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The emergence and attendant mortality of vaccine-induced immune thrombocytopenia and thrombosis (VITT) as a consequence of vaccination against severe acute respiratory syndrome coronavirus 2 have resulted in some patients with VITT being considered as deceased organ donors. Outcomes after kidney transplantation in this context are poorly described. Because the disease seems to be mediated by antiplatelet factor 4 antibodies, there is a theoretical risk of transmission via passenger leukocytes within the allograft.We analyzed the experience of kidney transplantation from donors with VITT in the United Kingdom between January and June 2021. We followed-up all recipients of kidney-only transplants from donors with VITT to detect major postoperative complications or features of disease transmission and assess graft survival and function.There were 16 kidney donors and 30 single kidney transplant recipients in our study period. Of 11 preimplantation biopsies, 4 showed widespread glomerular microthrombi. After a median of 5 mo, patient and graft survival were 97% and 90%, respectively. The median 3-mo estimated glomerular filtration rate was 51 mL/min/1.73 m 2 . Two recipients had detectable antiplatelet factor 4 antibodies but no evidence of clinical disease after transplantation. Major hemorrhagic complications occurred in 3 recipients, all of whom had independent risk factors for bleeding, resulting in the loss of 2 grafts. The involvement of VITT could not be completely excluded in one of these cases.The UK experience to date shows that favorable outcomes are possible after kidney transplantation from donors with VITT but highlights the need for ongoing vigilance for donor-related complications in these patients.

Vaccine-induced thrombosis and thrombocytopenia (VITT) may follow immunisation with the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Autoantibodies to platelet factor 4 (PF4) may mediate VITT through antibody-dependent platelet activation, though the underlying etiology is uncertain. Anti-PF4 antibodies are also seen in heparin-induced thrombocytopenia, though most cases of VITT do not have prior heparin exposure. More than 20 million people in the United Kingdom (UK) have received the ChAdOx1 nCoV-19 vaccine.

Background: \ud In order to expand the pool of usable donors from circulatory death (DCD) there is increasing interest in normothermic regional perfusion (NRP) to assess and improve liver viability.1,2 NRP may also improve outcomes in kidney transplantation.We present our single center experience of outcomes in imported kidneys following NRP.\ud \ud Methods: \ud Data was obtained from a prospectively maintained database between December 2012 and September 2018. Primary endpoints were incidence of delayed graft function (DGF) and estimated glomerular filtration rate (eGFR).\ud \ud Results: \ud Six-hundred and thirty-two decease donor kidneys were transplanted, 229 from DCD donors, 29 of which had NRP. The DGF rate was lower for NRP versus DCD (six of 29, 20.7% vs. 70 of 200, 35.0%) with reduced duration of DGF. Multivariate analysis demonstrated transplant type to be a statistically significant independent predictor of eGFR at 7 and 14 days. Early transplant function in NRP kidneys was comparable to DBD. There were no graft losses within 30 days in the NRP group. One-year graft loss rate was 3.4% for NRP and 6.0% for standard DCD.\ud \ud Conclusion: \ud This data suggests NRP is safe, and reduces rates of DGF and improves early renal transplant function.

Purpose of Review:\ud Solid organ transplantation is limited by lack of suitable donor organs. Older and comorbid organs are frequently discarded on the basis that they will not withstand the overall process—principally the degree of ischemia reperfusion injury associated with preservation and transplantation. Interventions to prevent injury and promote regeneration are badly needed. Recent stem cells of multiple types including mesenchymal stem cells (MSCs) and adipose-derived regenerative cells (ADRCs) have been demonstrated to protect against tissue injury in multiple models relevant to transplantation.\ud \ud Recent Findings:\ud Recent studies have improved our understanding of the multiple mechanisms underlying these beneficial effects including immunomodulatory and anti-inflammatory actions. Evidence suggests extracellular vesicular transfer of therapeutic factors, such as Sox9, cytokines, IL-17A, CCR2, and S1P has a key role in these effects.\ud \ud Summary:\ud Several novel approaches such as stress treatments, culture techniques, and exogenous chemical manipulation show significant promise in improving the efficacy of stem cell populations in preventing tissue injury. There is even the possibility to harness the body’s own sources of such cells through interventions such as point-of-care fat modulation or mobilization of endogenous bone marrow-derived cells. The many unanswered questions and barriers to translating this promising technology to clinical transplantation are discussed.

The role of ex vivo normothermic perfusion (EVNP) in both organ viability assessment and reconditioning is increasingly being demonstrated. We report the use of this emerging technology to facilitate the transplantation of a pair of donor kidneys with severe acute kidney injury (AKI) secondary to rhabdomyolysis. Donor creatinine was 10.18 mg/dl with protein (30 mg/dl) present in urinalysis. Both kidneys were declined by all other transplantation units and subsequently accepted by our unit. The first kidney was perfused with red cell-based perfusate at 37°C for 75 min, mean renal blood flow was 110 ml/min/100 g and produced 85 ml of urine. Having demonstrated favorable macroscopic appearance and urine output, the kidney was transplanted into a 61-year-old peritoneal dialysis dependent without complication. Given the reassuring information from the first kidney provided by EVNP, the second kidney was not perfused with EVNP and was directly implanted to a 64-year-old patient. The first kidney achieved primary function and the second functioned well after delayed graft function. Recipient eGFR have stabilized at 88.5 and 55.3, respectively (ml/min/1.73 m2 ), at 2 months posttransplant.

Background and Aims UK NHSBT kidney matching scheme changed in September 2019, aiming to better match graft and patient survival through stratification of donors and recipients into risk quartiles. We present data on two years of transplants aiming to highlight discrepancies between our unit and the model on which the scheme is based, and the potential implications on service provision of its’ introduction. Method We reviewed all deceased donor transplants in our centre in 2015 and 2016. Recipients and donors were re-classified into the risk index quartiles and endpoint data included inpatient days in first year, 1 year eGFR, survival, imaging, and infection episodes. Comparisons were made with NHSBT literature. Results 196 deceased donor transplants were performed. Distribution of D1-4 kidneys to R1-4 recipients in our cohort did not reflect those presented in the allocation scheme models, with our population skewed toward higher risk R4 category (73.4%), including 55 D4R4 (83% of D4 kidneys), see Figure 1. 2.0% had an age difference between donor and recipient of >25years, and 12.8% 15-25 years, compared with the NHSBT proposed targets of 8% and 20% respectively. Within the R4 group, recipients receiving a D4 graft were associated with a higher rate of DGF (41.7%, vs 23.2% D1-D3 grafts, p=0.009), longer index admission (median 11 days vs 8 days, p=0.038) and more readmissions within the first post-operative year (median 18 vs 11 days, p = 0.005) – Figure 2. D4 grafts demonstrated lower mean eGFR at one year (35.7, vs. 54.8 ml/min, p Day ward attendances, bacteraemia, and CT imaging events did not differ by R or D category; D4 was associated with higher rates of transplant ultrasound (5.6 vs R1-3 4.25, p=0.009), and R4 with higher rates of urinary tract infection (3.6 vs R1-3 1.5, p=0.03). Conclusion Firstly, our transplant population is weighted to higher risk R4 recipients; secondly, intended principals of the allocation scheme are already largely being observed. Thirdly, our data does suggest that increasing R4D4 transplants will have a significant impact on transplant centres, with resource burden primarily within the first year. But despite poorer graft function, patient survival appears to be equivalent and improved matching may in the longer term reduce need for re-implantation as the scheme intends.

Solid organ transplantation has progressed dramatically over the last 50 years. However, rejection still remains one of the barriers to successful transplantation. Immunological processes underlying the mechanisms of rejection are well described and numerous pharmacological agents exist to help suppress a recipient's immune system in order to prolong graft survival. Furthermore, clinician decisions and actions during both the work-up of a potential transplant recipient and in the perioperative phase can impact upon the immunological status of an individual and the likelihood of successful solid organ transplantation. In this article we aim to describe the key processes involved in solid organ immunology and their relevance in anaesthetic practice.

High intrapatient tacrolimus variability has been associated with worse clinical outcomes postrenal transplantation. Theoretically, tacrolimus levels consistently outside the target therapeutic window may result in allograft dysfunction as subtherapeutic tacrolimus levels predispose to episodes of acute rejection, whereas supratherapeutic levels may cause nephrotoxicity.We investigated the effect of tacrolimus variability in a "Symphony" style low-dose tacrolimus based regime, by collecting data from 432 patients over a 4-year period.Three hundred seventy-six patients were included, with a mean follow-up of 1495 days. Tacrolimus variability 6 to 12 months after renal transplantation was calculated, and outcomes were compared in low (n = 186) and high variability (n = 190) groups.High variability patients were found to be at increased risk of rejection during the first posttransplant year (P = 0.0054) and to have reduced rejection-free survival (hazard ratio, 1.953; 95% confidence interval, 1.234-3.093; P = 0.0054). High variability patients had significantly worse (P0.0001) glomerular filtration rates at 1, 2, 3, and 4 years posttransplant. High variability patients were at increased risk of allograft loss (hazard ratio, 4.928; 95% confidence interval, 2.050-11.85; P = 0.0004).This suggests that highly variable tacrolimus levels predict worse outcomes postrenal transplantation, although the causal nature of this relationship remains unclear. High tacrolimus variability may identify a subset of patients who warrant increased surveillance and patient education regarding dietary and medication compliance.

BACKGROUND Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as prophylaxis against Pneumocystis pneumonia (PCP) in renal transplant recipients. The optimal duration of prophylaxis is unknown. Longer duration of prophylaxis may increase the risk of adverse effects. The aim of this retrospective observational cohort study was to assess the impact of increasing duration of TMP-SMX prophylaxis from 3 to 6 months after transplant on drug-resistant urinary tract infection (UTI), hyperkalemia, peripheral blood cytopenias, and incidence of PCP. MATERIAL AND METHODS Patients transplanted over a 4.5-year period before and after a change in protocol from 3- to 6-months TMP-SMX prophylaxis in our unit were grouped according to planned duration of prophylaxis, and results were analyzed on an intention-to-treat basis. Baseline characteristics, laboratory values, and all urine microbiology results in the 6 months after transplant were analyzed. RESULTS The overall UTI incidence rate was higher in the 3-month (3-m) treatment group than the 6-month (6-m) treatment group (0.52 vs. 0.33 UTI per 100 patient days; rate ratio 1.56 [95% CI 1.27-1.95]). However, this was not attributable to TMP-SMX: the incidences were significantly different in months 0-3 but not months 4-6. Twenty-eight multi-resistant UTIs occurred in the 3-m group, but there were none in the 6-m group (p=0.004). There were no significant differences in renal function, serum potassium, or cytopenias during the first 6 months. There were 15 cases of PCP in the 3-m group, 3 cases in the 6-m group, and no cases during prophylaxis. CONCLUSIONS Extending the duration of TMP-SMX prophylaxis was not associated with change in frequency of UTIs or multi-drug-resistant UTIs, nor was it associated with increased adverse events. TMP-SMX is an effective PCP prophylaxis, and these data support recommendations to extend the duration of prophylaxis after transplant.

Background The benefits of cold pulsatile machine perfusion (MP) for the storage and transportation of kidneys donated after circulatory death are disputed. We conducted a UK-based multicenter, randomized controlled trial to compare outcomes of kidneys stored with MP versus static cold storage (CS). Methods Fifty-one pairs of kidneys donated after circulatory death were randomly allocated to receive static CS or cold pulsatile MP. The primary endpoint, delayed graft function, was analyzed by "intention-to-treat" evaluation. Results There was no difference in the incidence of delayed graft function between CS and MP (32/51 (62.8%) and 30/51 (58.8%) P = 0.69, respectively), although the trial stopped early due to difficulty with recruitment. There was no difference in the incidence of acute rejection, or in graft or patient survival between the CS and MP groups. Median estimated glomerular filtration rate at 3 months following transplantation was significantly lower in the CS group compared with MP (CS 34 mL/min IQR 26-44 vs MP 45 mL/min IQR 36-60, P = 0.006), although there was no significant difference in estimated glomerular filtration rate between CS and MP at 12 months posttransplant. Conclusions This study is underpowered, which limits definitive conclusions about the use of MP, as an alternative to static CS. It did not demonstrate that the use of MP reduces the incidence of delayed graft function in donation after circulatory death kidney transplantation.

Supplemental Digital Content is available in the text., Background. Kidney and liver transplantation is the standard of care for end-stage renal or liver disease. However, long-term survival of kidney and liver grafts remain suboptimal. Our study aimed to understand the healthcare resources utilized and their associated costs in the years before graft failure. Methods. Two noninterventional, retrospective, observational studies were conducted in cohorts of kidney or liver transplant patients. Once identified, patients were followed using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics databases from the date of transplantation to the date of the first graft failure. Total healthcare costs in the year before graft failure (primary endpoint) and during years 2–5 before graft failure (secondary endpoint) were collected. Results. A total of 269 kidney and 81 liver transplant patients were analyzed. The mean total costs were highest for all resource components in the last year before graft failure, except for mean costs of immunosuppressive therapy per patient, which decreased slightly by index date (ie, graft failure). The mean total healthcare costs in the last year before graft failure were £8115 for kidney and £9988 for liver transplant patients and were significantly (P < 0.05) higher than years 2–5 before graft failure. Mean healthcare costs for years 2, 3, 4, and 5 before graft failure were £5925, £5575, £5469, and £5468, respectively, for kidney, and £6763, £7042, £6020, and £5651, respectively, for liver transplant patients. Conclusions. Total healthcare costs in the last year before graft failure are substantial and statistically significantly higher than years 2–5 before graft failure, in both kidney and liver transplant patients. Our findings show the economic burden placed on healthcare services in the years before graft failure.

Introduction: Kidney transplantation offers superior quality of life and survival compared to dialysis although involves invasive procedures, hospitalisation, clinic attendances, and risk of intercurrent illness. In this study we demonstrate visually and numerically the breadth and depth of activity incurred by transplantation when considering the patient journey. Methods: Consecutive patients in the Glasgow Renal and Transplant Unit (UK) in receipt of a kidney transplant during 2015 were studied. Demographics and events of interest were collated from electronic patient records for 2 years following transplantation. Results: 132 patients were transplanted. The median number of clinical contact days over 2 years was 47; 12 in-patient days, 3 day ward attendances, and 28 out-patient appointments. 46% of clinical contact days occurred in the first 90 days. In-patient days, were higher in both BMI >30kg/m2 and in extended criteria donor subgroups. 64/132 (48.5%) experienced at least one clinically significant infection requiring antibiotics, antivirals, and/or a reduction in immune-suppression; 9/132 (6.8%) experienced 10 or more infections. An average of 8.2 imaging studies were undertaken per patient; half of these within the first 90 days (540/1090, 49.5%). Transplant biopsy was performed on 86 occasions in 50/132 (37.9%); 45/86 biopsies (52.3%) occurred in the first 90 days. 16/132 (12.1%) experienced an episode of biopsy-proven acute rejection. Over 2 years, 11/132 lost graft function (8.3%), and 8/132 recipients died (6.1%). Discussion: The effect of aggregating these data is to provide a granular map of the post-transplant period. This offers greater insights into what patients may expect following receipt of their kidney transplant, the resources required to support care longitudinally, and seeks to assist in the evolution of care models and definitions of quality.

Stroke incidence is high in end-stage renal disease, and risk factors differ between the dialysis and general populations. However, risk factors and outcomes following renal transplantation remain unclear. We analyzed all adult patients with a functioning renal transplant from 01/01/2007 to 12/31/2012. Data were extracted from the electronic patient record. Variables associated with stroke were identified by survival analyses; demographic, clinical, and imaging and laboratory variables were assessed and case fatality determined. Follow-up was until 05/12/2013. A total of 956 patients were identified (median age 40.1 years, 59.9% male). Atrial fibrillation (AF) prevalence was 9.2%, and 38.2% received a transplant during follow-up. A total of 26 (2.7%) experienced a stroke during 4409 patient-years of follow-up (84.6% ischemic). Stroke incidence was 5.96/1000 patient-years. Factors associated with stroke on regression analysis were prior stroke, diabetes, age, systolic hypertension, and hemoglobin. Atrial fibrillation was associated with time to stroke (P

No field in health sciences has more interest than organ transplantation in fostering progress in regenerative medicine (RM) because the future of no other field more than the future of organ transplantation will be forged by progress occurring in RM. In fact, the most urgent needs of modern transplant medicine, namely, more organs to satisfy the skyrocketing demand and immunosuppression-free transplantation, cannot be met in full with current technologies and are at risk of remaining elusive goals. Instead, in the past few decades, groundbreaking progress in RM is suggesting a different approach to the problem. New, RM-inspired technologies among which decellularization, 3-dimensional printing and interspecies blastocyst complementation, promise organoids manufactured from the patients' own cells and bear potential to render the use of currently used allografts obsolete. Transplantation, a field that has traditionally been immunology-based, is therefore destined to become a RM-based discipline. However, the contours of RM remain unclear, mainly due to the lack of a universally accepted definition, the lack of clarity of its potential modalities of application and the unjustified and misleading hype that often follows the reports of clinical application of RM technologies. All this generates excessive and unmet expectations and an erroneous perception of what RM really is and can offer. In this article, we will (1) discuss these aspects of RM and transplant medicine, (2) propose a definition of RM, and (3) illustrate the state of the art of the most promising RM-based technologies of transplant interest.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Disclosure and contributions: This supplement collects a number of the sessions from the meeting 'Advancing Transplantation: New Questions, New Possibilities'. The meeting was sponsored by Astellas Pharma Europe Ltd; the agenda was developed by Astellas in collaboration with the meeting's scientific committee: J Wadström, BG Ericzon, WO Bechstein, D Serón and PF Halloran. The event was approved by the Federation of the Royal Colleges of Physicians of the United Kingdom for 12 category 1 (external) CPD credits. The scientific committee and faculty developed their own content for the meeting with editorial support from iS Health Group. Editorial support for the meeting was funded by Astellas Pharma Europe Ltd. Previously unpublished data that could not be included, due to existing embargo policies or to protect intellectual property, have been excluded from this report. The unpublished data in this report were included at the discretion of the authors as personal communications. Based on the presentations given at the meeting and under the direction of the authors, iS LifeScience provided editorial support throughout the development of this supplement. Editorial support was funded by Astellas Pharma Europe Ltd. A.L., in his role as the Guest Editor, reviewed this supplement and advised on the content throughout the development process. The authors had final authority over the editorial content and approved the final version of this supplement before submission. Astellas Pharma and associated companies developed, manufacture and supply tacrolimus (tacrolimus hard capsules (Prograf), tacrolimus prolonged-release hard capsules (Advagraf)). Prescribing information and adverse event reporting information can be found on pages S40-S41. J.W. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. B-G.E reports nonfinancial support from Astellas, during the development of this supplement; honoraria and consultancy fees from Astellas, Pfizer and Novartis and clinical trial support from Novartis and Astellas, outside of the submitted work. P.H. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work shares in TSI, a university company with an interest in molecular diagnostics. W.B. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. 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Perioperative insults, including hypotension, hypovolaemia and pneumoperitoneum may occur during laparoscopic live donor nephrectomy. These may have deleterious effects to both donor and recipient. The extent and significance of these insults is poorly understood and difficult to quantify. The aim of this study was to evaluate acute kidney injury (AKI) in the donor using the novel biomarker neutrophil-gelatinase associated lipocalin (N-GAL). We report the results of a pilot study of 20 patients undergoing hand-assisted live donor nephrectomy. eGFR and serum NGAL measurements (Triage CardioRenal Panel, Alere) were obtained preoperatively, immediately post-operatively, day 1 and 6 weeks post-operatively. Mean pre-operative eGFR was 105.6+/-10.1ml/min/1.73m2. Mean eGFR 6 weeks postoperatively demonstrated a 29.4+/-8.8% reduction from baseline. Serum N-GAL increased by 34.1+/-16.7% following an overnight fast pre-operatively (day 0) (ΔNGAL 45.1+/-36.0ng/ml), by a further 14.9+/-7.2% following surgery (immediate post-op). The largest ΔNGAL was observed during the pre-operative fasting period. ΔNGAL [day -1 to day 0] and [day -1 to post-op] were found to correlate inversely with eGFR at 6 weeks (p2=0.47 and p2=0.52 respectively). We conclude that clinically significant AKI does occur in the donor following live donor nephrectomy. Optimisation of perioperative fluid management is likely to have a protective role.

Background: Proteinuria is associated with poorer outcomes in renal transplant recipients. Fractional excretion of total protein (FEPR) may better reflect kidney damage than urine protein-to-creatinine ratio (PCR). Methods: We assessed FEPR (FEPR = [serum creatinine x urine protein] / [serum protein x urine creatinine], %) and PCR ([urinary protein/urinary creatinine] x 1000, mg/mM) 1 year after first renal transplantation as predictors of transplant failure. The primary endpoints were transplant failure and death. The use of the tests was analyzed by constructing receiver operator characteristic curves and comparing the area under the curve. Using receiver operator characteristic analysis, patients were stratified into high- and low-risk groups. Results: Two hundred nineteen recipients were followed up for a median of 4.9 years. At a median of 2.7 years, 11.4% (n=25) of the transplants failed. Eight percent (n=17) of the patients died. The area under the curve was higher for FEPR than PCR (0.92 vs. 0.84). Patients with an FEPR of 0.019% or higher had a 3.4-fold (P=0.003) increased risk of transplant failure and a 2.3-fold (P=0.02) increased risk of death compared with those with an FEPR of less than 0.019%. Patients with a PCR of 97 mg/mM or greater had a 2.1-fold (P=0.04) increased risk of transplant failure and a 1.6-fold (P=0.04) increased risk of death compared with those with a PCR of less than 97 mg/mM (P=0.04). In multivariate analysis with time to transplant failure as the dependent variable, FEPR and PCR were independent predictors of transplant failure (hazards ratio, 1.07 [P=0.013] and 1.03 [P=0.03], respectively). Conclusions: FEPR and PCR at 1 year are independent predictors of transplant failure, but FEPR may be superior.

Kidneys donated after cardiac death (DCD) represent an increasing proportion of transplant activity. There have been concerns that wider sharing of these kidneys increases the cold ischemic time (CIT) and leads to poorer outcomes.DCD kidney transplantation was implemented in Scotland in 2005, with each center transplanting locally donated kidneys. A national sharing scheme of DCD kidneys was introduced in 2007, whereby kidneys are shared between the 2 renal transplant centers in the country. A single national multiorgan retrieval team carries out retrievals and kidneys are shipped directly to the 2 units. Donor and recipient demographic data, cold ischemic time, and outcome data were prospectively collected and compared within each center and between centers pre- and postintroduction of the sharing policy.Since 2005, 152 DCD kidney transplants have been performed. Since 2007, 68 kidneys were shared between the centers. Recipient demographics were comparable before and after the introduction for the sharing scheme. The CIT was significantly higher in Glasgow (14.30 ± 3.79 hours) compared with Edinburgh (10.72 ± 2.99 hours; P.001, one-way analysis of variance [ANOVA] prior to the introduction of the sharing scheme. Following the implementation of kidney sharing, there was no significant difference in CIT between Glasgow and Edinburgh (10.50 ± 3.34 hours vs 10.53 ± 2.71 hours). A significant reduction in the CIT in Glasgow was noted after sharing was instituted (from 14.30 ± 3.79 hours to 10.50 ± 3.34 hours, P.001, one-way ANOVA). Patient and graft survivals, acute rejection, and delayed graft function as well as 1-year renal function were comparable in both centers before and after the introduction of the scheme.Wider sharing of DCD kidneys should be encouraged, as it does not compromise clinical outcomes. A transparent and well-established sharing agreement, with no delays in the offering of DCD kidneys, may lead to an improvement in CIT.

Background.Primary focal segmental glomerulosclerosis (FSGS) is one of the commonest causes of glomerular disease and if left untreated will often progress to established renal failure. In many cases the best treatment option is renal transplantation; however primary FSGS may rapidly recur in renal allografts and may contribute to delayed graft function. We present a case of primary nonfunction in a renal allograft due to biopsy-proven FSGS.Case Report.A 32-year-old man presented with serum albumin of 22 g/L, proteinuria quantified at 12 g/L, and marked peripheral oedema. Renal biopsy demonstrated tip-variant FSGS. Despite treatment, the patient developed progressive renal dysfunction and was commenced on haemodialysis. Cadaveric renal transplantation was undertaken; however this was complicated by primary nonfunction. Renal biopsies failed to demonstrate evidence of acute rejection but did demonstrate clear evidence of FSGS. The patient was treated to no avail.Discussion.Primary renal allograft nonfunction following transplantation is often due to acute kidney injury or acute rejection. Recurrent FSGS is recognised as a phenomenon that drives allograft dysfunction but is not traditionally associated with primary nonfunction. This case highlights FSGS as a potentially aggressive process that, once active in the allograft, may prove refractory to targeted treatment. Preemptive therapies in patients deemed to be at high risk of recurrent disease may be appropriate and should be considered.

Delayed graft function (DGF) is a major issue in kidney transplantation and is associated with reduced graft and patient survival. The condition results from the summative effects of multiple injurious processes associated with transplantation with many underlying factors being nonmodifiable. Reducing cold ischemic time and machine perfusion have decreased the DGF incidence but peri-/postoperative injury resulting from suboptimal perfusion may also be critical to the development of DGF. We investigated the effect of perfusion parameters and other key variables on the incidence of DGF in 149 consecutive renal transplants. The occurrence of any recorded subtarget (70 mm Hg) mean arterial pressure (MAP) was significantly associated with DGF (perioperative P = .005; postoperative P = .002) while the occurrence of a subtarget (8 cm H(2)O) central venous pressure (CVP) among other variables was not. Routine continuous blood pressure monitoring is rare postoperatively and is shown to be more accurate than CVP in assessing renal perfusion and guiding management in the postoperative period.

Background Donor kidneys contain a large reservoir of passenger leucocytes that contribute to acute rejection via direct alloantigen presentation and pro-inflammatory cytokine secretion. However, the early contribution of these cells following revascularization has not previously been described. We performed a secondary, high-volume preservation flush following cold storage to characterize the inflammatory contribution of the donor kidney upon reperfusion. Methods Porcine kidneys were retrieved using a protocol analogous to current UK clinical practice. Following 2 h of cold static preservation, kidneys underwent a secondary flush with Ringer's solution. The venous effluent was collected and leucocytes phenotyped via flow cytometry. Inflammatory mediators, including cytokines and cell-free DNA, were then assessed to determine the inflammatory contribution of the donor kidney. Results Upon reperfusion, a significant population of donor-derived CD45 + leucocytes mobilized from the renal vasculature via the renal vein [mean 4.738 × 10 8 (SD 1.348 × 10 8 )]. Within this population, T cells were dominant, representing >60% of the leucocyte repertoire. Granulocytes, monocytes and natural killer cells were also identified, but in comparatively lower numbers. Significant concentrations of cytokines and cell-free DNA were also eluted upon reperfusion. Conclusions The donor kidney contains a significant immune load that rapidly mobilizes following reperfusion. Performing a secondary preservation flush prior to implantation may reduce this inflammatory burden via diversion of donor leucocytes and inflammatory mediators from entry into the recipient circulation. This may modulate direct presentation and reduce the inflammatory contribution of the donor kidney following transplantation.

Introduction: Ex vivo normothermic perfusion offers an alternative method of organ preservation, allowing donor kidneys to be reanimated and evaluated prior to transplantation. Beyond preservation, it can be used to characterize the immunological contribution of the donor kidney in isolation. Furthermore, it has the potential to be used as an immunomodulatory strategy to manipulate donor kidneys prior to transplantation.\ud \ud \ud \ud Methods: Explanted porcine kidneys underwent 6 hours of perfusion. Sequential perfusate samples were collected and leukocytes characterized via flow cytometry. An inflammatory profile was generated via cytokine quantification. Cell-free DNA was also determined as markers of cell death.\ud \ud \ud \ud Results: All kidneys functioned within normal parameters and met the criteria for transplantation at the end of perfusion. Throughout perfusion there were continuous increases in pro-inflammatory cytokines, including large concentrations of interferon-γ, suggesting that perfusion drives a significant inflammatory response. Increasing concentrations in cell-free DNA were also observed, suggesting cell death. During perfusion there was a marked cellular diapedesis of T cells, B cells, natural killer (NK) cells, and monocytes from the kidney into the circuit. Minor populations of granulocytes and macrophages were also detected.\ud \ud \ud \ud Discussion: We demonstrate that ex vivo normothermic perfusion initiates an inflammatory cytokine storm and release of mitochondrial and genomic DNA. This is likely to be responsible for immune cell activation and mobilization into the circuit prior to transplantation. Interestingly this did not have an impact on renal function. These data therefore suggest that normothermic perfusion can be used to immunodeplete and to saturate the pro-inflammatory capacity of donor kidneys prior to transplantation.

BACKGROUND: Kidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown. METHODS/DESIGN: The Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating. DISCUSSION: Late graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01120028 and ISRCTN88894088.

Renal ischemia reperfusion injury (IRI) is a major problem, currently without treatments in clinical use. This reflects the failure of animal models to mimic the severity of IRI observed in clinical practice. Most described models lack both the ability to inflict a permanent reduction in renal function and the sensitivity to demonstrate the protective efficacy of different therapies in vivo. To test novel cell-based therapies, we have developed a model of renal IRI in Fisher 344 rats. Animals were subjected to 120 min of unilateral warm ischemia, during which they underwent an intra-renal artery infusion of therapeutic agents or vehicle. At either 2 or 6 weeks post-surgery, animals underwent terminal glomerular filtration rate (GFR) studies by inulin clearance to most accurately quantify renal function. Harvested kidneys underwent histological analysis. Compared to sham operations, saline treated animals suffered a long-term reduction in GFR of ≈50%. Histology revealed short- and long-term disruption of renal architecture. Despite the injury severity, post-operative animal losses are

Increasing numbers of older patients are developing established renal failure and considering kidney transplant as a renal replacement therapy (RRT) option. The probability of older patients actually receiving a deceased donor kidney transplant is unclear, preventing informed choice about pursuing the option of transplantation. We sought to analyse our RRT population to determine the probability of receiving a deceased donor kidney transplant in patients commencing RRT categorized by age and for whom there was no suitable living kidney donor.Patients commencing dialysis in our centre between 1992 and 2009 were identified. Time to listing on the deceased donor transplant waiting list and time to first deceased donor transplant were determined by Kaplan-Meier analysis for patients, categorized by age, with censoring at the date of first living donor kidney transplant, death or last dialysis.One-thousand-five-hundred-and-thirteen patients were categorized into groups by age in years [1:35 (n = 134), 2: 35-49.9 (n = 207), 3: 50-64.9 (n = 415), 4:65-74.9 (n = 438) and 5: ≥ 75 (n = 319)]. The probability of being listed for deceased donor transplant within 1 year of commencing RRT was 75, 54, 27, 4 and 0.8% in Groups 1-5, respectively. If listed, the probability of receiving a deceased donor transplant within 5 years of starting RRT was 81, 48, 26, 8 and 0% in Groups 1-5, respectively. In Groups 1-4, 93% (n = 63), 87% (n = 65), 76% (n = 45) and 100% (n = 7) of the patients, respectively, who received a deceased donor transplant were alive and off dialysis 1 year after transplant. The reason patients who were listed did not receive a transplant was usually death on the waiting list.The likelihood of being listed for transplant falls with increasing age at the time of starting RRT. Even for patients listed for transplant, the probability of older patients actually receiving a transplant is much lower than for younger patients, with only 8% of listed patients aged 65-74.9 years being transplanted within 5 years. This is partly the result of death on the waiting list but may also be related to organ allocation policies. Assessment for possible deceased donor transplantation involves a considerable investment in time and effort for the patient, as well as in health care resources, and a patient's decision whether to proceed with assessment should be informed by the kind of information we have produced. As there may be regional and national variations in practice, each centre should generate such data for use locally.

IntroductionStudies in our hybrid rat model of transplantation/ischemic reperfusion (IRI) have demonstrated improvement in kidney function post injection of adipose-derived regenerative cells (ADRCs) into the renal artery. The mechanism on how these cells establish regenerative conditions during IRI

BACKGROUND: Transplanted metanephroi vascularize and develop features of mature kidney. One group reported the intriguing finding that metanephric allografts and congenic, major histocompatibility complex-mismatched grafts developed without rejection in the absence of immunosuppression. Our experiments aim to investigate the hypothesis that metanephroi lack immunogenicity and identify immunosuppressives that do not inhibit development. METHODS: We transplanted syngeneic metanephric grafts, allografts, and class II mismatched transplants to adult rats along with control grafts to nude recipients. glomerular filtration rates (GFRs) were measured where possible and transplants assessed by histology, immunohistochemistry, electron microscopy, and polymerase chain reaction. RESULTS: Allografts underwent reliable growth and vascularization followed by vigorous rejection (n>200). Rejection was conserved across a class II-mismatched strain and when the earliest dissectable metanephric structures were transplanted. Immunosuppressive drugs other than cyclosporine demonstrated no in vivo toxicity to transplants and treatment with FTY720 and tacrolimus could ablate histologic evidence of allograft rejection. Syngeneic transplants exhibited function of up to 8% of a normal GFR. Renal mass reduction and growth factor treatment was associated with higher GFR than controls. The anatomical site of implantation was also linked strongly with achieved function. CONCLUSIONS: Fetal kidney rudiments can provide a source of functioning renal tissue. These results suggest that such structures are no less immunogenic than mature organs, but the observed rejection is controllable.

Renal failure and end-stage renal disease are prevalent diseases associated with high levels of morbidity and mortality, the preferred treatment for which is kidney transplantation. However, the gulf between supply and demand for kidneys remains high and is growing every year. A potential alternative to the transplantation of mature adult kidneys is the transplantation of the developing renal primordium, the metanephros. It has been shown previously, in rodent models, that transplantation of a metanephros can provide renal function capable of prolonging survival in anephric animals. The aim of the present study was to determine whether increasing the mass of transplanted tissue can prolong survival further. Embryonic day 15 rat metanephroi were transplanted into the peritoneum of anaesthetized adult rat recipients. Twenty-one days later, the transplanted metanephroi were anastomosed to the recipient's urinary system, and 35 days following anastomosis the animal's native renal mass was removed. Survival times and composition of the excreted fluid were determined. Rats with single metanephros transplants survived 29 h longer than anephric controls (P < 0.001); animals with two metanephroi survived 44 h longer (P < 0.001). A dilute urine was formed, with low concentrations of sodium, potassium and urea; potassium and urea concentrations were elevated in terminal serum samples, but sodium concentration and osmolality were comparable to control values. These data show that survival time is proportional to the mass of functional renal tissue. While transplanted metanephroi cannot currently provide life-sustaining renal function, this approach may have therapeutic benefit in the future.

Single-center experience of encapsulating peritoneal sclerosis inpatients on peritoneal dialysis for end-stage renal failure. Background Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). It is characterized by a progressive, intra-abdominal, inflammatory process resulting in sheets of fibrous tissue that cover, bind, and constrict the viscera, thereby compromising the motility and function of the bowel. Although recent therapeutic approaches have been reported with variable success, the ability to detect reliably at an early stage patients at risk for EPS would be beneficial and allow treatment standardization. The aim of this study was to evaluate the clinical features of EPS and identify possible risk factors for its development in CAPD and APD patients. Methods This was a review of all cases of EPS in a single center over the last 5 years. Results There were 810 CAPD and APD patients, managed in our program over this period. We identified 27 cases of EPS, giving an overall of 3.3% in this population. The mean duration of CAPD before diagnosis of EPS was 72.6 ± 39.7 months (range 16-172). Sixteen cases required surgical treatment and were classified as severe; others were treated conservatively (mild to moderate group). Ten patients received tamoxifen treatment with apparent benefit. The overall mortality rate was 29.6%. Eight patients from the severe group and the entire moderate group survived on hemodialysis or transplantation at 48.71 and 27.63 months follow-up, respectively. Peritonitis rates were not different between the 2 groups and peritoneal history was unremarkable compared to overall peritonitis rates in the unit. Data on small solute transport were not available in all patients in this retrospective analysis. Conclusion EPS is a serious, life-threatening complication of CAPD. Most cases had PD duration of more than 4 years. Careful monitoring by CT scans of the peritoneal membrane in patients beyond 5 years, and early catheter removal in patients with peritoneal thickening should be considered for long-term CAPD patients. Treatment with tamoxifen may be of benefit in these patients.

Background. Activation of the renin angiotensin system may contribute to the development of delayed graft function after renal transplantation. We, therefore, examined the impact of pretransplant treatment with blockers of the renin angiotensin system on early graft function after renal transplantation. Method. The case records of all patients who received a live donor transplant between January 2001 and August 2008 were reviewed. Results. Serum creatinine measurements were recorded for the first nine posttransplant days, in 94 recipients of live donor kidneys, where there were neither surgical nor hemodynamic complications and no documented rejection or infection. Forty patients (43%) were treated with a blocker of the renin-angiotensin-aldosterone system before transplantation. Serum creatinine levels fell more slowly in these patients (P = 0.02). Two patients required hemodialysis after transplantation; both were on an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Conclusion. Live donor renal transplant recipients who are taking a renin-angiotensin-aldosterone system blocker at the time of transplantation are more likely to have impaired graft function postoperatively in the absence of other explanations. This observation requires further exploration in live and deceased donor renal transplantation

Introduction The aim of this study was to evaluate donor acute kidney injury (AKI) using a novel biomarker (NGAL). Methodology A pilot study of 20 patients undergoing hand-assisted live donor nephrectomy was undertaken. eGFR and serum NGAL measurements were obtained pre-operatively, immediately post-operatively, day 1 and 6 weeks post-operatively. Results Mean age: 40.6 ± 11.1 years. Mean pre-operative eGFR: 105.6 ± 10.1 ml/min/1.73 m 2 . Mean day 1 post-op eGFR: 65.7 ± 10.4 ml/min/1.73 m 2 (37.7 ± 9.2% reduction from baseline). Mean eGFR 6 weeks post-operatively was 74.1 ± 8.6 ml/min/1.73 m 2 (29.4 ± 8.8% reduction from baseline). Serum NGAL increased by 34.1 ± 16.7% following an overnight fast pre-operatively (day 0) (ΔNGAL 45.1 ± 36.0 ng/ml), by a further 14.9 ± 7.2% following surgery (post-op) and a further 3.1 ± 1.2% by post-operative day 1. The largest ΔNGAL was observed during the pre-operative fasting period. ΔNGAL [day −1 to day 0] and [day −1 to post-op] were found to correlate inversely with eGFR at 6 weeks ( p r 2 = 0.47 and p r 2 = 0.52, respectively). Conclusion Significant AKI occurs with live donor nephrectomy. This is difficult to quantify using standard biochemistry due to the overwhelming effect of nephrectomy on eGFR. AKI is associated with poorer donor eGFR at 6 weeks. Pre-operative hypovolaemia plays a role in AKI. Optimisation of perioperative fluid management is likely to have a protective role.

Objectives: This study explored the pattern of Internet use by renal transplant patients in the West of Scotland. Materials and Methods: A 31-item questionnaire was used to obtain information about patient’s Internet use and the relations between Internet use and sex, age, education, and health requirements. Results: The study consists of 84 postrenal transplant patient surveys. Validation of the questionnaire showed an intraclass correlation coefficient 0.77 to 0.96 with 95% confidence interval (CI 0.75-0.99). The overall response rate was 65% (n=84/130). In all, 87% of the patients (n=73/84) had access to a computer and the Internet. And 94% of the patients (n=60/64) in age groups 21 to 60 years had access to the Internet with no difference in the access in various age subgroups, whereas 67% of the patients (n=12/18) in age group 61 to 70 years (P = .004) had Internet access. The Internet was a preferred source of health information for 70% of the patients (n=59/84) as compared to books 17% (n=14/84; P = .003) and magazines 12% (n=10/84; P = .001). Of the Internet group, 90% (n=53/59) looked up information on transplantation mostly about transplant operations (69%) and rejection (66%). Of all the patients, 85% (n=71/84) of them would like the transplant team to develop a Web site for information on transplantation and 52 (62%) would like to receive health advice by e-mail. Conclusions: The majority of renal transplant patients use the Internet for information on transplantation. Almost all patients under 60 years old had access to the Internet for this purpose; suggesting a trend toward the Internet as the favored way to get information. Transplant units should develop flexible, Web-based sources of transplant-related information. This would allow rapid adaptation to changes in prevalent practice, reflecting the preferences of the patient population.

Aims This paper presents an e-survey of current clinical practice of use of intra-operative diuretics during renal transplantation in the United Kingdom and a study to compare outcome of renal transplants carried out with or without intra-operative diuretics in our centre. Methods An e-mail questionnaire to renal transplant surgeons exploring their practice of renal transplantation with or without intra-operative diuretics, the type of a diuretic/s if used and the relevant doses. An observational study comparing the outcome of renal transplant recipients, group no-diuretics (GND, n = 80) carried out from 2004 to 2008 versus group diuretics (GD n = 69) renal transplant recipients who received intra-operative diuretics over a one year period is presented. Outcome measures were incidence of delayed graft function and a comparison of graft survival in both groups. Results Forty surgeons answered from 18 transplant centres with a response rate of 67%. 13 surgeons do not use diuretics. Mannitol is used by 10/40, Furosemide 6/40 and 11 surgeons use a combination of both. In comparative study there was no significant overall difference in one year graft survival of GD versus GND ( N = 65/69, 94% and 75/80, 94% respectively, p = 0.08) and the incidence of delayed graft function was also comparable (16/69, 23% and 21/80, 26% respectively, p = 0.07). The donor characteristics in both groups were comparable. Conclusion The study showed variation in clinical practice on the use of intra-operative diuretics in renal transplantation and it did not demonstrate that the use of diuretics can improve renal graft survival.

BACKGROUND: Transplantation of embryonic kidneys (metanephroi) offers a potential solution to the problem of kidney donor shortage. The aim of this study was to characterise the haemodynamic capacity of transplanted rat metanephroi and to determine the number and maturity of the tubules. METHODS: Metanephroi from E15 Lewis rat embryos were transplanted adjacent to the abdominal aorta of uninephrectomised adult female syngeneic Lewis rats. Twenty-one days later, a single metanephros ureter was anastomosed to the host's urinary system. Three months later animals were prepared for standard clearance measurements. RESULTS: Effective renal blood flow (149 +/- 33 microl min(-1) per g kidney weight) and glomerular filtration rate (17 +/- 9 microl min(-1) per g kidney weight), standardised to kidney weight, were significantly lower in transplanted metanephroi compared with control adult kidneys (P < 0.001); renal vascular resistance (934 +/- 209 mmHg ml min(-1) per g kidney weight) was significantly higher (P < 0.001). Nephron number in transplanted metanephroi was significantly greater than that of E21 kidneys (P < 0.01) but lower than that of postnatal day (PND) 1 kidneys (P < 0.001). Angiotensin II type 2 receptor mRNA expression, a marker of nephrogenesis, was markedly reduced in metanephroi. Aquaporins 1 and 2, epithelial Na channel and Na-K-2Cl cotransporter type 2 mRNA and protein were expressed in transplanted metanephroi; the urea transporters-A1, 2 and 3 were absent. Vascular markers (alpha-smooth muscle actin and CD31) were identified in metanephroi but their expression did not differ from that of E21 and PND 1 kidneys. CONCLUSIONS: This study shows that metanephroi continue to develop post-transplantation but only reach a stage of development equivalent to that of a normal rat kidney at birth.

A novel approach to circumventing the shortage in transplantable donor organs is the use of embryonic primordia that develop inside the host. Previously published work has shown that transplantation of rat fetal kidney primordia (metanephroi) onto the omentum of adult rat hosts results in growth and development of the metanephroi into functioning kidney units capable of providing a measurable renal function. However, for anatomical and physiological reasons the omentum may not provide the ideal site for transplantation and may limit the maximum renal function that the transplants can achieve. We postulate that it may be possible to increase the renal function of the transplants by transplantation to sites with increased blood flow. To test this we transplanted rat embryonic day 15 metanephroi into the retroperitoneal fat adjacent to major blood vessels in the peritoneum of unilaterally nephrectomized rats; 21 days later the transplants were examined and suitable transplants connected to the host urinary system. Approximately 130 days later the glomerular filtration rate of the connected transplants was analyzed. Our results show that transplantation of metanephroi to the regions highlighted in this study results in an increased presence of urinary cysts, suggesting increased early renal function in the transplants compared to metanephroi transplanted onto the omentum, but most importantly we show that we can increase the renal function of the transplants to a level comparable with other renal therapies such as dialysis. This work suggests life-sustaining renal function could be achieved through transplantation of renal primordia.