PROviding Better ACcess To ORgans: A comprehensive overview of organ-access initiatives from the ASTS PROACTOR Task Force.

The American Society of Transplant Surgeons (ASTS) PROviding better Access To Organs (PROACTOR) Task Force was created to inform ongoing ASTS organ access efforts. Task force members were charged with comprehensively cataloguing current organ access activities and organizing them according to stakeholder type. This white paper summarizes the task force findings and makes recommendations for future ASTS organ access initiatives.

Are hepatocellular carcinoma patients more likely to receive liver resection in regions with longer transplant wait times?

In areas with longer liver transplantation (LT) wait times, liver resection (LR) offers an appropriate alternative in selected patients with hepatocellular carcinoma (HCC). We identified adults with HCC undergoing LT or LR from the United States Nationwide Inpatient Sample from 1998-2008. United Network for Organ Sharing regions were assigned lower rank indicating shorter wait time for patients with Model for End-Stage Liver Disease (MELD) scores of 19-24 or ≥ 25. We used multivariate adjusted analysis to assess the odds of LR versus LT comparing patients by region. Of 4,516 patients, 40% received LT and 60% received LR. When ranked by wait times for MELD 19-24, the 3rd, 8th, and 11th ranked regions had decreased odds of LR versus LT (region 3: odds ratio [OR] 0.3, 95% confidence interval [CI] 0.2-0.6; region 8: OR 0.5, 95% CI 0.3-0.9; region 5: OR 0.3, 95% CI 0.2-0.6), whereas the 10th ranked region had increased odds (region 1: OR 1.9, 95% CI 1.1-3.4) compared with the region with the shortest wait time, region 10. When ranked by wait times for MELD ≥25, all regions except the 10th ranked region (region 5) had increased odds compared with the region with the shortest wait time, region 3 (OR 1.6-5.6; P < .001). Regional variations of LT versus LR are not completely explained by transplant wait times.

Accidental acetaminophen overdose results in liver transplant during second trimester of pregnancy: a case report.

Acetaminophen overdose is the most rapidly growing cause of fulminant hepatic failure in Western countries. Pregnant women are counseled that acetaminophen is safe during pregnancy and an alternative to nonsteroidal anti-inflammatory medications. This report describes a case of acetaminophen overdose during the second trimester of pregnancy with resultant fulminant hepatic failure requiring liver transplantation. The fetus was previable at the time of liver transplantation, and methods to preserve viability during and after transplantation are discussed. Despite the best attempts of the team, the fetus expired. The challenges and outcomes of fulminant hepatic failure in pregnancy are discussed in detail.

A technique for kidney retransplantation after simultaneous kidney pancreas transplantation.

Isolated failure of the renal graft after simultaneous kidney-pancreas transplantation (SPK) is a rare but potential outcome. Many of these patients are candidates for kidney retransplantation. This paper describes a series of 3 patients who underwent successful kidney retransplantation after SPK. The operation was completed through an extraperitoneal incision without disruption of the pancreas graft or need for a transplant nephrectomy.

Open sphincteroplasty for benign ampullary stricture after pancreas transplantation.

Ampullary and proximal pancreatic duct strictures are well known to result in recurrent episodes of pancreatitis in the native pancreas, which when benign in origin can often be treated with sphincteroplasty (open or endoscopic) and stenting in the native pancreas. However, recurrent episodes of pancreatitis in a transplanted pancreas allograft can have multiple potential etiologies, and if the diagnosis of pancreatic duct stricture is made, treatment with preservation of the pancreatic allograft can be challenging. This is the first case report to describe the open sphincteroplasty of a short benign ampullary stricture in a transplant pancreas allograft.

Outcomes after simultaneous pancreas and kidney transplantation and the discriminative ability of the C-peptide measurement pretransplant among type 1 and type 2 diabetes mellitus.

BACKGROUND: Earlier studies reporting outcomes after pancreas transplantation have included a combination of C-peptide cutoffs and clinical criteria to classify type 2 diabetes mellitus (T2DM). However, because the kidney is the major site for C-peptide catabolism, C-peptide is unreliable to discriminate the type of diabetes in patients with kidney disease. METHODS: To improve the discriminative power and better classify the type of diabetes, we used a composite definition to identify T2DM: presence of C-peptide, negative glutamic acid decarboxylase antibody, absence of diabetic ketoacidosis, and use of oral hypoglycemics. Additionally among T2DM patients with end-stage renal disease (ESRD), body mass index of <30 kg/m(2) and use of <1 u/kg of insulin per day were selection criteria for suitablity for simultaneous pancreas and kidney transplantation (SPKT). We compared graft and patient survival between T1DM and T2DM after SPKT. RESULTS: Our study cohort consisted of 80 patients, 10 of whom were assigned as T2DM based on our study criteria. Approximately 15% of patients with T1DM had detectable C-peptide. Cox regression survival analyses found no significant differences in allograft (pancreas and kidney) or patient survival between the 2 groups. The mean creatinine clearance at 1 year estimated by the modification of Diet in Renal Disease (MDRD) equation was not significantly different between the 2 groups. Among those with 1 year of follow-up, all patients with T2DM had glycosylate hemoglobin of <6.0 at 1 year versus 92% of those with T1DM. CONCLUSION: SPKT should be considered in the therapeutic armamentarium for renal replacement in selected patients with T2DM and ESRD. Use of C-peptide measurements for ESRD patients can be misleading as the sole criterion to determine the type of diabetes.

Impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy in kidney transplant recipients.

Our aim was to study the impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy (IF/TA) on a 1-year protocol biopsy in patients on rapid steroid withdrawal (RSW). A total of 256 patients were classified based on protocol biopsy findings at months 1 or 4. Group 1 is 172 patients with no inflammation, group 2 is 50 patients with subclinical inflammation (SCI), group 3 is 19 patients with subclinical acute rejection (SAR) and group 4 is 15 patients with clinical acute rejection (CAR). On the 1-year biopsy, more patients in group 2 (SCI) (34%, p = 0.004) and group 3 (SAR) (53%, p = 0.0002), had an IF/TA score > 2 compared to group 1 (control) (15%). IF/TA was not increased in group 4 (CAR) (20%). The percent with IF/TA score > 2 and interstitial inflammation (Banff i score > 0) was higher in group 2 (16%, p = 0.004) and group 3 (37%, p < 0.0001) compared to group 1 (3%). In a multivariate analysis, patients in groups 2 or 3 had a higher risk of IF/TA score > 2 on the 1-year biopsy (OR 6.62, 95% CI 2.68-16.3). We conclude that SCI and SAR increase the risk of developing IF/TA in patient on RSW.

Pilot study: association of traditional and genetic risk factors and new-onset diabetes mellitus following kidney transplantation.

INTRODUCTION: New-onset diabetes mellitus, which occurs after kidney transplant and type 2 diabetes mellitus (T2DM), shares common risk factors and antecedents in impaired insulin secretion and action. Several genetic polymorphisms have been shown to be associated with T2DM. We hypothesized that transplant recipients who carry risk alleles for T2DM are "tipped over" to develop diabetes mellitus in the posttransplant milieu. METHODS: We investigated the association of genetic and traditional risk factors present before transplantation and the development of new-onset diabetes mellitus after kidney transplantation (NODAT). Markers in 8 known T2DM-linked genes were genotyped using either the iPLEX assay or allelic discrimination (AD)-PCR in the study cohort testing for association with NODAT. We used univariate and multivariate logistic regression models for the association of pretransplant nongenetic and genetic variables with the development of NODAT. RESULTS: The study cohort included 91 kidney transplant recipients with at least 1 year posttransplant follow-up, including 22 who developed NODAT. We observed that increased age, family history of T2DM, pretransplant obesity, and triglyceridemia were associated with NODAT development. In addition, we observed positive trends, although statistically not significant, for association between T2DM-associated genes and NODAT. CONCLUSIONS: These findings demonstrated an increased NODAT risk among patient with a positive family history for T2DM, which, in conjunction with the observed positive predictive trends of known T2DM-associated genetic polymorphisms with NODAT, was suggestive of a genetic predisposition to NODAT.

Deceased donor kidney transplantation from donors with acute renal failure due to rhabdomyolysis.

With the current shortage of solid organs for transplant, the transplant community continues to look for ways to increase the number of organ donors, including extending the criteria for donation. In rhabdomyolysis, the byproducts of skeletal muscle breakdown leak into the circulation resulting in acute renal failure in up to 30% of patients. In nonbrain dead patients, this condition is reversible and most patients recover full renal function. Seven potential donors had rhabdomyolysis with acute renal failure as evidenced by the presence of urine hemoglobin, plasma creatinine kinase levels of greater than five times the normal and elevated creatinine. One donor required dialysis. At our institution, 10 kidneys were transplanted from the seven donors. Two grafts had immediate function, five grafts experienced slow graft function and three grafts had delayed graft function requiring hemodialysis. At a mean of 8.7 months posttransplant (2.4-25.2 months), all patients have good graft function, are off dialysis and have a mean creatinine of 1.3 (0.7-1.8). In conclusion, our experience suggests that rhabdomyolysis with acute renal failure should not be a contraindication for donation, although recipients may experience slow or delayed graft function.

Diffuse parenchymal urine leak after kidney transplantation following degloving injury during donor nephrectomy.

Laparoscopic donor nephrectomy can result in trauma to the kidney which may affect recipient graft function. In this case, the kidney sustained a complete degloving of the capsule during extraction. The kidney was transplanted and had immediate, good renal function, but postoperative course was complicated by a large urinoma that drained through the wound. Exploration was negative for a defined urine leak, but the surface of the denuded kidney was leaking a significant amount of unconcentrated urine. The patient was successfully treated with tissue glue treatment to the kidney surface and peritoneal window.

Effect of early recurrence of hepatitis C on late biliary anastomotic stricture after liver transplantation.

The aim of the current study was to clarify whether recurrence of hepatitis C (HCV) infection affects biliary complications after liver transplantation (OLT), with special reference to late biliary anastomotic strictures (LBAS). We reviewed 665 consecutive adult OLT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005. Biliary anastomotic stricture was confirmed by ERCP. The LBAS was defined as stricture that occurred 30 days or more after OLT. Recurrence of HCV was diagnosed by histological examination using liver biopsy specimen and confirmed by the presence of HCV-RNA. Early HCV recurrence was defined as recurrence that occurred within 6 months after OLT; LBAS occurred in 54 patients (8% of total). Mean duration from OLT to occurrence of LBAS was 6.9 months (1-44 months). Patients with HCV infection had higher occurrence of LBAS than did non-HCV patients (11% vs 5%, P = .0093). Among HCV patients, those with early HCV recurrence had exclusively high rate of LBAS (16%). In multivariate analyses, early recurrence of HCV (P < .001, relative risk [RR] 6.4), as well as occurrence of HAT (P = .0018, RR 8.0), and prolonged CIT (P = .034, RR 3.3) were independent risk factors affecting LBAS. In conclusion, patients with HCV infection have increased occurrence of LBAS after OLT. Additionally, early recurrence of HCV contributes to a higher rate of LBAS.

The ability of p53 to activate downstream genes p21(WAF1/cip1) and MDM2, and cell cycle arrest following DNA damage is delayed and attenuated in scid cells deficient in the DNA-dependent protein kinase.

scid mouse embryonic fibroblasts are deficient in DNA-dependent protein kinase activity due to a mutation in the C-terminal domain of the catalytic subunit (DNA-PKcs). When exposed to ionizing radiation, the increase in levels of p53 was the same as in normal mouse embryonic fibroblasts. However, the rise in p21(WAF1/cip1) and mdm2 was found to be delayed and attenuated, which correlated in time with delayed onset of G1/S arrest by flow cytometric analysis. The p53-dependent G1 checkpoint was not eliminated: inactivation of p53 by the E6 protein in scid cells resulted in the complete loss of detectable G1/S arrest after DNA damage. Immunofluorescence analysis of normal cells revealed p53 to be localized predominantly within the cytoplasm prior to irradiation and then translocate to the nucleus after irradiation. In contrast, scid cells show abnormal accumulation of p53 in the nucleus independent of irradiation, which was confirmed by immunoblot analysis of nuclear lysates. Taken together, these data suggest that loss of DNA-PK activity appears to attenuate the kinetics of p53 to activate downstream genes, implying that DNA-PK plays a role in post-translational modification of p53, without affecting the increase in levels of p53 in response to DNA damage.

Inactivation of p53 results in high rates of homologous recombination.

Using a plasmid substrate which integrates into the genome, we determined that the rate of homologous recombination was suppressed by p53. Human tumor cell lines, mutant or null for p53 had recombination rates 10000-times greater than primary fibroblasts. When isogenic cell pairs from tumor cells or primary fibroblasts were compared, differing only in one genetic change which inactivated p53, the recombination rate increased > 100-fold. Functional inactivation of p53 by dominant mutant p53, by large T antigen of SV40 virus, by E6 protein of human papilloma virus, or by genetic deletion led to the same result. Our results suggest that p53 suppresses spontaneous homologous recombination, and that p53 is not required for recombination to proceed. The mechanism of recombination suppression may be related to the reported association of p53 with Rad 51, but the functional consequences of this association are not yet established. It is suggested that suppression of homologous recombination is the means by which p53 maintains genetic stability.

High frequency and error-prone DNA recombination in ataxia telangiectasia cell lines.

The only specific DNA repair defect found in ataxia telangiectasia (A-T) cells is mis-repair of cleaved DNA. In this report we measured DNA recombination, given its role in DNA repair and genetic instability. Using plasmids containing selectable reporter genes, we found a higher frequency of both chromosomal recombination (>100 times) and extra-chromosomal recombination (27 times) in SV40-transformed A-T cell lines compared with in an SV40-transformed normal fibroblast cell line. Southern analysis of single A-T colonies exhibiting post-integration recombination revealed that 24/27 had undergone aberrant rearrangements; recombination in normal fibroblast colonies was achieved by gene conversion in 8/11 clones and 10/11 clones showed unchanged copies of the plasmid. Using co-transfection of two integrating plasmids, each containing a separate deletion in the xgprt reporter gene, the 27 times difference in extra-chromosomal recombination was found when the plasmids were cleaved at a distance from the reporter gene. When the plasmids were cleaved within the reporter gene, the co-transfection frequency was reduced in A-T, but was increased in normal cells. We conclude that A-T cell lines have not only a high frequency chromosomal and extra-chromosomal recombination, but also exhibit error-prone recombination of cleaved DNA.