Presence of Cytotoxic Extracellular Histones in Machine Perfusate of Donation After Circulatory Death Kidneys.

BACKGROUND: Extracellular histones are cytotoxic molecules that are related to cell stress and death. They have been shown to play a crucial role in multiple pathophysiologic processes like sepsis, inflammation, vascular dysfunction, and thrombosis. Their role in organ donation and graft function and survival is still unknown. The aim of this study was to assess whether an association exists between the presence of extracellular histones in machine perfusates and deceased donor kidney viability. METHODS: Machine perfusates of 390 donations after circulatory death kidneys were analyzed for histone concentration, and corresponding graft function and survival were assessed. RESULTS: Extracellular histone concentrations were significantly higher in perfusates of kidneys with posttransplant graft dysfunction (primary nonfunction and delayed graft function) and were an independent risk factor for delayed graft function (odds ratio, 2.152; 95% confidence interval [95% CI], 1.199-3.863) and 1 year graft failure (hazard ratio, 1.386; 95% CI, 1.037-1.853), but not for primary nonfunction (odds ratio, 1.342; 95% CI, 0.900-2.002). One year graft survival was 12% higher in the group with low histone concentrations (P = 0.008) as compared with the group that contained higher histone concentrations. CONCLUSIONS: This study warrants future studies to probe for a possible role of cytotoxic extracellular histones in organ viability and suggests that quantitation of extracellular histones might contribute to assessment of posttransplant graft function and survival.

Measurement of renovascular circulating volume during hypothermic organ perfusion.

BACKGROUND: Kidney donation after cardiac death leads to vascular damage as a result of warm ischemia, affecting renovascular circulating volume. Novel ultrasound dilution techniques may be used to measure renovascular circulating volumes during hypothermic machine perfusion of donor kidneys. METHODS: Renovascular circulating volumes of machine-perfused porcine kidneys were repeatedly measured by ultrasound dilution at different perfusion pressures (30, 40, 50, and 60 mm Hg), durations of perfusion (1 and 24 hr), and warm ischemia times (15 and 45 min). Validity of ultrasound dilution was assessed by comparing volume changes after clamping of renal artery branches. RESULTS: Repeatability of ultrasound dilution measurements of renovascular circulating volumes was good (mean coefficient of variation, 7.6%). Renovascular circulating volumes significantly increased with higher perfusion pressures, remained constant over time, and significantly decreased with longer warm ischemia times. Changes in ultrasound dilution measurements after renal artery branch clamping did not correlate with changes in actual perfused volumes. CONCLUSIONS: Ultrasound dilution is a reproducible method to assess renovascular circulating volumes in machine-perfused kidneys, which is susceptible to changes in warm ischemia times. Future studies should evaluate the value of renovascular volume in pretransplantation kidney viability testing.

Improvements in kidney transplantation from donors after cardiac death.

To reduce the growing waiting list for kidney transplantation, we explored the limits of kidney transplantation from donors after cardiac death by liberally accepting marginal donor kidneys for transplantation. As the percentage of primary non-function (PNF) increased, we evaluated our transplantation program and implemented changes to reduce the high percentage of PNF in 2005, followed by a second evaluation over the period 2006-2009. Recipients of a kidney from a donor after cardiac death between 1998 and 2005 were analyzed, with PNF as outcome measure. During the period 2002-2005, the percentage of PNF increased and crossed the upper control limits of 12% which was considered as unacceptably high. After implementation of changes, this percentage was reduced to 5%, without changing the number of kidney transplantations from donors after cardiac death. Continuous monitoring of the quality of care is essential as the boundaries of organ donation and transplantation are sought. Meticulous donor, preservation, and recipient management make extension of the donor potential possible, with good results for the individual recipient. Liberal use of kidneys from donors after cardiac death may contribute to a reduction in the waiting list for kidney transplantation and dialysis associated mortality.

Machine perfusion viability testing.

PURPOSE OF REVIEW: Pretransplant assessment of kidney graft viability may help clinicians to decide whether to accept or discard a kidney for transplantation. With the increasing demand for donor kidneys and the increased use of marginal kidneys, the need of viability markers has increased to pursue superior transplant outcomes. Hypothermic machine perfusion (HMP) provides the theoretical opportunity to assess the viability of donor kidneys. We discuss the novel developments in viability testing during HMP and address the future prospects. RECENT FINDINGS: HMP viability testing has focused on the analysis of machine perfusion parameters and perfusate biomarkers. Renal resistance and the biomarkers lactate dehydrogenase, aspartate transaminase, glutathione-S-transferase, N-acetyl-ß-D-glucosaminidase, heart-type fatty acid binding protein, lipid peroxidation products, redox-active iron and IL-18 are correlated with transplant outcome in terms of development of delayed graft function or graft survival. However, they all lack adequate predictive value for transplant outcome. New techniques including contrast-enhanced ultrasound, three-dimensional ultrasound and magnetic resonance spectrometry are promising methods to test kidney viability during HMP, but their value has to be established. The introduction of normothermic machine perfusion offers other promising opportunities for viability testing. SUMMARY: Machine perfusion characteristics and perfusate biomarkers have been extensively studied. They often correlate with the transplant outcome, but the present viability tests are not reliable predictors of transplant outcome. New developments in kidney graft viability assessment are necessary to have a chance of being clinically useful in the future.

The value of machine perfusion biomarker concentration in DCD kidney transplantations.

BACKGROUND: Donation after cardiac death (DCD) increases the number of donor kidneys but is associated with more primary nonfunction (PNF) and delayed graft function (DGF). It has been suggested that biomarkers in the preservation solution of machine perfused kidneys may predict PNF, although evidence is lacking. METHODS: We analyzed the diagnostic accuracy of the perfusate biomarkers glutathione S-transferase, lactate dehydrogenase (LDH), heart-type fatty acid binding protein, redox-active iron, interleukin (IL)-18, and neutrophil gelatinase-associated lipocalin to predict PNF and DGF in 335 DCD kidneys preserved by hypothermic machine perfusion at our center between 1 January 1997 and 1 January 2008. The diagnostic accuracy of these biomarkers to predict PNF was evaluated with the area under the receiver operating characteristics curves. Additionally, the risk of DGF and graft failure was assessed. RESULTS: LDH and IL-18 concentrations were associated with PNF (odds ratio [95% confidence interval], 1.001 [1.000-1.002]; P=0.005 and 1.001 [1.000-1.002]; P=0.003, respectively) in a multivariate analysis; the diagnostic accuracy for PNF was "poor" for all biomarkers but increased to "fair" for redox-active iron and IL-18 in a multivariate analysis (area under the receiver operating characteristics curves, 0.701 and 0.700, respectively). LDH and IL-18 concentrations were associated with DGF; biomarker concentration was not associated with 1-year graft survival. CONCLUSIONS: The diagnostic accuracy of the perfusate biomarkers glutathione S-transferase, LDH, heart-type fatty acid binding protein, redox-active iron, IL-18, and neutrophil gelatinase-associated lipocalin to predict viability of DCD kidneys varies from "poor" to "fair". Therefore, DCD kidneys should not be discarded because of high biomarker perfusate concentration.

Preservation techniques for donors after cardiac death kidneys.

PURPOSE OF REVIEW: The purpose of the present review is to describe the techniques currently used to preserve kidneys from donors after cardiac death. RECENT FINDINGS: Automated chest compression devices may be used to improve organ perfusion between cardiac death and preservation measures. Normothermic extracorporeal membrane oxygenation reduces warm ischemic injury and has the ability to improve organ viability in donors after cardiac death. SUMMARY: Kidneys from donors after cardiac death expand the donor pool but are inevitably subjected to a period of warm ischemia. Reduction of warm ischemic injury to the organs improves transplant outcome. To reduce this injury in organs from donors after cardiac death, different preservation techniques are used. Automated chest compression devices improve organ perfusion between cardiac death and the start of organ preservation. In-situ preservation with double-balloon triple-lumen catheter is an easy technique to preserve organs in uncontrolled donors and is used in many centers to cool and flush the organs. In controlled donors, organs can also be flushed after laparotomy and direct cannulation of the aorta. Extracorporeal membrane oxygenation reduces warm ischemic injury and the use of normothermic perfusion seems promising. Optimal preservation is essential to improve the viability of kidneys from donors after cardiac death, to fully utilize this large donor pool.

DCD kidney transplantation: results and measures to improve outcome.

PURPOSE OF REVIEW: The purpose of the present review is to describe the current kidney preservation techniques for donors after cardiac death and to give insight in new developments that may reduce warm ischemia times and therefore improve graft function after transplantation. RECENT FINDINGS: There is still a general reluctance to use donors after cardiac death for kidney donation and transplantation, because of a relatively high incidence of delayed graft function and primary nonfunction compared to conventional donors after brain death. New clinically applicable methods, such as automated chest compression devices and extracorporeal membrane oxygenation, may reduce warm ischemia time. SUMMARY: Kidneys from donors after cardiac death sustain an increased incidence of delayed graft function and primary nonfunction. However, transplanted kidneys that do not experience these complications survive as long as conventional kidneys from donors after brain death. Maintaining adequate organ perfusion after cardiac death by using automated chest compression devices and extracorporeal membrane oxygenation reduces warm ischemia time. Optimal organ preservation and careful selection of kidneys from donors after cardiac death may reduce the risk of delayed graft function and primary nonfunction. Major efforts should continue to be made to improve the quality of kidneys from donors after cardiac death and thereby expand the utilization of this large pool of donor kidneys to its full potential.