal redox balance by assessing oxidative and antioxidative processes in kidneys of brain-dead rats after fast and slow BD induction., Methods: Brain death was induced in 64 ventilated male Fisher rats by inflating a 4.0F Fogarty catheter in the epidural space. Fast and slow inductions were achieved by an inflation speed of 0.45 and 0.015 mL/min, respectively, until BD confirmation. Healthy non-brain-dead rats served as reference values. Brain-dead rats were monitored for 0.5, 1, 2, or 4 hours, after which organs and blood were collected., Results: Increased MDA levels became evident at 2 hours of slow BD induction at which increased superoxide levels, decreased glutathione peroxidase (GPx) activity, decreased glutathione levels, increased inducible nitric oxide synthase and heme-oxygenase 1 expression, and increased plasma creatinine levels were evident. At 4 hours after slow BD induction, superoxide, MDA, and plasma creatinine levels increased further, whereas GPx activity remained decreased. Increased MDA and plasma creatinine levels also became evident after 4 hours fast BD induction., Conclusion: Brain death leads to increased superoxide production, decreased GPx activity, decreased glutathione levels, increased inducible nitric oxide synthase and heme-oxygenase 1 expression, and increased MDA and plasma creatinine levels. These effects were more pronounced after slow BD induction. Modulation of these processes could lead to decreased incidence of delayed graft function.
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- 2017
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13. The fate of sulfate in chronic heart failure.
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Koning AM, Meijers WC, Minović I, Post A, Feelisch M, Pasch A, Leuvenink HG, de Boer RA, Bakker SJ, and van Goor H
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- Aged, Biomarkers metabolism, Chronic Disease, Creatinine blood, Female, Heart Failure drug therapy, Heart Failure physiopathology, Humans, Kaplan-Meier Estimate, Kidney metabolism, Kidney physiopathology, Male, Middle Aged, Sulfates blood, Sulfates urine, Survival Analysis, Treatment Outcome, Heart Failure metabolism, Sulfates metabolism
- Abstract
New leads to advance our understanding of heart failure (HF) pathophysiology are urgently needed. Previous studies have linked urinary sulfate excretion to a favorable cardiovascular risk profile. Sulfate is not only the end product of hydrogen sulfide metabolism but is also directly involved in various (patho)physiological processes, provoking scientific interest in its renal handling. This study investigates sulfate clearance in chronic HF (CHF) patients and healthy individuals and considers its relationship with disease outcome. Parameters related to renal sulfate handling were determined in and compared between 96 previously characterized CHF patients and sex-matched healthy individuals. Among patients, sulfate clearance was analyzed for associations with clinical and outcome parameters. In CHF patients, plasma sulfate concentrations are significantly higher, whereas 24-h urinary excretion, fractional excretion, and clearance of sulfate are significantly lower, compared with healthy individuals. Among patients, sulfate clearance is independently associated with diuretics use, creatinine clearance and 24-h urinary sodium excretion. Sulfate clearance is associated with favorable disease outcome [hazard ratio per SD increase 0.38 (95% confidence interval 0.23-0.63), P < 0.001]. Although significance was lost after adjustment for creatinine clearance, the decrease of sulfate clearance in patients is independent of this parameter, indicating that sulfate clearance is not merely a reflection of renal function. This exploratory study reveals aberrant sulfate clearance as a potential contributor to CHF pathophysiology, with reduced levels in patients and a positive association with favorable disease outcome. Further research is needed to unravel the nature of its involvement and to determine its potential as a biomarker and target for therapy. NEW & NOTEWORTHY Sulfate clearance is decreased in chronic heart failure patients compared with healthy individuals. Among patients, sulfate clearance is positively associated with favorable disease outcome, i.e., a decreased rehospitalization rate and increased patient survival. Hence, decreased sulfate clearance may be involved in the pathophysiology of heart failure., (Copyright © 2017 the American Physiological Society.)
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- 2017
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14. Chronic Inguinal Pain After Kidney Transplantation, a Common and Underexposed Problem.
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Zorgdrager M, Lange JF, Krikke C, Nieuwenhuijs GJ, Hofker SH, Leuvenink HG, and Pol RA
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- Adult, Aged, Delayed Graft Function complications, Female, Follow-Up Studies, Humans, Inguinal Canal, Male, Middle Aged, Pain Measurement, Reoperation adverse effects, Risk Factors, Surveys and Questionnaires, Body Mass Index, Chronic Pain etiology, Kidney Transplantation adverse effects, Pain, Postoperative etiology
- Abstract
Background: The incidence and impact of chronic inguinal pain after kidney transplantation is not clearly established. A high incidence of pain after inguinal hernia repair, a comparable surgical procedure, suggests an underexposed problem., Methods: Between 2011 and 2013, 403 consecutive patients who underwent kidney transplantation were invited to complete the Caroline Comfort Scale (CCS) and Visual Analog Scale (VAS) in order to assess the incidence of chronic inguinal pain and movement disabilities, complemented by questions regarding comorbidity during follow-up., Results: The response rate was 58 % (n = 199) with a median follow-up of 22 months (IQR 12-30). In total, 90 patients (45 %) reported a CCS > 0 and 64 patients (32 %) experienced at least mild but bothersome complaints. Most inguinal complaints were reported during bending over and walking with a mean CCS score of 1.1 (SD ± 2.2) and 1.2 (SD ± 2.4), respectively. A high body mass index (BMI), delayed graft function, and the need for a second operation were associated with a higher CCS score on univariate analysis. Using multivariate analysis, only BMI (p = 0.02) was considered an independent risk factor for chronic inguinal pain., Conclusions: The incidence of chronic inguinal pain is a common though underexposed complication after kidney transplantation. More awareness to prevent neuropathic pain seems indicated., Competing Interests: The authors of this manuscript have no conflicts of interest to disclose.
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- 2017
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15. Kidney temperature course during living organ procurement and transplantation.
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Kuipers TG, Hellegering J, El Moumni M, Krikke C, Haveman JW, Berger SP, Leuvenink HG, and Pol RA
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- Adult, Aged, Female, Humans, Living Donors, Male, Middle Aged, Young Adult, Kidney Transplantation, Temperature, Tissue and Organ Harvesting, Warm Ischemia
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Little is known about the actual kidney graft temperature during the 2nd warm ischemia time (WIT2). We aimed to determine the actual temperature course of the WIT2, with emphasis on the 15 °C metabolic threshold. Data of 152 consecutive adult living donor kidney transplantations were collected. The mean WIT2 was 41.3 ± 10.1 (SD) minutes with a temperature of 5.4 °C at baseline which gradually increased to 13.7, 17.4, and 20.2 °C after 10, 20, and 30 min, respectively. The percentage of kidneys with a temperature of 15 °C or higher was 81.2% after 20 min and 97.5% after 30 min. Duration of surgery (95% CI: -0.017 to -0.002, P = 0.02), multiple veins (95% CI: 0.0003-2.720, P = 0.05) and WIT2 (95% CI: 0.016-0.099, P = 0.006) were associated with a rapid temperature increase. No correlation could be determined between a rapid temperature rise and diminished graft function. This study showed a rapid increase in kidney temperature during WIT2, wherein the 15 °C threshold was reached within 20 min in more than 80% of the patients., (© 2016 Steunstichting ESOT.)
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- 2017
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16. Outcome of pancreas transplantation from donation after circulatory death compared to donation after brain death.
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van Loo ES, Krikke C, Hofker HS, Berger SP, Leuvenink HG, and Pol RA
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- Graft Survival, Humans, Odds Ratio, Outcome Assessment, Health Care, Brain Death, Pancreas Transplantation mortality, Shock, Tissue Donors, Tissue and Organ Procurement methods
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Introduction: To overcome the gap of organ shortage grafts from donation after circulatory death (DCD) can be used. This review evaluates the outcomes after DCD pancreas donation compared to donation after brain death (DBD)., Materials and Methods: A literature search was performed using Medline, Embase, and PubMed databases. All comparative cohort studies reporting the outcome after DCD and DBD pancreas transplantation were included. All data were assessed according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. To evaluate the event rates, pooled odds ratios (ORs) as well as the 95% confidence intervals (CI) were calculated. Since the number of studies is small we used the random-effects model only to overcome heterogeneity., Results: There is no difference in 1-year pancreas graft survival (OR 1.092, CI 95% 0.649-1.837, P = 0.741) or patient survival (OR 0.699, CI 95% 0.246-1.985, P = 0.502). Simultaneous pancreas-kidney (SPK) transplantation showed significantly higher graft survival rates compared to pancreas transplantation alone (87.2% vs. 76.6%, P < 0.001 in DBD and 86.5% vs. 74.9%, P < 0.001 in DCD). DCD SPK grafts show a higher delayed kidney graft function rate compared to DBD SPK-grafts (OR 0.209, CI 95% 0.104-0.421, P < 0.001). There is significantly less pancreas graft thrombosis after DBD-donation (OR 0.567, CI 95% 0.340-0.946, P = 0.030). We found no difference in the HbA1c level at 1-year follow-up with a median of 5.4% in both groups and a mean of 5.63% (DCD) vs 5.43% (DBD)., Discussion: DCD pancreas transplantation has comparable patient and 1-year graft survival rates and should be considered a safe alternative for DBD pancreas transplantation., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)
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- 2017
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17. The role of hydrogen sulfide in aging and age-related pathologies.
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Perridon BW, Leuvenink HG, Hillebrands JL, van Goor H, and Bos EM
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- Aging pathology, Animals, Epigenesis, Genetic, Genomic Instability, Humans, Aging metabolism, Hydrogen Sulfide metabolism, Signal Transduction physiology
- Abstract
When humans grow older, they experience inevitable and progressive loss of physiological function, ultimately leading to death. Research on aging largely focuses on the identification of mechanisms involved in the aging process. Several proposed aging theories were recently combined as the 'hallmarks of aging'. These hallmarks describe (patho-)physiological processes that together, when disrupted, determine the aging phenotype. Sustaining evidence shows a potential role for hydrogen sulfide (H
2 S) in the regulation of aging. Nowadays, H2 S is acknowledged as an endogenously produced signaling molecule with various (patho-) physiological effects. H2 S is involved in several diseases including pathologies related to aging. In this review, the known, assumed and hypothetical effects of hydrogen sulfide on the aging process will be discussed by reviewing its actions on the hallmarks of aging and on several age-related pathologies., Competing Interests: The authors have no conflicts of interest to declare.- Published
- 2016
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18. Multiple Renal Arteries in Kidney Transplantation: A Systematic Review and Meta-Analysis.
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Zorgdrager M, Krikke C, Hofker SH, Leuvenink HG, and Pol RA
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- Delayed Graft Function etiology, Graft Rejection, Graft Survival, Humans, Kidney Transplantation adverse effects, Kidney Transplantation mortality, Postoperative Complications etiology, Renal Artery surgery, Survival Analysis, Tissue and Organ Harvesting methods, Treatment Outcome, Donor Selection methods, Kidney Transplantation methods, Renal Artery abnormalities
- Abstract
Background: The use of grafts with multiple renal arteries (MRA) in renal transplantation has not been clearly established., Material/methods: A systematic literature review used predefined terms to search PubMed, EMBASE, and the Cochrane Library for all studies since 1985 that included more than 50 MRA grafts. A total of 23 studies, comprising a total of 18,289 patients, were eligible to be included in the meta-analysis., Results: Patients who received an MRA graft compared to single renal artery (SRA) grafts showed significantly higher complication rates (13.8% vs. 11.0%, OR 1.393, p<0.0001), more delayed graft function (10.3% vs. 8.2%, OR 1.333, p=0.022), and had an associated significantly lower 1-year graft survival (93.2% vs. 94.5%, OR 0.819, p=0.034). Both the creatinine level and the warm ischemia time (WIT) were significantly higher in patients with MRA grafts but showed high heterogeneity (I² 98% for WIT and I² 70% for creatinine level). Although MRA grafts were associated with more complications compared to SRA grafts, long-term outcomes were similar for 5-year graft survival (81.4% vs. 81.6%) and 1- and 5-year patient survival (95.4% and 89.6% in MRA group vs. 95.4% and 87.0% in SRA group, respectively)., Conclusions: MRA grafts were associated with a higher risk of complication and delayed graft function but had comparable long-term outcomes for graft and patient survival.
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- 2016
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19. Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers.
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Op den Dries S, Karimian N, Westerkamp AC, Sutton ME, Kuipers M, Wiersema-Buist J, Ottens PJ, Kuipers J, Giepmans BN, Leuvenink HG, Lisman T, and Porte RJ
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- Animals, Bile Ducts cytology, Bile Ducts ultrastructure, Biomarkers blood, Cold Ischemia adverse effects, Epithelium metabolism, Epithelium pathology, Humans, L-Lactate Dehydrogenase blood, Liver surgery, Male, Microscopy, Electron, Scanning, Microscopy, Electron, Transmission, Mitochondria pathology, Mitochondria ultrastructure, Organ Preservation instrumentation, Perfusion instrumentation, Rats, Rats, Inbred Lew, Reperfusion adverse effects, Temperature, Tissue and Organ Harvesting adverse effects, gamma-Glutamyltransferase blood, Bile Ducts pathology, Liver Transplantation adverse effects, Organ Preservation methods, Perfusion methods, Reperfusion Injury prevention & control
- Abstract
Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS-preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 ± 0.02 and 7.74 ± 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 ± 0.02 and 7.49 ± 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation. Liver Transplantation 22 994-1005 2016 AASLD., (© 2016 American Association for the Study of Liver Diseases.)
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- 2016
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20. New insight into the effects of heparinoids on complement inhibition by C1-inhibitor.
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Poppelaars F, Damman J, de Vrij EL, Burgerhof JG, Saye J, Daha MR, Leuvenink HG, Uknis ME, and Seelen MA
- Subjects
- Blood Coagulation drug effects, Complement Pathway, Alternative drug effects, Complement Pathway, Classical drug effects, Complement Pathway, Mannose-Binding Lectin drug effects, Dose-Response Relationship, Drug, Drug Combinations, Drug Synergism, Humans, Partial Thromboplastin Time, Complement Activation drug effects, Complement C1 Inhibitor Protein pharmacology, Heparinoids pharmacology
- Abstract
Complement activation is of major importance in numerous pathological conditions. Therefore, targeted complement inhibition is a promising therapeutic strategy. C1-esterase inhibitor (C1-INH) controls activation of the classical pathway (CP) and the lectin pathway (LP). However, conflicting data exist on inhibition of the alternative pathway (AP) by C1-INH. The inhibitory capacity of C1-INH for the CP is potentiated by heparin and other glycosaminoglycans, but no data exist for the LP and AP. The current study investigates the effects of C1-INH in the presence or absence of different clinically used heparinoids on the CP, LP and AP. Furthermore, the combined effects of heparinoids and C1-INH on coagulation were investigated. C1-INH, heparinoids or combinations were analysed in a dose-dependent fashion in the presence of pooled serum. Functional complement activities were measured simultaneously using the Wielisa(®) -kit. The activated partial thrombin time was determined using an automated coagulation analyser. The results showed that all three complement pathways were inhibited significantly by C1-INH or heparinoids. Next to their individual effects on complement activation, heparinoids also enhanced the inhibitory capacity of C1-INH significantly on the CP and LP. For the AP, significant potentiation of C1-INH by heparinoids was found; however, this was restricted to certain concentration ranges. At low concentrations the effect on blood coagulation by combining heparinoids with C1-INH was minimal. In conclusion, our study shows significant potentiating effects of heparinoids on the inhibition of all complement pathways by C1-INH. Therefore, their combined use is a promising and a potentially cost-effective treatment option for complement-mediated diseases., (© 2016 British Society for Immunology.)
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- 2016
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21. Slow induction of brain death leads to decreased renal function and increased hepatic apoptosis in rats.
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Rebolledo RA, Hoeksma D, Hottenrott CM, Bodar YJ, Ottens PJ, Wiersema-Buist J, and Leuvenink HG
- Subjects
- Animals, Biomarkers blood, Blood Pressure, Brain Death blood, Brain Death metabolism, Caspase 3 metabolism, Gene Expression Regulation, Inflammation blood, Inflammation genetics, Inflammation pathology, Interleukin-6 genetics, Male, Malondialdehyde metabolism, Neutrophils metabolism, Rats, Inbred F344, Real-Time Polymerase Chain Reaction, bcl-2-Associated X Protein metabolism, Apoptosis, Brain Death physiopathology, Kidney physiopathology, Kidney Function Tests, Liver pathology
- Abstract
Background: Donor brain death (BD) is an independent risk factor for graft survival in recipients. While in some patients BD results from a fast increase in intracranial pressure, usually associated with trauma, in others, intracranial pressure increases more slowly. The speed of intracranial pressure increase may be a possible risk factor for renal and hepatic graft dysfunction. This study aims to assess the effect of speed of BD induction on renal and hepatic injury markers., Methods: BD induction was performed in 64 mechanically ventilated male Fisher rats by inflating a 4.0F Fogarty catheter in the epidural space. Rats were observed for 0.5, 1, 2 or 4 h following BD induction. Slow induction was achieved by inflating the balloon-catheter at a speed of 0.015 ml/min until confirmation of BD. Fast induction was achieved by inflating the balloon at 0.45 ml/min for 1 min. Plasma, kidney and liver tissue were collected for analysis., Results: Slow BD induction led to higher plasma creatinine at all time points compared to fast induction. Furthermore, slow induction led to increased renal mRNA expression of IL-6, and renal MDA values after 4 h of BD compared to fast induction. Hepatic mRNA expression of TNF-α, Bax/Bcl-2, and protein expression of caspase-3 was significantly higher due to slow induction after 4 h of BD compared to fast induction. PMN infiltration was not different between fast and slow induction in both renal and hepatic tissue., Conclusion: Slow induction of BD leads to poorer renal function compared to fast induction. Renal inflammatory and oxidative stress markers were increased. Liver function was not affected by speed of BD induction but hepatic inflammatory and apoptosis markers increased significantly due to slow induction compared to fast induction. These results provide initial proof that speed of BD induction influences detrimental renal and hepatic processes which could signify different donor management strategies for patients progressing to BD at different speeds.
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- 2016
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22. Using an Integrated -Omics Approach to Identify Key Cellular Processes That Are Disturbed in the Kidney After Brain Death.
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Akhtar MZ, Huang H, Kaisar M, Lo Faro ML, Rebolledo R, Morten K, Heather LC, Dona A, Leuvenink HG, Fuggle SV, Kessler BM, Pugh CW, and Ploeg RJ
- Subjects
- Animals, Male, Rats, Rats, Inbred F344, Signal Transduction, Biomarkers analysis, Brain Death physiopathology, Kidney physiopathology, Metabolomics methods, Oxidative Stress genetics, Proteomics methods
- Abstract
In an era where we are becoming more reliant on vulnerable kidneys for transplantation from older donors, there is an urgent need to understand how brain death leads to kidney dysfunction and, hence, how this can be prevented. Using a rodent model of hemorrhagic stroke and next-generation proteomic and metabolomic technologies, we aimed to delineate which key cellular processes are perturbed in the kidney after brain death. Pathway analysis of the proteomic signature of kidneys from brain-dead donors revealed large-scale changes in mitochondrial proteins that were associated with altered mitochondrial activity and morphological evidence of mitochondrial injury. We identified an increase in a number of glycolytic proteins and lactate production, suggesting a shift toward anaerobic metabolism. Higher amounts of succinate were found in the brain death group, in conjunction with increased markers of oxidative stress. We characterized the responsiveness of hypoxia inducible factors and found this correlated with post-brain death mean arterial pressures. Brain death leads to metabolic disturbances in the kidney and alterations in mitochondrial function and reactive oxygen species generation. This metabolic disturbance and alteration in mitochondrial function may lead to further cellular injury. Conditioning the brain-dead organ donor by altering metabolism could be a novel approach to ameliorate this brain death-induced kidney injury., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2016
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23. Oxygenated Hypothermic Machine Perfusion After Static Cold Storage Improves Hepatobiliary Function of Extended Criteria Donor Livers.
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Westerkamp AC, Karimian N, Matton AP, Mahboub P, van Rijn R, Wiersema-Buist J, de Boer MT, Leuvenink HG, Gouw AS, Lisman T, and Porte RJ
- Subjects
- Adenosine Triphosphate metabolism, Aged, Bicarbonates metabolism, Bile metabolism, Bilirubin metabolism, Biomarkers metabolism, Energy Metabolism drug effects, Female, Humans, Liver enzymology, Liver pathology, Liver physiopathology, Liver Function Tests, Liver Transplantation adverse effects, Male, Middle Aged, Necrosis, Oxygen Consumption drug effects, Time Factors, Tissue Survival, Cold Ischemia adverse effects, Donor Selection, Hypothermia, Induced, Liver surgery, Liver Transplantation methods, Oxygen pharmacology, Perfusion methods, Tissue Donors supply & distribution
- Abstract
Background: The mechanism through which oxygenated hypothermic machine perfusion (HMP) improves viability of human extended criteria donor (ECD) livers is not well known. Aim of this study was to examine the benefits of oxygenated HMP after static cold storage (SCS)., Methods: Eighteen ECD livers that were declined for transplantation underwent ex situ viability testing using normothermic (37 °C) machine perfusion (NMP) after traditional SCS (0 °C-4 °C) for 7 to 9 hours. In the intervention group (n = 6), livers underwent 2 hours of oxygenated HMP (at 12 °C) after SCS and before NMP. Twelve control livers underwent NMP without oxygenated HMP after SCS., Results: During HMP, hepatic ATP content increased greater than 15-fold, and levels remained significantly higher during the first 4 hours of NMP in the HMP group, compared with controls. Cumulative bile production and biliary secretion of bilirubin and bicarbonate were significantly higher after HMP, compared with controls. In addition, the levels of lactate and glucose were less elevated after HMP compared with SCS preservation alone. In contrast, there were no differences in levels of hepatobiliary injury markers AST, ALT, LDH, and gamma-GT after 6 hours of NMP. Hepatic histology at baseline and after 6 hours of NMP revealed no differences in the amount of ischemic necrosis between both groups., Conclusions: Two hours of oxygenated HMP after traditional SCS restores hepatic ATP levels and improves hepatobiliary function but does not reduce (preexisting) hepatobiliary injury in ECD livers.
- Published
- 2016
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24. Warming Up--Not Only Essential for Athletes?
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Leuvenink HG
- Subjects
- Female, Humans, Male, Cold Ischemia, End Stage Liver Disease surgery, Hepatectomy, Liver Transplantation methods, Oxygen therapeutic use, Perfusion methods, Rewarming methods
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- 2016
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25. Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation.
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Dessing MC, Kers J, Damman J, Leuvenink HG, van Goor H, Hillebrands JL, Hepkema BG, Snieder H, van den Born J, de Borst MH, Bakker SJ, Navis GJ, Ploeg RJ, Florquin S, Seelen M, and Leemans JC
- Subjects
- Adult, Case-Control Studies, Female, Gene Frequency, Humans, Male, Middle Aged, Treatment Outcome, Delayed Graft Function genetics, Graft Rejection genetics, Kidney Failure, Chronic genetics, Kidney Failure, Chronic therapy, Kidney Transplantation, Polymorphism, Single Nucleotide, Toll-Like Receptors genetics
- Abstract
Toll-like receptors (TLRs) play a crucial role in innate- and adaptive immunity. The TLR pathways were shown to play key functional roles in experimental acute and chronic kidney injury, including the allo-immune response after experimental renal transplantation. Data about the precise impact of TLRs and their negative regulators on human renal transplant outcomes however are limited and contradictory. We studied twelve non-synonymous single nucleotide polymorphisms (SNPs) of which eleven in TLR1-8 and one in SIGIRR in a final cohort comprising 1116 matching donors and recipients. TLR3 p.Leu412Phe and SIGIRR p.Gln312Arg significantly deviated from Hardy-Weinberg equilibrium and were excluded. The frequency distribution of the minor alleles of the remaining 10 TLR variants were compared between patients with end-stage renal disease (recipients) and controls (kidney donors) in a case-control study. Secondly, the associations between the minor allele frequency of the TLR variants and delayed graft function, biopsy-proven acute rejection and death-censored graft failure after transplantation were investigated with Cox regression. Carrier frequencies of the minor alleles of TLR1 p.His305Leu (OR = 4.79, 95% CI = 2.35-9.75, P = 0.0002), TLR1 p.Asn248Ser (OR = 1.26, 95% CI = 1.07-1.47, P = 0.04) and TLR8 p.Met1Val (OR = 1.37, 95% CI = 1.14-1.64, P = 0.008) were significantly higher in patients with ESRD, with little specificity for the underlying renal disease entity (adjusted for age, gender and donor-recipient relatedness). The minor allele frequency of none of the TLR variants significantly associated with the surrogate and definite outcomes, even when multivariable models were created that could account for TLR gene redundancy. In conclusion, genetic variants in TLR genes were associated with the prevalence of ESRD but not renal transplant outcomes. Therefore, our data suggests that specific TLR signaling routes might play a role in the final common pathway of primary renal injury. A role for TLR signaling in the context of renal transplantation is probably limited.
- Published
- 2015
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26. Anti-Apoptotic Effects of 3,3',5-Triiodo-L-Thyronine in the Liver of Brain-Dead Rats.
- Author
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Rebolledo RA, Van Erp AC, Ottens PJ, Wiersema-Buist J, Leuvenink HG, and Romanque P
- Subjects
- Animals, Brain Death metabolism, Liver metabolism, Male, Mitosis drug effects, Oxidative Stress drug effects, Rats, Rats, Inbred F344, Apoptosis drug effects, Brain Death pathology, Liver drug effects, Liver pathology, Triiodothyronine pharmacology
- Abstract
Background: Thyroid hormone treatment in brain-dead organ donors has been extensively studied and applied in the clinical setting. However, its clinical applicability remains controversial due to a varying degree of success and a lack of mechanistic understanding about the therapeutic effects of 3,3',5-Triiodo-L-thyronine (T3). T3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury. Therefore, we aimed to study the effects of T3 pre-conditioning in the liver of brain-dead rats., Methods: Brain death (BD) was induced in mechanically ventilated rats by inflation of a Fogarty catheter in the epidural space. T3 (0.1 mg/kg) or vehicle was administered intraperitoneally 2 h prior to BD induction. After 4 h of BD, serum and liver tissue were collected. RT-qPCR, routine biochemistry, and immunohistochemistry were performed., Results: Brain-dead animals treated with T3 had lower plasma levels of AST and ALT, reduced Bax gene expression, and less hepatic cleaved Caspase-3 activation compared to brain-dead animals treated with vehicle. Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1β) or the presence of pro-mitotic markers (Cyclin-D and Ki-67) were found in brain-dead animals treated with T3 compared to vehicle-treated animals., Conclusion: T3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T3 hormone therapy in the management of brain-dead donors.
- Published
- 2015
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27. End-ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature.
- Author
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Westerkamp AC, Mahboub P, Meyer SL, Hottenrott M, Ottens PJ, Wiersema-Buist J, Gouw AS, Lisman T, Leuvenink HG, and Porte RJ
- Subjects
- Adenosine Triphosphate metabolism, Animals, Bile Duct Diseases etiology, Bile Duct Diseases metabolism, Bile Duct Diseases pathology, Bile Ducts pathology, Biomarkers metabolism, Energy Metabolism, Hepatectomy, Liver Transplantation adverse effects, Male, Mitochondria metabolism, Oxygen metabolism, Oxygen Consumption, Perfusion adverse effects, Rats, Inbred Lew, Reperfusion Injury etiology, Reperfusion Injury metabolism, Reperfusion Injury pathology, Temperature, Time Factors, Bile Duct Diseases prevention & control, Bile Ducts metabolism, Cold Ischemia adverse effects, Liver Transplantation methods, Oxygen administration & dosage, Perfusion methods, Reperfusion Injury prevention & control, Warm Ischemia adverse effects
- Abstract
A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation., (© 2015 American Association for the Study of Liver Diseases.)
- Published
- 2015
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28. Novel preservation methods to increase the quality of older kidneys.
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Brat A, Pol RA, and Leuvenink HG
- Subjects
- Aging, Delayed Graft Function, Humans, Kidney Transplantation, Tissue Donors, Kidney physiology, Organ Preservation methods
- Abstract
Purpose of Review: The purpose of this review was to summarize the novel developments in preservation of older kidneys., Recent Findings: The importance of older donors as a source of renal grafts is increasing, with a concomitant increase of posttransplant failure. Preservation of kidneys retrieved from older donors through hypothermic machine perfusion reduces delayed graft function rate and increases long-term graft survival. Assessment of renal function and selection through biomarkers or perfusion criteria to predict posttransplant function are limited. Normothermic perfusion offers the benefit of reperfusion under ideal circumstances, thereby reducing ischemic injury while having the opportunity to test graft viability and preselect kidneys on graft-specific characteristics. Both preservation methods enable active treatment of the isolated graft prior to transplantation, with stem cells or pharmaceuticals., Summary: Older kidneys are more prone to acute kidney injury during ischemic periods combined with an impaired ability to fully recover after transplantation. Novel preservation and resuscitation methods provide the opportunity to select transplantable kidneys better founded or even repair re-existing damage reducing the risk of impaired graft function and improving survival.
- Published
- 2015
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29. Hypoxia and Complement-and-Coagulation Pathways in the Deceased Organ Donor as the Major Target for Intervention to Improve Renal Allograft Outcome.
- Author
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Damman J, Bloks VW, Daha MR, van der Most PJ, Sanjabi B, van der Vlies P, Snieder H, Ploeg RJ, Krikke C, Leuvenink HG, and Seelen MA
- Subjects
- Allografts, Blood Coagulation, Cohort Studies, Cold Ischemia, Complement Activation, Delayed Graft Function prevention & control, Humans, Hypoxia prevention & control, Malondialdehyde urine, Reperfusion, Tissue and Organ Harvesting, Transcriptome, Treatment Outcome, Graft Survival immunology, Graft Survival physiology, Kidney Transplantation, Tissue Donors
- Abstract
Background: In the last few decades, strategies to improve allograft survival after kidney transplantation have been directed to recipient-dependent mechanisms of renal injury. In contrast, no such efforts have been made to optimize organ quality in the donor. Optimizing deceased donor kidney quality opens new possibilities to improve renal allograft outcome., Methods: A total of 554 kidney biopsies were taken from donation after brain death (DBD) and donation after cardiac death (DCD) kidneys before donation, after cold ischemia and after reperfusion. Healthy living donor kidney biopsies served as controls. Transcriptomics was performed by whole genome microarray analyses followed by functional pathway analyses., Results: Before organ retrieval and before cessation of blood circulation, metabolic pathways related to hypoxia and complement-and-coagulation cascades were the major pathways enhanced in DBD donors. Similar pathways were also enriched in DCD donors after the first warm ischemia time. Shortly after reperfusion of DCD grafts, pathways related to prolonged and worsening deprivation of oxygen were associated with delayed graft function in the recipient., Conclusion: In conclusion, this large deceased donor study shows enrichment of hypoxia and complement-and-coagulation pathways already in DBD donors before cessation of blood flow, before organ retrieval. Therefore, future intervention therapies should target hypoxia and complement-and-coagulation cascades in the donor to improve renal allograft outcome in the recipient.
- Published
- 2015
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30. Ex Situ Normothermic Machine Perfusion of Donor Livers.
- Author
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Karimian N, Matton AP, Westerkamp AC, Burlage LC, Op den Dries S, Leuvenink HG, Lisman T, Uygun K, Markmann JF, and Porte RJ
- Subjects
- Cryopreservation methods, Humans, Male, Middle Aged, Oxygen administration & dosage, Perfusion methods, Tissue Donors, Liver blood supply, Liver Transplantation methods, Organ Preservation methods
- Abstract
In contrast to conventional static cold preservation (0-4 °C), ex situ machine perfusion may provide better preservation of donor livers. Continuous perfusion of organs provides the opportunity to improve organ quality and allows ex situ viability assessment of donor livers prior to transplantation. This video article provides a step by step protocol for ex situ normothermic machine perfusion (37 °C) of human donor livers using a device that provides a pressure and temperature controlled pulsatile perfusion of the hepatic artery and continuous perfusion of the portal vein. The perfusion fluid is oxygenated by two hollow fiber membrane oxygenators and the temperature can be regulated between 10 °C and 37 °C. During perfusion, the metabolic activity of the liver as well as the degree of injury can be assessed by biochemical analysis of samples taken from the perfusion fluid. Machine perfusion is a very promising tool to increase the number of livers that are suitable for transplantation.
- Published
- 2015
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31. Hydrogen sulfide in renal physiology, disease and transplantation--the smell of renal protection.
- Author
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Koning AM, Frenay AR, Leuvenink HG, and van Goor H
- Subjects
- Animals, Humans, Kidney metabolism, Kidney physiopathology, Kidney Diseases metabolism, Kidney Diseases therapy, Hydrogen Sulfide metabolism, Hydrogen Sulfide pharmacology, Kidney drug effects, Kidney physiology, Kidney Diseases physiopathology, Kidney Transplantation
- Abstract
Hydrogen sulfide (H2S), the third gasotransmitter, next to nitric oxide and carbon monoxide, is a key mediator in physiology and disease. It is involved in homeostatic functions, such as blood pressure control, electrolyte balance and apoptosis, and regulates pathological mechanisms, including oxidative stress and inflammation. Besides, it is believed to serve as an oxygen sensor under ischemic conditions. The kidney plays a decisive role in many of these processes, indicating an interplay between H2S and renal (patho)physiology. In this review we focus on the (protective) functions of H2S in the kidney. We first discuss endogenous renal H2S production and signaling and elaborate on its regulatory functions in renal physiology. Next, we present data on the role of aberrant H2S levels in the onset and progression of renal disease and suggest the use of H2S metabolites as biomarkers. Finally, we describe that exogenous H2S can protect the kidney against various forms of injury and conclude that modulation of renal H2S levels holds promise for renal patients in the future., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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32. Novel organ preservation methods: not only cool but supercool!
- Author
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Leuvenink HG
- Subjects
- Animals, Hepatectomy, Humans, Liver pathology, Time Factors, Cold Temperature, Cryopreservation methods, Cryoprotective Agents pharmacology, Liver drug effects, Organ Preservation methods, Organ Preservation Solutions pharmacology
- Published
- 2015
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- View/download PDF
33. Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia.
- Author
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Bos EM, van Goor H, Joles JA, Whiteman M, and Leuvenink HG
- Subjects
- Animals, Gasotransmitters metabolism, Humans, Hydrogen Sulfide administration & dosage, Hypoxia therapy, Ischemia therapy, Hydrogen Sulfide metabolism, Hypoxia physiopathology, Ischemia physiopathology
- Abstract
Hydrogen sulfide (H2 S) has become a molecule of high interest in recent years, and it is now recognized as the third gasotransmitter in addition to nitric oxide and carbon monoxide. In this review, we discuss the recent literature on the physiology of endogenous and exogenous H2 S, focusing upon the protective effects of hydrogen sulfide in models of hypoxia and ischaemia., (© 2014 The British Pharmacological Society.)
- Published
- 2015
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34. Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats.
- Author
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Snijder PM, Frenay AR, de Boer RA, Pasch A, Hillebrands JL, Leuvenink HG, and van Goor H
- Subjects
- Angiotensin II toxicity, Animals, Antihypertensive Agents pharmacology, Blood Pressure drug effects, Cardiomegaly etiology, Cardiomegaly prevention & control, Disease Models, Animal, Hypertension complications, Hypertension physiopathology, Male, Oxidative Stress drug effects, Rats, Rats, Sprague-Dawley, Hydrogen Sulfide metabolism, Hypertension drug therapy, Sulfides pharmacology, Thiosulfates pharmacology
- Abstract
Background and Purpose: Hypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2 S donor substance, in angiotensin II (Ang II)-induced hypertensive cardiac disease in rats., Experimental Approach: Male Sprague Dawley rats were infused with Ang II (435 ng kg min(-1)) or saline (control) for 3 weeks via s.c. placed osmotic minipumps. During these 3 weeks, rats received i.p. injections of either STS, NaHS or vehicle (0.9% NaCl)., Key Results: Compared with controls, Ang II infusion caused an increase in systolic and diastolic BP with associated cardiac damage as evidenced by cardiac hypertrophy, an increase in atrial natriuretic peptide (ANP) mRNA, cardiac fibrosis and increased oxidative stress. Treatment with NaHS and STS prevented the development of hypertension and the increase in ANP mRNA levels. Furthermore, the degree of cardiac hypertrophy, the extent of histological fibrosis in combination with the expression of profibrotic genes and the levels of oxidative stress were all significantly decreased., Conclusions and Implications: Ang II-induced hypertensive cardiac disease can be attenuated by treatment with STS and NaHS. Although BP regulation is the most plausible mechanism of cardiac protection, the antifibrotic and antioxidant properties of released sulfide may also contribute to their effects. Our data show that H2 S might be a valuable addition to the already existing antihypertensive and cardioprotective therapies., (© 2014 The British Pharmacological Society.)
- Published
- 2015
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35. Steroid Anti-Inflammatory Effects Did Not Improve Organ Quality in Brain-Dead Rats.
- Author
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Rebolledo RA, Liu B, Akhtar MZ, Ottens PJ, Zhang JN, Ploeg RJ, and Leuvenink HG
- Subjects
- Animals, Apoptosis drug effects, Cytokines blood, Inflammation physiopathology, Kidney drug effects, Kidney metabolism, Kidney physiopathology, Liver drug effects, Liver metabolism, Liver physiopathology, Rats, Brain Death physiopathology, Cytokines biosynthesis, Inflammation drug therapy, Prednisolone administration & dosage
- Abstract
Effect of glucocorticoid administration on improving the outcomes of kidney and liver allografts has not been clearly elucidated. This study investigated the effect of prednisolone administration after onset of brain death (BD) on kidney and liver in a controlled rat model of BD. BD was induced in rats by inflating an epidurally placed balloon catheter. Animals were treated with saline or prednisolone (5, 12.5, or 22.5 mg/kg) one hour after the onset of BD. After 4 hours of BD, experiments were terminated and serum and tissues were collected. Tissue gene and protein expression were measured for markers of inflammation, apoptosis, and cellular stress response markers. Prednisolone caused a reduction of plasma levels of IL-6, while the tissue expression of IL-6, IL-1β, and MCP-1 in both kidney and liver were also reduced. Creatinine plasma levels, complement (C3) expression, HSP-70, HO-1, Bcl2/BAX ratio, and PMN influx did not significantly change in kidney nor liver. Plasma AST and LDH levels were increased in the prednisolone treated group. Our results demonstrate prednisolone can has an anti-inflammatory effect mediated through reducing serum circulating cytokines. However, this anti-inflammatory effect does not translate into improved kidney function and indeed was associated with increased liver injury markers.
- Published
- 2015
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36. Sodium thiosulfate attenuates angiotensin II-induced hypertension, proteinuria and renal damage.
- Author
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Snijder PM, Frenay AR, Koning AM, Bachtler M, Pasch A, Kwakernaak AJ, van den Berg E, Bos EM, Hillebrands JL, Navis G, Leuvenink HG, and van Goor H
- Subjects
- Animals, Base Sequence, DNA Primers, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Angiotensin II physiology, Hypertension chemically induced, Kidney drug effects, Proteinuria chemically induced, Thiosulfates pharmacology
- Abstract
Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H(2)S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H(2)S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H(2)S donor NaHS and major H(2)S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup, NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H(2)S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H(2)S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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37. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion.
- Author
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Sutton ME, op den Dries S, Karimian N, Weeder PD, de Boer MT, Wiersema-Buist J, Gouw AS, Leuvenink HG, Lisman T, and Porte RJ
- Subjects
- Aged, Bile metabolism, Biomarkers metabolism, Blood Gas Analysis, Demography, Female, Humans, Hydrogen-Ion Concentration, Liver pathology, Liver Transplantation, Male, Middle Aged, Time Factors, Tissue Donors, Tissue Preservation, Liver metabolism
- Abstract
Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37 °C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥ 30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial.
- Published
- 2014
- Full Text
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38. Histopathologic and molecular evaluation of the Organ Procurement and Transplantation Network selection criteria for intestinal graft donation.
- Author
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Roskott AM, van Haaften WT, Leuvenink HG, Ploeg RJ, van Goor H, Blokzijl T, Ottens PJ, Dijkstra G, and Nieuwenhuijs VB
- Subjects
- Adolescent, Adult, Aged, C-Reactive Protein genetics, C-Reactive Protein metabolism, C-Reactive Protein standards, Child, Child, Preschool, Claudin-3 genetics, Claudin-3 metabolism, Claudin-3 standards, Endotoxemia etiology, Endotoxemia pathology, Humans, Ileum metabolism, Infant, Interleukin-6 biosynthesis, Interleukin-6 genetics, Interleukin-6 standards, Jejunum metabolism, Middle Aged, Organ Transplantation adverse effects, Young Adult, Ileum pathology, Ileum transplantation, Jejunum pathology, Jejunum transplantation, Organ Transplantation standards, Tissue and Organ Procurement standards
- Abstract
Background: The Organ Procurement and Transplantation Network (OPTN) has formulated criteria for the selection of donors for intestinal transplantation. To date, however, no study has correlated histologic findings of intestinal injury with the OPTN criteria. We aimed to describe histopathologic and molecular features of allograft injury in relation to donor conditions defined by the OPTN criteria., Materials and Methods: Graft histology (Park Score), Claudin-3 staining, systemic inflammatory markers (C-reactive protein/lipopolysaccharide-binding protein) and expression of heat shock protein 70, heme oxygenase 1, and interleukin 6 were evaluated in multiorgan deceased donors (donation after brain death [DBD] and donation after cardiac death [DCD])., Results: Ninety-seven samples (52 jejunum/45 ileum) were recovered from 59 donors (46 DBD/13 DCD). The OPTN criterion cold ischemia time correlated with histologic injury (Park score) to which the jejunum appeared more susceptible than the ileum. Claudin-3 staining was higher, and heat shock protein 70 expression lower in donors meeting the OPTN criteria compared with donors not meeting the criteria and in DBD versus DCD. In DBD donors, interleukin 6 expression was higher compared with DCD donors and inversely related to C-reactive protein., Conclusions: Our multiparameter analysis suggests that the OPTN criteria can be discriminative concerning intestinal graft quality. Our data suggest that DCD intestinal allografts are qualitatively inferior and that the jejunum is more sensitive to ischemia than the ileum., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
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39. Prednisolone has a positive effect on the kidney but not on the liver of brain dead rats: a potencial role in complement activation.
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Rebolledo R, Liu B, Akhtar MZ, Ottens PJ, Zhang JN, Ploeg RJ, and Leuvenink HG
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- Animals, Base Sequence, Biomarkers blood, DNA Primers, Kidney metabolism, Liver metabolism, Male, Rats, Rats, Inbred F344, Real-Time Polymerase Chain Reaction, Brain Death, Complement Activation drug effects, Kidney drug effects, Liver drug effects, Prednisolone pharmacology
- Abstract
Background: Contradictory evidence has been published on the effects of steroid treatments on the outcomes of kidney and liver transplantation from brain dead (BD) donors. Our study aimed to evaluate this disparity by investigating the effect of prednisolone administration on BD rats., Methods: BD induction was performed in ventilated rats by inflating a Fogarty catheter placed in the epidural space. Prednisolone (22.5 mg/kg) was administered 30 min prior to BD induction. After four hours of determination of BD: serum, kidney and liver tissues samples were collected and stored. RT-qPCR, routine biochemistry and immunohistochemistry were performed., Results: Prednisolone treatment reduced circulating IL-6 and creatinine plasma levels but not serum AST, ALT or LDH. Polymorphonuclear influx assessed by histology, and inflammatory gene expression were reduced in the kidney and liver. However, complement component 3 (C3) expression was decreased in kidney but not in liver. Gene expression of HSP-70, a cytoprotective protein, was down-regulated in the liver after treatment., Conclusions: This study shows that prednisolone decreases inflammation and improves renal function, whilst not reducing liver injury. The persistence of complement activation and the negative effect on protective cellular mechanisms in the liver may explain the disparity between the effects of prednisolone on the kidney and liver of BD rats. The difference in the molecular and cellular responses to prednisolone administration may explain the contradictory evidence of the effects of prednisolone on different organ types from brain dead organ donors.
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- 2014
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40. Reply: To PMID 24355874.
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Buddingh KT, Koudstaal LG, Leuvenink HG, Ploeg RJ, Nieuwenhuijs VB, van Santvoort HC, Nijmeijer RM, Gooszen H, Besselink MG, Timmer R, Rosman C, and van Goor H
- Subjects
- Female, Humans, Male, Angiopoietin-2 blood, Bacterial Infections diagnosis, Multiple Organ Failure diagnosis, Pancreatitis complications, Severity of Illness Index
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- 2014
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41. α-Melanocyte stimulating hormone treatment in pigs does not improve early graft function in kidney transplants from brain dead donors.
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van Rijt WG, Secher N, Keller AK, Møldrup U, Chynau Y, Ploeg RJ, van Goor H, Nørregaard R, Birn H, Frøkiaer J, Nielsen S, Leuvenink HG, and Jespersen B
- Subjects
- Acute Kidney Injury urine, Animals, Aquaporins metabolism, Biomarkers urine, Blood Glucose drug effects, Brain Death, Hemodynamics drug effects, Kidney drug effects, Kidney metabolism, Kidney physiopathology, Models, Animal, Swine, Tissue Donors, Graft Survival drug effects, Kidney Transplantation, alpha-MSH pharmacology
- Abstract
Delayed graft function and primary non-function are serious complications following transplantation of kidneys derived from deceased brain dead (DBD) donors. α-melanocyte stimulating hormone (α-MSH) is a pleiotropic neuropeptide and its renoprotective effects have been demonstrated in models of acute kidney injury. We hypothesized that α-MSH treatment of the recipient improves early graft function and reduces inflammation following DBD kidney transplantation. Eight Danish landrace pigs served as DBD donors. After four hours of brain death both kidneys were removed and stored for 18 hours at 4°C in Custodiol preservation solution. Sixteen recipients were randomized in a paired design into two treatment groups, transplanted simultaneously. α-MSH or a vehicle was administered at start of surgery, during reperfusion and two hours post-reperfusion. The recipients were observed for ten hours following reperfusion. Blood, urine and kidney tissue samples were collected during and at the end of follow-up. α-MSH treatment reduced urine flow and impaired recovery of glomerular filtration rate (GFR) compared to controls. After each dose of α-MSH, a trend towards reduced mean arterial blood pressure and increased heart rate was observed. α-MSH did not affect expression of inflammatory markers. Surprisingly, α-MSH impaired recovery of renal function in the first ten hours following DBD kidney transplantation possibly due to hemodynamic changes. Thus, in a porcine experimental model α-MSH did not reduce renal inflammation and did not improve short-term graft function following DBD kidney transplantation.
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- 2014
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42. Erythropoietin-mediated protection in kidney transplantation: nonerythropoietic EPO derivatives improve function without increasing risk of cardiovascular events.
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van Rijt WG, van Goor H, Ploeg RJ, and Leuvenink HG
- Subjects
- Animals, Cardiovascular Diseases etiology, Cardiovascular Diseases prevention & control, Erythropoietin adverse effects, Erythropoietin therapeutic use, Hematinics adverse effects, Humans, Kidney blood supply, Kidney drug effects, Kidney injuries, Nitric Oxide Synthase Type III metabolism, Oligopeptides therapeutic use, Receptors, Erythropoietin physiology, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Reperfusion Injury prevention & control, Risk Factors, Translational Research, Biomedical, Cytoprotection, Erythropoietin analogs & derivatives, Kidney Transplantation
- Abstract
The protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high-dose EPO treatment following renal transplantation did not reveal any protective effect for short-term renal function and even reported an increased risk of thrombosis. This review focusses on the current status of protective pathways mediated by EPO, the safety concerns using high EPO dosage and discusses the discrepancies between pre-clinical and clinical studies. The protective effects are mediated by binding of EPO to a heteromeric receptor complex consisting of two β-common receptors and two EPO receptors. An important role for the activation of endothelial nitric oxide synthase is proposed. EPO-mediated cytoprotection still has enormous potential. However, only nonerythropoietic EPO derivatives may induce protection without increasing the risk of cardiovascular events. In preclinical models, nonerythropoietic EPO derivatives, such as carbamoylated EPO and ARA290, have been tested. These EPO derivatives improve renal function and do not affect erythropoiesis. Therefore, nonerythropoietic EPO derivatives may be able to render EPO-mediated cytoprotection useful and beneficial for clinical transplantation., (© 2013 Steunstichting ESOT.)
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- 2014
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43. Hypothermic oxygenated machine perfusion prevents arteriolonecrosis of the peribiliary plexus in pig livers donated after circulatory death.
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Op den Dries S, Sutton ME, Karimian N, de Boer MT, Wiersema-Buist J, Gouw AS, Leuvenink HG, Lisman T, and Porte RJ
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- Animals, Arterioles drug effects, Aspartate Aminotransferases blood, Biliary Tract blood supply, Biliary Tract drug effects, Death, Epithelium drug effects, Epithelium pathology, Hepatocytes drug effects, Hepatocytes pathology, L-Lactate Dehydrogenase blood, Liver drug effects, Liver pathology, Liver Transplantation, Necrosis, Nerve Fibers drug effects, Organ Preservation, Oxidative Stress drug effects, Reperfusion, Sus scrofa, Tissue and Organ Procurement, Arterioles pathology, Biliary Tract innervation, Hypothermia, Induced, Liver blood supply, Nerve Fibers pathology, Oxygen pharmacology, Perfusion
- Abstract
Background: Livers derived from donation after circulatory death (DCD) are increasingly accepted for transplantation. However, DCD livers suffer additional donor warm ischemia, leading to biliary injury and more biliary complications after transplantation. It is unknown whether oxygenated machine perfusion results in better preservation of biliary epithelium and the peribiliary vasculature. We compared oxygenated hypothermic machine perfusion (HMP) with static cold storage (SCS) in a porcine DCD model., Methods: After 30 min of cardiac arrest, livers were perfused in situ with HTK solution (4°C) and preserved for 4 h by either SCS (n = 9) or oxygenated HMP (10°C; n = 9), using pressure-controlled arterial and portal venous perfusion. To simulate transplantation, livers were reperfused ex vivo at 37°C with oxygenated autologous blood. Bile duct injury and function were determined by biochemical and molecular markers, and a systematic histological scoring system., Results: After reperfusion, arterial flow was higher in the HMP group, compared to SCS (251±28 vs 166±28 mL/min, respectively, after 1 hour of reperfusion; p = 0.003). Release of hepatocellular enzymes was significantly higher in the SCS group. Markers of biliary epithelial injury (biliary LDH, gamma-GT) and function (biliary pH and bicarbonate, and biliary transporter expression) were similar in the two groups. However, histology of bile ducts revealed significantly less arteriolonecrosis of the peribiliary vascular plexus in HMP preserved livers (>50% arteriolonecrosis was observed in 7 bile ducts of the SCS preserved livers versus only 1 bile duct of the HMP preserved livers; p = 0.024)., Conclusions: Oxygenated HMP prevents arteriolonecrosis of the peribiliary vascular plexus of the bile ducts of DCD pig livers and results in higher arterial flow after reperfusion. Together this may contribute to better perfusion of the bile ducts, providing a potential advantage in the post-ischemic recovery of bile ducts.
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- 2014
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44. Early angiopoietin-2 levels after onset predict the advent of severe pancreatitis, multiple organ failure, and infectious complications in patients with acute pancreatitis.
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Buddingh KT, Koudstaal LG, van Santvoort HC, Besselink MG, Timmer R, Rosman C, van Goor H, Nijmeijer RM, Gooszen H, Leuvenink HG, Ploeg RJ, and Nieuwenhuijs VB
- Subjects
- Acute Disease, Aged, Bacterial Infections blood, Bacterial Infections etiology, Bacterial Infections prevention & control, Biomarkers blood, Case-Control Studies, Decision Support Techniques, Double-Blind Method, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Multiple Organ Failure blood, Multiple Organ Failure etiology, Multiple Organ Failure prevention & control, Pancreatitis blood, Pancreatitis diagnosis, Pancreatitis mortality, Pancreatitis, Acute Necrotizing blood, Pancreatitis, Acute Necrotizing diagnosis, Pancreatitis, Acute Necrotizing mortality, Pancreatitis, Acute Necrotizing prevention & control, Predictive Value of Tests, Probiotics therapeutic use, Prognosis, Prospective Studies, ROC Curve, Angiopoietin-2 blood, Bacterial Infections diagnosis, Multiple Organ Failure diagnosis, Pancreatitis complications, Severity of Illness Index
- Abstract
Background: Acute pancreatitis is a severe condition that requires early identification of patients at risk of developing potentially lethal complications. Current clinical scoring systems and biochemical parameters are insufficient. In this study, we aimed to assess whether early plasma Angiopoietin-2 (Ang-2) is associated with adverse outcomes in patients with predicted severe acute pancreatitis (SAP)., Study Design: This analysis is a substudy of the PROPATRIA trial (probiotics vs placebo in patients with predicted SAP). The Ang-2 levels were measured prospectively in plasma in the first 5 days after admission in 115 patients., Results: Early Ang-2 levels were higher in patients who developed SAP: 6.4 vs 3.1 μg/L (p < 0.001) and also were higher in patients who developed multiorgan failure in the first week (p = 0.001) and after the first week (p = 0.049). Furthermore, high Ang-2 levels were associated with infectious complications in the first week (p < 0.001) and after the first week (p < 0.001). Finally, plasma Ang-2 was significantly higher in patients who died (p < 0.001) and in patients who developed bowel ischemia (p < 0.001). As a predictor of adverse outcomes, plasma Ang-2 was superior to a number of current scores, such as the APACHE II score, the Imrie score, C-reactive protein, lipopolysaccharide binding protein, and procalcitonin., Conclusions: In the setting of this randomized controlled trial, early plasma Ang-2 was found to be an accurate predictor of SAP, multiorgan failure, and infectious complications. As a biomarker, it did outperform all of the investigated conventional predictors that are currently used in clinical practice., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)
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- 2014
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45. Emerging role of gasotransmitters in renal transplantation.
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Snijder PM, van den Berg E, Whiteman M, Bakker SJ, Leuvenink HG, and van Goor H
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- Animals, Apoptosis, Cytoprotection, Humans, Incidence, Kidney Failure, Chronic physiopathology, Mice, Oxidative Stress, Prevalence, Signal Transduction, Carbon Monoxide chemistry, Gasotransmitters chemistry, Hydrogen Sulfide chemistry, Kidney Failure, Chronic therapy, Kidney Transplantation methods, Nitric Oxide chemistry
- Abstract
Once patients with kidney disease progress to end-stage renal failure, transplantation is the preferred option of treatment resulting in improved quality of life and reduced mortality compared to dialysis. Although 1-year survival has improved considerably, graft and patient survival in the long term have not been concurrent, and therefore new tools to improve long-term graft and patient survival are warranted. Over the past decades, the gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) have emerged as potent cytoprotective mediators in various diseases. All three gasotransmitters are endogenously produced messenger molecules that possess vasodilatory, anti-apoptotic, anti-inflammatory and anti-oxidant properties by influencing an array of intracellular signaling processes. Although many regulatory functions of gasotransmitters have overlapping actions, differences have also been reported. In addition, crosstalk between NO, CO and H2S results in synergistic regulatory effects. Endogenous and exogenous manipulation of gasotransmitter levels modulates several processes involved in renal transplantation. This review focuses on mechanisms of gas-mediated cytoprotection and complex interactions between gasotransmitters in renal transplantation., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)
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- 2013
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46. Renoprotective capacities of non-erythropoietic EPO derivative, ARA290, following renal ischemia/reperfusion injury.
- Author
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van Rijt WG, Nieuwenhuijs-Moeke GJ, van Goor H, Ottens PJ, Ploeg RJ, and Leuvenink HG
- Subjects
- Acute Kidney Injury prevention & control, Animals, Base Sequence, DNA Primers, Inflammation diagnosis, Kidney blood supply, Male, Rats, Rats, Inbred Lew, Reverse Transcriptase Polymerase Chain Reaction, Kidney drug effects, Oligopeptides pharmacology, Reperfusion Injury physiopathology
- Abstract
Background: ARA290 is a non-erythropoietic EPO derivative which only binds to the cytoprotective receptor complex (EPOR2-βcR2) consisting of two EPO-receptors (EPOR) and two β common receptors (βcR). ARA290 is renoprotective in renal ischemia/reperfusion (I/R). In a renal I/R model we focussed on timing of post-reperfusional administration of ARA290. Furthermore, we investigated the anti-inflammatory properties of ARA290., Methods: Twenty-six male Lewis/HanHsd rats were exposed to unilateral ischemia for 30 minutes, with subsequent removal of the contralateral kidney. Post-reperfusion, ARA290 was administered early (one hour), late (four hours) or repetitive (one and four hours). Saline was used as vehicle treatment. Rats were sacrificed after three days., Results: Early ARA290 treatment improved renal function. Late- or repetitive treatment tended to improve clinical markers. Furthermore, early ARA290 treatment reduced renal inflammation and acute kidney injury at three days post-reperfusion. Late- or repetitive treatment did not affect inflammation or acute kidney injury., Conclusions: ARA290 attenuated renal ischemia/reperfusion injury. This study showed the anti-inflammatory effect of ARA290 and suggests early administration in the post-reperfusional phase is most effective. ARA290 is a candidate drug for protection against ischemic injury following renal transplantation.
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- 2013
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47. Nonesterified fatty acids and development of graft failure in renal transplant recipients.
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Klooster A, Hofker HS, Navis G, Homan van der Heide JJ, Gans RO, van Goor H, Leuvenink HG, and Bakker SJ
- Subjects
- Adult, Cohort Studies, Fatty Acids, Nonesterified blood, Female, Follow-Up Studies, Graft Rejection blood, Graft Rejection epidemiology, Humans, Kaplan-Meier Estimate, Kidney Transplantation mortality, Male, Middle Aged, Prospective Studies, Proteinuria blood, Proteinuria physiopathology, Regression Analysis, Retrospective Studies, Risk Factors, Transplantation, Homologous, Fatty Acids, Nonesterified physiology, Graft Rejection physiopathology, Kidney Transplantation physiology, Transplantation
- Abstract
Background: Chronic transplant dysfunction is the most common cause of graft failure on the long term. Proteinuria is one of the cardinal clinical signs of chronic transplant dysfunction. Albumin-bound fatty acids (FA) have been hypothesized to be instrumental in the etiology of renal damage induced by proteinuria. We therefore questioned whether high circulating FA could be associated with an increased risk for future development of graft failure in renal transplant recipients (RTR). To this end, we prospectively investigated the association of fasting concentrations of circulating nonesterified FA (NEFA) with the development of graft failure in RTR., Methods: Baseline measurements were performed between 2001 and 2003 in outpatient RTR with a functioning graft of more than 1 year. Follow-up was recorded until May 19, 2009. Graft failure was defined as return to dialysis or retransplantation., Results: We included 461 RTR at a median (interquartile range [IQR]) of 6.1 (3.3-11.3) years after transplantation. Median (IQR) fasting concentrations of NEFA were 373 (270-521) μM/L. Median (IQR) follow-up for graft failure beyond baseline was 7.1 (6.1-7.5) years. Graft failure occurred in 23 (15%), 14 (9%), and 9 (6%) of RTR across increasing gender-specific tertiles of NEFA (P=0.04). In a gender-adjusted Cox-regression analysis, log-transformed NEFA level was inversely associated with the development of graft failure (hazard ratio, 0.61; 95% confidence interval, 0.47-0.81; P<0.001)., Conclusions: In this prospective cohort study in RTR, we found an inverse association between fasting NEFA concentrations and risk for development of graft failure. This association suggests a renoprotective rather than a tubulotoxic effect of NEFA. Further studies on the role of different types of NEFA in the progression of renal disease are warranted.
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- 2013
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48. Gaseous hydrogen sulfide protects against myocardial ischemia-reperfusion injury in mice partially independent from hypometabolism.
- Author
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Snijder PM, de Boer RA, Bos EM, van den Born JC, Ruifrok WP, Vreeswijk-Baudoin I, van Dijk MC, Hillebrands JL, Leuvenink HG, and van Goor H
- Subjects
- Animals, Atrial Natriuretic Factor genetics, Blood Pressure drug effects, Carbon Dioxide metabolism, Cell Line, Disease Models, Animal, Gene Expression, Heart Rate drug effects, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Male, Membrane Glycoproteins genetics, Mice, Myoblasts, Cardiac drug effects, Myoblasts, Cardiac metabolism, Myocardial Reperfusion Injury genetics, Myocardium metabolism, Myocardium pathology, NADPH Oxidase 2, NADPH Oxidase 4, NADPH Oxidases genetics, Oxidative Stress drug effects, Rats, Hydrogen Sulfide administration & dosage, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury prevention & control
- Abstract
Background: Ischemia-reperfusion injury (IRI) is a major cause of cardiac damage following various pathological processes. Gaseous hydrogen sulfide (H2S) is protective during IRI by inducing a hypometabolic state in mice which is associated with anti-apoptotic, anti-inflammatory and antioxidant properties. We investigated whether gaseous H2S administration is protective in cardiac IRI and whether non-hypometabolic concentrations of H2S have similar protective properties., Methods: Male C57BL/6 mice received a 0, 10, or 100 ppm H2S-N2 mixture starting 30 minutes prior to ischemia until 5 minutes pre-reperfusion. IRI was inflicted by temporary ligation of the left coronary artery for 30 minutes. High-resolution respirometry equipment was used to assess CO2-production and blood pressure was measured using internal transmitters. The effects of H2S were assessed by histological and molecular analysis., Results: Treatment with 100 ppm H2S decreased CO2-production by 72%, blood pressure by 14% and heart rate by 25%, while treatment with 10 ppm H2S had no effects. At day 1 of reperfusion 10 ppm H2S showed no effect on necrosis, while treatment with 100 ppm H2S reduced necrosis by 62% (p<0.05). Seven days post-reperfusion, both 10 ppm (p<0.01) and 100 ppm (p<0.05) H2S showed a reduction in fibrosis compared to IRI animals. Both 10 ppm and 100 ppm H2S reduced granulocyte-influx by 43% (p<0.05) and 60% (p<0.001), respectively. At 7 days post-reperfusion both 10 and 100 ppm H2S reduced expression of fibronectin by 63% (p<0.05) and 67% (p<0.01) and ANP by 84% and 63% (p<0.05), respectively., Conclusions: Gaseous administration of H2S is protective when administered during a cardiac ischemic insult. Although hypometabolism is restricted to small animals, we now showed that low non-hypometabolic concentrations of H2S also have protective properties in IRI. Since IRI is a frequent cause of myocardial damage during percutaneous coronary intervention and cardiac transplantation, H2S treatment might lead to novel therapeutical modalities.
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- 2013
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49. Are brain and heart tissue prone to the development of thiamine deficiency?
- Author
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Klooster A, Larkin JR, Wiersema-Buist J, Gans RO, Thornalley PJ, Navis G, van Goor H, Leuvenink HG, and Bakker SJ
- Subjects
- Animals, Male, Random Allocation, Rats, Rats, Inbred Lew, Thiamine Deficiency complications, Brain metabolism, Myocardium metabolism, Thiamine Deficiency metabolism
- Abstract
Thiamine deficiency is a continuing problem leading to beriberi and Wernicke's encephalopathy. The symptoms of thiamine deficiency develop in the heart, brain and neuronal tissue. Yet, it is unclear how rapid thiamine deficiency develops and which organs are prone to development of thiamine deficiency. We investigated these issues in a thiamine deficient animal model. Twenty-four male Lewis rats were fed a thiamine deficient diet, which contained 0.04% of normal thiamine intake. Six control rats were fed 200 μg of thiamine per day. Every week a group of six rats on the thiamine-deficient diet was sacrificed and blood, urine and tissue were stored. Blood and tissue transketolase activity, thiamine and thiamine metabolites were measured and PCR of thiamine transporter-1 (ThTr-1) was performed. Transketolase activity was significantly reduced in red blood cells, liver, lung, kidney and spleen tissue after two weeks of thiamine deficient diet. In brain tissue, transketolase activity was not reduced after up to four weeks of thiamine deficient diet. The amount of thiamine pyrophosphate was also significantly conserved in brain and heart tissue (decrease of 31% and 28% respectively), compared to other tissues (decrease of ~70%) after four weeks of thiamine deficient diet. There was no difference between tissues in ThTr-1 expression after four weeks of thiamine deficient diet. Despite the fact that the heart and the brain are predilection sites for complications from thiamine deficiency, these tissues are protected against thiamine deficiency. Other organs could be suffering from thiamine deficiency without resulting in clinical signs of classic thiamine deficiency in beriberi and Wernicke's encephalopathy., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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50. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers.
- Author
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op den Dries S, Karimian N, Sutton ME, Westerkamp AC, Nijsten MW, Gouw AS, Wiersema-Buist J, Lisman T, Leuvenink HG, and Porte RJ
- Subjects
- Adult, Female, Follow-Up Studies, Humans, Male, Middle Aged, Retrospective Studies, Temperature, Graft Survival, Ischemic Preconditioning methods, Liver blood supply, Liver Transplantation, Organ Preservation methods, Perfusion methods
- Abstract
In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion may reduce preservation injury, improve graft viability and potentially allows ex vivo assessment of graft viability before transplantation. We have studied the feasibility of normothermic machine perfusion in four discarded human donor livers. Normothermic machine perfusion consisted of pressure and temperature controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion for 6 h. Two hollow fiber membrane oxygenators provided oxygenation of the perfusion fluid. Biochemical markers in the perfusion fluid reflected minimal hepatic injury and improving function. Lactate levels decreased to normal values, reflecting active metabolism by the liver (mean lactate 10.0 ± 2.3 mmol/L at 30 min to 2.3 ± 1.2 mmol/L at 6 h). Bile production was observed throughout the 6 h perfusion period (mean rate 8.16 ± 0.65 g/h after the first hour). Histological examination before and after 6 h of perfusion showed well-preserved liver morphology without signs of additional hepatocellular ischemia, biliary injury or sinusoidal damage. In conclusion, this study shows that normothermic machine perfusion of human donor livers is technically feasible. It allows assessment of graft viability before transplantation, which opens new avenues for organ selection, therapeutic interventions and preconditioning., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2013
- Full Text
- View/download PDF
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