Jay Nath

Metabolomic analysis of perfusate during hypothermic machine perfusion of human cadaveric kidneys.

Background The metabolic processes occurring within the preserved kidney during hypothermic machine perfusion (HMP) are not well characterized. The aim of this study was to use nuclear magnetic resonance (NMR) spectroscopy to examine the metabolomic profile of HMP perfusate from human cadaveric kidneys awaiting transplantation and to identify possible discriminators between the profiles of kidneys with delayed graft function (DGF) and immediate graft function (IGF). Methods Perfusates from HMP kidneys were sampled at 45 min and 4 hr of preservation with the LifePort Kidney Transporter 1.0 (Organ Recovery Systems, Chicago, IL) using KPS-1. Prepared samples underwent 1-D Proton-NMR spectroscopy, and resultant spectra were analyzed. Clinical parameters were collected prospectively. Results Perfusate of 26 transplanted cadaveric kidneys was analyzed; 19(73%) with IGF and 7(27%) with DGF. Glucose concentrations were significantly lower in DGF kidneys compared to those with IGF at both 45 min (7.772 vs. 9.459 mM, P = 0.006) and 4 hr (8.202 vs. 10.235 mM, P = 0.003). Concentrations of inosine and leucine were significantly different between DGF and IGF kidneys at 45 min (0.002 vs. 0.013 mM, P = 0.009 and 0.011 vs. 0.006 mM, P = 0.036), and gluconate levels were also significantly different between DGF and IGF kidneys at 4 hr (49.099 vs. 59.513 mM, P = 0.009). Conclusion Significant metabolic activity may be occurring in kidneys during HMP. The NMR spectroscopy of the perfusate can identify differences in the metabolomic profiles of DGF and IGF kidneys that might have a predictive role in viability assessment. Modification of harmful metabolic processes may improve outcomes for HMP kidneys.

Metabolomic Perfusate Analysis during Kidney Machine Perfusion: The Pig Provides an Appropriate Model for Human Studies

Introduction Hypothermic machine perfusion offers great promise in kidney transplantation and experimental studies are needed to establish the optimal conditions for this to occur. Pig kidneys are considered to be a good model for this purpose and share many properties with human organs. However it is not established whether the metabolism of pig kidneys in such hypothermic hypoxic conditions is comparable to human organs. Methods Standard criteria human (n = 12) and porcine (n = 10) kidneys underwent HMP using the LifePort Kidney Transporter 1.0 (Organ Recovery Systems) using KPS-1 solution. Perfusate was sampled at 45 minutes and 4 hours of perfusion and metabolomic analysis performed using 1-D 1H-NMR spectroscopy. Results There was no inter-species difference in the number of metabolites identified. Of the 30 metabolites analysed, 16 (53.3%) were present in comparable concentrations in the pig and human kidney perfusates. The rate of change of concentration for 3-Hydroxybutyrate was greater for human kidneys (p<0.001). For the other 29 metabolites (96.7%), there was no difference in the rate of change of concentration between pig and human samples. Conclusions Whilst there are some differences between pig and human kidneys during HMP they appear to be metabolically similar and the pig seems to be a valid model for human studies.

Complex Kidneys for Complex Patients: The Risk Associated With Transplantation of Kidneys With Multiple Arteries Into Obese Patients

Conflicting evidence surrounds clinical outcomes in obese individuals after transplantation; nonetheless, many are denied the opportunity to receive a transplant. Allografts with complex vascular anatomy are regularly used in both deceased and living donor settings. We established the risk of transplanting kidneys with multiple renal arteries into obese recipients. A retrospective analysis of data from 1095 patients undergoing renal transplantation between January 2004 and July 2013 at a single centre was conducted. Of these, 24.2% were obese (body mass index >30 kg/m(2)), whereas 25.1% of kidneys transplanted had multiple arteries, thereby making the transplantation of kidneys of complex anatomy into obese recipients a relatively common clinical occurrence. Vessel multiplicity was associated with inferior 1-year graft survival (85.8.% vs 92.1%, P = .004). Obese patients had worse 1-graft survival compared to those of normal BMI (86.8% vs 93.8%, P = .001). The risk of vascular complications and of graft loss within a year after transplantation were greater when grafts with multiple arteries were transplanted into obese recipients as compared to their nonobese counterparts (RR 2.00, CI 95% 1.07-3.65, and RR 1.95, CI 95% 1.02-3.65). Additionally, obese patients faced significantly higher risk of graft loss if receiving a kidney with multiple arteries compared to one of normal anatomy (RR 1.97, 95% CI 1.02-3.72). Thus, obese patients receiving complex anatomy kidneys face poorer outcomes, which should be considered when allocating organs, seeking consent, and arranging for aftercare.

Evolution of renal transplant practice over the past decade: a U.K. center experience

OBJECTIVE As renal transplantation continues to evolve, there appears to be a change in both donor and recipient populations. Traditional markers of high-risk donor (e.g. donation after cardiac death [DCD]/expanded criteria donor [ECD]) and recipient (e.g. obese, highly sensitized) operations appear to be more common without any noticeable worsening of patient outcome. The present study aimed to compare outcome and define the change in donor and recipient populations for cadaveric transplants over a 10-year period at a large U.K. center. METHODS Single-center analysis of all adult patients undergoing cadaveric renal transplantation between January 2004 and January 2014 (n = 754). Transplants were divided into 3 groups (early, middle, and late) depending on the era, with donor, recipient and outcomes compared. RESULTS There were considerable changes in both donor and recipient factors between the 3 eras, with a greater proportion of high-risk operations performed, as reflected by significant increases in Donor Risk Index (median: 1.11-1.16, P = .022), and the proportions of ECD (22.2%-33.9%, P = .003) and DCD kidneys (10.8%-19.4% P = .011). However, 1-year graft survival was comparable between the eras, with a decrease in the average 1-year serum creatinine between the early and late cohort (median: 161 μmol/L vs 132 μmol/L, P < .001). There was no significant increase in body mass index (BMI) in either the donor or recipient population across the eras. CONCLUSION Improvement in transplant outcome continues despite a greater proportion of transplants previously considered as high risk being performed. This is likely to reflect a considerable improvement in pre- and postoperative management. BMI remains a major continuing block to transplantation.

End-stage vascular access failure: can we define and can we classify?

Background Renal replacement therapy using dialysis has evolved dramatically over recent years with an improvement in patient survival. With this increased longevity, a cohort of patients are in the precarious position of having exhausted the standard routes of vascular access. The extent of this problem of failed access or ‘desperate measures’ access is difficult to determine, as there are no uniform definitions or classification allowing standardization and few studies have been performed. The aim of this study is to propose a classification of end-stage vascular access (VA) failure and subsequently test its applicability in a dialysis population. Methods Using anatomical stratification, a simple hierarchical classification is proposed. This has been applied to a large dialysis population and in particular to patients referred to the complex access clinic dedicated to patients identified as having exhausted standard VA options and also those dialysing on permanent central venous catheters (CVC). Results A simple classification is proposed based on a progressive anatomical grading of (I) standard upper arm options exhausted, (II) femoral options exhausted and (III) other options exhausted. These are further subdivided anatomically to allow ease of classification. When applied to a complex group of patients (n = 145) referred to a dedicated complex access clinic, 21 patients were Class I, 26 Class II and 2 Class III. Ninety-six patients did not fall into the classification despite being referred as permanent CVC. Conclusions The numbers of patients who have exhausted definitive access options will continue to increase. This simple classification allows the scope of the problem and proposed solutions to be identified. Furthermore, these solutions can be studied and treatments compared in a standardized fashion. The classification may also be applied if patients have the option of transplantation where iliac vessel preservation is desirable and prioritization policies may be instituted.

Risk of post-transplantation diabetes mellitus is greater in South Asian versus Caucasian kidney allograft recipients

South Asians have increased risk for type 2 diabetes mellitus compared with Caucasians in the general population, but data for the development of post‐transplantation diabetes mellitus (PTDM) is scarce. In this retrospective analysis, data was extracted from electronic patient records at a single centre (2004–2014). Caucasians were more likely to be male, with higher age and BMI than South Asians. Case–control matching was therefore undertaken to remove this bias, resulting in 102 recipient pairs. Median follow‐up was 50 months (range 4–127 months). Matched groups had similar baseline characteristics, although South Asians compared with Caucasians received more deceased‐donor kidneys (74% vs. 43%, respectively, P < 0.001) and were more likely to be CMV positive (77% vs. 43%, respectively, P < 0.001). PTDM incidence was significantly higher in South Asians versus Caucasians (35% vs. 10%, respectively, subhazard ratio 4.2 [95% CI: 2.1–8.5, P < 0.001]). Donor type had significant interaction with ethnicity, with the observed difference in PTDM rates between ethnicities most visible with receipt of deceased‐donor kidneys. No significant difference was detected in allograft function, rejection episodes, adverse cardiovascular events or patient/graft survival. South Asians have increased risk of PTDM, especially recipients of deceased kidneys, and recognition of this allows appropriate patient counselling and development of targeted strategies.

Effect of cold ischaemia time on outcome after living donor renal transplantation

The aim of the present study was to determine the effects of cold ischaemia time (CIT) on living donor kidney transplant recipients in a large national data set.

The impact of donor body mass index on outcomes after deceased kidney transplantation - a national population-cohort study

The aim of this study was to determine the effect of donor body mass index (BMI) on deceased donor kidney transplant outcomes. Data were collected from the UK Transplant Registry for all deceased donor kidney transplant recipients between January 2003 and January 2015. Univariable and multivariable analyses were undertaken to assess the impact of donor BMI on a range of outcomes. Donor BMI (kg/m2) was stratified as <18.5 (n = 380), 18.5–25.0 (n = 6890), 25.1–30.0 (n = 6669), 30.1–35.0 (n = 2503) and >35.0 (n = 1148). The prevalence of delayed graft function increased significantly with donor BMI (P < 0.001), with an adjusted odds ratio of 1.38 (95% CI: 1.16–1.63) for the >35.0 vs. 18.5–25.0 groups. However, there was no significant association between donor BMI and 12‐month creatinine (P = 0.550), or patient (P = 0.109) or graft (P = 0.590) survival. In overweight patients, increasing donor BMI was associated with a significant increase in warm ischaemia time and functional warm ischaemia time, by an average of 4.6% (P = 0.043) and 5.2% (P = 0.013) per 10.0 kg/m2. However, rising warm ischaemic time and functional warm ischaemic time was not significantly associated with delayed graft function, 12‐month creatinine levels, graft loss or patient death. In this population cohort study, we identified no significant association between donor BMI and long‐term clinical outcomes in deceased donor kidney transplantation.

Outcomes of donation after circulatory death kidneys undergoing hypothermic machine perfusion following static cold storage: A UK population‐based cohort study

Evidence is currently lacking regarding the outcomes of kidneys undergoing hypothermic machine perfusion (HMP) in patients in the United Kingdom. Using the National Health Service Blood and Transplant database, the authors compared outcomes for recipients of single‐organ donation after circulatory death (DCD) kidneys preserved with HMP with those preserved using only static cold storage (SCS). Between 2007 and 2015, HMP was used in 19.1% (864/4,529) of kidneys. Rates of delayed graft function (DGF) were significantly lower in organs preserved with HMP than for organs preserved with SCS (34.2% vs 42.0%, P < .001), despite a slightly longer cold ischemic time (median: 14.8 vs 14.1 hours, P < .001). Multivariable analysis found the effect of preservation modality to remain significant, with HMP organs having a significantly lower rate of DGF (odds ratio 0.65, 95% confidence interval 0.53‐0.80, P < .001) and significantly shorter times to DGF resolution (average: 6.1 vs 7.4 days, P = .003) than SCS organs. The patient (P = .313) and graft (P = .263) survival rates were similar in the 2 preservation groups. HMP was associated with a marginal functional benefit in 1‐year creatinine values (P = .044), with adjusted averages of 1.36 mg/dL (HMP) versus 1.40 mg/dL (SCS). This study supports the use of HMP and aids decision‐making over its instigation, which may improve short‐term patient outcomes.

Cancer-related outcomes in kidney allograft recipients in England versus New York State: a comparative population-cohort analysis between 2003 and 2013

It is unclear whether cancer‐related epidemiology after kidney transplantation is translatable between countries. In this population‐cohort study, we compared cancer incidence and all‐cause mortality after extracting data for every kidney‐alone transplant procedure performed in England and New York State (NYS) between 2003 and 2013. Data were analyzed for 18,493 and 11,602 adult recipients from England and NYS respectively, with median follow up 6.3 years and 5.5 years respectively (up to December 2014). English patients were more likely to have previous cancer at time of transplantation compared to NYS patients (5.6% vs. 3.5%, P < 0.001). Kidney allograft recipients in England versus NYS had increased cancer incidence (12.3% vs. 5.9%, P < 0.001) but lower all‐cause mortality during the immediate postoperative stay (0.7% vs. 1.0%, P = 0.011), after 30‐days (0.9% vs. 1.8%, P < 0.001) and after 1‐year post‐transplantation (3.0% vs. 5.1%, P < 0.001). However, mortality rates among patients developing post‐transplant cancer were equivalent between the two countries. During the first year of follow up, if patients had an admission with a cancer diagnosis, they were more likely to die in both England (Odds Ratio 4.28 [95% CI: 3.09–5.93], P < 0.001) and NYS (Odds Ratio 2.88 [95% CI: 1.70–4.89], P < 0.001). Kidney allograft recipients in NYS demonstrated higher hazard ratios for developing kidney transplant rejection/failure compared to England on Cox regression analysis. Our analysis demonstrates significant differences in cancer‐related epidemiology between kidney allograft recipients in England versus NYS, suggesting caution in translating post‐transplant cancer epidemiology between countries.