Suitability of Estimated Glomerular Filtration Rate for Live Kidney Donor Selection.

INTRODUCTION: The assessment of the glomerular filtration rate (GFR) in kidney donor candidates is required for determining donor candidate acceptability. This assessment can be done using an estimated GFR (eGFR) or a measured GFR (mGFR). The primary objective of the present study was to compare, in healthy adult kidney donor candidates, GFR measured by the clearance of iothalamate to GFR estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and to determine if eGFR was a suitable stand-alone assessment. A secondary objective was to explore demographic factors that affect the relationship of the eGFR and the mGFR. METHODS: A retrospective review of kidney donor candidates' records at the J. C. Walter, Jr., Transplant Center, Houston Methodist Hospital, from January 2013 to March 2016 was undertaken. GFR was measured by the plasma clearance of radioisotopic iothalamate and estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The median mGFR was 108 mL/min/1.73 m2. The eGFR underestimated the mGFR by 11.5%. The underestimation was greatest in subjects with an mGFR of ≥90 mL/min/1.73 m2. The eGFR overestimated the mGFR in donor candidates of black race. CONCLUSIONS: The Chronic Kidney Disease Epidemiology Collaboration eGFR can be used for screening potential kidney donors restricting the use of iothalamate (mGFR) to those donors with an eGFR below the transplant centers' acceptable GFR threshold for donation, thereby effecting cost savings and greater donor convenience. The eGFR in black donor candidates should be used with caution.

Transplantation for Hepatocellular Carcinoma: Is There a Tumor Size Limit?

BACKGROUND: The advent of tumor-size-based criteria (Milan and University of California, San Francisco [UCSF]) for the transplantation of hepatocellular carcinomas (HCC) has facilitated tumor patients' access to transplantation. Recent success in transplanting patients with larger tumors (beyond UCSF) necessitates an understanding of the patient, the tumor, and biological criteria that determine successful outcomes for HCC transplantation across all size criteria. METHODS: We analyzed 11,928 patients who received OLT between 2002 and 2013 from the United Network for Organ Sharing Standard Transplant Analysis and Research file. Clinical outcomes were compared by tumor size at transplant; Milan (n = 11,555), beyond Milan within UCSF (n = 291), and beyond both Milan and UCSF (n = 82). A statistical analysis was conducted to determine the factors impacting survival. RESULTS: There were no statistically significant differences in the 1-, 3-, and 5-year survival rates between the 3 patient groups (within Milan 91.1%, 74.8%, and 60.3%; beyond Milan within UCSF, 92.7%, 71.1%, and 51.6%; and beyond Milan and UCSF 95.8%, 75.9%, and 58.1%). In a multivariate analysis, factors significantly affecting survival included, AA race, AFP >3000, and hepatitis C infection, while age, diabetes and largest tumor diameter had a more modest impact. Total tumor burden and time to transplantation were not significant predictors of survival. CONCLUSIONS: These data indicate that, based on current clinical selection criteria, a small number of large tumors can be successfully treated by transplantation and points to the need to include markers of HCC biologic behavior beyond size and tumor burden to transplant criteria.

Treatment of Refractory Gastrointestinal Bleeding in Patients With Portal Hypertension: A Case Series and Treatment Algorithm.

In patients with portal hypertension, ectopic varices can develop at any site along the gastrointestinal tract outside the classically described gastroesophageal location. Like esophageal variceal hemorrhage, bleeding from ectopic varices can be life-threatening. Diagnosis and treatment of ectopic varices can be challenging; to date, no effective treatment algorithm has been described. A systematic teamwork approach to diagnosing and treatment of ectopic varices is required to successfully manage hemorrhage from ectopic varices.

Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome.

BACKGROUND/OBJECTIVES: Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-ß (TRß)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings. SUBJECTS/METHODS: Diet-induced obese C57BL/J6 male mice were fed a very high-fat diet (VHFD) and received NMD implants subcutaneously. Ten mice per group received capsules containing GC-1 or phosphate-buffered saline (control). Weight, lean and fat mass, as well as cholesterol, triglycerides, insulin and glucose, were monitored for 24 days. After treatment, plasma levels of thyroid-stimulating hormone (TSH) and thyroxine were compared. mRNA levels of a panel of thermogenic markers were examined using real-time PCR in white adipose tissue (WAT) and brown adipose tissue (BAT). Adipose tissue, liver and local inflammatory response to the implant were examined histologically. Pancreatic islet number and ß-cell area were assessed. RESULTS: GC-1 released from the NMD reversed VHFD-induced obesity and normalized serum cholesterol and glycemia. Significant reductions in body weight and fat mass were observed within 10 days, whereas reductions in serum cholesterol and glucose levels were seen within 7 days. The significant decrease in TSH was consistent with TRß selectivity for GC-1. Levels of transcript for Ucp1 and thermogenic genes PGC1a, Cidea, Dio2 and Cox5a showed significant upregulation in WAT in NMD-GC-1-treated mice, but decreased in BAT. Although mice treated by NMD-GC-1 showed a similar number of pancreatic islets, they exhibited significant increase in ß-cell area. CONCLUSIONS: Our data demonstrate that the NMD implant achieves steady administration of GC-1, offering an effective and tightly controlled molecular delivery system for treatment of obesity and metabolic disease, thereby addressing compliance.

Combination Drug Products for HIV-A Word of Caution for the Transplant Clinician.

Modern-day treatment regimens for human immunodeficiency virus (HIV) are not only highly effective, but are now more often available as convenient fixed-dose combination products. Furthermore, as medication adherence is of utmost importance in this setting, national guidelines endorse the use of such products. Transplant providers of HIV-infected patients will undoubtedly encounter these products, some of which contain medications known to drastically alter the metabolism of certain immunosuppressants. Herein, we describe an instance of drug interaction-induced calcineurin inhibitor (CNI) nephrotoxicity in a renal transplant recipient being started on a cobicistat-containing combination product for HIV. CNI toxicity, in turn, was resolved with the aid of phenytoin as an inducer of drug metabolism. This case underscores the importance of familiarity with newer combination products on the market and constant communication with HIV-positive transplant recipients and their providers.

Symptomatic BK Virus Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

Osteocalcin Effect on Human ß-Cells Mass and Function.

The osteoblast-specific hormone osteocalcin (OC) was found to regulate glucose metabolism, fat mass, and ß-cell proliferation in mice. Here, we investigate the effect of decarboxylated OC (D-OC) on human ß-cell function and mass in culture and in vivo using a Nonobese diabetic-severe combined immunodeficiency mouse model. We found that D-OC at dose ranges from 1.0 to 15 ng/mL significantly augmented insulin content and enhanced human ß-cell proliferation of cultured human islets. This was paralleled by increased expression of sulfonylurea receptor protein; a marker of ß-cell differentiation and a component of the insulin-secretory apparatus. Moreover, in a Nonobese diabetic-severe combined immunodeficiency mouse model, systemic administration of D-OC at 4.5-ng/h significantly augmented production of human insulin and C-peptide from the grafted human islets. Finally, histological staining of the human islet grafts showed that the improvement in the ß-cell function was attributable to an increase in ß-cell mass as a result of ß-cell proliferation indicated by MKI67 staining together with the increased ß-cell number and decreased α-cell number data obtained using laser scanning cytometry. Our data for the first time show D-OC-enhanced ß-cell function in human islets and support future exploitation of D-OC-mediated ß-cell regulation for developing useful clinical treatments for patients with diabetes.

New-Onset Diabetes After Transplantation: Results From a Double-Blind Early Corticosteroid Withdrawal Trial.

New-onset diabetes after transplantation (NODAT) is an important complication following kidney transplantation. Data from the 5-year early steroid withdrawal double-blind randomized trial were analyzed to determine if steroid avoidance reduced the NODAT risk. Incidence, timing and risk factors for NODAT were evaluated using eight definitions. By American Diabetes Association definition, 36.3% of patients on chronic corticosteroids (CCS) and 35.9% on early corticosteroid withdrawal (CSWD) were diagnosed with NODAT by 5 years. The definition combining fasting blood glucose ≥126 mg/dL on two occasions or treatment identified slightly more cases of NODAT: CCS (39.3%) and CSWD (39.4%). Through 5 years posttransplant, the proportion of NODAT patients requiring treatment were similar (CSWD 22.5% vs. CCS 21.5%); however, insulin therapy was lower with CSWD (3.7% vs. 11.6%; p = 0.049). By multivariate analysis, only age, but not corticosteroid use, was a significant risk factor for NODAT for more than one definition. Numerical, but not statistically significant trends toward lower NODAT rates with CSWD were observed through 5 years for insulin use, HbA1c ≥6.0% and ≥6.5% on two occasions. This prospective, randomized trial of CSWD indicates that CSWD has a limited impact in reducing NODAT when compared to low-dose prednisone (5 mg/day from month 6 to 5 years).

Observations on the use of cidofovir for BK virus infection in renal transplantation.

BACKGROUND: In renal transplantation, BK virus infection can result in significant graft nephropathy and loss. While reduction in immunosuppression (IS) is considered standard therapy, adjunct agents may be warranted. Data are suggestive of a possible role of cidofovir for the management of BK. This study aims to describe the course of BK viremia (BKV) in a large cohort of renal transplant patients receiving adjunct cidofovir. METHODS: We evaluated kidney and kidney-pancreas recipients who received cidofovir combined with reduced IS for management of high-level BKV or BK virus nephropathy (BKVN). We examined the rate and timing of BKV clearance, and performed a multivariate analysis to identify risk factors associated with long-term (>6 months) viremia. RESULTS: In total, 75 patients received a median of 13 doses of cidofovir in conjunction with reduced IS; 32 patients (43%) had short-term BKV (≤6 months), and 43 (57%) had long-term BKV. Overall, 53 of 75 patients (71%) eventually cleared BKV at a median of 4.2 months (interquartile range 2.1-9.3 months). Independent factors associated with long-term BKV included older age (odds ratio [OR] 1.1, P = 0.02), delayed graft function (OR 31.4, P = 0.01), and higher peak BKV (OR 12.8, P = 0.02), while BKV reduction by at least 1 log(10) copies/mL at 1 month of treatment was associated with clearance within 6 months (OR 49.3, P < 0.01). Patients with earlier clearance maintained stable graft function and no graft losses, while long-term BKV was associated with a 15% decline in estimated glomerular filtration rate. CONCLUSIONS: Adjunct cidofovir resulted in preservation of renal function when viral clearance occurred within 6 months of initiation. This retrospective review defines factors predicting response to cidofovir in conjunction with reduced IS for BKVN or high-level BKV. Still, considering cost, frequency of administration, and treatment duration, a randomized trial is necessary to define the exact utility of cidofovir in the setting of BK virus infection.

Liver transplantation in an adult with adenomatosis and congenital absence of the portal vein: a case report.

Congenital absence of the portal vein (CAPV) is a rare congenital anomaly in which the superior mesenteric veins (SMV) and splenic veins converge and bypass the liver, effectively draining directly into the systemic venous circulation via the inferior vena cava (IVC), or alternatively the renal or iliac vein, creating a native portosystemic shunt. Portosystemic shunting results in clinical manifestations of hepatic encephalopathy as well as a predisposition to focal nodular hyperplasia and tumors, including adenomas, hepatoblastoma, and hepatocellular carcinoma (HCC), by the disruption of enterohepatic blood flow. Historically, CAPV has been thought to be a rare condition found mainly at autopsy, however, in recent years due to advances in radiological techniques, CAPV detection has increased. Herein we describe a patient with known CAPV who initially underwent hepatic resection for HCC. During surveillance, additional masses were discovered and were identified as recurrent HCC. Unfortunately, this patient was not a candidate for further resection or locoregional therapy. We demonstrate that transplantation is a challenging but technically viable option for treatment of HCC complicating adenomatosis-associated CAPV.

Quantifying the risk of incompatible kidney transplantation: a multicenter study.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention.

Outcomes of living donor renal transplants with a negative cross-match and pretransplant donor-specific antibody.

INTRODUCTION: Management of renal transplant recipients with a negative complement-dependent cytotoxicity-antihuman globulin (CDC-AHG) cross-match and pretransplant donor-specific antibody (DSA) is controversial. We sought to compare outcomes of immunologically high-risk living donor (LD) renal transplant recipients with and without DSA. METHODS: We conducted a single-center, retrospective review of all high immune-risk LD renal transplant recipients with a negative CDC-AHG cross-match performed between January 2008 and December 2010. Pretransplant desensitization for DSA was not utilized. Immunosuppression consisted of thymoglobulin induction, followed by tacrolimus, myeophenolate mofetil, and prednisone. DSA was assessed pretransplant and at 1, 3, 6, 9, and 12 months, and every 6 months thereafter. RESULTS: Between January 2008 and December 2010, 44 LD renal transplants were performed in high immune-risk recipients with a negative CDC-AHG cross-match. Outcomes of 14 recipients with pretransplant DSA were compared with 30 recipients with no DSA. After a median follow-up of 26 months (range, 12-40), overall death-censored graft survival was 100%, with no acute rejection episodes in the DSA group and 1 antibody-mediated rejection in the non-DSA cohort. Mean serum creatinines of the DSA and non-DSA groups at 1 year post-transplant were 1.0 ± 0.4 and 1.2 ± 0.6 mg/dL (P = NS), respectively. Among the pretransplant DSA cohort, 5 of the 14 (36%) developed persistent post-transplant DSA at a median of 9 months (range, 3-24) versus 2 of 30 (7%; P = .025) at a median of 12 months post-transplant in the non-DSA cohort. All recipients in the pretransplant DSA group underwent renal biopsy for persistent post-transplant DSA. Three of 5 biopsies showed C4D deposition in peritubular capillaries without glomerulopathy or arteriopathy. CONCLUSIONS: Early post-transplant outcomes for LD recipients with a negative cross-match and pretransplant DSA were excellent. In recipients with good and stable renal function, the significance of persistent post-transplant DSA in combination with C4D deposition on biopsy is unclear at this time.

Effect of corticosteroid withdrawal on tacrolimus and mycophenolate mofetil exposure in a randomized multicenter study.

As corticosteroid-sparing protocols are increasingly utilized in kidney transplant recipients, it is crucial to understand potential drug interactions between tacrolimus (TAC) and the effect of corticosteroid withdrawal as well as to characterize dose adjustments of mycophenolate mofetil (MMF) in this setting. This prospective, multicenter, randomized, double-blind study included 397 patients who were randomized on posttransplant day 8 to receive either placebo (CSWD) or corticosteroid continuance (CCS). TAC trough levels at week two posttransplant were significantly greater in the CSWD group whereas TAC doses were comparable to the CCS group. This interaction was not observed in the African American subgroup. Higher serum creatinine and potassium levels were also observed in the CSWD group. MMF dose was significantly reduced in the CSWD group by the investigators because of decreased WBC counts, mostly outside of study protocol criteria, despite similar incidence of neutropenia and reported cytomegalovirus infection. Understanding TAC and MMF exposure in the context of corticosteroid-sparing protocols should allow for improved dosing of immunosuppressants and better management of posttransplant patients.

The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation.

Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic-pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low-dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high-dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r(2) = 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6-month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low- and medium-exposure groups, and potentially associated with a reduced incidence of NODAT.

De novo donor specific antibodies and patient outcomes in renal transplantation.

Single antigen identification of HLA antibodies is used to detect donor specific antibodies (DSAs). However, the impact of DSA elements such as class, relative strength, duration, and longitudinal effect on graft function and survival, remains unclear. Routine DSAs (LabScreen, One Lambda, Inc., Canoga Park, CA) and metabolic studies were performed at 1, 3, 6, 9, and 12 months post-transplant, and every 6 months for renal transplant recipients from 7/2007-7/2010 (n = 389). Biopsies were evaluated by updated Banff 2005 guidelines after two consecutive positive DSAs. Based on these tests, 25% of recipients developed de novo DSA. Those with DSA had increased acute rejection episodes (AR), higher creatinine (Scr), and worse graft survival. Three subgroups of these patients were identified based on duration: persistent DSA (> 1), isolated DSA, or no DSA. Persistent DSA patients were more likely to be African American, and have higher mean fluorescence intensity (MFI) and AR rates. Persistent DSA patients, with or without AR, had elevated Scr. Recipients with DQ-only DSA had higher rates of antibody mediated rejection (AMR). From this, we conclude that routine posttransplant DSA monitoring identifies recipients at risk for graft damage or loss. Persistent de novo DSAs correlated with inferior graft outcomes and AMR. With or without AR, DSA persistence was associated with worse outcomes, possibly warranting intervention. De novo DQ-DSA may be a biomarker for chronic damage and/or AMR, while an isolated DSA determination appears clinically insignificant.

Simultaneous kidney-pancreas transplantation for end-stage renal disease patients with insulin-dependent diabetes and detectable C-peptide.

INTRODUCTION: There is controversy regarding the place of simultaneous pancreas-kidney (SPK) transplantation in end-stage renal disease (ESRD) patients with insulin-dependent diabetes mellitus (IDDM) and detectable c-peptide. We sought to compare outcomes of recipients with and without pretransplantation c-peptide. METHODS: This retrospective single-center review included consecutive primary SPK transplantations performed between September 2007 and May 2010. Demographic characteristics and outcomes were compared between recipients with and without pretransplantation c-peptide. RESULTS: Seven of 25 (28%) consecutive SPK transplant recipients with a diagnosis of IDDM and ESRD had detectable c-peptide prior to transplantation. The mean c-peptide level was 6.3 ± 6.1 ng/mL. For those recipients with and without c-peptide, mean age at diagnosis of IDDM (12.4 ± 7.8 vs 17.1 ± 6.6 years; P = not significant [NS]), duration of IDDM prior to transplantation (30 ± 10 vs 23 ± 9 years; P = NS), and body mass index (25.9 ± 4.5 vs 26.7 ± 4.5 kg/m(2); P = NS) were equivalent between the groups. With a median follow-up of 17 months (range, 3-35 months) there was 1 graft loss (due to cardiovascular death) among the 25 patients. At the most recent follow-up, for recipients with and without c-peptide, both the mean serum creatinine (1.3 ± 0.6 vs 1.0 ± 0.2 ng/mL; P = NS) and the mean HbA1c level (5.3 ± 0.4 vs 5.3 ± 0.5; P = NS) were equivalent between the groups. CONCLUSION: For nonobese ESRD patients diagnosed with IDDM at a young age, the presence of detectable c-peptide should not influence the decision to proceed with SPK transplantation.

Serial analysis of biomarkers of acute pancreas allograft rejection.

Pancreas transplant recipients experience graft loss in spite of improvements in immunosuppressant therapies and diagnostic technologies. Therefore, a method to improve detection and management of acute rejection is needed. This longitudinal study investigated the usefulness of three biomarkers, granzyme B, perforin, and human leukocyte antigen-DR alpha (HLA-DR) measured by real-time PCR on peripheral blood mononuclear cells, for their ability to detect acute rejection and its resolution in 13 recipients of pancreas allograft. Data demonstrated that pre-transplant baseline expression of biomarkers decreased following the initiation of immunosuppression. Throughout follow-up (range 3-27 months), individuals without acute rejection episodes had little variation in their biomarker levels. Recipients with biopsy-proven rejection had a significant increase in the levels of biomarkers as early as five wk before clinical rejection diagnosis. Furthermore, all seven patients with biopsy-proven rejection demonstrated a decrease in the levels of granzyme B and perforin following the increased immunosuppression for the treatment of rejection. This is the first clinical serial measurement of biomarkers in recipients of pancreas transplants. The data demonstrate that upregulation of granzyme B, perforin, and HLA-DR in peripheral blood mononuclear cells are sensitive to changes in the immune environment and could possibly be used to identify those patients at higher risk of rejection.

Prospects for future advancements in islet cell transplantation.

Islet cell transplantation holds great promise for treating patients with type 1 diabetes mellitus (T1DM), and for preventing unstable metabolic state commonly refereed to as brittle diabetes in patients that undergo pancreatic resection given that it is a relatively noninvasive procedure and an attractive alternative to pancreas transplantation for restoring endogenous insulin secretion. The success of recent clinical trials for allogeneic islet transplantation as well as the increasing centers that perform auto-transplantation is showing that the beta cell replacement therapy for the treatment of patients with diabetes or total pancreatectomy has been firmly established. It needs only to be improved and made more widely available to the millions of desperate patients who search for alternatives to a life of insulin injections, hypoglycemia and the risks of end-organ damage. Steady progress has been achieved in recent years in different areas in the pancreatic islet transplantation process including islet cell processing, preservation, and immune therapies that justify optimism. To implement this therapeutic approach to larger cohorts of patients that would benefit from the restoration of beta cell function requires multiple interventions and the standardization of the different stages of islet transplant process. This article will review the possible areas of intervention and the ongoing research toward this important goal.

Changes in abdominal wounds following treatment with sirolimus and steroids in a rat model.

Wound healing complications have been observed in patients receiving sirolimus (SLR). This study examined the degree and duration of delayed healing in various protocols using SLR. Sprague-Dawley rats underwent a standard midline abdominal incision and wound closure. Groups of 6 rats each were randomized to receive different doses of SLR (2 and 5 mg/kg) with or without loading dose (10 mg/kg x3 days), and with or without steroids (20 mg/kg x3 days followed by 5 mg/kg for 2 weeks). Rats were humanely killed on postoperative days 5, 10, or 15. Wound breaking force was measured using the EHMI BIAX-II instrument and tensile strength was calculated. Wounds in control animals had gradual increase in tensile strength during the 15-day observation. In contrast, high and loading doses of SLR caused reduction in wound strength until day 10, but the wounds' tensile strength became equivalent to control by day 15. The addition of steroids prolonged wound recovery with low doses of SLR until day 15 and had very profound effects on healing in high-dose SLR-treated animals (>50% reduction) that continued beyond the 2 weeks of observation. Low doses of SLR in non-steroid-treated animals had a short-term (5-day) impact on wound healing; high dose and loading doses delayed healing for 10 to 15 days. The addition of steroids had a synergistic effect on delayed wound healing, particularly in animals receiving high-dose SLR, which demonstrated prolonged wound weakness. These results may provide practical guidelines for postoperative introduction of SLR in the context of various clinical protocols.

Serial peripheral blood cytotoxic lymphocyte gene expression measurements for prediction of pancreas transplant rejection.

Acute rejection after pancreas transplantation remains a significant problem and contributes to immunological graft loss. No clinical markers of pancreas rejection have been universally accepted. The purpose of this study was to investigate the use of genetic markers; granzyme B, perforin, and HLA-DRA in the peripheral blood of pancreas transplant recipients. These genes have been identified in renal and islet cell transplant recipients as noninvasive tools to predict acute rejection. Blood samples were collected weekly for up to 1 year posttransplant. Surveillance biopsies of the pancreas were scheduled at weeks 2, 4, 8, and 12 as part of the typical posttransplant protocol for patients with pancreas alone or pancreas after kidney transplantation. Exclusion criteria included a diagnosis of biopsy-proven chronic rejection alone, pancreatitis, or kidney rejection within 2 months after pancreas biopsy. Gene expression levels of granzyme B, perforin, and HLA-DRA were compared in patients with (n = 7) and without biopsy proven acute rejection (n = 7). Recipients with acute rejection showed increased expression of granzyme B, HLA-DRA, as well as perforin genes compared to patients without biopsy-proven rejection. In addition, we observed that elevation of these genes occurred as early as 4 weeks before the traditional biopsy diagnosis, while the recipients with no rejection showed no change in gene expression. Our data indicated that serial measurements of peripheral blood granzyme B, perforin, and HLA-DRA gene expression can be a useful tool to predict pancreas rejection in its earliest stage.