The Impact of Cold Ischaemia Time on Outcomes of Living Donor Kidney Transplantation in the UK Living Kidney Sharing Scheme.

OBJECTIVE: To assess the impact of CIT on living donor kidney transplantation (LDKT) outcomes in the UKLKSS versus outside the scheme. BACKGROUND: LDKT provides the best treatment option for end-stage kidney disease patients. end-stage kidney disease patients with an incompatible living donor still have an opportunity to be transplanted through Kidney Exchange Programmes (KEP). In KEPs where kidneys travel rather than donors, cold ischaemia time (CIT) can be prolonged. METHODS: Data from all UK adult LDKT between 2007 and 2018 were analysed. RESULTS: 9969 LDKT were performed during this period, of which 1396 (14%) were transplanted through the UKLKSS, which we refer to as KEP. Median CIT was significantly different for KEP versus non-KEP (339 versus 182 minutes, P < 0.001). KEP LDKT had a higher incidence of delayed graft function (DGF) (2.91% versus 5.73%, P < 0.0001), lower 1-year (estimated Glomerular Filtration Rate (eGFR) 57.90 versus 55.25 ml/min, P = 0.04) and 5-year graft function (eGFR 55.62 versus 53.09 ml/min, P = 0.01) compared to the non-KEP group, but 1- and 5-year graft survival were similar. Within KEP, a prolonged CIT was associated with more DGF (3.47% versus 1.95%, P = 0.03), and lower graft function at 1 and 5-years (eGFR = 55 vs 50 ml/min, P = 0.02), but had no impact on graft survival. CONCLUSION: Whilst CIT was longer in KEP, associated with more DGF and lower graft function, excellent 5-year graft survival similar to non-KEP was found.

Heterogeneity of Human Pancreatic Islet Isolation Around Europe: Results of a Survey Study.

BACKGROUND: Europe is currently the most active region in the field of pancreatic islet transplantation, and many of the leading groups are actually achieving similar good outcomes. Further collaborative advances in the field require the standardization of islet cell product isolation processes, and this work aimed to identify differences in the human pancreatic islet isolation processes within European countries. METHODS: A web-based questionnaire about critical steps, including donor selection, pancreas processing, pancreas perfusion and digestion, islet counting and culture, islet quality evaluation, microbiological evaluation, and release criteria of the product, was completed by isolation facilities participating at the Ninth International European Pancreas and Islet Transplant Association (EPITA) Workshop on Islet-Beta Cell Replacement in Milan. RESULTS: Eleven islet isolation facilities completed the questionnaire. The facilities reported 445 and 53 islet isolations per year over the last 3 years from deceased organ donors and pancreatectomized patients, respectively. This activity resulted in 120 and 40 infusions per year in allograft and autograft recipients, respectively. Differences among facilities emerged in donor selection (age, cold ischemia time, intensive care unit length, amylase concentration), pancreas procurement, isolation procedures (brand and concentration of collagenase, additive, maximum acceptable digestion time), quality evaluation, and release criteria for transplantation (glucose-stimulated insulin secretion tests, islet numbers, and purity). Moreover, even when a high concordance about the relevance of one parameter was evident, thresholds for the acceptance were different among facilities. CONCLUSIONS: The result highlighted the presence of a heterogeneity in the islet cell product process and product release criteria.

Implementing local cooling to increase skin tolerance to ischemia during normal seating in people with spinal cord injury.

The purpose of this study was to investigate the effectiveness of local cooling in reducing reactive hyperemia after ischemia at the ischial tuberosities for people with spinal cord injury (SCI) during normal seating. The degree of the reactive hyperemic response is indicative of the extent of cellular stress caused by the ischemia. We hypothesized that reactive hyperemic skin blood flow (SBF) responses will be lower when local cooling is implemented by the wheelchair seat cushion. This study used a repeated measures design, and each subject underwent two conditions: normal seating with temperature control 'on' (cooling) and 'off' (non-cooling) for 30 min. Twenty-three participants with traumatic SCI were recruited. SBF and skin temperature were collected before, during and after seating. SBF signals were processed with short-time Fourier analyses to examine the underlying vascular control mechanisms, including the following (corresponding frequency bands): metabolic (0.0095-0.02 Hz), neurogenic (0.02-0.05 Hz), and myogenic (0.05-0.15 Hz) spectral densities. Our results showed that with cooling, skin temperature decreased (range -0.4 ~ -3.1 °C, p = 0.002), and reactive hyperemia parameters (normalized peak SBF and perfusion area) were reduced (p = 0.02, p = 0.033, respectively). In addition, changes in normalized peak SBF (non-cooling - cooling) was moderately correlated with changes in normalized metabolic and neurogenic spectral densities. Our findings suggested that local cooling has a positive effect on reducing the cellular stress caused by ischemia during normal seating. Metabolic and neurogenic SBF control mechanisms may play a minor role. Further exploration of the effect of temperature control on pressure injury prevention is warranted.

A systematic review and meta-analysis of cold in situ perfusion and preservation of the hepatic allograft: Working toward a unified approach.

The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes. The aim of this study was to determine whether there is evidence to substantiate a preference for a particular perfusion route (aortic or dual) or perfusion/preservation solution in donation after brain death (DBD) liver transplantation. The Embase, MEDLINE, and Cochrane databases were used (1980-2017). Random effects modeling was used to estimate effects on transplantation outcomes based on (1) aortic or dual in situ perfusion and (2) the use of University of Wisconsin (UW), histidine tryptophan ketoglutarate (HTK), Celsior, and/or Institut Georges Lopez-1 (IGL-1) solutions for perfusion/preservation. A total of 22 articles were included (2294 liver transplants). The quality of evidence ranged from very low to moderate Grading of Recommendations, Assessment, Development and Evaluations score. Meta-analyses were conducted for 14 eligible studies. Although there was no difference in the primary nonfunction (PNF) rate, a higher peak alanine aminotransferase (ALT) was recorded in dual compared with aortic-only UW-perfused livers (standardized mean difference, 0.24; 95% confidence interval, 0.01-0.47); a back-table portal venous flush was undertaken in the majority of aortic-only perfused livers. There were no relevant differences in peak enzymes, PNF, thrombotic graft loss, biliary complications, or 1-year graft survival in comparisons between dual-perfused livers using UW, HTK, Celsior, or IGL-1. In conclusion, there is no significant evidence that aortic-only perfusion of the DBD liver compromises transplantation outcomes, and it may be favored because of its simplicity. However, there is currently insufficient evidence to advocate for the use of any particular perfusion/preservation fluid over the others. Liver Transplantation 23 1615-1627 2017 AASLD.

Application of the statistical process control method for prospective patient safety monitoring during the learning phase: robotic kidney transplantation with regional hypothermia (IDEAL phase 2a-b).

BACKGROUND: Traditional evaluation of the learning curve (LC) of an operation has been retrospective. Furthermore, LC analysis does not permit patient safety monitoring. OBJECTIVES: To prospectively monitor patient safety during the learning phase of robotic kidney transplantation (RKT) and determine when it could be considered learned using the techniques of statistical process control (SPC). DESIGN, SETTING AND PARTICIPANTS: From January through May 2013, 41 patients with end-stage renal disease underwent RKT with regional hypothermia at one of two tertiary referral centers adopting RKT. Transplant recipients were classified into three groups based on the robotic training and kidney transplant experience of the surgeons: group 1, robot trained with limited kidney transplant experience (n=7); group 2, robot trained and kidney transplant experienced (n=20); and group 3, kidney transplant experienced with limited robot training (n=14). INTERVENTION: We employed prospective monitoring using SPC techniques, including cumulative summation (CUSUM) and Shewhart control charts, to perform LC analysis and patient safety monitoring, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes assessed included post-transplant graft function and measures of surgical process (anastomotic and ischemic times). CUSUM and Shewhart control charts are time trend analytic techniques that allow comparative assessment of outcomes following a new intervention (RKT) relative to those achieved with established techniques (open kidney transplant; target value) in a prospective fashion. RESULTS AND LIMITATIONS: CUSUM analysis revealed an initial learning phase for group 3, whereas groups 1 and 2 had no to minimal learning time. The learning phase for group 3 varied depending on the parameter assessed. Shewhart control charts demonstrated no compromise in functional outcomes for groups 1 and 2. Graft function was compromised in one patient in group 3 (p<0.05) secondary to reasons unrelated to RKT. In multivariable analysis, robot training was significantly associated with improved task-completion times (p<0.01). Graft function was not adversely affected by either the lack of robotic training (p=0.22) or kidney transplant experience (p=0.72). CONCLUSIONS: The LC and patient safety of a new surgical technique can be assessed prospectively using CUSUM and Shewhart control chart analytic techniques. These methods allow determination of the duration of mentorship and identification of adverse events in a timely manner. A new operation can be considered learned when outcomes achieved with the new intervention are at par with outcomes following established techniques. PATIENT SUMMARY: Statistical process control techniques allowed for robust, objective, and prospective monitoring of robotic kidney transplantation and can similarly be applied to other new interventions during the introduction and adoption phase.

Robotic partial nephrectomy with cold ischemia and on-clamp tumor extraction: recapitulating the open approach.

We describe a reproducible technique for achieving cold ischemia with intraoperative tumor assessment during robotic partial nephrectomy (RPN) that recapitulates the open approach: intracorporeal cooling and extraction (ICE). A total of seven patients underwent the ICE modification of RPN by transperitoneal (n=5) and retroperitoneal (n=2) approaches. A Gelpoint access port was used for the camera and assistant ports. Following hilar clamping, ice slush was introduced through the Gelpoint via syringes and applied over the kidney surface. The excised tumor was immediately extracted through the Gelpoint, allowing gross margin assessment by pathology during the renorrhaphy. RPN was achieved in all cases with successful introduction of ice slush and tumor extraction while on clamp. Median RENAL nephrometry score was 8 (range: 6-10), and there was one solitary kidney. Mean cold ischemia time was 19.6 min (range: 8-37) and mean estimated blood loss was 296.4 ml (range: 50-1000). Renal parenchymal temperatures <16°C were achieved within 7 min of cold ischemia and there was no drop in core body temperature >0.5°C during any procedures. Intraoperative assessment of the excised tumor showed adequate gross margins in all cases and final pathology confirmed negative surgical margins.

The challenge and importance of standardizing pre-analytical variables in surgical pathology specimens for clinical care and translational research.

The introduction of targeted cancer therapies into clinical practice, in which patients are selected for novel treatments based on results of companion molecular testing of their tumor specimens, has created significant new challenges for the surgical pathology laboratory. These include standardization of tissue handling and sample preparation with accurate documentation to ensure optimal quality of clinical samples to reduce the risk of errors in molecular biology tests. The assay of tumor tissues for biomarkers that can provide predictive data for prognosis or treatment should enable selection of the most appropriate therapies (Yaziji et al. 2008, Hicks and Kulkarni 2008). Major advances have been made in the ability to profile clinical samples for research at the DNA, RNA and protein levels. To translate this new information into the clinical setting, however, the quality of the starting material, in this case the tumor tissue, determines the accuracy and reliability of companion diagnostic assay results and therefore optimal therapeutic strategies. Inaccurate results owing to compromised tissue quality can lead to false positive or false negative results with therapeutic consequences that can harm patients and affect their eventual outcome.

Determination of renal hypothermic temperature adequacy for renoprotection during ischemia using renal interstitial glycerol concentrations in a porcine model.

OBJECTIVES: To determine the effect of renal cooling on interstitial glycerol concentration during renal ischemia. The rate of cellular release of glycerol into the interstitial fluid at various hypothermic temperatures during ischemia was used to assess adequacy for renoprotection at those temperatures. METHODS: Twenty-four renal units in 12 pigs underwent ischemia during measurement of renal interstitial fluid glycerol concentration. Kidneys were categorized into a body temperature control group or various hypothermic temperature groups (n = 4): 5°, 10°, 15°, 20°, and 25°. RESULTS: The glycerol concentration of all kidneys increased directly with ischemic time. The rate of increase in glycerol concentrations over ischemic time decreased sequentially as renal temperature decreased. The glycerol concentration of the kidneys cooled to 25°C during ischemia was significantly less (P = .03) relative to the glycerol levels obtained from the kidneys subjected to warm ischemia at 120 minutes. CONCLUSIONS: Renal hypothermia decreases the rate of cellular release of glycerol into the interstitial fluid. Hypothermia at 25°C doubles the time required for renal interstitial glycerol to accumulate to levels associated with irreparable renal function damage. Therefore, relatively warmer hypothermic temperatures may be sufficient to extend a significant renoprotective effect during ischemia.

Report of the Paris consensus meeting on expanded criteria donors in liver transplantation.

Because of organ shortage and a constant imbalance between available organs and candidates for liver transplantation, expanded criteria donors are needed. Experience shows that there are wide variations in the definitions, selection criteria, and use of expanded criteria donors according to different geographic areas and different centers. Overall, selection criteria for donors have tended to be relaxed in recent years. Consensus recommendations are needed. This article reports the conclusions of a consensus meeting held in Paris in March 2007 with the contribution of experts from Europe, the United States, and Asia. Definitions of expanded criteria donors with respect to donor variables (including age, liver function tests, steatosis, infections, malignancies, and heart-beating versus non-heart-beating, among others) are proposed. It is emphasized that donor quality represents a continuum of risk rather than "good or bad." A distinction is made between donor factors that generate increased risk of graft failure and factors independent of graft function, such as transmissible infectious disease or donor-derived malignancy, that may preclude a good outcome. Updated data concerning the risks associated with different donor variables in different recipient populations are given. Recommendations on how to safely expand donor selection criteria are proposed.

Kinetics of PME/Pi in pig kidneys during cold ischemia.

Quality assessment of renal grafts via (31)P magnetic resonance spectroscopy (MRS) has been investigated since 1986. As ATP concentrations decay rapidly during cold ischemia, the ratio of phosphomonoesters (PME) to inorganic phosphate (Pi(O)) within the organ (PME/Pi(O)) is commonly used as a quality marker and is considered to be the most reliable parameter. MRS did not lead to any delay in the transplantation procedure since it was performed during the time necessary for immunological matching (cross-match). Differences in the time period until transplantation call for extrapolation of the measured ratio to the end of cold ischemia before correlating with graft performance after transplantation. Therefore, quantitative determination of PME/Pi(O) kinetics is essential. As a model for metabolite decay in human renal grafts, pig kidneys obtained from a slaughterhouse were monitored for up to 80 h via (31)P MRS at 2 T. By employing chemical shift imaging (CSI) with a spatial resolution of approximately 1 x 1 x 4 cm(3), it was possible to reduce partial volume effects significantly. The improved spectral resolution gained through CSI enabled reliable PME/Pi(O) ratios to be determined only from those voxels containing renal tissue. Spectra were fitted automatically using the magnetic resonance user interface (MRUI), with prior knowledge obtained from unlocalized spectra when necessary. A monoexponential time dependence of PME/Pi(O) for histidine-tryptophane-alpha-ketoglutarate (HTK)-perfused kidneys during cold ischemia was observed, and the determined value of the decay constant alpha was 0.0099 +/- 0.0012 h(-1). In University of Wisconsin solution (UW)-perfused kidneys, an alpha of 0.0183 +/- 0.0053 h(-1) was determined. Determination of the decay constant enables a usable extrapolation of PME/Pi(O) for quality assessment of UW perfusion and a reliable extrapolation for HTK-perfused human renal grafts.