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The Year in Review – ATC 2002

2003; Elsevier BV; Volume: 3; Issue: 4 Linguagem: Inglês

10.1034/j.1600-6143.2003.00115.x

1600-6143

Peter G. Stock,

Liver Disease and Transplantation

Strategies for dealing with the exponential growth of the waiting lists for solid organ transplants were the hottest clinical topics in 2002, and dominated the abstracts presented at ATC 2002. Other clinical topics that were prominent in the 2002 literature and received the highest scores at ATC 2002 included: the development of immunosuppressive regimens minimizing calcineurin inhibitors and eliminating steroids; the increasing frequency and severity of hepatitis C recurrence following transplantation; the safety and efficacy of solid organ transplantation in HIV-positive recipients; the induction of tolerance with donor stem cell infusion and recipient preconditioning; the increasing incidence of BK virus; and beta-cell replacement for the treatment of diabetes mellitus. Strategies for dealing with the exponential growth of the waiting lists for solid organ transplants were the hottest clinical topics in 2002, and dominated the abstracts presented at ATC 2002. Other clinical topics that were prominent in the 2002 literature and received the highest scores at ATC 2002 included: the development of immunosuppressive regimens minimizing calcineurin inhibitors and eliminating steroids; the increasing frequency and severity of hepatitis C recurrence following transplantation; the safety and efficacy of solid organ transplantation in HIV-positive recipients; the induction of tolerance with donor stem cell infusion and recipient preconditioning; the increasing incidence of BK virus; and beta-cell replacement for the treatment of diabetes mellitus. The exponential growth in the number of patients on the liver transplant list was emphasized in the New England Journal of Medicine medical progress report on adult-to-adult transplantation of the right hepatic lobe from a living donor (1Trotter JF Wachs M Everson GT et al.Adult-to-adult transplantation of the right hepatic lobe from a living donor.N Engl J Med. 2002; 346: 1074-1082Crossref PubMed Scopus (413) Google Scholar). Although the number of cadaveric liver transplants performed in the USA each year has leveled off at around 4000, the number of patients on the waiting list increased from less than 4000 in 1994 to over 16 000 by 2002. This increasing disparity is now being reflected in significant increases in the number of deaths on the waiting list, prompting the universal interest in adult-to-adult living-donor liver transplantation (LDLT). The increasing interest in living-donor liver transplantation was the impetus of a consensus conference at the National Institutes of Health (NIH) (2Shiffman ML Brown RS Olthoff KM et al.Living donor liver transplantation: summary of a conference at the National Institutes of Health.Liver Transpl. 2002; 8: 174-188Crossref PubMed Scopus (133) Google Scholar). A summary report from this conference reported a significant frequency of complications in both living donors and recipients of the living-donor segment. The most frequent donor complications were related to the biliary tract, and leaks, bilomas, and stenosis were reported at a frequency ranging between 3 and 8% in US centers performing LDLT. A high rate of complications was reported in recipients of LDLT, with biliary complications being reported with an incidence between 15 and 30%, and hepatic artery thrombosis being reported at a rate between 3 and 10%. At ATC 2001, there were a large number of abstracts related to the technical issues involved in LDLT, mostly related to differing opinions as to the necessity for reimplantation of the middle hepatic vein. Despite the increasing frequency and interest in LDLT, there was only one report at ATC 2002 on complications and outcomes following LDLT, from the Lahey Clinic (3Pomposelli JJ Pomfret EA Kreske E et al.Patterns of postoperative complications and surgical outcome after live donor liver transplantation (abstract 837).Am J Transplant. 2002; 2: 348Google Scholar). This paper compared 2-year graft and patient survival in 49 LDLT to 153 primary cadaveric liver transplants. The 2-year graft survival for cadaveric transplants was 89.4%, compared to 80.1% for the LDLT. The rate of biliary complications in recipients of LDLT was 18.1%, and hepatic artery thrombosis was reported at 6.6%. The rates of both donor and recipient complications were consistent with the reports published from the NIH Consensus Conference (2Shiffman ML Brown RS Olthoff KM et al.Living donor liver transplantation: summary of a conference at the National Institutes of Health.Liver Transpl. 2002; 8: 174-188Crossref PubMed Scopus (133) Google Scholar), and the authors of this abstract concluded that, given the relatively high rate of donor and recipient morbidity, the indications for LDLT need careful consideration. In light of the well-publicized death of a living donor and two US donor deaths reported at the NIH consensus conference, the early risks of donating a lobe of the liver are evident and continue to be the topic of ethical debates. Nonetheless, the judicious utilization of living donors for liver transplantation will continue to expand as a result of public demand for this procedure, and represents the most viable solution to a rapidly expanding waiting list that far outstrips the number of cadaveric donors. Increasing the number of cadaveric livers using non-heart-beating donors and split livers was addressed as another potential solution to the increasing demand. The transplant group from the University of Pennsylvania, Philadelphia looked at the feasibility of non-heart-beating donors in 16 recipients of cadaveric livers (4Abt P Desai N Crawford M et al.Liver transplantation from non-heart-beating donors: an increased incidence of biliary complications (abstract 386).Am J Transplant. 2002; 2: 235Google Scholar). The 3-year patient and graft survival was 76% and 69%, respectively. Of the 14 patients who survived more than 6 months, five (36%) experienced significant biliary complications requiring multiple interventional radiologic procedures, surgical revision and retransplantation. These patient and graft survival rates were inferior to those from brain-dead donors, and the rate of biliary complications represented a significant source of morbidity and mortality. The feasibility of splitting cadaveric transplants for two adults was addressed in an abstract presented by the group at the University of Minnesota (5Humar A Sielaff TD Kandaswamy R et al.Split-liver transplants (SLTS) for 2 adult recipients: the key is proper donor and recipient selection (abstract 839).Am J Transplant. 2002; 2: 348Google Scholar). Nine livers were split for 18 recipients, and at a mean follow-up of 18 months, patient and graft survival for the recipients of right and left lobes was 78%. It should be noted that the cadaveric donors utilized for the split were optimal donors, and the recipients for the split lobe were highly selected. The incidence of biliary complications was 27%, and the incidence of hepatic artery thrombosis was 11%. Although the true split provided two adult recipients with tissue, the increased morbidity and decreased graft survival as compared to standard orthotopic liver transplants suggest that use of true split livers will be limited. The importance of minimizing the duration of pretransplant dialysis was demonstrated in data presented by Kaplan et al. (6Meier-Kriesche H Kaplan B Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis.Transplantation. 2002; 74: 1377-1381Crossref PubMed Scopus (618) Google Scholar). They reported a marked difference in graft survival for both living-related and cadaveric kidney transplants when comparing patients who underwent a pre-emptive transplant vs. patients who were maintained on dialysis for over 2 years. The use of the laparoscopic technique for donor nephrectomies has increased the number of willing donors, evidenced by increasing numbers of living-donor kidney transplants at institutions which have adopted this technique. The safety and efficacy of this technology were addressed in a large retrospective series analyzing 10 828 living-donor nephrectomies from 171 centers, representing 84% of cases reported to UNOS between 1/99 and 7/01 (7Matas A Leichtman A Bartlett S et al.Kidney donor (LD) morbidity and mortality, 1/1999–7/2001 (abstract 2).Am J Transplant. 2002; 2: 3Google Scholar). The complication rate ( 2.5 mg/dL, and renal failure was evaluated in 76 177 recipients of extrarenal organ transplants performed between 1/87 and 11/2000 (20Ojo AO Webb RL Arndorfer JA et al.Kidney failure in recipients of liver, heart, lung and intestinal transplantation (abstract 1307).Am J Transplant. 2002; 2: 467PubMed Google Scholar). Renal insufficiency developed in 11 552 patients (11.2%) and renal failure was found in 3387 patients (4.5%) during a mean follow-up of 85 months following transplantation. Both renal insufficiency and failure were associated with significant increases in the relative risk of death. The continued high frequency of post-transplant diabetes and renal insufficiency/failure justifies further development of protocols which are attempts to minimize or eliminate calcineurin inhibitors in the immunosuppressive protocols. The continued high frequency of significant complications associated with current immunosuppressive regimens is the impetus to further development of strategies leading to transplantation tolerance. The literature is replete with tolerizing strategies involving the generation of bone-marrow chimerism as a means for tolerance induction in small animal models, but there has been a paucity of clinical trials. Millan and colleagues from Stanford University presented a clinical strategy for the induction of bone-marrow chimerism utilizing hematopoietic stem cells in conjunction with renal transplantation (21Millan MT Shizuru JA Hoffmann P et al.Mixed chimerism and drug withdrawal after kidney transplantation and blood progenitor cell infusion (abstract 3).Am J Transplant. 2002; 2: 138PubMed Google Scholar). The protocol used induction therapy with thymoglobulin and sublethal total body irradiation. Twelve days following induction therapy and renal transplantation, patients received an infusion of donor stem cells. Maintenance immunosuppression consisted of prednisone and cyclosporine. At the time of the presentation at ATC 2002, two of four patients who underwent the induction protocol had achieved a state of macrochimerism and donor-specific unresponsiveness in a mixed lymphocyte reaction (MLR). Both patients were withdrawn from immunosuppression, although one of the patients developed an acute rejection episode and was re-initiated on immunosuppressive therapy. The long-term results from this interesting protocol are pending, but the early results suggest that macrochimerism and donor-specific unresponsiveness in an MLR are not synonymous with tolerance. In a protocol described as a ‘tolerance enhancing’ strategy, Abu-Elmagd and colleagues from the University of Pittsburgh pretreated small-bowel recipients with high-dose thymoglobulin (5–10 mg/kg) (22Bond G Reyes J Mazariegos G et al.Induction therapy and intestinal transplantation: long-term results (abstract 844).Am J Transplant. 2002; 2: 350Google Scholar). The donor small bowel was irradiated to eliminate passenger leukocytes, and recipients were infused with ‘repopulating’ donor bone-marrow cells. Patients were subsequently maintained on tacrolimus monotherapy. In the first 13 patients who underwent this aggressive ‘preconditioning’ regimen, early graft survival was 85%, with a rejection rate of 15%. Although none of the patients have been withdrawn from immunosuppression, these low rejection rates are particularly impressive for the highly immunogenic small-bowel transplant. Clinical evidence suggestive of a ‘tolerant’ state was presented by the transplant group from Kyoto University, Japan (23Ogura Y Oike F Kiuchi T et al.Complete withdrawal of immunosuppression in living donor liver transplantation (abstract 1287).Am J Transplant. 2002; 2: 462Google Scholar). Immunosuppression was withdrawn in 114 pediatric recipients of living-donor liver transplants (LDLT) who had survived for more than 2 years after LDLT, maintained good graft function, and had no rejection in the preceding 2 months. Of the 114 pediatric patients, 48 (42%) achieved complete withdrawal with a median drug-free period of 22.8 months. Forty-six patients were still being weaned at the time of the presentation, and 20 (17.5%) had encountered rejection and had been placed back on immunosuppression. This study suggests that there are potential candidates for weaning off immunosuppression following LDLT. The introduction of model for end stage liver disease (MELD) and pediatric model for end stage liver disease (PELD) into the organ allocation system for liver transplantation this year was implemented to provide a strategy utilizing concrete parameters [bilirubin, international normalized ratio (INR), creatinine] to predict the mortality of patients with liver insufficiency and prioritize the patients according to severity of illness. Two groups, UCLA (24Ghobrial R Gornbein J Anselmo D et al.Pretransplant model to predict post-transplant survival in OLT for HCV (abstract 455).Am J Transplant. 2002; 2: 252PubMed Google Scholar) and University of Pennsylvania (25Desai N Crawford MD Mange KC et al.Pretransplant MELD score predicts patient and graft survival following liver transplantation (abstract 452).Am J Transplant. 2002; 2: 251Google Scholar), presented data which challenged the potential utility of this system, and suggested that the MELD score may actually predict postoperative mortality. The merits of this MELD and PELD will undoubtedly be the focus of future analysis pending the accumulation of data in the first few years of this new allocation scheme. The role of HLA matching in allocation of kidneys and kidney/pancreas transplants in the current era of immunosuppression continues to evolve, with improvement in immunosuppressive regimens. De-emphasizing HLA matching will increase minority access, but may negatively impact graft survival. Data from the Midwest Transplant Network suggested allocation based on an HLA-based point system did not provide patients with a better long-term graft survival (26Harrell KM Warady BA Aeder M et al.The HLA points assigned in local cadaveric kidney allocation should not be maintained. an analysis using HLA-DR molecularly typed and allocated patients and donors (abstract 37).Am J Transplant. 2002; 2: 147Google Scholar). Roberts et al. presented SRTR/URREA data that will be incorporated in UNOS allocations schemes, which recommended elimination of allocation points for HLA-B but maintaining points for HLA-DR (27Roberts JP Port FK Wolfe RA et al.Eliminating points for HLA B matches benefits access to kidney transplantation for minorities with minimally increased risk of graft loss (abstract 32).Am J Transplant. 2002; 2: 145Google Scholar). This would reduce the disadvantage for minorities in access to transplantation, while minimizing graft loss related to increased HLA disparity. The most convincing evidence for the decreasing importance of HLA in organ allocation was reported in a multivariable analysis of the UNOS data on simultaneous pancreas-kidney transplants, which demonstrated that the highly immunogenic simultaneous pancreas/kidney transplants had excellent outcomes independent of HLA matching (28Mancini MJ Connors AF Wang XQ et al.HLA matching for simultaneous pancreas-kidney transplantation in the United States. a multivariable analysis of the UNOS data.Clin Nephrol. 2002; 57: 27-37Crossref PubMed Scopus (12) Google Scholar). The increasing incidence and problems associated with what Newsweek recently referred to as the ‘stealth virus’ was evident in multiple presentations at ATC 2002 (29Cowley G Hepatitis C – the insidious spread of a killer virus.Newsweek. 4/22/2002; Volume CXXXIX, No. 16: 47-53Google Scholar). Recurrence of hepatitis C continues be the most significant problem following transplantation without effective therapy. A concerning report from the transplant group at Baylor University Medical Center (Dallas) suggested that a more aggressive recurrence of hepatitis C has been observed in the last 2 years, compared with liver transplants performed between 1990 and 1998 (30Fasola C Netto GJ Christensen LL et al.Evolution of hepatitis C recurrence (HCVR) post liver transplantation (OLT) in the last ten years: more aggressive recurrence in recent years (abstract 6).Am J Transplant. 2002; 2: 139Google Scholar). This aggressive recurrence was manifested by a higher percentage of severe fibrosis at 1 year, as well as a higher frequency of histologic progression of hepatitis C between year 1 and year 2. Furthermore, this increase in severe recurrence in recent years was independent of immunosuppressive regimens, suggesting the evolution of a more aggressive virus. A more rapid recurrence of hepatitis C was also noted following living-donor liver vs. cadaveric liver transplants. Two independent reports, one from the University of Colorado (31Taniguchi M Wachs M Bak T et al.Hepatitis C recurrence in living donor liver transplantation (abstract 4).Am J Transplant. 2002; 2: 138PubMed Google Scholar) and the other from UCLA (32Ghobrial RM Amersi F Farmer DG et al.Rapid and severe early HCV recurrence following adult living donor liver transplantation (abstract 104).Am J Transplant. 2002; 2: 163Google Scholar), suggested that graft fibrosis induced by recurrent hepatitis C may be accelerated by graft regeneration. The rapid recurrence of hepatitis C noted in the ambiance of the regenerating liver may offset the survival benefits of early transplantation. Furthermore, a large series from Mt. Sinai reported an extremely poor prognosis following retransplantation for hepatitis C as compared to other disease, with patient survival at 1 year of approximately 50% (33Roayaie S Schiano T Kim-Schluger L et al.Results of retransplantation for recurrent hepatitis C (abstract 106).Am J Transplant. 2002; 2: 164Google Scholar). Despite these reports raising concerns about increasing severity and frequency of hepatitis C following liver transplantation, there were no abstracts at ATC 2002 on therapy for prophylaxis or treatment of hepatitis C following transplantation. A report from the peginterferon alfa-2a (40KD) (PEGASYS®) trial for the treatment of recurrent C following liver transplantation reported a 36% response rate at 48 weeks as defined by HCV RNA negativity (34Ferenci P Peck-Radosavljevic M Wolfgang V et al.Peginterferon alfa-2a (40KD:) for hepatitis C recurrence in liver transplant recipients (abstract 937).Hepatology. 2001; 34: 406Google Scholar). Interestingly, there were two reports at ATC 2002 from Spain (35Cruzado JM Casanovas-Taltavull JT Salvador GV et al.Pre-transplant interferon prevents hepatitis C virus-associated glomerulonephritis in renal allografts (abstract 489).Am J Transplant. 2002; 2: 260PubMed Google Scholar) and Japan (36Tokumoto T Tanabe K Shimmura H et al.Outcome of interferon-alpha treatment in hemodialysis patients and renal transplant recipients with chronic hepatitis C (abstract 493).Am J Transplant. 2002; 2: 261Google Scholar) which reported a > 60% hepatitis C clearance by HCV RNA PCR when patients were treated with interferon prior to kidney transplant. The reason for a greater degree of success in uremic patients awaiting kidney transplantation is unclear, but may relate to differences in the metabolism of the interferon. Successful therapy prevented hepatitis C-associated glomerulonephritis in the transplanted kidney. It should be noted that it was important that patients underwent interferon therapy prior to transplantation, as post-transplant therapy was associated with increased incidences of rej