Faculty Bibliography

One of the greatest obstacles to the implementation of regional or national kidney paired donation programs (KPD) is the need for the donor to travel to their matched recipient's hospital. While transport of the kidney is an attractive alternative, there is concern that prolonged cold ischemia time (CIT) would diminish the benefits of live donor transplantation (LDTx). To examine the impact of increased CIT in LDTx, 1-year serum creatinine (SCr), delayed graft function (DGF), acute rejection (AR) and allograft survival (AS) were analyzed in 38 467 patients by 2 h CIT groups (0-2, 2-4, 4-6 and 6-8 h) using data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN). Adjusted probabilities of DGF and AR were estimated in multivariate logistic regression models and AS was examined in multivariate Cox proportional hazards models. Although some increase in DGF was observed between the 0-2 h (4.7%) and 4-6 h (8.3%) groups, prolonged CIT did not result in inferior SCr, increased AR or compromised AS in any group with >2 h CIT compared with the 0-2 h group. Comparable long-term outcomes for these grafts suggests that transport of live donor organs may be a feasible alternative to donor travel in KPD regions where CIT can be limited to 8 h.

Elderly liver donors (ELDs) represent a possible expansion of the donor pool, although there is great reluctance to use ELDs because of reports that increasing donor age predicts graft loss and patient death. The goal of this study was to identify a subgroup of recipients who would be least affected by increased donor age and thus best suited to receive grafts from ELDs. A national registry of deceased donor liver transplants from 2002-2005 was analyzed. ELDs aged 70-92 (n = 1043) were compared with average liver donors (ALDs) aged 18-69 (n = 15,878) and ideal liver donors (ILDs) aged 18-39 (n = 6842). Recipient factors that modified the effect of donor age on outcomes were identified via interaction term analysis. Outcomes in recipient subgroups were compared using Kaplan-Meier survival analysis. Recipients preferred for ELD transplants were determined to be first-time recipients over the age of 45 with body mass index <35, non-status 1 registration, cold ischemic time <8 hours, and either hepatocellular carcinoma or an indication for transplantation other than hepatitis C. In preferred recipients, there were no differences in outcomes when ELD livers were used (3-year graft survival: ELD 75%, ALD 75%, ILD 77%, P > 0.1; 3-year patient survival: ELD 81%, ALD 80%, ILD 81%, P > 0.1). In contrast, there were significantly worse outcomes when ELD livers were used in nonpreferred recipients (3-year graft survival: ELD 50%, ALD 71%, ILD 75%, P < 0.001; 3-year patient survival: ELD 64%, ALD 77%, ILD 80%, P < 0.001). CONCLUSION: The risks of ELDs can be substantially minimized by appropriate recipient selection.

Several treatment options exist for the management of Budd-Chiari syndrome (BCS), yet the relative role and timing of liver transplantation (LT) remain poorly defined. Small case series published to date have not been able to delineate the impact of comorbidities and thromboembolic complications of BCS on survival after LT. To better understand the outcomes after LT for BCS, we analyzed 510 liver transplants performed for this disease in the United States between 1987 and 2006. Risk factors predicting graft loss or patient death included increased recipient age, hyperbilirubinemia, elevated creatinine, life support or hospitalization at the time of transplantation, prior transplantation, prior abdominal surgery, increased donor age, and prolonged cold ischemic time (CIT). Prior transjugular intrahepatic portosystemic shunt (TIPS) was not associated with worse outcomes. Transplantation in the Model for End-Stage Liver Disease (MELD) era was associated with significantly lower risk of graft loss (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.30-0.86; P = 0.012) and death (HR, 0.52; 95% CI, 0.29-0.93; P = 0.027). Similarly, MELD era was associated with significantly lower risk of early graft loss (odds ratio [OR], 0.35; 95% CI, 0.16-0.79, P = 0.012) and early death (odds ratio, 0.37; 95% CI, 0.14-0.95; P = 0.040). However, patients with BCS transplanted in the MELD era were less likely to have life support, hospitalization, prior transplants, and prolonged cold ischemia times. In conclusion, outcomes of LT for BCS are excellent, with further improvements since 2002 associated with a selection shift imposed by MELD-based organ allocation.

Aberrant promoter hypermethylation, also known as epigenetics, is thought to be a promising biomarker approach to diagnose malignancies. Kidney repair after injury is a recapitulation of normal morphogenesis, with similarities to malignant transformation. We hypothesized that changes in urine epigenetics could be a biomarker approach during early kidney transplant injury and repair. We examined urine DNA for aberrant methylation of two gene promoters (DAPK and CALCA) by quantitative methylation-specific polymerase chain reaction from 13 deceased and 10 living donor kidney transplant recipients on postoperative day 2 and 65 healthy controls. Results were compared with clinical outcomes and to results of the kidney biopsy. Transplant recipients were significantly more likely to have aberrant hypermethylation of the CALCA gene promoter in urine than healthy controls (100% vs 31%; P < .0001). There was increased CALCA hypermethylation in the urine of deceased versus living donor transplants (21.60 +/- 12.5 vs 12.19 +/- 4.7; P = .04). Furthermore, there was a trend toward increased aberrant hypermethylation of urine CALCA in patients with biopsy-proven acute tubular necrosis versus acute rejection and slow or prompt graft function (mean: 20.40 +/- 6.9, 13.87 +/- 6.49, 17.17 +/- 13.4; P = .67). However, there was no difference of CALCA hypermethylation in urine of patients with delayed graft function versus those with slow or prompt graft function (16.9 +/- 6.2 vs 18.5 +/- 13.7, respectively; P = .5). There was no aberrant hypermethylation of DAPK in the urine of transplant patients. Urine epigenetics is a promising biomarker approach for acute ischemic injury in transplantation that merits future study.

Biopsies of ABO-incompatible and positive crossmatch (HLA-incompatible) renal allografts were retrospectively examined to compare results of C4d and C3d staining, and the correlation between such staining and histologic findings suggestive of antibody-mediated rejection (AMR). A total of 75 biopsies (55 protocol, 17 for graft dysfunction, 3 for other indications) of 24 ABO-incompatible grafts and 244 biopsies (103 protocol, 129 for graft dysfunction, 12 for other indications) of 66 HLA-incompatible grafts were examined; all were stained for C4d and approximately 40% for C3d. In ABO-incompatible grafts, 80% of protocol biopsies and 59% performed for graft dysfunction showed C4d staining in peritubular capillaries (PTC); this staining was not correlated with neutrophil margination in PTC. In HLA-incompatible grafts, PTC C4d was present in 26% of protocol biopsies and 60% of biopsies for graft dysfunction; 92% of biopsies with >1+ (0-4+ scale), diffuse PTC C4d had > or =1+ margination and/or thrombotic microangiopathy (TMA), compared with 12% of C4d-negative biopsies. C3d was somewhat more predictive of margination than C4d in ABO-incompatible, but not HLA-incompatible, grafts. In summary, while PTC C4d deposition indicates probable AMR in biopsies of HLA-incompatible grafts, including protocol biopsies, there is no histologic evidence that C4d deposition is correlated with injury in most ABO-incompatible grafts.