Abdominal Organ Transplant Center Tobacco Use Policies Vary by Organ Program Type.

BACKGROUND: Smoking is a modifiable risk factor for cardiovascular disease, malignancy, and surgical complications. Transplant center practices toward smokers vary widely and evoke the classic tension between the ethical principles of justice and utility. We sought to assess current smoking policy variation in U.S. kidney, liver, and pancreas transplant centers. METHODS: An online survey was sent to program directors of all United Network for Organ Sharing-approved solid abdominal organ transplant programs regarding their policies toward prior and current tobacco use. RESULTS: Responses were received from 26% of kidney, 31% of liver, and 37% of pancreas transplant centers. Across organ programs, virtually all centers (97% to 100%) reported transplantations for former smokers, whereas 59% of kidney, 62% of liver, and 33% of pancreas programs reported transplantations for current smokers. Organ programs reported similar rates of having smoking cessation programs (74% to 77%) and performing serum cotinine testing (31% to 38%). Smoking was an absolute contraindication to transplantation at 38% of kidney, 15% of liver, and 50% of pancreas programs. Programs with absolute contraindication policies were less likely to perform transplantations in current smokers and more likely to check serum cotinine levels, but no more likely to have smoking cessation programs. CONCLUSIONS: There is variation in tobacco use policies among abdominal organ transplant programs and centers. Balancing equity and justice when deciding which patients to waitlist requires an individualized approach to the tobacco-using patient, consideration of organ-specific factors, tobacco-related disease burden, and overall patient health. Such multifaceted assessments might be favorable to inflexible tobacco use policies.

Utilization of kidneys with similar kidney donor risk index values from standard versus expanded criteria donors.

With the shortage of standard criteria donor (SCD) kidneys, efficient expanded criteria donor (ECD) kidney utilization has become more vital. We investigated the effects of the ECD label on kidney recovery, utilization and outcomes. Using data from the Scientific Registry of Transplant Recipients from November 2002 to May 2010, we determined recovery and transplant rates, and modeled discard risk, for kidneys within a range of kidney donor risk index (KDRI) 1.4-2.1 that included both SCD and ECD kidneys. To further compare similar quality kidneys, these kidneys were again divided into three KDRI intervals. Overall, ECD kidneys had higher recovery rates, but lower transplant rates. However, within each KDRI interval, SCD and ECD kidneys were transplanted at similar rates. Overall, there was increased risk for discard for biopsied kidneys. SCD kidneys in the lower two KDRI intervals had the highest risk of discard if biopsied. Pumped kidneys had a lower risk of discard, which was modulated by KDRI for SCD kidneys but not ECD kidneys. Although overall ECD graft survival was worse than SCD, there were no differences within individual KDRI intervals. Thus, ECD designation adversely affects neither utilization nor outcomes beyond that predicted by KDRI.

Conversion from cyclosporine to tacrolimus results in improved creatinine but does not alter lipid profile.

INTRODUCTION: While cyclosporine and tacrolimus use results in similar renal graft survival, the side effect profiles of the drugs are substantially different. We examined the electrolyte and lipid alterations that occurred in our patient population following conversion from cyclosporine to tacrolimus. METHODS: Data for electrolytes, lipid profile, and immunosuppression were analyzed from 98 patients with kidney or kidney-pancreas transplants who were converted from cyclosporine to tacrolimus between October 1994 and June 2001. Results, expressed as mean +/- SEM, were compared to baseline values using the Wilcoxon signed-rank test (P < .05 considered significant). RESULTS: Among these patients, there were 56 men, 42 women, 75 primary transplants, 15 repeat transplants, and 26 multiorgan transplants. The mean time to tacrolimus conversion was 769 +/- 122 days. Creatinine, BUN, and glucose improved after conversion to tacrolimus. Surprisingly, cholesterol, low-density lipoproteins, and high-density lipoproteins levels were not significantly altered, although triglyceride levels demonstrated a significant difference at 1 year. CONCLUSION: Significant improvements in creatinine and BUN were observed following conversion from cyclosporine to tacrolimus. While hypomagnesemia was also seen, there was surprisingly little alteration in lipid profile.

Effects of rapamycin on the arterial inflammatory response in atherosclerotic plaques in Apo-E knockout mice.

Because of its antiproliferative properties and its known effects on plasma lipids, we evaluated the mechanisms underlying the effect of rapamycin (RPM) on endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases in Apo-E knockout mice. Apo-E-/- mice fed a high-cholesterol diet were given RPM (3 mg/kg per day intraperitoneally) or no treatment for 10 weeks (n = 8 each). Blood was drawn for serum lipid analysis. Protein was extracted from the abdominal aortas for Western immunoblotting and zymography. Cellular localization was assessed by histology and immunohistochemistry. The data, expressed as mean +/- SEM, were compared by Student's t test or analysis of variance (ANOVA). Lipid levels at 10 weeks were similar in both groups except for higher triglyceride levels in RPM-treated animals. RPM-treated mice expressed greater amounts of eNOS and p-eNOS compared with controls (P < .05). Akt, p-Akt, Caveolin-1, and p-Caveolin-1 were not significantly affected by RPM treatment. RPM treatment was associated with increased activation of pro-MMP-9, a significant decrease in MMP-2 tissue levels, and corresponding increases in TIMP-2 and TIMP-3 expression. The increased expression and phosphorylation of eNOS with RPM appears to be regulated by mechanisms other than Akt or Caveolin-1. Alterations in eNOS expression, in addition to changes in MMP/TIMP ratios and MMP-2 and MMP-9 activation, may partially explain the changes observed in the aorta of treated Apo-E-/- mice induced by RPM.

T-lymphocyte apoptosis is increased by non-interleukin-2-dependent induction in human mixed lymphocyte cultures.

INTRODUCTION: Transplant tolerance is dependent on the apoptotic deletion of allospecific T lymphocytes following interleukin-2 (IL-2)-dependent T-lymphocyte activation. Current immunosuppressive strategies block IL-2 and may prevent T-cell activation. We examined apoptotic alterations in mixed lymphocyte culture (MLC), a model of allospecific lymphocyte activation, by polyclonal rabbit antithymocyte antibody thymoglobulin (rATG) and monoclonal anti-IL-2 receptor antibody basiliximab. METHODS: Human lymphocytes were isolated using Ficoll-Paque gradient. Cesium-irradiated (2500 rad) stimulator cells (10(6) cells/mL) were cocultured with equal numbers of responder cells. Apoptosis was measured using annexin-V staining and propidium iodide exclusion using flow cytometry. Isolated protein was analyzed using Western blotting with densitometry. RESULTS: Apoptosis increased at days 3 and 7 in rATG MLC compared with control and basiliximab MLC. Fas was up-regulated in rATG MLC in a dose-dependent manner, whereas basiliximab did not alter fas. FasL was increased initially and at late time points in rATG MLC. CONCLUSIONS: Polyclonal rATG increased apoptosis and production of the proapoptotic proteins fas and fasL. In contrast, monoclonal basiliximab did not change lymphocyte apoptosis or apoptotic protein production. These results suggest that a specific IL-2 pathway blockade may prevent allospecific tolerance and that a non-IL-2 pathway blockade may encourage apoptosis of allospecifically activated T cells.

Disseminated Pseudallescheria boydii (Scedosporium apiospermum) infection in a renal transplant patient.

Transplant recipients receive a number of immunosuppressive medications that result in an increased risk of infection, including infections with microbes that are normally not pathogenic. We describe a patient with end-stage renal disease who underwent kidney transplantation. Six months postoperatively, he presented with a lesion on his ankle, multiple thigh nodules, and right testicular pain. Biopsy of the ankle lesion demonstrated Pseudallescheria boydii (Scedosporium apiospermum), a common environmental fungus. Following orchiectomy, multiple fungal elements were found that were initially described as Aspergillus species, but later identified as P. boydii. In addition, multiple brain abscesses were found on magnetic resonance imaging. Despite treatment with multiple antifungal medications, the patient died of cardiac dysrhythmia. Current diagnostic and therapeutic alternatives for P. boydii are reviewed.

Progression of hepatic damage during cold storage after procurement in a liver and kidney donor with HELLP syndrome.

BACKGROUND: HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome and acute fatty liver of pregnancy are associated with preeclampsia and fetal defects in fatty acid metabolism. This defect causes the accumulation of metabolites that are harmful to the maternal liver. CASE REPORT: We report a liver and kidney donor with HELLP syndrome and describe the progression of disease in the liver during cold storage. Before procurement, liver biopsy demonstrated minimal necrosis. However, after cold storage, repeat biopsy demonstrated more than 30% necrosis. The liver was not engrafted; the kidneys were transplanted without complication. CONCLUSION: Livers procured from patients with HELLP syndrome should be carefully evaluated for progression of hepatic damage during cold storage and transport.

Specific requirement for CD3epsilon in T cell development.

T cell antigen receptor (TCR) and pre-TCR complexes are composed of clonotypic heterodimers in association with dimers of signal transducing invariant subunits (CD3gamma, -delta, -epsilon, and zeta). The role of individual invariant subunits in T cell development has been investigated by generating gene-specific mutations in mice. Mutation of CD3gamma, -delta, or zeta results in an incomplete block in development, characterized by reduced numbers of mature T cells that express low levels of TCR. In contrast, mature T cells are absent from CD3epsilon-/- mice, and thymocyte development is arrested at the early CD4(-)CD8(-) stage. Although these results suggest that CD3epsilon is essential for pre-TCR and TCR expression/function, their interpretation is complicated by the fact that expression of the CD3gamma and CD3delta genes also is reduced in CD3epsilon-/- mice. Thus, it is unclear whether the phenotype of CD3epsilon-/- mice reflects the collective effects of CD3gamma, -delta, and -epsilon deficiency. By removing the selectable marker (PGK-NEO) from the targeted CD3epsilon gene via Cre/loxP-mediated recombination, we generated mice that lack CD3epsilon yet retain normal expression of the closely linked CD3gamma and CD3delta genes. These (CD3epsilonDelta/Delta) mice exhibited an early arrest in T cell development, similar to that of CD3epsilon-/- mice. Moreover, the developmental defect could be rescued by expression of a CD3epsilon transgene. These results identify an essential role for CD3epsilon in T cell development not shared by the CD3gamma, CD3delta, or zeta-family proteins and provide further evidence that PGK-NEO can influence the expression of genes in its proximity.

Prospective multivariate analysis of donor monoethylglycine xylidide (MEGX) testing in liver transplantation. Transplantation Society of Michigan Scientific Studies Committee.

Measurement of the metabolism of lidocaine to MEGX by the hepatic cytochrome P450 system has been proposed as a means to assess liver function and metabolic activity of cadaveric organ donors. This prospective study of 102 potential liver donors from the State of Michigan sought to determine the role of MEGX determinations alone and in conjunction with traditional measures of donor acceptability. High MEGX values (> 80 microg/L) did not correlate with the acceptability of donor livers, and had no significant association with early posttransplant graft function, as determined by SGOT, SGPT, alkaline phosphatase, bilirubin, prothrombin time, or bile production. However, livers procured from donors with high MEGX values had improved actuarial graft survival when compared to low MEGX donors at 30 d (95% vs. 84%) and at 1 yr (68% vs. 43%) (p < 0.04). Multivariate analysis demonstrated a significant independent association of both shorter cold ischemic time and high MEGX value with improved graft survival (p < 0.002). We conclude that the MEGX test offers limited incremental value in predicting early function of donor livers when used in conjunction with traditional criteria of clinical evaluation, laboratory tests, and histology. However, knowledge of the results of MEGX determinations may be of value in predicting graft survival after liver transplantation.