Multiple Organ Transplantation Research Articles

The Ethics of Organ Transplantation: Shortages and Strategies

1 Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2 Chen Su Lan Centennial Professor of Medical Ethics, Director of the Centre for Biomedical Ethics, Singapore Address for Correspondence: Mr Voo Teck-Chuan, Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, Block MD 11, #02-04, Clinical Research Centre, 10 Medical Drive, Singapore 117597 Email: medvtc@nus.edu.sg Introduction One of the most significant advances in critical care medicine during the last 40 years is the development of organ transplantation. Successful transplantations give patients with otherwise untreatable degenerative diseases a new lease on life, or enable them to lead a more fulfilling or productive existence. In cases such as renal failure, transplantation offers patients a better clinical outcome than other treatment options such as dialysis; being more cost-effective, it may also free up much needed resources for other healthcare areas.1 However, these benefits have not been maximised due to the persistent shortage of organs available for transplants. Even so, more and more patients are being considered for transplantation because of advances in technologies and immunosuppression, the relaxation of eligibility criteria for waiting list consideration, and the rising incidence of organ diseases and failures in ageing populations. Repeat and multiple organ transplants have also increased. As in many other countries, demand in Singapore has far outpaced supply. At the end of 2007, the number of people on the national waiting list for kidney transplantation was 563 but a total of only 46 transplants were performed.2 The waiting time can apparently go up to 9 years.3 Such circumstances invite an “ethics of triage” in which decisions about allocation become decisions about who will die and who will live. The trope of an “organ crisis” thus appears frequently in the bioethics literature and in media around the world. This has been resisted by some commentators for obscuring the reality of gradual but definite strides in medical progress, and more importantly, for prompting the implementation of initiatives to increase the number of organs procured from both deceased and living persons with less than desired forethought to potential ethical problems or pitfalls.4 The purpose of this paper is to highlight and comment on the ethical issues and dilemmas raised by some of the strategies implemented or proposed to address the inadequate supply of organs for transplantation, namely the use of (a) an opt-out (or presumed consent) system; (b) donation after controlled cardiac death; (c) extended criteria for deceased donors; and (d) financial inducement in live kidney donation. The aim is to inform and stimulate discussion and debate on moving forward with ethically responsible (or at least acceptable) organ procurement practices in the Singapore context.

Fluid Management of Patients Undergoing Intestinal and Multivisceral Transplantation

Small bowel transplantation can be associated with large fluid shifts due to massive blood loss, dehydration, vascular clamping, long ischemia times, intraoperative visceral exposure, intestinal denervation, ischemic damage, and lymphatic interruption. Fluid management is the major intra- and postoperative problem after small bowel and multiple organ transplantation, because of the highly variable fluid and electrolyte needs of the transplant recipient. Third-space fluid requirements can be massive; inadequate replacement leads to end-organ dysfunction, particularly renal failure. Several liters of fluid may be required in the initial 24 to 48 hours postoperatively to simply maintain an adequate central pressure to provide a satisfactory urine output. During this time patients may develop extensive peripheral edema, which dissipates over the next few days as the fluids are mobilized and requirements stabilize. Based on our experience in 29 cases of intestinal transplantation and 4 cases of multivisceral transplantation, we have herein described the intraoperative fluid management and hemodynamic changes. Our study confirmed a large quantity of fluid administration during and after small bowel transplantation that required adequate volume monitoring.

Liver Transplantation for Hepatocellular Carcinoma: Impact of the MELD Allocation System and Predictors of Survival

Since February 27, 2002, patients with early-stage hepatocellular carcinoma (HCC) have received priority for liver transplantation in the United States under the Model for End-Stage Liver Disease (MELD) allocation system. We aimed to determine the impact of this system on liver transplantation for HCC. Data were provided by the United Network for Organ Sharing on 19,404 first-time, cadaveric, adult liver transplantations performed in the United States between 2002 and 2007 and 15,906 performed between 1997 and 2002, an equal-duration period immediately preceding the MELD allocation system. In 1997-2002, 4.6% of liver transplant recipients had HCC compared with 26% in 2002-2007, the majority of whom received "HCC-MELD-exceptions" allowing expedited transplantation. Posttransplantation survival of patients with HCC without an "HCC-MELD-exception" was significantly worse than the survival of patients without HCC. In 2002-2007, patients with an "HCC-MELD-exception" had similar survival to patients without HCC. However, for the subgroup of patients with tumors 3-5 cm in size had significantly worse survival. When compared with patients with similar MELD scores, patients in the "HCC-MELD-exception" group had worse posttransplantation survival than patients without HCC. The most important predictors of poor posttransplantation survival were MELD score >/=20 (hazard ratio, 1.61; 95% CI: 1.3-2.1) and serum alpha-fetoprotein level >/=455 ng/mL (hazard ratio, 2.15; 95% CI: 1.5-2.0). The adoption of the MELD allocation system has led to a 6-fold increase in the proportion of transplantation patients with HCC. Patients with larger (3-5 cm) tumors, serum alpha-fetoprotein level >/=455 ng/mL, or a MELD score >/=20 have poor posttransplantation survival.

FTY720, a New and Alternative Strategy for Treating Blast Crisis CML and Ph1 ALL Patients.

Abstract Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome positive (Ph1) acute lymphoblastic leukemia (ALL) are two fatal BCR/ABL-driven leukemias against which the current therapy with Abl kinase inhibitors fails to induce a long-term response, as the majority of patients are either refractory or relapse after a few months of treatment. We recently reported that functional loss of the PP2A tumor suppressor occurs during CML disease progression and that restoration of PP2A activity impairs in vitro and in vivo BCR/ABL leukemogenesis. Here we assessed the therapeutic potential of the PP2A activator FTY720 in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. FTY720 (500 nM-2.5 mM) induces caspase-dependent apoptosis (70–98% annexin V+) and impairs the clonogenic potential (70–95% inhibition) of imatinib/dasatinib-sensitive and -resistant (T315I) p210 and p190 BCR/ABL-expressing myeloid and lymphoid progenitor cell lines (Ph1 K562, 32D-p210BCR/ABL, 32D-p210(T315I)BCR/ABL and BaF3-p190BCR/ABL), respectively, and of primary bone marrow CML-BCCD34+ (n=11) and Ph1 ALLCD34+/CD19+ (n=12) patients cells. Interestingly the cytokine (IL-3 or IL-7)-dependent growth and differentiation of normal CD34+ myeloid and CD34+/CD19+ lymphoid progenitors (n=8) is not affected by FTY720 treatment. Furthermore, pharmacologic doses of FTY720 markedly suppress leukemogenesis in SCID mice (n=13 per group) transplanted with myeloid and lymphoid progenitor cells transformed with p210BCR/ABL and p190BCR/ABL, respectively. In fact, the median survival has not yet been reached in FTY720-treated (10 mg/kg/day) BCR/ABL+ cell-injected mice. Conversely, all of untreated 32D-p210BCR/ABL, 32D-p210BCR/ABL(T315I) and BaF3-p190BCR/ABL leukemic mice died of an overt acute leukemia-like process with a median survival of 4.3, 4.8 and 4.1 weeks, respectively (P<0.001). After 11 weeks of FTY720 treatment, 80% and 90% of p210 and p190 mice, respectively, were alive and in molecular remission. Moreover, long-term (189 days) FTY720 daily administration (10 mg/kg/day) did not induce any adverse effect, and achieved sustained absence of BCR/ABL+ cells (assessed by nested RT-PCR) in 50% of mice transplanted with myeloid progenitors expressing the imatinib/dasatinib-resistant T315I p210BCR/ABL mutant. Mechanistically, the anti-leukemic effects of FTY720 are sphingosine 1-phosphate receptor 1 (SIP1)-mediated and dependent on the ability of FTY720 to activate PP2A phosphatase. That, in turn, inhibits the activity and expression of wild type and mutant p210 and p190 BCR/ABL oncoproteins and important regulators (e.g. Akt) of malignant cell survival and proliferation. Altogether, these results not only reinforce the importance of the PP2A tumor suppressor in the biology of Ph1 leukemias but, because FTY720 has been shown to be feasible in Phase I-III clinical trials for multiple sclerosis or solid organ transplant patients, they strongly support the use of this PP2A activator as a novel therapeutic approach for CML-BC and Ph1 ALL.

Intestinal Replacement Therapy: Timing and Indications for Referral of Patients to an Intestinal Rehabilitation and Transplant Program

Current treatment options for patients suffering from intestinal insufficiency include all forms of intestinal replacement therapy (IRT). Parenteral nutrition has achieved extended success for the majority of patients requiring interval treatment, however, complications leading to failure of this treatment increases with the duration of therapy. There is currently no consensus as to the appropriate timing for transplantation of the intestine or the timing of referral for evaluation at a center experienced with this therapy. Certain patient characteristics warrant evaluation. Those patients with no jejunoileum who have guaranteed lifelong parenteral dependence, both adult and pediatric, should be immediately referred to a transplant center due to the high likelihood of the development of liver disease. Patients with metastatic infectious complications from catheter sepsis, patients with cholestasis seen intermittently with sepsis episodes, patients who are not successfully weaning and who demonstrate progressive thrombocytopenia, and patients with motility disorder experiencing deterioration should also warrant early referral to an intestinal rehabilitation and transplant program. The objective of evaluation is to maximize the opportunities for rehabilitation while not missing the critical window of opportunity for successful transplantation when needed. We favor an aggressive directed approach to rehabilitation, coupled with psychological preparation for both transplantations and other options. Early referral requires trust between the patient, referring physician, and the transplant team to assure that a rush to judgment will not lead to a premature transplant. The current wait list mortality is high, mandating early referral and listing with an approach aimed at maximizing both the success of gastrointestinal support, as well as of transplantation when necessary.

Role of the Urban Academic Medical Center in US Health Care

MEDICAL SCHOOLS AND AFFILIATED TEACHING hospitals (academic medical centers) in the United States educate and train physicians and other health professionals, perform the majority of National Institutes of Health–sponsored biomedical research, treat the sickest and most debilitated patients, and deliver substantial health care to the poor. The ability of academic medical centers to perform these vital health care roles is threatened by stagnating National Institutes of Health support for research, declining insurance reimbursement rates, skyrocketing malpractice insurance costs, a crisis in government health care programs, and an expanding population of uninsured and underinsured patients needing care. These threats are particularly acute for academic medical centers located in urban areas; many of these centers are surrounded by dense populations of economically marginalized and low-income individuals. Some would argue that these urban medical centers are logically bound to provide all care, including routine primary care, to the surrounding neighborhood. This argument is overly simplistic and may ignore the existence of important communitybased health care assets. University-based urban academic medical centers, in particular those without affiliated safety-net hospitals, function most effectively and for the greater good when their care is a complement to, and not a substitute for, community health care providers (ie, centers and clinicians). Academic medical centers excel at delivering highly specialized and complex care. Multiple organ transplants, intricate cardiac surgery, minimally invasive robotic surgery, and cutting-edge clinical trials are examples of highly advanced medical care concentrated in clinical facilities owned by or associated with US medical schools. A reasonable ethical argument is that this type of specialized care should be broadly allocated to all who need it most: not only those in the area immediately surrounding the institution but also those living some distance away who do not have local access to such a facility. This argument logically forces a redefinition of what the term “community” really means. The community served by an urban academic medical center should not be thought of as solely the population geographically surrounding the center but rather must include a much broader population—the local neighborhood, the city, the suburbs, the home state, and the region—incorporating all patients most in need of the complex specialized care academic medical centers provide. This argument does not depend on defining groups by ability to pay or type of insurance; rather, it defines groups by the complexity of disease and the corresponding requirement for a facility dedicated to, and capable of, treating patients with such illnesses. As the capacity of academic medical centers to deliver complex care continues to evolve, so too does the cost to deliver it. On average, hospitals that are components of academic medical centers spend 60% more per patient day than community hospitals, reflecting the simultaneous training of physicians, the pursuit of clinical research, and the capital-intensive concentration of highly sophisticated medical technology. As a consequence of these high costs, academic medical centers are not as efficient as lower-cost health centers in delivering routine care. From a purely economic standpoint, this cost disadvantage argues for an exclusive focus on specialized, complex care so that the resource of such high-intensity centers be available to all those who truly need it. When the urban academic medical center becomes the major source for the provision of routine care for the immediate neighborhood, the health status of the neighborhood may erode rather than improve as the academic center competes with other neighborhood health care centers. This is a particularly acute problem for organizations such as Federally Qualified Health Centers, which are provided a competitive advantage through governmental financial incentives to provide primary care to inner-city patients. When urban academic medical centers directly compete with Federally Qualified Health Centers, either through lack of appreciation of their existence or through advertising that inadvertently stimulates patients to bypass local health care centers, academic centers can drive these clinical care centers out of business. This in turn detracts from the neigh-

Short‐term postliver transplant survival after the introduction of MELD scores for organ allocation in the United States

It has been suggested that the introduction of model for end-stage liver disease (MELD) for organ allocation may reduce overall graft and patient survival since elevated serum creatinine is an important predictor of poor outcome after liver transplantation. In this study, we determined the outcomes of liver transplantation before (PreMELD group, 1998-February, 2002) and after (MELD group, March-December, 2002, n = 4642) the introduction of MELD score, and examined the impact of MELD scores on the outcome in the United States (US). After excluding patients for a variety of reasons (children, live-donor, fulminant liver failure, patients with hepatoma and others who received extra MELD points, multiple organ transplantation, re-transplantation, incomplete data), there were 3227 patients in the MELD group. These patients were compared with 14,593 patients in the preMELD group after applying similar exclusion criteria. The survival was compared using Kaplan-Meier survival analysis and Cox regression survival analysis. There was no difference in short-term (up to 10 months) graft and patient survival between MELD and preMELD groups. However, graft and patient survival was lower in patients with MELD score > or = 30 when compared with those with MELD score <30 after adjusting for the confounding variables. Introduction of MELD score for organ prioritization has not reduced the short-term survival of patients, but patients with MELD score of 30 or higher had a relatively poor outcome.

Expanding the donor pool: use of renal transplants from non‐heart‐beating donors supported with extracorporeal membrane oxygenation

In response to organ shortage, we used the renal grafts from non-heart-beating donors (NHBDs). Extracorporeal membrane oxygenation (ECMO) was used to maintain NHBDs before organ procurement. We compared the results of renal transplantation from different donors, including heart-beating donors (HBDs), living-related donors (LDs), and NHBDs supported with ECMO. From February 1998 to June 2003, we recruited 219 patients receiving renal transplantation at National Taiwan University Hospital. Among them, 31 received kidneys from NHBDs supported with ECMO, 120 from HBDs, and 68 from LDs. Multiple organ transplant recipients were not included in this study. We compared the graft survival, serum creatinine levels, and estimated glomerular filtration rates of the three groups. The rate of delayed graft function was higher in NHBD recipients (41.9%) than in HBD recipients (27.0%) and LD recipients (10.9%) (p = 0.003). In the NHBD group, the recipients of grafts with delayed function had significantly longer ECMO runs (63.1 +/- 3.0 min) than those without delayed function (53.7 +/- 2.5 min) (p = 0.024). Estimated glomerular filtration rate (p = 0.472) and mean serum creatinine level (p = 0.286) were not significantly different between the three groups using a longitudinal approach. The 5-yr graft survival rates for NHBD (88.4%, 95% CI: 0.680-0.962), HBD (83.2%, 95% CI: 0.728-0.899), and LD transplant recipients (89.3%, 95% CI: 0.619-0.974) were not significantly different (p = 0.239). The 5-yr patient survival rates for NHBD, HBD, and LD transplant recipients were 100, 93.0 (95% CI: 0.859-0.966) and 100% respectively. The long-term allograft survival and function of kidneys from NHBDs supported by ECMO, HBD, and LD did not differ significantly. Long ECMO running time tended to delay graft function.

A Multicenter Pilot Study of Early (4-Day) Steroid Cessation in Renal Transplant Recipients Under Simulect, Tacrolimus and Sirolimus

This study presents the first prospective multicenter study assessing sirolimus-based immunosuppression with early (4-day) corticosteroid withdrawal (CSWD) in renal transplantation. Immunosuppression included: anti-IL-2 receptor antibody and tacrolimus/sirolimus. Inclusion criteria included adult primary recipients. Exclusion criteria included: (i) African Americans, (ii) current PRA >50%, (iii) multiple organ transplants, (iv) WBC < 3000 cells/microL and (v) fasting hypercholesterolemia/hypertriglyceridemia. The primary endpoints were acute rejection and the proportion of patients off corticosteroids. Seventy-seven patients were enrolled: mean age of 49.7 +/- 12 years. Transplants included: cadaveric (26%) and living donor (74%). Patient and graft survival were 100%. Biopsy proven acute rejection occurred in 13%; presumptive rejection in 10.5%. Banff grades included: IA (seven patients), IB (one patient), IIA (one patient) and IIB (one patient). Renal function at 1 year: serum creatinine (1.18 +/- 0.06 mg/dL). Mean weight gain was minimal at 1 year: 3 +/- 2 kg/patient. Mild increases in total, LDL and HDL cholesterol were observed and new antilipid agent use occurred in 26 patients. In conclusion, early CSWD under tacrolimus/sirolimus-based immunosuppression in selected, low-risk renal transplant recipients provides: (i) excellent patient and graft survival, (ii) good renal function, (iii) reduced hyperlipidemia and antilipid agent use and (iv) low acute rejection rates.

PG490-88, a new immunosuppressant, effectively prevents acute and chronic rejection in rat renal allografts

PG490-88 is a semisynthetic derivative of the novel compound PG490 (triptolide) purified from a Chinese herb. It has been shown to prolong acute allograft survival in multiple experimental organ transplant models. However, the effect of PG490-88 on prevention of acute and chronic renal allograft rejection has not been determined. Kidneys of ACI or F344 rats were transplanted into bilaterally nephrectomized LEW recipients as the acute or chronic allograft rejection models, respectively. Treatment of LEW recipients with PG490-88 significantly prolonged ACI kidney graft survival in a dose-dependent manner when compared with the untreated allograft controls. LEW recipients of F344 kidney grafts who received PG490-88 for 90 days with a brief course of low-dose FK506 showed normal serum creatinine levels and markedly reduced histological changes of chronic rejection at day 90 after transplantation. These results suggest that PG490-88 significantly prolongs kidney allograft survival in an acute rejection model and prevents chronic allograft rejection in rats.

Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3

The chemokines (CXCL9, CXCL10 and CXCL11) and associated CXCR3 receptor are expressed during the inflammatory process from multiple sclerosis, atherosclerosis or organ transplantation resulting in the recruitment of lymphocytes leading to tissue damage. It is hypothesized that blocking of the ligand/CXCR3 receptor interaction has potential to provide opportunity for development of agents that would block tissue rejection. In this paper, four classes of natural product inhibitors (IC50 ranging 0.1-41 microM) have been described that block the CXCR3 receptor interaction of IP-10 ligand. These include a cyclic thiopeptide (duramycin), polyketide glycosides (roselipins), steroidal glycosides (hypoglausin A and dioscin) and a novel alkyl pyridinium alkaloid that were isolated by bioassay-guided fractionation of the organic extracts derived from actinomycete, fungal, plant and marine sources and discovered using 125I IP-10/CXCR3 binding assay. Duramycin was the most potent with an IC50 of 0.1 microM. Roselipins 2A, 2B and 1A showed IC50 values of 14.6, 23.5, and 41 microM, respectively. Diosgenin glycosides dioscin, hypoglaucin A and kallstroemin D exhibited IC50 values of 2.1, 0.47 and 3 microM, respectively. A novel cyclic 3-alkyl pyridinium salt isolated from a sponge displayed a binding IC50 of 0.67 microM.

INFLUENCE OF EARLY (5 DAY) CORTICOSTEROID CESSATION ON WOUND COMPLICATIONS ASSOCIATED WITH SIROLIMUS: 1 YEAR RESULTS FROM A MULTICENTER TRIAL

P304 Aims: Sirolimus and corticosteroids have been associated with an increased risk of wound healing complications. The promise of new available immunosuppressive drugs have inspired protocols that eliminate corticosteroids in the early posttransplant period. The purpose of this study was to evaluate the influence of early (5 day) corticosteroid cessation (ECSC) on wound healing complications associated with sirolimus (SRL) therapy in kidney transplant recipients. Methods: The study was a single limb, open label, multicenter (8 sites) pilot study. Inclusion criteria included: 1) age>18 yr, 2) primary transplant recipient. Exclusion criteria included: 1) African Americans, 2) current PRA>50%, 3) multiple organ transplant, 4) WBC<3000/ul, 5) fasting hypercholesterolemia or hypertriglyceridemia. Immunosuppression included: 1) Simulect 20 mg post transplant day (PTD) 0, 4, 2) tacrolimus 0.05 mg/kg/d target level 6-9 ng/ml PTD 1-30, then 4-8 ng/ml, 3) sirolimus 15 mg PTD 1; 10 mg PTD 2,3; 6 mg PTD 4 then adjust to level 8-15 ng/ml, 4) Solumedrol PTD 0-4 250, 250, 125, 65, 30 mg, DC. Results: 77 pts were enrolled. Data was available on wound complications in 77 pts. The following table presents the incidence of wound complications and demographic features of those pts.FigureConclusions: ECSC (5 day) under simulect, tacrolimus, and sirolimus results in: 1) a lower incidence of lymphocele formation (7.8%) than is reported in SRL/CS based immunosuppression regimens (8-20%), 2) a low incidence of wound abscesses. ECSC appears to offer a promising approach for avoiding wound complications associated with SRL therapy.

Transmission of Donor Melanoma to Multiple Organ Transplant Recipients

Malignant melanoma represents the most common tumour responsible for donor-derived post transplantation malignancies. We report the varied presentation and outcome of three graft recipients (two kidney and hepatic) who developed metastatic melanoma following cadaveric organ transplantation from a single multiorgan donor. Two of the recipients presented with symptomatic metastatic lesions and the third patient, despite being carefully monitored, developed evidence of metastatic cutaneous melanoma. Two of the patients died as a direct result of their melanomas. The recipients of corneal and cardiac grafts remain disease-free. We conclude that despite careful screening, donor-derived tumours remain a not uncommon clinical entity. The identification of a lesion in one recipient should prompt immediate examination and investigation of the remaining recipients of multiorgan donations.

Graft and patient survival after adult live donor liver transplantation compared to a matched cohort who received a deceased donor transplantation.

Live donor liver transplantation (LDLT) has become increasingly common in the United States and around the world. In this study, we compared the outcome of 764 patients who received LDLT in the United States and compared the results with a matched population that received deceased donor transplantation (DDLT) using the United Network for Organ Sharing (UNOS) database. For each LDLT recipient (n = 764), two DDLT recipients (n = 1,470), matched for age, gender, race, diagnosis, and year of transplantation, were selected from the UNOS data after excluding multiple organ transplantation or retransplantation, children, and those with incomplete data. Despite our matching, recipients of LDLT had more stable liver disease, as shown by fewer patients with UNOS status 1 or 2A, in an intensive care unit, or on life support. Creatinine and cold ischemia time were also lower in the LDLT group. Primary graft nonfunction, hyperacute rejection rates, and patient survival by Kaplan-Meier analysis were similar in both groups (2-year survival was 79.0% in LDLT vs. 80.7% in case-controls; P = .5), but graft survival was significantly lower in LDLT (2-year graft survival was 64.4% vs. 73.3%; P < .001). Cox regression (after adjusting for confounding variables) analysis showed that LDLT recipients were 60% more likely to lose their graft compared to DDLT recipients (hazard ratio [HR] 1.6; confidence interval 1.1-2.5). Among hepatitis C virus (HCV) patients, LDLT recipients showed lower graft survival when compared to those who received DDLT. In conclusion, short-term patient survival in LDLT is similar to that in the DDLT group, but graft survival is significantly lower in LDLT recipients. LDLT is a reasonable option for patients who are unlikely to receive DDLT in a timely fashion.

Study 1: a prospective, randomized, double-blind, multicenter trial of early (7-day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy under tacrolimus and mycophenolate mofetil therapy with antibody induction

M odern corticosteroid therapy for prevention and treatment of rejection continues to be associated with significant morbidity. To date, only 3 randomized, double-blind, placebo-controlled trials of corticosteroid withdrawal (CSWD) have been conducted in renal transplantation. These trials, however, all evaluated withdrawal at 3 months and beyond, and antibody induction therapy was not standardized among centers. The current study is the first randomized, double-blind, placebo-controlled CSWD trial that includes corticosteroid cessation before 3 months after transplantation, as well as standardized antibody induction therapy. The study was designed as a 2-limb study with 1:1 enrollment to either early (7-day) CSWD or longterm corticosteroid maintenance therapy (taper to 5 mg/d by 6 months after transplantation). Inclusion criteria included primary cadaveric and live donor renal transplant patients aged 18 to 70 years. Exclusion criteria included peak panel reactive antibody 50%, current panel reactive antibody 25%, repeat transplant, and multiple organ transplant. The primary end point was treatment failure defined as death, graft loss, or moderate acute rejection (by Banff criteria and treatment) at 6 months and years 1 to 5. Secondary end points included Framingham cardiac risk estimates at 6 months and years 1 to 5, acute rejection, study drug discontinuation, posttransplant diabetes, weight, infection, and malignancy. Patients received tacrolimus (target, 10-20 ng/mL on posttransplant days 1-90; 5-15 ng/mL after posttransplant day 90) and mycophenolate mofetil (2 g/d). Induction therapy was varied by center with interleukin 2 receptor (IL-2R) antibody or Thymoglobulin (1.5 mg/kg 4 doses) (IMTIX-SangStat, Lyon, France). Patients with a decrease in creatinine level of 30% by posttransplant day 3 were randomized either to stop corticosteroids on posttransplant day 7 or to receive long-term corticosteroids. Longterm corticosteroids were given at 5 mg/d after posttransplant day 180. To assess long-term graft survival and cardiac risk, blinding is planned for 5 years. The study included 396 patients who were enrolled before October 2002. Data presented are blinded data from 176 patients. Follow-up lengths included 12 months in 67% of patients, 6 months in 10%, and 3 months in 23%. Eight percent of patients withdrew from the study. Mean age was 46 12 years; 70% of patients were male, 65% white, 25% African American, 45% cadaveric recipients, and 25% had diabetes before transplantation. Mean number of human leukocyte antigen mismatches per patient was 3.3; 94% of patients had current panel reactive antibody 10%. Mean cold ischemia time was 18.8 6.6 hours, 59% received Thymoglobulin induction, and 41% received IL-2R antibody. Biopsyproven acute rejection occurred in 8% of patients, From the Division of Transplantation, Cincinnati, OH; and Fujisawa Healthcare, Inc, Deerfield, IL. The Fujisawa Steroid Withdrawal Study Group consists of the following: E. Steve Woodle, William Fitzsimmons, John D. Pirsch, Fuad Shihab, Osama Gaber, Laurence Chun, Mark Stegall, Alan Langnas, Jonathan Bromberg, Okechukwu Ojogho, Kenneth Washburn, Kristene Gugliuzza, Ravi Parasuraman, Oleh G. Pankewycs, Eugene Schweitzer, John Sorenson, Christopher Johnson, George Loss, George Francos, Paul Morrissey, Raphael Mendez, David Shaffer, Sandip Kapur, J.R. Thistlethwaite, Richard Freeman, Nasimul Ahsan, Thomas Johnston, Arthur Matas, Donald Hricik, Sameh Abul-Ezz, and Rita Alloway. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.028

Renal transplantation in children with lupus nephritis

This study was conducted to determine renal allograft and patient survival for children with lupus nephritis compared with pediatric allograft recipients with other causes of end-stage renal disease. Data from the United Network for Organ Sharing registry for children aged 1 to 21 years who received an initial renal transplant between 1987 and 1997 were included. Subjects with kidney failure caused by other vasculitides were excluded, as were those with multiple organ transplants. A total of 7,926 children (n = 254 children with lupus) were available for evaluation. Patients with lupus were older (median age, 19 versus 15 years; P < 0.01) and more commonly female (80% versus 40%; P < 0.01) and black (34% versus 20%; P < 0.01) than patients without lupus. Median follow-up was 4.2 years (range, 0.03 to 13 years). Renal allograft survival was not different between groups when adjusting for sex, race, age, and cadaveric (CAD) transplant (P = 0.98). Among patients with lupus, those with CAD allografts were 1.9 times (95% confidence interval [CI], 1.1 to 3.3; P = 0.02) more likely to lose their graft than those with living donor grafts. This increased risk for graft failure with CAD transplants was observed to a lesser degree in subjects without lupus (hazard ratio, 1.3; 95% CI, 1.2 to 1.5). Patients with lupus were 1.8 times more likely to die compared with patients without lupus in multivariate analysis (95% CI, 1.14 to 2.74; P = 0.01). Although allograft survival is not different, patient survival after renal transplantation is less for pediatric patients with lupus compared with other pediatric renal allograft recipients.

無酸素／再酸素化により誘導される白血球と血管内皮細胞の相互作用

It has long been recognized that the microvasculature is exquisitely sensitive to ischemia/reperfusion (I/R) and that hyperadhesiveness of leukocytes to endothelial cells contributes to I/R-induced tissue injury. The phenomenon of I/R has been implicated in the microvascular and parenchymal cell injury associated with several pathological conditions, including gastric ulcer formation, multiple organ failure, cancer metastasis, and organ transplantation. In an effort to define the mechanisms responsible for reperfusion-induced vascular injury, a number of in vitro models have been developed to simulate the responses of endothelial cells to I/R. Due to its simplicity, many investigators have employed monolayers of cultured endothelial cells exposed to anoxia, followed by reoxygenation (A/R) as a model system to mimic I/R-induced vascular changes in vivo. This review will provide an overview of our current understanding of leukocyte-endothelial cell interactions derived from in vitro studies of endothelial cell monolayers exposed to anoxia/reoxygenation, with specific emphasis on the molecular determinants mediating this inflammatory process and the contribution of reoxygenationinduced oxidative stress to the activation of NF-kB and the expression of endothelial surface adhesion molecules.

Outbreak of Pseudomonas aeruginosa via multiple organ transplantation from a common donor

Outbreak of Pseudomonas aeruginosa via multiple organ transplantation from a common donor

Perspective: The Ethics of Multiple Vital Organ Transplants

In September 2001, the British medical journal Lancet published a retrospective report of nine British patients who received combined heart-lung-liver transplants between 1986 and 1999.1 In each of these cases, three vital organs went to a single recipient when they might otherwise have gone to as many as four. This kind of transplantation works against the received wisdom that transplantation works best when focused on a single vital system or at least no more than two. According to the study, four of the recipients lived no longer than four months after the transplant, three died after a period of years (2.5, 7.5, and 12), and two were still alive at the time of the report. The authors believe that different approaches could help control the infection that caused most of the sickness and death in the cases reviewed. Because five patients survived beyond the immediate posttransplant period for a time measurable in years, the authors recommend the procedure for patients of a certain kind, especially since it does not require new skills for experienced transplant teams. The procedure does require more organs, however, and not only for this reason raises many ethical questions that should be addressed before transplantation of this kind continues on any large scale. The report contains no information about how consent was obtained f om patients involved in this procedure. One hopes ha the informed consent procedure fully emphasized the risks of the intervention. Especially for these early attempts, on hopes that the experimental nature of the procedure was emphasized. Of course, in the United States, federal regulations do not require that physicians obtain prior review and approval for clinical innovations aimed at the care of a particular patient. This means that physicians in this kind of situation are under no obligation to submit their informed on ent process to the scrutiny of others. While the Belmont Report was not written for a British audience, its counsel is nonetheless wise about clinical innovat on. That 1976 report recommends that radical innovations should be made the object of formal investigation as soon as practical after first being tried. It seems to me that the time is more than ripe to treat multiple organ transplant as experim ntal in a formal sense and to subject it to scrutiny in regard to its procedures and informed consent process. I say this not to cast any aspersions on the practices of the physicians who were involved in the cases reported, about which no information is available. I say this because institutional review boards can, on balance, offer important assistance both

Sildenafil citrate: lessons learned from 3 years of clinical experience.

In the 3 y since its initial approval, sildenafil has become the most widely used treatment for erectile dysfunction (ED) and has been prescribed to more than 13 million patients worldwide. Significant improvements in erectile function have been demonstrated in double-blind, placebo-controlled studies in diverse patient populations. A significant treatment effect has been shown with sildenafil in men with ED and a history of diabetes, cardiovascular disease, minor depression, spinal cord injury and multiple sclerosis. In addition, promising results have been shown in patients with treated prostate cancer, end-stage renal disease, Parkinson's disease and spina bifida and in multiple-organ transplant recipients. Postmarketing data of the use of sildenafil in clinical practice confirm the efficacy and safety found in clinical trials and high satisfaction with treatment. Public awareness of the common occurrence of ED and the high likelihood of a potentially favorable response to an oral treatment increased dramatically with the introduction of sildenafil. Physicians, however, are still not comfortable with ED management, which negatively affects pharmacotherapy response rates and patients' compliance to treatment. Continuing medical education seems mandatory to overcome existing problems in ED management.