Multiply imputing missing values arising by design in transplant survival data.

In this article, we address a missing data problem that occurs in transplant survival studies. Recipients of organ transplants are followed up from transplantation and their survival times recorded, together with various explanatory variables. Due to differences in data collection procedures in different centers or over time, a particular explanatory variable (or set of variables) may only be recorded for certain recipients, which results in this variable being missing for a substantial number of records in the data. The variable may also turn out to be an important predictor of survival and so it is important to handle this missing-by-design problem appropriately. Consensus in the literature is to handle this problem with complete case analysis, as the missing data are assumed to arise under an appropriate missing at random mechanism that gives consistent estimates here. Specifically, the missing values can reasonably be assumed not to be related to the survival time. In this article, we investigate the potential for multiple imputation to handle this problem in a relevant study on survival after kidney transplantation, and show that it comprehensively outperforms complete case analysis on a range of measures. This is a particularly important finding in the medical context as imputing large amounts of missing data is often viewed with scepticism.

Mid- and Long-Term Health Risks in Living Kidney Donors: A Systematic Review and Meta-analysis.

Background: Long-term health risks for adults who donate kidneys are unclear. Purpose: To summarize evidence about mid- and long-term health risks associated with living kidney donation in adults. Data Sources: PubMed, Embase, Scopus, and PsycINFO without language restriction from April 1964 to July 2017. Study Selection: Observational studies with at least 1 year of follow-up that compared health outcomes in adult living kidney donors versus nondonor populations. Data Extraction: Two investigators independently extracted study data and assessed study quality. Data Synthesis: 52 studies, comprising 118 426 living kidney donors and 117 656 nondonors, were included. Average follow-up was 1 to 24 years. No evidence suggested higher risk for all-cause mortality, cardiovascular disease, hypertension, type 2 diabetes, or adverse psychosocial health outcomes in living kidney donors than in nondonor populations. Donors had higher diastolic blood pressure, lower estimated glomerular filtration rates, and higher risk for end-stage renal disease (ESRD) (relative risk [RR], 8.83 [95% CI, 1.02 to 20.93]) and preeclampsia in female donors (RR, 2.12 [CI, 1.06 to 4.27]). Despite the increased RR, donors had low absolute risk for ESRD (incidence rate, 0.5 event [CI, 0.1 to 4.9 events] per 1000 person-years) and preeclampsia (incidence rate, 5.9 events [CI, 2.9 to 8.9 events] per 100 pregnancies). Limitation: Generalizability was limited by selected control populations, few studies reported pregnancy-related outcomes, and few studies were from low- and middle-income countries. Conclusion: Although living kidney donation is associated with higher RRs for ESRD and preeclampsia, the absolute risk for these outcomes remains low. Compared with nondonor populations, living kidney donors have no increased risk for other major chronic diseases, such as type 2 diabetes, or for adverse psychosocial outcomes. Primary Funding Source: National Health Service Blood and Transplant and National Institute for Health Research. (PROSPERO: CRD42017072284).

The effect of differing kidney disease treatment modalities and organ donation and transplantation practices on health expenditure and patient outcomes.

The Effect of Differing Kidney Disease Treatment Modalities and Organ Donation and Transplantation Practices on Health Expenditure and Patient Outcomes (EDITH) aims to obtain information on long-term kidney transplant outcomes, long-term health outcomes of living kidney donors and detailed outcomes and costs related to the different treatment modalities of end-stage kidney disease. Nine partners from seven European Union countries will participate in this project.

Protocol of a randomised controlled, open-label trial of ex vivo normothermic perfusion versus static cold storage in donation after circulatory death renal transplantation.

INTRODUCTION: Ex vivo normothermic perfusion (EVNP) is a novel technique that reconditions the kidney and restores renal function prior to transplantation. Phase I data from a series of EVNP in extended criteria donor kidneys have established the safety and feasibility of the technique in clinical practice. METHODS AND ANALYSIS: This is a UK-based phase II multicentre randomised controlled trial to assess the efficacy of EVNP compared with the conventional static cold storage technique in donation after circulatory death (DCD) kidney transplantation. 400 patients receiving a kidney from a DCD donor (categories III and IV, controlled) will be recruited into the study. On arrival at the transplant centre, kidneys will be randomised to receive either EVNP (n=200) or remain in static cold storage (n=200). Kidneys undergoing EVNP will be perfused with an oxygenated packed red cell solution at near body temperature for 60 min prior to transplantation. The primary outcome measure will be determined by rates of delayed graft function (DGF) defined as the need for dialysis in the first week post-transplant. Secondary outcome measures include incidences of primary non-function, the duration of DGF, functional DGF defined as <10% fall in serum creatinine for 3 consecutive days in the first week post-transplant, creatinine reduction ratio days 2 and 5, length of hospital stay, rates of biopsy-proven acute rejection, serum creatinine and estimated glomerular filtration rate at 1, 3, 6 and 12 months post-transplant and patient and allograft survival. The EVNP assessment score will be recorded and the level of fibrosis and inflammation will also be measured using tissue, blood and urine samples. Ethics and dissemination. The study has been approved by the National Health Service (NHS) Health Research Authority Research Ethics Committee. The results are expected to be published in 2020. TRIAL REGISTRATION NUMBER: ISRCTN15821205; Pre-results.

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.

Intracranial haemorrhage in thrombocytopenic haematology patients--a nested case-control study: the InCiTe study protocol.

INTRODUCTION: Intracranial haemorrhage (ICH) is one of the most serious side-effects of severe thrombocytopenia in haematology patients. ICH is rare, but can have devastating consequences (death or major morbidity). It is unknown why some patients with severe thrombocytopenia bleed and others do not. STUDY AIMS: Primary aim was to identify risk factors for ICH in patients with haematological malignancies. Secondary aims were to identify short-term outcomes for these patients at 30 days (major morbidity and mortality) and produce a more accurate estimate of ICH incidence in this population. This information is key to identifying means to improve treatment and quality of care. METHODS/ANALYSIS: This is a UK-wide case-control study of ICH nested within a 4-year prospective surveillance study set up specifically for the case-control study. Each case will be matched to one control. Cases will be adult haematology patients (≥16 years) who have had any type or severity of ICH who are receiving, about to receive or have just received myeloablative chemotherapy (defined as chemotherapy expected to cause a significant thrombocytopenia <50×10(9)/L for >5 days) or a haemopoietic stem cell transplant. Only patients being treated with curative intent will be included. Controls will be patients who fulfil the same inclusion criteria as cases (apart from ICH) and were treated at the same hospital immediately before the index case. Cases and controls will be matched to type of treatment (myeloablative chemotherapy or haemopoietic stem cell transplant). Hospitals across the UK will participate in a monthly email reporting strategy (started June 2011), as to whether a case of ICH occurred during the preceding calendar month. Case and control forms will be sent to any hospital reporting an eligible case. Conditional logistic regression will be used to calculate ORs. Denominator data for incidence estimates will use national registry data. STUDY REGISTRATION: ISRCTN05026912 (prospective registration). NIHR Portfolio (UKCRN ID 10712).

The making of a pan-European organ transplant registry.

A European patient registry to track the outcomes of organ transplant recipients does not exist. As knowledge gleaned from large registries has already led to the creation of standards of care that gained widespread support from patients and healthcare providers, the European Union initiated a project that would enable the creation of a European Registry linking currently existing national databases. This report contains a description of all functional, technical, and legal prerequisites, which upon fulfillment should allow for the seamless sharing of national longitudinal data across temporal, geographical, and subspecialty boundaries. To create a platform that can effortlessly link multiple databases and maintain the integrity of the existing national databases crucial elements were described during the project. These elements are: (i) use of a common dictionary, (ii) use of a common database and refined data uploading technology, (iii) use of standard methodology to allow uniform protocol driven and meaningful long-term follow-up analyses, (iv) use of a quality assurance mechanism to guarantee completeness and accuracy of the data collected, and (v) establishment of a solid legal framework that allows for safe data exchange.

Strategies for expanding the UK pool of potential intestinal transplant donors.

BACKGROUND: The pool of suitable donors and listed recipients for intestinal transplantation is small, resulting in difficulties in donor-to-recipient matching and significant mortality on the waiting list. This study aims to help define the pool of potential donors for intestinal transplantation and propose methods for an increased utilization of donor bowels in the United Kingdom. METHODS: Data on bowel offering from 657 donors after brain stem death (DBD) and on 46 patients on the active intestinal transplant list over 12 months from 14 April 2011 were obtained from the UK Transplant Registry. RESULTS: Family consent for bowel donation was lower than for the other transplantable organs. Only 57% of bowels from DBD donors with consent and meeting the bowel offering criteria were offered for transplantation. A lack of suitable recipients was the most common reason cited for not offering. Only 10% of offered bowels were accepted and transplanted by centers. Donor size discrepancy and human leukocyte antigen incompatibility were common reasons for declining offers of the bowel. There was a scarcity of young and small donors compared with the number of young and small patients requiring a transplant. Two patients who were on the active list during the time period died. CONCLUSIONS: An increased awareness of bowel donation is needed to improve the low offering rate of bowels from DBD donors. A more robust UK bowel allocation system and a formalized European-wide intestinal donor organ sharing program should lead to an increased utilization of available donor bowels and a lower waiting list mortality rate.

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.

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.

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.

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.

Social deprivation, ethnicity, and access to the deceased donor kidney transplant waiting list in England and Wales.

BACKGROUND: Socioeconomic and ethnic inequity in access to kidney transplant waiting list has been described in the United States but not examined in a universal healthcare system. METHODS: Eleven thousand two hundred ninety-nine patients aged 18 to 69 years starting renal replacement therapy (January 1, 1997 to December 31, 2004) in England and Wales were included. Multivariable Cox proportional hazards models were used to assess time to activation on the transplant waiting list for socially deprived patients among white patients. The effect of ethnic origin (South Asians and blacks compared with whites) was examined among all patients. RESULTS: Among white patients, in the fully adjusted model, the hazard ratio (HR) for the most deprived quintile was 0.60 (95% confidence interval [CI] 0.54-0.68, P trend <0.0001) compared with the least deprived. Deprivation effects were more pronounced among those 50 years and older (P value for interaction <0.0001). Non-whites had a lower risk of being waitlisted than whites (for blacks: HR 0.89, 95% CI 0.79-1.01; for South Asians: HR 0.91, 95% CI 0.83-0.99, P value for heterogeneity=0.03). These differences were attenuated in a fully adjusted model. However non-whites who were 50 years and older were more likely to be transplant waitlisted than whites (interaction P=0.002). CONCLUSIONS: Individuals living in socially deprived areas have reduced access to the transplant waiting list. Understanding the reasons for this apparent inequity is important if we wish to ensure equitable access to renal transplants. There were no major differences by ethnicity, and if anything, older white patients were less likely to be waitlisted.

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.

Organ allocation in the United Kingdom.

Organ allocation procedures in the United Kingdom are monitored on a regular basis. Changes are frequently made to improve equity of access and outcomes, based on the performance of a current scheme and simulations of alternatives. This article summarizes current arrangements for the allocation of kidneys, livers and cardiothoracic organs, and illustrates the monitoring process. A new national pancreas allocation scheme is outlined and forthcoming developments in the allocation of livers and DCD donor kidneys are summarized.

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.

The effect of mycophenolate mofetil and azathioprine dose on renal allograft outcome in the United kingdom.

BACKGROUND: Mycophenolate mofetil (MMF) therapy compared with azathioprine has not led to improved long-term renal allograft outcomes perhaps as MMF dose is limited by tolerability and dose reduction is associated with inferior graft outcome. The consequences, however, of dose reduction of mycophenolate mofetil relative to azathioprine have not been reported. METHOD: We studied dosing patterns of MMF and azathioprine in the first year after transplantation and their impact on graft outcome after renal transplantation between 1999 and 2002 in the United Kingdom. RESULTS: Sixty-two percent of patients were found to be taking less than 2 g of MMF and 45% were taking less than 100 mg of azathioprine at 1 year after transplantation. Graft outcome was comparable in patients receiving 2 g or more of MMF (n=209), 1 to 2 g of MMF (n=267), and 100 mg or more of azathioprine (n=504) at 1 year after transplantation. Less than 1 g of MMF (n=71) and less than 100 mg of azathioprine (n=413) was associated with a 3-fold and 2-fold increased 4.5 year risk-adjusted hazard ratio (HR) of graft failure, respectively, with reduced graft function. Finally, less than 1 g of MMF was not superior to less than 100 mg of azathioprine. CONCLUSION: Azathioprine levels are not routinely measured and long-term results of concentration controlled MMF studies are awaited. Currently, dose is a useful measure of drug exposure. This study suggests that less than 1 g of MMF and less than 100 mg of azathioprine are associated with inferior graft outcome.

Kidney donation and transplantation in the UK from 1998 to 2007.

There are many changes happening in donation and transplantation in the UK and this review provides a baseline against which the success of future developments can be assessed. There has been a decrease in donation after brain death over the 10-year review period, but increases in both donation after cardiac death and living kidney donation. Antibody incompatible transplantation and paired and altruistic donation programmes are starting to have an impact on the number of living donor transplants carried out and are expected to make a more marked impact in the years ahead. A new national Kidney Allocation Scheme for deceased donors after brain death was introduced in 2006 to replace the previous scheme implemented in 1998. The 2006 scheme aims to improve equity of access to transplant and is showing significant benefits for long-waiting patients. To ensure that all UK transplant centres continue to achieve high standards, both within- and across-centre monitoring of graft and patient outcomes is routinely undertaken and reported. The most important factor in increasing organ donation and transplantation in the UK is the government funding that has been provided to develop national organ donation infrastructures. These major changes are expected to have a significant impact on numbers of donors and transplants in the next 5 years.

Splitting livers - balancing the gain and the pain.

Division of donor livers has allowed effective expansion of the donor pool and has been associated with a reduction in the mortality of children awaiting liver transplantation. However, adult recipients of a split graft tend to have inferior transplant survival, compared with recipients of a whole graft. We have analysed the impact of the splitting programme at a particular centre on the life-years lost or gained in both adult and paediatric recipients. We estimate that at 1 year after transplantation, splitting livers has resulted in a gain of five life-years for the paediatric recipients with a loss of six adult patient years; at 5 years post-transplant, a gain of 25 life-years for the paediatric recipients balances a loss of 30 life-years for adult recipients. While this analysis is based on a number of assumptions, and so the results must be treated with caution, it does give rise to a number of ethical considerations which require open and public debate.