When the living and the deceased cannot agree on organ donation: a survey of US organ procurement organizations (OPOs).

The legal concept of first person authorization (FPA) is based on the principle that a decision by a person with decision-making capacity should be respected even after he or she dies. Although the transplant community largely supports this concept, its implementation has not been universal. We conducted a web-based survey of all 58 Organ Procurement Organization (OPO)executive directors in the United States to assess OPOs' procurement policies and practices in the context of family objections. All 58 respondents(100%) responded to our survey. All OPOs except one have an online donor registration website. Most OPOs(89%) (51 of 57 respondents) estimated that the frequency of family objecting to organ donation in cases of registered donors was <10%. No OPOs reported the frequency to be higher than 25%. Only 50% (27 of 54) of the OPOs have a written policy on handling family objections. Approximately 80% of the OPOs reported honoring FPA. However, in the past 5 years, 20 OPOs (35%) have not yet participated in organ procurement from a registered deceased donor over family objection. Further research to identify the barriers and possible solutions to implementing FPA is warranted.

A K-nearest neighbors survival probability prediction method.

We introduce a nonparametric survival prediction method for right-censored data. The method generates a survival curve prediction by constructing a (weighted) Kaplan-Meier estimator using the outcomes of the K most similar training observations. Each observation has an associated set of covariates, and a metric on the covariate space is used to measure similarity between observations. We apply our method to a kidney transplantation data set to generate patient-specific distributions of graft survival and to a simulated data set in which the proportional hazards assumption is explicitly violated. We compare the performance of our method with the standard Cox model and the random survival forests method.

Equal Opportunity Supplemented by Fair Innings: equity and efficiency in allocating deceased donor kidneys.

For 7 years, the Kidney Transplantation Committee of the United Network for Organ Sharing/Organ Procurement Transplantation Network has attempted to revise the kidney allocation algorithm for adults (≥18 years) in end-stage renal disease awaiting deceased donor kidney transplants. Changes to the kidney allocation system must conform to the 1984 National Organ Transplant Act (NOTA) which clearly states that allocation must take into account both efficiency (graft and person survival) and equity (fair distribution). In this article, we evaluate three allocation models: the current system, age-matching and a two-step model that we call "Equal Opportunity Supplemented by Fair Innings (EOFI)". We discuss the different conceptions of efficiency and equity employed by each model and evaluate whether EOFI could actually achieve the NOTA criteria of balancing equity and efficiency given current conditions of growing scarcity and donor-candidate age mismatch.

Effect of class II antigen matching on renal allograft survival in miniature swine.

The benefit of class II major histocompatibility complex (MHC) antigen matching to renal allograft survival, in the absence of immunosuppression, has been studied in partially inbred miniature swine. Permanent (greater than 6 mo) renal allograft survival was found in 30% of recipients of either class II only or fully matched grafts. Analysis of the survival of the class II-only matched grafts by specific recipient/donor haplotype combinations indicated that survival was regulated by at least three genetic factors, including antigen gene dose, a class I MHC allele-dependent effect, and non-MHC-linked immune response phenomenon. Animals accepting class II-matched kidneys developed spontaneous tolerance to the graft, despite mounting an initial immune response marked by renal damage and the development of serum cytotoxic antibodies directed at the donor MHC antigens. The antibodies were only of the IgM class, suggesting that conversion of the humoral response to IgG was blocked. After acceptance of the kidney, three out of five animals showed specific prolongation of donor skin grafts. At the time of rejection of these skin grafts, no decrease in renal function nor reappearance of anti-donor antibodies was observed.

How different conceptions of risk are used in the organ market debate.

The success of kidney and liver transplantation is hindered by a shortage of organs available for transplantation. Although currently illegal in nearly all parts of the world, a living 'donor' or 'vendor' kidney market has been proposed as a means to reduce or even end this shortage. Physician members of the American Society of Transplantation, the American Society of Transplant Surgeons and the American Association for the Study of Liver Disease were surveyed regarding organ markets for both living kidney and living liver transplantation. The survey queried respondents about their attitudes toward directed living donation, nondirected living donation, the potential legalization of living donor organ markets and the reasons for their support or opposition to organ markets. Partial or completed surveys were returned by 346 of 697 eligible respondents (50%). While virtually all supported or strongly supported directed living donation (98% and 95% for kidney and liver lobes, respectively), the vast majority disagreed or strongly disagreed with the legalization of living donor organ markets (80% for kidneys and 90% for liver lobes). Both those who support and those who oppose a legalized living donor organ market rate risk to the donor among the most important factors to justify their position.

Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg.

Antigen-specific T cell activation depends on T cell receptor-ligand interaction and costimulatory signals generated when accessory molecules bind to their ligands, such as CD28 to the B7 (also called BB1) molecule. A soluble fusion protein of human CTLA-4 (a protein homologous to CD28) and the immunoglobulin (lg) G1 Fc region (CTLA4lg) binds to human and murine B7 with high avidity and blocks T cell activation in vitro. CTLA4lg therapy blocked human pancreatic islet rejection in mice by directly affecting T cell recognition of B7+ antigen-presenting cells. In addition, CTLA4lg induced long-term, donor-specific tolerance, which may have applications to human organ transplantation.

Muscle strength and pressor response.

The purpose of this study was to determine if muscle strength influences the hyperemic response to dynamic exercise. Men with low (n=8) and high (n=9) maximal forearm strength performed dynamic handgrip exercise as the same absolute workload increased in a ramp function (0.5 kg x min (-1)). Forearm blood flow (FBF) was measured instantaneously by ultrasound Doppler and blood pressure was measured by auscultation. The pressor response to exercise was greater (P<0.05) for low strength men at workloads >1.5 kg allowing volumetric FBF (ml x min (-1)) and vascular conductance to increase in proportion to absolute workload similar to high strength men. When FBF was expressed relative to forearm volume (ml x min (-1).100 ml (-1)) the hyperemic response to exercise (slope of relative FBF vs. workload) was greater in low strength men (3.2+/-1.5 vs. 1.7+/-0.4 ml x min (-1).100 ml (-1) x kg (-1), P<0.05) as was relative FBF at workloads >1.5 kg. However, when relative FBF was compared across relative work intensity, no difference was found between low and high strength groups. Together, these findings suggest men with low strength require a greater pressor response to match blood flow to exercise intensity as compared to high strength men.

Insulin secretory profiles and C-peptide clearance kinetics at 6 months and 2 years after kidney-pancreas transplantation.

Glucose, insulin secretion, and insulin secretory pulses were measured by deconvolution of peripheral C-peptide concentrations in 10 IDDM recipients of a combined kidney-pancreas allograft 6 mo post-transplantation and were compared with 10 matched nondiabetic control subjects. Seven of the 10 recipients were restudied 2 yr post-transplantation. To control for immunosuppressive therapy, 6 patients with a kidney allograft also were studied. Pancreatic insulin secretion rates were evaluated over a 24-h period with three mixed meals. Six months post-transplantation, fasting (5.3 +/- 0.1 vs. 5.3 +/- 0.1 mM), average 24-h (6.0 +/- 0.1 vs. 5.7 +/- 0.1 mM), and meal-related (6.1 +/- 0.3 vs. 5.8 +/- 0.2 mM) plasma glucose levels were not different in control subjects and recipients, respectively. Total 24-h insulin secretion rates were similar between the two groups (150 +/- 15 vs. 182 +/- 24 nmol.m-2.24 h-1). However, post-transplantation, the relationship between basal and meal-stimulated insulin secretion was altered with increased basal insulin secretion (52.2 +/- 6.4 vs. 97.4 +/- 12.5 pmol.m-2.min-1, P less than 0.004) and reduced meal-related secretion. The proportion of total 24-h insulin secretion comprised by basal secretion was 44 +/- 4% in the control subjects vs. 73 +/- 5% in recipients. The number of ultradian oscillations of insulin secretion identified in each 24-h period by pulse analysis was similar in control subjects and recipients (11.9 +/- 0.9 vs. 10.4 +/- 0.5 oscillations/24 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreas-graft immunogenicity and pretreatment with anti-class II monoclonal antibodies.

Pretreatment of organ allografts to reduce graft immunogenicity is an attractive and potentially clinically applicable concept. We have studied the effect of perfusing rat pancreases with anti-class II monoclonal antibody (MoAb), to remove class II- positive accessory cells from the intact organ, on prolongation of allograft survival after transplantation. The capacity of pancreatic islets obtained from these perfused organs to stimulate proliferation of allogeneic T-lymphocytes was studied in a mixed islet-lymphocyte culture (MILC). There was a significant prolongation in pancreas-allograft survival when intact pancreases were transplanted after a 3-h normothermic perfusion with MoAb reactive with class II antigens (16.2 +/- 3.6 days, n = 19) compared with control animals (11.0 +/- 1.4 days, n = 24). In vitro treatment of islets with MoAb and complement (CI) inhibited their stimulatory capacity in the MILC, as measured by [3H]thymidine uptake. Similarly, the stimulatory capacity of islets removed from perfused pancreases was also abrogated when MoAb was included in the perfusate. Although reduction in graft immunogenicity, by increasing allograft survival, was achieved by a 3-h pretreatment regimen, it was not sufficient to inhibit rejection altogether in our transplant model.

Oscillatory insulin secretion after pancreas transplant.

In vivo studies of beta-cell secretory function have demonstrated the existence of rapid insulin oscillations of small amplitude recurring every 8-15 min in normal subjects. This study evaluated the effects of pancreas transplant on rapid insulin oscillations. Samples for glucose, insulin, and C-peptide were drawn during constant glucose infusion at 2-min intervals for 90 min from six successful Px patients with type I diabetes mellitus, from six normal nondiabetic control subjects, and from three Kx subjects. A computerized algorithm (ULTRA) was used for pulse detection. In the Px group, the average insulin pulse period was significantly shorter than in both the control and Kx groups (Px 8.1 +/- 0.5, control 12.5 +/- 0.7, Kx 12.4 +/- 0.5 min, P < 0.0005). By contrast, the C-peptide pulse periods (Px 16.8 +/- 2.3, control 14.7 +/- 1.2, Kx 15.3 +/- 1.5 min) were similar in the three groups. Spectral analysis confirmed that the frequency of the insulin pulses was increased in the Px group. The absolute amplitude of the insulin pulses was greater in the Px group (P < 0.001) while the amplitude of the C-peptide pulses did not differ between the groups. Cross-correlation analysis demonstrated maximal correlation coefficients at a lag of 0 min between insulin and C-peptide (control r = 0.33, P < 0.0001; Kx r = 0.17, P = 0.06) and between insulin and glucose (control r = 0.21, P < 0.001; Kx r = 0.20, P < 0.02) in the control and Kx groups, respectively, whereas no significant correlations were observed at any lag in the Px group.(ABSTRACT TRUNCATED AT 250 WORDS)

The correlation between donor characteristics and the success of human islet isolation.

Clinical islet allotransplantation is dependent on the ability to achieve a high yield and purity of islets isolated from human cadaver pancreas donors. The aim of this study was to determine the factors influencing the pancreas prior to islet isolation that may alter yield and purity. The results of 50 consecutive islet isolations from cadaver donor human pancreati at the University of Chicago Medical Center from December 1991 to April 1993 were analyzed. All pancreati were first offered for whole pancreas transplantation before being considered for islet isolation. Human pancreatic islet isolation was accomplished by a modified automated method. Some islet isolations resulted in a high islet yield but low islet purity. Other resulted in well-purified islets, but a low yield. Arbitrarily, successful islet isolation is defined as that yielding over 250,000 islet equivalents (EQN) with a purity of at least 80%. The success rate of human pancreatic islet isolation was 70%. The mean final islet yield obtained from these 50 pancreati was 300,000 +/- 131,000 islet EQN. The mean purity of the final preparation was 73% +/- 25%. By univariate analysis, five factors were found to affect significantly the yield, purity, or overall success rate of islet isolation: organ cold ischemic time, donor age, donor plasma glucose levels, donor body weight, and cause of donor death. Even when islet isolation was successful, the function of islets from hyperglycemic and older donors appear to be impaired both in vitro and in vivo. These results suggest that islet yield and purity are affected by multiple donor-related factors. Even when adequate yield and purity are obtained, islet function is also dependent on donor variables.

Treatment with either anti-CD4 or anti-CD8 monoclonal antibodies blocks alphabeta T cell-mediated rejection of intestinal allografts in mice.

BACKGROUND: Rejection is the major barrier preventing the more widespread application of intestinal transplantation as treatment for intestinal failure. For this study, a one-way host-versus-graft murine model was used to investigate the contribution of T cell subsets to the rejection of allogeneic intestinal allografts. METHODS: Intestinal grafts consisting of the donor jejunum and ileum were procured from C57BL/6J (syngeneic group) and B6C3F1/J (C57BL/6 x C3H/HeJ, allogeneic group) mice. These grafts were then transplanted into (1) normal, (2) antibody-treated, or (3) genetically mutated C57BL/6 mice. Mice were killed at predetermined intervals and the grafts assessed for rejection by a blinded pathologist. RESULTS: No syngeneic mice demonstrated any evidence of rejection. In contrast, the recipients of allografts experienced progressive rejection. Recipient mice treated with tacrolimus developed significantly less severe allograft rejection. None of the alphabeta T cell-deficient recipient mice (T cell receptor beta chain knockout mice) experienced allograft rejection with follow-up ranging from 8 to 28 days. However, mice deficient in gammadelta T cells (T cell receptor delta chain knockout mice) rejected intestinal allografts in a manner indistinguishable from normal recipients. In order to investigate the role of CD4+ and CD8+ T cells, recipient mice were treated 2 days before transplantation with depleting monoclonal antibodies specific for either CD4+ cells or CD8+ cells. Depletion of either population of cells significantly inhibited allograft rejection. CONCLUSIONS: These data demonstrate that rejection of intestinal allografts in the murine model was absolutely dependent on alphabeta but not gammadelta T cells. Furthermore, both CD4+ and CD8+ T cells were necessary for small bowel allograft rejection. Additional studies will be required to determine whether the effects of monoclonal antibody treatment were due solely to depletion of T cells or were mediated at least in part through an active process that altered the functional properties of the targeted T cell subset.

Reduced acute rejection and superior 1-year renal allograft survival with basiliximab in patients with diabetes mellitus. The Global Simulect Study Group.

BACKGROUND: Renal allograft recipients with diabetes mellitus often demonstrate poorer clinical outcomes than nondiabetic patients. Basiliximab (Simulect), a chimeric anti-interleukin-2 receptor monoclonal antibody, reduced the incidence of acute rejection in renal allograft recipients in 2 multicenter, placebo-controlled, phase III trials. METHODS: An analysis of pooled results from the 2 trials was conducted to compare the efficacy and safety of basiliximab with placebo in renal transplant recipients with and without prior diabetes. Patients received either basiliximab (20 mg on day 0 and day 4 posttransplantation) or placebo in combination with cyclosporine for microemulsion (Neoral) and steroids. RESULTS: A total of 722 patients (150 diabetic, 572 nondiabetic) were eligible for intent-to-treat analysis. At 12 months, basiliximab as compared with placebo reduced the proportion of patients experiencing first acute rejection by 41% in diabetics (P<0.01) and by 29% in nondiabetics (P<0.001). Biopsy-confirmed rejection was reduced by 44% in diabetics (P<0.01) and by 26% in nondiabetics (P<0.01). The first acute rejection episode requiring augmented immunosuppression other than steroids was reduced by 49% in diabetics (P<0.01) and by 41% in nondiabetics (P<0.001); death, graft loss, or first rejection episode was reduced by 43% in diabetics (P=0.001) and by 22% in nondiabetics (P<0.01). Superior graft survival was maintained in diabetic recipients treated with basiliximab versus placebo (96% vs. 86%; P=0.022). There were no significant differences in safety between basiliximab and placebo in both diabetic and nondiabetic patients. CONCLUSIONS: Basiliximab is associated with a significant reduction in acute rejection and an excellent safety profile in renal transplant recipients with and without diabetes mellitus. Superior graft survival was evident in diabetic patients.

Reexposure to OKT3 in renal allograft recipients.

Between 40% and 80% of patients treated with the monoclonal antibody OKT3 develop blocking antibody against its idiotypic region. Thus a major concern with the use of OKT3 as part of a baseline immunosuppressive regimen is that formation of blocking antibodies might preclude its subsequent use. Between 7/86 and 2/87, 32 patients received prophylactic OKT3 in addition to low-dose prednisone, azathioprine, and cyclosporine. Prophylactic OKT3 did not prevent rejection, as 21 of 32 patients studied developed rejection. Retreatment of 13 patients with OKT3 successfully reversed 12 rejections and lowered the number of T3-positive cells in spite of a low level of blocking antibody in two patients in this group. Of the patients analyzed, 38% developed blocking antibody on initial exposure to OKT3, but OKT3 reuse was denied only 4 patients due to the presence of these antibodies. Three of these had rejections reversed with steroids alone; the other patient lost the allograft. A high frequency of infectious complications occurred in the retreatment group, with viral infections predominating. Only one patient in the retreated group developed antibodies after the second use. Appearance of blocking antibodies after use of OKT3 as part of a base-line prophylactic immunosuppressive regimen did not significantly compromise access to OKT3 for treatment of subsequent rejection episodes, but multiple exposures to OKT3 did increase the frequency of infectious complications.

Immunologic characterization of MHC recombinant swine. Production of SLA class specific antisera and detection of Ia antigens on both B and non-B PBL.

Two intra-MHC recombinant haplotypes have been examined to document the nature of the recombination and to generate MHC-specific alloantisera. Cells from progeny of recombinant pigs have been compared by mixed lymphocyte reaction, by complement-dependent cytotoxicity with standard alloantisera, and by sodium dodecyl sulfate polyacrylamide gel electrophoretic (SDS-PAGE) analysis of immune precipitates of radio-labeled extracts. The results demonstrate that both recombinant haplotypes, f and g, have inherited the SLA-A,B loci of the c haplotype and the SLA-D loci of the d haplotype, and that no differences between the two recombinant chromosomes are detectable. Class specific anti-SLA-A,B and anti-SLA-DR sera were produced in or against the g haplotype. In terms of cytotoxicity and SDS-PAGE these sera exhibited the expected reactivities, except that the high-titered anti-SLA-DR sera gave an unexpectedly high percentage of lysis of swine peripheral blood lymphocytes. That cells other than pig B cells were being lysed by the anti-SLA-DR sera was confirmed by analyses of subpopulations of peripheral blood lymphocytes. Approximately 50% of nylon nonadherent T cells were specifically lysed by allo-anti-Ia sera. Similar lysis of T cells was found with crossreactive mouse anti-Ia sera. Thus, unlike other species in which Ia antigens are expressed on T cells at low levels and are difficult to detect, the SLA-D region products are readily detectable on swine peripheral blood T lymphocytes.

Inhibition of transplant rejection by pretreatment of xenogeneic pancreatic islet cells with anti-ICAM-1 antibodies.

Cognate recognition of antigen-presenting cells by antigen-specific T cells is critically dependent on non-cognate adhesive interactions. For instance, several studies have shown that in vivo anti-LFA-1 plus anti-ICAM-1 mAb treatment results in prolongation of allograft survival. We have developed a xenogeneic islet transplant model to investigate the role of various adhesion interactions in the xenogeneic response and study the effect of pretreating donor tissue with immunosuppressive drugs. Pancreatic islet cells were pretreated in vitro with anti-human ICAM-1 mAb, transplanted under the renal capsule of diabetic B6 mice in the absence of systemic immunosuppression and examined for long-term xenograft acceptance. The survival of human islets pretreated with anti-human ICAM-1 was significantly prolonged (MST = 53 days, with 40% of grafts surviving > 100 days). In contrast, the survival of human islets pretreated with the control antibody was similar to those of nontreated islets (MST = 7 days). A massive lymphocyte infiltrate into control xenografts was observed at 5 days post-transplant. In contrast, a lymphocyte infiltrate did not appear in the anti-ICAM-1-treated islets for at least 11 days. Only mAbs specific for the LFA-1 binding epitope of ICAM-1 were found to inhibit a mixed islet/lymphocyte reaction in vitro and block graft rejection in vivo. However, graft prolongation is not accompanied by systemic tolerance. Mice transplanted simultaneously with human islet cells treated with control Ig (left kidney) or anti-ICAM-1 (right kidney) rejected the control islets but not anti-ICAM-1-treated islets. These results suggest that the LFA-1/ICAM-1 interaction is a critical component for xenograft rejection and, more important, that pretreatment of islet tissue with anti-adhesion molecule antibodies can profoundly alter graft recognition and rejection in the absence of any systemic drug therapy. However, graft prolongation is not accompanied by systemic tolerance induction.

Activation of human T cells in vivo following treatment of transplant recipients with OKT3.

Sequential lymph node biopsies were obtained prior to and following OKT3 administration in 10 organ transplant recipients to determine whether activation of human T cells occurs in vivo during OKT3 administration. Within 2 hr after injection, OKT3 can be detected coating LN T cells, and LN T cells also demonstrate enhanced proliferation in vitro in the presence of recombinant interleukin-2 (rIL-2). Interleukin-2 receptor (IL-2R) is expressed on post-OKT3 LN T cells within 48 hr following administration of OKT3. In addition, when placed in a mixed lymphocyte reaction, post-OKT3 LN cells also demonstrate enhanced proliferation. This is the first direct demonstration of in vivo activation of human T cells by OKT3. These data support the hypothesis that T lymphocyte activation and concomitant production of lymphokines are responsible for the side effects associated with OKT3 treatment. Immune activation and possible enhancement of anti-donor MHC alloreactivity may have significant implications for anti-CD3 and anti-TCR monoclonal antibody therapy in clinical organ transplantation and for enhancement of the immune response in cancer patients.

OKT3 F(ab')2 fragments--retention of the immunosuppressive properties of whole antibody with marked reduction in T cell activation and lymphokine release.

Recent studies in mouse and man indicate that the first dose response to anti-CD3 mAbs likely results from in vivo T cell activation and concomitant lymphokine release. One approach toward amelioration of these effects involves the use of nonactivating digest fragment preparations of anti-CD3 mAbs. In the present study whole and F(ab')2 fragments of OKT3 were prepared and assayed for their immune-activating and -suppressing effects on human peripheral blood mononuclear cells. Immunosuppressive effects were evaluated by quantitation of TCR modulation and coating, and by inhibition of CTL activity. Whole mAb and F(ab')2 fragments both effectively coated the TCR complex. However, whole mAb was more efficient at modulating the TCR complex, suggesting that modulation is enhanced by FcR interactions. Whole and F(ab')2 fragments of OKT3 were equally efficacious in suppressing CTL activity. Immune activation was evaluated by quantitation of proliferation, activation marker expression (IL-2R and Leu-23), and lymphokine release (TNF-alpha, gamma-IFN, and GM-CSF). Rigorously purified F(ab')2 preparations demonstrated minimal T cell activation, suggesting TCR and macrophage FcR crosslinking as necessary. Whole OKT3 mAb induced expression of IL-2R and Leu-23 activation markers on the majority of CD4+ and CD8+ cells at mAb concentrations as low as 1 ng/ml, whereas F(ab')2 fragments induced detectable, but markedly reduced expression of these markers only at mAb concentrations greater than or equal to 100 ng/ml. Similarly, whole mAb induced release of TNF-alpha, gamma-IFN, and GM-CSF at low mAb concentrations, whereas F(ab')2 fragments induced detectable (though markedly reduced) levels of TNF-alpha only. However, increasing degrees of contamination with whole antibody resulted in increasing mitogenic potency of the F(ab')2 preparation, which in some cases, was actually enhanced compared with that observed with whole mAb alone. In conclusion, these studies indicate that OKT3 F(ab')2 digest fragments are markedly less potent than whole mAb in inducing T cell activation, yet they retain significant immunosuppressive effects. However, meticulous purification of F(ab')2 digest fragment preparations will likely be required to avoid T cell and macrophage activation following in vivo administration.

Liver transplantation with reduced-size donor organs.

Orthotopic liver transplantation (OLT) of the pediatric patient is often limited by the availability of a size-matched donor organ. Use of reduced liver transplantation (RLT) can increase the proportion of candidates transplanted and may reduce overall mortality. We report herein the initial clinical application of RLT in the United States. Indications for RLT included fulminant hepatic failure (n = 2), acute hepatic artery thrombosis (n = 3), and chronic liver disease unresponsive to inpatient support and more than 30 days on transplant list (n = 4). Donor hepatectomy was performed using standard techniques. Formal hepatic resection was performed ex-vivo to create a size-matched graft, from the larger donor organ, which was implanted in the orthotopic position. Between 11/84 and 4/87, 70 pediatric patients were evaluated for OLT, and 33 of these were transplanted. During this period only 5 patients (7%) died awaiting OLT. Of 33 patients treated at the University of Chicago, 5 received RLT. Donor: recipient weight ratios ranged from 2:1 to 8.1:1. For RLT median operative blood loss was 1.7 blood volumes (range 0.5-11.7) with an operative time of 9.3 + 3.5 hr. Acceptable early graft function was observed in five patients, all of whom were discharged from the hospital. Four of these five patients are alive between 2 and 48 months after transplantation. Marginal graft function with cholestasis and coagulopathy was associated with acute intracranial hemorrhage and neurologic death in one case. One patient died intraoperatively with non-function caused by the use of a liver from a donor with steatosis and a poor size match. Another patient died on day 5 with primary nonfunction and persistent hemorrhage. Systemic cytomegalovirus infection was the cause of death in the other two cases. RLT can provide life-sustaining liver function in urgent clinical settings. The graft can serve as a temporary or permanent liver replacement. With evolution of the technique RLT could eventually be offered to more elective candidates and increase the utilization of available donors by reducing size limitations in OLT.

OKT3 treatment of steroid-resistant renal allograft rejection.

The monoclonal antibody, Orthoclone OKT3 (OKT3), has been used with great efficacy in a prospective multicenter trial as therapy for first rejection episodes in cadaveric donor (CD) renal allograft recipients treated with azathioprine (AZA) and prednisone (P). However, although almost all rejection episodes were reversed, recurrent rejection occurred in approximately two-thirds of OKT3-treated patients in this earlier trial; infections also occurred in about two-thirds of patients, often related to the additional immunosuppression necessary to reverse the rerejection episodes. In the current series of patients, OKT3 was used to treat rejection in CD renal graft recipients in a protocol differing from the multicenter trial in two respects: baseline immunosuppression was cyclosporine (CsA) and P or CsA, AZA, and P (probably more potent immunosuppressive combinations than the AZA and P in the multicenter trial); and OKT3 treatment was reserved for rejection episodes resistant to 3 bolus infusions of methylprednisolone (MP), 5-10 mg/kg, rather than as primary therapy for first rejection episodes. Using this protocol, 46 of 74 rejection episodes (62%) diagnosed between 3/85 and 3/86 in CD renal allograft recipients were treated successfully with MP. Of the remaining 28 steroid-resistant rejection episodes, 27 (96%) were reversed with a 7-14-day course of OKT3, 5 mg/day. Only 5 recurrent rejection episodes (19%) have been observed in the 2-14-month follow-up period after OKT3 treatment; infections have occurred in 10 patients (36%), and three grafts (11%) have been lost in OKT3 treated patients. These results suggest that recurrent rejection and subsequent infection after OKT3 is used to treat rejection may be reduced in a protocol where CD renal allograft recipients are treated with baseline immunosuppression regimens including CsA and where OKT3 is reserved for steroid-resistant rejection. This approach appears to be both more cost-effective than, and as effective therapeutically as, treating all first rejection episodes with the monoclonal antibody.