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1
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O'Brien Laramy M, Robinson J, Venkatramani CJ, Horn S, Steiner C, Son YJ. Drug Development Considerations for Additives to Organ Preservation Solutions. Transplantation 2025; 109:764-773. [PMID: 39375888 DOI: 10.1097/tp.0000000000005221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
The addition of a novel therapeutic agent to an organ preservation solution has the potential to address unmet needs in organ transplantation and enhance outcomes for transplant recipients. However, the development expectations for novel therapeutic agents in this context are unclear because of limited precedence and published regulatory guidance documents. To address these gaps, we have articulated a drug development strategy that leverages expectations for parenteral drug products administered via more conventional routes (eg, intravenous) and provided considerations for when deviations may be justified. We have supplemented this strategy with a comparison to available regulatory guidance from the US Food and Drug Administration to highlight potential areas for further clarification. The strategy articulated here is based on Genentech's internal experience for a program intended for use in kidney transplantation.
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Affiliation(s)
| | - Jamie Robinson
- Pharma Technical Regulatory, Genentech, Inc., South San Francisco, CA
| | - C J Venkatramani
- Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA
| | - Stephanie Horn
- Pharma Technical Regulatory-Device and Combination Products, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Carine Steiner
- Analytical Research & Development, Pharma Technical Development, F. Hoffmann-La Roche, Basel, Switzerland
| | - Yoen-Ju Son
- Pharma Technical Development Project and Portfolio Development, South San Francisco, CA
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2
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Huang J, Zhou Y, Li H, Du L, Chen Y, Hu Z, Miao Y. Preservation solution protects isolated hair micrografts by inhibiting apoptosis of hair bulb. Life Sci 2025; 361:123292. [PMID: 39643038 DOI: 10.1016/j.lfs.2024.123292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/26/2024] [Accepted: 12/01/2024] [Indexed: 12/09/2024]
Abstract
AIMS To investigate the effectiveness of histidine-tryptophan-ketoglutarate (HTK) solution compared to Ringer's (RS) solution for preserving isolated hair follicles (HFs), focusing on structural integrity, cell viability, apoptosis prevention, and identifying the mechanisms of cell death during the preservation period. MATERIALS AND METHODS Isolated human HFs were preserved in HTK or RS solution for periods ranging from 2 to 12 h. Morphological changes were assessed using H&E staining and transmission electron microscopy (TEM). Cell viability, proliferation, and apoptosis were evaluated through Ki-67/TUNEL staining, live/dead cell staining, and immunofluorescence. Quantitative real-time PCR and Western blot analysis were conducted to examine apoptosis-related gene expression, and qPCR array analyses were performed to determine the pathways involved in HF apoptosis. KEY FINDINGS HTK solution preserved the structure of HFs more effectively than RS, maintaining collagen organization, preventing intercellular edema, and sustaining cell membrane integrity. HFs preserved in HTK solution exhibited significantly higher viability and proliferation rates, with a reduced rate of apoptosis compared to RS. Gene expression profiling indicated that HTK group inhibited the activation of the TNF signaling pathway and mitochondrial dysfunction, which were associated with apoptosis in RS-preserved HFs. SIGNIFICANCE This study demonstrates that HTK solution is more effective than RS solution for HF preservation, particularly in extended storage settings required for large-scale hair transplantation. By inhibiting apoptosis pathways and preserving cellular integrity, HTK solution may enhance the success and outcomes of hair transplant procedures, providing insights into optimizing micrograft preservation and reducing ischemia-hypoxia injury in isolated HFs.
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Affiliation(s)
- Junfei Huang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Yi Zhou
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Haoyuan Li
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China
| | - Lijuan Du
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Yangpeng Chen
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
| | - Zhiqi Hu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China.
| | - Yong Miao
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China.
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Rössler F, Kümmerli C, Hügli S, Jonas JP, Hübel K, Oberkofler CE, Müller PC, de Rougemont O. Effect of donor pancreas extraction time on pancreas transplantation-a Swiss tertiary center experience. Clin Transplant 2023; 37:e14846. [PMID: 36322914 DOI: 10.1111/ctr.14846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022]
Abstract
We aimed to assess the effect of donor pancreas extraction time (ET) on postoperative complications and graft function after pancreas transplantation (PT). We analyzed all consecutive donor pancreas procurements for the simultaneous pancreas and kidney transplantation (SPK) and the associated PT in a Swiss transplant center over a 20-year period. Pancreas ET was defined as the time from cold flush to static storage of the pancreas on ice. The primary endpoint was the effect of extraction time on surgical complications. Secondary endpoints comprised the effect of ET on graft function (insulin-free survival) and graft pancreatitis. Of 115 procured pancreas grafts the median donor pancreas ET was 65 min (IQR: 48-78 min). In multivariable analysis, ET did not negatively affect major complications (OR 1.41 [95% CI: .59-3.36]; p = .438) and insulin-free survival (HR 1.42 [95% CI: .55-3.63]; p = .459). The median CIT was 522 (441-608) min. CIT was associated with major complications (OR 2.51 [95% CI: 1.11-5.68]; p = .027), but without impact on insulin-free survival (HR 1.94 [95% CI: .84-4.48]; p = .119). Patients with and without graft pancreatitis had no statistically significant differences in ET and CIT (p = .164 and p = .47, respectively). In multivariable analysis, Amylase levels > 270 U/L on postoperative day 1 were significantly associated with major complications (OR 3.61 [95% CI: 1.06-12.32]; p = .040). Our results suggest that although no effect of ET on complications and graft function after PT was found, shorter CIT and less graft pancreatitis can have a positive impact on surgical complications. Results could possibly be influenced by the exceptional quality of the pancreas donors, with short travel distances and preservation times in Switzerland.
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Affiliation(s)
- Fabian Rössler
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Christoph Kümmerli
- Clarunis, University Centre for Gastrointestinal and Liver Diseases, University Hospital Basel, Basel, Switzerland
| | - Sandro Hügli
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Jan P Jonas
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Kerstin Hübel
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Christian E Oberkofler
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.,Vivèvis AG - Visceral, Tumor And Robotic Surgery Clinic Hirslanden Zürich, Zürich, Switzerland
| | - Philip C Müller
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Olivier de Rougemont
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
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Malekhosseini SA, Ghasemi Y, Rousta J, Aghaei R, Kianpour S, Negahdaripour M, Heidari R, Shamsaeefar A, Gholami S, Nikeghbalian S. Clinical Evaluation of an HTK Solution for Liver Transplantation: A Phase 3 Randomized Pilot Clinical Trial Study. ARCHIVES OF IRANIAN MEDICINE 2022; 25:617-623. [PMID: 37543887 PMCID: PMC10685771 DOI: 10.34172/aim.2022.97] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 02/27/2022] [Indexed: 08/07/2023]
Abstract
BACKGROUND Organ preservation solutions are not easily accessible in Iran, similar to many resource-limited countries. We aimed to evaluate the efficacy of a locally-produced HTK solution among adult liver transplantation candidates in a pilot clinical trial study. METHODS Adult patients undergoing liver transplantation were randomly allocated into two groups. One received the HTK solution (PharMedCina Inc., Shiraz, Iran), and the second received the commercially available HTK solution (Custodiol ®). RESULTS Overall, 28 individuals entered the study, including 11 and 9 males (78.6% and 64.3%) in the Custodiol® and local HTK groups, respectively. Clinical characteristics, including postoperative biliary complications, reperfusion syndrome, infection and primary non-function (PNF) rates, amount of intraoperative bleeding, length of hospital and ICU stay, peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and duration of follow-up were similar between the two groups (P>0.05). One patient died in the locally-produced HTK group. The patient underwent re-transplantation 20 days after his first liver transplantation due to PNF. Two patients died in the Custodiol group, both due to PNF of the liver, which occurred five and three days after transplantation. The two groups did not show any difference regarding serum levels of AST, ALT, alkaline phosphatase (ALP), bilirubin, platelet count, prothrombin time and international normalized ratio, white blood cell count, blood urea nitrogen, and creatinine on the first postoperative day and on the day of discharge (P>0.05). CONCLUSION Based on the findings of this pilot study with the current sample size, no statistically significant difference was found between our locally-produced HTK solution and Custodiol® regarding clinical outcomes.
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Affiliation(s)
- Seyed Ali Malekhosseini
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Younes Ghasemi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Javad Rousta
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roghayyeh Aghaei
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sedigheh Kianpour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Manica Negahdaripour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Shamsaeefar
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Siavash Gholami
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
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Correlation of Different Serum Biomarkers with Prediction of Early Pancreatic Graft Dysfunction Following Simultaneous Pancreas and Kidney Transplantation. J Clin Med 2022; 11:jcm11092563. [PMID: 35566689 PMCID: PMC9103915 DOI: 10.3390/jcm11092563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 01/27/2023] Open
Abstract
Background: Despite recent advances and refinements in perioperative management of simultaneous pancreas−kidney transplantation (SPKT) early pancreatic graft dysfunction (ePGD) remains a critical problem with serious impairment of early and long-term graft function and outcome. Hence, we evaluated a panel of classical blood serum markers for their value in predicting early graft dysfunction in patients undergoing SPKT. Methods: From a prospectively collected database medical data of 105 patients undergoing SPKT between 1998 and 2018 at our center were retrospectively analyzed. The primary study outcome was the detection of occurrence of early pancreatic graft dysfunction (ePGD), the secondary study outcome was early renal graft dysfunction (eRGD) as well as all other outcome parameters associated with the graft function. In this context, ePGD was defined as pancreas graft-related complications including graft pancreatitis, pancreatic abscess/peritonitis, delayed graft function, graft thrombosis, bleeding, rejection and the consecutive need for re-laparotomy due to graft-related complications within 3 months. With regard to analyzing ePGD, serum levels of white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), pancreatic lipase as well as neutrophil−lymphocyte ratio (NLR) and platelet−lymphocyte ratio (PLR) were measured preoperatively and at postoperative days (POD) 1, 2, 3 and 5. Further, peak serum levels of CRP and lipase during the first 72 h were evaluated. Receiver operating characteristics (ROC) curves were performed to assess their predictive value for ePGD and eRGD. Cut-off levels were calculated with the Youden index. Significant diagnostic biochemical cut-offs as well as other prognostic clinical factors were tested in a multivariate logistic regression model. Results: Of the 105 patients included, 43 patients (41%) and 28 patients (27%) developed ePGD and eRGD following SPKT, respectively. The mean WBC, PCT, NLR, PLR, CRP and lipase levels were significantly higher on most PODs in the ePGD group compared to the non-ePGD group. ROC analysis indicated that peak lipase (AUC: 0.82) and peak CRP levels (AUC: 0.89) were highly predictive for ePGD after SPKT. The combination of both achieved the highest AUC (0.92; p < 0.01) in predicting ePGD. Concerning eRGD, predictive accuracy of all analyzed serological markers was moderate (all AUC < 0.8). Additionally, multivariable analysis identified previous dialysis/no preemptive transplantation (OR 2.4 (95% CI: 1.41−4.01), p = 0.021), donor age (OR 1.07 (95% CI: 1.03−1.14), p < 0.010), donor body mass index (OR 1.32 (95% CI: 1.01−1.072), p = 0.04), donors cerebrovascular cause of death (OR 7.8 (95% CI: 2.21−26.9), p < 0.010), donor length of ICU stay (OR 1.27 (95% CI: 1.08−1.49), p < 0.010), as well as CIT pancreas (OR 1.07 (95% CI: 1.03−1.14), p < 0.010) as clinical relevant prognostic predictors for ePGD. Further, a peak of lipase (OR 1.04 (95% CI: 1.02−1.07), p < 0.010), peak of CRP levels (OR 1.12 (95% CI: 1.02−1.23), p < 0.010), pancreatic serum lipase concentration on POD 2 > 150 IU/L (OR 2.9 (95% CI: 1.2−7.13), p = 0.021) and CRP levels of ≥ 180 ng/mL on POD 2 (OR 3.6 (95% CI: 1.54−8.34), p < 0.01) and CRP levels > 150 ng/mL on POD 3 (OR 4.5 (95% CI: 1.7−11.4), p < 0.01) were revealed as independent biochemical predictive variables for ePGD after transplantation. Conclusions: In the current study, the combination of peak lipase and CRP levels were highly effective in predicting early pancreatic graft dysfunction development following SPKT. In contrast, for early renal graft dysfunction the predictive value of this parameter was less sensitive. Intensified monitoring of these parameters may be helpful for identifying patients at a higher risk of pancreatic ischemia reperfusion injury and various IRI- associated postoperative complications leading to ePGD and thus deteriorated outcome.
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Boggi U, Vistoli F, Andres A, Arbogast HP, Badet L, Baronti W, Bartlett ST, Benedetti E, Branchereau J, Burke GW, Buron F, Caldara R, Cardillo M, Casanova D, Cipriani F, Cooper M, Cupisti A, Davide J, Drachenberg C, de Koning EJP, Ettorre GM, Fernandez Cruz L, Fridell JA, Friend PJ, Furian L, Gaber OA, Gruessner AC, Gruessner RW, Gunton JE, Han D, Iacopi S, Kauffmann EF, Kaufman D, Kenmochi T, Khambalia HA, Lai Q, Langer RM, Maffi P, Marselli L, Menichetti F, Miccoli M, Mittal S, Morelon E, Napoli N, Neri F, Oberholzer J, Odorico JS, Öllinger R, Oniscu G, Orlando G, Ortenzi M, Perosa M, Perrone VG, Pleass H, Redfield RR, Ricci C, Rigotti P, Paul Robertson R, Ross LF, Rossi M, Saudek F, Scalea JR, Schenker P, Secchi A, Socci C, Sousa Silva D, Squifflet JP, Stock PG, Stratta RJ, Terrenzio C, Uva P, Watson CJ, White SA, Marchetti P, Kandaswamy R, Berney T. First World Consensus Conference on pancreas transplantation: Part II - recommendations. Am J Transplant 2021; 21 Suppl 3:17-59. [PMID: 34245223 PMCID: PMC8518376 DOI: 10.1111/ajt.16750] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 02/07/2023]
Abstract
The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts' recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas-kidney transplantation (SPK) and pancreas transplantation alone can improve long-term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long-term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st-world-consensus-conference-of-pancreas-transplantation/246.
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Blundell J, Shahrestani S, Lendzion R, Pleass HJ, Hawthorne WJ. Risk Factors for Early Pancreatic Allograft Thrombosis Following Simultaneous Pancreas-Kidney Transplantation: A Systematic Review. Clin Appl Thromb Hemost 2021; 26:1076029620942589. [PMID: 33052066 PMCID: PMC7573738 DOI: 10.1177/1076029620942589] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Simultaneous pancreas-kidney (SPK) transplantation remains the most effective treatment for providing consistent and long-term euglycemia in patients having type 1 diabetes with renal failure. Thrombosis of the pancreatic vasculature continues to contribute significantly to early graft failure and loss. We compared the rate of thrombosis to graft loss and systematically reviewed risk factors impacting early thrombosis of the pancreas allograft following SPK transplantation. We searched the MEDLINE, EMBASE, The Cochrane Library, and PREMEDLINE databases for studies reporting thrombosis following pancreas transplantation. Identified publications were screened for inclusion and synthesized into a data extraction sheet. Sixty-three studies satisfied eligibility criteria: 39 cohort studies, 22 conference abstracts, and 2 meta-analyses. Newcastle-Ottawa Scale appraisal of included studies demonstrated cohort studies of low bias risk; 1127 thrombi were identified in 15 936 deceased donor, whole pancreas transplants, conferring a 7.07% overall thrombosis rate. Thrombosis resulted in pancreatic allograft loss in 83.3% of reported cases. This review has established significant associations between donor and recipient characteristics, procurement and preservation methodology, transplantation technique, postoperative management, and increased risk of early thrombosis in the pancreas allograft. Further studies examining the type of organ preservation fluid, prophylactic heparin protocol, and exocrine drainage method and early thrombosis should also be performed.
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Affiliation(s)
- Jian Blundell
- Sydney Medical School, University of Sydney, New South Wales, Australia
| | - Sara Shahrestani
- Sydney Medical School, University of Sydney, New South Wales, Australia.,Department of Surgery, University of Sydney at Westmead Hospital, New South Wales, Australia
| | - Rebecca Lendzion
- Department of Surgery, University of Sydney at Westmead Hospital, New South Wales, Australia
| | - Henry J Pleass
- Sydney Medical School, University of Sydney, New South Wales, Australia.,Department of Surgery, University of Sydney at Westmead Hospital, New South Wales, Australia
| | - Wayne J Hawthorne
- Sydney Medical School, University of Sydney, New South Wales, Australia.,Department of Surgery, University of Sydney at Westmead Hospital, New South Wales, Australia.,The Centre for Transplant & Renal Research, Westmead Institute for Medical Research, New South Wales, Australia
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Grzella S, Hinzmann J, Pillokeit N, Lengenfeld T, Vaihinger HM, Zgoura P, Westhoff TH, Viebahn R, Schenker P. Impact of Histidine-Tryptophan-Ketoglutarate Versus University of Wisconsin Solution on the Outcome of Pancreas Transplant With Cold Ischemic Time ≥12 Hours: A Retrospective Study. EXP CLIN TRANSPLANT 2021; 19:842-848. [PMID: 34142940 DOI: 10.6002/ect.2020.0544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Histidine-tryptophan-ketoglutarate and University of Wisconsin solutions are currently used for pancreas graft preservation. Our hypothesis was whether the use of histidine-tryptophan-ketoglutarate solution is associated with worse pancreas graft survival than University of Wisconsin solution, in general and after prolonged cold ischemic time of ≥12 hours. MATERIALS AND METHODS This retrospective study investigated the impact of static cold storage in histidine-tryptophan-ketoglutarate (n = 133) versus University of Wisconsin (n = 107) solution on outcomes of 240 pancreas transplant procedures. Patient and graft survival rates were compared after 1, 3, and 5 years in both groups. Serum lipase, amylase, and C-reactive protein levels and incidence of surgical complications were evaluated at postoperative week 1. A subgroup analysis of 96 grafts (52 with histidine-tryptophanketoglutarate/44 with University of Wisconsin) with pancreas graft cold ischemic time ≥12 hours was also performed. RESULTS At mean follow-up of 75.2 ± 9.9 months, both groups demonstrated comparable short- and long-term patient survival. Overall, pancreas graft survival was slightly better in the histidine-tryptophan-ketoglutarate group (Kaplan-Meier analysis, log-rank P = .013). However, the subgroup analysis of grafts with cold ischemic time ≥12 hours showed slightly better pancreatic graft survival in the University of Wisconsin group, although not significantly (log-rank P = .95). Serum lipase and C-reactive protein levels at postoperative week 1 were higher in the histidinetryptophan-ketoglutarate group. Surgical complications were comparable. Multivariable Cox regression analysis identified neither solution as a risk factor affecting patient and graft survival. CONCLUSIONS Although a direct comparison between histidine-tryptophan-ketoglutarate and University of Wisconsin showed better pancreas graft survival with histidine-tryptophan-ketoglutarate, the multivariable analysis showed that the perfusion solution does not significantly influence patient and graft survival. However, in the analysis of transplants with cold ischemic time ≥12 hours, pancreas graft survival was slightly better in the University of Wisconsin group, although not significantly.
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Affiliation(s)
- Sascha Grzella
- From the Department of Surgery, University Hospital Knappschaftskrankenhaus Bochum GmbH, Ruhr-University Bochum, Bochum, Germany
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Zhao L, Hu C, Han F, Chen D, Ma Y, Cai F, Chen J. Combination of mesenchymal stromal cells and machine perfusion is a novel strategy for organ preservation in solid organ transplantation. Cell Tissue Res 2021; 384:13-23. [PMID: 33439348 PMCID: PMC8016762 DOI: 10.1007/s00441-020-03406-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 12/15/2020] [Indexed: 12/22/2022]
Abstract
Organ preservation is a prerequisite for an urgent increase in the availability of organs for solid organ transplantation (SOT). An increasing amount of expanded criteria donor (ECD) organs are used clinically. Currently, the paradigm of organ preservation is shifting from simple reduction of cellular metabolic activity to maximal simulation of an ex vivo physiological microenvironment. An ideal organ preservation technique should not only preserve isolated organs but also offer the possibility of rehabilitation and evaluation of organ function prior to transplantation. Based on the fact that mesenchymal stromal cells (MSCs) possess strong regeneration properties, the combination of MSCs with machine perfusion (MP) is expected to be superior to conventional preservation methods. In recent years, several studies have attempted to use this strategy for SOT showing promising outcomes. With better organ function during ex vivo preservation and the potential of utilization of organs previously deemed untransplantable, this strategy is meaningful for patients with organ failure to help overcome organ shortage in the field of SOT.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Fei Han
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Dajin Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Yanhong Ma
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Fanghao Cai
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
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10
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Mohr A, Brockmann JG, Becker F. HTK-N: Modified Histidine-Tryptophan-Ketoglutarate Solution-A Promising New Tool in Solid Organ Preservation. Int J Mol Sci 2020; 21:ijms21186468. [PMID: 32899772 PMCID: PMC7555843 DOI: 10.3390/ijms21186468] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/20/2020] [Accepted: 09/02/2020] [Indexed: 01/26/2023] Open
Abstract
To ameliorate ischemia-induced graft injury, optimal organ preservation remains a critical hallmark event in solid organ transplantation. Although numerous preservation solutions are in use, they still have functional limitations. Here, we present a concise review of a modified Histidine-Tryptophan-Ketoglutarate (HTK) solution, named HTK-N. Its composition differs from standard HTK solution, carrying larger antioxidative capacity and providing inherent toxicity as well as improved tolerance to cold aiming to attenuate cold storage injury in organ transplantation. The amino acids glycine, alanine and arginine were supplemented, N-acetyl-histidine partially replaced histidine, and aspartate and lactobionate substituted chloride. Several in vitro studies confirmed the superiority of HTK-N in comparison to HTK, being tested in vivo in animal models for liver, kidney, pancreas, small bowel, heart and lung transplantation to adjust ingredients for required conditions, as well as to determine its innocuousness, applicability and potential advantages. HTK-N solution has proven to be advantageous especially in the preservation of liver and heart grafts in vivo and in vitro. Thus, ongoing clinical trials and further studies in large animal models and consequently in humans are inevitable to show its ability minimizing ischemia-induced graft injury in the sequel of organ transplantation.
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Messner F, Yu Y, Etra JW, Krendl FJ, Berchtold V, Bösmüller C, Brandacher G, Oberhuber R, Scheidl S, Maglione M, Öfner D, Schneeberger S, Margreiter C. Donor cardiac arrest and cardiopulmonary resuscitation: impact on outcomes after simultaneous pancreas-kidney transplantation - a retrospective study. Transpl Int 2020; 33:657-666. [PMID: 32027055 PMCID: PMC7318239 DOI: 10.1111/tri.13591] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 12/12/2019] [Accepted: 02/03/2020] [Indexed: 01/16/2023]
Abstract
Donor cardiac arrest and cardiopulmonary resuscitation (CACPR) has been considered critically because of concerns over hypoperfusion and mechanical trauma to the donor organs. We retrospectively analyzed 371 first simultaneous pancreas–kidney transplants performed at the Medical University of Innsbruck between 1997 and 2017. We evaluated short‐ and long‐term outcomes from recipients of organs from donors with and without a history of CACPR. A total of 63 recipients received a pancreas and kidney graft from a CACPR donor. At 1, and 5‐years, patient survival was similar with 98.3%, and 96.5% in the CACPR and 97.0%, and 90.2% in the non‐CACPR group (log rank P = 0.652). Death‐censored pancreas graft survival was superior in the CACPR group with 98.3%, and 91.4% compared to 86.3%, and 77.4% (log rank P = 0.028) in the non‐CACPR group, which remained statistically significant even after adjustment [aHR 0.49 (95% CI 0.24–0.98), P = 0.044]. Similar relative risks for postoperative complications Clavien Dindo > 3a, pancreatitis, abscess, immunologic complications, delayed pancreas graft function, and relative length of stay were observed for both groups. Donors with a history of CACPR are, in the current practice, safe for transplantation. Stringent donor selection and short CPR durations may allow for outcomes surpassing those of donors without CACPR.
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Affiliation(s)
- Franka Messner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Yifan Yu
- Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Joanna W Etra
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Felix J Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Valeria Berchtold
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Claudia Bösmüller
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Gerald Brandacher
- Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Scheidl
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
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Jing L, Yao L, Zhao M, Peng LP, Liu M. Organ preservation: from the past to the future. Acta Pharmacol Sin 2018; 39:845-857. [PMID: 29565040 DOI: 10.1038/aps.2017.182] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Accepted: 12/31/2017] [Indexed: 12/13/2022]
Abstract
Organ transplantation is the most effective therapy for patients with end-stage disease. Preservation solutions and techniques are crucial for donor organ quality, which is directly related to morbidity and survival after transplantation. Currently, static cold storage (SCS) is the standard method for organ preservation. However, preservation time with SCS is limited as prolonged cold storage increases the risk of early graft dysfunction that contributes to chronic complications. Furthermore, the growing demand for the use of marginal donor organs requires methods for organ assessment and repair. Machine perfusion has resurfaced and dominates current research on organ preservation. It is credited to its dynamic nature and physiological-like environment. The development of more sophisticated machine perfusion techniques and better perfusates may lead to organ repair/reconditioning. This review describes the history of organ preservation, summarizes the progresses that has been made to date, and discusses future directions for organ preservation.
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Hameed AM, Wong G, Laurence JM, Lam VWT, Pleass HC, Hawthorne WJ. A systematic review and meta-analysis of cold in situ perfusion and preservation for pancreas transplantation. HPB (Oxford) 2017; 19:933-943. [PMID: 28844527 DOI: 10.1016/j.hpb.2017.07.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 07/20/2017] [Accepted: 07/24/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND This study aimed to identify the most effective solution for in situ perfusion/preservation of the pancreas in donation after brain death donors, in addition to optimal in situ flush volume(s) and route(s) during pancreas procurement. METHODS Embase, Medline and Cochrane databases were utilized (1980-2017). Articles comparing graft outcomes between two or more different perfusion/preservation fluids (University of Wisconsin (UW), histidine-tryptophan-ketoglutarate (HTK) and/or Celsior) were compared using random effects models where appropriate. RESULTS Thirteen articles were included (939 transplants). Confidence in available evidence was low. A higher serum peak lipase (standardized mean difference 0.47, 95% CI 0.23-0.71, I2 = 0) was observed in pancreatic grafts perfused/preserved with HTK compared to UW, but there were no differences in one-month pancreas allograft survivals or early thrombotic graft loss rates. Similarly, there were no significant differences in the rates of graft pancreatitis, thrombosis and graft survival between UW and Celsior solutions, and between aortic-only and dual aorto-portal perfusion. CONCLUSION UW cold perfusion may reduce peak serum lipase, but no quality evidence suggested UW cold perfusion improves graft survival and reduces thrombosis rates. Further research is needed to establish longer-term graft outcomes, the comparative efficacy of Celsior, and ideal perfusion volumes.
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Affiliation(s)
- Ahmer M Hameed
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW, Australia; Department of Surgery, Westmead Hospital, Westmead, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Germaine Wong
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW, Australia; Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia; Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Jerome M Laurence
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Surgery, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Institute of Academic Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia
| | - Vincent W T Lam
- Department of Surgery, Westmead Hospital, Westmead, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Henry C Pleass
- Department of Surgery, Westmead Hospital, Westmead, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Surgery, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Wayne J Hawthorne
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW, Australia; Department of Surgery, Westmead Hospital, Westmead, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
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Pancreas Preservation With Viaspan, Celsior, and Custodiol Solutions: An Initial Experience. Transplant Proc 2016; 48:3040-3042. [PMID: 27932142 DOI: 10.1016/j.transproceed.2016.07.042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 07/27/2016] [Indexed: 11/20/2022]
Abstract
BACKGROUND There is still controversy about which preservation solution in pancreas transplantation could be the best. The aim of this study was to analyze our initial experience with Custodiol solution (CuS) compared with Viaspan solution (VS) and Celsior solution (CS) in pancreas transplantation. METHODS A retrospective study included 94 consecutive pancreatic transplants, from 2007 until 2015. We compared 3 groups, depending on preservation solution: Viaspan (n = 41), Celsior (n = 40), or Custodiol (n = 13). The primary end point was patient and pancreas survival at 1 year after pancreas transplantation. RESULTS The recipient and donor characteristics were similar except in cold ischemia time; it was higher with Celsior. No differences were found in postoperative complications and pancreas graft function at 3 months, 6 months, and 1 year (glucose, HbA1c, C-peptide, creatinine). The pancreas and patient survival at 1 year was comparable (pancreas survival: VS, 80%; CS, 90%; CuS, 92%; log-rank, 0.875; and patient survival: VS, 92%; CS, 97%; CuS, 100%; log-rank, 0.9). CONCLUSIONS In our institution, the Custodiol solution in pancreas transplantation presented similar outcomes in terms of postoperative complications, pancreas graft function, and 1-year survival.
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Evaluation of the modified HTK solution in pancreas transplantation—An experimental model. Asian J Surg 2016. [DOI: 10.1016/j.asjsur.2015.03.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Latchana N, Peck JR, Whitson BA, Henry ML, Elkhammas EA, Black SM. Preservation solutions used during abdominal transplantation: Current status and outcomes. World J Transplant 2015; 5:154-164. [PMID: 26722644 PMCID: PMC4689927 DOI: 10.5500/wjt.v5.i4.154] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/01/2015] [Accepted: 11/11/2015] [Indexed: 02/05/2023] Open
Abstract
Organ preservation remains an important contributing factor to graft and patient outcomes. During donor organ procurement and transportation, cellular injury is mitigated through the use of preservation solutions in conjunction with hypothermia. Various preservation solutions and protocols exist with widespread variability among transplant centers. In this review of abdominal organ preservation solutions, evolution of transplantation and graft preservation are discussed followed by classification of preservation solutions according to the composition of electrolytes, impermeants, buffers, antioxidants, and energy precursors. Lastly, pertinent clinical studies in the setting of hepatic, renal, pancreas, and intestinal transplantation are reviewed for patient and graft survival as well as financial considerations. In liver transplants there may be some benefit with the use of histidine-tryptophan-ketoglutarate (HTK) over University of Wisconsin solution in terms of biliary complications and potential cost savings. Renal grafts may experience increased initial graft dysfunction with the use of Euro-Collins thereby dissuading its use in support of HTK which can lead to substantial cost savings. University of Wisconsin solution and Celsior are favored in pancreas transplants given the concern for pancreatitis and graft thrombosis associated with HTK. No difference was observed with preservation solutions with respect to graft and patient survival in liver, renal, and pancreas transplants. Studies involving intestinal transplants are sparse but University of Wisconsin solution infused intraluminally in combination with an intra-vascular washout is a reasonable option until further evidence can be generated. Available literature can be used to ameliorate extensive variation across centers while potentially minimizing graft dysfunction and improving associated costs.
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Oberhuber R, Ritschl P, Fabritius C, Nguyen AV, Hermann M, Obrist P, Werner ER, Maglione M, Flörchinger B, Ebner S, Resch T, Pratschke J, Kotsch K. Treatment with tetrahydrobiopterin overcomes brain death-associated injury in a murine model of pancreas transplantation. Am J Transplant 2015; 15:2865-76. [PMID: 26104062 PMCID: PMC4744967 DOI: 10.1111/ajt.13364] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 04/05/2015] [Accepted: 04/23/2015] [Indexed: 02/06/2023]
Abstract
Brain death (BD) has been associated with an immunological priming of donor organs and is thought to exacerbate ischemia reperfusion injury (IRI). Recently, we showed that the essential nitric oxide synthase co-factor tetrahydrobiopterin (BH4) abrogates IRI following experimental pancreas transplantation. We therefore studied the effects of BD in a murine model of syngeneic pancreas transplantation and tested the therapeutic potential of BH4 treatment. Compared with sham-operated controls, donor BD resulted in intragraft inflammation reflected by induced IL-1ß, IL-6, VCAM-1, and P-selectin mRNA expression levels and impaired microcirculation after reperfusion (p < 0.05), whereas pretreatment of the BD donor with BH4 significantly improved microcirculation after reperfusion (p < 0.05). Moreover, BD had a devastating impact on cell viability, whereas BH4-treated grafts showed a significantly higher percentage of viable cells (p < 0.001). Early parenchymal damage in pancreatic grafts was significantly more pronounced in organs from BD donors than from sham or non-BD donors (p < 0.05), but BH4 pretreatment significantly ameliorated necrotic lesions in BD organs (p < 0.05). Pretreatment of the BD donor with BH4 resulted in significant recipient survival (p < 0.05). Our data provide novel insights into the impact of BD on pancreatic isografts, further demonstrating the potential of donor pretreatment strategies including BH4 for preventing BD-associated injury after transplantation.
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Affiliation(s)
- R Oberhuber
- Center for Operative Medicine, Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - P Ritschl
- Center for Operative Medicine, Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - C Fabritius
- Center for Operative Medicine, Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - A-V Nguyen
- Center for Operative Medicine, Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - M Hermann
- Department of Anaesthesiology and Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria
| | - P Obrist
- Department of Pathology, St. Vincent's Hospital, Zams, Innsbruck, Austria
| | - E R Werner
- Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
| | - M Maglione
- Center for Operative Medicine, Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - B Flörchinger
- Department of Cardiothoracic Surgery, Regensburg University Hospital, Regensburg, Germany
| | - S Ebner
- Center for Operative Medicine, Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - T Resch
- Center for Operative Medicine, Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - J Pratschke
- Department of Visceral, Abdominal and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany
| | - K Kotsch
- Center for Operative Medicine, Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
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Abstract
PURPOSE OF REVIEW Shortage of donor organs has increased consideration for use of historically excluded grafts. Ex-vivo machine perfusion is an emerging technology that holds the potential for organ resuscitation and reconditioning, potentially increasing the quality and number of organs available for transplantation. This article aims to review the recent advances in machine perfusion and organ preservation solutions. RECENT FINDINGS Flow and pressure-based machine perfusion has shown improved kidney graft function and survival, especially among expanded criteria donors. Pressure-based machine perfusion is demonstrating promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. August 2014 marked Food and Drug Administration approval of XPS XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA), a device for preserving and resuscitating lung allografts initially considered unsuitable for transplantation. Although there is no consensus among physicians about the optimal preservation solution, adding antiapoptotic and cell protective agents to preservation solutions is an interesting research area that offers potential to improve preservation. SUMMARY Ex-vivo machine perfusion of solid organs is a promising method that provides the opportunity for resuscitation and reconditioning of suboptimal grafts, expanding the number and quality of donor organs.
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Abstract
PURPOSE OF REVIEW To summarize the history of organ preservation and place into this context the current trends in preservation. RECENT FINDINGS Multiple large retrospective studies have analyzed cold preservation solutions in an attempt to determine superiority with largely negative results. Experimental and some clinical studies have examined machine perfusion of procured grafts, in both hypothermic and normothermic contexts with variable, but promising, results. Lastly, there are experimental efforts to evaluate mesenchymal stem cell therapy on rehabilitation of marginal donor organs. SUMMARY New trends in organ preservation may soon translate into more efficient use of the limited donor pool.
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Cardini B, Watschinger K, Hermann M, Obrist P, Oberhuber R, Brandacher G, Chuaiphichai S, Channon KM, Pratschke J, Maglione M, Werner ER. Crucial role for neuronal nitric oxide synthase in early microcirculatory derangement and recipient survival following murine pancreas transplantation. PLoS One 2014; 9:e112570. [PMID: 25389974 PMCID: PMC4229216 DOI: 10.1371/journal.pone.0112570] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Accepted: 10/08/2014] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Aim of this study was to identify the nitric oxide synthase (NOS) isoform involved in early microcirculatory derangements following solid organ transplantation. BACKGROUND Tetrahydrobiopterin donor treatment has been shown to specifically attenuate these derangements following pancreas transplantation, and tetrahydrobiopterin-mediated protective effects to rely on its NOS-cofactor activity, rather than on its antioxidant capacity. However, the NOS-isoform mainly involved in this process has still to be defined. METHODS Using a murine pancreas transplantation model, grafts lacking one of the three NOS-isoforms were compared to grafts from wild-type controls. Donors were treated with either tetrahydrobiopterin or remained untreated. All grafts were subjected to 16 h cold ischemia time and transplanted into wild-type recipients. Following 4 h graft reperfusion, microcirculation was analysed by confocal intravital fluorescence microscopy. Recipient survival was monitored for 50 days. RESULTS Transplantation of the pancreas from untreated wild-type donor mice resulted in microcirculatory damage of the transplanted graft and no recipient survived more than 72 h. Transplanting grafts from untreated donor mice lacking either endothelial or inducible NOS led to similar outcomes. In contrast, donor treatment with tetrahydrobiopterin prevented microcirculatory breakdown enabling long-term survival. Sole exception was transplantation of grafts from untreated donor mice lacking neuronal NOS. It resulted in intact microvascular structure and long-term recipient survival, either if donor mice were untreated or treated with tetrahydrobiopterin. CONCLUSION We demonstrate for the first time the crucial involvement of neuronal NOS in early microcirculatory derangements following solid organ transplantation. In this model, protective effects of tetrahydrobiopterin are mediated by targeting this isoform.
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Affiliation(s)
- Benno Cardini
- Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
- Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
| | - Katrin Watschinger
- Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
| | - Martin Hermann
- Department of Anaesthesiology and Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria
| | - Peter Obrist
- Institute of Pathology, St. Vinzenz Krankenhaus, Zams, Austria
| | - Rupert Oberhuber
- Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Gerald Brandacher
- Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Surawee Chuaiphichai
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Keith M. Channon
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Johann Pratschke
- Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Manuel Maglione
- Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Ernst R. Werner
- Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
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Preservation solutions for static cold storage of abdominal allografts: which is best? Curr Opin Organ Transplant 2014; 19:100-7. [PMID: 24553501 DOI: 10.1097/mot.0000000000000063] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW To update the reader on the recent literature in liver, kidney, pancreas, and intestine static cold preservation, and to identify which solutions are most advantageous for each organ. RECENT FINDINGS The comparison of randomized trials of histidine-tryptophan-ketoglutarate (HTK), Celsior, and University of Wisconsin solutions has shown equivalent risk of delayed graft function after kidney transplantation. Similar outcomes have been observed after pancreas preservation with University of Wisconsin, HTK, and Celsior solution. In live-donor liver transplantation, University of Wisconsin and HTK solution have shown equivalent results, whereas in the recent trials of deceased-donor liver transplantation, University of Wisconsin, HTK, and Celsior solutions have shown equivalence. Contrary to the most clinical trials, national registry data in kidney, pancreas, and liver transplantation demonstrate more detrimental effects and earlier graft loss after preservation with HTK versus University of Wisconsin solution. Early outcomes after intestinal transplantation with University of Wisconsin or HTK solution have shown no significant difference and animal studies indicate intraluminal preservation may be beneficial. SUMMARY The University of Wisconsin solution is the standard criterion static cold preservation for the procurement of liver, kidney, pancreas, and intestine. University of Wisconsin, HTK, and Celsior solutions all provide similar allograft outcomes in most clinical trials, but subtle differences have become more apparent in the recent studies and registry reports.
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Voigt MR, DeLario GT. Perspectives on abdominal organ preservation solutions: a comparative literature review. Prog Transplant 2014; 23:383-91. [PMID: 24311404 DOI: 10.7182/pit2013100] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Various preservation solutions are used for kidney, liver, pancreas, small intestine, and multiorgan recoveries and transplants. The effectiveness of these solutions, primarily measured by ability to preserve the organ and graft survival, was analyzed. The 2 most common solutions used for intra-abdominal organs are University of Wisconsin Solution (UW)/Viaspan and Histidine-tryptophan-ketoglutarate (HTK)/Custodiol solution. Outcomes for liver, pancreas, and kidney allografts preserved with these 2 solutions are similar. Although HTK solution shows conflicting results with respect to pancreatic cellular edema, researchers in several studies have noted that HTK solution may be more protective than UW solution against biliary complications in liver transplant. In kidney recoveries, HTK solution may be associated with higher graft loss and increased delayed graft function in marginal deceased donors but had lower incidence of delayed graft function in living donors when compared with UW. UW remains the reference standard for use during multiorgan recoveries but is experiencing strong competition from HTK and other alternative solutions. Some researchers suggest that Celsior's comparable results in abdominal organs and viability for thoracic organs makes it a strong competitor, especially in multiorgan recoveries. Each solution has benefits accompanied by disadvantages. Although it may not be feasible, when considering single-organ recoveries, consideration of alternative solutions may be warranted.
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Current state of pancreas preservation and implications for DCD pancreas transplantation. Transplantation 2013; 95:1419-24. [PMID: 23579769 DOI: 10.1097/tp.0b013e318285558f] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
One of the main factors limiting potential uptake of pancreas transplantation, particularly in the United Kingdom, is the shortage of grafts. There has therefore been a recent expansion, particularly in the United Kingdom, in the utilization of grafts from donation after cardiac death (DCD) donors. These grafts are subjected to a greater ischemic insult and are arguably at higher risk of poor functional outcome. Although conventional preservation techniques may be adequate for donation after brain death (DBD) and low-risk DCD pancreases, as the number of DCD pancreas transplants increase and the threshold for rejecting organs decreases, the importance of optimal preservation techniques is going to increase. Over recent years, there have been significant advances in preservation techniques for DCD kidneys, improving the outcome of these marginal grafts. However, the use of such techniques for pancreas preservation is extremely limited and mainly historical. This overview describes the background and results of the established method of pancreas preservation for DBD, namely, cold static storage, and describes the use of the two-layer method. It also reviews pulsatile machine perfusion and normothermic perfusion for pancreas preservation techniques, which have shown promise in the preservation of DCD kidney grafts. The use of these techniques in pancreas preservation is predominantly historical but warrants reevaluation as to the feasibility of applying these techniques to DCD pancreas grafts not only for preservation but also for viability assessment. Further areas for development of pancreas preservation are discussed.
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Donor risk factors, retrieval technique, preservation and ischemia/reperfusion injury in pancreas transplantation. Curr Opin Organ Transplant 2013; 18:83-8. [PMID: 23254698 DOI: 10.1097/mot.0b013e32835c29ef] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Pancreas transplantation is still hampered by a high incidence of early graft loss, and organ quality concerns result in high nonrecovery/discard rates. Demographic donor characteristics, surgical retrieval strategy, preservation fluid and ischemia time are crucial factors in the process of organ selection and are discussed in this review. RECENT FINDINGS The donor shortage is driving an increasing utilization of nonideal organs which would previously have been identified as unsuitable. Recent literature suggests that organs from extended criteria donors - older (>45 years), BMI >30 kg/m(2), and donation after cardiac death (DCD) - can achieve the same graft and patient survival as those from standard criteria donors, with the proviso that the accumulation of risk factors and long ischemic times should be avoided. Visual assessment of the pancreas is advisable before declining/accepting a pancreas. University of Wisconsin represents the gold standard solution; however, histidine-tryptophan-ketoglutarate and Celsior result in equal outcomes if cold ischemia time (CIT) is less than 12 h. Currently in pancreas transplantation, there is no proven effective ischemia/reperfusion injury prophylaxis than trying to keep CIT as short as possible. SUMMARY Demographic risk factors, inspection of the pancreas by an experienced surgeon and predicted CIT are crucial factors in deciding whether to accept a pancreas for transplantation. However, there is a need for an improved evidence base to determine where to set the 'cut-off' for unsuitable pancreatic grafts.
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Patel SR, Hakim N. Prevention and management of graft thrombosis in pancreatic transplant. EXP CLIN TRANSPLANT 2013; 10:282-9. [PMID: 22631067 DOI: 10.6002/ect.2012.0003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Pancreatic transplant effectively cures type 1 diabetes mellitus and maintains consistent long-term euglycemia. However, technical failure, and in particular graft thrombosis, accounts for the vast majority of transplants lost in the early postoperative period. The pancreas' inherently low microvascular flow state makes it vulnerable to vascular complications, as does the hypercoagulable blood of diabetic patients. Ultimately, the phenomenon is most definitely multifactorial. Prevention, as opposed to treatment, is key and should focus on reducing these multiple risk factors. This will involve tactical donor selection, optimal surgical technique and some form of anticoagulation. Close monitoring and early intervention will be crucial when treating thrombosis once preventative methods have failed. This may be achieved by further anticoagulation, graft salvage, or pancreatectomy with retransplant. This article will explore the multiple factors contributing to graft thrombus formation and the ways in which they may be addressed to firstly prevent, or more likely, reduce thrombosis. Secondly, we will consider the management strategies which can be implemented once thrombosis has occurred.
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Affiliation(s)
- Shaneel R Patel
- The West London Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
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Paushter DH, Qi M, Danielson KK, Harvat TA, Kinzer K, Barbaro B, Patel S, Hassan SZ, Oberholzer J, Wang Y. Histidine-tryptophan-ketoglutarate and University of Wisconsin solution demonstrate equal effectiveness in the preservation of human pancreata intended for islet isolation: a large-scale, single-center experience. Cell Transplant 2012; 22:1113-21. [PMID: 23031661 DOI: 10.3727/096368912x657332] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
We previously reported a small-scale study on the efficacy of histidine-tryptophan-ketoglutarate (HTK) solution versus University of Wisconsin (UW) solution on pancreas preservation for islet isolation. In this large-scale, retrospective analysis (n = 252), we extend our initial description of the impact of HTK on islet isolation outcomes and include pancreatic digestion efficacy, purification outcomes, and islet size distribution. Multivariable linear regression analysis, adjusted for donor age, sex, BMI, cold ischemia time, and enzyme, demonstrated similar results for the HTK group (n = 95) and the UW group (n = 157), including postpurification islet yields (HTK: 289,702 IEQ vs. UW: 283,036 IEQ; p = 0.76), percentage of digested pancreatic tissue (HTK: 66.9% vs. UW: 64.1%; p = 0.18), and islet loss from postdigestion to postpurification (HTK: 24,972 IEQ vs. UW: 39,551 IEQ; p = 0.38). Changes in islet size between the postdigestion and postpurification stages were comparable within each islet size category for HTK and UW (p = 0.14-0.99). Tissue volume distribution across purification fractions and islet purity in the top fractions were similar between the groups; however, the HTK group had significantly higher islet purity in the middle fractions (p = 0.003-0.008). Islet viability and stimulation indices were also similar between the HTK and the UW groups. In addition, we analyzed a small sample of patients transplanted either with HTK (n = 7) or UW (n = 8) preserved islets and found no significant differences in posttransplant HbA1c, β-score, and frequency of insulin independence. This study demonstrates that HTK and UW solutions offer comparable pancreas preservation for islet transplantation. More in vivo islet outcome data are needed for a complete analysis of the effects of HTK on islet transplantation.
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Affiliation(s)
- Daniel H Paushter
- Department of Transplant/Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA
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Review of Randomized Clinical Trials of Donor Management and Organ Preservation in Deceased Donors. Transplantation 2012; 94:425-41. [DOI: 10.1097/tp.0b013e3182547537] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Caballero-Corbalán J, Brandhorst H, Malm H, Felldin M, Foss A, Salmela K, Tibell A, Tufveson G, Korsgren O, Brandhorst D. Using HTK for Prolonged Pancreas Preservation Prior to Human Islet Isolation. J Surg Res 2012; 175:163-8. [DOI: 10.1016/j.jss.2011.03.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Revised: 02/22/2011] [Accepted: 03/03/2011] [Indexed: 10/18/2022]
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Dragu A, Taeger CD, Buchholz R, Sommerfeld B, Hübner H, Birkholz T, Kleinmann JA, Münch F, Horch RE, Präbst K. Online oxygen measurements in ex vivo perfused muscle tissue in a porcine model using dynamic quenching methods. Arch Orthop Trauma Surg 2012; 132:655-61. [PMID: 22246464 DOI: 10.1007/s00402-011-1458-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Indexed: 02/09/2023]
Abstract
INTRODUCTION Transplantation of autologous free tissue flaps is the best applicable technique for treating large and complex tissue defects and still has one major failure criterion. Tissue--and in particular muscle tissue--is strongly sensitive to ischemia, thus after a critical period of oxygen depletion the risk of a partial or total flap loss is high. MATERIALS AND METHODS For that reason a miniaturized ex vivo perfusion system has been developed, that supplies the tissue during operational delays. The purpose of this study was to determine the oxygenation levels during such a perfusion using different perfusates and therefore to objectify if a complementary oxygenation unit is required to improve perfusion quality. The oxygen levels of the tissue, as well of the perfusate, were measured by using minimal invasive optical oxygen sensors that are based on dynamic quenching. The ex vivo perfused tissue was the porcine rectus abdominis muscle. RESULTS Results show, that during perfusion with heparinized crystalloid fluid (Jonosteril) and heparinized autologous whole blood, additional oxygenation of the perfusion reactor led to different ex vivo oxygen tissue saturations, which can be detected by dynamic quenching. CONCLUSION Dynamic quenching methods are a promising and valuable technique to perform online oxygen measurements in ex vivo perfused muscle tissue in a porcine model.
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Affiliation(s)
- Adrian Dragu
- Department of Plastic and Hand Surgery, Friedrich-Alexander-University of Erlangen-Nürnberg, University Hospital, Krankenhausstrasse 12, 91054 Erlangen, Germany.
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Circulating AST, H-FABP, and NGAL are Early and Accurate Biomarkers of Graft Injury and Dysfunction in a Preclinical Model of Kidney Transplantation. Ann Surg 2011; 254:784-91; discussion 791-2. [DOI: 10.1097/sla.0b013e3182368fa7] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Squifflet JP, LeDinh H, de Roover A, Meurisse M. Pancreas Preservation for Pancreas and Islet Transplantation: A Minireview. Transplant Proc 2011; 43:3398-401. [DOI: 10.1016/j.transproceed.2011.09.052] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Maglione M, Oberhuber R, Cardini B, Watschinger K, Hermann M, Obrist P, Hengster P, Mark W, Schneeberger S, Werner-Felmayer G, Pratschke J, Margreiter R, Werner ER, Brandacher G. Donor pretreatment with tetrahydrobiopterin saves pancreatic isografts from ischemia reperfusion injury in a mouse model. Am J Transplant 2010; 10:2231-40. [PMID: 20883557 PMCID: PMC3249459 DOI: 10.1111/j.1600-6143.2010.03262.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Depletion of the nitric oxide synthase cofactor tetrahydrobiopterin (H4B) during ischemia and reperfusion is associated with severe graft pancreatitis. Since clinically feasible approaches to prevent ischemia reperfusion injury (IRI) by H4B-substitution are missing we investigated its therapeutic potential in a murine pancreas transplantation model using different treatment regimens. Grafts were subjected to 16 h cold ischemia time (CIT) and different treatment regimens: no treatment, 160 μM H4B to perfusion solution, H4B 50 mg/kg prior to reperfusion and H4B 50 mg/kg before recovery of organs. Nontransplanted animals served as controls. Recipient survival and endocrine graft function were assessed. Graft microcirculation was analyzed 2 h after reperfusion by intravital fluorescence microscopy. Parenchymal damage was assessed by histology and nitrotyrosine immunohistochemistry, H4B tissue levels by high pressure liquid chromatography (HPLC). Compared to nontransplanted controls prolonged CIT resulted in significant microcirculatory deterioration. Different efficacy according to route and timing of administration could be observed. Only donor pretreatment with H4B resulted in almost completely abrogated IRI-related damage showing graft microcirculation comparable to nontransplanted controls and restored intragraft H4B levels, resulting in significant reduction of parenchymal damage (p < 0.002) and improved survival and endocrine function (p = 0.0002 each). H4B donor pretreatment abrogates ischemia-induced parenchymal damage and represents a promising strategy to prevent IRI following pancreas transplantation.
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Affiliation(s)
- M Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Center of Operative Medicine, Innsbruck Medical University, Austria.
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Cytomegalovirus Mismatch as Major Risk Factor for Delayed Graft Function After Pancreas Transplantation. Transplantation 2010; 90:666-71. [DOI: 10.1097/tp.0b013e3181ea67a1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Fridell JA, Mangus RS, Powelson JA. Histidine-tryptophan-ketoglutarate for pancreas allograft preservation: the Indiana University experience. Am J Transplant 2010; 10:1284-9. [PMID: 20353471 DOI: 10.1111/j.1600-6143.2010.03095.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Histidine-tryptophan-ketoglutarate solution (HTK) has been scrutinized for use in pancreas transplantation. A recent case series and a United Network for Organ Sharing data base review have suggested an increased incidence of allograft pancreatitis and graft loss with HTK compared to the University of Wisconsin solution (UW). Conversely, a recent randomized, controlled study failed to show any significant difference between HTK and UW for pancreas allograft preservation. This study was a retrospective review of all pancreas transplants performed at Indiana University between 2003 and 2009 comparing preservation with HTK or UW. Data included recipient and donor demographics, 7-day, 90-day and 1-year graft survival, peak 30-day serum amylase and lipase, HbA1c and C-peptide levels. Of the 308 pancreas transplants, 84% used HTK and 16% UW. There were more SPK compared to pancreas after kidney and pancreas transplant alone in the HTK group. Donor and recipient demographics were similar. There was no significant difference in 7-day, 90-day or 1-year graft survival, 30-day peak serum amylase and lipase, HbA1c or C-peptide. No clinically significant difference between HTK and UW for pancreas allograft preservation was identified. Specifically, in the context of low-to-moderate flush volume and short cold ischemia time (<or=10 h), no increased incidence of allograft pancreatitis or graft loss was observed.
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Affiliation(s)
- J A Fridell
- The Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
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Margreiter C, Mark W, Wiedemann D, Sucher R, Öllinger R, Bösmüller C, Freund M, Maier HT, Greiner A, Fritsch H, Pratschke J, Margreiter R, Aigner F. Pancreatic graft survival despite partial vascular graft thrombosis due to splenocephalic anastomoses. Am J Transplant 2010; 10:846-851. [PMID: 20420640 DOI: 10.1111/j.1600-6143.2010.03060.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Thrombotic complications following pancreas transplantation are still the most common cause of nonimmunologic graft loss. The aim of this study was to analyze pancreatic graft function after partial arterial graft thrombosis and the investigation of the pancreatic arterial anatomy with regard to intraparenchymal anastomoses. We retrospectively analyzed the data for 175 consecutive pancreas transplants performed between January 2002 and October 2007. Selective Y-graft angiography was performed in 10 and rubber-milk injection in 5 fresh pancreas specimens. Thrombosis of one leg of the Y-graft was diagnosed in 18 (10.3%) patients. Only one of these patients with thrombosis of the splenic artery required exogenous insulin. Sufficient graft perfusion was demonstrated in all of the remaining grafts. One graft was lost due to acute rejection. In all specimens angiography showed an excellent perfusion of the pancreaticoduodenal arcade, even after selective cannulation of the splenic artery. Arterial collaterals between the gastroduodenal, splenic artery and the superior mesenteric artery were demonstrated. Our results demonstrate that global perfusion of the pancreatic graft and sufficient graft function is sustained after the thrombotic occlusion of one branch of the Y-graft by a complex system of intraparenchymal anastomoses. These anatomical findings may have consequences for resection strategies in pancreas surgery.
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Affiliation(s)
- C Margreiter
- Department of Visceral, Transplant and Thoracic Surgery
| | - W Mark
- Department of Visceral, Transplant and Thoracic Surgery
| | | | - R Sucher
- Department of Visceral, Transplant and Thoracic Surgery
| | - R Öllinger
- Department of Visceral, Transplant and Thoracic Surgery
| | - C Bösmüller
- Department of Visceral, Transplant and Thoracic Surgery
| | - M Freund
- Department of Diagnostic Radiology
| | - H T Maier
- Department of Visceral, Transplant and Thoracic Surgery
| | | | - H Fritsch
- Department of Anatomy, Histology and Embryology, Division of Clinical and Functional Anatomy, Innsbruck Medical University, Innsbruck, Austria
| | - J Pratschke
- Department of Visceral, Transplant and Thoracic Surgery
| | - R Margreiter
- Department of Visceral, Transplant and Thoracic Surgery
| | - F Aigner
- Department of Visceral, Transplant and Thoracic Surgery
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Current world literature. Curr Opin Organ Transplant 2010; 15:254-61. [PMID: 20351662 DOI: 10.1097/mot.0b013e328337a8db] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
PURPOSE OF REVIEW The history of transplantation of the pancreas, unlike that of transplantation of other abdominal organs, has largely been shaped by the associated surgical complications. After more than three decades of progress, surgical-technical pancreas graft failure rates have decreased to approximately 8%. The most recent developments in this area are systematically reviewed in this article. RECENT FINDINGS Vascular graft thrombosis remains, by far, the most common cause of technical graft failure. Recent reports suggested that pancreas preservation with histidine-tryptophan-ketoglutarate solution (HTK) might be a risk factor for reperfusion pancreatitis, graft thrombosis and decreased short- and long-term graft survival. It remains unclear whether these results are, at least in part, related to HTK flush volumes and extended preservation (e.g.,>12 h). For selected thrombosed pancreas grafts, there has been renewed interest in pharmacological, interventional, and surgical salvage. For selected recipients with early pancreas graft thrombosis not amenable to a salvage intervention, transplant pancreatectomy in conjunction with immediate retransplantation has emerged as a viable option. For graft thrombosis prevention, the enhanced backtable pancreas vascular reconstruction techniques (e.g., gastroduodenal artery revascularization) proposed by some authors await more formal study. For prevention of native vascular complications in high-risk recipients, several technical modifications have been reported. Developments with respect to other surgical complications (wound infection, pancreatitis, leak, and bleeding) have been more incremental. CONCLUSION Recent evidence underscores the importance of judicious donor and recipient selection and of optimization of preservation and surgical factors for excellent short- and long-term pancreas transplant outcomes.
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Abstract
PURPOSE OF REVIEW The goal of pancreas transplantation is to restore normoglycemia in patients with labile diabetes. The results of this procedure improved over the years, but, although pancreas transplantation is not considered experimental anymore, there is often reluctance to recommend this procedure because of the complexity, especially for solitary pancreas transplants. This article reviews the current status of pancreas transplantation. RECENT FINDINGS Many improvements have been made in the surgical techniques and immunosuppressive regimens. The overall rate of technical problems decreased, yet immunologic graft loss is still a problem in solitary pancreas transplants. Careful donor selection significantly decreased the risk of graft failure and therefore improved patient survival. SUMMARY With modern immunosuppressive protocols and careful donor selection, patient survival rates and pancreas transplant graft function can be further improved in all three pancreas transplant categories.
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Kondo Y, Ishitsuka Y, Kadowaki D, Nagatome M, Saisho Y, Kuroda M, Hirata S, Irikura M, Hamasaki N, Irie T. Phosphoenolpyruvic Acid, an Intermediate of Glycolysis, Attenuates Cellular Injury Induced by Hydrogen Peroxide and 2-Deoxy-D-glucose in the Porcine Proximal Kidney Tubular Cell Line, LLC-PK1. ACTA ACUST UNITED AC 2010. [DOI: 10.1248/jhs.56.727] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yuki Kondo
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Yoichi Ishitsuka
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Daisuke Kadowaki
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
- Center for Clinical Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kumamoto University
| | - Minako Nagatome
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Yusuke Saisho
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Masataka Kuroda
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Sumio Hirata
- Center for Clinical Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kumamoto University
| | - Mitsuru Irikura
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Naotaka Hamasaki
- Department of Clinical Chemistry and Laboratory Medicine, Nagasaki International University
| | - Tetsumi Irie
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
- Center for Clinical Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kumamoto University
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Ridgway D, Manas D, Shaw J, White S. Preservation of the donor pancreas for whole pancreas and islet transplantation. Clin Transplant 2010; 24:1-19. [DOI: 10.1111/j.1399-0012.2009.01151.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Worku D, Laluf S, McGee J, Goswami M, VanMeter K, Slakey DP. P-selectin expression in cold preserved kidneys in University of Wisconsin and histidine-tryptophan-ketoglutarate solutions. J Surg Res 2009; 169:125-31. [PMID: 20036384 DOI: 10.1016/j.jss.2009.09.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Revised: 08/15/2009] [Accepted: 09/09/2009] [Indexed: 01/08/2023]
Abstract
The differences and efficacy of standard preservation solutions in kidney transplantation, University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK), remain a topic of debate in recent clinical studies. P-selectins represent glycoproteins expressed on endothelial cells and platelets responsible for the earliest events in ischemia/reperfusion injury in kidney transplantation. This study aimed to compare the levels of P-selectin expression between cold preserved kidney tissues in UW and HTK solutions. Thirty kidneys were procured from male Lewis rats and stored in cold (4°C) solutions for periods of 4, 12, 16, 20, and 24h. Group 1 (n=15) kidneys were stored in UW solutions, and group 2 (n=15) kidneys were submerged in HTK solutions. At the end of each time point, the kidneys underwent preparation and levels of P-selectin expression in the tissues were measured using Immunoblot analyses and adjusted volumetric quantification of Western blot signals. For all periods of cold preservation, P-selectin expression was significantly down-regulated in kidney tissues stored in UW compared with HTK solutions (P<0.001). In summary, UW demonstrated a significant benefit over HTK solution in down-regulating P-selectin expression in cold preserved kidney grafts.
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Affiliation(s)
- Dawit Worku
- Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
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