Response to Letter to Editor: Kidney Machine Perfusion and Improved Long-Term Graft Survival.

Recent evidence suggests that hypothermic machine perfusion of donor kidneys reduces delayed graft function (DGF). This study addresses the effect of machine perfusion (MP) on allograft rejection in the United States. We assembled a retrospective cohort of patients undergoing kidney-alone transplants in the UNOS database from June 30, 2004 to May 31, 2017. DGF was defined as dialysis requirement in the first week post-transplant; graft rejection was defined at 6months and 1year. Multivariable logistic regression adjusted for recipient and donor factors evaluated the effect of MP on DGF and graft rejection. Records for 79300 kidney transplants meeting inclusion criteria were abstracted, 42% of which underwent MP. MP kidneys came from older donors, were more likely to have been obtained following donation after cardiac death, and had longer cold ischemic times. Rates of DGF and rejection were similar between MP and static storage kidneys. Following adjustment, recipients of MP kidneys were less likely to experience rejection at 1year (OR 0.91 [95% CI 0.86-0.97] P=.002), but not at 6months post-transplantation (OR 0.94 [0.88-1.02] P=.07). This effect persisted following adjustment for cold ischemic time. This study adds to the accumulating evidence demonstrating improved outcomes following MP of kidneys. We encourage protocolized consideration of MP for kidney grafts.

Kidney machine perfusion (MP) prevents delayed graft function (DGF). Whether this benefit translates into improved long-term graft survival (LGS) remains uncertain. We evaluated the association between MP and LGS and its potential mediation by DGF. UNOS analysis of adult deceased donor kidney transplant recipients (KTRs) from January 2010 to June 2019. We selected KTRs with cold ischemia time (CIT) > 12 h and on tacrolimus maintenance. We included KTRs from dual-kidney donors and compared outcomes where one mate kidney received MP and the other did not. The primary endpoint was all-cause graft failure (GF) analyzed using a stratified multivariable Cox proportional hazards model. We assessed the association of MP and DGF with conditional logistic regression. We evaluated the mediation effect of DGF by combining the predictor and outcome models and bootstrapping with 1000 iterations to calculate 95% confidence intervals (CI). We included 2355 mate-kidney pairs with 5.8 years (IQR 4-8) median follow-up. MP was associated with lower GF risk (aHR 0.86, 95% CI 0.75-0.98) and DGF odds (aOR 0.41, 95% CI 0.34-0.51) than no MP. DGF fully mediated the association between MP and GF, as the effect was no longer statistically significant after adjusting for DGF (aHR 0.89, 95% CI 0.78-1.03). DGF explained 76.8% of the association between MP and GF. In mate-kidney pairs with discordant MP use and CIT > 12 h, MP was associated with decreased GF risk, mediated by decreased DGF likelihood. MP both mate kidneys with CIT > 12 h should be considered to potentially improve LGS.

The demand for renal transplantation has increasingly outstripped the supply of donor organs especially over the past 10 years. Although related and unrelated live donation is being promoted as one option for increasing the donor pool, it is unlikely that this will in itself be able to bridge the gap. Non-heart beating donors (NHBD) can provide an alternative supply of organs, which should substantially increase the donor pool. In Newcastle, NHBD kidneys have been used for transplantation for a period of 10 years. In the early period (1988-1993) excellent results were obtained (90.5% success); however, these donors were controlled NHBD, Maastricht category III. In the second phase (1994-1998) increasing numbers of donors were obtained from the Accident and Emergency Department unit. These were failed resuscitation for cardiac arrest (category II). The rates of success in this period were poor (45.5% success) and the program was halted. The third phase of the program used machine perfusion of the kidneys and glutathione S transferase enzyme analysis to assess viability. Using such approaches renal transplants from largely category II donors produced a success rate of 92.3% which was significantly better than the phase II period of the program (P=0.023, Fisher two-tail test). Machine perfusion and viability assessment of NHB kidneys in phase III of the program has increased our donor pool as well as improved the graft survival. This is particularly relevant for the use of the category II NHB donor where the incidence of primary nonfunction was high, illustrated by phase II where machine perfusion/viability assessment was not used.

Mesenchymal stromal cell treatment of donor kidneys during ex vivo normothermic machine perfusion: A porcine renal autotransplantation study.

Background: The use of the elderly (age>60 years) DCD donors in UK is rising in recent years. Hypothermic pulsatile machine perfusion of donor kidneys results in lower incidence as well as duration of DGF. The use and potential benefit of machine perfusion of kidneys retrieved from elderly DCD donors is not well established. Aim: To investigate the impact of hypothermic pulsatile machine perfusion on short term outcome of recipient transplanted with kidneys from elderly DCD donors. Material and methods: From 10/2009 to 06/2013 sixty patients were transplanted with kidneys from DCD donors which were machine perfused prior the implantation. Recipients were grouped in two groups. Group A: donor age< 60 years and Group B: donor age>60years. Donor and recipient characteristics, renal function, 1 year patient and graft survival and perfusion characteristics were compared between the two groups. Continuous variables were compared using student's t-test and categorical variables using Fisher's exact test. Results: The overall DGF rate in patients transplanted with kidneys from DCD donors decreased to 28% compare to 40% prior the machine perfusion era.Table: No Caption available.Summary: The overall DGF rate is decreased using machine perfusion to 28%. The short term results of recipients transplanted with kidneys from elderly and younger donors are comparable. The beneficial effect of machine perfusion on donor kidneys retrieved from elderly DCD donors is worth future studies.

With increasing demands for 'less than ideal' kidneys for transplantation, machine perfusion of kidneys has been utilized to improve the preservation of kidneys during storage. Hypothermic machine perfusion (HMP) of renal allografts has been shown to reduce delayed graft function rates in both expanded criteria and donation after cardiac death renal allografts. However, the beneficial impact upon long-term graft function is unclear. There has been emerging evidence that both subnormothermic (room temperature) and normothermic machine perfusion (NMP) of allografts have beneficial effects with regards to early graft function, survival and injury in pre-clinical and early clinical studies. Additionally, machine perfusion allows functional assessment of the organ prior to transplantation. Ultimately, the greatest benefit of machine perfusion may be the ability to treat the organ with agents to protect the graft against ischemia reperfusion injury, while awaiting transplantation.

After completing this article, readers should be able to: 1. Compare and contrast end-stage renal disease in children and adults. 2. Describe the anomalies that may accompany congenital urologic abnormalities. 3. List the primary causes of kidney graft losses in infants. 4. List the common infections encountered posttransplant. Kidney transplantation is the preferred mode of treatment for most children who have end-stage renal disease (ESRD). Despite advances in dialysis management, children who undergo this treatment modality experience stunting in growth and development,1 and mortality rates are higher for children on dialysis compared with those who receive transplants for all age groups.2 In the past, results of kidney transplantation in infants had made the procedure prohibitive, and success rates were extremely low. Compared with adults and larger pediatric patients, infants who have ESRD are at the highest risk for early graft loss and consistently have had the highest mortality rates. Recent advances in the medical and surgical management of these infants have led to improved results in survival and long-term renal transplant function. However, survival rates vary among transplant centers, and the infant subgroup remains the most challenging of any age group receiving transplantation. According to analyses of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) and the United Network of Organ Sharing (UNOS) data, 15% of living donor grafts and 35% of cadaver grafts in infants are lost in the early posttransplant period due to technical complications, vascular thrombosis, or irreversible acute rejection.33,4 Graft survival at 7 years for infants receiving transplantation from living donors (those in whom the best possible outcome is expected) is approximately 71% nationally,4 although results vary. This long-term graft survival is surprisingly high, considering that graft survival at 1 year was only 80% nationally. In our experience with 45 consecutive kidney transplants …

Optimal kidney graft outcomes after simultaneous liver-kidney (SLK) transplant may be threatened by the increased cold ischemia time and hemodynamic perturbations of dual organ transplantation. Hypothermic machine perfusion (MP) of kidney allografts may mitigate these effects. We analyzed U.S. trends and renal outcomes of hypothermic non-oxygenated MP vs. static cold storage (CS) of kidney grafts from 6,689 SLK transplants performed between 2005 and 2020 using the United Network for Organ Sharing database. Outcomes included delayed graft function (DGF), primary non-function (PNF), and kidney graft survival (GS). Overall, 17.2% of kidney allografts were placed on MP. Kidney cold ischemia time was longer in the MP group (median 12.8 vs. 10.0h; p < 0.001). Nationally, MP utilization in SLK increased from <3% in 2005 to >25% by 2019. Center preference was the primary determinant of whether a graft underwent MP vs. CS (intraclass correlation coefficient 65.0%). MP reduced DGF (adjusted OR 0.74; p = 0.008), but not PNF (p = 0.637). Improved GS with MP was only observed with Kidney Donor Profile Index <20% (HR 0.71; p = 0.030). Kidney MP has increased significantly in SLK in the U.S. in a heterogeneous manner and with variable short-term benefits. Additional studies are needed to determine the ideal utilization for MP in SLK.

Deceased-donor acute kidney injury is not associated with kidney allograft failure

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.

Chapter 16 - Machine Perfusion of Kidneys Donated After Circulatory Death: The Carrel and Lindbergh Legacy

Retrospective evidence suggests that lactate dehydrogenase, aspartate aminotransferase, total glutathione-S-transferase (GST), alanine-aminopeptidase, N-acetyl-β-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. 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. 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. 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.

Kidney Machine Perfusion and Improved Long-Term Graft Survival.

GRAFT FUNCTION AFTER KIDNEY TRANSPLANTATION FROM NON-HEARTBEATING DONORS ACCORDING TO MAASTRICHT CATEGORY

Modulating biochemical perturbations during 72-hour machine perfusion of kidneys: Role of preservation solution