Highlights of the World Transplant Congress 2006

2006年7月22－27日

美国麻萨诸塞州波士顿

July 22 - 27, 2006, Boston, Massachusetts
Alemtuzumab: A New Player in Induction Therapy in Renal Transplantation
Ron Shapiro, MD   
Introduction
The field of transplantation has benefitted enormously from the increased number of new agents that have become available over the past 12 years. Among these, a number of antibodies, depleting and nondepleting, have been introduced into clinical practice, and the use of antibody induction therapy has substantially increased over the past decade. In the last 3 years, one of these preparations, alemtuzumab, a humanized anti-CD52 monoclonal antibody, has been utilized by a growing number of programs, although it accounts for only 7% of antibody use in the United States. A number of presentations at this World Transplant Congress focused on the results associated with alemtuzumab induction. In contrast to earlier, more optimistic reports from previous meetings and publications, a few single-center studies and registry reviews were rather more pessimistic. There were also several single-center reports and a single-center and a multicenter randomized trial that reported favorable outcomes. Highlights from these presentations are used in an attempt to explain these somewhat disparate findings.

Alemtuzumab: Cause for Optimism?
Two studies of the innovative combination of alemtuzumab, rituximab, and intravenous immunoglobulin were reported. In the first by Vo and colleagues,[1] 30 sensitized patients underwent living-donor or deceased-donor renal transplantation. Of particular interest was the use of subcutaneous vs intravenous (IV) alemtuzumab, in 2 x 15 mg (0.5 mL) doses in the buttocks or thighs; no diminution of lymphocyte depletion or immunosuppressive efficacy was noted, and tolerability was excellent. Maintenance immunosuppression was with tacrolimus (TAC), mycophenolate mofetil (MMF), and corticosteroids. One-year patient and graft survival rates were 100% and 97%, respectively. The incidence of acute humoral rejection was 17%, and the incidence of acute cellular rejection was 10%. Cytomegalovirus (CMV) infection occurred in 3% and BK viremia (BKV) occurred in 17% of patients, although BKV nephropathy was not observed in any patients. Leflunomide, intravenous immunoglobulin (IVIG), and reduction in immunosuppression were used to treat BKV infection. In general, the authors were quite pleased with the successful outcomes and the low rate of infectious complications in this difficult-to-manage group of patients.

Another report describing the use of alemtuzumab in sensitized patients was presented by Leventhal and colleagues.[2] Eleven living-donor transplant recipients with positive crossmatches, with a titer of 1:256 or less, were treated with rituximab 1-2 weeks prior to transplantation and started on TAC and MMF. Plasmapheresis and IVIG were used to achieve a negative crossmatch, or failing that, an 8-fold reduction in the antibody titer. Alemtuzumab 30 mg IV was administered in the operating room, and TAC, MMF, and steroids were continued after transplantation. At 20 months of follow-up, patient and graft survival rates were 100% and 91%, respectively; the only graft loss was due to recurrent disease. One late acute rejection episode and 2 subclinical acute rejection episodes were noted, but no acute humoral rejection was observed. Neither posttransplant lymphoproliferative disease (PTLD) nor BKV was observed, and the mean serum creatinine (SCr) concentration was < 2.0 mg/dL. The results with this small but challenging subgroup of approximately 1000 patients treated at Northwestern who received alemtuzumab were quite favorable.

A single-center report on the use of alemtuzumab and TAC monotherapy in 64 patients was presented by Chan and colleagues.[3] Also described for the purposes of comparison were 106 immediately preceding cases who received daclizumab, TAC, MMF, and 1 week of steroids. The alemtuzumab-treated patients had 1-year patient and graft survival rates of 100% and 95.3%, respectively, and an acute rejection rate of 3.1%. The historical control patients had a similarly good outcome at 1 year, with 97% patient and 94% graft survival rates, and an acute rejection incidence of 14.2%. Infectious complications were less frequent in the alemtuzumab-treated patients, 27.2% vs 44.3%. The cost savings in the alemtuzumab group averaged $11,000/patient. The authors were pleased with these results and plan to initiate a randomized trial of alemtuzumab.

Light and colleagues[4] presented data on 195 patients (of whom 76 [39%] were African-Americans), who received 1 (n = 115 [59%]) or 2 (n = 80 [41%]) doses of alemtuzumab, along with tacrolimus and MMF, and no steroids. Patient and graft survival rates at 1 year were 100% and 94%, respectively. The authors noted an increase in BKV viruria (up to 27%) with no BKV nephropathy. The incidence of acute rejection was 30% in the BKV group, and was thought to be associated with a reduction in immunosuppression in response to the BKV. The incidence of acute rejection in the patients who did not develop BKV was 7.7%. There was a higher incidence of BKV in patients who received 2 doses of alemtuzumab (65%), and the authors noted in the discussion that they were discontinuing the practice of giving 2 doses.

Patients on a regimen that allowed steroid avoidance and eventual calcineurin inhibitor withdrawal had a low incidence of rejection and good renal function, according to Zilvetti and colleagues.[5] Thirty patients received 2 doses of IV alemtuzumab 30 mg, with MMF 500 mg twice daily for 12 months and TAC for the first 6 months, followed by sirolimus (eventual sirolimus monotherapy). Patient and graft survival rates were 93%, and 1 patient was withdrawn from the regimen for a possible drug reaction. The incidence of acute rejection was 10%, and PTLD occurred in 3%. The mean SCr concentration was 1.5 mg/dL.

At 23 months of follow-up, patient and graft survival rates were 92% and 89%, respectively (death-censored graft survival was 97%) in 75 patients treated with a regimen of alemtuzumab induction and TAC monotherapy, with early (at 2 months) steroid withdrawal, according to Potdar and colleagues.[6] The mean SCr concentration was 1.4 mg/dL and the incidence of acute rejection was 13%. The incidence of infectious complications was 10%. Ninety-two percent of the patients with functioning kidneys were being maintained on TAC monotherapy, leading the authors to be enthusiastic about this regimen.

Medium-term outcomes in 280 unselected adults receiving alemtuzumab preconditioning with TAC monotherapy (with subsequent spaced weaning of TAC) were reported by Shapiro and colleagues.[7] One- and 2-year patient survival rates were 97% and 95%, and 1- and 2-year graft survival rates were 94% and 89%, respectively. The preweaning incidence of acute rejection was 8%, and the incidence of steroid-resistant rejection was 2%. The mean SCr concentration at 1 and 2 years was 1.5 mg/dL and 1.6 mg/dL, respectively. Spaced weaning was attempted in 80% of the patients at a mean of 8 months posttransplantation, and was associated with a 26% incidence of postweaning rejection (10% steroid resistant). Weaning was abandoned in other patients when they developed donor-specific antibody, and they were returned to once-daily TAC monotherapy, with subsequent elimination of the donor-specific antibody in some cases. At most recent follow-up, 55% of the patients were on spaced weaning, including 19% who were on every other day, 31% who were on thrice-weekly, 4% who were on twice-weekly, and 1% who were on once-weekly TAC monotherapy. The incidence of CMV disease was 0%, the incidence of PTLD was 0.4%, the incidence of BKV was 0.9%, and the incidence of posttransplant diabetes (PTDM) was 1.2%. The authors concluded that preconditioning with alemtuzumab and maintenance with TAC monotherapy and subsequent spaced weaning is a reasonable regimen, with a low rate of early rejection and a very low rate of viral complications and PTDM. Patients were serially monitored for the development of donor-specific antibody as a potential marker for the risk of developing post-weaning rejection, and the abandonment of weaning was associated with the disappearance of donor-specific antibody.

Alemtuzumab: Cause for Pessimism?
In contrast to the above-mentioned reports, 3 multicenter registry analyses of alemtuzumab from the United Network for Organ Sharing/Organ Procurement Transplantation Network database were decidedly more pessimistic in tone.[8-10] All suggested that alemtuzumab was associated with a lower rate of early (first 6 months) acute rejection, but with a higher rate of acute rejection by 1 year when compared with other antibody preparations, including interleukin-2 receptor antagonists and rabbit antithymocyte globulin (rATG). One of the analyses, by Helderman and colleagues,[8] further suggested an increased risk of graft loss in patients receiving alemtuzumab, although the difference was not statistically significant. These reports underscore the need for a large, multicenter, randomized trial comparing alemtuzumab with other induction agents.

In fact, 3 randomized trials were presented at this meeting; 2 single-center trials[11,12] and 1 multicenter trial.[13] Ciancio and colleagues[11] compared alemtuzumab, daclizumab, and rATG (30 patients in each group). All patients received TAC, MMF, and steroids, except for the alemtuzumab group, which did not receive steroids. Although there were no differences in the incidence of acute rejection or infectious complications among the 3 groups, there was statistically worse graft survival, worse kidney function, and a higher incidence of chronic allograft nephropathy in the alemtuzumab group. The alemtuzumab group received less MMF because of a higher incidence of neutropenia, and the authors speculated that this may have accounted for the disparity in outcomes among the 3 groups.

Farney and colleagues[12] randomized patients to alemtuzumab (n = 48) vs rATG (n = 50) in kidney and pancreas transplantation; recipients were given TAC, MMF, and prednisone-based maintenance immunosuppression and showed excellent patient (99%), kidney (96%), and pancreas (95%) survival rates, with no differences between the alemtuzumab and rATG groups. Less acute rejection was seen in the alemtuzumab (8%) than the rATG (20%) group. Infectious complications were similar in both groups.

The European multicenter trial conducted by Margreiter and colleagues[13] randomized patients to 2 doses of IV alemtuzumab 20 mg, with TAC monotherapy (n = 65) vs TAC + MMF + steroids (n = 66). Patient survival was comparable between the 2 groups, while graft survival favored the alemtuzumab group (96.9% vs 90.9%), but did not reach statistical significance (P = .06). Less rejection was observed in the alemtuzumab group (18.5%) than in the control group (41%). There were more viral complications in the alemtuzumab group and fewer cases of PTDM. Sixty-one of the alemtuzumab patients (94%) remained off steroids, while all of the control patients were on steroids.

Summary
Most of the single-center experiences, both randomized and nonrandomized, suggested favorable outcomes with alemtuzumab, but registry reports suggested more late rejection and perhaps worse graft survival compared with other antibody preparations. There are at least 2 potential explanations for this disparity. The first is that the favorable single-center data reflect insufficient follow-up, and that some deterioration in outcomes will be observed over a longer period of follow-up. The second is that alemtuzumab is such a powerful agent that using it with conventional immunosuppression is a mistake, and it should instead be used with minimal posttransplant immunosuppression. Certainly, the favorable reports from Chan and colleagues,[3] Potdar and colleagues,[6] Shapiro and colleagues,[7] and Margreiter and colleagues,[13] all of whom used TAC monotherapy and steroid avoidance or early withdrawal, are consistent with this explanation. It will, however, be difficult to organize pivotal large randomized trials along the lines of Margreiter and colleagues'[13] design, as the economics of drug development are not favorable — the concern is that the market for induction agents is too small to justify the expense of a large trial. Obviously, more follow-up will be needed to assess long-term outcomes, and it will be of particular interest to see the results in patients treated with minimal immunosuppression after alemtuzumab induction.

References
Vo AA, Wechsler E, Jagolino J, et al. Monitoring for infectious complications of campath-1H and Rituxan induction therapy in crossmatch (CMX) positive kidney transplant recipients receiving intravenous gammaglobulin desensitization. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 164.
Leventhal JR, Friedewald JJ, Gallon L, et al. Desensitization of living donor renal transplant recipients using rituximab and alemtuzumab induction therapy. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 915.
Chan K, Casian A, McLean A, et al. Campath 1H and tacrolimus monotherapy without steroids or mycophenolate mofetil in renal transplantation. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 331.
Light JA, Ghasemian SR, Jain E, Moore J. Alemtuzumab (C1-H) and polyoma virus (POV) infections; What is the connection? Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 168.
Zilvetti MA, Trzonkowski P, Brockmann, et al. Alemtizumab enables steroid avoidance and calcineurin-inhibitor minimization after kidney transplantation. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 660.
Potdar S, Malek SK, Obmann MA, et al. Campath-1H induction and maintenance monotherapy after kidney transplant with 12-33 month follow-up and analysis of spectrum of acute rejections. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 667.
Shapiro R, Tan HP, Basu A, et al. Alemtuzumab preconditioning and tacrolimus monotherapy in adult kidney transplant recipients. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 670.
Helderman JH, Gilmore AS, Marehbian J, Legorreta AP. Patient outcomes Assessment of campath induction therapy in renal transplant recipients. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 672.
Huang E, Cho Y, Shah T, et al. Alemtuzumab induction in living donor kidney transplantation: a multivariate analysis of the OPTN/UNOS database. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 917.
Huang E, Cho Y, Shah T, et al. Alemtuzumab induction in deceased donor kidney transplantation: a multivariate analysis of the OPTN/UNOS database. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 918.
Ciancio G, Sageshima J, Burke GW, et al. Evaluation of a randomized trial of three induction antibodies in deceased donor (DD) renal transplantation at 18 months follow-up. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 919.
Farney A, Sundberg A, Moore P, et al. A prospective randomized comparison of alemtuzumab versus rabbit antithymocyte globulin in kidney and pancreas transplantation. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 923.
Margreiter R, Klempnauer J, Neuhaus P, Muehlbacher F, Bosmueller C. Alemtuzumab (campath-1H) induction followed by tacrolimus monotherapy vs. tacrolimus based triple drug immunosuppression in cadaveric renal transplantation - early results of a multicenter trial. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 921.

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New Clinical Trials in Kidney Transplantation: Survival of the Fittest
Flavio Vincenti, MD   
Introduction
The results of clinical trials with new agents are always received with great anticipation by the transplant community because of the continuing interest in novel immunosuppression that can lead to improved transplant outcomes.

FK778
FK778 is an analog of the active metabolite of leflunomide, but has a shorter half-life. FK778 reversibly blocks the de novo pathway of pyrimidine synthesis by binding and inhibiting dihydro-orotate dehydrogenase, affecting rapidly proliferating lymphocytes. FK778 suppresses T-cell-mediated responsiveness as well as B cells and antibody production. In experimental studies, FK778 in combination with either tacrolimus (TAC) or cyclosporine (CsA), resulted in prolongation of allograft survival as well as abrogation of the typical histologic changes associated with chronic rejection.[1] In addition, it inhibited growth factor and inflammation genes, noted Yves Vanrenterghem, MD.[2]

In a multicenter trial, patients who received their first renal transplant were randomized to 3 groups: Group 1 received FK778, targeting high levels (100-200 ng/mL); group 2 received FK778, targeting low levels (10-100 ng/mL); and group 3 received placebo. All patients were treated with TAC and corticosteroids.[3] Acute rejection occurred in 26.5% in group 1, 25.9% in group 2, and 39.1% in group 3. Patients who were treated with high-target-level FK778 required approximately 2 weeks to achieve desired levels. Patients who achieved FK778 levels of 100-200 ng/mL within the first 2 weeks post transplantation had a rejection rate of 7.7%. The side effects of FK778 were anemia, especially in group 1 (high-level group), but this was reversible upon discontinuation of the drug.

The drug manufacturer (Astellas) recently decided not to proceed with further clinical development of FK778 for organ transplantation because of a lack of demonstrable benefits over mycophenolate mofetil (MMF) and apparently no evidence that in vivo it inhibited BK viremia.

JAK Inhibitors
The Janus family of proteins (JAK1, JAK2, JAK3, and tyrosine kinase) is named after the 2-faced god Janus because of their dual roles in membrane and cytoplasmic activation as well as the side-by-side relationship of kinase and pseudokinase domains. JAK3 is highly expressed in lymphoid cells, binding specifically to the gammac receptor, a shared component of the interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. Mutations of the gammac chain of JAK3 result in severe combined immunodeficiency syndromes. Thus, inhibition of JAK3 disrupts signals from the gammac chain, thus blocking proliferation and differentiation of lymphocytes. Although several small molecules have been reported to inhibit JAK3, CP690,550, a rationally designed inhibitor of JAK3, is currently in clinical development in renal transplantation, according to Dr. Vanrenterghem.[2]

Changelian and colleagues[4] reported a study of CP690,500 used as monotherapy in a nonhuman primate renal transplant model. Experimental animals were dosed with CP690,550, targeting either a high trough level of 200-400 ng/mL or a lower trough level of 50-200 ng/mL. Although vehicle-controlled animals rapidly rejected their allografts (6 ± 1 days), CP690,550 significantly prolonged graft survival when compared with the vehicle agent — 62 ± 8 and 83 ± 6 days, respectively — for the low and high trough level groups (P < .001). Anemia was the most common side effect, occurring more frequently in the high-dose group vs the low-dose group.

CP690,550 is currently in a phase 2 clinical trial in primary renal transplant recipients. Two immunosuppression regimens are being compared: 2 doses of CP690,550 plus MMF and steroids vs TAC, MMF, and steroids. It is anticipated that the results of this study will be reported in 2007 or 2008.

FTY720
FTY720 is the first drug in a new class, sphingosine-1-phosphate 1 (S1P1) receptor agonists. FTY720 modulates lymphocyte trafficking from blood and peripheral tissues to lymph nodes.[5] FTY720 doesn't directly affect the function of T and B cells; however, following phosphorylation, it acts as a high-affinity agonist to the S1P1 receptor, resulting in internalization of the receptor, rendering lymphocytes unresponsive to the serum lipid S1P1 and depriving them of the obligatory signal to egress from lymphoid organs,[6] reported Barry Kahan, MD.[7] As a consequence, lymphocytes are unable to migrate to peripheral inflammatory tissues and graft sites. In addition to FTY720's effect on lymphocyte recirculation, it acts on endothelial cells and preserves vascular integrity.

Tedesco-Silva and colleagues[8] reported one of the first clinical studies with FTY720, and suggested that it was efficacious and safe and that the efficacy did not correlate with the level of peripheral lymphopenia. The manufacturer (Novartis) of FTY720 undertook a large phase 3 study comparing 2 doses of FTY: 5 mg with reduced-dose CsA and 2.5 mg with full-dose CsA vs full-dose CsA in the control arm. All patients were treated with MMF and prednisone. The results of this trial have not been published, but Novartis discontinued the development of FTY720 because of a lack of benefits of FTY720 compared with MMF. Patients who were treated with FTY720 were reported to develop bradycardia with the first dose, impairment of pulmonary function, and macular edema. Patients in the full-dose CsA group had impaired renal function. Although the FTY720 pathway remains very attractive (FTY720 is currently in clinical trials for multiple sclerosis), it's likely that more selective compounds will be reconsidered for organ transplantation.

T-Cell Antibodies: Induction Therapy
The rationale for induction therapy with a biologic agent is to block T-cell activation and antigen recognition at the time of transplantation, thus maximizing immunosuppression, sparing calcineurin inhibitors (CNIs), and ultimately improving long-term outcomes by minimizing maintenance immunosuppression therapy. Stuart Knechtle, MD,[9] reported on an analysis of data collected by Meier-Kriesche and colleagues[10] between 1994 and 2004 from the 2005 Scientific Registry of Transplant Recipients: Thirty-five percent of transplant recipients received thymoglobulin induction; 20% received one of the anti-IL-2 receptor antibodies (basiliximab or daclizumab); and 7% received alemtuzumab. There has been a steady decline of induction with OKT3 due to its severe side effects. Considerations for the use of induction as well as for the specific agent used include cost, side effects, need for central venous access, and outcomes data, such as rates of acute rejection, infection, graft function, and graft survival.

Dr. Knechtle reviewed the experience with over 600 patients at the University of Wisconsin-Madison from December 1, 1997 to August 31, 2005, with 3 induction agents: basiliximab, thymoglobulin, and alemtuzumab. All 3 agents were used with a combination of CNIs, MMF, and prednisone. Patients induced with alemtuzumab tended to be maintained on lower doses of CNIs and lower doses of MMF (due to the leukopenia). Acute rejection rates were lowest initially with alemtuzumab, compared with basiliximab or thymoglobulin. However, at 2 years there were no differences between the 3 agents in the cumulative incidence of acute rejection, and there were no significant differences in patient survival rates. Patients who were treated with basiliximab had a significantly higher graft survival rate than patients treated with thymoglobulin or alemtuzumab (P < .006). However, selection bias might have skewed the results in patients who were selected for basiliximab therapy. There was a lower overall incidence of infection, and specifically fewer fungal and viral infections, in patients who were treated with basiliximab compared with patients who were treated with thymoglobulin or alemtuzumab. Leukopenia (white blood cell count < 3.0) was observed in 30% of basiliximab-treated patients, 50% of thymoglobulin-treated patients, and 70% of alemtuzumab-treated patients.

A retrospective analysis showed that 2 doses of alemtuzumab were associated with better graft survival than 1 dose of alemtuzumab (P = .06). In a multivariate analysis, the relative risk for graft loss was greater in patients who received a kidney from a deceased donor, recipients with type 2 diabetes mellitus, patients who were treated with alemtuzumab, and patients who received a kidney from an older donor. In patients who were immunologically at high risk (ie, repeat transplants or highly sensitized patients), alemtuzumab was associated with better graft survival than thymoglobulin (P < .03). Dr. Knechtle acknowledged that this was not a prospective randomized trial; therefore, biases may have influenced the transplant physicians' selection of induction agent.

Chronic Biologics
Flavio Vincenti, MD,[11] discussed a new paradigm in immunosuppression therapy: chronic induction therapy or maintenance therapy with biologic agents.[12] The advantage of maintenance therapy with biologic agents is that their use may eliminate maintenance therapy with CNIs and steroids, and therefore minimize drug toxicities and prolong graft survival. Biologic agents that are being considered for chronic maintenance therapy include primarily agents that block costimulation.

The first biologics that were tested were monoclonal antibodies against CD80 and CD86, which were administered in a combined fashion. They were used in a promising phase 1 trial, but the challenge of administering 2 monoclonal antibodies simultaneously has discouraged further clinical development. The second agent was Hu5C8, a humanized monoclonal antibody targeting CD154 (CD40L). In a phase 1 clinical trial, patients were treated monthly with this monoclonal antibody in combination with MMF. Steroids were discontinued after the first 2 weeks and CNIs were not used. Unfortunately, Hu5C8 was associated with both rejection and thromboembolic events. No other anti-CD154 agent appears to be free of thromboembolic side effects. Targeting this pathway appears to be on hold indefinitely.

The most promising biologic agent is belatacept, a second-generation CTL4Ig with increased affinity to CD80 and CD86. In a recently published phase 2 study, 218 patients were randomized to receive 1 of 2 regimens of belatacept (low intensity vs high intensity) and compared with a control group that was treated with CNIs.[13] The belatacept-treated patients were CNI-free, and all 3 groups of patients were treated with basiliximab induction (2 doses of 20 mg) and were maintained on MMF and steroids. Acute rejection (defined as serum creatinine of ≥ 0.5 mg with histologic confirmation) was comparable between the belatacept and CsA treatment groups. Patient and graft survival were not significantly different between the 3 treatment arms. However, patients who were treated with belatacept had significantly higher measured glomerular filtration rates, and on kidney biopsy at 1 year, a significantly lower incidence of chronic allograft nephropathy. In addition, patients who were treated with belatacept had a more favorable cardiovascular risk profile. Three patients who were treated with belatacept developed posttransplant lymphoproliferative disease (PTLD), 2 in the first year of therapy. PTLD in both patients was associated with Epstein-Barr virus infection.

Currently, belatacept is being tested in 2 phase 3 trials (one in expanded-criteria donor kidneys and the other in standard kidneys), and in a study at the University of California, San Francisco, and Emory University, Atlanta, Georgia, to facilitate drug withdrawal.[14] This study will enroll patients who receive kidneys from living donors and will use belatacept and sirolimus for maintenance immunosuppression. Maintenance therapy with biologic agents offers the potential of improved compliance, less toxicity, and possibly prolongation of graft half-life. However, maintenance therapy with belatacept will require final confirmation of efficacy and safety in phase 3 trials. Chronic maintenance biologic therapy may offer an attractive alternative to current maintenance immunosuppression regimens.

References
Pan F, Ebbs A, Wynn C, et al. FK778, a powerful new immunosuppressant, effectively reduces functional and histologic changes of chronic rejection in rat renal allografts. Transplantation. 2003;75:1110-1114. Abstract
Vanrenterghem Y. New clinical trials in kidney transplantation. FK778/JAK3 inhibitors. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts.
Vanrenterghem Y, van Hooff JP, Klinger M, et al. The effects of FK778 in combination with sirolimus and steroids: a phase II multicenter study in renal transplant patients. Transplantation. 2004;78:9-14. Abstract
Changelian PS, Flanagan ME, Ball DJ, et al. Prevention of organ allograft rejection by a specific Janus Kinase 3 inhibitor. Science. 2003;302:875-878. Abstract
Kahan BD. FTY720: from bench to bedside. Transplant Proc. 2004;36(suppl):531S-543S.
Brinkmann V, Cyster JG, Hla T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant. 2004;4:1019-1025. Abstract
Kahan BD. New clinical trials in kidney transplantation. Sphingosine receptor blockers. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts.
Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation. 2004;77:1826-1833. Abstract
Knechtle SJ. New clinical trials in kidney transplantation. Cell antibodies. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts.
Meier-Kriesche H-U, Li S, Gruessner RWG, et al. Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant. 2006;6(pt 2):1111-1131.
Vincenti F. New clinical trials in kidney transplantation. Chronic biologicals: a new era of immunosuppression? Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts.
Vincenti F. Chronic induction. What's new in the pipeline. Contrib Nephrol. 2005;146:22-29. Abstract
Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353:770-781. Abstract
Vincenti F. What's in the pipeline? New immunosuppressive drugs for transplantation. Am J Transplant. 2002;2:898-903. Abstract

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Advancing the Science and Practice of Simultaneous Kidney-Pancreas Transplantation
Robert J. Stratta, MD   
Introduction
The principal focus of the simultaneous kidney-pancreas transplantation (SKPT) session at World Transplant Congress 2006 was to highlight new immunosuppressive regimens. A number of centers are gaining experience with depleting antibody induction strategies in combination with eliminating corticosteroids, minimizing or avoiding calcineurin inhibitors, or both.

Antibody Induction in Simultaneous Pancreas-Kidney Transplantation
Two studies addressed the issue of alemtuzumab induction followed by maintenance monotherapy with tacrolimus (TAC). Thai and colleagues[1] retrospectively reported their experience with alemtuzumab induction (a single intravenous dose of 30 mg) and 2 perioperative methylprednisolone boluses in 100 consecutive pancreas transplant recipients. The study authors hypothesized that T-lymphocyte depletion creates the optimal milieu for graft acceptance and accommodation, leading to a tolerogenic state. Group 1 (n = 60, 30 SKPT) received TAC monotherapy (target 12-hour trough levels 10-12 ng/mL) and Group 2 (n = 40, 23 SKPT) received low-dose TAC (target levels 6-8 ng/mL) in combination with mycophenolate mofetil (MMF) 1 g twice daily. Patient survival rates were 95% in both groups with a mean follow-up of 22 months in Group 1 and 9 months in Group 2 (sequential cohorts). Pancreas and kidney graft survival rates in both groups were 93% and 92%, respectively. The mean serum creatinine (SCr) was 1.2 ± 0.3 mg/dL in the TAC + MMF group compared with 1.4 ± 0.4 in the TAC monotherapy group. The incidences of acute rejection (TAC 30% vs TAC + MMF 35%) and posttransplant lymphoproliferative disease (1 case in each group) were similar. However, the incidence of cytomegalovirus (CMV) infection/disease was 12% with TAC monotherapy compared with 28% with TAC + MMF (P = .06). Moreover, the incidence of steroid-resistant acute rejection was numerically higher in the TAC + MMF group. The study authors concluded that alemtuzumab preconditioning and TAC monotherapy is an effective immunosuppressive regimen compared with TAC + MMF, and appears to have a similar nephrotoxic profile in short-term follow-up.

In a parallel study also conducted by Thai and associates[2] of the same patient population as in the study above, the ImmuKnow Immune Cell Function Assay (Cylex, Inc; Columbia, Maryland) was used to compare T-cell responses with various clinical states. These assays were performed pretransplantation and at approximately 3-month intervals posttransplantation in a subset of patients. A total of 290 samples were analyzed in 69 patients, including 51 during periods of clinical stability, 14 during infectious complications, and 4 during episodes of acute rejection. In patients with stable graft function, the Cylex assay ranged from 100 to 350 ATP ng/mL (mean of 374 ATP ng/mL pretransplantation, mean of ATP 148 ng/mL at 3-6 months posttransplantation, and mean of 190 ATP ng/mL thereafter). By comparison, the mean level during episodes of acute rejection was 550 ATP ng/mL (P = NS), while the mean level during infectious complications was 48 ATP ng/mL (P < .001). On the basis of these preliminary results, the study authors speculated that an assay level < 100 ATP ng/mL was indicative of overimmunosuppression and a higher risk for infection, whereas a level > 500 ATP ng/mL indicated underimmunosuppression and was associated with a higher risk for rejection. The optimal level for maintenance immunosuppression appeared to be approximately 200 ATP ng/mL.

Knight and colleagues[3] also used ImmuKnow assay monitoring in their study of 24 primary SKPT patients who received rabbit antithymocyte globulin (rATG) induction (5 doses at 1.5 mg/kg/d), followed by a regimen of sirolimus (SRL)(target trough levels of 10-15 ng/mL for 3 months, then 8-10 ng/mL thereafter), prednisone, and delayed administration of reduced-dose cyclosporine (CsA) (target 12-hour trough levels of 50-125 ng/mL). Patients were divided into low and high immune responders, with the latter defined as either being black or having a panel-reactive antibody titer (PRA) > 30%. The low responders (n = 17) had steroids stopped on postoperative day 5, whereas the high responders (n = 7) remained on steroids. At 6 months, all patients were converted from CsA to mycophenolic acid (MPA) over 2 months under the umbrella of immune monitoring with the ImmunKnow assay and flow-PRA, which were performed at 2-week intervals during the period of conversion. With a mean follow-up of 13 months, there was 1 pancreas graft loss due to pancreatitis, no deaths, and 1 episode of acute rejection. All 17 low responders were steroid-free at 6 months, and 12 were successfully converted from CsA to MPA. Three patients were study withdrawals (2 joint pain, 1 thrombocytopenia). A total of 11 of 12 patients displayed a regulated immune response (ATP generation < 250 ng/mL, flow-PRA low), whereas 1 patient maintained a high PRA and transient increases in donor-specific antibody without the occurrence of rejection. All patients exhibited good kidney and pancreas allograft function. On the basis of these results, the study authors concluded that rATG induction with SRL maintenance therapy may permit steroid elimination and calcineurin inhibitor (CNI) minimization, with eventual withdrawal in patients demonstrating a diminished immune response.

In an investigation of immunosuppressive minimization using SRL, Kaufman and associates[4] retrospectively analyzed data from sequential cohorts of SKPT patients receiving alemtuzumab induction (1-2 doses of 30 mg) in combination with SRL (target trough levels 8-10 ng/mL), rapid steroid elimination (3 doses total), and either maintenance TAC (n = 50, target trough levels of 7-9 ng/mL) or MMF (n = 54, complete CNI avoidance). The TAC + SRL group had a mean follow-up of 3.5 years, whereas the CNI-free (SRL+ MMF) group had a mean follow-up of 2 years. Patient and kidney graft survival rates were slightly lower in the SRL + MMF group (P = .17 and P = .32, respectively), whereas pancreas graft survival rates were similar. However, the incidence of acute rejection (6% for TAC + SRL vs 27% for SRL + MMF, P = .01) was higher in the CNI-free group. In addition, the severity of acute rejection (Banff 1B) was greater in the CNI-free group. A total of 30% of patients were converted to a CNI, usually because of acute rejection. No differences in SCr levels or calculated Modified Diet in Renal Disease study formula for glomerular filtration rates (GFRs) were noted in the 2 groups on the basis of intent-to-treat analysis. However, in the 70% of patients without rejection who were successfully maintained on SRL + MMF, the 1- and 2-year GFRs were significantly (P = .002) improved compared with patients in the TAC + SRL group. The study authors concluded that CNI avoidance and steroid elimination are possible in the majority of SKPT recipients, despite a higher rate of rejection. It is notable, however, that no grafts were lost due to rejection, and CNI avoidance is associated with an improvement in renal function out to 2 years.

Sollinger and colleagues[5] retrospectively reported their experience with 331 consecutive SKPTs in sequential cohorts, including 226 who received 2-dose basiliximab induction compared with 105 who received 2-dose alemtuzumab induction. All patients received triple maintenance therapy with TAC (target trough levels 6-10 ng/mL), MMF (2 g/d), and tapered steroids. All pancreas transplants were performed with enteric drainage. Demographic characteristics were similar between groups. Mean follow-up was 6+ years and 3+ years, respectively. Two-year patient, kidney, and pancreas graft survival rates were numerically but not statistically higher in the alemtuzumab group; the incidence of acute rejection was lower (P = .09) with alemtuzumab. However, patients in the basiliximab group had a significantly lower (P = .002) risk for CMV disease. The incidences of posttransplant lymphoproliferative disorder, polyomavirus, sepsis, and other infections were no different between groups; graft function was likewise comparable. The study authors concluded that the use of alemtuzumab induction results in favorable survival trends and less rejection without incurring a risk for increased infection or malignancy except for CMV. In addition, alemtuzumab appears to be more cost-effective than do other induction strategies.

The final 3-year results of a prospective, randomized, multicenter trial of 2 dosing strategies of daclizumab compared with no antibody induction in 298 SKPT recipients receiving TAC, MMF, and prednisone were presented by Stratta and colleagues.[6] Although the 1-year results of this study suggested less rejection in the 2 groups receiving daclizumab, the 3-year outcomes showed no significant differences in rates of patient or graft survival, graft function, acute rejection, infection, morbidity, noncompliance, or readmission. Event-free survival (no death, graft loss, or rejection) was slightly improved in patients receiving 2-dose daclizumab (2 mg/kg on days 0 and 14; 57%) compared with conventional 5-dose daclizumab (1 mg/kg on days 0, 14, 28, 42, and 56, 51%, P = NS) or no antibody induction (45%, P = .048). Although the 3-year cumulative incidence of acute rejection was slightly lower (31%) in the 2 daclizumab groups compared with no antibody induction (40%), P = .40), the median time to first acute rejection was delayed in patients receiving daclizumab (265 days vs 151 days, P = .07). In a multivariate risk factor analysis, kidney delayed graft function was the major risk factor for kidney graft rejection (hazard ratio [HR] 2.8, P = .002), whereas kidney acute rejection was the only risk factor for kidney graft loss (HR 3.1, P = .003). Kidney graft loss was the only independent risk factor for mortality (HR 5.5, P = .02). On the basis of these findings, the study authors concluded that the alternative dosing regimen of daclizumab (2 mg/kg for 2 doses) is safe and effective in preventing early acute rejection and delaying the onset of first rejection, but no sustaining long-term benefits at 3-year follow-up were noted. Moreover, preventing kidney delayed graft function and acute rejection may play a pivotal role in optimizing long-term outcomes in SKPT recipients.

The preliminary 6-month results of the Euro-SPK 002 trial, which is an open, prospective, multicenter study of 4 doses of rATG induction in combination with TAC, short-term steroids, and randomization either to MMF (n = 118) or SRL (n = 123), were reported by Margreiter and colleagues.[7] Patients underwent steroid withdrawal at 4-6 weeks following SKPT. Donor and recipient characteristics were similar between groups; 83% of patients underwent SKPT with systemic-enteric drainage and the remaining 17% with portal-enteric drainage. At 6-month follow-up, patient and kidney graft survival rates were similar, but pancreas graft survival rates were slightly higher in the TAC/MMF group (87% vs 81%, P = NS). The incidences of acute rejection were comparable (28% for TAC + MMF vs 33% for TAC + SRL), but the severity of rejection was greater in the TAC + MMF group (P < .05). There were no differences in infectious complications, but the TAC + SRL group had higher rates of delayed wound healing and hyperlipidemia (both P < .01). Study withdrawal was also more common in the TAC + SRL group (39% vs 25% for TAC + MMF, P < .05), and the majority of study dropouts were due to either graft loss or specific drug toxicities. SCr level was lower and GFR was significantly higher in the TAC + MMF group at 2-, 3-, and 6-month follow-up (P < .05). On the basis of this analysis, the study authors are planning to continue the study and conclude that the TAC + MMF group has fewer dropouts, improved renal function, reduced wound problems, and less hyperlipidemia, but greater severity (but not frequency) of rejection.

Conclusion
The results of SKPT continue to improve as immunosuppressive strategies become more targeted. Although corticosteroid elimination/avoidance and CNI minimization are a clinical reality, CNI elimination remains a work in progress. The ongoing results with alemtuzumab induction are promising, although it appears to be more effective when used as a conventional induction agent rather than as a tolerizing agent. Monotherapy or CNI elimination can be achieved in a proportion of patients, but it remains unclear which regimen is most effective and safe. Future clinical studies will continue to focus on long-term outcomes, immunologic monitoring, immunosuppressive reduction, and outcomes-based research.

References
Thai N, Khan A, Basu A, et al. Campath-1H induction in pancreas transplantation: FK monotherapy and FK/MMF. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 111.
Thai N, Blisard D, Basu A, et al. Pancreas transplantation under campath-1H and tacrolimus: correlation between low T cell responses and infection. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 113.
Knight RJ, Kerman RH, McKissick E, et al. Immunosuppression minimization after kidney-pancreas transplantation (SPK) utilizing thymoglobulin induction and sirolimus maintenance therapy. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 116.
Kaufman DB, Leventhal JR, Parker MA, Gallon LG. Calcineurin inhibitor-free/rapid steroid elimination immunosuppression in simultaneous pancreas-kidney transplantation. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 112.
Sollinger HW, Odorico JS, Becker YT, et al. Campath vs basiliximab after simultaneous pancreas-kidney transplantation in 331 patients. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 110.
Stratta RJ, Alloway RR, Lo A, Hodge EE, Rogers J. A prospective, randomized, multicenter trial of daclizumab induction in simultaneous kidney-pancreas transplantation: risk factors for rejection and adverse long-term outcomes at 3 years. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 114.
Margreiter R, Malaise J, Pratschke J, et al. Sirolimus versus mycophenolate mofetil in tacrolimus based primary simultaneous pancreas-kidney (SPK) transplantation: 6-month results of a multicenter trial. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 115.

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Donor-Transmitted and Community-Acquired Viral Disease in Organ Transplant Recipients
Atul Humar, MD, MSc, FRCPC   
Introduction
Transplant patients are uniquely predisposed to emerging infections.[1] Furthermore, if exposed to a pathogen, they are more likely to develop symptomatic disease, and once exposed are more likely to develop rapidly progressive, lethal disease, according to Atul Humar, MD.[2] Viruses are among the most common causes of opportunistic infection after transplantation and the most important.[3] The risk for viral infection is a function of the specific virus encountered, the intensity of immunosuppression, and other host factors governing susceptibility. Viral infection causes the direct effects (invasive disease) and indirect effects, including immunosuppression, that predispose the recipient to other opportunistic infections and oncogenesis.[3] Prophylactic measures prior to transplantation are evolving on the basis of recent reports of emerging infectious diseases.[4]

Hepatitis C Virus (HCV)
A kidney from a donor who is seropositive for HCV has been identified as an independent risk factor for mortality after renal transplantation,[5] and HCV-seropositive organ donors are common, according to Brian Pereira, MD,[6] who presented an analysis from the United States Renal Data System database showing that, between 1996 and 2001, 873/36,956 (2.4%) kidney donors were HCV-seropositive and, of these, approximately one third were donors for seronegative recipients.[7] Seroprevalance in organ donors, measured by second-generation ELISA for HCV antibodies, varies according to geographic location, ranging from 2.3% to 8.3%. Although not all antibody-seropositive donors are polymerase chain reaction (PCR)-positive, they are still considered infectious. However, transmission from the HCV-positive donor is more likely if the donor is PCR-positive.[8] In fact, nearly all the recipients of organs from anti-HCV-seropositive donors become infected with HCV.[6]

There is a high prevalence of liver disease among recipients of organs from anti-HCV-seropositive donors.[6] The risk of developing HCV-related liver disease is dependent on the relative donor-recipient pretransplant HCV status.[9] The risk is highest in donor-positive/recipient-negative pairs, followed by donor-positive/recipient-positive pairs, and then donor-negative-recipient-positive pairs. The risk is lowest in donor-negative-recipient-negative pairs. This reflects a situation similar to that seen with cytomegalovirus disease. Recipients of organs from HCV-positive donors also have a higher risk of death, especially donor-positive/recipient-negative pairs.[7]

The incidences of liver disease and survival (5-year) appear to be similar in HCV-seropositive recipients, regardless of whether the donor was HCV-seropositive or HCV-seronegative. Furthermore, recipients of kidneys from HCV-seropositive donors do better than patients on the transplantation waiting list; the death rate/100 patient years is 5.76 vs 11.63, respectively.[10,11]

In summary, organs from HCV-seropositive donors should not be used in unselected HCV-seronegative recipients; even HCV-negative recipients with limited life expectancy may have an increased risk of death. However, consideration may be given to the use of these organs in HCV-seropositive recipients, as limited data suggest a lack of adverse outcomes. Ultimately, this decision is best made between an informed patient and the physician.

Polyomaviruses
Polyomavirus-associated nephropathy (PVAN) is an emerging cause of kidney transplant failure, estimated to affect 1% to 10% of kidney recipients.[12] The polyomaviruses are double-stranded DNA viruses and include BK virus (BKV), JC virus (JCV), and SV40. More than 95% of all cases are caused by the human polyomavirus type 1 called the BK virus,[13] and most cases are caused by BKV in the setting of intense immunosuppression. Although no specific drug is independently associated with PVAN, most cases reported to date arise while the patient is being treated with triple maintenance immunosuppression.

Primary infection with BKV usually occurs during childhood, after which the virus establishes latency in the renal epithelium. Reactivation infection occurs in 3 stages: latent infection (no viruria or viremia), limited low-level viral replication (viruria but no viremia), and high-level viral replication (viremia) leading to allograft injury. Clinical manifestations in transplant recipients include asymptomatic viruria, ureteric stenosis, hemorrhagic cystitis, and PVAN.

Screening patients to prevent PVAN may be useful, noted Emilio Ramos, MD,[14] who outlined the following screening algorithm:

Urine cytology at 3, 6, 9, and 12 months post transplantation;

If urine cytology is positive, repeat testing in 1 month along with a quantitative blood or urine PCR assay; and

If the quantitative blood or urine PCR assay is positive above a certain threshold for a given laboratory, a kidney biopsy is indicated.
Definitive diagnosis of PVAN requires an allograft biopsy. There are 3 histopathologic patterns of PVAN: pattern A (minimal inflammation), pattern B (significant inflammation), and pattern C (significant atrophy and fibrosis).[12] Protocol biopsy in the patient with positive urine cytology may identify PVAN prior to the development of overt graft dysfunction, noted Dr. Ramos, which is important because reduction of immunosuppression appears to be more effective in this setting than in patients with established PVAN.

For patients with established PVAN, available treatment options are limited; reduction in immunosuppression is helpful in some patients. No antiviral treatments have been approved for PVAN. The antiviral drug cidofovir has shown in vitro activity against polyomaviruses and has been used in some patients in lower doses in an effort to minimize the nephrotoxic effects of cidofovir while treating PVAN.[13] Small series of PVAN patients treated with leflunomide, intravenous immune globulin therapy, and fluoroquinolones have also recently been reported, but their efficacies are unproven.

West Nile Virus (WNV)
In August 2002, fever and mental-status changes developed in recipients of organs from a common donor[15]; transmission of WNV through solid organ transplantation was suspected. Transplant recipients can acquire WNV in 1 of 3 ways: (1) transfusion transmission, (2) organ donor transmission, and (3) transmission in the community, according to Atul Humar, MSc, MD, FRCPC.[16] Posttransplant immunosuppression increases the risk of developing severe disease after WNV infection. In the general population, WNV causes severe neurologic disease in < 1% of infected patients. However, data from a seroprevalence study suggest that the incidence is as high as 40% in organ transplant recipients.[17]

Transfusion-Transmitted WNV (TTWNV)
It was determined that multiple blood transfusions were the probable source of WNV viremia in the organ donor of the first documented case in 2002.[15] The risk of TTWNV has decreased as a result of screening blood donor samples with nucleic acid testing, although a second case of donor organ transmission was recently documented in the New York area due to community-acquired infection in the donor.[18]

Although prevention strategies are critical, there is disagreement within the transplant community about the use of nucleic acid testing for screening of organ donors for WNV because screening results can be affected by a number of factors, including local WNV activity, test availability, and test characteristics. The fear is that false-positive results could unnecessarily exclude potential organ donors.[19] Dr. Humar concluded that WNV screening in potential organ donors should be considered if there is significant WNV activity in the donor's community. The current Organ Procurement and Transplantation Network recommendation is that screening is not mandatory at this time.[19]

References
Kumar D, Humar A. Emerging viral infections in transplant recipients. Curr Opin Infect Dis. 2005;18:337-341. Abstract
Humar A. Rabies and West Nile virus. Donor-derived and new viruses. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts.
Kotton CN, Fishman JA. Viral infection in the renal transplant recipient. J Am Soc Nephrol. 2005;16:1758-1774. Abstract
Avery R. Prophylactic strategies before solid-organ transplantation. Curr Opin Infect Dis. 2004;17:353-357. Abstract
Abbott KC, Bucci JR, Matsumoto CS, et al. Hepatitis C and renal transplantation in the era of modern immunosuppression. J Am Soc Nephrol. 2003;14:2908-2918. Abstract
Pereira B. The HCV-infected donor. Donor-derived and new viruses. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts.
Abbott KC, Bucci JR, Matsumoto CS, et al. Hepatitis C and renal transplantation in the era of modern immunosuppression. J Am Soc Nephrol. 2003;14:2908-2918. Abstract
Pereira BJ, Milford EL, Kirkman RL, et al. Prevalence of hepatitis C virus RNA in organ donors positive for hepatitis C antibody and in the recipients of their organs. N Engl J Med. 1992;327:910-915. Abstract
Abbott KC, Lentine KL, Bucci JR, et al. Impact of diabetes and hepatitis after kidney transplantation on patients who are affected by hepatitis C virus. J Am Soc Nephrol. 2004;15:3166-3174. Abstract
Abbott KC, Lentine KL, Bucci JR, et al. The impact of transplantation with deceased donor hepatitis C-positive kidneys on survival in wait-listed long-term dialysis patients. Am J Transplant. 2004;4:2032-2037. Abstract
Abbott KC, Lentine KL, Bucci JR, et al. The impact of transplantation with deceased donor hepatitis C-positive kidneys on survival in wait-listed long-term dialysis patients. Am J Transplant. 2004;4:2032-2037. Abstract
Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005;79:1277-1286. Abstract
Trofe J, Hirsch HH, Ramos E. Polyomavirus-associated nephropathy: update of clinical management in kidney transplant patients. Transpl Infect Dis. 2006;8:76-85. Abstract
Ramos E. Polyoma and related viruses. Donor-derived and new viruses. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts.
Iwamoto M, Jernigan DB, Guasch A, et al. Transmission of West Nile virus from an organ donor to four transplant recipients. N Engl J Med. 2003;348:2196-2203. Abstract
Humar A. Rabies and West Nile virus. Donor-derived and new viruses. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts.
Kumar D, Drebot MA, Wong SJ, et al. A seroprevalence study of West Nile virus infection in solid organ transplant recipients. Am J Transplant. 2004;4:1883-1888. Abstract
Centers for Disease Control and Prevention (CDC). West Nile virus infections in organ transplant recipients--New York and Pennsylvania, August-September, 2005. MMWR Morb Mortal Wkly Rep. 2005;54:1021-1023. Abstract
Kiberd BA, Forward K. Screening for West Nile virus in organ transplantation: a medical decision analysis. Am J Transplant. 2004;4:1296-301. Abstract

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PTLD in Pediatric Transplantation: Monitoring, Prevention, Vaccination. Is There an Answer?
Steven A. Webber, MB, ChB   
Introduction
Posttransplant lymphoproliferative disorders (PTLD) remain an important cause of morbidity and mortality after pediatric solid organ transplantation. Prevention remains the primary goal. Children are significantly over-represented relative to the number of pediatric solid organ transplants performed. This primarily relates to their seronegative status for Epstein-Barr virus (EBV) at the time of transplantation and the frequent development of primary EBV infection in the first 1-2 years after transplantation.

EBV Polymerase Chain Reaction (PCR) Assay Monitoring Post Transplantation
One important area of development in recent years has been the widespread introduction of EBV viral load monitoring. Quantitative PCR assays are now available in many centers throughout the world. As with many new tests, the assays have been introduced before we know how best to use them. Michael Green, MD,[1] provided an update of current status of EBV-PCR monitoring post transplantation. Some of the pitfalls were detailed, and unanswered questions were summarized.[2] The lack of standardization of assays from center to center is apparent. Furthermore, there is not even general agreement on which fraction of blood should be tested — whole blood, peripheral blood mononuclear cells (PBMC), or plasma. Data from Dr. Green's center showed that whole blood assays correlate very closely with loads from PBMC. However, the correlation of PBMC with plasma is poor.[3]

There is now broad agreement that serial viral load monitoring is very helpful in defining the onset of primary EBV infection post transplantation (thus defining the patient as being at risk for PTLD), and in raising the suspicion of EBV disease/PTLD in the symptomatic patient. New-onset PTLD is generally (though not universally) associated with very high peripheral viral loads. However, high loads may occur in patients without symptoms at the time of primary infection, and in some patients, very high loads persist long term. Thus, high viral loads are sensitive for the diagnosis of PTLD, but not specific.

PTLD remains a tissue diagnosis, but surveillance viral load monitoring clearly contributes to heightened awareness and likely earlier diagnosis of EBV disease. Several attempts have been made to enhance the specificity of PCR monitoring. Assessment of sentinel EBV gene transcripts using reverse transcriptase PCR can help identify the state of the virus in the host (eg, lytic vs latent infection), but has not been correlated with clinical outcomes; nor has it been introduced into the clinic. Combining viral load monitoring with ELISPOT quantitation of EBV-specific T cells may enhance the predictive value of viral load monitoring. In a population of liver transplant recipients, PTLD was associated with high viral load and concomitant very low frequency of EBV-specific T cells.[4] Unfortunately, ELISPOT assays are not routinely available in clinical laboratories.

Dr. Green emphasized that during response to therapy, viral loads usually fall, often prior to clinical improvement. This, presumably, is an indirect marker for reconstitution of anti-EBV T-cell immunity. With reintroduction of immunosuppression, modest rebounds in viral load occur but do not correlate with recurrent PTLD. However, a proportion of patients with posttransplant primary EBV infection carry very high EBV loads long term. Most are asymptomatic. The precise significance of this is unknown and the role of long-term monitoring is unclear. However, Dr. Green reported that in the heart transplant population at his institution, chronic high-load carriers were at significantly increased risk for late-onset PTLD, including Burkitt's lymphoma. A high-load carrier state may not, therefore, be benign.

Disease Prevention
Sue McDiarmid, MD,[5] expanded on the theme of disease prevention. She emphasized the need to understand risk factors for PTLD and which ones can be influenced or modified and which cannot. It is unclear at this time whether primary EBV infection can be prevented, but there is increasing evidence that perhaps primary infection can be modified to decrease the risk of progression to symptomatic infection or PTLD. It is clear that over-immunosuppression can lead to increased risk of PTLD, and a recent multicenter, prospective trial in pediatric renal transplantation was terminated early because of an unacceptably high rate of PTLD. An obvious need is for new tools to assess the degree of immunosuppression, irrespective of results of therapeutic drug monitoring.

Ongoing controversy surrounds the role of antiviral agents in the prevention of PTLD. There is little evidence that acyclovir or ganciclovir prevents primary infection. Some authorities believe these agents can prevent transition to PTLD, but this has never been proven in large, randomized, clinical trials. Several centers have combined long-term antiviral therapy with surveillance PCR monitoring in liver transplantation. The development of primary infection is usually managed by immediate reduction in immunosuppression unless there is a history of recent rejection. If patients are not already on antiviral therapy, it is introduced at the time of evidence of primary infection. Because of the use of 2 simultaneous strategies, it is not possible to be sure which is contributing to disease prevention. Nonetheless, Dr. McDiarmid reported that several pediatric liver transplant centers, including her program at UCLA, have noted a marked reduction in incidence of PTLD using an aggressive preventive approach combining antiviral agents with PCR monitoring.

A recent, randomized, placebo-controlled, multicenter trial of cytomegalovirus intravenous immunoglobulin (CMV-IVIG) for prevention of EBV-PTLD was recently reported in pediatric liver transplant recipients by the Pittsburgh group.[6] The difference in adjusted 2-year EBV disease-free rate (CMV-IVIG 79%, placebo 71%) and PTLD-free rate (CMV-IVIG 91%, placebo 84%) between treatment and placebo groups did not reach statistical significance, though the trend was in favor of an effect. The absence of significance may be explained by a lack of efficacy of the drug or limitations of sample size.

What Do You Do When PTLD Fails to Respond to Decreased Immunosuppression?
Outcomes of PTLD overall may not be as good as those that are sometimes quoted from single centers — perhaps reflecting a reporting bias from centers with good results, noted Steven Webber, MBChB, MRCP, FAAP.[7] Dr. Webber and colleagues[8] evaluated outcomes among patients with PTLD followed at 19 centers within the Pediatric Heart Transplant Study (PHTS) from 1993 to 2002. Of 1184 primary transplant recipients, 56 (5%) developed PTLD. Probability of survival was 75% at 1 year, 68% at 3 years, and 67% at 5 years after diagnosis. Death from graft loss (acute and chronic rejection) was as frequent as death from progressive disease. Advances in management should, therefore, focus on strategies to protect the allograft as well as improved therapies for PTLD. More sophisticated monitoring of immune reconstitution, combined with viral load monitoring and frequent graft surveillance, could lead to improved ability to prevent graft rejection during initial reduction in immunosuppression.

Dr. Webber noted that the most commonly used therapy when reduction in immunosuppression fails is the anti-CD20 monoclonal antibody, rituximab. CD20 is expressed on the vast majority of pediatric PTLD lesions, almost all of which are of B-cell lineage. Rituximab has a good safety profile in adult nontransplant lymphomas, and initial experience in transplant recipients appears promising. There is some concern however, about the development of hypogammaglobulinemia in the pediatric transplant population, though this is not well quantified. Response rates in adult-refractory PTLD (where the most common histology is monomorphic disease, usually diffuse, large, B-cell lymphoma) are variable but generally do not exceed 50%. Relapse is also common, as high as 20% in some series, often occurring at around 6-9 months when B-cell reconstitution tends to occur.

There is much less experience with rituximab for refractory PTLD in the pediatric population. Dr. Webber described unpublished data from the Pediatric PTLD Rituximab Registry (n = 26) and from a small, multicenter, prospective study of rituximab in children with refractory PTLD (n = 15). In both studies, approximately two thirds of patients achieved complete responses with 4-8 doses of rituximab. These patients would otherwise have required multidrug chemotherapy. Chemotherapy has the advantage of protecting the graft from acute rejection, but infectious toxicity appears to be high in this group of patients (compared with the nontransplant population with lymphoma). This appears to be particularly true in adults, in whom multidrug chemotherapy has been associated with a toxic mortality as high as 26%.[9] Low-dose chemotherapy with cyclophosphamide and prednisone has produced response rates for refractory PTLD of greater than 80% in children, but with high relapse rates (19%).[10] In a follow-up study in children, the same regimen is being combined with rituximab and enrollment is approximately 50% completed at this time (personal communication Dr. Tom Gross, Columbus Children's Hospital, Ohio).

Active Immunization
The most obvious strategy to improve outcomes is to prevent primary EBV infection by active immunization, preferably prior to transplantation. Some 3 decades ago, Professor Epstein and his colleagues were confident that an EBV vaccine was just around the corner. The challenges range from biological to socioeconomic and political.

EBV is a very rare cause of serious disease in developed countries, and the financial incentive for the pharmaceutical industry to invest in vaccine development is weak. Lesley Rees, MD,[11] reported the early results of testing of a vaccine that has undergone primate and phase 1 human studies. The vaccine has been developed at the Cancer Research UK Formulation Unit and is based on the glycoprotein Gp350, the most abundant protein in lytically infected cell membranes. In healthy adult volunteers, and in a small group of children awaiting renal transplantation, the vaccine appears to have reasonable immunogenicity, though more than 1 injection and late booster doses may be required. The ability to prevent primary EBV infection remains unclear. A third of children developed injection site reactions, and 1 adult experienced a severe flu-like illness. Despite this very important work, it is clear that routine vaccination of transplant candidates may be many years away, and this specific vaccine may not necessarily be the one that is ultimately used to prevent EBV infection.

Perhaps the most encouraging observation gleaned from this symposium was that significant basic and clinical research is ongoing in this field, and advances in diagnosis and therapy are starting to be realized. This provides optimism for the future.

References
Green M. PTLD in pediatric transplantation. Is surveillance helpful? Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 667.
Green M, Webber SA. EBV viral load monitoring: Unanswered questions. Am J Transplant. 2002;2:894-895. Abstract
Wadowsky RM, Laus S, Green M, Webber SA, Rowe D. Comparison of Epstein-Barr virus DNA load measured in whole blood and plasma by TaqMan PCR and in peripheral blood lymphocytes by competitive PCR. J Clin Microbiol. 2003;41:5245-5249. Abstract
Smets F, Latinne D, Bazin H, et al. Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation. 2002;73:1603-1610. Abstract
McDiarmid SV. PTLD in pediatric transplantation. Can the incidence be reduced? Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 667.
Green M, Michaels MG, Katz BZ, et al. CMV-IVIG for prevention of Epstein-Barr virus disease and post-transplant lymphoproliferative disease in pediatric liver transplant recipients. Am J Transplant. 2006;6:1906-1912. Abstract
Webber S. PTLD in pediatric transplantation. Specific treatment if reduction in immunosuppression is ineffective. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 667.
Webber SA, Naftel DC, Fricker FJ, et al. Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study. Lancet. 2006;21:367:233-239.
Elstrom RL, Andreadis C, Aqui NA, et al. Treatment of PTLD with rituximab or chemotherapy. Am J Transplant. 2006;6:569-576. Abstract
Gross TG, Bucuvalas JC, Park JR, et al. Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol. 2005;23:6481-6488. Abstract
Rees L. PTLD in pediatric transplantation. Results of EBV vaccine. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 667.

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O Kidney, Where Art Thou?
Robert J. Stratta, MD   
Introduction
The aging of the donor and recipient populations has led to new challenges in kidney transplantation. Due to changing donor demographics, excessive waiting times, and the increasing disparity between organ supply and demand, guidelines for what defines an acceptable donor continue to evolve. These changes have occurred because of the convergence of demographic inevitability and medical advances. The burgeoning crisis in organ supply challenges the transplant community to reassess thresholds for acceptable risk and to maximize as well as optimize the use of organs from all donor sources.

Kidney Allocation: Registry, Network, and Collaborative Analyses
McCullough and colleagues[1] from the Scientific Registry of Transplant Recipients (SRTR) presented the Net Lifetime Survival Benefit (NLSB) Model as a new paradigm for determining kidney allocation. In this proposed model, the incremental NLSB, defined as the difference between estimated transplant life span with a given kidney minus predicted waiting list life span without a transplant, is determined for each donor kidney and prospective candidate on the waiting list, based on statistical modeling of donor and recipient factors. Important factors that have been demonstrated to influence the model include donor and recipient age, presence of diabetes, candidate body mass index, serum albumin, years of renal failure, previous transplantation, peak panel reactive antibody (PRA) status, and type of transplant (kidney vs kidney-pancreas). Notably, factors such as candidate gender and ethnicity do not appear to be predictive of outcomes in this model. The model also assumes that the quality-of-life benefit for 1 year with a functioning graft is comparable to 0.8 years on dialysis. The NLSB model predicted a median life span of 7.2 years for candidates on the active waiting list in 2004 compared with 12.3 years for candidates that were transplanted in 2004. Although the NLSB model suggested that transplantation increases overall life expectancy compared with remaining on the waiting list for most candidates, the greatest NLSB occurred in kidney-pancreas, diabetic, and younger transplant candidates.

In another study of kidney allocation, Hirose and colleagues[2] presented results from the California Transplant Donor Network (CTDN). In 1993, the CTDN received a variance from the United Network for Organ Sharing (UNOS) permitting local kidney allocation based exclusively on waiting time independent of HLA-matching (other than participation in the 0-antigen mismatch national sharing system). From 1993 through 1999, 1301 locally allocated kidney transplants were compared with 37,858 concurrent kidney transplants performed nationally, with the latter group receiving kidney allocation based primarily on HLA-matching. Locally transplanted kidneys had less HLA-matching but shorter cold ischemia times compared with the kidneys transplanted outside of the CTDN variance during the period of study. Patient and graft survival rates out to 10 years were no different between groups. However, the distribution of allocated kidneys according to recipient ethnicity was significantly more diverse and equitable within the CTDN compared with the rest of the United States. In addition, no differences in the patterns of relative risk of graft loss were found in the 2 groups. On the basis of their findings, the authors question the necessity and fairness of a kidney allocation system predicated on HLA-matching.

In another study, McBride and colleagues[3] presented recent UNOS data on the 0-antigen mismatch national sharing system that went into effect in 1995 and was subsequently amended to generate a mandatory payback kidney to the national pool. All deceased-donor kidney alone transplants performed in 2003 and 2004 were included in the analysis. Transplants were categorized into 3 allocation groups: (1) 0 mismatch (n = 2611), (2) payback (n = 724), and (3) kidneys allocated based on the standard "points" system (n=14,082). In addition, donors were categorized into standard criteria donors ([SCD], 80%), expanded criteria donors ([ECD], 15%), and donation after cardiac death ([DCD], 5%) donors. The proportion of SCDs was highest in the payback (96%), intermediate in the 0-mismatch (91%), and lowest in the points (76%) categories. Cold ischemia times were longest in the payback, intermediate in the 0-mismatch, and shortest in the points categories. Despite the fact that the payback and points patient categories were poorly matched for HLA (77% with 4-6 mismatches), 1-year graft survival rates and renal function were comparable between 0-mismatch and payback groups and slightly inferior in the points group. On the basis of these findings, the authors concluded that the quality of the donor may be more important than the quality of the HLA-match. Moreover, a reevaluation of the mandatory 0-mismatch sharing policy may be necessary to determine which recipient populations (eg, highly sensitized) may achieve the most benefit.

Two studies highlighted accomplishments and challenges of the Organ Donation Breakthrough Collaborative (ODBC). The first, by Burdick and colleagues,[4] outlined the history of the ODBC initiative, including the formidable task of identifying, distributing, and disseminating best practices to the organ procurement organization (OPO), transplant, and donor hospital communities. The initial goal of the ODBC was to increase donor consent rates from a baseline of 46% in 2002 to 75% in 226 of the largest donor hospitals in the United States. The ODBC's model for improvement included determination of best practices among the highest performing OPOs, transplant centers, and donor hospitals; formation of multidisciplinary teams and setting of aims; establishment of measures; and selection, testing, and implementation of practices. The "Plan, Do, Study, and Act" process initiative was deployed at all levels. With initiation of the ODBC, unprecedented growth (10.7% increase in 2004, 6.2% increase in 2005) occurred in deceased organ donors nationwide, although the conversion rate only increased modestly from 52.1% in 2003 to 58.8% in 2005. The goal of achieving 10% of all donors coming from DCDs in each donor service area has yet to be realized. By focusing on outcomes and identifying a shared vision and purpose, systematic implementation of a collaborative, national initiative has had a markedly positive effect on organ donation. The second phase of the ODBC is to improve organ yield from a mean of 3.2 to 3.8 organs per donor.

In a related presentation, Howard and associates[5] reported on the impact of the ODBC on specific donation rates in concert with a report from the Institute of Medicine (IOM).[6] The ODBC is a nationwide quality improvement initiative sponsored by the Department of Health and Human Services consisting of a series of learning sessions attended by teams of hospital, transplant center, and OPO staff. In 95 hospitals that participated in the first phase of the ODBC, conversion rates increased from 52.6% to 63.2%. In 99 control hospitals that did not participate in the first phase of the ODBC, the conversion rate increased from 53% to 56% during the same study period. Assuming that organ transplants are associated with a gain of 31 life-years to recipients, the ODBC led to a gain of > 5000 life-years at a cost of only $3 million per year. The IOM report focused on a number of controversies, including financial incentives, preferential access, presumed consent, and DCD donation. Although the final IOM report is pending, it is thought that potential gains from presumed consent and preferential access are probably small, whereas the success of the ODBC and advances in DCD donation represent important avenues to improve organ donation rates in the United States.

Marginal Donors
Kumar and colleagues[7] presented their fascinating experience using deceased donors with terminal acute renal failure (ARF) for kidney transplantation. This 3-year, prospective study evaluated outcomes of kidneys from donors with ARF compared with concurrent SCD and ECD kidney transplants. ARF donors were defined as those admitted with a normal serum creatinine (SCr) and good urine output who experienced at least a 2-fold increase in SCr (minimum > 2.5 mg/dL) with persistent anuria or oliguria and no trend toward improvement up until the time of organ recovery. The mean terminal SCr in the ARF donors was 4.8 mg/dL. DCDs were excluded. In addition, ARF donors were excluded from the study if they were > 50 years of age or had any history of hypertension, diabetes, or chronic kidney disease. From October 2002 to March 2005, 55 kidneys were transplanted from 38 donors meeting the above criteria for ARF and were compared with 55 concurrent SCD and ECD kidney recipients. All ARF and ECD kidneys were biopsied prior to acceptance, and the vast majority were also preserved by pulsatile perfusion. All patients received basiliximab induction in combination with 2 doses of methylprednisolone, a calcineurin inhibitor, and either mycophenolate mofetil or sirolimus. Mean donor age was comparable in the ARF and SCD groups (31 years), which was significantly lower than the mean donor age in the ECD group (65 years). Mean recipient age was likewise comparable (51 years) in the ARF and SCD groups and significantly younger than the ECD group (66 years). The incidence (88%) and duration (mean 13 days) of delayed graft function (DGF) was increased in the ARF compared with the SCD (48%, mean 3 days) and ECD (60%, mean 9 days) groups. At 3 years of follow-up, survival, graft function, and histologic findings (subclinical acute rejection, chronic allograft nephropathy) were similar in the ARF and SCD groups, which were significantly improved compared with the ECD group (P = .02). The authors concluded that kidneys from selected donors with ARF are suitable for transplantation and provide equivalent 3-year results compared with SCD kidneys.

An SRTR analysis of factors predictive of ECD kidney discard rates and outcome was reported by Leichtman and colleagues.[8] Nationally, approximately 40% of recovered ECD kidneys are discarded. From February 2003 through September 2005, 3 OPOs and their 20 transplant centers prospectively biopsied and perfused ECD kidneys. Of 458 ECD kidneys that were recovered, 62% were transplanted and 38% were discarded. Multiple factors were significantly associated with an increased adjusted odds ratio of ECD kidney discard including donor age > 70 years, pump resistance > 0.4, reactive hepatitis B virus core antibody serology, glomerulosclerosis > 20% on biopsy, terminal SCr > 1.5 mg/dL, peripheral vascular disease, surgical injury, urine protein, and multiple cysts. However, the only risk factor that was associated with graft loss was terminal SCr >1.5 mg/dL, although glomerulosclerosis > 20% (P = 0.057) approached significance. None of these factors had an effect on DGF. On the basis of these findings, the authors concluded that several factors predictive of ECD kidney discard were not found to be predictive of worse graft outcomes.

Noeldeke and colleagues[9] presented a 5-year analysis of the Eurotransplant Senior Program (ESP), which attempts to allocate kidneys within a narrow geographic area from donors ≥ 65 years of age to recipients ≥ 65 years of age without regard to HLA-matching. From 1999 to 2004, the authors identified 1406 kidney transplants performed from old donors to recipients using the ESP, 446 transplants from old donor (age ≥ 65 years) to any age recipient (old donor to any age recipient [O/A]), and 1687 transplants from any age donor to recipients 60-64 years of age (any donor to old recipient [A/O]).

Since the initiation of the ESP, the availability of elderly donors has increased by 43% and waiting times for the elderly have been reduced from a mean of 3.9 to 3.5 years. With local allocation through the ESP, mean cold ischemia times have decreased from >17 hours to 11.9 hours (P < .001) and rates of DGF have decreased from 36% to 30% (P < .05). Patient and graft survival rates have not been negatively influenced by the ESP allocation (similar results for ESP and O/A), which are significantly lower than survival rates for A/O recipients. However, HLA-matching was significantly worse in ESP recipients, which may have contributed to a 5% to 10% higher rate of acute rejection in this group of patients. The outcome of younger recipients appeared to be worse if they received organs from older donors. The authors concluded that age matching of elderly donors and recipients is an effective organ allocation strategy that could potentially increase the number of elderly patients receiving transplants and decrease the number of deaths on the waiting list.

Two final presentations examined donors > 70 years of age and assessment of organ quality using a clinical scoring system.[10,11] Both studies used histopathologic assessment in combination with clinical characteristics of the donor to predict outcomes for marginal donors. Minimizing cold ischemia time, appropriate recipient selection, use of dual kidney transplants, and estimation of donor creatinine clearance were helpful in predicting outcomes, whereas histopathologic evaluation was useful in determining whether organs should be discarded.

Summary
Increases in organ donation rates in recent years are largely attributable to expanding the limits of donor acceptability (ie, older donors, donors with ARF, DCD donors), improving donor management, better assessment of donor quality, reducing organ discard rates, and improving conversion rates through systematic implementation of best practices. Because of the ever-changing landscape of kidney transplantation, it is inevitable that allocation schemes will evolve away from HLA-matching and toward some measure of donor and recipient matching based on functional characteristics and net benefit. Ultimately, a number of important goals can be achieved, including maximal and optimal utilization of all donor kidneys, minimizing kidney discard rates and waiting list deaths, improving equity, controlling resource utilization, and respecting individual autonomy.

References
McCullough KP, Leichtman AB, Guidinger MK, Stegall MD, Wolfe RA. Comparing candidate survival with and without kidney transplantation: the net lifetime survival benefit model. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 217.
Hirose K, Cherikh WS, Tomlanovich S, et al. Allocating kidneys without points for HLA matching distributes organs more equitably without adversely affecting outcomes. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 221.
Aeder MI, McBride MA, Schulak JA. Survival and function of zero antigen mismatched (0MM) kidneys: Is HLA the primary determinant? Abstract 220.
Burdick J, Wagner D, McBride V, et al. The organ donation breakthrough collaborative: Achieving systematic increases in organ donation and transplantation. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 224.
Howard DH, Siminoff L, Howard RJ. The impact of the organ donation breakthrough collaborative on donation rates. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 225.
Howard DH, Howard RJ. Institute of Medicine Report On Increasing Organ Donation Rates. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 226.
Kumar MSA, Jaglan S, Khan SM, et al. 3 year survival after transplantation of kidneys from deceased donors with acute renal failure. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 218.
Leichtman AB, Christensen LL, O'Connor K, et al. Factors predictive of discard of expanded criteria donor kidneys are poorly predictive of outcomes. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 219.
Noeldeke J, Fabrizii V, Arbogast H, et al. Prospective age-matching in elderly kidney transplant recipients - A 5-year analysis of the Eurotransplant Senior Program. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 223.
Baldan N, Margani G, Ekser B, et al. Negative impact of posttransplant diabetes mellitus after liver transplantation on patient and graft survival in long-term follow up. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 227.
Re LS, Cicora F, Petroni J, et al. Assessing organ quality in deceased donor kidney transplants: Correlation of a clinical and histopathological score with transplant outcome. Program and abstracts of the World Transplant Congress 2006; July 22-27, 2006; Boston, Massachusetts. Abstract 228.