Faculty Bibliography

BACKGROUND: Liver transplantation from donation after cardiac death (DCD) donors is an increasingly common approach for expansion of the donor organ supply. However, transplantation with DCD livers results in inferior graft survival. In this study, we examined donor and recipient characteristics that are associated with poor allograft outcomes and present a set of criteria that permit allograft survival that is comparable to that of donation after brain death (DBD) grafts in both low- and high-risk recipients. METHODS: The United Network for Organ Sharing/Organ Procurement and Transplantation Network Liver Transplantation Registry between January 1996 and March 2006 was investigated. Adult DCD liver transplants (n = 874) were included. RESULTS: A DCD risk index was developed using the statistically significant factors from a multivariate Cox model: history of previous transplantation, life support status at transplantation, donor age, donor warm ischemia time (DWIT), and cold ischemia time (CIT). Favorable DCD donor criteria were donor age < or =45 years, DWIT < or =15 min, and CIT < or =10 hr. Four risk groups were developed based upon index scores that showed different graft survival. Graft survival of the favorable DCD group (84.9% at 1 year, 75.2% at 3 years, and 69.4% at 5 years) was comparable to that for DBD liver transplantation irrespective of recipient condition. Increasing donor age was more highly predictive of poor outcomes in DCD compared to DBD, especially in recipients in poor preoperative condition. CONCLUSIONS: DCD livers from young donors with short DWIT and CIT should be given greater consideration in order to expand the number of available donor organs.

Mullerian inhibiting substance (MIS), a member of the TGFbeta superfamily, causes regression of the Mullerian duct in male embryos. The presence of MIS type II and type I receptors in tissues and cell lines derived from the prostate suggests that prostate is a likely target for MIS. In this report, we demonstrate that MIS inhibits androgen-stimulated growth of LNCaP cells and decreases their survival in androgen-deprived medium by preventing cell cycle progression and inducing apoptosis. Expression of dominant-negative Smad1 reversed the ability of MIS to decrease LNCaP cell survival in androgen-deprived medium but not androgen-stimulated growth, whereas abrogation of nuclear factor-kappaB (NFkappaB) activation ablated the suppressive effects of MIS on both androgen-stimulated growth and androgen-independent survival. The effect of MIS on androgen-induced growth was not due to changes in androgen receptor expression. However, MIS suppressed androgen-stimulated transcription of prostate-specific antigen; ablation of NFkappaB activation reversed MIS-mediated suppression of prostate-specific antigen. These observations suggest that MIS regulates androgen-induced gene expression and growth in prostate cancer cells through a NFkappaB-dependent but Smad1-independent mechanism. Thus, MIS, in addition to potentially regulating prostate growth indirectly by suppressing testicular testosterone synthesis, may also be a direct regulator of androgen-induced gene expression and growth in the prostate at the cellular level.

The number of candidates awaiting liver transplantation continues to exceed the available donor organ pool. This steadily increasing donor organ shortage calls for the widening of selection criteria for potential donor organs. Strategies to increase the number of liver allografts include liver splitting, use of donors over 70 years, use of steatotic donor livers, and reutilization of liver allografts after brain death of the first recipient. We report the successful use of a polycystic donor liver and review the experience with this donor population. We propose that the selective use of polycystic donor livers containing small (<5 cm) cysts with preserved liver parenchyma is safe and appropriate.

CONTEXT: First proposed 2 decades ago, live kidney paired donation (KPD) was considered a promising new approach to addressing the shortage of organs for transplantation. Ethical, administrative, and logistical barriers initially proved formidable and prevented the implementation of KPD programs in the United States. OBJECTIVE: To determine the feasibility and effectiveness of KPD for the management of patients with incompatible donors. DESIGN, SETTING, AND PATIENTS: Prospective series of paired donations matched and transplanted from a pool of blood type or crossmatch incompatible donors and recipients with end-stage renal disease (6 conventional and 4 unconventional KPD transplants) at a US tertiary referral center (between June 2001 and November 2004) with expertise in performing transplants in patients with high immunologic risk. INTERVENTION: Kidney paired donation and live donor renal transplantation. MAIN OUTCOME MEASURES: Patient survival, graft survival, serum creatinine levels, rejection episodes. RESULTS: A total of 22 patients received transplants through 10 paired donations including 2 triple exchanges at Johns Hopkins Hospital. At a median follow-up of 13 months (range, 1-42 months), the patient survival rate was 100% and the graft survival rate was 95.5%. Twenty-one of the 22 patients have functioning grafts with a median 6-month serum creatinine level of 1.2 mg/dL (range, 0.8-1.8 mg/dL) (106.1 micromol/L [range, 70.7-159.1 micromol/L]). There were no instances of antibody-mediated rejection despite the inclusion of 5 patients who were highly sensitized to HLA antigens due to previous exposure to foreign tissue. Four patients developed acute cellular rejection (18%). CONCLUSIONS: This series of patients who received transplants from a single-center KPD pool provides evidence that recipients with incompatible live donors, even those with rare blood type combinations or high degrees of HLA antigen sensitization, can receive transplants through KPD with graft survival rates that appear to be equivalent to directed, compatible live donor transplants. If these results can be generalized, broader availability of KPD to the estimated 6000 patients with incompatible donors could result in a large expansion of the donor pool

Most successful protocols for renal transplantation across ABO incompatible (ABOi) barriers have utilized splenectomy as part of the pre-conditioning process. We recently described successful ABOi transplantation using anti-CD20 monoclonal antibody in lieu of splenectomy. In the current study, we hypothesized that plasmapheresis (PP) and low dose CMV hyper-immunoglobulin (CMVIg) alone would be sufficient to achieve successful engraftment of ABOi kidneys. We describe four blood type incompatible patients who received live donor renal transplants from A1 (two patients), A2 (one patient), and B (one patient) donors. All patients started with antihuman globulin (AHG) phase titers of 64 or higher and were pre-conditioned with PP/CMVIg but not splenectomy or anti-CD20. All 4 patients underwent successful transplantation and have a mean current serum creatinine of 1.1 (range: 0.9-1.2). There were no episodes of antibody mediated rejection. Rapid allograft accommodation may limit the need for long-term antibody suppression provided by splenectomy or anti-CD20, thereby eliminating the added infectious risk of these modalities and removing another disincentive to ABOi transplantation.

A national kidney paired donation (KPD) program will substantially increase transplant opportunities for recipients with blood type incompatible or cross-match positive donors. It seems likely that donor-recipient pairs with certain blood types, races or restrictions will wait longer than others for a match, although no data exist to confirm this assumption. We simulated patients and characterized the predicted waiting times for different blood type sub-groups, as well as the effects of patient-imposed restrictions on waiting time. We also compared waiting times of different racial sub-groups. Almost all patients with panel-reactive antibody (PRA) less than 80% match within a few months in a national KPD program, with the longest waiting time seen by O recipients with AB donors. Highly sensitized patients wait considerably longer, especially those unwilling to travel or accept older donors, and those with AB or B donors may not match in a timely manner. Although patients are better served by matching in a combined pool than within their own race, racial inequalities exist and bonus points can offset some of these differences. These data provide the first waiting time predictions that can aid patients with incompatible donors in choosing between KPD and desensitization, and can also facilitate planning for a national KPD program.

Options for utilizing live donor kidneys from those who are blood type incompatible or crossmatch positive with their intended recipients include kidney paired donation (KPD), list paired donation (LPD) and desensitization. KPD provides live donor kidneys for both recipients but requires a match to another incompatible pair, while LPD utilizes the deceased donor pool but is restricted by ethical and logistic concerns. We simulated patients and their potential donors to determine which recipients could receive a kidney through KPD and LPD. With smaller populations (100 pairs or fewer), more kidneys were matched through LPD, although the greatest benefit was derived from a combination of LPD and KPD. With increasing population sizes, more patients were matched through KPD, including almost all patients who would have been eligible for LPD. At population sizes predicted to be achieved by a national paired donation system, the role of LPD became minimal, with only 3.9% of pairs unmatched through KPD eligible for LPD. Considerable overlap was seen between the pairs unmatchable by KPD and those ineligible for LPD, namely less-demanded donors and hard-to-match recipients. For this population, the best option may be desensitization.

BACKGROUND AND AIM/OBJECTIVE:Budd-Chiari syndrome (BCS) is a rare condition associated with hepatic venous outflow obstruction classically treated with portosystemic shunts or liver transplantation. Recent reports indicate promising results with the use of transjugular intrahepatic portosystemic shunts (TIPS) in the treatment of these patients. PATIENTS AND METHODS/METHODS:We reviewed a 10-year single-institution experience with TIPS in patients diagnosed with BCS. RESULTS:Eleven patients with BCS underwent TIPS procedures, 3 of whom carried a diagnosis of paroxysmal nocturnal hemoglobinuria, a relative contraindication for liver transplantation. One TIPS procedure was unsuccessful for technical reasons. No patient suffered mortality or major morbidity related to the TIPS procedure. The mean reduction of portal venous pressures was 43.7%, with a mean decrease of 73% in the pressure gradient. Of the 7 patients where long-term follow-up was available, 57% had shunts which remained patent but required several nonsurgical revisions for occlusion, with an average assisted patency of 37.5 months. CONCLUSIONS:TIPS is an effective modality in the treatment of patients with BCS, especially for those who are not candidates for liver transplantation. TIPS can be successfully used as a bridge to surgical portosystemic shunting, as well as liver transplantation, but may cause technical difficulties when performing transplantation.