Dave Collett

Factors Affecting Graft and Patient Survival After Live Donor Kidney Transplantation in the UK

Background. The outcome after living donor renal transplantation is superior to that for deceased donor transplantation, but the results are not uniformly successful. The factors responsible for the variable outcome after living donor transplantation have not been well defined. Methods. UK Transplant Registry data were analyzed to determine the outcomes of 3142 first adult kidney transplants from living donors (71% genetically related and 29% unrelated) performed between 2000 and 2007 inclusive. Kaplan-Meier survival estimates were determined, and factors that might be associated with graft and patient survival were analyzed using Cox proportional hazards regression modeling. Results. Patient survival at 5 years was better for recipients of grafts from related than unrelated donors (97% vs. 93%, P=0.0002), but conversely graft survival was better in recipients of genetically unrelated grafts (93% vs. 89%, P=0.06). After adjustment for the factors found to influence graft and patient survival, these differences were no longer apparent. In contrast to the expectations, the degree of human leukocyte antigen-A, -B, and -DR mismatch did not influence graft survival. Increasing donor age (but not recipient age), recipient diabetes, and grafts from adult offspring were independently associated with poorer patient survival in the first 3 years after transplantation. Poorer graft survival was independently associated with donor age older than 59 years, and female recipients. Conclusions. Advanced donor age, but not human leukocyte antigen mismatch, is associated with poorer outcome after live donor kidney transplantation. However, the results of live donor transplantation remain superior to deceased donor kidney transplantation.BACKGROUND Mesenchymal stem cells (MSCs), also known as multipotent progenitor cells, release several factors that support cell survival and enhance wound healing. We hypothesized that MSC-secreted molecules would induce a trophic effect in pancreatic islet culture conditions. METHODS Pancreatic islets were co-cultured with MSCs, and ADP/ATP ratios, glucose stimulated insulin secretion (GSIS), and DNA fragmentation were evaluated to measure islet quality and viability in vitro. The induction of signal molecules related to the control of survival, function, and angiogenesis was also analyzed. Cell quality assays, DNA fragmentation assays, and islet transplantation into streptozotocin-induced diabetic mice were performed using MSC-conditioned medium (CM)-cultured islets. Furthermore, we identified soluble molecules within MSC-CM. RESULTS Islets co-cultured with MSCs demonstrated lower ADP/ATP ratios, and higher GSIS indexes and viability. Furthermore, co-cultured islets revealed higher levels of anti-apoptotic signal molecules (X-linked inhibitor of apoptosis protein, Bcl-xL, Bcl-2, and heat shock protein-32) and demonstrated increased vascular endothelial growth factor receptor 2 and Tie-2 mRNA expression and increased levels of phosphorylated Tie-2 and focal adhesion kinase protein. Islets cultured in MSC-CM demonstrated lower ADP/ATP ratios, less apoptosis, and a higher GSIS indexes. Diabetic mice that received islet transplants (200 islet equivalent) cultured in MSC-CM for 48 hr demonstrated significantly lower blood glucose levels and enhanced blood vessel formation. In addition, interleukin-6, interleukin-8, vascular endothelial growth factor-A, hepatocyte growth factor, and transforming growth factor-beta were detected at significant levels in MSC-CM. CONCLUSIONS These results suggest that the trophic factors secreted by human MSCs enhance islet survival and function after transplantation.

Potential for organ donation in the United Kingdom: audit of intensive care records

Abstract Objectives To determine the true potential for solid organ donation from deceased heartbeating donors and the reasons for non-donation from potential donors. Design An audit of all deaths in intensive care units, 1 April 2003 to 31 March 2005. The study was hierarchic, in that information was sought on whether or not brain stem testing was carried out; if so, whether or not organ donation was considered; if so whether or not the next of kin were approached; if so, whether or not consent was given; if so, whether or not organ donation took place. Setting 341 intensive care units in 284 hospitals in the United Kingdom. Participants 46 801 dead patients, leading to 2740 potential heartbeating solid organ donors and 1244 actual donors. Main outcome measures Proportion of potential deceased heartbeating donors considered for organ donation, proportion of families who denied consent, and proportion of potential donors who became organ donors. Results Over the two years of the study, 41% of the families of potential donors denied consent. The refusal rate for families of potential donors from ethnic minorities was twice that for white potential donors, but the age and sex of the potential donor did not affect the refusal rate. In 15% of families of potential donors there was no record of the next of kin being approached for permission for organ donation. Conclusions Intensive care units are extremely good in considering possible organ donation from suitable patients. The biggest obstacle to improving the organ donation rate is the high proportion of relatives who deny consent.

Elective liver transplant list mortality: development of a United Kingdom end-stage liver disease score.

Background. Prediction of short-term survival probability is important in the selection and allocation of patients for liver transplantation, and the Mayo End-Stage Liver Disease (MELD) score has been used in these contexts. The aim of this study was to develop and validate a model for estimation of short-term prognosis of patients selected for elective liver transplantation in the United Kingdom. Methods. A modeling dataset was based on 1103 adult patients registered for a first elective liver transplant in the United Kingdom between April 1, 2003, and March 31, 2006, and a validation dataset based on 452 patients registered between April 1, 2006, and March 31, 2007. The final model (United Kingdom End-Stage Liver Disease) included international normalized ratio, serum creatinine, bilirubin, and sodium. Results. The model, based on the modeling dataset, accurately predicted mortality on the transplant list in the validation dataset and proved to be a better predictor than MELD or MELD-Na. The United Kingdom End-Stage Liver Disease score was not associated with overall posttransplant survival but was associated with both the duration of intensive care unit stay and overall initial hospital stay. Conclusion. This model, developed specifically for patients awaiting liver transplantation, provides a useful tool for the selection of patients for liver transplantation and the allocation of donor livers.

A simplified donor risk index for predicting outcome after deceased donor kidney transplantation.

Background. We sought to determine the deceased donor factors associated with outcome after kidney transplantation and to develop a clinically applicable Kidney Donor Risk Index. Methods. Data from the UK Transplant Registry on 7620 adult recipients of adult deceased donor kidney transplants between 2000 and 2007 inclusive were analyzed. Donor factors potentially influencing transplant outcome were investigated using Cox regression, adjusting for significant recipient and transplant factors. A United Kingdom Kidney Donor Risk Index was derived from the model and validated. Results. Donor age was the most significant factor predicting poor transplant outcome (hazard ratio for 18–39 and 60+ years relative to 40–59 years was 0.78 and 1.49, respectively, P<0.001). A history of donor hypertension was also associated with increased risk (hazard ratio 1.30, P=0.001), and increased donor body weight, longer hospital stay before death, and use of adrenaline were also significantly associated with poorer outcomes up to 3 years posttransplant. Other donor factors including donation after circulatory death, history of cardiothoracic disease, diabetes history, and terminal creatinine were not significant. A donor risk index based on the five significant donor factors was derived and confirmed to be prognostic of outcome in a validation cohort (concordance statistic 0.62). An index developed in the United States by Rao et al., Transplantation 2009; 88: 231–236, included 15 factors and gave a concordance statistic of 0.63 in the UK context, suggesting that our much simpler model has equivalent predictive ability. Conclusions. A Kidney Donor Risk Index based on five donor variables provides a clinically useful tool that may help with organ allocation and informed consent.

Variation between centres in access to renal transplantation in UK: longitudinal cohort study

Objective To assess whether equity exists in access to renal transplantation in the UK after adjustment for case mix in incident patients with end stage renal disease. Design Longitudinal cohort study. Setting UK Renal Registry and UK Transplant Registry. Participants All incident renal replacement treatment patients (n=16 202) from 65 renal centres submitting data to the UK Renal Registry between 1 January 2003 and 31 December 2005, followed until 31 December 2008 (or until transplantation or death, whichever was earliest). Outcome measures Proportion of incident dialysis patients at each renal centre who were registered on the national transplant list; time taken to achieve registration; and proportion of patients subsequently transplanted. Results We found that recipients’ age, ethnicity, and primary renal diagnosis were associated with the likelihood of accessing the waiting list or receiving a transplant. After adjustment for case mix, significant inter-centre variability existed in access to the transplant list (change in −2LogL=89.9, df=1, P<0.001), in the time taken to register patients on the waiting list (change in −2LogL=247.4, df=64, P<0.001), in receipt of a renal transplant from a donor after brain stem death (change in −2LogL=15.1, df=1, P=0.001), and in receipt of a renal transplant from a living donor or a donor after cardiac death (change in −2LogL=46.1, df=1, P<0.001). Conclusions Significant variation in access to renal transplantation exists between centres within the UK that cannot be explained by differences in case mix.

Cancer transmission from organ donors-unavoidable but low risk.

Background Donor origin cancer (DOC) in transplant recipients may be transmitted with the graft (donor-transmitted cancer [DTC]) or develop subsequently from the graft (donor-derived cancer [DDC]). Methods Recipients with DOC between January 1, 2001, and December 31, 2010, were identified from the United Kingdom Transplant Registry and database search at transplantation centers. Results Of 30,765 transplants from 14,986 donors, 18 recipients developed DOC from 16 donors (0.06%): 3 were DDC (0.01%) and 15 were DTC (0.05%). Of the 15 DTCs, 6 were renal cell cancer; 5, lung cancer; 2, lymphoma; 1, neuroendocrine cancer; and 1, colon cancer. Recipients with DTC underwent explant/excision (11), chemotherapy (4), and radiotherapy (1). Of 15 recipients, 3 (20%) recipients with DTC died as a direct consequence of cancer. Early DTC (diagnosed ⩽6 weeks of transplantation) showed a better outcome (no DTC-related deaths in 11 cases) as opposed to late DTC (DTC-related deaths in 3 of 4 cases). Five-year survival was 83% for kidney recipients with DTC compared with 93% for recipients without DTC (P=0.077). None of the donors resulting in cancer transmission was known to have cancer at donation. Conclusions DTC is rare but frequently results in graft loss and death. The risk of cancer transmission cannot be eliminated because, in every case, the presence of cancer was not known at donation. This information will allow informed consent for prospective recipients. Explantation/excision is likely to benefit recipients with localized cancer, but in transplants other than kidney/pancreas, the benefits should be balanced against the risks of retransplantation.

Social deprivation, ethnicity, and uptake of living kidney donor transplantation in the United Kingdom

Background. Socioeconomic disparities and their contribution to the ethnic differences in living kidney donor transplantation have not been adequately studied. Methods. A total of 12,282 patients aged 18 to 69 years starting renal replacement therapy (January 1, 1997, to December 31, 2004) in the United Kingdom were included. Logistic regression models were used to examine probability of living donor transplantation within 3 years of renal replacement therapy. The effect of area deprivation (Townsend index) was studied among whites only adjusted for patient characteristics and the effect of ethnic origin (South Asians and blacks compared with whites) was then examined among all patients adjusting for area deprivation. Results. Among whites, increasing social deprivation was associated with lower odds of living donor transplantation. In the fully adjusted model, odds ratio (OR) for the most deprived quintile was 0.40 (95% confidence interval [CI] 0.33, 0.49; P trend<0.0001) compared with the least deprived. These gradients were more pronounced among centers performing more live donor transplants (P value for interaction <0.0001). South Asians and blacks had lower odds of living donor transplantation compared with whites, but there was an interaction with age (P<0.0001), so that this disparity was observed only in those younger than 50 years (blacks: OR, 0.31; 95% CI, 0.18, 0.54; South Asians: OR, 0.55; 95% CI, 0.34, 0.90; P value <0.0001). Conclusions. Socially deprived and younger ethnic minority patients have lower probability of living kidney donor transplantation. The extent to which these inequalities reflect modifiable societal healthcare system barriers and donor/recipient factors requires further study.

Impact of Cytomegalovirus on Long-term Mortality and Cancer Risk After Organ Transplantation.

Background There is conflicting evidence of the effect of cytomegalovirus (CMV) infection on survival and the risk of cancer after transplantation. Methods All recipients of kidney, liver, heart, and lung transplants in the United Kingdom between 1987 and 2007 with known CMV immunoglobulin G status were identified from the U.K. Transplant Registry. Based on the donor-recipient CMV status, recipients were grouped into: donor (D) negative recipient (R) negative (D− R−), D−R+, D + R+ and D + R−. Cancer data were obtained from the Office for National Statistics. The impact of CMV infection on survival and cancer incidence was assessed. Results The 10-year posttransplant survival in D−R− recipients (73.6% [95%CI, 72.3, 74.9]) was significantly higher (P < 0.0001) than in other recipients (66.1% [65.3, 66.9]). Compared with the D− R− group, the risk-adjusted hazard of death within 10 years of transplantation for D+ R− group was 14% higher for kidney recipients (P = 0.0495), 13% higher for liver recipients (P = 0.16), 34% higher for heart recipients (P = 0.01), and 35% higher for lung recipients (P = 0.006). The proportion of recipients with a cardiovascular cause of death was higher (P = 0.03) among the recipients exposed to CMV (18%) as compared to the D− R− recipients (16%). The CMV status was not associated with an increased risk of cancer. Conclusions The results from this large study demonstrate that CMV is associated with a significantly increased long-term mortality in kidney and cardiothoracic transplant recipients and an increased risk of cardiovascular death but not of posttransplant cancer.

The UK scheme for mandatory continuous monitoring of early transplant outcome in all kidney transplant centers.

Mandatory continuous monitoring of early transplant outcome with centralized oversight was introduced in 2004 for all 23 UK adult kidney transplant units. Risk-adjusted cumulative sum charts are used to assess 30-day graft and patient survival against past performance for each center, and change in transplant center performance is assessed by tabular cumulative sum charts. The monitoring scheme has performed as predicted from simulations used to establish outcome thresholds and has been validated by comparison with 1- and 5-year outcome data for all UK transplant centers. The value and limitations of the scheme are discussed along with changes that may improve its utility as a tool for self-assessment and central oversight.

Implications of changing the minimal survival benefit in liver transplantation

The limited availability of livers donated by deceased donors for transplantation means that not everyone who might benefit from the procedure can receive a graft, so any selection and allocation system must have clearly defined goals. The United Kingdom, in common with many other countries, has adopted a minimum benefit criterion of a greater than 50% probability of survival 5 years after transplantation. We investigated the impact of changing this minimum benefit criterion on a case mix of listed patients. The analysis was based on 5330 adult elective patients who underwent transplantation with livers from donation after brain death donors between January 1994 and December 2007. We examined the impact of balancing the number of registrations on the list with the number of available donor livers while allowing a 10% mortality rate and found that this would require a survival threshold of at least 74% at 5 years. According to historical data, the application of this more stringent criterion would significantly reduce the eligibility of older and nonwhite patients and patients with hepatocellular carcinoma or hepatitis C virus infections. Thus, if such undesirable restrictions on access to liver transplantation are to be avoided, we must consider alternative strategies such as the acceptance of higher transplant list mortality. Liver Transpl, 2012.