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.

Twenty-eight years of intestinal transplantation in Paris: experience of the oldest European center.

Our aim was to describe our achievements in pediatric intestinal transplantation (ITx) and define areas for improvement. After a period (1987-1990) of nine isolated small bowel transplants (SBTx) where only one patient survived with her graft, 110 ITx were performed on 101 children from 1994 to 2014: 60 SBTx, 45 liver-small bowel, four multivisceral (three with kidneys), and one modified multivisceral. Indications were short bowel syndrome (36), motility disorders (30), congenital enteropathies (34), and others (1). Induction treatment was introduced in 2000. Patient/graft survival with a liver-containing graft or SBTx was, respectively, 60/41% and 46/11% at 18 years. Recently, graft survival at 5/10 years was 44% and 31% for liver-containing graft and 57% and 44% for SBTx. Late graft loss occurred in 13 patients, and 7 of 10 retransplanted patients died. The main causes of death and graft loss were sepsis and rejection. Among the 55 currently living patients, 21 had a liver-containing graft, 19 a SBTx (17 after induction), and 15 were on parenteral nutrition. ITx remains a difficult procedure, and retransplantation even more so. Over the long term, graft loss was due to rejection, over-immunosuppression was not a significant problem. Multicenter studies on immunosuppression and microbiota are urgently needed.

Who is the best donor for a related HLA haplotype-mismatched transplant?

The best donor for a related donor for a human leukocyte antigen (HLA) haplotype-mismatched transplant for hematological neoplasms is controversial. We studied outcomes in 1210 consecutive transplant recipients treated on a uniform protocol. Younger donors and male donors were associated with less nonrelapse mortality (NRM; hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.01-0.39; P = .008 and HR = 0.65; 95% CI = 0.49-0.85; P = .002) and better survival (HR = 0.73; 95% CI = 0.54-0.97; P = .033 and HR = 0.73; 95% CI = 0.59-0.91; P = .005). Father donors were associated with less NRM (HR = 0.65; 95% CI = 0.45-0.95; P = .02), acute graft-versus-host disease (GVHD) (HR = 0.69; 95% CI = 0.55-0.86; P = .001), and better survival (HR = 0.66; 95% CI = 0.50-0.87; P = .003) compared with mother donors. Children donors were associated with less acute GVHD than sibling donors (HR = 0.57; 95% CI = 0.31-0.91; P = .01). Older sister donors were inferior to father donors with regard to NRM (HR = 1.87; 95% CI = 1.10-3.20; P = .02) and survival (HR = 1.59; 95% CI = 1.05-2.40; P = .03). Noninherited maternal antigen-mismatched sibling donors were associated with the lowest incidence of acute GVHD compared with parental donors and noninherited paternal antigen-mismatched sibling donors. Specific HLA disparities were not significantly correlated with transplant outcomes. Our data indicate which HLA haplotype-mismatched related donors are associated with the best transplant outcomes in persons with hematological neoplasms.

Long-term mortality in adult orthotopic heart transplant recipients.

Heart transplantation is now regarded as the treatment of choice for end-stage heart failure. To improve long-term results of the heart transplantation, we analyzed causes of death relative to time after transplantation. A total of 201 consecutive patients, 154 (76.6%) males, aged ≥ 17 yr underwent heart transplantation between November 1992 and December 2008. Mean ages of recipients and donors were 42.8 ± 12.4 and 29.8 ± 9.6 yr, respectively. The bicaval anastomosis technique was used since 1999. Mean follow up duration was 6.5 ± 4.4 yr. Two patients (1%) died in-hospital due to sepsis caused by infection. Late death occurred in 39 patients (19.4%) with the most common cause being sepsis due to infection. The 1-, 5-, and 10-yr survival rates in these patients were 95.5% ± 1.5%, 86.9% ± 2.6%, and 73.5% ± 4.1%, respectively. The surgical results of heart transplantation in adults were excellent, with late mortality due primarily to infection, malignancy, and rejection. Cardiac deaths related to cardiac allograft vasculopathy were very rare.

Transplantation risks and the real world: what does 'high risk' really mean?

Candidates for, and recipients of, transplants face numerous risks that receive varying degrees of attention from the media and transplant professionals. Characterizations such as 'high risk donor' are not necessarily accurate or informative unless they are discussed in context with the other risks patients face before and after transplantation. Moreover, such labels do not provide accurate information for informed consent discussions or decision making. Recent cases of donor-transmitted diseases from donors labeled as being at 'high risk' have engendered concern, new policy proposals and attempts to employ additional testing of donors. The publicity and policy reactions to these cases do not necessarily better inform transplant candidates and recipients about these risks. Using comparative risk analysis, we compare the various risks associated with waiting on the list, accepting donors with various risk characteristics, posttransplant survival and everyday risks we all face in modern life to provide some quantitative perspective on what 'high risk' really means for transplant patients. In our analysis, donor-transmitted disease risks are orders of magnitude less than other transplantation risks and similar to many everyday occupational and recreational risks people readily and willingly accept. These comparisons can be helpful for informing patients and guiding future policy development.

Innovations in the assessment of transplant center performance: implications for quality improvement.

Continuous quality improvement efforts have become a central focus of leading health care organizations. The transplant community has been a pioneer in periodic review of clinical outcomes to ensure the optimal use of limited donor organs. Through data collected from the Organ Procurement and Transplantation Network (OPTN) and analyzed by the Scientific Registry of Transplant Recipients (SRTR), transplantation professionals have intermittent access to specific, accurate and clinically relevant data that provides information to improve transplantation. Statistical process control techniques, including cumulative sum charts (CUSUM), are designed to provide continuous, real-time assessment of clinical outcomes. Through the use of currently collected data, CUSUMs can be constructed that provide risk-adjusted program-specific data to inform quality improvement programs. When retrospectively compared to currently available data reporting, the CUSUM method was found to detect clinically significant changes in center performance more rapidly, which has the potential to inform center leadership and enhance quality improvement efforts.

Survival of patients identified as candidates for intestinal transplantation: a 3-year prospective follow-up.

BACKGROUND & AIMS: The US Medicare indications for intestinal transplantation are based on failure of home parenteral nutrition. The American Society of Transplantation also includes patients at high risk of death from their primary disease or with high morbidity intestinal failure. A 3-year prospective study evaluated the appropriateness of these indications. METHODS: Survival on home parenteral nutrition or after transplantation was analyzed in 153 (97 adult, 56 pediatric) candidates for transplantation and 320 (262 adult, 58 pediatric) noncandidates, enrolled through a European multicenter cross-sectional survey performed in 2004. Kaplan-Meier and chi-square test statistics were used. RESULTS: The 3-year survival was 94% (95% CI, 92%-97%) in noncandidates and 87% (95% CI, 81%-93%) in candidates not receiving transplants (P = .007). Survival was 80% (95% CI, 70%-89%), 93% (95% CI, 86%-100%), and 100% in parenteral nutrition failure, high-risk primary disease, and high-morbidity intestinal failure, respectively (P = .034). Fifteen candidates underwent transplantation. Six died, including all 3 of those who were in hospital, and 25% of those who were at home at time of transplantation (P = .086). Survival in the 10 patients receiving a first isolated small bowel transplant was 89% (95% CI, 70%-100%), compared with 85% (95% CI, 74%-96%) in the candidates with parenteral nutrition failure not receiving transplants because of central venous catheter complications, or 70% (95% CI, 53%-88%) in those with parenteral nutrition-related liver failure (P = .364). CONCLUSIONS: The results confirm home parenteral nutrition as the primary therapeutic option for intestinal failure and support the appropriateness and potential life-saving role of timely intestinal transplantation for patients with parenteral nutrition failure.

Preventable death: children on the transplant waiting list.

Children, especially those under 5 years of age, have the highest death rate on the transplant waiting list compared to any other age range. This article discusses the concept, supported by OPTN data, that there is an age range of small pediatric donors, which are almost exclusively transplanted into small pediatric transplant candidates. Allocation policies that allow broader sharing of small pediatric donors into small pediatric candidates are likely to decrease death rates of children on the waiting list. As well, although the number of pediatric deceased donors continues to decline, improving consent rates for eligible pediatric donors, and judicious use of pediatric donors after cardiac death, can enhance the pediatric deceased donor supply.

Survival advantage of pediatric recipients of a first kidney transplant among children awaiting kidney transplantation.

The mortality rate in children with ESRD is substantially lower than the rate experienced by adults. However, the risk of death while awaiting kidney transplantation and the impact of transplantation on long-term survival has not been well characterized in the pediatric population. We performed a longitudinal study of 5961 patients under age 19 who were placed on the kidney transplant waiting list in the United States. Of these, 5270 received their first kidney transplant between 1990 and 2003. Survival was assessed via a time-varying nonproportional hazards model adjusted for potential confounders. Transplanted children had a lower mortality rate (13.1 deaths/1000 patient-years) compared to patients on the waiting list (17.6 deaths/1000 patient-years). Within the first 6 months of transplant, there was no significant excess in mortality compared to patients remaining on the waiting list (adjusted Relative Risk (aRR) = 1.01; p = 0.93). After 6 months, the risk of death was significantly lower: at 6-12 months (aRR = 0.37; p < 0.001) and at 30 months (aRR 0.26; p < 0.001). Compared to children who remain on the kidney transplant waiting list, those who receive a transplant have a long-term survival advantage. With the potential for unmeasured bias in this observational data, the results of the analysis should be interpreted conservatively.

Classification of death causes after transplantation (CLASS): Evaluation of methodology and initial results.

Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry.

A recipient risk score for deceased donor renal allocation.

BACKGROUND: The current shortage of deceased donor kidneys makes it difficult to design a kidney allocation scheme that balances optimal utility with supply. The aim of this study is to derive a recipient risk score (RRS) that could be used with the deceased donor score (DDS) to maximize the total number of years of renal allograft function as a means to improve allocation. METHODS: We retrospectively reviewed 47,535 adult recipients of deceased donor renal transplants between 1995 and 2002 from the United Network for Organ Sharing Standard Transplant Analysis and Research Files. Multivariable Cox regression models were used to derive an RRS and estimate recipient and graft survival as a function of RRS. Annual rates of organ supply and recipient demand for deceased donor kidneys were estimated from expectancy data and expressed in renal years (years provided by a functioning kidney allograft). Renal-year analyses were used to optimize allocation. RESULTS: The strongest predictors of recipient survival after transplantation used in the RRS were recipient age, history of diabetes mellitus, history of angina, and time on dialysis therapy. When used with DDS, RRS provided a utility-based allocation system for deceased donor kidneys that theoretically increased the annual (2002) rate of supply by 15%. CONCLUSION: The RRS is a practical system that, when combined with a method to assess donor organs, such as DDS, may improve deceased donor renal allocation.

Excess risk of renal allograft loss and early mortality among elderly recipients is associated with poor exercise capacity.

BACKGROUND: Successful renal transplantation in the elderly offers substantial benefits in quality and life expectancy. However, in this group of patients there is an early increased risk of death compared with those remaining on dialysis. MATERIALS AND METHODS: Graft and patient outcomes in 64 older transplant recipients were compared with 338 patients aged 18 - 59 years. We identified potential risk factors that may predict clinical outcomes in older transplant recipients. A log-rank test and Cox regression analyses were performed to assess the impact of various patient characteristics on graft and patient survival. RESULTS: Among older patients, graft survival was 76.6% and 67% at 1 and 3 years, respectively. When graft survival was censored for death with functioning graft, the 1- and 3-year graft survival was 83% and 82%, respectively. Patient survival was 78% and 71% at 1 and 3 years, respectively. These survival rates were significantly lower than those of younger recipients. Pretransplant inactivity, delayed graft function, smoking history and longer waiting time predicted poor graft and patient survival. A history of chronic obstructive pulmonary disease, and peripheral vascular disease also predicted a higher mortality among older recipients. CONCLUSION: Older kidney transplant recipients are at high risk for allograft failure and early death. Poor functional capacity predicts a poor outcome for older patients undergoing renal transplantation. Therefore, careful patient selection is paramount, and every effort should be made to initiate timely interventions aimed at increasing physical activity in those with low fitness level.

Pediatric liver transplant recipients: mortality analysis over 20 years.

Orthotropic liver transplantation (OLT) has become standard and accepted care for pediatric patients with end-stage liver disease. Two large pediatric OLT series are analyzed to determine excess death rates (EDR) over 20 years. The EDR decreases over time and is lower with more recent transplant recipients who have benefited from improved tacrolimus-based immunosuppression and transplant techniques. Fifteen- to 20-year EDR is 5 deaths/1000. Biliary atresia is the most common pediatric indication, and these recipients do better than those with other types of liver disease. Most deaths occur in the first post-transplant year, with infection being the largest cause.

De novo colorectal cancer: five-year survival is markedly lower in transplant recipients compared with the general population.

INTRODUCTION: The biological behavior of most solid tumors in transplant recipients has not been adequately compared to the general population. The purpose of the present study was to compare outcomes in de novo colorectal cancer (CRC) following solid organ transplantation to those observed in the general population (SEER) database. METHODS: All transplant recipients with de novo CRC in the Israel Penn International Transplant Tumor Registry were identified and analyzed and the data were compared to CRC patients in the SEER National Cancer Institute (NCI) database. RESULTS: One hundred and fifty transplant recipients with de novo CRC were identified, among which were 93 (62%) kidney, 29 (19.3%) heart, 27 (18%) liver, and 1 (0.7%) lung recipients. Median age of transplant recipients was 54 years, compared to a median age of 72 years for patients in the SEER NCI database. However, compared to patients from the SEER NCI database, recipients with Duke's A through C stage disease were noted to experience a significant decrease in 5-year survival. The results in Duke's C patients were particularly dismal. CONCLUSIONS: The early age at presentation of CRC in transplant recipients suggests that the development of de novo CRC may be effected by immunosuppression. Decreased 5-year survival rates in transplant recipients compared to the general population suggest that CRC in transplant patients is biologically more aggressive. These data cannot distinguish whether the lower survival rates are because the CRC are inherently biologically more aggressive or whether immunosuppression allows for more aggressive clinical behavior of CRC.

Renal transplantation in the elderly--the Irish experience.

BACKGROUND: The aim of this paper was to evaluate patient and kidney graft survival rates in renal transplant recipients and compare the outcomes between the different patient age groups. METHODS: A retrospective review of all adult renal transplants performed at Beaumont Hospital between the years 1986-2001 was carried out. Patients were defined as 'elderly' if they were 65 years of age or older and 'younger' if less than 65 years at the time of transplantation. Patient and transplant graft survival rates were analysed for each age group. RESULTS: Data were analysed on 1462 'younger' patients and 105 'elderly' renal transplant recipients. Estimated patient survival at 1, 5 and 10 years were 96%, 87% and 74% in the younger patient group compared to 85%, 59% and 33% in the elderly group. The adjusted graft survival rates (adjusted for death due to other causes and with a functioning graft in situ) for the younger group were 89%, 77% and 64% at one, five and ten years respectively, while for the elderly group, adjusted one, five and ten year survival rates were 89%, 83% and 70% respectively. CONCLUSIONS: Although the elderly have a shorter life expectancy than the younger population they do benefit from renal transplantation similar to the younger recipients.

100 second renal allografts from a single transplantation institution.

Between January 1, 1968 and March 1977, 100 of 131 patients who lost their first transplant at the University of Minnesota received a second renal allograft. Overall patient survival in the retransplanted group was 10% less than that in the dialysis group. The best results (graft function and patient survival were seen in young patients, nondiabetics, patients who received two sequential living related groups, and in those whose first graft was lost secondary to chronic rejection. The poorest results were seen in older patients (greater than 40 years), diabetics, and patients with acute rejection during the initial graft. Shared donor antigens do not affect graft outcome. These findings, although not the product of a randomized prospective study, may be useful in advising patients of the relative risks of retransplantation or hemodialysis.