Outcomes of Kidney Perfusion Techniques in Transplantation from Deceased Donors: A Systematic Review and Meta-Analysis.

The high demand for organs in kidney transplantation and the expansion of the donor pool have led to the widespread implementation of machine perfusion technologies. In this study, we aim to provide an up-to-date systematic review of the developments in this expanding field over the past 10 years, with the aim of answering the question: "which perfusion technique is the most promising technique in kidney transplantation?" A systematic review of the literature related to machine perfusion in kidney transplantation was performed. The primary outcome measure was delayed graft function (DGF), and secondary outcomes included rates of rejection, graft survival, and patient survival rates after 1 year. Based on the available data, a meta-analysis was performed. The results were compared with data from static cold storage, which is still the standard of care in many centers worldwide. A total of 56 studies conducted in humans were included, and 43 studies reported outcomes of hypothermic machine perfusion (HMP), with a DGF rate of 26.4%. A meta-analysis of 16 studies showed significantly lower DGF rates in the HMP group compared to those of static cold storage (SCS). Five studies reported outcomes of hypothermic machine perfusion + O2, with an overall DGF rate of 29.7%. Two studies explored normothermic machine perfusion (NMP). These were pilot studies, designed to assess the feasibility of this perfusion approach in the clinical setting. Six studies reported outcomes of normothermic regional perfusion (NRP). The overall incidence of DGF was 71.5%, as it was primarily used in uncontrolled DCD (Maastricht category I-II). Three studies comparing NRP to in situ cold perfusion showed a significantly lower rate of DGF with NRP. The systematic review and meta-analysis provide evidence that dynamic preservation strategies can improve outcomes following kidney transplantation. More recent approaches such as normothermic machine perfusion and hypothermic machine perfusion + O2 do show promising results but need further results from the clinical setting. This study shows that the implementation of perfusion strategies could play an important role in safely expanding the donor pool.

Impact of Donor Hepatectomy Time During Organ Procurement in Donation After Circulatory Death Liver Transplantation: The United Kingdom Experience.

BACKGROUND: No data exist to evaluate how hepatectomy time (HT), in the context of donation after cardiac death (DCD) procurement, impacts short- and long-term outcomes after liver transplantation (LT). In this study, we analyze the impact of the time from aortic perfusion to end of hepatectomy on outcomes after DCD LT in the United Kingdom. METHODS: An analysis of 1112 DCD donor LT across all UK transplant centers between 2001 and 2015 was performed, using data from the UK Transplant Registry. Donors were all Maastricht Category III. Graft survival after transplantation was estimated using Kaplan-Meier method and logistic regression to identify risk factors for primary nonfunction (PNF) and short- and long-term graft survivals after LT. RESULTS: Incidence of PNF was 4% (40) and in multivariate analysis only cold ischemia time (CIT) longer than 8 hours (hazard ratio [HR], 2.186; 95% confidence interval [CI], 1.113-4.294; P = 0.023) and HT > 60 minutes (HR, 3.669; 95% CI, 1.363-9.873; P = 0.01) were correlated with PNF. Overall 90-day, 1-, 3-, and 5-year graft survivals in DCD LT were 91.2%, 86.5%, 80.9%, and 77.7% (compared with a donation after brain death cohort in the same period [n = 7221] 94%, 91%, 86.6%, and 82.6%, respectively [P < 0.001]). In multivariate analysis, the factors associated with graft survival were HT longer than 60 minutes, donor older than 45 years, CIT longer than 8 hours, and recipient previous abdominal surgery. CONCLUSIONS: There is a negative impact of prolonged HT on outcomes on DCD LT and although HT is 60 minutes or longer is not a contraindication for utilization, it should be part of a multifactorial assessment with established prognostic donor factors, such as age (>45 y) and CIT (>8 h) for an appropriately selected recipient.

Simultaneous Pancreas-Kidney Transplantation Versus Living Donor Kidney Transplantation Alone: an Outcome-Driven Choice?

PURPOSE OF REVIEW: The choice of optimum transplant in a patient with type 1 diabetes mellitus (T1DM) and chronic kidney disease stage V (CKD V) is not clear. The purpose of this review was to investigate this in more detail-in particular the choice between a simultaneous pancreas-kidney transplantation (SPKT) and living donor kidney transplantation (LDKT), including recent evidence, to aid clinicians and their patients in making an informed choice in their care. RECENT FINDINGS: Analyses of large databases have recently shown SPKT to have better survival rates than a LDKT in the long-term, despite an early increase in morbidity and mortality in SPKT recipients. This survival advantage has only been shown in those SPKT recipients with a functioning pancreas and not those who had early pancreas graft loss. The choice of SPKT or LDKT should not be based on patient and graft survival outcomes alone. Individual patient circumstances, preferences, and comorbidities, among other factors should form an important part of the decision-making process. In general, an SPKT should be considered in those patients not on dialysis and LDKT in those nearing or already on dialysis.

An analysis of the survival outcomes of simultaneous pancreas and kidney transplantation compared to live donor kidney transplantation in patients with type 1 diabetes: a UK Transplant Registry study.

Transplant options for patients with type 1 diabetes and end-stage renal disease (ESRD) include deceased donor kidney, live donor kidney (LDK) and simultaneous pancreas-kidney (SPK) transplantation. The aim of this study was to compare outcomes between LDK and SPK for patients with type 1 diabetes and ESRD in the UK. Data on all SPK (n = 1739) and LDK (n = 385) transplants performed between January 2001 and December 2014 were obtained from the UK Transplant Registry. Unadjusted patient and kidney graft survival were calculated using the Kaplan-Meier method. Multivariate analysis of kidney graft and patient survival was performed using Cox proportional hazards regression. There was no significant difference in patient (P = 0.435) or kidney graft survival (P = 0.204) on univariate analysis. On multivariate analysis there was no association between LDK/SPK and patient survival [HR 0.71 (0.47-1.06), P = 0.095]. However, LDK was associated with an overall lower risk for kidney graft failure [HR 0.60 (0.38-0.94), P = 0.025]. SPK recipients with a functioning pancreas graft had significantly better kidney graft and patient survival than LDK recipients or those with a failed pancreas graft. SPK transplantation does not confer an overall survival advantage compared to LDK. However, those SPK recipients with a functioning pancreas have significantly better outcomes.

A Double Blind Randomized Clinical Trial of Remote Ischemic Conditioning in Live Donor Renal Transplantation.

Ischemic conditioning involves the delivery of short cycles of reversible ischemic injury in order to induce protection against subsequent more prolonged ischemia. This randomized controlled trial was designed to determine the safety and efficacy of remote ischemic conditioning (RC) in live donor kidney transplantation.This prospective randomized clinical trial, 80 patients undergoing live donor kidney transplantation were randomly assigned in a 1:1 ratio to either RC or to a control group. RC consisted of cycles of lower limb ischemia induced by an arterial tourniquet cuff placed around the patient's thigh. In the RC treatment group, the cuff was inflated to 200 mm Hg or systolic pressure +25 mm Hg for 4 cycles of 5 min ischemia followed by 5 min reperfusion. In the control group, the blood pressure cuff was inflated to 25 mm Hg. Patients and medical staff were blinded to treatment allocation. The primary end-point was renal function measured by estimated glomerular filtration rate (eGFR) at 1 and 3 months posttransplant.Donor and recipient demographics were similar in both groups (P < 0.05). There were no significant differences in eGFR at 1 month (control 52 ±â€Š14 vs RC 54 ±â€Š17 mL/min; P = 0.686) or 3 months (control 50 ±â€Š14 vs RC 49 ±â€Š18 mL/min; P = 0.678) between the control and RC treatment groups. The RC technique did not cause any serious adverse effects.RC, using the protocol described here, did not improve renal function after live donor kidney transplantation.

Autophagy in diabetes: ß-cell dysfunction, insulin resistance, and complications.

Autophagy functions to degrade and recycle intracellular proteins and damaged organelles, maintaining the normal cellular function. Autophagy has been shown to play an important role in regulating normal function of pancreatic ß cells and insulin-target tissues, such as skeletal muscle, liver, and adipose tissue. Enhanced autophagy also acts as a protective mechanism against oxidative stress in these tissues. Altered autophagic activity has been implicated in the progression of obesity to type 2 diabetes through impaired ß-cell function and development of insulin resistance. In this review, we outline the normal regulation of autophagy in ß cells and insulin target tissues and explore the dysregulation of autophagy in diabetic animal models and human subjects with type 2 diabetes. Furthermore, we highlight the role of impaired autophagy in the pathophysiology of diabetic complications, including nephropathy and cardiomyopathy. Finally, we summarize how autophagy might be targeted as a therapeutic option in type 2 diabetes.

Staging laparoscopy for hilar cholangiocarcinoma in 100 patients.

PURPOSE: Accurate preoperative radiological staging of hilar cholangiocarcinoma remains difficult, and a number of patients are found to have irresectable advanced tumours or occult metastases at exploration. Staging laparoscopy can improve the detection of irresectable disease, avoiding unnecessary laparotomy. This study examines the role of staging laparoscopy in hilar cholangiocarcinoma, with a focus on yield over different time periods and identification of preoperative factors increasing the risk of irresectable disease. METHODS: Retrospective case note review of all patients undergoing staging laparoscopy for radiologically resectable hilar cholangiocarcinoma, identified from the hepatobiliary multidisciplinary team database, was performed. RESULTS: One hundred consecutive patients underwent staging laparoscopy between 1998 and 2011. Of these, 34 patients were found to be irresectable due to metastatic disease, and 11, due to extensive local disease. Fifty patients proceeded to exploratory laparotomy following staging laparoscopy, and 36 % (18/50) of whom were found to have irresectable disease: 12 patients due to advanced local disease and 6 patients due to metastases. The overall yield of laparoscopy was 45 %, and the accuracy was 71 %. There was no significant difference in age, preoperative bilirubin, neutrophil/lymphocyte ratio, Ca19-9 levels or T stage between patients with resectable disease and with irresectable disease on laparoscopy. There was also no change in the yield of laparoscopy over time, despite advances in radiological imaging. CONCLUSION: In this series, staging laparoscopy avoided unnecessary laparotomy in 45 % of patients with radiologically resectable hilar cholangiocarcinoma. No factor was able to predict positive yield, and therefore, all patients with potentially resectable hilar cholangiocarcinoma should undergo staging laparoscopy.

Evidence for rapamycin toxicity in pancreatic ß-cells and a review of the underlying molecular mechanisms.

Rapamycin is used frequently in both transplantation and oncology. Although historically thought to have little diabetogenic effect, there is growing evidence of ß-cell toxicity. This Review draws evidence for rapamycin toxicity from clinical studies of islet and renal transplantation, and of rapamycin as an anticancer agent, as well as from experimental studies. Together, these studies provide evidence that rapamycin has significant detrimental effects on ß-cell function and survival and peripheral insulin resistance. The mechanism of action of rapamycin is via inhibition of mammalian target of rapamycin (mTOR). This Review describes the complex mTOR signaling pathways, which control vital cellular functions including mRNA translation, cell proliferation, cell growth, differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms for rapamycin toxicity in ß-cells. These mechanisms include reductions in ß-cell size, mass, proliferation and insulin secretion alongside increases in apoptosis, autophagy, and peripheral insulin resistance. These data bring into question the use of rapamycin as an immunosuppressant in islet transplantation and as a second-line agent in other transplant recipients developing new-onset diabetes after transplantation with calcineurin inhibitors. It also highlights the importance of close monitoring of blood glucose levels in patients taking rapamycin as an anticancer treatment, particularly those with preexisting glucose intolerance.

Current state of pancreas preservation and implications for DCD pancreas transplantation.

One of the main factors limiting potential uptake of pancreas transplantation, particularly in the United Kingdom, is the shortage of grafts. There has therefore been a recent expansion, particularly in the United Kingdom, in the utilization of grafts from donation after cardiac death (DCD) donors. These grafts are subjected to a greater ischemic insult and are arguably at higher risk of poor functional outcome. Although conventional preservation techniques may be adequate for donation after brain death (DBD) and low-risk DCD pancreases, as the number of DCD pancreas transplants increase and the threshold for rejecting organs decreases, the importance of optimal preservation techniques is going to increase. Over recent years, there have been significant advances in preservation techniques for DCD kidneys, improving the outcome of these marginal grafts. However, the use of such techniques for pancreas preservation is extremely limited and mainly historical. This overview describes the background and results of the established method of pancreas preservation for DBD, namely, cold static storage, and describes the use of the two-layer method. It also reviews pulsatile machine perfusion and normothermic perfusion for pancreas preservation techniques, which have shown promise in the preservation of DCD kidney grafts. The use of these techniques in pancreas preservation is predominantly historical but warrants reevaluation as to the feasibility of applying these techniques to DCD pancreas grafts not only for preservation but also for viability assessment. Further areas for development of pancreas preservation are discussed.

Early graft function defined by area under the curve serum creatinine 7 days post-transplant in a series of live donor kidney transplantation.

BACKGROUND: There is a degree of variability in early graft function that is often not highlighted in live kidney donor transplantation. We used the calculation of area under the curve of serum creatinine (AUC Cr) in the first 7 d post-transplant to assess early graft function and examine the influence on longer term outcome. METHODS: A total of 188 live donor renal transplants performed between 1998 and 2007 were analyzed. AUC Cr was calculated over the first 7 d post-transplant and 12 mo serum creatinine levels recorded. Donor and recipient demographics were recorded, and univariable and multivariable analyses were used to determine influencing factors. The sensitivity and specificity of AUC Cr for the detection of reduced serum creatinine at 12 mo (cut-off 130 µmol/L) were assessed by the receiver operating characteristic (ROC) curve. RESULTS: There was a significant variation in levels of AUC Cr over the first 7 d post-transplant (range, 692-5765 µmol/L.d). The ROC curve had a relatively low predictive value for the AUC Cr calculation (AUC=0.735). However, multivariable analysis showed that higher levels of AUC Cr were associated with higher serum creatinine levels at 12 mo (slope 0.012; P=0.0005). The need for dialysis, lower kidney weight, and higher recipient weight were significant independent predictors of a higher serum creatinine at 12 mo. CONCLUSION: The calculation of AUC serum creatinine 7 d post-transplant highlighted the significant variation in early graft function following live donor transplantation and was associated with creatinine levels at 12 mo. This calculation may be used as a simple prognostic marker to highlight poorer graft outcome.

A pilot study assessing the feasibility of a short period of normothermic preservation in an experimental model of non heart beating donor kidneys.

BACKGROUND: Restoring metabolism to an organ after hypothermic storage and before transplantation could reverse some of the detrimental effects of ischemic injury. This may be particularly beneficial for kidneys from non-heart-beating (NHBD) donors that sustain significant periods of warm and cold ischemic injury. This pilot study assessed the feasibility of a short period of normothermic preservation (NP) in a porcine autotransplant model. METHODS: Kidneys were subjected to 30 min of warm ischemia, then preserved by hypothermic machine perfusion (HMP) for 22 h or 20 h HMP followed by 2 h of NP using autologous blood. Kidneys were then re-implanted, a contralateral nephrectomy performed, and renal function measured over 10 d. RESULTS: Post-transplant, 4/6 animals survived in the NP group compared with 5/6 in the HMP group (P = 1.00). Creatinine levels fell below 250 µmol/L in all four of the surviving animals in the NP group compared with 2/5 in the HMP group (P = 0.608). There was no difference in levels of renal function (peak creatinine, HMP = 1736 ± 866 versus NP = 1553 ± 516 µmol/L; P ≥ 0.990). Levels of lipid peroxidation were significantly lower 60 min post-transplant in the NP group (NP = 477 ± 118.0 versus HMP = 671 ± 99.4 pg/mL; P = 0.026). CONCLUSION: A period of NP at the end of the renal preservation period in NHB kidneys is a feasible method of kidney preservation. NP could prove to be a useful technique to predetermine graft function and allow pre-transplant modification of organs.

The performance of three estimates of glomerular filtration rate before and after live donor nephrectomy.

Serum creatinine-based estimates of glomerular filtration rate (GFR) are inaccurate in healthy individuals. Therefore, their use in assessment prior to live donor nephrectomy has been restricted. There are less data on their use postdonor nephrectomy. This study assessed three GFR estimates against Cr(51) EDTA radioisotope GFR (iGFR) in the same cohort of patients before and after donor nephrectomy. A total of 206 patients underwent iGFR measurement prior to donor nephrectomy and this was repeated in 187 patients 6-8 weeks postsurgery. The iGFR was compared with the modification of diet in renal disease (eGFR), Cockcroft-Gault (cgGFR) and Mayo Clinic equation (mcGFR) estimates of GFR. Preoperatively, all GFR estimates performed poorly against iGFR; however, mcGFR provided the most reliable estimate. The eGFR underestimated iGFR by 23.60 +/- 16.43 ml/min/1.73 m(2), cgGFR by 15.54 +/- 18.13 ml/min/1.73 m(2) and mcGFR overestimated by 0.72 +/- 18.11 ml/min/1.73 m(2). Postdonation, all estimates again performed poorly, but eGFR and mcGFR outperformed cgGFR. The eGFR underestimated iGFR by 9.13 +/- 10.11 ml/min/1.73 m(2), mcGFR by 9.44 +/- 13.80 ml/min/1.73 m(2) and cgGFR overestimated by 6.42 +/- 14.49 ml/min/1.73 m(2). No GFR estimate performed sufficiently well to supersede iGFR measurement prior to donor nephrectomy. Performance postdonation was little better. In addition, there was no correlation between fall in iGFR and fall in GFR estimates postdonation.

The great saphenous vein for central venous access and haemodialysis.

BACKGROUND: Utilising an open surgical technique the Great Saphenous vein in the proximal thigh can be used for the insertion of central venous catheters for haemodialysis. This approach is safe and efficacious, and may be performed under local or general anaesthesia. This technique is of particular importance in patients requiring vascular access for haemodialysis in whom the upper central veins are stenosed and the femoral vessels are not amenable to percutaneous cannulation. METHODS: The Great saphenous vein is exposed via a surgical incision in the thigh. The central venous catheter is then inserted and advanced until in the desired position, as confirmed on fluoroscopy. RESULTS: Seven Great saphenous catheters were placed over a period of six months. All catheters insertions were technical successes with completion of at least one dialysis session. Primary patency rates were 57%, 49%, 23% at 30, 60 and 90 days respectively. CONCLUSION: The great saphenous vein offers an additional site for the insertion of central venous catheters. These data demonstrate equivalence in patency between this novel technique and percutaneous femoral vein cannulation.