1
|
Preoperative Function Assessment of Ex Vivo Kidneys with Supervised Machine Learning Based on Blood and Urine Markers Measured during Normothermic Machine Perfusion. Biomedicines 2022; 10:biomedicines10123055. [PMID: 36551812 PMCID: PMC9776285 DOI: 10.3390/biomedicines10123055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/13/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Establishing an objective quality assessment of an organ prior to transplantation can help prevent unnecessary discard of the organ and reduce the probability of functional failure. In this regard, normothermic machine perfusion (NMP) offers new possibilities for organ evaluation. However, to date, few studies have addressed the identification of markers and analytical tools to determine graft quality. In this study, function and injury markers were measured in blood and urine during NMP of 26 porcine kidneys and correlated with ex vivo inulin clearance behavior. Significant differentiation of kidneys according to their function could be achieved by oxygen consumption, oxygen delivery, renal blood flow, arterial pressure, intrarenal resistance, kidney temperature, relative urea concentration, and urine production. In addition, classifications were accomplished with supervised learning methods and histological analysis to predict renal function ex vivo. Classificators (support vector machines, k-nearest-neighbor, logistic regression and naive bayes) based on relevant markers in urine and blood achieved 75% and 83% accuracy in the validation and test set, respectively. A correlation between histological damage and function could not be detected. The measurement of blood and urine markers provides information of preoperative renal quality, which can used in future to establish an objective quality assessment.
Collapse
|
2
|
Hamelink TL, Ogurlu B, De Beule J, Lantinga VA, Pool MBF, Venema LH, Leuvenink HGD, Jochmans I, Moers C. Renal Normothermic Machine Perfusion: The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool. Transplantation 2022; 106:268-279. [PMID: 33979315 DOI: 10.1097/tp.0000000000003817] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The increased utilization of high-risk renal grafts for transplantation requires optimization of pretransplant organ assessment strategies. Current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity. Normothermic machine perfusion (NMP) creates near-physiological conditions, which might facilitate a more objective assessment of organ quality before transplantation. NMP is rapidly gaining popularity, with various transplant centers developing their own NMP protocols and renal viability criteria. However, to date, no validated sets of on-pump viability markers exist nor are there unified NMP protocols. This review provides a critical overview of the fundamentals of current renal NMP protocols and proposes a framework to approach further development of ex vivo organ evaluation. We also comment on the potential logistical implications of routine clinical use of NMP, which is a more complex procedure compared with static cold storage or even hypothermic machine perfusion.
Collapse
Affiliation(s)
- Tim L Hamelink
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Baran Ogurlu
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Julie De Beule
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
| | - Veerle A Lantinga
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Merel B F Pool
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Leonie H Venema
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Henri G D Leuvenink
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Ina Jochmans
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Cyril Moers
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| |
Collapse
|
3
|
The evolution of donation after circulatory death donor kidney repair in the United Kingdom. Curr Opin Organ Transplant 2019; 23:130-135. [PMID: 29045248 DOI: 10.1097/mot.0000000000000477] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW The increasing reliance on marginal donors has driven research to investigate ways to repair and improve the quality of kidneys for transplantation. Normothermic perfusion technologies provide an opportunity for improved preservation, organ assessment and resuscitation/repair of damaged kidneys. This review describes the evolution of normothermic perfusion in kidney transplantation in the United Kingdom. RECENT FINDINGS One hour of normothermic perfusion can be used to restore function and improve early graft function of extended criteria donor kidneys. A large multicentre trial is investigating the impact of normothermic perfusion on delayed graft function in a series of donation after circulatory death kidneys. Normothermic perfusion is also a platform for the delivery of therapies to the kidney to upregulate and modulate repair mechanisms or prevent injurious processes, such as activation of caspase-3 with the delivery of caspase-3 targeted small interfering RNAs. Normothermic perfusion can also be used to assess the quality and anatomical structure of a kidney to judge suitability for transplantation. SUMMARY Normothermic perfusion technology is a useful adjunct in kidney transplantation. It can improve early graft function by upregulating protective mechanisms. It also has the advantage of providing a functional assessment of the kidney and as a platform for the delivery of therapies or graft manipulation to target ischaemia reperfusion injury or the immune response. This technology can be used to expand the organ donor pool and prevent the unnecessary discard of kidneys.
Collapse
|
4
|
Morsy M, Hossain MA, Bagul A. Exploring the Role of Mesenchymal Stem Cells During Normothermic Organ Perfusion: A New Paradigm to Enhance Outcome Following Allograft Transplantation. ACTA ACUST UNITED AC 2018. [DOI: 10.2174/1876893801805010047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background:
Normothermic Machine Perfusion (NMP) has been established in the field of solid organ transplantation for both liver and kidney allografts. The ability to perfuse organs at body temperature enables viability assessment as well as optimisation prior to implantation.
Discussion:
A recent in vitro report of the use of Mesenchymal Stem Cells (MSCs) in the use of a normothermic lung perfusion circuit has raised the possibility of their use in solid organ transplantation. The aim of this short review is to outline the potential uses of bone marrow derived MSCs for their use in renal allograft ex vivo NMP. An overview is provided of current literature of NMP as well as theorised uses for MSCs.
Collapse
|
5
|
Schmitt FCF, Salgado E, Friebe J, Schmoch T, Uhle F, Fleming T, Zemva J, Kihm L, Nusshag C, Morath C, Zeier M, Bruckner T, Mehrabi A, Nawroth PP, Weigand MA, Hofer S, Brenner T. Cell cycle arrest and cell death correlate with the extent of ischaemia and reperfusion injury in patients following kidney transplantation - results of an observational pilot study. Transpl Int 2018; 31:751-760. [PMID: 29505681 DOI: 10.1111/tri.13148] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 06/26/2017] [Accepted: 02/28/2018] [Indexed: 01/11/2023]
Abstract
A prolonged cold ischaemia time (CIT) is suspected to be associated with an increased ischaemia and reperfusion injury (IRI) resulting in an increased damage to the graft. In total, 91 patients were evaluated for a delayed graft function within 7 days after kidney transplantation (48 deceased, 43 living donors). Blood and urine samples were collected before, immediately after the operation, and 1, 3, 5, 7 and 10 days later. Plasma and/or urine levels of total keratin 18 (total K18), caspase-cleaved keratin 18 (cc K18), the soluble receptor for advanced glycation end products (sRAGE), tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) were measured. As a result of prolonged CIT and increased IRI, deceased donor transplantations were shown to suffer from a more distinct cell cycle arrest and necrotic cell death. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 were therefore demonstrated to be of value for the detection of a delayed graft function (DGF), as they improved the diagnostic performance of a routinely used clinical scoring system. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 measurements are potentially suitable for early identification of patients at high risk for a DGF following kidney transplantation from deceased or living donors.
Collapse
Affiliation(s)
- Felix C F Schmitt
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Eduardo Salgado
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Janina Friebe
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Schmoch
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Florian Uhle
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Fleming
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Johanna Zemva
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Lars Kihm
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Nusshag
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Christian Morath
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Martin Zeier
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Bruckner
- Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter P Nawroth
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany
| | - Markus A Weigand
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Hofer
- Department of Anesthesiology, Kaiserslautern Westpfalz Hospital, Kaiserslautern, Germany
| | - Thorsten Brenner
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| |
Collapse
|
6
|
Optimising renal cancer patients for nephron-sparing surgery: a review of pre-operative considerations and peri-operative techniques for partial nephrectomy. Urologia 2017; 84:20-27. [PMID: 28106241 DOI: 10.5301/uro.5000208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2016] [Indexed: 11/20/2022]
Abstract
Nonmodifiable factors including pre-operative renal function and amount of healthy renal tissue preserved are the most important predictive factors that determine renal function after partial nephrectomy. Ischaemia time is an important modifiable risk factor and cold ischaemia time should be used if longer ischaemia time is anticipated. New techniques may have a role in maximising postoperative kidney function, but more robust studies are required to understand their potential benefits and risks.
Collapse
|
7
|
Hamaoui K, Aftab A, Gowers S, Boutelle M, Cook T, Rudd D, Dobson GP, Papalois V. An ex vivo comparison of adenosine and lidocaine solution and University of Wisconsin solution for hypothermic machine perfusion of porcine kidneys: potential for development. J Surg Res 2017; 208:219-229. [PMID: 27993213 DOI: 10.1016/j.jss.2016.08.068] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 07/29/2016] [Accepted: 08/18/2016] [Indexed: 01/13/2023]
Abstract
BACKGROUND The optimal hypothermic machine perfusion (HMP) solution has not yet been developed. An adenosine and lidocaine (AL) solution has been shown to be protective in cardiac preservation. The aim of the present study was to examine a modified AL solution with low Ca2+, 16 mM Mg2+, and 4% albumin on kidney preservation compared with University Wisconsin solution (UW). METHODS Twenty donation of organs after cardiac death porcine kidneys underwent HMP for 10 h (AL, n = 10; UW, n = 10) and then 2 h of normothermic reperfusion. Perfusion dynamics, functional parameters, histology, and real-time microdialysis were used to assess kidney responses and viability. RESULTS During HMP, modified AL-perfused kidneys maintained higher flow rates (21.5 versus 17.9 mL/min/100 g, P = 0.01), with perfusion flow index during the first 3 h 25% greater than with UW (AL = 0.50 ± 0.2, UW = 0.40 ± 0.17 mL/min/100 g/mmHg; P = 0.03), followed by an increase in UW kidneys which was not significantly different to AL over the remaining 7 h (0.54 versus 0.55 mL/min/100 g/mmHg, respectively). During warm reperfusion, there were no significant differences between the two HMP groups in creatinine clearance, oxygen, and glucose consumption between groups. Modified AL kidneys had significantly lower perfusate lactates (3.1 versus 4.1 mmol/L, P = 0.04) during reperfusion and lower cortical lactate levels (AL = 0.66 ± 0.31, UW = 0.89 ± 0.53 mM, P = 0.33). Histology showed similar degrees of reperfusion injury. CONCLUSIONS We conclude that HMP with modified AL solution showed improved perfusion compared with UW and lower perfusate lactate levels during warm reperfusion. Further modification of the AL composition is warranted and may lead to more rapid kidney stabilization and improved graft viability assessment, potentially expanding donor pools.
Collapse
Affiliation(s)
- Karim Hamaoui
- Department of Surgery, Imperial College London, London, United Kingdom.
| | - Adeel Aftab
- Department of Surgery, Imperial College London, London, United Kingdom
| | - Sally Gowers
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Martyn Boutelle
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Terry Cook
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Donna Rudd
- College of Public Health, Medical and Vet Sciences, James Cook University, Townsville, Queensland, Australia
| | - Geoffrey P Dobson
- Heart, Trauma and Sepsis Research Laboratory, College of Medicine and Dentistry, AITHM, James Cook University, Townsville, Queensland, Australia
| | - Vassilios Papalois
- Department of Surgery, Imperial College London, London, United Kingdom; Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| |
Collapse
|
8
|
A triple-biomarker approach for the detection of delayed graft function after kidney transplantation using serum creatinine, cystatin C, and malondialdehyde. Clin Biochem 2015; 48:1033-8. [DOI: 10.1016/j.clinbiochem.2015.07.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 07/01/2015] [Accepted: 07/06/2015] [Indexed: 12/28/2022]
|
9
|
Hosgood SA, Yates PJ, Nicholson ML. 1400W reduces ischemia reperfusion injury in an ex-vivo porcine model of the donation after circulatory death kidney donor. World J Transplant 2014; 4:299-305. [PMID: 25540738 PMCID: PMC4274599 DOI: 10.5500/wjt.v4.i4.299] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 07/08/2014] [Accepted: 11/03/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase (iNOS) inhibitor in a model of donation after circulatory death (DCD) kidneys.
METHODS: Porcine kidneys were retrieved after 25 min warm ischemia. They were then stored on ice for 18 h before being reperfused ex vivo with oxygenated autologous blood on an isolated organ perfusion system. The selective iNOS inhibitor 1400W (10 mg/kg) was administered before reperfusion (n = 6) vs control group (n = 7). Creatinine (1000 μmol/L) was added to the system, renal and tubular cell function and the level of ischemia reperfusion injury were assessed over 3 h of reperfusion using plasma, urine and tissue samples.
RESULTS: Kidneys treated with 1400W had a higher level of creatinine clearance (CrCl) [area under the curve (AUC) CrCl: 2.37 ± 0.97 mL/min per 100 g vs 0.96 ± 0.32 mL/min per 100 g, P = 0.004] and urine output [Total: 320 ± 96 mL vs 156 ± 82 mL, P = 0.008]. There was no significant difference in levels of fractional excretion of sodium (AUC, Fr ex Na+: Control, 186.3% ± 81.7%.h vs 1400W, 153.4% ± 12.1%.h, P = 0.429). Levels of total protein creatinine ratio were significantly lower in the 1400W group after 1 h of reperfusion (1h Pr/Cr: 1400W 9068 ± 6910 mg/L/mmol/L vs Control 21586 ± 5464 mg/L/mmol/L, P = 0.026). Levels of 8-isoprostane were significantly lower in the 1400W group [8-iso/creatinine ratio: Control 239 ± 136 pg/L/mmol/L vs 1400W 139 ± 47 pg/L/mmol/L, P = 0.041].
CONCLUSION: This study demonstrated that 1400W reduced ischaemia reperfusion injury in this porcine kidney model of DCD donor. Kidneys had improved renal function and reduced oxidative stress.
Collapse
|
10
|
Mancina E, Kalenski J, Paschenda P, Beckers C, Bleilevens C, Boor P, Doorschodt BM, Tolba RH. Determination of the Preferred Conditions for the Isolated Perfusion of Porcine Kidneys. Eur Surg Res 2014; 54:44-54. [DOI: 10.1159/000366155] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 07/22/2014] [Indexed: 11/19/2022]
Abstract
Background: The isolated perfused porcine kidney (IPPK) model has been the method of choice for the early preclinical evaluation of kidney graft preservation techniques. The preferred reperfusion conditions have not yet been determined. Here, we examined the effects of pressure- or flow-controlled perfusion and oxygenation by pure oxygen or carbogen (95% O2/5% CO2) on normothermic reperfusion in the IPPK model. Methods: Porcine kidneys were cold-stored for 24 h in histidine-tryptophan-ketoglutarate solution and reperfused for 1 h with normothermic whole blood/Krebs-Henseleit buffer medium (20/80%). Kidneys (n = 5/group) were flow-controlled reperfused with pure oxygen (1 ml/min/g; Flow-O2) or pressure-controlled reperfused (85 mm Hg mean arterial pressure) and oxygenated with either pure oxygen (Pressure-O2) or carbogen (Pressure-O2/CO2). Renal function and damage were assessed during reperfusion and NGAL and HIF-1α levels were analyzed using an ELISA. Results: Pressure-O2 and Pressure-O2/CO2 were associated with significantly better renal hemodynamics and acid-base homeostasis compared to Flow-O2. Urine protein concentrations and the fractional excretion of sodium were lower with both Pressure-O2 and Pressure-O2/CO2 than with Flow-O2. NGAL and HIF-1α levels were also lower with Pressure-O2 and Pressure-O2/CO2 than with Flow-O2. Only Pressure-O2/CO2 could demonstrate a significantly increased urine production compared to Flow-O2. The structural integrity was well preserved in the Pressure-O2 and Pressure-O2/CO2 groups, whereas diffuse and global glomerular destruction was observed in the Flow-O2 group. Conclusion: In the IPPK model, the application of pressure-controlled reperfusion with carbogen oxygenation, and to a lesser extent with pure oxygen, maintained physiological renal function for 1 h, thus providing a reliable and reproducible ex vivo evaluation of kidney preservation quality.
Collapse
|
11
|
Brenner T, Fleming TH, Spranz D, Schemmer P, Bruckner T, Uhle F, Martin EO, Weigand MA, Hofer S. Reactive metabolites and AGE-RAGE-mediated inflammation in patients following liver transplantation. Mediators Inflamm 2013; 2013:501430. [PMID: 23766560 PMCID: PMC3677670 DOI: 10.1155/2013/501430] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 04/29/2013] [Indexed: 02/07/2023] Open
Abstract
Recent investigations have indicated that reactive metabolites and AGE-RAGE-mediated inflammation might play an important role in the pathogenesis of ischemia-reperfusion injury in liver transplantation. In this observational clinical study, 150 patients were enrolled following liver transplantation from deceased donors. The occurrence of short-term complications within 10 days of transplantation was documented. Blood samples were collected prior to transplantation, immediately after transplantation, and at consecutive time points, for a total of seven days after transplantation. Plasma levels of methylglyoxal were determined using HPLC, whereas plasma levels of L-arginine, asymmetric dimethylarginine, advanced glycation endproducts-carboxylmethyllysine, soluble receptor for advanced glycation endproducts, and total antioxidant capacity were measured by ELISA. Patients following liver transplantation were shown to suffer from increased RAGE-associated inflammation with an AGE load mainly dependent upon reactive carbonyl species-derived AGEs. In contrast, carboxylmethyllysine-derived AGEs were of a minor importance. As assessed by the ratio of L-arginine/asymmetric dimethylarginine, the bioavailability of nitric oxide was shown to be reduced in hepatic IRI, especially in those patients suffering from perfusion disorders following liver transplantation. For the early identification of patients at high risk of perfusion disorders, the implementation of asymmetric dimethylarginine measurements in routine diagnostics following liver transplantation from deceased donors should be taken into consideration.
Collapse
Affiliation(s)
- Thorsten Brenner
- Department of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
| | | | | | | | | | | | | | | | | |
Collapse
|
12
|
Yang B, Hosgood SA, Da Z, Harper SJF, Waller HL, Kay MD, Furness PN, Nicholson ML. Biomarkers assessing warm ischemic injury using an isolated porcine kidney hemoreperfusion model. Exp Biol Med (Maywood) 2013; 237:1462-73. [PMID: 23354405 DOI: 10.1258/ebm.2012.012050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Prolonged warm ischemia (WI) occurring in marginal kidney donors together with reperfusion injury determines allograft survival, in which apoptosis and inflammation play crucial roles. There is no single valid biomarker, so far, to assess the degree of kidney donor injury. To define new biomarkers for detecting initial donor ischemic injury, caspase-3, caspase-7, apoptosis, inflammation, HSP70 and renal histological changes were examined in porcine kidneys subjected to 7- 15- 25- or 40-min WI, two-hour cold storage and six-hour hemoreperfusion. Caspase-3 activity was gradually increased by prolonged reperfusion, with a decrease trend against WI time. This result was verified by raised 17 kDa active caspase-3 in postreperfusion kidneys, with elevated 12 kDa active caspase-3 and lowered precursor at seven-minute WI. Active caspase-7 was also doubled by reperfusion with decreased precursor at seven-minute WI, but declined against prolonged WI. Apoptotic cells in tubular and interstitial areas were greatly increased by reperfusion at seven-minute WI, but decreased against prolonged WI. In addition, myeloperoxidase (MPO)+ cells were dramatically increased by reperfusion and presented as a bell-shape against WI time, while HSP70 was significantly increased at 7-min WI, but decreased at 40-min WI after reperfusion. In postreperfusion kidneys, tubular dilation and cell shedding were observed at 7- and 15-min WI, while tubular vacuolation and cell debris were found in tubular lumens at longer WI times. At 40-min WI, early nuclear pyknosis, tubular epithelia detachment and peri-tubular capillary dilation were detected. Furthermore, caspase-3, caspase-7, apoptosis, but not MPO+ cells or HSP70, were correlated with renal function. In conclusion, caspase-3, caspase-7 and apoptosis appear to be better biomarkers than MPO+ cells or HSP70 for assessing warm ischemic injury in donor kidneys. Hemoreperfusion activates caspase-3 and caspase-7, promotes apoptosis of damaged cells in kidneys only with limited WI, which might be beneficial to renal structural re-modeling and functional recovery.
Collapse
Affiliation(s)
- Bin Yang
- Transplant Surgery Group, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, Leicester LE5 4PW, UK.
| | | | | | | | | | | | | | | |
Collapse
|
13
|
Sedaghat Z, Kadkhodaee M, Seifi B, Salehi E, Najafi A, Dargahi L. Remote preconditioning reduces oxidative stress, downregulates cyclo-oxygenase-2 expression and attenuates ischaemia-reperfusion-induced acute kidney injury. Clin Exp Pharmacol Physiol 2013; 40:97-103. [PMID: 23240616 DOI: 10.1111/1440-1681.12044] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Accepted: 12/12/2012] [Indexed: 11/29/2022]
Abstract
Remote preconditioning (rPeC) is a phenomenon by which short-time intermittent ischaemia-reperfusion (I/R) of a remote organ during ischaemia protects other organs from I/R injury (IRI). The aim of the present study was to investigate the protective effect of rPeC on renal IRI in rats. Rats were subjected to right nephrectomy and randomized as into a sham group (no additional intervention), an I/R group (subjected to 45 min left renal pedicle occlusion) and an rPeC group (subjected to four cycles of 5 min I/R of the left femoral artery administered at the beginning of renal ischaemia). After 24 h, blood, urine and tissue samples were collected. Compared with the sham group, I/R resulted in renal dysfunction, as evidenced by significantly lower creatinine clearance (CCr; 0.52 ± 0.06 vs 0.11 ± 0.02 mL/min, respectively) and higher fractional excretion of sodium (FE(Na) ; 0.80 ± 0.07% vs 2.46 ± 0.20%, respectively). This was accompanied by decreased superoxide dismutase (SOD; 6.9 ± 1.7 vs 26.7 ± 2.7 U/g tissue) and catalase (CAT; 20.2 ± 8.8 vs 32.2 ± 8.7 K/g tissue) activity in the I/R group, as well as decreased levels of reduced glutathione (GSH; 21.7 ± 8.1 vs 81.2 ± 20.2 μmol/g tissue) and increased malondialdehyde levels (MDA; 1.2 to 0.1 vs 0.5 ± 0.2 μmol/100 mg), cyclo-oxygenase (COX)-2 expression and histological damage. In the rPeC group, renal histology and function were significantly improved (CCr 0.32 ± 0.02 mL/min; FE(Na) 1.33 ± 0.12%) compared with the I/R group. Furthermore, compared with the I/R group, the rPeC group exhibited increases in SOD and CAT activity (22.8 ± 3.8 U/g tissue and 21.7 ± 8.6 K/g tissue, respectively), increased GSH levels (74.0 ± 4.9) and decreased MDA levels (1.1 ± 0.3 μmol/100 mg) and COX-2 expression. In conclusion, rPeC appears to exert protective effects against renal IRI. This protection may be a consequence of reductions in lipid peroxidation, intensification of anti-oxidant systems and downregulation of COX-2 expression. A simple approach, rPeC may be a promising strategy for protection against IRI in clinical practice.
Collapse
Affiliation(s)
- Zahra Sedaghat
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | | | | | | |
Collapse
|
14
|
Protective Effects of Reducing Renal Ischemia-reperfusion Injury During Renal Hilar Clamping: Use of Allopurinol as a Nephroprotective Agent. Urology 2013; 81:210.e5-10. [DOI: 10.1016/j.urology.2012.08.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Revised: 07/09/2012] [Accepted: 08/08/2012] [Indexed: 12/25/2022]
|
15
|
Wang Z, Colli JL, Keel C, Bailey K, Grossman L, Majid D, Lee BR. First Prize: Isoprostane: Quantitation of Renal Ischemia and Reperfusion Injury After Renal Artery Clamping in an Animal Model. J Endourol 2012; 26:21-5. [DOI: 10.1089/end.2011.0188] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Zijun Wang
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Janet L. Colli
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Christopher Keel
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kayleen Bailey
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Leah Grossman
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Dewan Majid
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Benjamin R. Lee
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
| |
Collapse
|
16
|
Abstract
Oxidatively damaged DNA is implicated in various diseases, including neurodegenerative disorders, cancer, diabetes, cardiovascular and inflammatory diseases as well as aging. Several methods have been developed to detect oxidatively damaged DNA. They include chromatographic techniques, the Comet assay, (32)P-postlabelling and immunochemical methods that use antibodies to detect oxidized lesions. In this review, we discuss the detection of 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxodG), the most abundant oxidized nucleoside. This lesion is frequently used as a marker of exposure to oxidants, including environmental pollutants, as well as a potential marker of disease progression. We concentrate on studies published between the years 2000 and 2011 that used enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry to detect 8-oxodG in humans, laboratory animals and in cell lines. Oxidative damage observed in these organisms resulted from disease, exposure to environmental pollutants or from in vitro treatment with various chemical and physical factors.
Collapse
Affiliation(s)
- Pavel Rossner
- Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine AS CR, Videnska 1083, 142 20 Prague, Czech Republic.
| | | |
Collapse
|
17
|
Hosgood SA, Barlow AD, Yates PJ, Snoeijs MG, van Heurn EL, Nicholson ML. A Pilot Study Assessing the Feasibility of a Short Period of Normothermic Preservation in an Experimental Model of Non Heart Beating Donor Kidneys. J Surg Res 2011; 171:283-90. [DOI: 10.1016/j.jss.2010.01.027] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2009] [Revised: 12/14/2009] [Accepted: 01/14/2010] [Indexed: 12/30/2022]
|
18
|
Abstract
PURPOSE OF REVIEW Kidneys from marginal or donation after cardiac death (DCD) donors are particularly susceptible to injury during hypothermic preservation and may benefit from alternative methods of preservation. Normothermic preservation can be adapted to improve the quality of kidneys for transplantation by a variety of techniques. RECENT FINDINGS Extracorporeal membrane support to maintain circulation before cooling and organ retrieval has been used to improve the condition of DCD donor kidneys, with lower rates of delayed graft function (DGF) compared with standard retrieval conditions. Experimentally, normothermic perfusion has been used in conjunction with hypothermic techniques as a resuscitation technique to improve graft outcome. An ex-vivo porcine kidney model showed that energy levels could be replenished to improve tissue perfusion during reperfusion. This technique was translated into a porcine transplant model demonstrating that it was a feasible and safe method of preservation. SUMMARY Normothermic preservation techniques have the potential to be adapted into an improved method of retaining tissue viability compared with hypothermic techniques. Furthermore, they may be used as a device to enhance and assess the condition of the kidney which would be particularly beneficial for kidneys from DCD donors.
Collapse
|
19
|
Haylor JL, Harris KPG, Nicholson ML, Waller HL, Huang Q, Yang B. Atorvastatin improving renal ischemia reperfusion injury via direct inhibition of active caspase-3 in rats. Exp Biol Med (Maywood) 2011; 236:755-63. [DOI: 10.1258/ebm.2011.010350] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Caspase-3 is a key molecule involved in the inflammation and apoptosis of ischemia reperfusion (IR) injury. Statins are known to inhibit IR injury, but the mechanism of action remains uncertain. In the present study, the effect and underlying mechanism of ischemia alone, and reperfusion with or without atorvastatin (AT) as a timed intervention were examined, since clinically the kidney is only exposed to drug delivery during reperfusion. Male Sprague‐Dawley rats were subjected to 45‐min clamping of the left renal hilus followed by four hours reperfusion with a right nephrectomy. AT 10 mg/kg was intravenously administered after clamping the renal hilus, but prior to kidney reperfusion. Ischemia alone did cause tubulointerstitial damage (TID), protein carbonylation and caspase-3 activation with an increase in 12 kDa subunit, while reperfusion further enhanced TID, monocyte (ED-1+ cell) infiltration, apoptosis and necrosis together with caspase-3 activity and 17 kDa subunit, but reversed protein carbonylation. AT significantly reduced TID (26%), ED-1+ cell infiltration (74%), tubular apoptosis (47%) and necrosis (73%), and interstitial apoptosis (64%), as well as caspase-3 activity (26%), but did not change serum creatinine and cholesterol. Importantly, without affecting either caspase-3 active protein cleavage or S-nitrosylation, AT directly inhibited caspase-3 active enzyme in a dose-dependent manner in vitro. In conclusions, IR and AT exerted opposing effects on caspase-3 activity by differing mechanisms, with IR stimulating caspase-3 proteolytic cleavage and AT inhibiting active caspase-3 enzyme. This new inhibitory mechanism of AT may improve reperfusion tolerance in ischemic kidneys and benefit transplant recipients.
Collapse
Affiliation(s)
- John L Haylor
- Academic Nephrology Unit, University of Sheffield, Sheffield
| | - Kevin P G Harris
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Michael L Nicholson
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Helen L Waller
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Qiang Huang
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Bin Yang
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
- Department of Nephrology, University of Nantong, Nantong, Jiangsu, PR China
| |
Collapse
|
20
|
Hosgood SA, Mohamed IH, Nicholson ML. The two layer method does not improve the preservation of porcine kidneys. Med Sci Monit 2011; 17:BR27-33. [PMID: 21169904 PMCID: PMC3524674 DOI: 10.12659/msm.881326] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The Two layer method (TLM) has been extremely successful in the preservation of the pancreas. However, this has not been thoroughly investigated in other organs or in clinically relevant large animal models. The aim of this study was to assess the effects of TLM in a large animal model of kidney preservation. MATERIAL/METHODS Porcine kidneys were retrieved after 10 minutes of warm ischaemic injury and flushed with 300 ml UW solution at 4°C. Kidneys were then either placed in University of Wisconsin solution (UW) or TLM using pre-oxygenated perfluorodecalin and UW. Kidneys were stored for 18 hours at 4°C then reperfused with oxygenated autologous blood to assess renal function. RESULTS Renal blood flow (RBF) was significantly lower and intra-renal resistance (IRR) higher in TLM compared to UW group [Area under the curve (AUC) RBF, UW; 427±168 vs TLM; 247±55 ml/min/100g.h; P=0.041, AUC IRR, UW; 7.7±2.2 vs TLM; 10.5±1.9 ml/min/mmHg; P=0.041]. Levels of creatinine clearance (CrCl) were significantly lower in TLM group [AUC CrCl, UW; 1.8±1.0 vs TLM; 0.6±0.4 ml/min/100 g.h; P=0.034]. Levels of lipid peroxidation were significantly lower in TLM group [8-isoprostane/Cr ratio 3h; UW 3338±896 vs TLM 2072±886 pg/ml/mmol/L; P=0.04]. Levels of total nitric oxide were significantly higher in TLM group (P=0.009). CONCLUSIONS TLM did not improve the preservation condition of porcine kidneys. Furthermore, there appeared to be increased inflammation, endothelial injury and reduced renal function compared to preservation with UW. Further experimental work is needed to determine the role of PFC in kidney preservation.
Collapse
Affiliation(s)
- Sarah A Hosgood
- Department of Infection, Immunity and Inflammation, Transplant Group, University of Leicester, University Hospitals of Leicester, Leicester General Hospital, U.K
| | | | | |
Collapse
|
21
|
Hosgood SA, Bagul A, Nicholson ML. Minimising cold ischaemic injury in an experimental model of kidney transplantation. Eur J Clin Invest 2011; 41:233-40. [PMID: 20955220 DOI: 10.1111/j.1365-2362.2010.02396.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Cold ischaemic (CI) injury is associated with reduced renal graft function and survival. However, there is little evidence on the benefits of reducing CI injury within a 24 h period in donation after cardiac death (DCD) kidney transplantation. METHODS Porcine kidneys subjected to 10-min warm ischaemia were retrieved and flushed with hyperosmolar citrate (HOC) preservation solution at 4 °C. They were stored on ice for periods of 2, 6, 18 or 24 h (n = 6). Renal function and injury were assessed during 3 h of ex-vivo reperfusion with oxygenated autologous blood. RESULTS Area under the curve (AUC) serum creatinine (Cr) levels were significantly higher in the 18- and 24-h groups and creatinine clearance (CrCl) lower compared to the 2-h group (P = 0·001, 0·003). Urinary biomarkers of ischaemic damage (Endothelin-1, Total nitric oxide) and renal and tubular cell function significantly correlated with the duration of CI time (r = 0·726, 0·642; P ≤ 0·001). CONCLUSIONS This study demonstrated the progressive effects of CI injury in DCD porcine kidneys over a 24 h hypothermic storage period. This highlights the need to minimise the cold storage period to improve graft function in DCD kidney transplantation.
Collapse
Affiliation(s)
- Sarah A Hosgood
- Department of Infection, Immunity and Inflammation, Transplant Group, University of Leicester, Leicester General Hospital, LE5 4PW, UK.
| | | | | |
Collapse
|
22
|
A comparison of hypothermic machine perfusion versus static cold storage in an experimental model of renal ischemia reperfusion injury. Transplantation 2010; 89:830-7. [PMID: 20098357 DOI: 10.1097/tp.0b013e3181cfa1d2] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION There is increasing support for the use of hypothermic machine perfusion (HMP) in an attempt to reduce preservation injury. However, experimental evidence is needed to further examine the effects of HMP on renal ischemia reperfusion injury. METHODS Porcine kidneys were subjected to 10 min of warm ischemia followed by 18 hr of static cold storage with hyperosomolar citrate (HOC), histidine-tryptophan-ketoglutarate (HTK), or University of Wisconsin (UW) solutions or 18 hr HMP with Kidney Perfusion Solution using the Lifeport perfusion system. Renal function, oxidative damage, and morphology were assessed during 3 hr of reperfusion with autologous blood using an isolated organ perfusion system. RESULTS During reperfusion, intrarenal resistance was significantly lower in the HMP group compared with HOC and UW (area under the curve; HMP 3.8+/-1.7, HOC 9.1+/-4.3, UW 7.7+/-2.2, HTK 5.6+/-1.9 mm Hg/min; P=0.006), and creatinine clearance was significantly higher compared with the UW group (area under the curve creatinine clearance; HMP 9.8+/-7.3, HOC 2.2+/-1.7, UW 1.8+/-1.0, HTK 2.1+/-1.8 mL/min/100 g; P=0.004). Tubular function was significantly improved in the HMP group (P<0.05); however, levels of lipid peroxidation were significantly higher (P=0.005). CONCLUSION HMP demonstrated a reduced level of preservation injury compared with the static techniques resulting in improved renal and tubular function and less tubular cell inflammation during reperfusion.
Collapse
|
23
|
Hosgood SA, Nicholson ML. Hydrogen sulphide ameliorates ischaemia-reperfusion injury in an experimental model of non-heart-beating donor kidney transplantation. Br J Surg 2010; 97:202-9. [PMID: 20034052 DOI: 10.1002/bjs.6856] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND : Therapies to alleviate ischaemia-reperfusion (IR) injury have an important role in kidney transplantation. This study used a porcine model of non-heart-beating (NHB) donor kidneys to investigate the effects of hydrogen sulphide on IR injury. METHODS : Porcine kidneys were subjected to 25 min of warm ischaemia and 18 h of cold storage. They were reperfused ex vivo with autologous oxygenated blood to assess renal function. A group treated with hydrogen sulphide (0.5 mmol/l) infused 10 min before and after reperfusion (n = 6) was compared with an untreated control group (n = 7). RESULTS : Hydrogen sulphide significantly improved renal blood flow compared with control values (mean(s.d.) area under the curve (AUC) 614.9(165.5) versus 270.3(86.7) ml per min per 100 g.h; P = 0.001) and renal function (AUC creatinine: 1640(248) versus 2328(154) micromol/l.h; P = 0.001; AUC creatinine clearance: 6.94(5.03) versus 0.96(0.32) ml per min per 100 g.h; P = 0.004). Oxidative damage was also reduced by hydrogen sulphide (urinary 8-isoprostane at 1 h of reperfusion: 478.9(237.1) versus 1605.6(632.7) pg/ml per mmol/l creatinine; P = 0.032). CONCLUSION : Hydrogen sulphide ameliorated the renal dysfunction associated with ischaemic damage, and has potential as a therapy against IR injury in NHB donor kidney transplantation.
Collapse
Affiliation(s)
- S A Hosgood
- Department of Infection, Immunity and Inflammation, Transplant Group, University of Leicester, Leicester General Hospital, Leicester LE5 4PW, UK
| | | |
Collapse
|
24
|
Function and quality of kidneys after cold storage, machine perfusion, or retrograde oxygen persufflation: results from a porcine autotransplantation model. Cryobiology 2009; 59:19-23. [PMID: 19345683 DOI: 10.1016/j.cryobiol.2009.03.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2008] [Revised: 03/22/2009] [Accepted: 03/23/2009] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Especially for preservation of marginal donor organs, machine perfusion (MP) and retrograde oxygen persufflation (ROP) are alternatives to cold storage (CS). Using a porcine kidney autotransplantation model we compared metabolic and morphologic effects of CS, ROP, and MP on kidneys exposed to warm ischemia. METHODS Kidneys of 21 pigs were exposed in situ to warm ischemia for 60min. The kidneys were randomly allocated to three experimental groups, each receiving a 4-h treatment of either cold storage, machine perfusion, or retrograde oxygen persufflation. Tissue samples were examined for malondialdehyde and histological changes. Daily blood samples were examined for creatinine levels. RESULTS Seven days after transplantation, the plasma creatinine levels in the CS and MP groups were still significantly elevated above the baseline values. In the ROP group, all animals exhibited nearly normal creatinine levels. Malondialdehyde, an indicator of lipidperoxidation, was dramatically increased in the machine perfused kidneys on day 7, whereas the malondialdehyde levels in the other two groups were near normal values. The MP kidneys exhibited the most striking histological changes. CONCLUSION Though MP has been well introduced in organ transplantation, in our opinion, it must still be optimized and standardized. It is necessary to clarify questions such as whether there is a need for oxygenation during perfusion, the length of perfusion, the impact of pressure, and the effects of additional scavengers. The results of the present study suggest the reconsideration of the ROP-technique for the preservation of predamaged donor grafts especially of NHBD and further studies, comparing MP and ROP upon long term preservation are strongly encouraged.
Collapse
|
25
|
Mozaffarieh M, Grieshaber M, Orgül S, Flammer J. The Potential Value of Natural Antioxidative Treatment in Glaucoma. Surv Ophthalmol 2008; 53:479-505. [DOI: 10.1016/j.survophthal.2008.06.006] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
26
|
Hosgood SA, Bagul A, Kaushik M, Rimoldi J, Gadepalli RS, Nicholson ML. Application of nitric oxide and carbon monoxide in a model of renal preservation. Br J Surg 2008; 95:1060-7. [DOI: 10.1002/bjs.6174] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Abstract
Background
Nitric oxide and carbon monoxide exert vasodilatory effects that minimize ischaemia–reperfusion injury. An isolated porcine kidney model was used to assess the effects of administering the nitric oxide donor sodium nitroprusside (SNP) and carbon monoxide-releasing molecule (CORM) 3 during a period of warm preservation followed by reperfusion.
Methods
Kidneys were perfused under warm preservation conditions after 10 min of warm ischaemia and 16 h of cold storage in four groups: SNP, control, CORM-3 and inactive CORM-3 (inactive control). Renal function and viability were assessed.
Results
SNP and CORM-3 increased renal blood flow (RBF) during warm preservation (P = 0·014). After reperfusion, RBF was significantly improved in the CORM-3 group compared with the control group (P = 0·019). The reduction in creatinine clearance was significantly less in the CORM-3 group than in the inactive CORM-3 group (P = 0·021), and serum creatinine levels were significantly lower (P = 0·029). There was a negative correlation between RBF during warm preservation and functional parameters during reperfusion (creatinine concentration: rs = − 0·722, P < 0·001; sodium excretion: rs = − 0·912, P < 0·001).
Conclusion
The beneficial vasodilatory effects of CORM-3 during warm preservation improved renal function during reperfusion; SNP exerted similar, although less pronounced, effects.
Collapse
Affiliation(s)
- S A Hosgood
- Department of Transplant Surgery, University Hospitals of Leicester, Leicester, UK
| | - A Bagul
- Department of Transplant Surgery, University Hospitals of Leicester, Leicester, UK
| | - M Kaushik
- Department of Transplant Surgery, University Hospitals of Leicester, Leicester, UK
| | - J Rimoldi
- Department of Medicinal Chemistry, University of Mississippi, 331 Faser Hall, University, MS 38677, USA
| | - R S Gadepalli
- Department of Transplant Surgery, University Hospitals of Leicester, Leicester, UK
| | - M L Nicholson
- Department of Transplant Surgery, University Hospitals of Leicester, Leicester, UK
| |
Collapse
|
27
|
Iloprost Pretreatment Before Unilateral Nephrectomy: An Experimental Study in Rats. Asian J Surg 2008; 31:69-74. [DOI: 10.1016/s1015-9584(08)60061-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
|
28
|
Waller HL, Harper SJF, Hosgood SA, Bagul A, Kay MD, Kaushik M, Yang B, Bicknell GR, Nicholson ML. Differential expression of cytoprotective and apoptotic genes in an ischaemia-reperfusion isolated organ perfusion model of the transplanted kidney. Transpl Int 2007; 20:625-31. [PMID: 17639610 DOI: 10.1111/j.1432-2277.2007.00489.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The optimal kidney preservation system and methods to ameliorate reperfusion injury are major factors in accomplishing successful graft function following transplantation. Ischaemia and reperfusion lead to cellular stress and the adaptive response may include the activation of genes involved in cellular protection and/or cell death by apoptosis. We investigated the expression of cytoprotective heme oxygenase-1 (HO-1), anti-apoptotic Bcl-2 and pro-apoptotic Bax after 6 h isolated organ perfusion in porcine kidneys that had been given 10 and 40 min warm ischaemic time. The level of HO-1 was shown to be significantly higher in the 10-min warm ischaemic group compared with 40-min group (0.90 +/- 0.03 vs. 0.83 +/- 0.03; P = 0.002). The levels of HO-1 showed a significant positive correlated with parameters of renal function, creatinine clearance, and renal blood flow and urine output (AUC; r = 0.8042, P = 0.03; r = 0.6028, P = 0.04; r = 0.6055, P = 0.04), demonstrating a possible protective role of this gene in this model of renal transplantation.
Collapse
Affiliation(s)
- Helen L Waller
- Transplant Surgery Group, Department of Cardiovascular Sciences, Leicester General Hospital, Gwendolen Road, Leicester, UK.
| | | | | | | | | | | | | | | | | |
Collapse
|
29
|
Zhang F, Stott WT, Clark AJ, Schisler MR, Grundy JJ, Gollapudi BB, Bartels MJ. Quantitation of 8-hydroxydeoxyguanosine in DNA by liquid chromatography/positive atmospheric pressure photoionization tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2007; 21:3949-3955. [PMID: 17990277 DOI: 10.1002/rcm.3299] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
A methodology has been developed and validated for quantifying 8-hydroxydeoxyguanosine (8-OHdG) in both commercial DNA and DNA isolated from livers of male Sprague-Dawley rats by liquid chromatography/positive atmospheric pressure photoionization tandem mass spectrometry. The analytical method conditions, including conditions for stabilizing 8-OHdG during complex nuclease P1 enzymatic digestion, were also evaluated. The limit of detection for 8-OHdG was 1.0 ng/mL (17.6 fmol on-column), and the linearity of the calibration curve was greater than 0.998 from 1.0 to 500 ng/mL. The intraday assay precision relative standard deviation (RSD) value for quality control (QC) samples was < or =5.59% with accuracies ranging from 91.84 to 117.61%. The interday assay precision (RSD) value was < or =1.76% with accuracies ranging from 91.84 to 116.67%. This method, combined with the LC/UV analysis of deoxyguanosine (dG), was used for determination of the levels of 8-OHdG/10(6) dG in DNA nuclease P1 enzymatic hydrolysates from both commercial DNA and rat liver DNA.
Collapse
Affiliation(s)
- Fagen Zhang
- Toxicology and Environmental Research & Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, USA.
| | | | | | | | | | | | | |
Collapse
|