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.

Avaliação de uma coorte de transplante cardíaco por escore relacionado ao doador / Assessment of a heart transplantation cohort using a donor-related scoring system

Existem poucos sistemas de avaliação de mortalidade após transplante cardíaco (TC) que se baseiem em fatores relacionados com o doador e que sejam capazes de predizer o prognóstico. Identificar características dos doadores que têm impacto na sobrevida depois do TC pode contribuir para melhorar os resultados e a alocação de órgãos. Aplicamos um sistema de avaliação americano para predizer a mortalidade pós-TC em uma coorte brasileira. Objetivo: Avaliar um escore americano como preditor de mortalidade depois de TC em uma coorte brasileira. Métodos: Análise de uma base de dados de um centro de TC brasileiro de 2013 a 2015. Foram avaliadas quatro características dos doadores: tempo de isquemia, idade do doador, discordância racial doador/receptor e a função renal do doador. A sobrevida foi estimada pelo teste de log-rank em faixas de pontuação pré-determinadas. Resultados: Foram 110 doadores, 89% homens e 62% brancos. A principal causa de morte foi trauma (66,6%). Os doadores tinham em média 29,8 anos, 18,6 de relação Nitrogênio da ureia sanguínea / Creatinina, 175 minutos de tempo de isquemia e 42% de discordância racial com o receptor. Não houve diferença de sobrevida entre as faixas de pontuação. Conclusão: Apesar de preditor de mortalidade após transplante cardíaco em uma população americana, esse escore não foi útil para uma coorte de transplante brasileira. As diferenças, inclusive a alta taxa de miscigenação pode ser uma explicação para esses achados

here are few systems to assess mortality after heart transplantation (CT) that are based on donor-related factors and can predict prognosis. Identifying donor characteristics that impact post-CT survival can contribute to improved outcomes and organ allocation. We applied a US evaluation system to predict mortality after CT in a Brazilian cohort. Objective: To evaluate an American score as a predictor of mortality following CT in a Brazilian cohort. Method: Database analysis of a Brazilian CT center from 2013 to 2015. Four donor characteristics were evaluated: ischemia time, donor age, donor-recipient race mismatch, and donor renal function. Survival was estimated by the log-rank test in predetermined score ranges. Results: There were 110 donors, 89% male and 62% white. The main cause of death was trauma (66.6%). Donors had a mean age of 29.8 years, a mean blood urea nitrogen / creatinine ratio of 18.6, a mean ischemia time of 175 minutes, and race mismatch with the recipient of 42%. There was no difference in survival between the score ranges. Conclusion: Although it was a predictor of mortality after cardiac transplantation in an American population, this score was not useful for a Brazilian transplant cohort. Differences, including the high rate of miscegenation, may explain these findings

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.

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.

Clostridium difficile infection increases mortality risk in lung transplant recipients.

BACKGROUND: Clostridium difficile infection (CDI) and associated mortality in solid organ transplant recipients is rising, but data are scarce in lung transplant recipients. We aimed to characterize CDI and its effect on mortality in a large cohort of lung transplant recipients. METHODS: Lung transplant recipients were identified from our transplant database from 2000 to 2011. Cox proportional hazard models were used to calculate hazard ratios for CDI and death after adjusting for potential confounders identified from bivariate analysis. RESULTS: We identified 388 patients (196 female, 192 male), with a median age of 56 years (range, 8-75 years), during the study period. CDI developed after transplant in 89 (22.9%), with 27 (7.0%) developing CDI during the initial hospitalization at a mean diagnosis of 12.7 ± 11.4 days. Incidence varied widely each year (median, 24%; range, 5%-32%), with the highest rates in 2007 to 2008. Post-operative length of stay was identified as a significant predictor of CDI (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01-1.03). Early CDI was an independent significant predictor of death (HR, 1.96; 95% CI, 1.14-3.36) as well as CDI anytime after transplant (HR, 1.61; 95% CI, 1.02-2.52). CONCLUSIONS: CDI rates varied widely from 2000 through 2011, with the highest rates in 2007 to 2008. Lung transplant recipients who developed CDI had a higher risk of death, especially when CDI occurred in the first 6 months after transplant.

Alcohol consumption, new onset of diabetes after transplantation, and all-cause mortality in renal transplant recipients.

BACKGROUND: Renal transplant recipients (RTR) are often advised to refrain from alcohol because of possible interaction with their immunosuppressive medication. Although moderate alcohol consumption is associated with reduced risk of diabetes and mortality in the general population, this is unknown for RTR. Therefore, we investigated the association of alcohol consumption with new onset of diabetes after transplantation (NODAT), mortality, and graft failure in RTR. METHOD: RTR were investigated between 2001 and 2003. Alcohol consumption was assessed by self-report. Mortality and graft failure was recorded until May 2009. RESULTS: Six hundred RTR were studied (age 51 ± 12 years, 55% men). Of these RTR, 48% were abstainers, 38% had light alcohol intake, 13% had moderate intake, and 1% were heavy consumers. Moderate alcohol consumption was associated with a lower risk of developing NODAT over the follow-up period than was abstention (OR = 0.36 [0.2-0.6], P = <0.001). During follow-up for 7.0 years [6.2-7.5 years], 133 recipients died. In Cox regression analyses, moderate alcohol consumption was associated with lower mortality period than was abstention (hazard ratio = 0.40 [0.2-0.8], P = 0.009). Adjustment for confounders, including age and smoking, did not materially change this association. No association was found between alcohol consumption and graft failure. CONCLUSIONS: Moderate alcohol consumption is associated with low prevalence of NODAT and reduced risk for mortality in RTR, in line with findings in the general population. These findings refute the common advice to refrain from alcohol in RTR.

Long-term outcome in kidney transplant recipients over 70 years in the Eurotransplant Senior Kidney Transplant Program: a single center experience.

BACKGROUND: Kidney transplantation in the elderly is complicated by comorbidities and a higher incidence of death. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys from older donors to the increasing number of older recipients. In this retrospective, single center data analysis, we compare the outcome of recipients older than 70 years with younger recipients transplanted under the ESP protocol. METHODS: Between 1999 and 2009, a total of 83 kidneys were transplanted under the ESP protocol in Innsbruck and 19 of the recipients were older than 70 years (mean, 72.7 years). Cold ischemia time was kept short in both groups by giving preference to regional donor organs. RESULTS: Patient survival at 1 and 5 years were 95% and 67% in the 70+ group and 94.4% and 82.6% in the 70- group. Graft survival was 95% and 52% at 1 and 5 years in the 70+ group and 94.4% and 79.0% in the 70- group. When censored for death, graft survival at year 1 and 5 were 100% and 82% in the 70+ group and 98.1% and 92.7% in the 70- group. The delayed graft function rate was high in both groups (36.8% and 41.1%, respectively). Morbidities were largely related to hemodynamic, oncologic, and infectious events. Cardiac failure was the major cause of death. CONCLUSION: Relatively good results can be achieved with renal transplantation in patients older than 70 years under careful pretransplant evaluation and postoperative management of comorbidities.

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.

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 > or = 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.

European homograft bank: twenty years of cardiovascular tissue banking and collaboration with transplant coordination in Europe.

Established in 1989 in Brussels as an international nonprofit association, the European Homograft Bank (EHB) has been collaborating closely with the transplant coordination of the different centers in Belgium and other European countries. Donor selection is made after discussion of exclusion criteria with the transplant coordinator of the procurement center. EHB collaborates with 15 Belgian, 11 German, 10 French, 10 Swiss, 3 Italian, 3 Dutch, and some other procurement and/or implantation centers. Donor ages range from newborn to 65 years. Tissue preparation, morphologic evaluation, and functional testing are performed under Class A laminar flow. After decontamination in a cocktail of 3 antibiotics (lincomycin, vancomycin, and polymixin B) during 20-48 hours, the tissues cryopreserved with liquid nitrogen to -100 degrees C are stored in vapors of liquid nitrogen below -150 degrees C for a maximum of 5 years. Systematic virologic examination of donor blood is performed for HIV, HTLV, hepatitis B/C, and syphilis, as well as for enteroviruses, Q fever, malaria, and West Nile virus by indication. Bacteriologic examination for anaerobic and aerobic contamination is performed at the different steps of processing. Histologic examination for malignant disease and infection is performed systematically. Indications for implantation are discussed with the requesting surgeon. Transport to the implantation center is carried out safely in a dry shipper at -150 degrees C or in dry ice at -76 degrees C. The EHB received 4,511 hearts and 1,169 batches of arteries from January 1989 to December 2008. The 5,133 heart valves (1,974 aortic, 3,106 pulmonary, and 53 mitral) and 2,066 arterial segments have been prepared and stored; 4,600 cryopreserved valvular (2,717 pulmonary, 1,835 aortic, and 48 mitral) and 1,937 arterial allografts have been distributed for implantation in various European Cardiovascular Centers. EHB is not always able to meet the increased demand for heart valves and arterial allografts. Collaboration between the EHB and the Transplant Coordination is satisfactory. Donor selection criteria are discussed with the transplant coordinator; whereas, implantation indication, with the implanting surgeon. Because the EHB is not always able to meet demands for the cryopreserved valves and arterial segments, there is a need to increase number of procurements. Cardiovascular surgeons need to play more active roles in the resolution of this problem.

Period analysis for more up-to-date graft and patient survival estimates in transplantation: an evaluation using united network for organ sharing data.

BACKGROUND: Traditional, cohort-based survival analysis approaches may provide outdated graft and patient survival estimates in times when clinical progress is rapid. Period analysis, a survival analysis method that uses left truncation and was shown to provide more up-to-date survival estimates than traditional, cohort-based methods in other medical fields, may improve the timeliness of survival monitoring in transplantation. METHODS: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we evaluated, through a series of comparisons, how well most up-to-date 5-year survival estimates potentially derivable by two commonly used cohort-based methods and the period method would have been able to predict the later observed survival of corresponding most recent transplants in the dataset between 1992 to 1994 and 2001 to 2003. RESULTS: In the analysis of overall survival, period analysis provided a best prediction for 93 of the 100 evaluated point estimates, whereas among 350 evaluated point estimates of age-specific survival, period analysis provided a best estimate on 254 occasions (72.6%), compared with 49 (14.0%) and 82 (23.4%) occasions for the cohort-based approaches. Mean average absolute differences between period estimates and the later observed survival were meaningfully lower than those obtained by traditional methods, indicating that period estimates may provide much better survival predictions for recently transplanted grafts and patients than estimates derivable at the same time by traditional survival analysis approaches. CONCLUSION: The timeliness of survival monitoring can be meaningfully improved by the application of period analysis. The use of period analysis for providing more up-to-date survival estimates in transplantation may be encouraged.

Low volume is associated with worse patient outcomes for pediatric liver transplant centers.

BACKGROUND: An inverse association between hospital procedure volume and postoperative mortality has been demonstrated for a variety of pediatric surgical procedures. The objective of our study was to determine whether such an association exists for pediatric liver transplantation. METHODS: We performed a retrospective analysis of pediatric liver transplant procedures included in the Scientific Registry of Transplant Recipients over a 7.5-year time period from July 1, 2000, through December 31, 2007. Pediatric liver transplant centers were divided into three volume categories (high, middle, low) based on absolute annual volume. Mean 1-year patient survival rates and aggregate 1-year observed-to-expected (O:E) patient death ratios were calculated for each hospital volume category and then compared using ordered logistic regression and chi square analyses. RESULTS: High-volume pediatric liver transplant centers achieved significantly lower aggregate 1-year O:E patient death ratios than low-volume centers. When freestanding children's hospitals (FCH), children's hospitals within adult hospitals (CAH), and other centers (OC) were considered separately, we found that a significant volume-outcomes association existed among OC centers but not among FCH or CAH centers. Low-volume OC centers, which represent 41.6% of all pediatric liver transplant centers and perform 10% of all pediatric liver transplantation, had the least favorable aggregate 1-year O:E patient death ratio of all groups. CONCLUSIONS: We demonstrate that a significant center volume-outcomes relationship exists among OC pediatric liver transplant centers but not among FCH or CAH centers. These findings support the possible institution of minimum annual procedure volume requirements for OC pediatric liver transplant centers.

Impact of donor cause of death on transplant outcomes: UNOS registry analysis.

Donor cause of death (DCOD) has been described to influence allograft survival. Whether this effect is independent of other donor characteristics and whether it is similar across different solid organ allografts is not known. The aim of our study was to determine the impact of DCOD on organ utilization and on transplantation outcomes-graft rejection, function, and survival. The registry data were provided by the United Network for Organ Sharing/Organ Procurement and Transplantation Network. Stroke, head trauma, and anoxia were the cause of brain death in 97% of the more than 86,000 donors whose data were recorded between 1989 and 2008. In univariate analysis, stroke DCOD was associated with worse graft survival across all organs. After adjustment in a multivariable analysis, modest differences persisted in survival of heart, kidney, and liver allografts. DCOD also appeared to affect the incidence of allograft rejection. Anoxia DCOD was associated with significantly less rejection relative to donor death caused by head trauma and stroke. In summary, this multi-institutional study confirms that DCOD is a modest predictor of survival and rejection of solid organ allografts of different types.

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.

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.