A comparison of portal venous versus systemic venous drainage in pancreas transplantation.

BACKGROUND: The decision to utilize portal or systemic venous drainage in pancreas transplantation is surgeon- and center-dependent. Information regarding the superior method is based on single-center reports and animal models. METHODS: UNOS data on adults receiving pancreas and kidney-pancreas transplants from 1987 to 2016 were analyzed (n = 29 078). The groups analyzed were: systemic venous pancreas graft drainage (SVD, n = 24 512) or portal venous pancreas graft drainage (PVD, n = 4566). A Cox proportional hazard model compared patient and allograft survival between groups. RESULTS: No statistically significant differences were observed for patient and allograft survival at 1, 3, 5, 10, or 15 years post-transplant at each time interval and cumulatively (patient - HR:1.041; 95% CI:0.989-1.095; allograft - HR:0.951; 95% CI:0.881-1.027). PVD reduced the risk of death by 22.0% (P = 0.017) compared to SVD for patients undergoing pancreas after kidney transplant (PAK); no statistically significant difference was found for patients undergoing other types of transplants. CONCLUSION: There is no significant clinical difference in patient or allograft survival between PVD and SVD in pancreas transplantation for the majority of patients. For the subgroup of PAK, PVD was associated with decreased mortality. For individual surgeons, center and patient scenarios should dictate which technique is performed.

Kidney transplantation in Icelandic patients, 2000-2019: are outcomes affected by low volume?

Background: In Iceland, a small number of kidney transplants from living donors (LDs) are performed at Landspitali University Hospital (LUH) in Reykjavik, while deceased donor transplants have until recently invariably been carried out abroad. In this study, we evaluated the outcome of kidney transplantation in Icelandic patients. Methods: This was a retrospective study that included all Icelandic residents who underwent kidney transplantation between 1 January 2000 and 31 December 2019. Data were obtained from the Icelandic End-Stage Kidney Disease Registry, medical records at LUH, and the Scandiatransplant database. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate estimated glomerular filtration rate from serum creatinine for recipients and donors aged >18 years, and the modified Schwartz equation for those aged ≤18 years. Survival was estimated using the Kaplan-Meier method, and the log-rank test was employed for group comparisons. Results: A total of 229 kidney transplants in 221 patients were performed during the 20-year period, of which 135 (58.9%) were from LDs. Transplants carried out at LUH were 118 (51.5%), of which 116 were from LDs. During a median follow-up of 7.4 years (range 0.1-20), 27 (12.2%) patients died, 20 (74%) of whom had a functioning graft. One-year patient survival was 99.1% [95% confidence interval (CI), 97.9-100], 5-year survival was 95.7% (95% CI, 92.7-98.7), and 10-year survival was 87.7% (95% CI, 82.4-93.4). Death-censored graft survival was 98.3% (95% CI, 96.6-100), 96.8% (95% CI, 94.4-99.2), and 89.2% (95% CI, 84.1-94.7) at 1, 5, and 10 years, respectively. Conclusions: Patient and graft survival are comparable with those of large transplant centers, demonstrating the feasibility of running a quality kidney transplant program in a small nation in collaboration with a larger center abroad.

Hepatic stellate cell and myofibroblast-like cell gene expression in the explanted cirrhotic livers of patients undergoing liver transplantation.

BACKGROUND: Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells. AIMS: To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis. METHODS: Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR. RESULTS: Differential expression of some genes, such as IL-1beta, IL-1alpha, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality. CONCLUSIONS: These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.

Use of Mammalian Target of Rapamycin Inhibitors for Pancreas Transplant Immunosuppression Is Associated With Improved Allograft Survival and Improved Early Patient Survival.

OBJECTIVES: Mammalian targets of rapamycin inhibitors (mTORi) are considered second-line immunosuppression agents because of associated increases in rejection and impaired wound healing. Recent reports indicate mTORi have been linked to improved survival, decreased inflammatory response in pancreatitis, and antiproliferative and antiangiogenic activity. Mammalian targets of rapamycin inhibitors have not been extensively analyzed in pancreas transplant recipients. METHODS: Adults with pancreas and kidney-pancreas transplants from 1987 to 2016 in the United Network for Organ Sharing database were analyzed (N = 25,837). Subjects were stratified into 2 groups: use of mTORi (n = 4174) and use of non-mTORi-based immunosuppression (n = 21,663). The log-rank test compared survival rates. Univariate and multivariate Cox regression analyses assessed patient and graft survival. RESULTS: Mammalian targets of rapamycin inhibitors were associated with a 7% risk reduction in allograft failure (hazard ratio, 0.931; P = 0.006). Allograft survival rates were significantly different between mTORi versus non-mTORi (P < 0.0001).The mTORi group showed a significantly higher patient survival rate 1, 3, 5, and 10 years posttransplant compared. Patient survival at 15 years was not significantly different. CONCLUSIONS: The use of mTORi for immunosuppression in pancreas transplant is associated with improved allograft survival and early patient survival posttransplant (up to 10 years).

Bladder Versus Enteric Drainage of Exocrine Secretions in Pancreas Transplantation: A Retrospective Analysis of the United Network for Organ Sharing Database.

OBJECTIVES: The method for drainage of exocrine secretions in pancreas transplantation remains a matter of debate. Different methods have evolved over time. Most data on these methods are from single-center studies with small sample sizes. Larger studies have yielded conflicting results. METHODS: Data from the United Network for Organ Sharing database on all adult subjects who received pancreas and kidney-pancreas transplants between 1996 and 2012 were analyzed (n = 19,934). Subjects were divided into 3 groups: enteric drainage with Roux-en-Y (n = 4308), enteric drainage without Roux-en-Y (n = 11,145), and bladder drainage (n = 4481). Primary end points were patient and graft survival at 1, 3, 5, 10, and 15 years. RESULTS: There was a patient and graft survival advantage with enteric drainage without Roux-en-Y reconstruction compared with the other methods. This was consistent at 1, 3, 5, 10, and 15 years. CONCLUSIONS: Our study demonstrated increased graft and patient survival when comparing enteric drainage of the transplanted pancreas without Roux-en-Y reconstruction to enteric drainage with Roux-en-Y and bladder drainage at 1, 3, 5, 10, and 15 years. Based on this study, we recommend enteric drainage without Roux-en-Y reconstruction as the method of choice in pancreas transplantation.

Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay.

BACKGROUND: Long-term use of immunosuppressants is associated with significant morbidity and mortality in transplant recipients. A simple whole blood assay that has U.S. Food and Drug Administration clearance directly assesses the net state of immune function of allograft recipients for better individualization of therapy. A meta-analysis of 504 solid organ transplant recipients (heart, kidney, kidney-pancreas, liver and small bowel) from 10 U.S. centers was performed using the Cylex ImmuKnow assay. METHODS: Blood samples were taken from recipients at various times posttransplant and compared with clinical course (stable, rejection, infection). In this analysis, 39 biopsy-proven cellular rejections and 66 diagnosed infections occurred. Odds ratios of infection or rejection were calculated based on measured immune response values. RESULTS: A recipient with an immune response value of 25 ng/ml adenosine triphosphate (ATP) was 12 times (95% confidence of 4 to 36) more likely to develop an infection than a recipient with a stronger immune response. Similarly, a recipient with an immune response of 700 ng/ml ATP was 30 times (95% confidence of 8 to 112) more likely to develop a cellular rejection than a recipient with a lower immune response value. Of note is the intersection of odds ratio curves for infection and rejection in the moderate immune response zone (280 ng/ml ATP). This intersection of risk curves provides an immunological target of immune function for solid organ recipients. CONCLUSION: These data show that the Cylex ImmuKnow assay has a high negative predictive value and provides a target immunological response zone for minimizing risk and managing patients to stability.

Early Kidney Allograft Dysfunction (Threatened Allograft): Comparative Effectiveness of Continuing Versus Discontinuation of Tacrolimus and Use of Sirolimus to Prevent Graft Failure: A Retrospective Patient-Centered Outcome Study.

BACKGROUND: Due to lack of treatment options for early acute allograft dysfunction in the presence of tubular-interstitial injury without histological features of rejection, kidney transplant recipients are often treated with sirolimus-based therapy to prevent cumulative calcineurin inhibitor exposure and to prevent premature graft failure. METHODS: We analyzed transplant recipients treated with sirolimus-based (n = 220) compared with continued tacrolimus-based (n = 276) immunosuppression in recipients of early-onset graft dysfunction (threatened allograft) with the use of propensity score-based inverse probability treatment weighted models to balance for potential confounding by indication between 2 nonrandomized groups. RESULTS: Weighted odds for death-censored graft failure (odds ratio [OR], 1.20; 95% confidence interval [95% CI], 0.66-2.19, P = 0.555) was similar in the 2 groups, but a trend for increased risk of greater than 50% loss in estimated glomerular filtration rate from baseline in sirolimus group (OR, 1.90; 95% CI, 0.96-3.76; P = 0.067) compared with tacrolimus group. Sirloimus group compared with tacrolimus group had increased risk for death with functioning graft (OR, 2.01; 95% CI, 1.29-3.14; P = 0.002) as well as increased risk of late death (death after graft failure while on dialysis) (OR, 2.39; 95% CI, 1.59-3.59; P < 0.001). Analysis of subgroups based on the absence or presence of T cell-mediated rejection or tubulointerstitial inflammation in the index biopsy, or the use of different types of induction agents, and all subgroups had increased risk of death with functioning graft and late death if exposed to sirolimus-based therapy. CONCLUSIONS: Use of sirolimus compared with tacrolimus in recipients with early allograft dysfunction during the first year of transplant may not prevent worsening of allograft function and could potentially lead to poor survival along with increased risk of late death.

A multicenter, prospective study of C2-monitored cyclosporine microemulsion in a U.S. population of de novo renal transplant recipients.

BACKGROUND: Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2) has been reported to optimize the efficacy and safety of CsA-ME therapy. The addition of induction therapy to a maintenance regimen including CsA-ME C2 monitoring has not been evaluated. METHODS: In all, 123 adult renal transplant recipients were recruited at 14 U.S. centers for this 6-month study. CsA-ME dose was to be titrated to attain C2 targets of 1700 and 1500 ng/ml during posttransplant months 1 and 2, respectively. After 2 months, patients were randomized to one of two groups with different, decreasing C2 targets. Basiliximab, mycophenolate mofetil, and corticosteroids completed the study immunosuppression. RESULTS: Of the 119 evaluable patients, 76% were male, 22% African American, and 66% deceased donor recipients. Biopsy-proven acute rejection occurred in 10 patients (9.3%); there were two failed grafts and one death. Serum creatinine and calculated GFR values suggest good renal function, with month 6 medians of 1.5 ng/ml and 67 ml/min/1.73 m. Safety and tolerability assessments revealed no unexpected outcomes. Observed C2 levels were generally lower than protocol targets, particularly in the first weeks posttransplantation. CONCLUSIONS: The striking efficacy and outcomes may have been achieved in this study with lower C2 levels of CsA-ME because of the addition of basiliximab induction.

Retransplantation in patients with graft loss caused by polyoma virus nephropathy.

The characteristics and outcome in 10 patients who underwent retransplantation after losing their renal grafts to BK virus-associated nephropathy (BKAN) are described. The patients underwent retransplantation at a mean of 13.3 months after failure of the first graft. Nephroureterectomy of the first graft was performed in seven patients. Maintenance immunosuppression regimens after the first and second grafts were similar, consisting of a combination of a calcineurin inhibitor, mycophenolate mofetil, and prednisone. BKAN recurred in one patient 8 months after retransplantation, but stabilization of graft function was achieved with a decrease in immunosuppression and treatment with low-dose cidofovir. After a mean follow-up of 34.6 months, all patients were found to have good graft function with a mean creatinine of 1.5 mg/dL. From this collective experience from five transplant centers (although the follow-up after retransplantation was not extensive), it can be concluded that patients with graft loss caused by BKAN can safely undergo retransplantation. The risk of recurrence does not seem to be increased in comparison with the first graft.

A genomic strategy for predicting androgen receptor activity in prostate tumors.

Mendiratta et al. have developed an AR signature for prostate cancer that is based on the expression of 300 genes. The AR signature is decreased with androgen deprivation therapy, and in the development of androgen independent prostate cancer, however significant inter-individual variation in AR activity was noted. Decreased AR activity was also related to the expression of SRC kinase, and sensitivity to dasatinib. The work by Mendiratta et al. may be useful to determine the AR status of tumors in order to inform therapy and individualize treatment.