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Avoidance of Cyclosporine in Renal Transplantation

Effects of Daclizumab, Mycophenolate Mofetil, and Steroids

HUONG T. B. TRAN^*,, MURALIDHAR K. ACHARYA^*, DIANNE B. MCKAY^*, MOHAMED H. SAYEGH^*, CHARLES B. CARPENTER^*, HUGH AUCHINCLOSS, JR., ROBERT L. KIRKMAN and EDGAR L. MILFORD^*

^* Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Department of Internal Medicine, Ho Chi Minh City University of Medicine and Pharmacy, Viet Nam.

Correspondence to Dr. Edgar L. Milford, Renal Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-5872; Fax: 617-566-6176; E-mail: emilford{at}rics.bwh.harvard.edu

	Abstract

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Abstract. Cyclosporine (CsA) has been implicated in both acute and chronic graft dysfunction. The addition of humanized IL-2 receptor antibody daclizumab (DZB) to CsA-based immunosuppression decreases the rate of acute renal transplant rejection. Therefore, 45 patients were evaluated in an immunosuppressive protocol that included DZB, mycophenolate mofetil (MMF), and steroids without CsA. This was a prospective, nonrandomized, open-label trial of the efficacy and safety of the treatment. DZB was given intravenously at 2 mg/kg before transplantation and then at 1 mg/kg every 2 wk for four doses, MMF was given orally at 3 g/d, and methylprednisolone/prednisone was given at 7 mg/kg per day and tapered to 15 mg/d at 6 mo. CsA was added to the regimen when patients developed acute rejection episodes or adverse effects to steroids or MMF; 49% of patients were spared CsA maintenance. Patients without CsA had lower serum creatinine at 6 mo and needed fewer medications to control BP. Incidence of biopsyproven rejections was 31% and occurred early (median, 10 d). These rejection episodes occurred earlier in cadaver transplants (median, 7 d) and later in living donor transplants (median, 62 days). Acute rejections occurred at a higher frequency (46% versus 34%) and earlier (6.5 versus 15 d) in patients with delayed graft function compared with patients without delayed graft function. Most of the rejections were moderate and easily reversible. The actuarial 1-yr graft survival was 95% with 100% patient survival.

	Introduction

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The introduction of cyclosporine (CsA) to the immunosuppressive armamentarium in the early 1980s resulted in 1-yr graft survival of 70 to 80% for cadaver renal transplants. Presently, most transplant centers achieve 85 to 90% 1-yr graft survival (1). Improvement in long-term graft survival after the first year, however, has been less impressive (2,3). CsA nephrotoxicity is a risk factor for acute and chronic graft dysfunction (4,5). CsA has also been implicated in the development of hypertension and hyperlipidemia, which can contribute to increased cardiovascular morbidity and chronic allograft dysfunction (6,7). These limitations constitute a rationale for the development of an immunosuppressive protocol that includes the humanized anti—IL-2 receptor monoclonal antibody daclizumab (DZB), mycophenolate mofetil (MMF), and steroids, without CsA.

DZB used in conjunction with CsA, prednisone, and/or azathioprine (AZA) as standard maintenance immunosuppression has been successful in the prevention of acute renal allograft rejection (8,9,10). Humanization of monoclonal antibodies from other species prolongs antibody half-life in vivo and markedly reduces risk of inducing xenoantibodies. DZB therapy was well tolerated and did not result in increased incidence of infection or malignancy.

DZB binds the subunit of the high-affinity IL-2 receptor that is expressed on activated T cells and blocks the interaction between IL-2 and the receptor. IL-2 promotes the clonal expansion of T cells, thereby enhancing the inflammatory response against an allograft (11).

MMF is a potent immunosuppressive agent that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. It can replace AZA when used with CsA as maintenance immunosuppression. It is not nephrotoxic and has less bone marrow toxicity than AZA (12). Recent studies have revealed that patients who were treated with MMF had lower incidence of rejection, compared with AZA (13,14,15).

We report a prospective, nonrandomized, open-label trial of treating patients with DZB, MMF, and steroids as initial immunosuppressive therapy. The objective was to add CsA only if rejection occurred.

	Materials and Methods

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Patients
The study group consisted of 45 consecutive recipients of renal allografts (26 cadaver, 13 living related, and 6 living unrelated donors) in the Brigham and Women's Hospital. Two patients with primary nonfunction, one with renal artery thrombosis, and one with hyperacute rejection were excluded from enrollment. There were no differences in demographic characteristics between cadaver and living donor transplants (Table 1).

Humanized Monoclonal Anti—IL-2 Receptor Antibody
DZB (Zenapax, Hoffman LaRoche, Nutley, NJ) is a humanized IgG1 anti—IL-2 receptor monoclonal antibody directed against the chain of the IL-2 receptor. The humanized antibody is composed of 90% human and 10% murine sequences. The latter compose the antigen binding region.

Immunosuppressive Treatment
A loading dose of 2 mg/kg DZB was administered intravenously within 12 h of transplantation. Four subsequent doses of 1 mg/kg per day were given every fortnight as an outpatient. MMF was given at orally 1.5 g twice a day starting at transplantation. Methylprednisolone (Solu-Medrol, Pharmacia, Peapack, NJ) was started intravenously at 7 mg/kg in the operating room and reduced to 3 mg/kg and 2 mg/kg on days 2 and 3, respectively. Oral prednisone was continued at 100 mg on day 4 and then tapered to 30 mg/d and maintained at that dose for the first month. Afterward, prednisone dose was reduced to the target dose of 15 mg/d by 6 mo. CsA was added to the immunosuppressive regimen when there was a clinical rejection episode or when MMF needed to be discontinued because of leukopenia or severe diarrhea. Blood CsA level was maintained at 250 to 300 ng/ml.

Diagnosis and Treatment of Acute Rejection Episodes
Clinical acute rejection was presumed when the creatinine rose by 20% with no other explanation or when creatinine failed to drop below 2.5 mg/dl in the first 6 d posttransplantation. Histologic diagnosis of rejection was based on the presence of acute tubulitis with or without vasculitis and was graded according to the Banff 1993 classification (16). Routine treatment for first rejection episodes was methylprednisolone, 1 g/d intravenously for 3 d. Antilymphocyte monoclonal antibody (OKT3) was used for 10 to 14 d when the patient experienced steroid-resistant rejection or the biopsy displayed severe vascular rejection. In addition to adding CsA to the regimen and reducing MMF dose to 1 g twice a day, the course of DZB infusions was continued in patients with rejection.

Infection Prophylaxis
Oral ganciclovir (Cytovene, Hoffman-LaRoche) prophylaxis for cytomegalovirus (CMV) infection was administered to all patients for 3 mo, except for CMV seronegative recipients of a CMV seronegative kidney. Trimethoprim-sulfamethoxazole (Bactrim DS, Hoffman-LaRoche) 160/800 mg orally three times a week was given for Pneumocystis carinii prophylaxis for 3 mo posttransplantation.

Statistical Analyses
Continuous variables such as patient and donor age, weight, serum creatinine, and systolic BP were analyzed using univariate ANOVA and t test. Categoric variables such as gender and race were compared using ² test.

	Results

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All but one patient completed the five doses of DZB. None of the DZB-treated patients developed a cytokine-release syndrome or other symptoms attributed to the infusion of the DZB. It was safe to give the infusion of DZB in an outpatient setting, as infusions were not associated with any acute side effects or allergic reactions. The median follow-up time was 8 mo (range, 2 wk to 13 mo).

Acute Rejection
The incidence of presumptive and biopsy-proven rejection, the timing to first rejection, and the severity of rejection are presented in Table 2. Fourteen of 45 patients (31%) had biopsy-proven rejection, and in 3 additional cases, the diagnosis was presumptive for a total of 17 of 45 (38%) rejections. There were only two patients who had recurrent acute rejection, one with chronic diarrhea and medication intolerance and another with noncompliance. Both patients lost their grafts after 6 mo. Fifty percent of the biopsy-proven rejection episodes occurred early (median time to rejection, 10 d), before the second infusion of DZB. Ten of the 14 biopsy-proven rejection episodes occurred before the full course of the DZB was completed. Although the frequency of biopsy-proven rejection episodes in the cadaver and living donor groups was similar (35% and 26%, respectively), median time to rejection was 7 d for cadaver and 62 d for living donor transplants.

Thirteen of 14 (93%) of the rejection episodes were mild to moderate (Banff class I, II). Five patients had mixed cellular and vascular pathology on biopsy. Treatment of first presumptive or biopsy-proven rejection episodes with steroid pulse therapy was successful in 12 of 17 patients. The other five patients required OKT3 treatment (three for refractory rejection and two for vascular rejection).

There was no statistically significant difference in the demographic characteristics between the two groups (Table 3). None of the four patients who failed a previous kidney transplantation experienced rejection. With the reduction of MMF dose after rejection and addition of CsA, the rejection group had a significantly lower mean MMF dose than did the non-rejection group (P = 0.001; Table 4). The length of the first hospitalization for transplantation was significantly longer for the patients with rejection compared with those without rejection (P = 0.04). There were no differences in infectious complications after transplantation. Most of the infections were urinary tract or wound infections and had minor clinical significance. No patients had tissue-invasive CMV infection. Two patients with both CMV donor and recipient seropositive had mild clinical infection with CMV antigenemia after completing 3 mo of anti-CMV prophylaxis.

Delayed Graft Function
Delayed graft function (DGF) was defined as requiring hemodialysis during the first week after transplantation. The incidence of DGF, all of the cases of which occurred in the cadaver kidneys, was 13 of 26 (50%). There was an increase in the incidence of biopsy-proven rejection of 46% versus 34% in the group with DGF compared with recipients with immediate kidney function (Table 5); however, this difference was not statistically significant (P = 0.46, ² test). The median time to first rejection was 6.5 d versus 15 d in DGF and non-DGF, respectively.

Graft Function and Graft and Patient Survival
Six of 28 patients with no clinical evidence of rejection had CsA added because of either leukopenia from MMF or steroid-induced myopathy. The mean serum creatinine levels were significantly higher in the rejection group with CsA than in the nonrejection group without CsA at 3 mo posttransplantation (P = 0.02; Table 6). Two patients returned to dialysis, and no patients died during the follow-up period. Actuarial graft survival was 95%, and patient survival was 100%.

The rejection group with CsA use had higher mean systolic BP at 1 mo compared with that of the nonrejection group without CsA use (P = 0.03). By 6 mo posttransplantation, these groups had similar mean systolic BP of 125 mmHg; however, the number of drugs required in the rejection group was higher than in the nonrejection group (P = 0.03). These data show a trend toward more severe hypertension in patients who have rejection episodes and are receiving CsA. The nonrejection group that was spared the use of CsA had better graft function and less severe hypertension.

	Discussion

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This study was undertaken to assess the potential risks and benefits of using a new combination of recently approved immunosuppressive agents for the prevention of rejection in place of CsA or tacrolimus. The actuarial 1-yr graft survival of patients initiated on DZB, MMF, and steroids was 95%, with 100% patient survival.

Twenty-two of 45 recipients (49%) who received DZB, MMF, and steroids were spared CsA maintenance. The patients who remained off CsA had lower mean serum creatinine at 6 mo and required fewer medications to control BP than those who required CsA. Thirty-one percent of our patients had biopsy-proven acute rejection episodes. The incidence of acute rejection episodes was lower when compared with the similar avoidance CsA study, using the same protocol of DZB with MMF and steroids (50%) (17). However, it was higher when compared with the previous studies utilizing DZB with CsA and steroids with or without AZA (22% and 28%, respectively) (8,10). The episodes were mild to moderate in nature and were readily reversed. The interpretation of these results is limited by the fact that this trial is nonrandomized, open-label, and without matching controls. However, our study had 50% DGF in cadaver kidneys in the absence of CsA. All of the rejections occurred at a higher frequency (46%) and earlier (6.5 d) in patients with DGF compared with those without DGF (34%, 15 d; difference not significant) (Table 3). In contrast, in Vincenti's (17) CsA avoidance study, they did not find any correlation between acute rejection and DGF (F. Vincenti, personal communication, December 1999). Our observation of a higher incidence of acute rejection episodes in DGF is consistent with observations in previous studies (18,19,20). In addition to the above mechanisms, this finding could represent an acquisition bias as a consequence of the clinical practice of performing routine renal biopsies when DGF persists beyond 5 d.

Our observation of rejection timing is at variance with other studies using a combination of DZB, CsA, steroids, and/or AZA (8,10). The latter studies showed a significant delay in the onset of the first acute rejection episode. In contrast to our observation of early rejection episodes with the median time to rejection of 10 d, Vincenti (17), using the same protocol, reported prolonged median time to rejection of 37 d. However, half of his patients have remained off a calcineurin inhibitor, an observation similar to ours. Kirkman et al. (21) observed the early rejection episodes in four patients who were treated in one arm of study with murine IL-2 receptor antibody with the delayed CsA induction. Soulillou et al. (22) using a rat anti-human IL-2 receptor antibody, AZA, and steroids also found a numeric increase in rejection episodes in the first 2 wk after transplantation when CsA was withheld. This study was undertaken during the era without MMF. The use of DZB in the absence of CsA could result in continued transcription and synthesis of IL-2, and the IL-2 can presumably still interact with the ß and subunits that form the intermediate affinity IL-2 receptor, which is not blocked by DZB (11,23,24,25). In addition, our finding of earlier rejection episodes in patients with DGF supports the hypothesis that ischemia may increase the immunogenicity of the graft by the upregulation of MHC antigens (26,27,28) and release of inflammatory cytokines and chemokines (27,28,29). Ischemia/reperfusion has also been shown to upregulate the expression of B7 co-stimulatory molecules (28), which may augment the transcription of IL-2 and result in earlier rejection episodes. Acute rejection episodes may also be due to IL-15, a growth factor that stimulates T-cell proliferation in a fashion similar to IL-2, via a different receptor not blocked by DZB (30). Pavlakis et al. (31) showed that intragraft IL-15 transcripts were increased in patients who rejected renal allografts as compared with nonrejecting grafts.

Suppression of IL-2 transcription and secretion may be required to prevent early rejection in some patients who are treated with IL-2 receptor blocking drugs. Consequently, one may consider future use of low-dose CsA (4 mg/kg per day) in addition to IL-2 receptor blockade at the time of transplantation along with MMF and steroids to decrease the incidence of rejection without concomitant nephrotoxicity. This low-dose CsA may be continued indefinitely or for the first 6 mo in patients who do not develop acute rejection episodes. Kirkman et al. (32) showed a significant delay in the time to first rejection episode in a randomized prospective trial with murine monoclonal IL-2 receptor antibody along with low-dose CsA. One can also envision that blockade of co-stimulation along with IL-2 receptor blockade may offer both decreased rejection and donor-specific tolerance by blocking the translation and transduction of cytokines (33). Addition of rapamycin to IL-2 receptor blockade, which has a different mechanism of action, different from blockade of the IL-2 receptor, downstream in the intracellular signaling pathway of IL-2, may further decrease incidence of rejection episodes (34).

Even though with the usual five doses of 1 mg/kg DZB the subunit of IL-2 receptor is saturated up to 120 d posttransplantation (8), we used the higher loading dose of 2 mg/kg in the hope of preventing acute rejection episodes that occur in the absence of calcineurin inhibitors in the early posttransplantation period. However, the majority of our acute rejection episodes occurred in the first 30 d. Consequently, it might be possible to shorten the period of administration to only two to three doses of DZB and still realize the benefits of IL-2 receptor blockade. Such trials are ongoing. Basilixumab, which is a chimeric anti—IL-2 receptor monoclonal antibody, has been shown to significantly decrease the incidence of acute rejection episodes with two doses (35,36).

In conclusion, our study demonstrates that IL-2 receptor blockade with monoclonal antibody can be effectively used in a calcineurin inhibitor-sparing regimen of MMF and steroids in approximately 50% of the patients, without compromising renal function and graft and patient survival. However, the question of whether this protocol has any advantages over other protocols can be established only with randomized trials of appropriate size and duration. With this protocol, one must be vigilant in identifying and treating acute rejection.

	References

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