Gene expression analysis in human renal allograft biopsy samples using high-density oligoarray technology.

BACKGROUND: High-density oligoarray technology is a novel method for screening the expression of thousands of genes in a small tissue sample. Oligoarray analysis of genes expressed during human renal allograft rejection has not been reported previously. METHODS: Seven human renal allograft biopsies with histologic evidence of acute cellular rejection and three renal allograft biopsies without evidence of rejection (control) were analyzed for the expression of 6800 human genes using high-density oligoarrays (GeneChip, Affymetrix, Santa Clara, CA). Quantitative expression of gene transcripts was determined and a comparison analysis between acute rejection and control biopsy samples was performed. Up-regulation of a specific gene transcript during acute rejection was considered to be significant if transcript abundance increased fourfold or more relative to control biopsy samples. RESULTS: Comparison analysis revealed that between 32 and 219 gene transcripts are up-regulated (>fourfold) during acute rejection. Of these transcripts, only four (human monokine induced by interferon-gamma, T-cell receptor active beta-chain protein, interleukin-2 stimulated phosphoprotein, and RING4 (a transporter involved in antigen presentation)) were consistently up-regulated in each acute rejection sample relative to at least two of three control biopsy samples. Six other genes were up-regulated in six of seven acute rejection samples. These were interferon-stimulated growth factor-3, complement factor 3, nicotinamide N-methyltransferase, macrophage inflammatory protein-3beta, myeloid differentiation protein, and CD18. Only two gene transcripts were down-regulated in five of seven acute rejection samples. Significant up-regulation of cytotoxic T-cell effector molecules, previously reported as markers of acute renal rejection in humans, was not detected. CONCLUSIONS: High-density oligoarray technology is useful for screening gene expression in transplanted tissues undergoing acute rejection. Because this method does not rely on a priori knowledge of which genes are involved in acute rejection, it is likely to yield novel insights into the mechanisms and diagnosis of rejection.

Tacrolimus, cyclosporine and plasma lipoproteins in renal transplant recipients.

To compare the effect of tacrolimus (FK506) and cyclosporine (CsA) on plasma lipoproteins in renal transplant recipients receiving maintainance therapy, the following prospective study was undertaken. Blood from nineteen recipients on tacrolimus (FK group) and from twenty-one on CsA (CsA group) was collected at baseline, 3-, 6-, and 10-month intervals. Plasma lipids, lipoproteins and oxidation properties of lipoproteins were determined. Plasma total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) were substantially increased in both groups, although only the CsA group showed significant differences at all time intervals and at the baseline. High density lipoprotein cholesterol, triglycerides, and apolipoprotein A varied in both groups at time intervals from the baseline, but not significantly. The susceptibility to oxidation of LDL isolated from the FK group at all times was uninfluenced by the tacrolimus treatment, and values were comparable to those obtained from LDL isolated from healthy individuals. A significantly higher susceptibility to oxidation as indicated by the shorter time required to start the formation of conjugated dienes was observed in LDL isolated from the CsA group at 3 and at 6 months of therapy. Tacrolimus-treated patients appear to have less hyperlipidemic and have LDL less susceptible to oxidation than patients treated with CsA.

Payment for immunosuppression after organ transplantation. American Society of Transplantation.

Dramatic improvements in organ transplantation have meant that a growing number of patients must take expensive immunosuppressive medications for the rest of their lives. Currently, Medicare covers most transplantation procedures in the United States, but ends coverage for outpatient immunosuppressive medications after 36 months. Evidence suggests that at least some patients have reduced immunosuppression and their transplants fail because they cannot afford these medication costs. In the years since the advent of effective immunosuppressive therapy, the US Congress has struggled with this issue, and in 1999 temporarily extended medication coverage for eligible patients (based on age and disability) by 8 months. However, a more permanent solution is needed. We advocate that Medicare should cover the cost of all immunosuppressive therapy for all solid organ transplant recipients who cannot afford to pay. A number of potentially cost-effective approaches could be taken, but, in any case, something must be done to ensure that transplants do not fail because recipients cannot pay for immunosuppression.

Prevention of primary cytomegalovirus disease in organ transplant recipients with oral ganciclovir or oral acyclovir prophylaxis.

BACKGROUND: Optimal prophylaxis against cytomegalovirus (CMV) disease for organ transplant patients at risk for primary infection (donor seropositive, recipient seronegative, D+R-) remains to be determined. We hypothesized that prolonged oral ganciclovir therapy following intravenous therapy would provide increased protection. METHODS: A total of 155 evaluable D+R- organ transplant recipients from 13 transplant centers were entered into the study: all received intravenous ganciclovir (5 mg/kg/day) for 5-10 days and then either oral acyclovir (400 mg tid) or oral ganciclovir (1 g tid) for an additional 12 weeks. Patients were assigned to their treatment groups at a central randomization site, with a separate randomization scheme for each of the organs transplanted (kidney, heart, or liver). In the case of kidney transplants, the patients were stratified according to source of the kidney (living related vs. cadaveric donor). The primary endpoint was the incidence of CMV disease in the first six months post-transplant. RESULTS: Treatment with oral ganciclovir was associated with a significant decrease in the incidence of symptomatic disease or viremia when compared with the oral acyclovir group (32% vs. 50%, P<0.05). This difference was most marked in terms of tissue invasive disease: only 3 of 15 symptomatic patients in the ganciclovir group vs. 10 of 21 in the acyclovir group developed tissue-invasive infection (P<0.05). There was a significant difference in the time to CMV disease or viremia in the two groups: mean time 212+/-17 days post-transplant for the acyclovir group vs. 291+/-13 days for the ganciclovir group (P<0.001). The incidence of allograft rejection was 34% in the ganciclovir group and 46% in the acyclovir group (P=NS). Leukopenia was more common in the ganciclovir group (P<0.05), but in no case did it require drug discontinuation. Ganciclovir resistance did not develop in this study. CONCLUSION: Prophylaxis with oral ganciclovir following a brief course of intravenous ganciclovir provides useful protection against primary CMV disease.

Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group.

BACKGROUND: The novel agent sirolimus (SRL; Rapamune; rapamycin) inhibits the immune response by a mechanism distinct from those of calcineurin antagonists or antimetabolites. This randomized, controlled, multicenter, single blind, phase II trial examined the combination of SRL, steroids, and full versus reduced doses of cyclosporine (CsA) for prophylaxis of acute renal allograft rejection. METHODS: A total of 149 recipients of mismatched cadaveric- or living-donor primary renal allografts were randomized into six groups. Three groups received placebo or 1 or 3 mg/m2/day SRL, as well as steroids and full-dose CsA (Sandimmune). Three groups received steroids, reduced-dose CsA (target trough level 50% of full-dose range), and 1, 3, or 5 mg/m2/day SRL. RESULTS: The incidence of biopsy-proven acute rejection episodes within the first 6 months after transplant was reduced from 32.0% in the control group to 8.5% in patients receiving SRL (1 or 3 mg/m2/day) and full-dose Sandimmune CsA (P=0.018). Similar low rates of acute rejection episodes were observed among non-African-Americans, but not African-Americans, treated with SRL and reduced-dose Sandimmune CsA. Despite the augmented immunosuppression, 1-year patient and graft survival rates did not differ significantly across groups. Adverse effects attributable to CsA, including hypertension and new-onset diabetes mellitus, were not exacerbated by SRL. Except for an increased incidence of pneumonia among patients receiving full-dose CsA and 3 mg/m2/day SRL, the incidences of opportunistic infections were similar in all treatment groups. Although SRL produced more frequent, but reversible, hematological and lipid abnormalities, it had no apparent nephrotoxic effects to exacerbate CsA-induced renal dysfunction. CONCLUSIONS: SRL in combination with CsA and steroids not only lowers the incidence of biopsy-proven acute renal allograft rejection episodes, but also may permit CsA sparing, at least among Caucasian patients, without an increased risk of rejection.

The role of tacrolimus in adult kidney transplantation: a review.

The use of tacrolimus (FK506) in adult kidney-transplant recipients has been the subject of a number of single- and multi-center studies. This review article focuses on those studies in which tacrolimus was used either as rescue therapy in patients who developed refractory rejection on cyclosporine (CyA)-based regimens or as primary immunosuppression in adult renal-allograft recipients. Twenty-five prospective and retrospective studies conducted in the US, Japan and Europe, including single- and multi-center experiences, were identified in the medical literature. Of these studies, most show a 74-98% initial success rate for tacrolimus rescue therapy. Comparative studies reviewed herein demonstrate comparable patient- and graft-survival rates between tacrolimus- and CyA-treated patients. Many studies have shown that rejection episodes occur with similar or lower frequency among patients treated with tacrolimus than among those given CyA as primary immunosuppression. The major toxicities associated with tacrolimus are nephrotoxicity, neurotoxicity and diabetogenicity. Results from several studies have also demonstrated an association between these tacrolimus side effects and high whole-blood trough levels of tacrolimus. In many cases, a reduction in dosage can reverse these adverse effects. In summary, based on both single- and multi-center data, tacrolimus has been demonstrated to be efficacious when used for either primary immunosuppression or as rescue therapy for refractory acute rejection in adult renal-allograft recipients.

Assessment of the frequency and costs of posttransplantation hospitalizations in patients receiving tacrolimus versus cyclosporine.

We assessed the frequency and costs of hospitalizations in patients receiving tacrolimus (FK506) compared with patients receiving cyclosporine A for immunosuppression during 1 year after kidney transplantation. Four hundred twelve cadaveric kidney transplant recipients were randomized onto a phase III, prospective, multicenter, clinical trial. Hospital billing data were collected for 1 year posttransplantation. Total inpatient costs were calculated from billed charges and standardized to 1995 US dollars. Medical resource utilization rates and inpatient costs were compared between treatment groups using unpaired Student's t-tests. Complete billing data (transplantation and all posttransplantation hospitalizations) were available for 65% (268 of 412) of the study patients. Among tacrolimus and cyclosporine patients with complete billing data, the rates of allograft rejection were 32% and 47%, respectively (P=0.009), and the rates of rehospitalization during the year after transplantation were 53% and 63%, respectively (P=0.080). The mean per-episode rehospitalization costs were significantly lower among tacrolimus-treated patients compared with cyclosporine-treated patients ($7,495 v $11,497; P=0.031), and the mean total rehospitalization costs were significantly lower in the tacrolimus group compared with the cyclosporine group ($8,550 v $14,869; P=0.029). In addition, the total 1-year hospitalization costs (including transplantation and posttransplantation hospitalizations) were significantly lower in the tacrolimus group compared with the cyclosporine group ($53,435 v $61,191; P=0.046). Compared with cyclosporine-based immunosuppression, tacrolimus-based immunosuppression for kidney transplant recipients was associated with a significantly lower rate of rejection, which was associated with significantly lower per-episode rehospitalization costs, lower total 1-year rehospitalization costs, and lower total 1-year hospitalization costs.

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. FK506 Kidney Transplant Study Group.

BACKGROUND: Results of a multicenter, randomized, clinical trial demonstrated that tacrolimus was more effective than cyclosporine in preventing acute rejection in cadaveric renal transplant patients. As African-Americans comprised approximately 25% of the study population, their outcome was analyzed relative to the experience of Caucasian patients. METHODS: Of the 205 patients randomized to tacrolimus, 56 (27.3%) were African-American and 114 (55.6%) were Caucasian. Of the 207 patients randomized to cyclosporine, 48 (23.2%) were African-American and 123 (59.4%) were Caucasian. The efficacy variables were 1-year patient survival, graft survival, and incidence of acute rejection. RESULTS: The incidence of acute rejection was significantly lower in African-American and Caucasian patients treated with tacrolimus than with cyclosporine. Additionally, no African-American patient who was treated with tacrolimus experienced moderate or severe acute rejection, as determined by blinded independent review. The incidence of nephrotoxicity, cardiovascular and gastrointestinal events, malignancies, and opportunistic infections was similar between treatments and race groups. However, there was an increased incidence of posttransplant diabetes mellitus in tacrolimus-treated patients, particularly in African-Americans, and tacrolimus was associated with significantly lower lipid levels in both Caucasians and African-Americans. African-American patients required a 37% mean higher dose of tacrolimus than Caucasian patients to achieve comparable blood concentrations. CONCLUSIONS: Tacrolimus is more effective than cyclosporine in preventing acute rejection in both African-American and Caucasian patients. However, tacrolimus was associated with an increased risk of posttransplant diabetes mellitus, particularly in African-Americans, which was reversible in some patients.

Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group.

BACKGROUND: Monoclonal antibodies that block the high-affinity interleukin-2 receptor expressed on alloantigen-reactive T lymphocytes may cause selective immunosuppression. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the alpha chain of the interleukin-2 receptor and may thus reduce the risk of rejection after renal transplantation. METHODS: We administered daclizumab (1.0 mg per kilogram of body weight) or placebo intravenously before transplantation and once every other week afterward, for a total of five doses, to 260 patients receiving first cadaveric kidney grafts and immunosuppressive therapy with cyclosporine, azathioprine, and prednisone. The patients were followed at regular intervals for 12 months. The primary end point was the incidence of biopsy-confirmed acute rejection within six months after transplantation. RESULTS: Of the 126 patients given daclizumab, 28 (22 percent) had biopsy-confirmed episodes of acute rejection, as compared with 47 of the 134 patients (35 percent) who received placebo (P=0.03). Graft survival at 12 months was 95 percent in the daclizumab-treated patients, as compared with 90 percent in the patients given placebo (P=0.08). The patients given daclizumab did not have any adverse reactions to the drug, and at six months, there were no significant differences between the two groups with respect to infectious complications or cancers. The serum half-life of daclizumab was 20 days, and its administration resulted in prolonged saturation of interleukin-2alpha receptors on circulating lymphocytes. CONCLUSIONS: Daclizumab reduces the frequency of acute rejection in kidney-transplant recipients.

Immunosuppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group.

BACKGROUND: Numerous studies have demonstrated that renal allograft survival is reduced in African-Americans (AAs). This posthoc racial subgroup analysis (AAs vs. non-AAs) tested whether mycophenolate mofetil (MMF) might have favorable implications for the treatment of AA renal allograft recipients. METHODS: Patients received a triple therapy regimen of corticosteroids, cyclosporine, and azathioprine (AZA) 1-2 mg/kg/day, MMF 2 g/day (MMF 2 g), or MMF 3 g/day (MMF 3 g). RESULTS: AAs in the AZA group had the highest biopsy-proven rejection/treatment failure (BPR/TF) rate (57.5% vs. 43.5% for non-AAs). AAs in the MMF 3 g group showed a significant reduction in BPR/TF (57.5% vs. 24.2%, P=0.0008). BPRs were more frequent for AAs in either the AZA (47.5%) or MMF 2 g group (31.8%) than in the MMF 3 g group (12.1%), whereas rejections were reduced for non-AAs receiving either MMF dosage (AZA, 35.5%; MMF 2 g, 15.7%; MMF 3 g, 18.8%). AAs in the AZA group experienced BPR/TF earlier than AAs in the MMF 3 g group (median onset at 64 days vs. > 183 days, P=0.0012). But AAs in the MMF 3 g experienced BPR/TF the latest among the six subgroups of treatment and race. AAs had more severe rejection episodes and higher serum creatinine levels at 6 months after transplant, regardless of treatment group. CONCLUSIONS: Dose-dependent prevention of acute rejection in AAs is best afforded by a dosage of MMF at 3 g/day, whereas 2 g/day provides a superior benefit/risk ratio for non-AAs. MMF at 3 g/day thus provides an improvement over conventional immunosuppressive strategies in reducing the frequency of acute rejections in this immunologically high-risk group.

Drainage of the exocrine pancreas in clinical transplantation: comparison of bladder versus enteric drainage in a consecutive series.

The purpose of this study was to define the incidence of urologic and metabolic complications after simultaneous kidney/pancreas transplantation (SKPT) with bladder drainage (BD). Review of 55 SKPT with BD performed between 1989 and 1995 demonstrated patient, kidney, and pancreas survival rates of 95%, 89%, and 78%, respectively, with a mean follow-up of 41 months (range 12-78 months). Over this follow-up period 78% of these patients experienced a urinary tract infection, 27% had hematuria, and 38% had at least one hospital admission for dehydration. Recent experience with primary enteric drainage of the exocrine secretions of the transplanted pancreas (n = 11) has demonstrated the total absence of these complications (follow-up range 2-12 months). These results suggest the value of continuous re-evaluation of surgical techniques as the care of transplant patients evolve.

Microchimerism and rejection in clinical transplantation.

BACKGROUND: Haemopoietic microchimerism has been identified in recipients of solid-organ transplants and is thought by some to be critical for the development and maintenance of immunological tolerance. The aim of this study was to correlate prospectively the persistence of donor cells with clinical outcome in recipients of kidney, kidney and pancreas, and liver transplants. METHODS: Persistence of donor cells in recipient peripheral blood was assessed at 3 days, and at 1, 3, 6, and 12 months after transplantation by a two-stage nested PCR technique to detect donor MHC HLA DR gene specifically. A pretransplant blood sample was collected from each patient to serve as an individual negative control. Seven liver, six kidney and pancreas, and 17 kidney patients were enrolled. 12 of the 17 kidney patients and all of the kidney and pancreas, and liver recipients were suitable for analysis. Exact matches for donors and recipients at the HLA DR loci (n = 1) or inability to obain primer pair specificity among similar HLA DR types (n = 4), meant that we were unable to analyse five patients. FINDINGS: Donor DNA was detected in 20 (80%) of 25, ten (40%) of 25, seven (30%) of 23, five (22%) of 23, and six (32%) of 19 recipients at 3 days, and 1, 3, 6 and 12 months post-transplant, respectively. Within individuals, the detection of donor DNA varied over time; only two patients had detectable donor DNA at all times. Analysis of the whole group of transplant patients showed a similar frequency and severity of rejection episodes in patients with and without microchimerism as defined by detectable donor DR genes. INTERPRETATION: These data suggest that a significant percentage of the recipients had persistent donor class II DNA in the peripheral circulation for at least 1 year after transplantation. We showed that a pretransplant blood sample is critical to avoid a false-positive result, and suggest that detectable chimerism may vary over time in individual patients. Therefore, analysis of microchimerism with a single, post-transplant analysis may not help in making clinical decisions for individual patients.

An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group.

This was a multicenter, open-label, concentration-ranging trial of FK506 and cyclosporine in 120 patients undergoing primary cadaveric kidney transplant. Patients were randomized to a cyclosporine-based regimen or to one of three FK506-based regimens designed to achieve low (5-14 ng/ml), medium (15-25 ng/ml), or high (26-40 ng/ml) trough whole blood levels. Corresponding initial doses of FK506 were 0.2, 0.3, and 0.4 mg/kg/day. Patients were evaluated at 42 days after transplant for the occurrence of the first episode of acute rejection or toxicity, necessitating a dosage reduction. There was no significant difference among the three FK506-based regimens and the cyclosporine-based regimen for rejection or toxicity at 42 days. However, the incidence of acute rejection was significantly lower (14% for FK506 and 32% for cyclosporine; P=0.048) for the aggregate of all FK506-treated patients versus cyclosporine. The incidence of neurotoxic and gastrointestinal events was higher among FK506-treated patients during the first month after transplant. A significant trend was observed for increasing toxicity with increasing maximum trough FK506 concentrations (P=0.01) and for decreasing rates of rejection with increasing minimum trough FK506 concentrations (P=0.021). FK506 was effective in preventing early rejection in kidney transplant recipients. The target range of whole blood levels that optimizes efficacy and minimizes toxicity seems to be 5-15 ng/ml. The corresponding recommended initial dose of FK506 for kidney transplant recipients seems to be 0.2 mg/kg/day.

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.