Cyril Moers

Machine Perfusion or Cold Storage in Deceased-Donor Kidney Transplantation

BACKGROUND Static cold storage is generally used to preserve kidney allografts from deceased donors. Hypothermic machine perfusion may improve outcomes after transplantation, but few sufficiently powered prospective studies have addressed this possibility. METHODS In this international randomized, controlled trial, we randomly assigned one kidney from 336 consecutive deceased donors to machine perfusion and the other to cold storage. All 672 recipients were followed for 1 year. The primary end point was delayed graft function (requiring dialysis in the first week after transplantation). Secondary end points were the duration of delayed graft function, delayed graft function defined by the rate of the decrease in the serum creatinine level, primary nonfunction, the serum creatinine level and clearance, acute rejection, toxicity of the calcineurin inhibitor, the length of hospital stay, and allograft and patient survival. RESULTS Machine perfusion significantly reduced the risk of delayed graft function. Delayed graft function developed in 70 patients in the machine-perfusion group versus 89 in the cold-storage group (adjusted odds ratio, 0.57; P=0.01). Machine perfusion also significantly improved the rate of the decrease in the serum creatinine level and reduced the duration of delayed graft function. Machine perfusion was associated with lower serum creatinine levels during the first 2 weeks after transplantation and a reduced risk of graft failure (hazard ratio, 0.52; P=0.03). One-year allograft survival was superior in the machine-perfusion group (94% vs. 90%, P=0.04). No significant differences were observed for the other secondary end points. No serious adverse events were directly attributable to machine perfusion. CONCLUSIONS Hypothermic machine perfusion was associated with a reduced risk of delayed graft function and improved graft survival in the first year after transplantation. (Current Controlled Trials number, ISRCTN83876362.)

Machine Perfusion Versus Cold Storage for the Preservation of Kidneys Donated After Cardiac Death A Multicenter, Randomized, Controlled Trial

Objective:Hypothermic machine perfusion may improve outcome after transplantation of kidneys donated after cardiac death (DCD), but no sufficiently powered prospective studies have been reported. Because organ shortage has led to an increased use of DCD kidneys, we aimed to compare hypothermic machine perfusion with the current standard of static cold storage preservation. Methods:Eighty-two kidney pairs from consecutive, controlled DCD donors 16 years or older were included in this randomized controlled trial in Eurotransplant. One kidney was randomly assigned to machine perfusion and the contralateral kidney to static cold storage according to computer-generated lists created by the permuted block method. Kidneys were allocated according to standard rules, with concealment of the preservation method. Primary endpoint was delayed graft function (DGF), defined as dialysis requirement in the first week after transplantation. All 164 recipients were followed until 1 year after transplantation. Results:Machine perfusion reduced the incidence of DGF from 69.5% to 53.7% (adjusted odds ratio: 0.43; 95% confidence interval 0.20–0.89; P = 0.025). DGF was 4 days shorter in recipients of machine-perfused kidneys (P = 0.082). Machine-perfused kidneys had a higher creatinine clearance up to 1 month after transplantation (P = 0.027). One-year graft and patient survival was similar in both groups (93.9% vs 95.1%). Conclusions:Hypothermic machine perfusion was associated with a reduced risk of DGF and better early graft function up to 1 month after transplantation. Routine preservation of DCD kidneys by hypothermic machine perfusion is therefore advisable.

Machine perfusion versus cold storage for preservation of kidneys from expanded criteria donors after brain death.

The purpose of this study was to analyze the possible effects of machine perfusion (MP) versus cold storage (CS) on delayed graft function (DGF) and early graft survival in expanded criteria donor kidneys (ECD). As part of the previously reported international randomized controlled trial 91 consecutive heart‐beating deceased ECDs – defined according to the United Network of Organ Sharing definition – were included in the study. From each donor one kidney was randomized to MP and the contralateral kidney to CS. All recipients were followed for 1 year. The primary endpoint was DGF. Secondary endpoints included primary nonfunction and graft survival. DGF occurred in 27 patients in the CS group (29.7%) and in 20 patients in the MP group (22%). Using the logistic regression model MP significantly reduced the risk of DGF compared with CS (OR 0.460, P = 0.047). The incidence of nonfunction in the CS group (12%) was four times higher than in the MP group (3%) (P = 0.04). One‐year graft survival was significantly higher in machine perfused kidneys compared with cold stored kidneys (92.3% vs. 80.2%, P = 0.02). In the present study, MP preservation clearly reduced the risk of DGF and improved 1‐year graft survival and function in ECD kidneys.

The Prognostic Value of Renal Resistance During Hypothermic Machine Perfusion of Deceased Donor Kidneys

Vascular renal resistance (RR) during hypothermic machine perfusion (HMP) is frequently used in kidney graft quality assessment. However, the association between RR and outcome has never been prospectively validated. Prospectively collected RR values of 302 machine‐perfused deceased donor kidneys of all types (standard and extended criteria donor kidneys and kidneys donated after cardiac death), transplanted without prior knowledge of these RR values, were studied. In this cohort, we determined the association between RR and delayed graft function (DGF) and 1‐year graft survival. The RR (mmHg/mL/min) at the end of HMP was an independent risk factor for DGF (odds ratio 21.12 [1.03–435.0]; p = 0.048) but the predictive value of RR was low, reflected by a c‐statistic of the receiver operator characteristic curve of 0.58. The RR was also found to be an independent risk factor for 1‐year graft failure (hazard ratio 12.33 [1.11–136.85]; p = 0.004). Determinants of transplant outcome are multifactorial in nature and this study identifies RR as an additional parameter to take into account when evaluating graft quality and estimating the likelihood of successful outcome. However, RR as a stand‐alone quality assessment tool cannot be used to predict outcome with sufficient precision.

The value of machine perfusion perfusate biomarkers for predicting kidney transplant outcome

Background. Retrospective evidence suggests that lactate dehydrogenase, aspartate aminotransferase, total glutathione-S-transferase (GST), alanine-aminopeptidase, N-acetyl-&bgr;-d-glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) measured during kidney machine perfusion (MP) could have predictive value for posttransplant outcome. However, these data may be biased due to organ discard based on biomarker measurements, and previous analyses were not adjusted for likely confounding factors. No reliable prospective evidence has been available so far. Nevertheless, some centers already use these biomarkers to aid decisions on accepting or discarding a donor kidney. Methods. From 306 deceased-donor kidneys donated after brain death or controlled cardiac death and included in an international randomized controlled trial, these six biomarkers were measured in the MP perfusate. In this unselected prospective data set, we tested whether concentrations were associated with delayed graft function, primary nonfunction, and graft survival. Multivariate regression models investigated whether the biomarkers remained independent predictors when adjusted for relevant confounding factors. Results. GST, NAG, and H-FABP were independent predictors of delayed graft function but not of primary nonfunction and graft survival. Lactate dehydrogenase, aspartate aminotransferase, and alanine-aminopeptidase had no independent prognostic potential for any of the endpoints. Perfusate biomarker concentrations had no relevant correlation with cold ischemic time or renal vascular resistance on the pump. Conclusions. Increased GST, NAG, or H-FABP concentrations during MP are an indication to adjust posttransplant recipient management. However, this study shows for the first time that perfusate biomarker measurements should not lead to kidney discard.

Systemic complement activation in deceased donors is associated with acute rejection after renal transplantation in the recipient.

Background. Acute rejection after renal transplantation has been shown to be negatively associated with long-term graft survival. Identifying donor factors that are associated with acute rejection in the recipient could help to a better understanding of the relevant underlying processes that lead to graft injury. Complement activation has been shown to be an important mediator of renal transplant related injury. In this study, we analyzed the effect of systemic complement activation in deceased donors before transplantation of their kidneys on posttransplant outcome in the recipient. Methods. Plasma from 232 deceased brain-dead and deceased cardiac-dead donors were analyzed for the complement activation markers C5b-9, C4d, Bb, and complement component mannan binding lectin by ELISA. The association of these parameters with posttransplant outcome in recipients was analyzed in a multivariate regression model. Results. It was found that C5b-9 level in donor plasma is associated with biopsy-proven acute rejection in the recipient during the first year after renal transplantation (P=0.035). Both in deceased brain-dead and deceased cardiac-dead donors increased complement activation was found. Conclusions. In conclusion, we found C5b-9 in the donor to be associated with acute rejection of renal transplants in the recipient. Whether targeting complement activation in the donor may ameliorate acute rejection in the recipient needs to be studied.

Non-heart beating organ donation: overview and future perspectives.

New indications for organ transplantation combined with a stagnating number of available donor grafts have severely lengthened the waiting list for almost all types of transplantations. This has led to a renewed interest in non‐heart beating (NHB) donation, as a possible solution to bridge the gap between supply and demand. In this review, we present an overview of current NHB donation practice, outcome, existing problems and future perspectives. We focus on possible improvements in donor management, recipient care and new methods of organ preservation that may be better suited for these marginal organs. Successful institution of NHB protocols depends on adapting current transplantation practice at all levels, which is one of the greatest challenges for researchers and professionals in this interesting re‐emerging field.

Cost‐Effectiveness of Hypothermic Machine Preservation Versus Static Cold Storage in Renal Transplantation

Static cold storage (CS) is the most widely used organ preservation method for deceased donor kidney grafts but there is increasing evidence that hypothermic machine perfusion (MP) may result in better outcome after transplantation. We performed an economic evaluation of MP versus CS alongside a multicenter RCT investigating short‐ and long‐term cost‐effectiveness. Three hundred thirty‐six consecutive kidney pairs were included, one of which was assigned to MP and one to CS. The economic evaluation combined the short‐term results based on the empirical data from the study with a Markov model with a 10‐year time horizon. Direct medical costs of hospital stay, dialysis treatment, and complications were included. Data regarding long‐term survival, quality of life, and long‐term costs were derived from literature. The short‐term evaluation showed that MP reduced the risk of delayed graft function and graft failure at lower costs than CS. The Markov model revealed cost savings of

The influence of deceased donor age and old-for-old allocation on kidney transplant outcome.

86 750 per life‐year gained in favor of MP. The corresponding incremental cost‐utility ratio was minus

Machine perfusion versus cold storage for the preservation of kidneys from donors ≥65 years allocated in the Eurotransplant Senior Programme

496 223 per quality‐adjusted life‐year (QALY) gained. We conclude that life‐years and QALYs can be gained while reducing costs at the same time, when kidneys are preserved by MP instead of CS.