Suzanne V. McDiarmid

Immunosuppression and the Risk of Post-Transplant Malignancy Among Cadaveric First Kidney Transplant Recipients

The success of renal transplantation may be counterbalanced by serious adverse medical events. The effect of immunosuppression on the incidence of de novo neoplasms among kidney recipients should be monitored continuously. Using data from the Scientific Registry of Transplant Recipients, we studied the association of induction therapy by immunosuppression with antilymphocyte antibodies, with the development of de novo neoplasms. The study population included more than 41 000 recipients who received a cadaveric first kidney transplant after December 31, 1995, and were followed through February 28, 2002.

Improving liver allocation: MELD and PELD.

On February 27, 2002, the liver allocation system changed from a status‐based algorithm to one using a continuous MELD/PELD severity score to prioritize patients on the waiting list. Using data from the Scientific Registry of Transplant Recipients, we examine and discuss several aspects of the new allocation, including the development and evolution of MELD and PELD, the relationship between the two scoring systems, and the resulting effect on access to transplantation and waiting list mortality. Additional considerations, such as regional differences in MELD/PELD at transplantation and the predictive effects of rapidly changing MELD/PELD, are also addressed.

One hundred in situ split-liver transplantations: a single-center experience.

Objective: To identify predictors of graft and recipient survival from a single-institution series of in situ split-liver transplantations and compare outcomes to living donor and whole organs for adults and children. Summary Background Data: Split-liver transplantation is a surgical technique that creates 2 allografts from a single cadaver donor. We have applied split-liver transplantation to all indications and categories of medical urgency for initial as well as retransplantation to expand the current donor pool and decrease reliance upon living donation. Methods: A retrospective analysis was conducted of 100 consecutive in situ split-liver transplantations yielding a left lateral segment and right trisegment graft that were performed at the University of California Los Angeles between 9/91 and 02/03. These 100 transplantations generated 190 allografts for transplantation into 105 children and 60 adults, with the sharing of 25 allografts among transplant centers across the United States. Outcomes and incidence of complications were compared with living donor and whole organ recipients receiving liver transplantation during the same time period with independent predictors of split-liver graft and recipient survival identified by multivariate analysis. Results: The incidence of biliary and vascular complications observed in recipients of left lateral segment grafts created by split-liver transplantation was not statistically different from recipients of left lateral segment grafts created from living donation or children receiving whole-organ grafts from pediatric donors. Kaplan-Meier survival estimations of left lateral segment graft and recipient survival also demonstrated no statistical difference among split-liver, living donor, and whole-organ recipients. Right trisegment grafts from split-liver transplantation demonstrated a 10% incidence of biliary and 7% incidence of vascular complications. Long-term graft function was excellent with patient and graft survival equal to 1086 recipients of cadaver whole-organ grafts from donors ages 10–40 years who underwent transplant operations during the same time period. Predictors of split-liver transplantation graft and recipient survival included United Network for Organ Sharing status at transplantation, indication, occurrence of a complication, donor creatinine, and donor length of hospitalization. Conclusions: Split-liver transplantation is an effective mechanism for immediate expansion of the cadaver donor pool that can reduce dependence upon living donation in adults and children.

Liver Transplantation for Fulminant Hepatic Failure: Experience With More Than 200 Patients Over a 17-Year Period

ObjectiveTo analyze outcomes after liver transplantation (LT) in patients with fulminant hepatic failure (FHF) with emphasis on pretransplant variables that can potentially help predict posttransplant outcome. Summary Background DataFHF is a formidable clinical problem associated with a high mortality rate. While LT is the treatment of choice for irreversible FHF, few investigations have examined pretransplant variables that can potentially predict outcome after LT. MethodsA retrospective review was undertaken of all patients undergoing LT for FHF at a single transplant center. The median follow-up was 41 months. Thirty-five variables were analyzed by univariate and multivariate analysis to determine their impact on patient and graft survival. ResultsTwo hundred four patients (60% female, median age 20.2 years) required urgent LT for FHF. Before LT, the majority of patients were comatose (76%), on hemodialysis (16%), and ICU-bound. The 1- and 5-year survival rates were 73% and 67% (patient) and 63% and 57% (graft). The primary cause of patient death was sepsis, and the primary cause of graft failure was primary graft nonfunction. Univariate analysis of pre-LT variables revealed that 19 variables predicted survival. From these results, multivariate analysis determined that the serum creatinine was the single most important prognosticator of patient survival. ConclusionsThis study, representing one of the largest published series on LT for FHF, demonstrates a long-term survival of nearly 70% and develops a clinically applicable and readily measurable set of pretransplant factors that determine posttransplant outcome.

Early graft function after pediatric liver transplantation: Comparison between in situ split liver grafts and living-related liver grafts

Background. The systematic application of living-related and cadaveric, in situ split-liver transplantation has helped to alleviate the critical shortage of suitable-sized, pediatric donors. Undoubtedly, both techniques are beneficial and advantageous; however, the superiority of either graft source has not been demonstrated directly. Because of the potential living-donor risks, we reserve the living donor as the last graft option for pediatric recipients awaiting liver transplantation. Inasmuch as no direct comparison between these two graft types has been performed, we sought to perform a comparative analysis of the functional outcomes of left lateral segmental grafts procured from these donor sources to determine whether differences do exist. Methods. A retrospective analysis of all liver transplants performed at a single institution between February 1984 and January 1999 was undertaken. Only pediatric (<18 years) recipients of left lateral segmental grafts procured from either living-related (LRD) or cadaveric, in situ split-liver (SLD) donors were included. A detailed analysis of preoperative, intraoperative, and postoperative variables was undertaken. Survival was estimated using the Kaplan-Meier method, and comparison of variables between groups was undertaken using the t test of Wilcoxon rank sum test. Results. There were no significant differences in the preoperative variables between the 39 recipients of SLD grafts and 34 recipients of LRD grafts. The donors did differ significantly in mean age, ABO blood group matching, and preoperative liver function testing. Postoperative liver function testing revealed significant early differences in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, prothrombin time, and alkaline phosphatase, with grafts from LRD performing better than those from SLD. SLD grafts also had significantly longer ischemia times and a higher incidence of graft loss owing to primary nonfunction and technical complications (9 vs. 2, P <0.05). However, six of these graft losses in the SLD group were because of technical or immunologic causes, which, theoretically, should not differ between the two groups. Furthermore, these graft losses did not negatively impact early patient survival as most patients were successfully rescued with retransplantation (30-day actuarial survival, 97.1% SLD vs. 94.1% LRD, P =0.745). In the surviving grafts, the early differences in liver function variables normalized. Conclusions. Inherent differences in both donor sources exist and account for differences seen in preoperative and intraoperative variables. Segmental grafts from LRD clearly performed better in the first week after transplantation as demonstrated by lower liver function variables and less graft loss to primary nonfunction. However, the intermediate function (7–30 days) of both grafts did not differ, and the early graft losses did not translate into patient death. Although minimal living-donor morbidity was seen in this series, the use of this donor type still carries a finite risk. We therefore will continue to use SLD as the primary graft source for pediatric patients awaiting liver transplantation.

Pretransplant Predictors of Survival After Intestinal Transplantation: Analysis of a Single-center Experience of More Than 100 Transplants

Introduction. Outcomes after intestinal transplantation (ITx) have steadily improved. There are few studies that assess factors associated with these enhanced results. The purpose of this study was to examine peri-ITx variables and survival. Methods. A review of a prospectively maintained database was undertaken and included all patients undergoing ITx from 1991 to 2010. The study endpoints were patient and graft survival. Data collection included 44 variables. Survival was computed using Kaplan-Meier methods. Univariate analysis was conducted (log-rank test) with significance set at P less than or equal to 0.20. Multivariate analysis of significant variables was conducted using model reduction by backward elimination variable selection method with significance set at P less than 0.05. Results. Eighty-eight patients received 106 ITx. The majority of recipients were male, Latino, and children. The leading causes of intestinal and liver failure were gastroschisis and parenteral nutrition. Grafts transplanted were isolated intestine (24%), liver-intestine (62%), and multivisceral (14%). Overall 1- and 5-year patient and graft survival were 80% and 65%, and 74% and 64%, respectively. Significant univariate survival predictors were weight less than 20 kg, children, liver-inclusive allograft, panel reactive antibody less than 20%, absence of donor-specific antibody, negative crossmatch, warm ischemia time less than 60 min, absence of recipient splenectomy, interleukin-2 receptor antagonist induction, and era. Significant multivariate survival predictors were absence of donor-specific antibody, absence of recipient splenectomy, and liver-inclusive graft type. Conclusion. This large, single-center ITx experience confirms a marked improvement in outcome over time. Several important factors were associated with survival, and these factors can potentially be adjusted before ITx. These findings should refocus future efforts on strategies to improve treatment and prevent graft loss.

Post-transplant diabetes mellitus in pediatric liver transplantation

Abstract:  To determine the characteristics of pediatric liver transplant recipients who develop GI and/or PTDM, data on children undergoing their first liver transplant from the SPLIT database were analyzed (n = 1611). Recipient and donor characteristics that were evaluated included age at transplant, gender, race, primary disease, hospitalization status at transplant, BMI, recipient and donor CMV status, donor type, donor age, and primary immunosuppression. GI/PTDM was found in 214 individuals (13%) of whom 166 (78%) were diagnosed within 30 days of transplantation (early GI/PTDM). Multivariate analyses suggests that age >5 yr at transplant, hospitalization at transplant, a primary diagnosis other than BA, early steroid use, and tacrolimus use are associated with increased incidence of early GI. Routine monitoring for the development of GI and post‐transplant diabetes is indicated in the short‐ and long‐term care of children after liver transplantation.

The OKT3 antibody response study: a multicentre study of human anti-mouse antibody (HAMA) production following OKT3 use in solid organ tranplantation

Human anti-murine antibody titres following patient exposure to the monoclonal antibody Orthoclone OKT3 (muromonab-CD3) are determined by laboratories using diverse analytical methods which are not standardized and whose concordance is not established. A multicentre study group therefore compared testing for IgG anti-OKT3 antibody among seven laboratories. A set of 270 sera was obtained from 30 heart, 30 kidney and 30 liver transplant recipients with no previous exposure to OKT3 who were receiving OKT3 for induction immunosuppression. Sera were collected from each patient prior to and at 24 +/- 2 days and 31 +/- 2 days following initial OKT3 exposure. Identical aliquots of all 270 sera were tested for IgG anti-OKT3 antibody by each laboratory. In addition, the limit of detection of each laboratorys method was estimated by titration of an affinity-purified IgG anti-OKT3 reference material of known concentration. Anti-OKT3 antibody formation differed greatly among the three organ groups. Cardiac patients demonstrated the least sensitization and almost exclusively lower titres, while kidney recipients had more frequent and higher titre antibody formation. Liver recipients yielded the highest sensitization rate and the most frequent high titre sera. Importantly, the seven laboratories differed widely in the number of pretreatment sera reported as positive (ranging from 0% to 41% among laboratories), the number of post-OKT3 sera reported as positive (17-63%), the number of post-OKT3 samples with titre > or = 1000 (2-31%), and the number of patients sensitized 19-69%). Concordance among laboratories was highly variable, with interlaboratory agreement ranging from 38% to 83% on the sample titres assigned to 180 post-OKT3 sera. Many of the discordant results were consistent with differences in the limit of detection of the analytical methods, which ranged from 0.19 microgram/ml to > or = 15 micrograms/ml, a nearly 100-fold difference among laboratories. This study demonstrated the presence of both good concordance and significant discordance among laboratories in determining human anti-mouse antibody titres, and demonstrated that common titre categories (100, 1000, 10,000) were not equivalent among laboratories. The level of concordance among methods should be considered when comparing anti-OKT3 antibody results from different centres and their correlation with clinical events. Universal comparative testing, patterned after proficiency testing programmes, is needed to assess differences among laboratories and to bring uniformity and a sound interpretative basis to this field of testing.

The impact of microsurgical hepatic arterial reconstruction on the outcome of liver transplantation for congenital biliary atresia

BACKGROUND Hepatic artery thrombosis (HAT) after liver transplantation for biliary atresia (BA) is a serious complication that most often leads to retransplantation (re-OLT). The purpose of the present study was: (1) to identify risk factors associated with HAT and (2) to analyze the impact of recently introduced microsurgical hepatic arterial reconstruction (MHR) on the incidence of HAT, subsequent need for re-OLT, and patient survival. METHODS A retrospective review of 194 patients transplanted for BA was performed. One hundred and sixty-six patients (group 1) underwent conventional arterial reconstruction and 28 (group 2) had MHR. RESULTS Actuarial survival for patients with HAT was significantly worse than for patients without HAT at 1, 2, and 5 years (71%, 61%, and 57% versus 85%, 85%, and 85%, P = 0.0007). Stepwise logistic regression analysis revealed that the risk of HAT correlated best with the type of arterial reconstruction (P = 0.007) followed by pretransplant bilirubin concentration (P = 0.04) and the number of acute rejection episodes (P = 0.03). In group 1, 32 patients developed HAT (19%), and of these, 18 underwent re-OLT for HAT. No patient in group 2 developed HAT (P = 0.006 versus group 1). One-year actuarial patient survival was 81% in group 1 and 100% in group 2 (P = 0.02). CONCLUSIONS In OLT for BA, (1) the predominant risk factor for HAT is the technique of arterial reconstruction, and (2) MHR markedly reduces the incidence of HAT and the need for re-OLT while improving patient survival.

Marked left ventricular hypertrophy in children on tacrolimus (FK506) after orthotopic liver transplantation.

Although the cardiac effects of tacrolimus (FK506) have not been well documented, clinical cases of children on FK506 who developed hypertrophic obstructive cardiomyopathy have been reported. We report 2 cases of marked concentric hypertrophy of the left ventricular myocardium found at autospy in children on FK506.