Ina Jochmans

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.

The histology of kidney transplant failure: a long-term follow-up study.

Background The relative impact on renal allograft outcome of specific histological diagnoses versus nonspecific chronic histological damage remains unclear. Methods All 1,197 renal allograft recipients who were transplanted at a single center between 1991 and 2001 were included. All posttransplant renal allograft indication biopsies performed in this cohort during follow-up (mean, 14.5±2.80 years after transplantation) were rescored according to the current histological criteria and associated with death-censored graft outcome. Results In this cohort, 1,365 allograft indication biopsies were performed. Specific diagnoses were present in 69.4% of graft biopsies before graft loss, but 30.6% of grafts did not have specific diagnoses in the last biopsy before graft loss. Only 14.6% of the patients did never have any specific disease diagnosed before graft loss. Extensive interstitial fibrosis and tubular atrophy without a clear cause was identified as the single cause of graft loss in only 6.9% of the cases. Acute T-cell–mediated rejection and changes suggestive of acute antibody-mediated rejection, diagnosed after the first year posttransplant, associated independently with graft survival. Transplant glomerulopathy increased over time after transplantation and represented a major risk for graft loss, as well as de novo or recurrent glomerular pathologies and polyomavirus nephropathy. Chronic histological injury associated with graft outcome, independent of specific diagnoses. Conclusion Renal allograft loss is multifactorial. Chronic histological damage and specific diseases had additive and independent impact on graft outcome. Chronic damage should be taken into account in prognostication of renal allograft outcome and could be implemented in treatment algorithms for specific diseases of kidney allografts.

Graft quality assessment in kidney transplantation: not an exact science yet!

Purpose of reviewThe enduring donor shortage necessitates the development of tools capable of objectively assessing kidney graft quality and thereby allowing the safer and wider use of expanded criteria donors and kidneys donated after cardiac death. We summarize current assessment tools available prior to procurement and during preservation. Recent findingsSeveral donor risk scores, combining donor and recipient risk factors of inferior graft outcome, exist but all lack predictive power. Histological scoring of glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular damage in pretransplantation kidney biopsies can supply reliable, reproducible data on the actual kidney state but prospective data on their use in graft assessment are lacking. Renal resistance and certain perfusate biomarker concentrations during machine perfusion are independent risk factors of delayed graft function, but neither method has sufficient predictive power to allow kidney discard. SummaryAvailable tools for graft quality assessment have their intrinsic value but none offer the necessary power to predict graft outcome for a specific donor–recipient pair. This is probably due to the multitude of donor, preservation, and recipient factors at stake. Only combining these factors might improve prediction of graft outcome and allow safer use of expanded criteria donors and kidneys donated after cardiac death.

Septuagenarian and octogenarian donors provide excellent liver grafts for transplantation.

BACKGROUND Wider utilization of liver grafts from donors ≥ 70 years old could substantially expand the organ pool, but their use remains limited by fear of poorer outcomes. We examined the results at our center of liver transplantation (OLT) using livers from donors ≥ 70 years old. METHODS From February 2003 to August 2010, we performed 450 OLT including 58 (13%) using donors ≥ 70 whose outcomes were compared with those using donors <70 years old. RESULTS Cerebrovascular causes of death predominated among donors ≥ 70 (85% vs 47% in donors <70; P < .001). In contrast, traumatic causes of death predominated among donors <70 (36% vs 14% in donors ≥ 70; P = .002). Unlike grafts from donors <70 years old, grafts from older individuals had no additional risk factors (steatosis, high sodium, or hemodynamic instability). Both groups were comparable for cold and warm ischemia times. No difference was noted in posttransplant peak transaminases, incidence of primary nonfunction, hepatic artery thrombosis, biliary strictures, or retransplantation rates between groups. The 1- and 5-year patient survivals were 88% and 82% in recipients of livers <70 versus 90% and 84% in those from ≥ 70 years old (P = .705). Recipients of older grafts, who were 6 years older than recipients of younger grafts (P < .001), tended to have a lower laboratory Model for End-Stage Liver Disease score (P = .074). CONCLUSIONS Short and mid-term survival following OLT using donors ≥ 70 yo can be excellent provided that there is adequate donor and recipient selection. Septuagenarians and octogenarians with cerebrovascular ischemic and bleeding accidents represent a large pool of potential donors whose wider use could substantially reduce mortality on the OLT waiting list.

The Predictive Value of Kidney Allograft Baseline Biopsies for Long-Term Graft Survival

The effect of baseline histology and individual histologic lesions at the time of transplantation on long-term graft survival has been evaluated using different scoring systems, but the predictive capacity of these systems has not been adequately validated. All kidney recipients transplanted in a single institution between 1991 and 2009 who underwent a baseline kidney allograft biopsy at transplantation were included in this prospective study (N=548). All baseline biopsies were rescored according to the updated Banff classification, and the relationship between the individual histologic lesions and donor demographics was assessed using hierarchical clustering and principal component analysis. Survival analysis was performed using Cox proportional hazards analysis and log-rank testing. Mean follow-up time was 6.7 years after transplantation. Interstitial fibrosis, tubular atrophy, and glomerulosclerosis associated significantly with death-censored graft survival, whereas arteriolar hyalinosis and vascular intimal thickening did not. Notably, donor age correlated significantly with interstitial fibrosis, tubular atrophy, and glomerulosclerosis and associated independently with graft survival. On the basis of these findings, a novel scoring system for prediction of 5-year graft survival was constructed by logistic regression analysis. Although the predictive performance of previously published histologic scoring systems was insufficient to guide kidney allocation in our cohort (receiver operating characteristic area under the curve ≤0.62 for each system), the new system based on histologic data and donor age was satisfactory for prediction of allograft loss (receiver operating characteristic area under the curve = 0.81) and may be valuable in the assessment of kidney quality before transplantation.

Autophagy and the Kidney: Implications for Ischemia-Reperfusion Injury and Therapy

Autophagy, an evolutionary conserved intracellular lysosome-dependent catabolic process, is an important mechanism for cellular homeostasis and survival during pathologic stress conditions in the kidney, such as ischemia-reperfusion injury (IRI). However, stimulation of autophagy has been described to both improve and exacerbate IRI in the kidney. We summarize the current understanding of autophagy in renal IRI and discuss possible reasons for these contradictory findings. Furthermore, we hypothesize that autophagy plays a dual role in renal IRI, having both protective and detrimental properties, depending on the duration of the ischemic period and the phase of the IRI process. Finally, we discuss the influence of currently used diuretics and immunosuppressive drugs on autophagy, underscoring the need to clarify the puzzling role of autophagy in renal IRI.

Hypothermic machine perfusion of kidneys retrieved from standard and high-risk donors

Hypothermic machine perfusion (HMP) of kidneys is a long‐established alternative to static cold storage and has been suggested to be a better preservation method. Today, as our deceased donor profile continues to change towards higher‐risk kidneys of lower quality, we are confronted with the limits of cold storage. Interest in HMP as a preservation technique is on the rise. Furthermore, HMP also creates a window of opportunity during which to assess the viability and quality of the graft before transplantation. The technology might also provide a platform during which the graft could be actively repaired, making it particularly attractive for higher‐risk kidneys. We review the current evidence on HMP in kidney transplantation and provide an outlook for the use of the technology in the years to come.