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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

ABSTRACTS in PERSPECTIVE based on presentations from the American Transplant Congress 2008

May 30-June 4, 2008 / Toronto, Ontario

EDITORIAL OVERVIEW

R. Jean Shapiro, MD, ABIM, FRCPC

Medical Director, Renal Transplantation Medical Manager, Solid Organ Transplantation Vancouver General Hospital Clinical Associate Professor of Medicine University of British Columbia Vancouver, British Columbia

Aparadox in renal allograft transplantation today is the discrepancy between the excellent short-term success and the more limited gains in longer-term graft survival. While death with a functioning graft has now become the most common reason for graft loss, histologic changes that describe chronic allograft nephropathy (CAN) also have significant impact on graft longevity.

The natural history of renal transplantation suggests that the development of CAN, now renamed interstitial fibrosis and tubular atrophy not otherwise specified (IF/TA NOS), may be an inevitable end point. The relative contribution of immunologic and non-immunologic factors is not clear. Treatment with calcineurin inhibitors (CNI) has until recently been regarded as a major culprit in this lesion, but this is now felt to represent an oversimplification of the fibrosing process, and that the changes noted in graft histology more likely reflect a repair mechanism to a variety of injuries. Thus, the exact role of CNIs in the development of CAN has not been fully elucidated.

The impetus to identify immunosuppressive regimens that minimize or eliminate exposure to the CNIs has given rise to a number of novel combinations, including regimens based on sirolimus (SRL), an mTOR inhibitor with potent immunosuppressant potential and appealing antineoplastic properties.

Results from the STN (Spare-the-Nephron) trial presented by Dr. Thomas Pearson, Emory University Hospital, Atlanta, Georgia, showed a mean percentage change in measured glomerular filtration rate (GFR) from baseline to 12 months in the SRL conversion arm of 27.9% vs. 11% in the CNI arm. While it did not quite reach statistical significance, when patients given tacrolimus (TAC) were analyzed separately (over 80% of CNI patients), the difference from baseline to month 12 at 6% in the TAC arm was significant compared to the SRL conversion arm. In contrast, biopsyproven acute rejection (BPAR) rates were low and similar between the two groups as was the incidence of graft loss and mortality. The proportion of patients withdrawn from the mycophenolate mofetil (MMF)/SRL was greater compared to the MMF/CNI arm (18.7% vs. 7.1%).

Renal function outcomes from the same trial presented by Dr. Shamkant Mulgaonkar, St. Barnabas Medical Center, Livingston, New Jersey, also showed that the mean per cent change in calculated GFR from baseline to month 12 at 7.4% for the MMF/SRL group, 1.3% for the MMF/CNI group, and - 0.1% for the MMF/TAC subset was again significant in favour of the SRL conversion group. SRL conversion patients also had significantly greater changes in serum creatinine (SCr) from baseline compared with CNI patients, while a mean 6% change in calculated creatinine clearance (CrCl) from baseline was also seen in the MMF/SRL arm vs. a -0.7% change for MMF/CNI patients and a -1.9% change in the MMF/TAC subset. These findings suggest that an MMF/SRL-based regimen better preserves renal function compared with a CNIcontaining regimen and may be worth considering in kidney transplant patients at higher risk for declining renal function. Critical information missing from their reports however were the target and actual CNI drug levels, and the starting measures of renal function. This data would be necessary in order to assure that the patient groups were comparable prior to the switch.

Maximizing Immunosuppression and Minimizing Nephrotoxicity

In the ORION trial, some 443 de novo renal transplant recipients underwent induction with daclizumab plus corticosteroids, and subsequently randomized to receive maintenance therapy with SRL/TAC with TAC elimination at week 13, de novo CNI-free SRL/MMF or MMF/TAC. As reported by ORION lead investigator Dr. Stuart Flechner, Cleveland Clinic Foundation, Ohio, renal function was significantly better in patients on the CNI-free regimen at three months’ posttransplantation but this advantage was later lost. The incidence of BPAR in the CNI-free arm was higher at 28.3% at two years than for either the TAC elimination arm at 13.5% and 9.4% for the MMF/TAC arm, and this group was terminated after all patients were accrued because of the high BPAR. Noting that sub-therapeutic levels of SRL were observed in 40% to 50% of the CNI-free arm, it has been suggested that had SRL levels been kept to recommended doses of between 10 and 15 ng/mL during the first six months, BPAR outcomes might have been very different.

Striking a balance between potent immunosuppression during the early post-transplant period, when the risk of acute rejection is highest, and minimizing nephrotoxicity is now more possible with the use of SRL early on in the posttransplant course. Fifty unselected renal transplant recipients received SRL, TAC and prednisone for three months, target trough levels for SRL being 10 ng/mL and 8 to 12 ng/mL for TAC. Three months later, investigators decreased the TAC dose by 50% and maintenance TAC trough levels were 3 ng/mL. As noted by Dr. David J. Conti, Director and Chair, Kidney/Pancreas Transplant Program, Albany Medical Center, New York, acute rejection occurred in 10% of the group, all very early following transplantation. More importantly, no patient had an episode of acute rejection following reduction in TAC at three months and graft survival at six years on this CNI-sparing regimen was 72%. Renal function was also stable across the six-year follow-up.

Potential for Reducing Skin Cancer Rates

Perhaps one of the strongest arguments in favour of SRL as an immunosuppressant agent is its antineoplastic activity. As is well known, long-term immunosuppression greatly magnifies the risk for basal and squamous cell skin carcinoma in transplant recipients. To that end, Dr. R. Jean Shapiro, University of British Columbia, sought to explore the use of SRL with CNI minimization or elimination in renal transplant patients with multiple skin cancers. Only stable patients were chosen for the study, with no proteinuria and good kidney function prior to switching them to SRL while minimizing all other immunosuppressants. Followup after conversion to SRL ranged from 35 to 2763 days. Results are preliminary and involve only 30 patients but a reduction in the number of new skin cancers has been observed, from a mean of 5.36 per patient prior to SRL conversion to 1.57 new skin cancers following conversion.

Importantly, no significant change in renal function or increase in acute rejection rates following SRL conversion were observed. Follow-up of this cohort is still too limited to say with certainty that a SRL-based immunosuppressive regimen will reduce the number of skin cancers in renal allograft recipients. Nevertheless, the literature suggests this may be the case, which would then offer hope of mitigating the development and perpetuation of skin cancer that currently affects so many of our renal transplant recipients.

Promising CNI-sparing Regimens

Other presenters detailed updated findings from CNI-sparing or elimination protocols. In SYMPHONY, patients all received MMF plus either low-dose TAC, standard-dose cyclosporine A (CsA), low-dose CsA or low-dose SRL. As presented by Dr. Henrik Ekberg, Lund University, Malmö, Sweden, BPAR rates remained low and similar during the second and third year of the trial at under 4% in all arms; only minor changes in renal function were observed in the second and third year as well. The incidence of graft loss between the second and third year of the trial was also low at <6%. At one year, the MMF/low-dose TAC arm was still associated with the best outcomes in SYMPHONY, suggesting this protocol has considerable merit.

Another strategy explored in the OPTICEPT study involved 720 renal transplant recipients randomly assigned to either concentration-controlled MMF (MMFcc) and reduced-level CNI, MMFcc and standard-dose CNI, or to fixed-dose MMF (MMFfd) and standard-dose CNI. Mycophenolic Acid trough levels were adjusted depending on the CNI involved (CsA or TAC). According to Dr. Robert Gaston, University of Alabama, Birmingham, treatment failure—defined as BPAR, graft loss, death and loss to follow-up—was documented in 20.6% of patients receiving MMFcc/reduced-level CNI, 28.7% of the MMFcc/standard-dose CNI cohort and 26.7% of those in the MMFfd/standard-dose CNI arm. BPAR rates for the same three groups were 6.2%, 9.7% and 9.6%, respectively. Although patients received higher MMF doses at most time points in the MMFcc/low-level CNI group, withdrawal due to adverse events (AEs) occurred at half the rate as the other two treatment arms. In this non-inferiority trial, investigators suggested that a therapeutic monitored dose of MMF with a reduced level of CNI exposure might better preserve kidney function. Not specified however were target trough levels or drug levels achieved for either MMF or CNI, thus rendering it difficult to properly interpret the data.

Another approach to minimize CNI exposure is antibody induction with the pan T-cell depleting, rabbit antithymocyte globulin (rATG). In a prospective trial by Dr. Brian Stevens, University of Nebraska Medical Center, Omaha, patients received either a single fixed dose of rATG (6 mg/kg) or four divided doses (1.5 mg/kg) together with methylprednisolone, after which they were maintained on SRL and TAC for six months. The drug levels were not specified. At that point, the groups were further divided to either remain on SRL/TAC or switch to SRL/MMF. In updated data presented with an average follow-up of almost 20 months, 54 patients had been withdrawn from the SRL/TAC regimen and remained CNI- and steroid-free. For an average of 22 months, 70% were also successfully maintained on this CNI- and steroid-free protocol, the others required CNI reintroduction, at least temporarily. To date, patient, graft and rejection-free graft survival rates have been similar across all treatment groups, with better early recovery of renal function in the CNI-withdrawal groups.

Dr. John Gill, St-Paul’s Hospital, Vancouver, British Columbia, presented exploratory results of replacing CNIs with basiliximab, a monoclonal antibody that blocks the interleukin-2 (IL-2) receptor, inhibiting IL-2-mediated activation of T lymphocytes and thereby a pathway for allograft rejection. In the five out of seven patients who completed the six-month feasibility study, investigators found that monthly treatment with basiliximab induced serum concentrations that remained above the threshold associated with CD25 saturation and the targeted lymphocyte population decreased substantially in five patients. There was one graft loss following reduction of MMF but no episodes of acute or chronic rejection. Thus, basiliximab may represent another novel strategy by which to reduce or eliminate exposure to the CNIs and with it, potentially reduce the risk of nephrotoxicity in renal allograph recipients.

129 Efficacy and Safety of Mycophenolate Mofetil (MMF)/Sirolimus (SRL) Maintenance Therapy After Calcineurin Inhibitor (CNI) Withdrawal in Renal Transplant Recipients: Final Results of the Spare-the- Nephron (STN) Trial T.C. Pearson, S. Mulgaonkar, A. Patel, J. Scandling, H. Shidban, M. Weir, D. Patel

Purpose: To evaluate the efficacy and safety of a maintenance immunosuppressive regimen of MMF and SRL compared with that of MMF and a CNI in renal allograft recipients over a 2-year period.

Methods: This open-label, prospective, multicenter study, randomized 305 patients (maintained on MMF and a CNI) 30-180 days post-transplant to receive either MMF (1-1.5 g BID) plus SRL (2-10 mg followed by at least 2 mg/day; trough 5-10 ng/mL) and discontinue the CNI (MMF/SRL) or to continue their current regimen (MMF/CNI). Antibody induction and/or corticosteroids were administered according to individual center practice. Efficacy endpoints included the proportions of patients with biopsyproven acute rejection (BPAR), graft loss, and death at 12 months, and the percent change in measured glomerular filtration rate (GFR; cold iothalamate) from randomization.

Results: 12-month data from the first 249 patients receiving either MMF/SRL (n=123) or MMF/CNI (n=126) are described here; final outcomes of all 305 patients will be presented at the congress. Mean time from transplant to randomization in both groups was 117 days. Baseline characteristics and measured GFR values were similar in the treatment groups; 98 patients in the MMF/CNI group were receiving tacrolimus. Within the first 12 months, BPAR was reported in 8/123 (6.5%) MMF/SRL-treated patients and 9/126 (7.1%) receiving MMF/CNI. Graft loss occurred in 2/123 (1.6%) in the MMF/SRL group and 3/126 (2.4%) of those in the MMF/CNI group. No patients receiving MMF/SRL and 3/126 (2.4%) in the MMF/CNI group died. The number and proportion of patients withdrawn for adverse events at 12 months were 23/123 (18.7%) in the MMF/SRL group and 9/126 (7.1%) in the MMF/CNI group. The percent change from baseline in GFR at 12 months was 25.8±75.0 and 11.3±61.5 for the MMF/SRL and MMF/CNI groups, respectively.

Conclusions: MMF/SRL maintenance therapy appears to be associated with improved renal function when compared with MMF/CNI-containing regimens without increasing the risk of acute rejection and is tolerated in almost 80% of patients. Final results presented at the congress will provide definitive conclusions about the effects of this regimen.

Commentary on abstract 129

One of the most common causes of late graft loss is chronic rejection and the CNIs are thought to be a contributing factor. The STN trial was designed to evaluate the validity of SRL/MMF as a CNI-free regimen and its effect on renal function. All patients received MMF and a CNI (either TAC or CsA) and then continued on a CNI or were converted to SRL 30 to 180 days’ post-transplantation. The mean percentage change in measured GFR from baseline to month 12 was numerically better in the SRL conversion arm at 27.9% vs. 11% of the CNI arm, but not significantly so. The difference became significant in favour of the SRL when measuring only those using TAC (6.1%). At 12 months, the urinary protein:creatinine ratio was also higher in the SRL group compared with CNI maintenance. BPAR rates were identical across all three groups (7%) and rates of graft loss, at between 2% and 3%, were similarly low. The most common reasons for withdrawal in the SRL arm were mouth ulcerations and proteinuria, while diarrhea and polyomavirus infection were the most common reasons for withdrawal from the CNI arm.

Questions and Answers with Dr. Thomas Pearson, Emory University Hospital, Atlanta, Georgia

Q: How do the CNIs cause nephrotoxicity?

A: The CNIs inhibit T-cell activation, which is great for immunosuppression, but they also cause vasoconstriction, and this leads to loss of function and scarring in the kidney over time. If you are a recipient of other organs such as heart, lung or liver, 20% to 30% of patients will have developed end-stage renal disease after about 10 years’ post-transplant and this is presumably contributed to in large part by the CNIs.

Q: What accounts for the different results between the STN trial and the SYMPHONY trial which had a similar design?

A: Actually, the designs of the two trials were quite different. In SYMPHONY, the different therapies in that trial were begun at the time of transplantation, whereas they were introduced later in the STN trial. The STN trial was also an American trial with a significant number of African Americans and it excluded people who had a lot of rejection episodes, whereas the SYMPHONY trial was a non-American trial with very few African Americans and included people who were high immunologic responders. And the STN trial is a much smaller trial so it’s dangerous to compare the two trials.

530 Final Renal Function Outcomes from the Spare-the- Nephron (STN) Trial: Mycophenolate Mofetil (MMF)/Sirolimus (SRL) Maintenance Therapy and CNI Withdrawal in Renal Transplant Recipients S. Mulgaonkar, T. C. Pearson, A. Patel, J. Scandling, H. Shidban, M. Weir, D. Patel

Purpose: To compare the effect on renal function of maintenance immunosuppression with MMF and SRL to that of MMF and a CNI in renal allograft recipients.

Methods: In a 2-year open-label, prospective, randomized, controlled, multicenter study, 305 subjects maintained on MMF and a CNI were randomized 30-180 days post-transplantation to either MMF (1-1.5 g BID) plus SRL (2-10 mg followed by 2 mg/day; trough 5-10 ng/mL) and to discontinue the CNI (MMF/SRL) or to continue their current regimen containing either tacrolimus (Tac) or cyclosporine (CsA; MMF/CNI). Antibody induction and/or corticosteroids were administered according to individual center practice. The primary endpoint was the percent change in measured glomerular filtration rate (GFR; cold iothalamate) at 12 months post-randomization. Additional renal endpoints included calculated GFR (Nankivell equation), serum creatinine (SCr), and calculated creatinine clearance (CrCl; Cockroft-Gault) at 12 and 24 months.

Results: Outcomes of the first 123 subjects receiving MMF/SRL and 126 receiving MMF/CNI (Tac, n=98; CsA, n=28) completing 1 year of follow-up will be reported here. Final outcomes of all 305 subjects will be presented at the congress. Mean time from transplant to randomization in both groups was 117 days. Groups were similar at baseline for all reported renal function endpoints. Measured GFRs were 60.6±24.7, 60.0±28.8 and 62.1±29.6 at baseline and 66.3±26.1, 60.8±38.4 and 58.7±33.2 mL/min/1.7m2 at month 12 for the MMF/SRL and MMF/CNI treatment groups, and the subset receiving MMF/TAC, respectively.

Conclusions: After 12 months of therapy, maintenance immunosuppression with MMF/SRL after CNI withdrawal appears to preserve renal function when compared with a MMF/CNI-containing regimen. Final results will be presented at the congress.

Commentary on abstract 530

In the STN trial, patients were randomly assigned to continue on an MMF/CNI regimen or were switched to MMF/SRL at a mean of 117 days’ post-transplant. A total of 148 patients were gradually withdrawn from CNI therapy after transplantation whereas 150 continued to receive CNI therapy, 119 receiving TAC. There was no statistically significant difference between the two groups in mean percentage change in measured GFR from baseline to 12 months, although there was a large numerical difference in favour of the SRLcontaining arm. However, the mean percentage change in calculated GFR from baseline to month 12 was 7.4% for the MMF/SRL group, 1.3% for the MMF/CNI group and -0.1% for the MMF/TAC subset, a difference which was significant. SRL conversion patients also had significantly greater changes in SCr from baseline compared with CNI-patients, suggesting better kidney function. A mean 6% change in calculated CrCl from baseline was also seen in the SRL conversion arm, vs. a -0.7% change for MMF/CNI patients and -1.9% in the MMF/TAC subset. Investigators concluded that an MMF-based regimen in combination with SRL better preserved renal function compared to a CNI-based regimen as reflected by improvements in calculated GRF, serum creatinine levels and calculated creatinine clearance.

Questions and Answers with Dr. Shamkant Mulgaonkar, St. Barnabas Medical Centre, Livingston, New Jersey

Q: Does an improvement in GFR over time suggest patients are less likely to lose their kidney allograft over time?

A: That was the goal of the STN study. We were looking for long-term outcomes and benefits, so I think the improvement we saw was significant enough to suggest we would have fewer graft losses down the road.

Q: How do you think findings from the STN trial should affect the choice of immunosuppressive therapy for kidney transplant recipients?

A: I don’t think this study will change our choice of immunosuppressant therapy that drastically. For that, clinicians expect to see major differences between regimens and we saw differences but not major ones. To choose a regimen, you really need to look at the overall picture—donor characteristics, recipient characteristics and so on. So the study may not influence choice of immunosuppressive regimen overall, but it will certainly make most physicians think of it as one option.

287 A Randomized, Open-Label Study to Compare the Efficacy and Safety of Two Different Sirolimus (SRL) Regimens with Tacrolimus (TAC) + Mycophenolate Mofetil (MMF) in De Novo Renal Allograft Recipients: Preliminary 2-Year Efficacy Results from the ORION Trial S. M. Flechner, S. Cockfield, J. Grinyo, G. Russ, K. M. Wissing, C. Legendre, J. B. Copley, The ORION Trial Investigators

Purpose: We present preliminary 2-year results from a worldwide trial comparing 2 SRL regimens with TAC+MMF.

Methods: Renal transplant recipients (N=451) were randomly assigned to the following treatment regimens: Group 1: SRL (8-15 ng/mL, then 12-20 ng/mL after week 13) + TAC (6-15 ng/mL) with elimination at 13 weeks (n=155); Group 2: SRL (10-15 ng/mL through week 26, 8-15 ng/mL thereafter) + MMF (up to 2 g/day) (n=155); or Group 3: TAC (8-15 ng/mL through week 26, 5-15 ng/mL thereafter) + MMF (up to 2 g/day) (n=141). All patients received corticosteroids and daclizumab. In June 2006, Group 2 was terminated (after all patients were accrued) because of increased acute rejection (AR) rates.

Results: Demographic characteristics were similar between groups except for more females in Group 3. Patient and graft survival were also similar among groups (see Table). Biopsy-confirmed AR (BCAR) was significantly greater in Group 2 compared with Groups 1 and 3, p<0.001, and most occurred in the first 6 months posttransplant with preponderance during the first 3 months. Subtherapeutic SRL trough concentrations were reported in a large number of rejectors in Group 2. Most of the rejections in Group 1 occurred within the first 3 months before TAC was eliminated. All ARs were mild to moderate; grade II ARs were proportionally greater in Group 3. Mean Nankivell GFR was numerically higher in Group 2.

Conclusion: Preliminary results at 2 years show excellent patient and graft survival and similar renal function among treatment groups, despite higher AR rates in Group 2. Early adequate exposure to sirolimus is mandatory to achieve desired (low BCAR rates) results.

Commentary on abstract 287

The Optimizing Renal Transplant Immunosuppression to Overcome Nephrotoxicity trial involved 443 de novo renal transplant recipients, all of whom underwent induction therapy with daclizumab plus corticosteroids. Group 1 received SRL plus TAC, with TAC elimination at 13 weeks; group 2 received de novo CNI-free SRL plus MMF; group 3 received TAC plus MMF. At two years, there was no significant difference in either patient survival (>94%) or graft survival (>93%) between the groups. In the first three months, renal function as measured by creatinine clearance was significantly better in CNI-free patients but this advantage was lost at about six months. The incidence of BPAR in de novo CNI-free patients at 28.3% was significantly higher than for the other two arms at 13.5% in the TAC elimination arm and 9.4% for controls, and group 2 was terminated after all patients were accrued because of increased acute rejection rates. Some 75% of acute rejections in CNI-free patients were Banff grade 1. At two years, hyperlipidemia and delayed wound healing were more frequent in patients on SRL, while tremor was more frequent in patients on TAC plus MMF. Increases in proteinuria, although greater in the TAC elimination group, were minimal in all groups and not different between SRL plus MMF and TAC plus MMF. In the aggregate, investigators concluded all regimens were safe.

Questions and Answers with Dr. Stuart Flechner, Cleveland Clinic Learner College of Medicine, Ohio

Q: Could you comment on the acute rejection rate which was higher in the CNI-free group and when most of these acute rejections occurred? Is this acute rejection rate cause for concern?

A: The higher number of acute rejections in CNI-free patients occurred between days 30 and 100 but between 40% and 50% of this group had subtherapeutic SRL drug levels. The de novo CNI-free group were designed to received SRL in a dose range of at least 10 to 15 ng/mL for the first six months and then 8 to 15 ng/mL after six months, but many patients failed to meet target therapeutic levels as they were not monitored properly by study organizers.

Q: Could you elaborate on one of your conclusion points, i.e. that early adequate exposure to SRL is critically important to achieve the desired effect of low BPAR rates?

A: Several randomized trials have reported acute rejection rates of 10% to 13% when SRL levels are kept to between 10 and 15 ng/mL during the first six months. So this is why early adequate exposure to SRL is important in order to achieve low acute rejection rates.

Q: What do you believe are the most important lessons learned from the ORION trial?

A: Multicentre trials need to be properly monitored, especially when centres are recruited with little experience. Blood level monitoring was done by a central lab, which is not ideal. The combination of [sirolimus]/MMF/prednisone is not easy to administer and needs careful monitoring. In ORION, seven centres entered more than five patients into the study and the acute rejection rate was less than 15%, suggesting there was a centre effect in this trial that affected outcomes.

1296 Safe Conversion to Sirolimus for Skin Cancer in Stable Renal Transplant Recipients (RTR) R. J. Shapiro, E. D. Greanya, C. P. Argentin, Y. Sun, G. Y. Li, N. Partovi

30 (28 male) stable RTR with biopsy-proven recurrent squamous or basal cell cancer (SCC, BCC) were converted from calcineurin inhibitor (CNI) and/or antimetabolite based therapy to sirolimus, with minimization or elimination of all other immunosuppression. Prior to conversion, 20 patients were on triple therapy and nine were on double therapy; one patient was on cyclosporine monotherapy. All patients were Caucasian, with mean age 56.2±11.5 years. 21 were recipients of first, 8 second, and one third transplant. Followup ranged from 35 to 2763 days post conversion. The mean time to diagnosis of skin cancer after first transplant was 10.2±7.2 years, and the mean time to sirolimus initiation was 16.1±7.0 years posttransplant. Mean serum creatinine prior to conversion was 167±82 µmol/L with negligible proteinuria (<800 mg/day). Following conversion, renal function worsened slightly with mean creatinine 178±87 µmol/L at 12 months. Estimated GFR per MDRD correspondingly changed from 46.35±14.75 ml/min pre-conversion to 44.76±19.31 at 12 months. No episodes of acute rejection were documented post-conversion. Hemoglobin remained stable from a mean pre-conversion of 128±14 g/L to 131±18 g/L at 12 months. Total cholesterol increased from 4.47±0.79 mmol/L prior to conversion 5.54±1.34 mmol/L at 12 months; LDL cholesterol increased from 2.63±0.89 mmol/L prior to conversion to 3.14±1.27 mmol/L at 12 months. Seven patients were given a loading dose of sirolimus; maintenance dose was started at 2-3 mg daily. Sirolimus with low dose prednisone was the most common regimen used (n=17). Mean sirolimus level ranged from 6.8 to 7.7 ng/mL over the first 12 months of therapy. Four patients discontinued sirolimus because of adverse drug reactions (pneumonitis, hepatitis, diarrhea, psoriasis flare). The majority had significant improvement in the overall appearance of the skin, with diminution of the number of new skin cancers from a mean of 5.36 total cancers per individual (BCC 0.91; SCC 4.45) pre-conversion to 1.57 cancers following implementation of sirolimus. Eleven patients have had no recurrent skin lesions since conversion. We conclude that conversion to low dose sirolimus with minimization of other agents for SCC and BCC is safe, and potentially beneficial for RTR.

Commentary on abstract 1296

Long-term immunosuppression is associated with a greatly magnified risk of skin cancer relative to a non-immunosuppressed population. The mTOR inhibitor, sirolimus (SRL), is now recognized to have antineoplastic activity, suggesting that a SRL-based immunosuppressive regimen may lessen the risk of skin cancer. In this observational study, 30 Caucasian renal transplant recipients on a CNI plus or minus an antimetabolite were converted to SRL with minimization or suppression of all other immunosuppressants. The average time after transplant to diagnosis of skin cancer was 12 years while the mean follow-up following conversion ranged from 35 to 2763 days. No episodes of acute rejection were documented following conversion to SRL. The number of new skin cancers was reduced from a mean of 5.36 total cancers per patient prior to conversion to 1.57 new cancers following conversion to SRL. For the 19 patients with a high number of skin cancers prior to conversion, eight have yet to develop a new skin cancer, six have developed one to two new cancers and five patients have developed three. Conversion from a CNI plus or minus antimetabolite agents to SRL with minimization of other agents thus may be of potential benefit for renal transplant recipients with basal or squamous cell carcinoma.

Questions and Answers with Dr. Jean Shapiro, University of British Columbia, Vancouver

Q: How extensive is skin cancer in the kidney transplant population?

A: We don’t have prevalence figures for our own local population but observational data would suggest the risk is greatly magnified in transplant recipients. Certainly we have a significant burden of skin cancer in our own clinic and there is no standard approach to treating it in most Canadian centres. But among the things transplant physicians do try to do is modify the immunosuppressive regimen following the diagnosis of skin cancer. About the time we started this study, information was emerging showing that SRL has anti-cancer properties that are not shared with other immunosuppressant agents.

Q: Can you describe the kind of patients you involved in this conversion study?

A: The initial population included patients who were very stable, had no proteinuria and with reasonable kidney function before we made the switch. They also had awful skin cancer; they were visiting a dermatologist very frequently to have the lesions removed and they weren’t very happy about it.

Q: So can you now say that a SRL-based regimen will reduce the risk of skin cancer in renal transplant recipients?

A: Follow-up is still too short-term to say definitively if SRL reduces the risk of skin cancer. But certainly I would say subjectively that patients’ skin looked so much better within as little as two months of converting to SRL. And the literature would suggest that you delay the next skin cancer as well as the severity of the next skin cancer, so I expect that this is what we will see even though this is still preliminary data.

1525 Sirolimus-Based Calcineurin Inhibitor-Sparing Immunotherapy: Six-Year Results D. J. Conti, M. H. Gallichio

The immunosuppressive efficacy of sirolimus (SIRO) has stimulated efforts to limit calcineurin inhibitor (CNI) exposure in SIRO treated patients. We report our 6-year experience, patients enrolled between 5/01 and 8/02, with a CNI-sparing protocol in 50 consecutive primary renal transplant recipients. Patient characteristics were as follows: mean age 46 years, male 64%, Caucasian 80%, deceased-donor 54%, diabetes 40%. Recipients were treated with a triple drug regimen consisting of SIRO, tacrolimus and prednisone. SIRO dosing was adjusted to target a trough level of 10 ng/mL. Tacrolimus dosing in the first three months was targeted to trough levels of 8- 12 ng/mL. At 90 days tacrolimus dosing was decreased by 50% with subsequent maintenance dosing targeted to a trough level of 3 ng/mL.

The mean follow-up at 12/1/07 was 72 months (64- 79 months). At 90 days post-transplant the mean SIRO trough level was 10.9 ng/mL (6-21) and the mean 12-hour trough tacrolimus level was 8.4 ng/mL (4.4-13.3). Subsequent to tacrolimus dose reduction at three months, the mean trough tacrolimus level at 6 months was 3.1 ng/mL (1.7-6.5).

Patient and allograft survival at 1-year was 98%. Long-term actual patient and allograft survival, as of 12/1/07, was 82% and 72% respectively. Mortalities were due to cardiovascular events (n=5, at 13, 16, 30, 36 and 48 months), infection (n=2, at 8 and 42 months), malignancy (n=1, at 45 months), and unknown causes (n=1, 49 months). Five additional grafts have been lost to, chronic nephropathy at 28, 58 and 68 months, recurrent disease at 66 months and BK nephropathy at 44 months. There have been no graft losses to acute rejection. Acute rejection developed in 5 patients (10%), with all episodes occurring within 14 days of transplantation. No acute rejection episodes have been identified more than 90 days post-transplant when CNI dosing was reduced. Mean serum creatinine levels at 12 (n=49), 24 (n=47), 36 (n=45), 48 (n=41), 60 (n=37) and 72 (n=21) months were 1.5, 1.5, 1.5, 1.6, 1.6, and 1.6 mg/dL, respectively.

This SIRO, CNI-sparing and steroid regimen provided potent immunotherapy for primary renal transplant recipients. The incidence of acute rejection was only 10%. In addition, subsequent to reduced Prograf dosing and target levels, acute rejection did not occur. Furthermore, 6-year renal allograft survival is excellent and serum creatinine levels have remained stable long-term. SIRO maintenance immunotherapy safely allows for a 50% reduction in tacrolimus dosing and levels at three months.

Commentary on abstract 1525

The mTOR inhibitor SRL has proven to be a potent immunosuppressant. It offers an opportunity to reduce exposure to the CNI inhibitors, thereby reducing the risk of CNI-driven nephrotoxicity. At the same time, early CNI elimination may increase the risk of acute rejection. In a single-centre experience, 50 consecutive renal transplant patients received SRL, TAC and prednisone for three months. Target trough levels were 10 ng/mL for SRL and target trough levels for TAC ranged from 8 to 12 ng/mL. Three months’ post-transplant, TAC was decreased by 50% and target maintenance trough levels were set at 3 ng/mL. Acute rejection occurred in five patients, all within 21 days of transplant. Eighty per cent were Banff 1A and 80% were steroid-responsive. There were no episodes of recurrent acute rejection and no episode of acute rejection developed following reduction of TAC dose at three months. At six years, 82% of patients were alive and graft survival was 72%. Renal function remained remarkably stable out to a mean follow-up of 72 months. This experience suggests that SRL maintenance immunotherapy can reduce the need for TAC exposure by 50% three months’ post-transplant and that it is associated with excellent preservation of both graft and renal function.

Questions and Answers with Dr. David Conti, Albany Medical College, New York

Q:What made you want to explore a CNI-sparing as opposed to a CNI-elimination regimen?

A: CNIs are very potent immunosuppressants so our aim was to reduce nephrotoxicity without stimulating rejection. This is why we opted for a minimization rather than complete withdrawal strategy.

Q: Was the target trough level you chose for SRL higher than is usual at 10 ng/mL? If so, did you do that to ensure that patients would not reject their allograft when the dose of TAC was reduced? And did the trough levels remain constant throughout the follow-up?

A: Our SRL 24-hour trough level target was not all that much higher than recommended, but yes, since we were reducing CNI dosing and levels, we wanted to maintain adequate immunosuppression to prevent rejection, and yes, SRL levels remained fairly constant throughout follow-up.

Q: The patients you enrolled in this CNI-sparing protocol were consecutive primary renal transplant patients so it does not sound as if they were highly selected for this particular regimen. In other words, can this regimen be applied with relative confidence across the spectrum of kidney transplant patients?

A: Our data are only valid for our patient population, primary renal transplant patients, so it would be conjecture for me to speculate on other patient populations with this long-term data. We have applied this protocol to other patient populations, but do not have an equivalently long follow-up.

Q: Finally could you expect a 50% reduction in TAC dosing and levels to be associated with less nephrotoxicity and AEs relevant to CNIs?

A: Absolutely, yes, as evidenced by the stability of renal function long-term in our patients.

531 Improved Outcomes After De Novo Renal Transplantation: 2-Year Results from the Symphony Study H. Ekberg, H. Tedesco-Silva, A. Demirbas, S. Vitko, J. Klempnauer, A. Gurkan, R. Margreiter, C. Hugo, J. Grinyo, U. Frei, Y. Vanrenterghem, P. Daloze, P. Halloran

Introduction: Results from the 1-year Symphony core study showed that a regimen with 2 g mycophenolate mofetil (MMF)+low-dose tacrolimus (3-7ng/mL)+ daclizumab+steroids results in lower acute rejection rates and improved renal function compared with 2g MMF+steroids and either standard-dose cyclosporine (CsA), low-dose CsA (50-100ng/mL)+daclizumab, or low-dose sirolimus (4-8ng/mL)+daclizumab.

Methods: 968 patients were included in an optional 1-year observational follow-up study (61% of the core ITT population). Glomerular filtration rate (GFR) data from 84% of patients were available at 2 years.

Results: At inclusion into follow-up, 47% of patients received a regimen containing standard- or low-dose CsA, 34% tacrolimus and 17% sirolimus, whereas about 25% were included in each group at randomization, indicating that follow-up patients are likely to have been switched to tacrolimus, especially from sirolimus. Most patients were maintained on MMF over the study period: 96% and 85% at years 1 and 2. The incidences of biopsy-proven acute rejection (2-4%) and graft loss (1-3%) were low in year 2 in all groups. At 2 years, the rate of uncensored graft loss was lowest in patients receiving tacrolimus (8% vs 10-13% in other groups; Kaplan-Meier estimates). GFR at the end of the core study was slightly better in the follow-up ITT patients (65-70 mL/min) than in the core study ITT patients (57-65 mL/min), suggesting inclusion of betterperforming patients in the follow-up. Renal function was generally stable over year 2. A slight improvement in GFR in the sirolimus group (+1.6 mL/min) was observed, whereas the tacrolimus group still had superior GFR (69 vs 65- 67 mL/min in other groups).

Conclusions: In follow-up patients, renal function was stable during the second year and GFR differences were less marked than at 1 year. The favorable outcomes of a regimen consisting of MMF+low-dose tacrolimus+daclizumab+steroids on renal function, acute rejection and graft loss were confirmed by this follow-up study.

Commentary on abstract 531

The SYMPHONY trial was the largest trial ever conducted in renal transplant recipients. At one year, renal allograft patients in SYMPHONY on MMF plus low-dose TAC had fewer acute rejection episodes and an improved GFR compared with those on MMF and standard-dose CsA, MMF with low-dose CsA, or those on MMF with low-dose SRL. BPAR was best prevented by low-dose TAC (12%) vs. 25% in both CsA groups and 37% in the SRL group. During the second and third year, there was a further reduction in the proportion of patients who received CsA and SRL, and more who received TAC. Still, 95% of patients remained on MMF and 70% remained on steroids. BPAR rates during the second and third year were similar at under 4% and only minor changes in renal function were seen during the second and third year. The incidence of graft loss in the three groups was low at under 6%. Nevertheless, at 36 months, renal function and graft survival were still superior in the low-dose TAC group. These findings suggest that low-dose TAC plus MMF improve renal function and rates of acute rejection and graft loss at three years, although differences between the groups were less marked than they were at one year.

Questions and Answers with Dr. Henrik Ekberg, Lund University Hospital, Malmö, Sweden

Q: Can you describe the patients who took part in the two- and three-year extension trial and did they differ in any significant way from the original cohort?

A: Approximately 60% of the original cohort took part in the two-year follow-up study and we had GFR data on 768 patients in the extension study for analyses. More patients from the original low-dose TAC and lowdose CsA groups were followed up but it was still more or less 25% in each treatment group who were part of the extension study, so the follow-up intent-to-treat was really representative of the original cohort, although GFR was slightly higher in the follow-up cohort.

Q: Did you see much polyomavirus in any of the treatment groups?

A: The BK virus is one that is becoming more important in transplantation today, but only about 0.5% of patients were reported to have BK viral problems across all treatment groups, and there was no significant difference between the groups in the incidence of this.

289 Successful Calcineurin-Inhibitor (CI) Discontinuation Following Early Steroid Withdrawal (ESW) in Renal Allograft Recipients: Reduced Chronic Allograft Nephropathy (CAN) and Improved Renal Function Without Increased Rejection or Graft Loss R. B. Stevens, L. Wrenshall, D. Mercer, T. Rigley, K. Nielsen, M. Henning, J. Skorupa, A. Skorupa, J. Sandoz, A. Kellogg, C. Miles, V. Rao, G. Groggel

We hypothesized that rATG induction would enable safe discontinuation of CI maintenance in renal transplant patients on steroid-free immunosuppression. We compared two rATG induction protocols (6/mg/kg x 1 dose vs. 1.5 mg/kg x 4 doses) in a prospective randomized trial of CI discontinuation (tacrolimus/ sirolimus vs. mycophenolate mofetil/sirolimus) combined with ESW in kidney recipients (Fig. 1A).

We enrolled 152 patients (Table 1) with an average follow-up of 19.7±11.7 months. Subjects 19-65 years old included primary and re-transplants, with primary endpoints of renal function and CAN. Followup averaged 16.6±9.5 months in 47 patients withdrawn from CI (26 from Group 3, 21 from Group 4). We found no increased rejection after CI discontinuation and that both rATG induction dosing regimen and CI discontinuation significantly impacted renal function and the development of CAN.

Conclusions: We successfully discontinued both calcineurin inhibitors and steroids with either single or divided-dose rATG induction, and single-dose rATG induction independently associated with
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Commentary on abstract 289

Antibody induction is a mainstay in contemporary immunosuppression, particularly in patients at high immunologic risk. Both depleting and non-depleting antibodies are used for induction therapy, including rabbit antithymocyte globulin (rATG), a pan T-cell-depleting agent. This randomized prospective trial used a single fixed-dose of rATG (6 mg/kg) for induction, or four divided doses (1.5 mg/kg) given together with methylprednisolone. Patients were then maintained on SRL and TAC for six months and either remained on SRL/TAC or were switched to SRL/MMF. Patients from both induction regimens were each randomized to the two regimens so there were four groups in total. In updated data with an average follow-up of almost 20 months, the CNI component of SRL/TAC was withdrawn in 54 patients. Seventy per cent of this group has been maintained on a CNI-free, steroid-free maintenance regimen out to an average of 22 months. The other 30% had to go back on CNI therapy, at least temporarily. There was no difference in patient, graft or rejection-free graft survival rates between the four groups, but there was an improvement in recovery of early renal function in the CNI-withdrawal groups vs. a decline in those who remained on SRL plus TAC. Investigators concluded that single-dose rATG induction is well tolerated, as was the SRL plus MMF regimen, and the rejection-free graft survival rate was similar to the cohort in whom CNI was not withdrawn.

Questions and Answers with Dr. Brian Stevens, University of Nebraska Medical Center, Omaha

Q: You reported an improvement in early renal function in the CNI-withdrawal groups. How much of an improvement was there?

A: Two months following CNI withdrawal, there was about a 2% increase in calculated GFR in the singledose rATG induction group, and about a 4% increase in calculated GFR in those who received the divided dose regimen vs. about a 5% decrease in both induction groups who were not withdrawn from CNI therapy.

Q: What about the probability of patients having evidence of CAN?

A: The probability of group 2 who remained on SRL plus TAC of developing CAN was significantly greater than it was for group 3 who were receiving SRL plus MMF following divided-dose rATG induction.

Q: Did you evaluate proteinuria in patients?

A: We routinely do, it is part of our standard analysis, and at this point in their follow-up, there was no difference in proteinuria between any of the groups. In our experience, only a very small subset of these patients risks developing clinically important proteinuria.

Q: Do you think this immunosuppressive regimen is a reasonable one for others to emulate?

A: If you ask me what I think the best strategy is, I think it is reasonable to withdraw steroids because I think there is a benefit to steroid-free regimens; but if you have to choose between steroids and the CNIs, we’ll keep the CNIs off and the steroids on. My other bias is induction with a single large dose of rATG and having a CNI-free maintenance protocol, at least for some patients. But I also think multiple protocols have to be used and you need to individualize the regimen for each patient.

526 Opticept Trial: Efficacy and Safety of Monitored MMF in Combination with CNI in Renal Transplantation at 12 Months R. Gaston, B. Kaplan, H.-U. Meier-Kriesche, L. Shaw, T. Shah, D. Patel, R. Bloom

Opticept is a 2-year open-label, prospective, randomized, multicenter study involving 720 singleorgan renal allograft recipients administered either A) concentration-controlled MMF and reduced level CNI (MMFCC/CNIRL) B) concentration-controlled MMF and standard level CNI (MMFCC/CNISL) or C) fixed-dose MMF (1 g BID) and standard level CNI (MMFFD/CNISL). Trough-based dose adjustments were made in the MMFCC arms. Antibody induction and/or corticosteroids were administered according to center practice. Primary endpoints were the proportion of patients with treatment failure (biopsy-proven acute rejection [BPAR], graft loss, death), and mean percent change in calculated glomerular filtration rate (GFR; Nankivell equation) at 12 months. Safety endpoints were incidences of adverse events (AEs) and serious AEs. Non-inferiority (a=0.05) of A vs. C (MMFCC/CNIRL vs. MMFFD/CNISL) for treatment failure was tested.

Baseline characteristics did not differ among treatment groups with living donors accounting for approximately 50% of grafts. 82% received tacrolimus (Tac) and 18% cyclosporine (CyA): CNI doses and levels were significantly lower in Group A. MMF doses were greater in CyA-treated subjects in all groups.

Serum creatinine tended to be lower at 12 months in the Tac vs. CyA treated patients and in Group A (p=0.08); stability of renal function over time was greatest in Group A. Despite higher MMF doses in Group A (p<0.001) at most time points, significantly fewer MMF withdrawals occurred in Group A vs. Groups B and C.

Conclusions: A concentration-controlled MMF and reduced level CNI regimen is not inferior to that of fixed-dose MMF and standard-dose CNI as regards BPAR and other end points. This regimen facilitated higher MMF dosing without an overall increase in adverse effects, and with a trend toward preservation of kidney functi
e CNI regimens. Longer follow-up may provide additional insights into the impact of these short-term findings.

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Commentary on abstract 526

OPTICEPT included 720 renal allograft recipients assigned to either concentration-controlled MMF and a reduced-level CNI (A n=243); concentration-controlled MMF and standard-dose CNI (B n=237); or fixeddose MMF and standard CNI (C n=240). MMF dose was adjusted to achieve MPA troughs of at least 1.3 µg/mL for CsA patients and 1.9 µg/mL for those on TAC. At 12 months, treatment failure (BPAR, graft loss, death, loss to follow-up)—the primary end point of the study—had occurred in 20.6% of group A, 28.7% in group B and 26.7% in group C. BPAR rates for groups A, B and C were 6.2%, 9.7% and 9.6%, respectively, while rates of graft loss were 2.1%, 1.7% and 1.7%, respectively. Renal function stability was greatest in group A and significantly fewer MMF withdrawals occurred in this group than in the other two groups, despite higher MMF doses. Withdrawals due to AEs occurred in 7% of group A, and 14% in groups B and C. OPTICEPT thus demonstrated that a therapeutic monitored dose of MMF plus reduced-dose CNI is not inferior to that of fixed-dose MMF plus standard CNI with a trend towards better preservation of kidney function vs. standard-dose CNI.

Questions and Answers with Dr. Robert Gaston, OPTICEPT principal investigator, University of Alabama, Birmingham

Q: What was the rationale behind the OPTICEPT study?

A: Data gathered over the last decade has indicated there is a benefit of MMF individualized dosing, and the hope in this study was that by individualizing dosing, you would be able to reduce the doses of the more toxic CNI drug. Indeed, this study seems to point in that direction.

Q: What advantages would a regimen such as the one you used have in its ability to facilitate higher MMF dosing?

A: When MMF dosing was higher in the monitored group, there were fewer withdrawals due to AEs, so it seems as if this strategy allows you to administer higher doses of the drug with fewer AEs.

Q: Was there a relationship between MMF exposure and rejection risk?

A: There was a strong relationship, particularly in the TAC population, between MMF exposure measured as trough or as AUC and the risk of rejection, and this relationship was true when we looked at data at six months, 12 months and even 24 months’ post-transplantation. So the higher the exposure to MMF, the lower the risk for rejection, whether the patient received TAC or CsA; regardless of which arm they were on, if they maintained a mean MPA trough in the first year above 1.6 µg/m, the risk of rejection was quite low.

1536 Six-Month Feasibility Study to Evaluate Replacement of Calcineurin Inhibitors (CNI) with Basiliximab in CNIIntolerant Maintenance Kidney Transplant Recipients J. Gill, R. Dandavino, R. Prasad, A. Shoker, J. M. Kovarik

The long-term use of CNIs is potentially associated with progressive renal function impairment, hypertension, and metabolic abnormalities. We explored the feasibility of replacing CNIs with basiliximab (Simulect) in CNI-intolerant maintenance kidney transplant recipients.

Study design: In this multicenter, open-label study, patients treated with mycophenolic acid and steroids were given 40mg basiliximab iv once-monthly for 6 months. The CNI dose was reduced to 50% on day 1, to 25% at week 2, and discontinued at month 1. In addition to standard clinical data, basiliximab serum levels and percent CD25+ T-cells were measured.

Patient characteristics: Seven patients were enrolled (mean age 54 years; 87% white) at a median 7.2 years post-transplantation. CNIs were cyclosporine (5 patients) and tacrolimus (2 patients). Two patients discontinued the study after the first and fourth basiliximab dose because of protocol violation and graft loss, respectively.

Basiliximab pharmacokinetics: The peak basiliximab concentration (Cmax) after dose 1 was 12.2 ±4.1 mcg/mL. All predose basiliximab concentrations (C0) during treatment were above the level usually associated with CD25 saturation (>0.2 mcg/mL). Cmax after dose 6 was 9.8±5.1 mcg/mL. Basiliximab accumulation in serum was minor amounting to 1.5-fold from month 1 to month 6.

CD25 saturation: For 25 of the 32 trough blood samples, CD25 measurements were also available. In the 5 patients with long-term data, their individual CD25 inhibition level was established and maintained after the first dose (n=3), second dose (n=1) or third dose (n=1).

Clinical observations: There was 1 graft loss due to chronic rejection, following reduction of MMF dose due to GI side effects; there were no acute rejection episodes. Serum creatinine was 167.4±18.5 µmol/L prestudy and 161.6±21.0 µmol/L at month 6.

Conclusions: Once monthly dosing of 40 mg basiliximab successfully maintained serum drug levels above the target of 0.2 mcg/mL over
ements indicated that stable CD25 inhibition was reached at or before dose 3. Additional clinical experience with such a replacement approach is warranted.

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Commentary on abstract 1536

Basiliximab is a monoclonal antibody that binds to and blocks the interleukin-2 (IL-2) receptor on the surface of T-lymphocytes, thereby inhibiting IL-2-mediated activation of T-lymphocytes, a critical pathway in allograft rejection. A previous study suggested that basiliximab may permit reduction in CNI dosing in certain heart transplant recipients (Transplantation 2002;73:1169-72). Investigators thus evaluated the feasibility of replacing CNIs with basiliximab in CNI-intolerant kidney transplant recipients. Five out of seven enrolled patients completed the study. After six months of treatment, serum concentrations of basiliximab remained above 0.1 µg/mL, a threshold associated with CD25 saturation. CD25-positive lymphocytes decreased by 92% to 100% from baseline in three patients and 85% and 62% in the other two patients. One patient experienced graft loss following dose reduction of MMF due to AEs but no new chronic rejection episode occurred. There were also no treated acute rejection episodes or deaths. Serum creatinine levels remained steady at 161.6 µmol/L at six months compared to 167.4 µmol/L at study entry. Investigators concluded that the monthly dosing regimen as explored in this study was able to maintain basiliximab serum concentrations above the threshold usually associated with CD25 saturation in all seven patients over six months.

Questions and Answers with Dr. John Gill, University of British Columbia, Vancouver

Q: Your secondary objectives were to evaluate the risk of sensitization against the chimeric antibody by looking for neutralizing antibodies or anaphylaxis-mediating antibodies or clinical anaphylaxis. What did you find?

A: Human anti-drug antibodies were detectable in five out of the seven patients who received the drug six months after treatment but we did not identify any clinical consequences. Patients did not show a positive skin test nor did they have signs of sensitization against basiliximab.

Q: What types of AEs did you observe?

A: One patient experienced a serious AE due to complications of transplant surgery and chronic renal failure and was discontinued from the study due to graft loss. Two others experienced an AE suspected by the investigator to be related to study medication, one being anemia, and both patients developed one or more infections, but neither of them had to discontinue treatment because of AEs.