The Novel Application of Genomic Profiling Assays to Shorten Inactive Status for Potential Kidney Transplant Recipients With Breast Cancer.

The concern about cancer recurrence has traditionally resulted in delaying kidney transplantation for 2-5 years after a cancer diagnosis in patients who are otherwise eligible for transplant. This period of inactive status to observe the tumor biology can result in significant morbidity and decreased quality of life for patients with end-stage renal disease (ESRD). We reported the novel application of genomic profiling assays in breast cancer to identify low-risk cancers in two patients with ESRD who were able to have the mandatory inactive status eliminated prior to kidney transplantation.

Splenic Vein Thrombosis Following Pancreas Transplantation: Identification of Factors That Support Conservative Management.

Prophylaxis for graft portal/splenic venous thrombosis following pancreas transplant varies between institutions. Similarly, treatment of venous thrombosis ranges from early re-exploration to conservative management with anticoagulation. We wished to determine the prevalence of graft splenic vein (SV) thrombosis, as well as the clinical significance of non-occlusive thrombus observed on routine imaging. Records of 112 pancreas transplant recipients over a 5-year period at a single center were reviewed. Venous thrombosis was defined as absence of flow or presence of thrombus identified in any part of the graft SV on ultrasound. Thirty patients (27%) had some degree of thrombus or absence of flow in the SV on postoperative ultrasound. There were 5 graft losses in this group. Four were due to venous thrombosis, and occurred within 20 days of transplant. All patients with non-occlusive partial SV thrombus but normal arterial signal on Doppler ultrasound were successfully treated with IV heparin followed by warfarin for 3-6 months, and remained insulin independent. Findings of arterial signal abnormalities, such as absence or reversal of diastolic flow within the graft, require urgent operative intervention since this finding can be associated with more extensive thrombus that may lead to graft loss.

Social and Financial Outcomes of Living Liver Donation: A Prospective Investigation Within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2).

Because results from single-center (mostly kidney) donor studies demonstrate interpersonal relationship and financial strains for some donors, we conducted a liver donor study involving nine centers within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2) consortium. Among other initiatives, A2ALL-2 examined the nature of these outcomes following donation. Using validated measures, donors were prospectively surveyed before donation and at 3, 6, 12, and 24 mo after donation. Repeated-measures regression models were used to examine social relationship and financial outcomes over time and to identify relevant predictors. Of 297 eligible donors, 271 (91%) consented and were interviewed at least once. Relationship changes were positive overall across postdonation time points, with nearly one-third reporting improved donor family and spousal or partner relationships and >50% reporting improved recipient relationships. The majority of donors, however, reported cumulative out-of-pocket medical and nonmedical expenses, which were judged burdensome by 44% of donors. Lower income predicted burdensome donation costs. Those who anticipated financial concerns and who held nonprofessional positions before donation were more likely to experience adverse financial outcomes. These data support the need for initiatives to reduce financial burden.

Pancreas-After-Islet Transplantation in Nonuremic Type 1 Diabetes: A Strategy for Restoring Durable Insulin Independence.

Islet transplantation offers a minimally invasive approach for ß cell replacement in diabetic patients with hypoglycemic unawareness. Attempts at insulin independence may require multiple islet reinfusions from distinct donors, increasing the risk of allogeneic sensitization. Currently, solid organ pancreas transplant is the only remaining surgical option following failed islet transplantation in the United States; however, the immunologic impact of repeated exposure to donor antigens on subsequent pancreas transplantation is unclear. We describe a case series of seven patients undergoing solid organ pancreas transplant following islet graft failure with long-term follow-up of pancreatic graft survival and renal function. Despite highly variable panel reactive antibody levels prior to pancreas transplant (mean 27 ± 35%), all seven patients achieved stable and durable insulin independence with a mean follow-up of 6.7 years. Mean hemoglobin A1c values improved significantly from postislet, prepancreas levels (mean 8.1 ± 1.5%) to postpancreas levels (mean 5.3 ± 0.1%; p = 0.0022). Three patients experienced acute rejection episodes that were successfully managed with thymoglobulin and methylprednisolone, and none of these preuremic type 1 diabetic recipients developed stage 4 or 5 chronic kidney disease postoperatively. These results support pancreas-after-islet transplantation with aggressive immunosuppression and protocol biopsies as a viable strategy to restore insulin independence after islet graft failure.

Complications and Their Resolution in Recipients of Deceased and Living Donor Liver Transplants: Findings From the A2ALL Cohort Study.

The purpose of this study was to explore long-term complications in recipients of deceased donor liver transplant (DDLT) and living donor liver transplant (LDLT) in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). We analyzed 471 DDLTs and 565 LDLTs from 1998 to 2010 that were followed up to 10 years for 36 categories of complications. Probabilities of complications and their resolutions were estimated using the Kaplan-Meier method, and predictors were tested in Cox proportional hazards models. Median follow-up for DDLT and LDLT was 4.19 and 4.80 years, respectively. DDLT recipients were more likely to have hepatocellular carcinoma and higher disease severity, including Model for End-Stage Liver Disease score. Complications occurring with higher probability in LDLT included biliary-related complications and hepatic artery thrombosis. In DDLT, ascites, intra-abdominal bleeding, cardiac complications and pulmonary edema were significantly more probable. Development of chronic kidney disease stage 4 or 5 was less likely in LDLT recipients (hazard ratio [HR] 0.41, p = 0.02). DDLT and LDLT had similar risk of grade 4 complications (HR 0.89, p = 0.60), adjusted for other risk factors. Once a complication occurred, the time to resolution did not differ between LDLT and DDLT. Future efforts should be directed toward reducing the occurrence of complications after liver transplantation.

Complications of living donor hepatic lobectomy--a comprehensive report.

A wider application of living donor liver transplantation is limited by donor morbidity concerns. An observational cohort of 760 living donors accepted for surgery and enrolled in the Adult-to-Adult Living Donor Liver Transplantation cohort study provides a comprehensive assessment of incidence, severity and natural history of living liver donation (LLD) complications. Donor morbidity (assessed by 29 specific complications), predictors, time from donation to complications and time from complication onset to resolution were measured outcomes over a 12-year period. Out of the 760 donor procedures, 20 were aborted and 740 were completed. Forty percent of donors had complications (557 complications among 296 donors), mostly Clavien grades 1 and 2. Most severe counted by complication category; grade 1 (minor, n = 232); grade 2 (possibly life-threatening, n = 269); grade 3 (residual disability, n = 5) and grade 4 (leading to death, n = 3). Hernias (7%) and psychological complications (3%) occurred >1 year postdonation. Complications risk increased with transfusion requirement, intraoperative hypotension and predonation serum bilirubin, but did not decline with the increased center experience with LLD. The probability of complication resolution within 1 year was overall 95%, but only 75% for hernias and 42% for psychological complications. This report comprehensively quantifies LLD complication risk and should inform decision making by potential donors and their caregivers.

Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.

Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.

Organ donation and utilization in the United States, 1997-2006.

Deceased organ donation has increased rapidly since 2002, coinciding with implementation of the Organ Donation Breakthrough Collaborative. The increase in donors has resulted in a corresponding increase in the numbers of kidney, liver, lung and intestinal transplants. While transplants for most organs have increased, discard and nonrecovery rates have not improved or have increased, resulting in a decrease in organs recovered per donor (ORPD) and organs transplanted per donor (OTPD). Thus, the expansion of the consent and recovery of incremental donors has frequently outpaced utilization. Meaningful increases in multicultural donation have been achieved, but donations continue to be lower than actual rates of transplantation and waiting list registrations for these groups. To counteract the decline in living donation, mechanisms such as paired donation and enhanced incentives to organ donation are being developed. Current efforts of the collaborative have focused on differentiating ORPD and OTPD targets by donor type (standard and expanded criteria donors and donors after cardiac death), utilization of the OPTN regional structure and enlisting centers to increase transplants to match increasing organ availability.

Recipient morbidity after living and deceased donor liver transplantation: findings from the A2ALL Retrospective Cohort Study.

Patients considering living donor liver transplantation (LDLT) need to know the risk and severity of complications compared to deceased donor liver transplantation (DDLT). One aim of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) was to examine recipient complications following these procedures. Medical records of DDLT or LDLT recipients who had a living donor evaluated at the nine A2ALL centers between 1998 and 2003 were reviewed. Among 384 LDLT and 216 DDLT, at least one complication occurred after 82.8% of LDLT and 78.2% of DDLT (p = 0.17). There was a median of two complications after DDLT and three after LDLT. Complications that occurred at a higher rate (p < 0.05) after LDLT included biliary leak (31.8% vs. 10.2%), unplanned reexploration (26.2% vs. 17.1%), hepatic artery thrombosis (6.5% vs. 2.3%) and portal vein thrombosis (2.9% vs. 0.0%). There were more complications leading to retransplantation or death (Clavien grade 4) after LDLT versus DDLT (15.9% vs. 9.3%, p = 0.023). Many complications occurred more commonly during early center experience; the odds of grade 4 complications were more than two-fold higher when centers had performed 40). In summary, complication rates were higher after LDLT versus DDLT, but declined with center experience to levels comparable to DDLT.

HIV-infected liver and kidney transplant recipients: 1- and 3-year outcomes.

Improvements in human immunodeficiency virus (HIV)-associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR [interquartile range] 2.9-4.9). One- and 3-year liver recipients' survival was 91% and 64%, respectively; kidney recipients' survival was 94%. One- and 3-year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999-2004 transplants in the national database. CD4+ T-cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1- and 3-year cumulative incidence (95% confidence intervals [CI]) of rejection episodes for kidney recipients was 52% (28-75%) and 70% (48-92%), respectively. Two-thirds of hepatitis C virus (HCV)-infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV-related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV-infected patients cared for at centers with adequate expertise.

Major histocompatibility complex class I deficiency prolongs islet allograft survival.

Because of islet allograft rejection, nonimmunosuppressed pancreatic islet allotransplantation has been unsuccessful for the treatment of type I diabetes. The role of major histocompatibility complex class I antigen expression on islet allograft survival was evaluated with the use of mice homozygous for a beta 2-microglobulin gene disruption. These mice express little if any functional major histocompatibility complex class I antigen. When these major histocompatibility complex class I-deficient islets were used as donors in an allogenic murine transplantation model, islet allograft survival was markedly prolonged. These results demonstrate a major importance for the alloresponse directed against major histocompatibility complex class I antigen.

Ischemic preconditioning improves rat kidney graft function after severe ischemia/reperfusion injury.

UNLABELLED: Ischemic preconditioning (IP) has been shown to ameliorate renal ischemia reperfusion injury. Using a rat kidney transplantation model we determined if IP improves graft function after prolonged cold storage. MATERIALS AND METHODS: Syngeneic rat kidneys were divided into two groups. Prior to 42 hours of cold storage in UW and transplantation, one group (n = 10) received IP (15 minutes of warm ischemia/10 minutes of reperfusion), whereas another group (n = 10) received no treatment. Early graft function and 1-week recipient survival were assessed. RESULTS: Recipient survival was not significantly different between groups [70% (IP) vs 40% (non-IP); P = .28]. IP treatment led to a quicker recovery of renal function. On PODs 3 and 6, serum creatinine levels in the IP group were significantly lower compared with the untreated group. In conclusion, one cycle of IP (15/10) accelerates recovery of renal graft function after severe ischemia reperfusion injury. This simple treatment modality may improve outcomes of renal transplants with prolonged cold storage.

The lignan (+)-episesamin interferes with TNF-α-induced activation of VSMC via diminished activation of NF-ĸB, ERK1/2 and AKT and decreased activity of gelatinases.

AIM: Activation of vascular smooth muscle cells (VSMC), a key event in the pathogenesis of atherosclerosis, is triggered by inflammatory stimuli such as tumour necrosis factor-alpha (TNF-α) causing a mitogenic VSMC response. The polyphenol (+)-episesamin (ES) was shown to counteract TNF-α-induced effects, for example in macrophages. Aiming for novel therapeutic options, we here investigated whether ES protects VSMC from TNF-α-induced growth and migration, which both contribute to the onset and progression of atherosclerosis. METHODS: Human and murine VSMC were treated with combinations of ES and TNF-α. Expressions of mRNA were analyzed by RT-PCR. Enzymatic activities and proliferation were determined by specific substrate assays. Cell signalling was analyzed by Western blot and reporter gene assays. Migration was assessed by wound healing assays. RESULTS: ES at 1-10 µm reduced basal and TNF-α-induced VSMC proliferation and migration due to impaired activation of extracellular signal-regulated kinases (ERK)1/2, Akt (protein kinase B), nuclear factor-kappa B (NF-ĸB) and vascular cell adhesion molecule (VCAM)-1. This was accompanied by reduced expression and secretion of matrix metalloproteinases (MMP)-2/-9, which are known to promote VSMC migration. Specific inhibitors of Akt, NF-ĸB and MMP-2/-9 reduced TNF-α-induced VSMC proliferation, confirming ES-specific effects. Besides, ES reduced TNF-α- and H2O2 -induced oxidative stress and in parallel induces anti-inflammatory haem oxygenase (HO)-1 expression. CONCLUSION: ES interferes with inflammation-associated VSMC activation and subsequent decreased proliferation and migration due to anti-oxidative properties and impaired activation of NF-ĸB, known contributors to atherogenesis. These results suggest ES as a complemental treatment of VSMC specific vascular diseases such as atherosclerosis.

Effect of systemic cyclosporine on tumor recurrence after liver transplantation in a model of hepatocellular carcinoma.

BACKGROUND: Long-term results after liver transplantation for hepatocellular carcinoma have been disappointing, largely because of the high recurrence rate. It is controversial whether the immunosuppressed state of the recipient contributes to this recurrence rate. We have developed a model in the rat system to examine the effect of immunosuppression on tumor recurrence after transplantation, as well as to evaluate other treatment strategies to decrease the recurrence rate. METHODS: A 2-mm3 nodule of Morris hepatoma 3924a was implanted intrahepatically at day 0. At postimplant day 16, the animals underwent syngeneic orthotopic liver transplantation. Two treatment groups were established. Group I received saline injections subcutaneously for 2 weeks, while group II received subcutaneous cyclosporine injections at 3 mg/kg/day for 14 days. Animal survival, tumor recurrence rate, and sites of recurrence and number of pulmonary nodules were recorded. RESULTS: Overall survival rate was reduced in animals receiving cyclosporine. The mean survival time was 74.4 days (SEM 6.39 days) in saline-treated animals and 50.4 days (SEM 7.63 days) in the cyclosporine-treated animals. The proportion surviving in group 1 was 47% and in group 2 was 18%. This difference in survival was statistically significant (P=0.025). The incidence of pulmonary nodules was increased in the cyclosporine-treated animals, and tumor recurrence in extrapulmonary sites was seen only in the cyclosporine-treated animals. CONCLUSION: Results from this study suggest that cyclosporine has an adverse effect on tumor recurrence after transplantation. This model will be useful to further examine treatment strategies to improve the outcome of transplantation for hepatocellular carcinoma.

Demonstration of local immunosuppression with methylprednisolone in the sponge matrix allograft model.

This study evaluated the effect of locally delivered methylprednisolone on the systemic and local immune response in the sponge matrix allograft model. Polyurethane sponges were coated with peritoneal exudate cells from DBA/2 (H-2d) or C57Bl/6 mice (H-2b) and placed subcutaneously in C57BL/6 recipients 24 hr later. Each mouse received both a syngeneic and an allogeneic sponge graft. Local immunosuppression was effected by placement on day 0 of cellulose/matrix pellets containing a preparation of increasing quantity of controlled release MP or by daily intrasponge injection of MP. Local immunosuppression was demonstrated by decreased cytotoxicity on day 12 in the allogeneic sponge receiving MP directly, as compared with the groups that received MP in the opposite syngeneic sponge or no MP. This effect was noted at a specific MP dose (0.5 mg/kg/day). Absolute numbers of precursor cytolytic cells and mature cytolytic cells (determined by limiting dilution analyses) infiltrating the allografts were also decreased in the sponges receiving MP directly, relative to the groups receiving MP in the opposite syngeneic sponge. Maintenance of systemic (in contrast to local) immunity was also demonstrated. Animals treated with local MP into a simultaneously placed syngeneic sponge or in whom no MP was delivered became sensitized to a synchronous DBA/2 sponge and rejected a subsequent DBA/2 skin graft in second-set fashion. Conversely, animals that received local MP into their synchronous DBA/2 sponge rejected a subsequent DBA/2 skin graft or a third-party graft with first-set kinetics. The presence of local MP at the initial graft site prevented the animals from becoming sensitized to the presented alloantigen but did not keep the animal from developing a rejection response to a third-party skin graft with first-set kinetics. It appears that delivery of MP locally to the site of antigen is an effective method to modulate alloreactivity. In addition, the sponge matrix allograft appears to be a useful model for studying local immunosuppression.

The increased efficacy and decreased nephrotoxicity of a cyclosporine liposome.

A potential approach to avoid the complications of systemic immunosuppression is to deliver immunosuppressive agents locally to the site of the allograft. Liposomes are phospholipid particles that allow delivery of drugs preferentially to the reticuloendothelial system. Since the liver is a primary component of the RES, we hypothesized that liposome technology could be utilized to deliver immunosuppressive agents locally to a transplanted liver, thereby avoiding the complications of systemically delivered immunosuppression. We evaluated this hypothesis with a prototypic cyclosporine liposome in a rat model. Pharmacokinetic studies of this liposome indicated earlier clearance from the systemic circulation and increased hepatic uptake relative to the standard intravenous form of CsA. Decreased nephrotoxicity was also shown in an ischemic kidney model in the rat. The immunosuppressive efficacy of this liposome was also tested in a rat liver transplant model. There was a significant increase in survival compared with standard intravenous CsA when both drugs were administered at a dose of 1.75 mg/kg/day for seven days posttransplant (P < .05, CsA liposome-treated versus CsA/saline-treated). There were no demonstrable early toxic effects or late toxic effects observed with follow-up to 100 days. These data indicate that CsA liposomes have potential for use as an immunosuppressive agent with increased efficacy and decreased nephrotoxicity relative to the commercially available form of intravenous CsA. This improved therapeutic index of a locally targeted drug may lead to fewer complications attributed to systemic immunosuppression.

Experience with daclizumab in liver transplantation: renal transplant dosing without calcineurin inhibitors is insufficient to prevent acute rejection in liver transplantation.

BACKGROUND: Daclizumab is a monoclonal antibody directed against the alpha chain of the interleukin 2 receptor. We review our experience with the use of daclizumab in liver transplant recipients. METHODS: Thirty-two patients were given daclizumab as induction therapy in the setting of hepatic transplantation. Seven of these patients were enrolled in a pilot study to determine the efficacy of daclizumab in conjunction with corticosteroids and mycophenolate mofetil without the initial use of calcineurin inhibitors (CI). The remaining 25 patients received daclizumab, mycophenolate mofetil, and steroids, with the institution of CI generally within the first postoperative week. The majority of these patients (n = 17) had some degree of renal insufficiency. RESULTS: The pilot study was halted after the first seven patients were enrolled because of an unacceptably high rate of rejection (7/7 = 100%). The patients outside of this pilot study, however, had a much lower rate of rejection (36%). The incidence and severity of rejection correlated with the delay in institution of CI. The described dosing schedule resulted in subtherapeutic daclizumab levels in liver transplant recipients. CONCLUSIONS: Daclizumab used in liver transplant recipients without any CI was ineffective and can potentially lead to steroid-resistant rejection. The dosing regimen used in renal transplant recipients is most likely insufficient for liver transplant patients. However, daclizumab can be used safely in patients with preexisting or postoperative renal dysfunction in conjunction with low doses of CI given within the first week postoperatively.

Risks associated with conversion of stable patients after liver transplantation to the microemulsion formulation of cyclosporine.

BACKGROUND: Neoral is a microemulsion formulation of cyclosporine that has a better pharmacokinetic profile than the standard formulation (Sandimmune). To prove the safety of converting stable liver transplant patients from Sandimmune to Neoral, we conducted a prospective trial involving 54 patients. METHOD: The average time from transplantation to conversion was 48.5+/-21.6 months. Thirty of 54 patients (55%) required a dose reduction during the study for various reasons. Five of 30 patients had the first dose reduction because of increased levels of cyclosporine. Seven patients required more than one dose reduction. RESULTS: Sixteen patients suffered serious adverse events. Six patients had a biopsy-proven rejection. Four of 6 patients had trough cyclosporine levels within 20% of baseline value immediately before developing rejection. CONCLUSION: Converting patients from the standard formulation to the microemulsion formulation of cyclosporine seems to expose stable patients to unnecessary risks.