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Conversion to Combined Therapy with Sirolimus and Mycophenolate Mofetil Improved Renal Function in Stable Renal Transplant Recipients
ORIGINAL ARTICLE
Conversion to Combined Therapy with Sirolimus and Mycophenolate Mofetil Improved Renal Function in Stable Renal Transplant Recipients Meng-Kun Tsai, Chih-Yuan Lee, Rey-Heng Hu, Po-Huang Lee* Background/Purpose: Information is needed on renal function improvement after late elimination of calcineurin inhibitors (CNIs) and conversion to combined therapy of sirolimus (SRL) and mycophenolate mofetil (MMF) in Asian renal transplant recipients. Methods: A single-arm prospective study was undertaken to assess the outcome of stable Taiwanese renal transplant recipients who had CNI withdrawn and received combined SRL and MMF therapy. The primary endpoints were acute rejection and renal function. The secondary endpoints were graft and patient survival, side effects and infectious complications. Therapeutic drug monitoring of SRL and MMF was conducted during the study period. Results: Thirty patients were recruited at 9–72 (31.7 ± 18.6) months post-transplantation. The graft and patient survival rates were both 100% at 12 months, though one of the 30 patients (3.33%, 1/30) had biopsyproven acute rejection. On paired t test, the estimated glomerular filtration rates (GFR) from 4 to 12 months were significantly higher than the baseline GFR. The average trough level of SRL was 7.38 ± 3.74 ng/mL at 12 months and the average abbreviated area under the concentration curve of mycophenolic acid was 64.86 ± 36.62 mg/L·hour at an average MMF dose of 1.56 ± 0.45 g/day. However, two patients (6.67%, 2/30) had tuberculosis (TB) reactivation at 3 and 4 months, respectively, after the combined SRL and MMF therapy. Conclusion: Conversion to combined SRL and MMF therapy improved renal function in stable renal transplant recipients, though the risk of TB reactivation should be kept in mind when the combined therapy is employed in the Asian countries with a high prevalence of TB. [J Formos Med Assoc 2007;106(5):372–379] Key Words: mycophenolate mofetil (MMF), renal function, sirolimus (SRL)
Long-term treatment with a calcineurin inhibitor (CNI) has been shown to cause renal toxicity and chronic renal allograft dysfunction.1,2 Sirolimus (SRL), a new immunosuppressant without nephrotoxicity has provided a great opportunity to improve long-term graft survival in renal transplantation.3,4 The Rapamune Maintenance Regimen Study Group recently
reported that early withdrawal of cyclosporine from a cyclosporine/SRL/steroid regimen improved renal function and graft survival.5,6 In addition, early tacrolimus withdrawal from a regimen with SRL and tacrolimus has also been shown to bring about better renal function and significantly lower diastolic blood pressure.7 Therefore, CNI-free SRL-based maintenance
©2007 Elsevier & Formosan Medical Association .
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Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Received: September 29, 2006 Revised: November 6, 2006 Accepted: December 5, 2006
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*Correspondence to: Dr Po-Huang Lee, Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: [email protected]
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therapy might be beneficial for renal transplant recipients. Hyperlipidemia is a matter of serious concern to patients taking high-dose SRL and steroids, and so are pulmonary complications, including interstitial pneumonitis and tuberculosis (TB).8–11 As Renders et al recently demonstrated that lowdose SRL in combination with mycophenolate mofetil (MMF) improves kidney graft function late after renal transplantation, combined SRL and MMF therapy might confer the benefit of CNI elimination and avoid the troublesome side effects of high-dose SRL.12 Early clinical studies have documented that MMF, as compared with azathioprine, decreased the incidence of acute rejection in cyclosporine-based regimens.13 Moreover, pharmacokinetic studies suggested a 12-hour area under the concentration curve (AUC) of 30–60 mg/L· hour or a trough mycophenolic acid (MPA) concentration of 1–3.5 mg/L for reduction of acute rejection episodes in the early post-transplant period.14 Continued MMF therapy for 12 months or longer was shown to preserve renal allograft function from progressive decline.15 While Flechner et al demonstrated excellent results in de novo renal transplants using SRL and MMF in combination with anti-CD25 antibody induction and steroids, it appeared that elimination of CNIs and conversion to maintenance SRL and MMF therapy could provide adequate immunosuppression.16 However, the pharmacokinetic interaction between MMF and SRL has not been well characterized, nor has the dosage of combined SRL and MMF therapy in Asians. We thus conducted an investigator-initiated pilot study to determine any advantage and/or disadvantage of CNI elimination and conversion to combined SRL/MMF/steroid therapy in stable Taiwanese renal transplant recipients. Therapeutic drug monitoring of SRL and MMF was therefore performed.
Materials and Methods A single-arm prospective study was undertaken to determine the advantages and disadvantages of late J Formos Med Assoc | 2007 • Vol 106 • No 5
elimination of CNI and conversion to combined SRL and MMF therapy in stable Taiwanese renal transplant recipients. The study protocol was approved by the National Taiwan University Hospital Research Ethics Committee and patients gave their consent to receive the CNI-free immunosuppressive therapy. Adult renal transplant recipients on de novo cyclosporine- (Sandimmune Neoral, Novartis, Basel, Switzerland) or tacrolimus-based (Prograf, Fujisawa, London, UK) immunosuppressive therapy for at least 6 months were recruited. Recipients were excluded if they had recent acute rejection or deterioration of renal function (> 30%) within 12 weeks prior to enrolment. The screening procedures included complete blood counts, biochemistry tests, abdominal and renal sonography, chest X-ray, urinalysis and fasting blood sugar. Patients with steroid withdrawal, obstructive uropathy, multiple organ transplants, malignancy, hepatitis B, hepatitis C or active infection were excluded. The primary immunosuppressive regimens before CNI withdrawal were a CNI combined with either SRL (Rapamune, Wyeth-Ayerst, Philadelphia, USA) or MMF (Cellcept, Roche, Humacao, Puerto Rico). CNI elimination was accomplished through a 3-month transitional period of CNI minimization in combination with SRL/MMF/steroids before cyclosporine or tacrolimus was completely withdrawn. For those on primary CNI/MMF/ steroids therapy, 2 mg of SRL was added to the immunosuppression regimen with 50% dose reduction of the primary CNI and MMF during the first month of the 3-month transitional period. And, during the second month of the transitional period, CNI doses were further reduced to one fourth of the primary doses, and the dose of SRL adjusted to hit the target trough level, 8 nm/mL (monoclonal immunoassay). Then, the doses of CNI were further reduced, and MMF adjusted to reach a minimal daily dose of 1.5 g/day or white blood cell (WBC) counts around 4000/mm3 during the third month of the transitional period. As to patients on primary CNI/SRL/steroids therapy, CNI doses were gradually reduced and eventually eliminated, and MMF introduced during the transitional period. After CNI withdrawal, the SRL 373
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whole blood trough levels were checked monthly, and the doses were adjusted to maintain trough levels between 8 and 12 ng/mL. The target MMF dose was 2 g/day unless there was a WBC < 4000/ mm3 or intolerance to MMF. For patients with intolerance, the MMF dose was reduced. Neither antacids nor H2-blockers were administered to relieve gastrointestinal side effects. A pharmacokinetic monitoring of MMF was conducted at least 6 months after CNI withdrawal when a steady state of immunosuppression was achieved. The enzymemultiplied immunoassay technique was employed and validated by the Proficiency Testing Program.17 A three-sample method (C0, C0.5 and C2) by Shaw et al18 was used to calculate the abbreviated AUC of MPA.18 The abbreviated AUC0–12h of MPA was calculated using the regression equation: 7.75 + 6.49C0 + 0.76C0.5 + 2.43C2 (r2 = 0.862) The primary endpoints of this study were incidence of acute rejection and renal function after CNI elimination. The secondary endpoints were graft and patient survival, side effects and infectious complications. Patients with significant deterioration of renal function (> 30%) underwent graft renal biopsy, and biopsy-proven acute rejection was treated with corticosteroids. The glomerular filtration rate (GFR) immediately before and after CNI withdrawal was estimated by the Cockcroft–Gault formula, with a correction factor of 0.85 for women and compared by paired t test. History taking, physical examination, complete blood count, platelet counts, urinalysis and fasting blood chemistries, including blood urea nitrogen, serum creatinine, glucose, serum aspartate aminotransferase and alanine aminotransferase, triglycerides, cholesterol, alkaline phosphate and lactate dehydrogenase were regularly checked for identification of side effects. If hypertriglyceridemia (> 200 mg/dL) and hypercholesterolemia (> 240 mg/dL) were sustained for more than 3 months, treatment with fibrates and statins was initiated, respectively. The doses of fibrate and statin therapies were minimized if the follow-up lipid profiles normalized. Patients resumed their 374
original CNIs when SRL or MMF dose was significantly reduced because of side effects. Infectious complications were treated with empirical and then pathogen-specific antimicrobial therapy. Immunosuppressive therapy was not reduced during infectious episodes unless the episodes were life threatening.
Results Seventeen male and 13 female patients were enrolled to receive the combined SRL/MMF/steroid maintenance immunosuppressive therapy between June and August 2004. Seven of the 30 patients had been taking tacrolimus-based immunosuppressive therapy and the others cyclosporine-based regimens. The patients ranged in age from 19 to 67 years (43.5 ± 12.4 years). They were placed on the study immunosuppressive regimen at 9–72 months (31.7 ± 18.6 months) post-transplantation. The average serum creatinine level before elimination of CNIs was 1.48 ± 0.42 mg/dL (1.0–2.8 mg/ dL), and the average GFR 49.45 ± 19.40 mL/minute (24.6–116.4 mL/min). During the transition period and the 12-month study period, two patients resumed cyclosporine because of elevation of liver enzymes and two resumed tacrolimus, one because of IgA nephropathy and patient’s request (Patient 10) at 10 months and the other because of ventral hernia repair at 8 months. One patient with leukopenia stopped receiving MMF 1 month after CNI withdrawal but remained CNI-free. The graft and patient survival rates were both 100% at 1 year, although one of the 30 patients (3.33%, 1/30) had biopsy-proven acute rejection (Banff 97 IA). The specimen of renal biopsy showed Banff IA acute cellular rejection, and the patient received steroid pulse therapy in addition to the maintenance combined SRL/MMF/ steroid therapy. The rejection episode resolved smoothly and the patient was maintained on the study regimen without further decline in renal function. On intent-to-treat analysis, the average serum creatinine levels were 1.39 ± 0.39 and 1.41 ± 0.60 mg/dL at 6 and 12 months, respectively, and J Formos Med Assoc | 2007 • Vol 106 • No 5
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* * * ‡ ‡ † † † *
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Figure 1. Average serum creatinine levels (sCre) and estimated glomerular filtration rates (GFR) of renal transplant patients before and after withdrawal of calcineurin inhibitors (CNI) and conversion to combined sirolimus and mycophenolate mofetil therapy in (A) intent-to-treat analysis and (B) on-therapy analysis compared with baseline renal function just before CNI withdrawal. *p < 0.05; †p < 0.01; ‡p < 0.001; §p < 0.0001.
Table. Demographics and outcomes of the 30 patients enrolled for the combined SRL and MMF therapy after withdrawal of CNIs Patient demographics and outcomes*
Mean
Range
Patient age (yr) Graft age (months post-transplant) Gender (male/female) Primary CNI (cyclosporine/tacrolimus) Baseline sCre (mg/dL) Baseline estimated GFR (mL/min) sCre at 12 mo (mg/dL) Estimated GFR at 12 mo (mL/min) Acute rejection at 12 mo Graft survival at 12 mo Leukopenia (< 4000/mm3) Anemia (Hb < 10 g/dL) Hyperlipidemia (> 200 mg/dL) Hypercholesterolemia (> 240 mg/dL) Major infections
43.5 ± 12.4 31.7 ± 18.6 17/13 23/7 1.48 ± 0.42 49.45 ± 19.40 1.41 ± 0.60 54.02 ± 20.34 3.33% (1/30) 100% (30/30) 3.33% (1/30) 3.33% (1/30) 33.33% (10/30) 30.00% (9/30) 16.67% (5/30)
19–67 9–72 – – 1.0–2.8 24.6–116.4 0.9–4.0 17.3–98.5 – – – – – – –
*Results of intent-to-treat analysis are shown. SRL = sirolimus; MMF = mycophenolate mofetil; CNI = calcineurin inhibitor; sCre = serum creatinine; GFR = glomerular filtration rate; Hb = hemoglobin.
the average GFRs were 52.94 ± 18.40 and 54.02 ± 20.34 mL/minute at 6 and 12 months, respectively (Figure 1A). One patient (Patient 10) among the 30 patients had significant deterioration in renal function because of biopsy-proven IgA nephropathy. The GFR from 4 to 12 months after withdrawal of CNIs was significantly higher than the baseline GFR on the paired t test. However, we could not identify any subgroup (including patient age, gender, graft age, primary CNI and baseline J Formos Med Assoc | 2007 • Vol 106 • No 5
GFR upon CNI elimination) of patients who would be predicted to benefit from combined SRL and MMF therapy. Details of patient demographics and outcomes are summarized in the Table. As for on-therapy analysis, the average serum creatinine levels of patients on CNI-free therapy were 1.4 ± 0.41 and 1.29 ± 0.35 mg/dL at 6 and 12 months, respectively, and the average on-therapy GFRs were 51.09 ± 16.74 and 54.82 ± 17.86 mL/minute at 6 and 12 months, respectively 375
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10,000
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Figure 2. Average mycophenolate mofetil (MMF) and sirolimus (SRL) daily doses and trough SRL levels for renal transplant recipients on combined SRL and MMF therapy. CNI = calcineurin inhibitors.
(Figure 1B). The on-therapy GFR from 4 to 12 months was also significantly higher than the corresponding baseline GFR on the paired t test. After CNI withdrawal, the average doses of SRL were 2.38 ± 0.81 and 2.25 ± 0.89 mg/day at 6 and 12 months, respectively, and the trough blood levels were 7.87 ± 3.84 and 7.38 ± 3.74 ng/mL at 6 and 12 months, respectively. Details of SRL doses and trough blood levels are shown in Figure 2. The average MMF doses were 1.50 ± 0.44 and 1.45 ± 0.56 g/day at 6 and 12 months, respectively (Figure 2). Eighteen of the 25 patients who remained on the combined SRL/MMF/steroid regimen agreed to undergo the pharmacokinetic study of MPA. Their albumin levels ranged from 3.9 to 5.0 g/dL. The average MPA C0 was 3.21 ± 2.55 mg/L, average C0.5 21.81 ± 13.67 mg/L and average C2 8.10 ± 6.28 mg/L. The abbreviated AUC0-12h of MPA ranged from 26.0 to 150.3 mg/L·hour, and the average AUC0–12h of MPA was 64.86 ± 36.62 mg/L· hour at an average MMF dose of 1.56 ± 0.45 g/day. Although SRL and MMF both have the side effect of bone marrow suppression, the platelet and WBC counts of patients with CNI elimination were maintained above 4000/mm3 except in the case of one patient who stopped MMF therapy due to marked leukopenia. The average on-therapy platelet and WBC counts are shown in Figure 3. Besides, there was one patient with persistent symptomatic anemia (hemoglobin < 10 g/dL). The average hemoglobin level at 6 months was 376
600
WBC/μL PLT/1000 μL
3 6 9 Months post-CNI elimination
12
Figure 3. Average platelet (PLT) and white blood cell (WBC) counts for renal transplant recipients on combined sirolimus and mycophenolate mofetil therapy. CNI = calcineurin inhibitors.
500
CHO (mg/dL) TG (mg/dL)
400 300 200 100 0 0
3 6 9 Months post-CNI elimination
12
Figure 4. Average triglyceride (TG) and cholesterol (CHO) levels for renal transplant recipients on combined sirolimus and mycophenolate mofetil therapy. CNI = calcineurin inhibitors.
12.7 ± 1.6 g/dL (range, 9.6–16.3 g/dL). As for hyperlipidemia, 10 patients (33.3%, 10/30) received fibrates and nine patients (30.0%, 9/30) were given statins to normalize their lipid profiles. The average on-therapy triglyceride levels were 154.3 ± 81.9 and 152.2 ± 72.5 mg/dL at 6 and 12 months, respectively. The average on-therapy cholesterol levels were 247.4 ± 39.9 at 6 months and 226.7 ± 35.4 mg/dL at 12 months (Figure 4). During the study period, three female patients were hospitalized because of urinary tract infection and sepsis. The pathogens were found to be Escherichia coli in two patients and Enterococcus species in the other. Based on sensitivity tests, antibiotics were given and the infections were controlled. Another two patients, Patient 3 and Patient 22, had severe productive cough and weight loss at 4 and 3 months, respectively, after CNI J Formos Med Assoc | 2007 • Vol 106 • No 5
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A
B
Figure 5. Representative chest films of Patient 3 (A) before and (B) 4 months after calcineurin inhibitor withdrawal and conversion to combined sirolimus and mycophenolate mofetil therapy.
withdrawal. Both patients had chest films showing interstitial infiltration and cavitations over bilateral upper lung fields. Representative chest X-ray films of Patient 3 before and after CNI withdrawal are shown in Figure 5. Expectorated sputum cultures and sensitivity tests in the two patients both yielded Mycobacterium tuberculosis with susceptibility to isoniazid, rifampin, ethambutol and streptomycin. Both patients primarily received a four-drug combination which included isoniazid, rifampin, ethambutol and pyrazinamide for the initial 2 months followed by three-drug therapy for 7 months with pyrazinamide discontinued. However, isoniazid was replaced by moxifloxacin in Patient 3 because of elevated liver enzymes. Both patients completed the 9-month anti-TB therapy and recovered very well. No evidence of relapse was detected after the anti-TB therapy was stopped. To differentiate the causes of TB infection in our patients, we reviewed all the screening chest films obtained before our study. Among the 30 patients recruited, four, including the two patients with pulmonary TB, had had fibrocalcified change in the upper lung fields on the screening chest films, which was suggestive of inactive pulmonary TB before our study. The other J Formos Med Assoc | 2007 • Vol 106 • No 5
26 patients whose chest films showed no evidence of previous TB lesions did not have TB during the study period. In this study, the incidence of pulmonary TB was found to be significantly higher (p = 0.0138, Fisher’s exact test) among patients with inactive TB lesions (50%, 2/4) than among those without such lesions (0%, 0/26).
Discussion The findings from this pilot study in Taiwan are consistent with those from previous reports in the US and Europe, which showed beneficial effects of CNI withdrawal even late after renal transplantation.19,20 The risk of acute rejection was low (3.33%) and renal function improved significantly from 4 months after CNI withdrawal to the end of the 12-month study period. Our results suggest that CNIs at their maintenance doses are nephrotoxic to renal transplants. Withdrawal of CNIs and conversion to a CNI-free regimen ameliorated the detrimental effects of CNIs and hopefully can promote long-term graft survival in stable renal transplant patients. However, we introduced MMF to our CNI-free regimen in order to lessen 377
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the dyslipidemic side effect of high-dose SRL. The mean SRL dose (2.25 ± 0.89 mg/day) and whole blood level (7.38 ± 3.74 ng/mL, measured by immunoassay) at 12 months were lower than those reported by Watson et al21 (3.5 mg/day and 8.8 ng/ mL by high-performance liquid chromatography) using SRL and steroids only. Furthermore, to normalize the serum total cholesterol levels, statins were only needed in 30.0% of our patients (9/30), which was lower than the incidences (43.9–78.9%) reported in the literature.5,21,22 Our results showed that conversion to a combined SRL and MMF regimen provides good renal function with minimal dyslipidemia. While combined therapy of SRL and MMF lessened dyslipidemia, bone marrow suppression, which is a common side effect of SRL and MMF was a cause for considerable concern. Interestingly, the average WBC counts in our study were all above 6000/mm3 with only one patient having to stop MMF because of leukopenia. Also, the platelet counts of our patients were above the lower normal limit. Combined SRL and MMF therapy seemed to produce only a limited effect on the bone marrow. However, two of our patients suffered from pulmonary TB at 3 and 4 months after combined SRL and MMF therapy. The active TB infections in the two patients seemed to be caused by reactivation of old pulmonary foci, which were evident on the screening chest films. Fortunately, the sputum cultures and sensitivity tests in the two patients did not yield multidrug-resistant M. tuberculosis, which is now an increasingly serious health problem in Taiwan.23 Even though there is a noticeable drug interaction between SRL and rifampin, we were still able to apply the combined SRL and MMF therapy to patients on anti-TB treatment by increasing the daily dose of SRL and maintaining the same target trough level. Combined SRL and MMF therapy might increase the risk of TB infection in long-term immunosuppressed transplant recipients, as SRL and MMF both suppress T-cell proliferation, which is important for immunity against mycobacterium.24 Therapeutic drug monitoring of SRL and MMF should be employed because it is crucial for the 378
success of this CNI-free regimen. We found that MMF at an average daily dose of 1.56 ± 0.45 g/day, when combined with SRL, could achieve a satisfactory MPA AUC0–12h of 64.86 ± 36.62 mg/L· hour, which was higher than the average AUC0–12h (48.70 ± 19.01 mg/L·hour, n = 5) in our other study which employed similar doses of MMF (1.60 ± 0.55 g/day) in combination with cyclosporine (FDCC [Fixed Dose vs. Concentration Controlled study], data exposure approved by Roche). Our findings support Render’s suggestion that there might be a pharmacokinetic interaction between SRL and MMF.12 While adequate MPA exposure significantly decreased the risk of acute rejection, dosage of SRL should be reduced to avoid overt T-cell suppression, especially in Asian countries where TB is prevalent. Renal transplant recipients should be screened for latent TB infection before receiving potent immunosuppressive agents such as MMF and SRL. Reactivation has been noted to be the most common form of TB in renal transplant recipients, and Ataserver et al showed that MMF was associated with the development of TB at a younger age and at a higher frequency when compared with conventional therapy.25,26 Additionally, SRL has been found to be frequently associated with pulmonary complications, including TB and pneumonitis.9–11 While the tuberculin skin test is not relevant to screening latent TB infection in Taiwan, we found that chest films provide valuable information. In this study, we showed that patients with apical fibrocalcified lesions on chest films carried a very high risk of TB reactivation (50%, 2/4) when receiving combined MMF and SRL therapy. On the contrary, there was little risk of primary pulmonary TB (0%, 0/26) for patients without latent infection. To receive potent immunosuppressive therapy targeting T-cell proliferation, such as SRL and MMF, transplant patients should be screened for latent TB infection. Isoniazid chemoprophylaxis might be necessary in countries where TB is endemic.27 In conclusion, we demonstrated that withdrawal of CNIs and conversion to combined SRL and MMF therapy improved renal function in stable renal transplant patients, although there was J Formos Med Assoc | 2007 • Vol 106 • No 5
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a risk of TB reactivation for those with latent TB infection.
Acknowledgments The authors would like to thank Professor Sir Roy Calne for his critical review of the manuscript.
References 1. Woolfson RG, Neilid GH. Cyclosporin nephrotoxicity following cardiac transplantation. Nephrol Dial Transplant 1997; 12:2054–6. 2. Nankivell BJ, Borrows RJ, Fung CL, et al. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation 2004;78:557–65. 3. Morales JM, Wramner L, Kreis H, et al. Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. Am J Transplant 2002;2:436–42. 4. Andoh TF, Burdmann EA, Fransechini N, et al. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int 1996;50:1110–7. 5. Kreis H, Oberbauer R, Campistol JM, et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol 2004;15:809–17. 6. Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transplant Int 2005;18:22–8. 7. Grinyo JM, Campistol JM, Paul J, et al. Pilot randomized study of early tacrolimus withdrawal from a regimen with sirolimus plus tacrolimus in kidney transplantation. Am J Transplant 2004;4:1308–14. 8. Kahan BD. Sirolimus-based immunosuppression: present state of the art. J Nephrol 2004;17:S32–9. 9. Morelon E, Stern M, Israel-Biet D, et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 2001;72:787–90. 10. Pham PT, Pham PC, Danovitch GM, et al. Sirolimusassociated pulmonary toxicity. Transplantation 2004;77: 1215–20. 11. Thaunat O, Morelon E, Stern M, et al. Mycobacterium xenopi pulmonary infection in two renal recipients under sirolimus therapy. Transplant Infect Dis 2004;6:179–82. 12. Renders L, Steinbach R, Valerius T, et al. Low-dose sirolimus in combination with mycophenolate mofetil improved kidney graft function late after renal transplantation and suggests pharmacokinetic interaction of both immunosuppressive drugs. Kidney Blood Press Res 2004;27:181–5. 13. Halloran P, Mathew T, Tomlanovich S, et al. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy
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Conversion to Combined Therapy with Sirolimus and Mycophenolate Mofetil Improved Renal Function in Stable Renal Transplant Recipients Meng-Kun Tsai, Chih-Yuan Lee, Rey-Heng Hu, Po-Huang Lee* Background/Purpose: Information is needed on renal function improvement after late elimination of calcineurin inhibitors (CNIs) and conversion to combined therapy of sirolimus (SRL) and mycophenolate mofetil (MMF) in Asian renal transplant recipients. Methods: A single-arm prospective study was undertaken to assess the outcome of stable Taiwanese renal transplant recipients who had CNI withdrawn and received combined SRL and MMF therapy. The primary endpoints were acute rejection and renal function. The secondary endpoints were graft and patient survival, side effects and infectious complications. Therapeutic drug monitoring of SRL and MMF was conducted during the study period. Results: Thirty patients were recruited at 9–72 (31.7 ± 18.6) months post-transplantation. The graft and patient survival rates were both 100% at 12 months, though one of the 30 patients (3.33%, 1/30) had biopsyproven acute rejection. On paired t test, the estimated glomerular filtration rates (GFR) from 4 to 12 months were significantly higher than the baseline GFR. The average trough level of SRL was 7.38 ± 3.74 ng/mL at 12 months and the average abbreviated area under the concentration curve of mycophenolic acid was 64.86 ± 36.62 mg/L·hour at an average MMF dose of 1.56 ± 0.45 g/day. However, two patients (6.67%, 2/30) had tuberculosis (TB) reactivation at 3 and 4 months, respectively, after the combined SRL and MMF therapy. Conclusion: Conversion to combined SRL and MMF therapy improved renal function in stable renal transplant recipients, though the risk of TB reactivation should be kept in mind when the combined therapy is employed in the Asian countries with a high prevalence of TB. [J Formos Med Assoc 2007;106(5):372–379] Key Words: mycophenolate mofetil (MMF), renal function, sirolimus (SRL)
Long-term treatment with a calcineurin inhibitor (CNI) has been shown to cause renal toxicity and chronic renal allograft dysfunction.1,2 Sirolimus (SRL), a new immunosuppressant without nephrotoxicity has provided a great opportunity to improve long-term graft survival in renal transplantation.3,4 The Rapamune Maintenance Regimen Study Group recently
reported that early withdrawal of cyclosporine from a cyclosporine/SRL/steroid regimen improved renal function and graft survival.5,6 In addition, early tacrolimus withdrawal from a regimen with SRL and tacrolimus has also been shown to bring about better renal function and significantly lower diastolic blood pressure.7 Therefore, CNI-free SRL-based maintenance
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Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Received: September 29, 2006 Revised: November 6, 2006 Accepted: December 5, 2006
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*Correspondence to: Dr Po-Huang Lee, Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: [email protected]
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therapy might be beneficial for renal transplant recipients. Hyperlipidemia is a matter of serious concern to patients taking high-dose SRL and steroids, and so are pulmonary complications, including interstitial pneumonitis and tuberculosis (TB).8–11 As Renders et al recently demonstrated that lowdose SRL in combination with mycophenolate mofetil (MMF) improves kidney graft function late after renal transplantation, combined SRL and MMF therapy might confer the benefit of CNI elimination and avoid the troublesome side effects of high-dose SRL.12 Early clinical studies have documented that MMF, as compared with azathioprine, decreased the incidence of acute rejection in cyclosporine-based regimens.13 Moreover, pharmacokinetic studies suggested a 12-hour area under the concentration curve (AUC) of 30–60 mg/L· hour or a trough mycophenolic acid (MPA) concentration of 1–3.5 mg/L for reduction of acute rejection episodes in the early post-transplant period.14 Continued MMF therapy for 12 months or longer was shown to preserve renal allograft function from progressive decline.15 While Flechner et al demonstrated excellent results in de novo renal transplants using SRL and MMF in combination with anti-CD25 antibody induction and steroids, it appeared that elimination of CNIs and conversion to maintenance SRL and MMF therapy could provide adequate immunosuppression.16 However, the pharmacokinetic interaction between MMF and SRL has not been well characterized, nor has the dosage of combined SRL and MMF therapy in Asians. We thus conducted an investigator-initiated pilot study to determine any advantage and/or disadvantage of CNI elimination and conversion to combined SRL/MMF/steroid therapy in stable Taiwanese renal transplant recipients. Therapeutic drug monitoring of SRL and MMF was therefore performed.
Materials and Methods A single-arm prospective study was undertaken to determine the advantages and disadvantages of late J Formos Med Assoc | 2007 • Vol 106 • No 5
elimination of CNI and conversion to combined SRL and MMF therapy in stable Taiwanese renal transplant recipients. The study protocol was approved by the National Taiwan University Hospital Research Ethics Committee and patients gave their consent to receive the CNI-free immunosuppressive therapy. Adult renal transplant recipients on de novo cyclosporine- (Sandimmune Neoral, Novartis, Basel, Switzerland) or tacrolimus-based (Prograf, Fujisawa, London, UK) immunosuppressive therapy for at least 6 months were recruited. Recipients were excluded if they had recent acute rejection or deterioration of renal function (> 30%) within 12 weeks prior to enrolment. The screening procedures included complete blood counts, biochemistry tests, abdominal and renal sonography, chest X-ray, urinalysis and fasting blood sugar. Patients with steroid withdrawal, obstructive uropathy, multiple organ transplants, malignancy, hepatitis B, hepatitis C or active infection were excluded. The primary immunosuppressive regimens before CNI withdrawal were a CNI combined with either SRL (Rapamune, Wyeth-Ayerst, Philadelphia, USA) or MMF (Cellcept, Roche, Humacao, Puerto Rico). CNI elimination was accomplished through a 3-month transitional period of CNI minimization in combination with SRL/MMF/steroids before cyclosporine or tacrolimus was completely withdrawn. For those on primary CNI/MMF/ steroids therapy, 2 mg of SRL was added to the immunosuppression regimen with 50% dose reduction of the primary CNI and MMF during the first month of the 3-month transitional period. And, during the second month of the transitional period, CNI doses were further reduced to one fourth of the primary doses, and the dose of SRL adjusted to hit the target trough level, 8 nm/mL (monoclonal immunoassay). Then, the doses of CNI were further reduced, and MMF adjusted to reach a minimal daily dose of 1.5 g/day or white blood cell (WBC) counts around 4000/mm3 during the third month of the transitional period. As to patients on primary CNI/SRL/steroids therapy, CNI doses were gradually reduced and eventually eliminated, and MMF introduced during the transitional period. After CNI withdrawal, the SRL 373
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whole blood trough levels were checked monthly, and the doses were adjusted to maintain trough levels between 8 and 12 ng/mL. The target MMF dose was 2 g/day unless there was a WBC < 4000/ mm3 or intolerance to MMF. For patients with intolerance, the MMF dose was reduced. Neither antacids nor H2-blockers were administered to relieve gastrointestinal side effects. A pharmacokinetic monitoring of MMF was conducted at least 6 months after CNI withdrawal when a steady state of immunosuppression was achieved. The enzymemultiplied immunoassay technique was employed and validated by the Proficiency Testing Program.17 A three-sample method (C0, C0.5 and C2) by Shaw et al18 was used to calculate the abbreviated AUC of MPA.18 The abbreviated AUC0–12h of MPA was calculated using the regression equation: 7.75 + 6.49C0 + 0.76C0.5 + 2.43C2 (r2 = 0.862) The primary endpoints of this study were incidence of acute rejection and renal function after CNI elimination. The secondary endpoints were graft and patient survival, side effects and infectious complications. Patients with significant deterioration of renal function (> 30%) underwent graft renal biopsy, and biopsy-proven acute rejection was treated with corticosteroids. The glomerular filtration rate (GFR) immediately before and after CNI withdrawal was estimated by the Cockcroft–Gault formula, with a correction factor of 0.85 for women and compared by paired t test. History taking, physical examination, complete blood count, platelet counts, urinalysis and fasting blood chemistries, including blood urea nitrogen, serum creatinine, glucose, serum aspartate aminotransferase and alanine aminotransferase, triglycerides, cholesterol, alkaline phosphate and lactate dehydrogenase were regularly checked for identification of side effects. If hypertriglyceridemia (> 200 mg/dL) and hypercholesterolemia (> 240 mg/dL) were sustained for more than 3 months, treatment with fibrates and statins was initiated, respectively. The doses of fibrate and statin therapies were minimized if the follow-up lipid profiles normalized. Patients resumed their 374
original CNIs when SRL or MMF dose was significantly reduced because of side effects. Infectious complications were treated with empirical and then pathogen-specific antimicrobial therapy. Immunosuppressive therapy was not reduced during infectious episodes unless the episodes were life threatening.
Results Seventeen male and 13 female patients were enrolled to receive the combined SRL/MMF/steroid maintenance immunosuppressive therapy between June and August 2004. Seven of the 30 patients had been taking tacrolimus-based immunosuppressive therapy and the others cyclosporine-based regimens. The patients ranged in age from 19 to 67 years (43.5 ± 12.4 years). They were placed on the study immunosuppressive regimen at 9–72 months (31.7 ± 18.6 months) post-transplantation. The average serum creatinine level before elimination of CNIs was 1.48 ± 0.42 mg/dL (1.0–2.8 mg/ dL), and the average GFR 49.45 ± 19.40 mL/minute (24.6–116.4 mL/min). During the transition period and the 12-month study period, two patients resumed cyclosporine because of elevation of liver enzymes and two resumed tacrolimus, one because of IgA nephropathy and patient’s request (Patient 10) at 10 months and the other because of ventral hernia repair at 8 months. One patient with leukopenia stopped receiving MMF 1 month after CNI withdrawal but remained CNI-free. The graft and patient survival rates were both 100% at 1 year, although one of the 30 patients (3.33%, 1/30) had biopsy-proven acute rejection (Banff 97 IA). The specimen of renal biopsy showed Banff IA acute cellular rejection, and the patient received steroid pulse therapy in addition to the maintenance combined SRL/MMF/ steroid therapy. The rejection episode resolved smoothly and the patient was maintained on the study regimen without further decline in renal function. On intent-to-treat analysis, the average serum creatinine levels were 1.39 ± 0.39 and 1.41 ± 0.60 mg/dL at 6 and 12 months, respectively, and J Formos Med Assoc | 2007 • Vol 106 • No 5
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* * * ‡ ‡ † † † *
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* * † § § ‡ § § §
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0 9
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–3
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Figure 1. Average serum creatinine levels (sCre) and estimated glomerular filtration rates (GFR) of renal transplant patients before and after withdrawal of calcineurin inhibitors (CNI) and conversion to combined sirolimus and mycophenolate mofetil therapy in (A) intent-to-treat analysis and (B) on-therapy analysis compared with baseline renal function just before CNI withdrawal. *p < 0.05; †p < 0.01; ‡p < 0.001; §p < 0.0001.
Table. Demographics and outcomes of the 30 patients enrolled for the combined SRL and MMF therapy after withdrawal of CNIs Patient demographics and outcomes*
Mean
Range
Patient age (yr) Graft age (months post-transplant) Gender (male/female) Primary CNI (cyclosporine/tacrolimus) Baseline sCre (mg/dL) Baseline estimated GFR (mL/min) sCre at 12 mo (mg/dL) Estimated GFR at 12 mo (mL/min) Acute rejection at 12 mo Graft survival at 12 mo Leukopenia (< 4000/mm3) Anemia (Hb < 10 g/dL) Hyperlipidemia (> 200 mg/dL) Hypercholesterolemia (> 240 mg/dL) Major infections
43.5 ± 12.4 31.7 ± 18.6 17/13 23/7 1.48 ± 0.42 49.45 ± 19.40 1.41 ± 0.60 54.02 ± 20.34 3.33% (1/30) 100% (30/30) 3.33% (1/30) 3.33% (1/30) 33.33% (10/30) 30.00% (9/30) 16.67% (5/30)
19–67 9–72 – – 1.0–2.8 24.6–116.4 0.9–4.0 17.3–98.5 – – – – – – –
*Results of intent-to-treat analysis are shown. SRL = sirolimus; MMF = mycophenolate mofetil; CNI = calcineurin inhibitor; sCre = serum creatinine; GFR = glomerular filtration rate; Hb = hemoglobin.
the average GFRs were 52.94 ± 18.40 and 54.02 ± 20.34 mL/minute at 6 and 12 months, respectively (Figure 1A). One patient (Patient 10) among the 30 patients had significant deterioration in renal function because of biopsy-proven IgA nephropathy. The GFR from 4 to 12 months after withdrawal of CNIs was significantly higher than the baseline GFR on the paired t test. However, we could not identify any subgroup (including patient age, gender, graft age, primary CNI and baseline J Formos Med Assoc | 2007 • Vol 106 • No 5
GFR upon CNI elimination) of patients who would be predicted to benefit from combined SRL and MMF therapy. Details of patient demographics and outcomes are summarized in the Table. As for on-therapy analysis, the average serum creatinine levels of patients on CNI-free therapy were 1.4 ± 0.41 and 1.29 ± 0.35 mg/dL at 6 and 12 months, respectively, and the average on-therapy GFRs were 51.09 ± 16.74 and 54.82 ± 17.86 mL/minute at 6 and 12 months, respectively 375
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10,000
10
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4
4000
400 200
2000
0
0
2
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0 0
3 6 9 Months post-CNI elimination
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Figure 2. Average mycophenolate mofetil (MMF) and sirolimus (SRL) daily doses and trough SRL levels for renal transplant recipients on combined SRL and MMF therapy. CNI = calcineurin inhibitors.
(Figure 1B). The on-therapy GFR from 4 to 12 months was also significantly higher than the corresponding baseline GFR on the paired t test. After CNI withdrawal, the average doses of SRL were 2.38 ± 0.81 and 2.25 ± 0.89 mg/day at 6 and 12 months, respectively, and the trough blood levels were 7.87 ± 3.84 and 7.38 ± 3.74 ng/mL at 6 and 12 months, respectively. Details of SRL doses and trough blood levels are shown in Figure 2. The average MMF doses were 1.50 ± 0.44 and 1.45 ± 0.56 g/day at 6 and 12 months, respectively (Figure 2). Eighteen of the 25 patients who remained on the combined SRL/MMF/steroid regimen agreed to undergo the pharmacokinetic study of MPA. Their albumin levels ranged from 3.9 to 5.0 g/dL. The average MPA C0 was 3.21 ± 2.55 mg/L, average C0.5 21.81 ± 13.67 mg/L and average C2 8.10 ± 6.28 mg/L. The abbreviated AUC0-12h of MPA ranged from 26.0 to 150.3 mg/L·hour, and the average AUC0–12h of MPA was 64.86 ± 36.62 mg/L· hour at an average MMF dose of 1.56 ± 0.45 g/day. Although SRL and MMF both have the side effect of bone marrow suppression, the platelet and WBC counts of patients with CNI elimination were maintained above 4000/mm3 except in the case of one patient who stopped MMF therapy due to marked leukopenia. The average on-therapy platelet and WBC counts are shown in Figure 3. Besides, there was one patient with persistent symptomatic anemia (hemoglobin < 10 g/dL). The average hemoglobin level at 6 months was 376
600
WBC/μL PLT/1000 μL
3 6 9 Months post-CNI elimination
12
Figure 3. Average platelet (PLT) and white blood cell (WBC) counts for renal transplant recipients on combined sirolimus and mycophenolate mofetil therapy. CNI = calcineurin inhibitors.
500
CHO (mg/dL) TG (mg/dL)
400 300 200 100 0 0
3 6 9 Months post-CNI elimination
12
Figure 4. Average triglyceride (TG) and cholesterol (CHO) levels for renal transplant recipients on combined sirolimus and mycophenolate mofetil therapy. CNI = calcineurin inhibitors.
12.7 ± 1.6 g/dL (range, 9.6–16.3 g/dL). As for hyperlipidemia, 10 patients (33.3%, 10/30) received fibrates and nine patients (30.0%, 9/30) were given statins to normalize their lipid profiles. The average on-therapy triglyceride levels were 154.3 ± 81.9 and 152.2 ± 72.5 mg/dL at 6 and 12 months, respectively. The average on-therapy cholesterol levels were 247.4 ± 39.9 at 6 months and 226.7 ± 35.4 mg/dL at 12 months (Figure 4). During the study period, three female patients were hospitalized because of urinary tract infection and sepsis. The pathogens were found to be Escherichia coli in two patients and Enterococcus species in the other. Based on sensitivity tests, antibiotics were given and the infections were controlled. Another two patients, Patient 3 and Patient 22, had severe productive cough and weight loss at 4 and 3 months, respectively, after CNI J Formos Med Assoc | 2007 • Vol 106 • No 5
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A
B
Figure 5. Representative chest films of Patient 3 (A) before and (B) 4 months after calcineurin inhibitor withdrawal and conversion to combined sirolimus and mycophenolate mofetil therapy.
withdrawal. Both patients had chest films showing interstitial infiltration and cavitations over bilateral upper lung fields. Representative chest X-ray films of Patient 3 before and after CNI withdrawal are shown in Figure 5. Expectorated sputum cultures and sensitivity tests in the two patients both yielded Mycobacterium tuberculosis with susceptibility to isoniazid, rifampin, ethambutol and streptomycin. Both patients primarily received a four-drug combination which included isoniazid, rifampin, ethambutol and pyrazinamide for the initial 2 months followed by three-drug therapy for 7 months with pyrazinamide discontinued. However, isoniazid was replaced by moxifloxacin in Patient 3 because of elevated liver enzymes. Both patients completed the 9-month anti-TB therapy and recovered very well. No evidence of relapse was detected after the anti-TB therapy was stopped. To differentiate the causes of TB infection in our patients, we reviewed all the screening chest films obtained before our study. Among the 30 patients recruited, four, including the two patients with pulmonary TB, had had fibrocalcified change in the upper lung fields on the screening chest films, which was suggestive of inactive pulmonary TB before our study. The other J Formos Med Assoc | 2007 • Vol 106 • No 5
26 patients whose chest films showed no evidence of previous TB lesions did not have TB during the study period. In this study, the incidence of pulmonary TB was found to be significantly higher (p = 0.0138, Fisher’s exact test) among patients with inactive TB lesions (50%, 2/4) than among those without such lesions (0%, 0/26).
Discussion The findings from this pilot study in Taiwan are consistent with those from previous reports in the US and Europe, which showed beneficial effects of CNI withdrawal even late after renal transplantation.19,20 The risk of acute rejection was low (3.33%) and renal function improved significantly from 4 months after CNI withdrawal to the end of the 12-month study period. Our results suggest that CNIs at their maintenance doses are nephrotoxic to renal transplants. Withdrawal of CNIs and conversion to a CNI-free regimen ameliorated the detrimental effects of CNIs and hopefully can promote long-term graft survival in stable renal transplant patients. However, we introduced MMF to our CNI-free regimen in order to lessen 377
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the dyslipidemic side effect of high-dose SRL. The mean SRL dose (2.25 ± 0.89 mg/day) and whole blood level (7.38 ± 3.74 ng/mL, measured by immunoassay) at 12 months were lower than those reported by Watson et al21 (3.5 mg/day and 8.8 ng/ mL by high-performance liquid chromatography) using SRL and steroids only. Furthermore, to normalize the serum total cholesterol levels, statins were only needed in 30.0% of our patients (9/30), which was lower than the incidences (43.9–78.9%) reported in the literature.5,21,22 Our results showed that conversion to a combined SRL and MMF regimen provides good renal function with minimal dyslipidemia. While combined therapy of SRL and MMF lessened dyslipidemia, bone marrow suppression, which is a common side effect of SRL and MMF was a cause for considerable concern. Interestingly, the average WBC counts in our study were all above 6000/mm3 with only one patient having to stop MMF because of leukopenia. Also, the platelet counts of our patients were above the lower normal limit. Combined SRL and MMF therapy seemed to produce only a limited effect on the bone marrow. However, two of our patients suffered from pulmonary TB at 3 and 4 months after combined SRL and MMF therapy. The active TB infections in the two patients seemed to be caused by reactivation of old pulmonary foci, which were evident on the screening chest films. Fortunately, the sputum cultures and sensitivity tests in the two patients did not yield multidrug-resistant M. tuberculosis, which is now an increasingly serious health problem in Taiwan.23 Even though there is a noticeable drug interaction between SRL and rifampin, we were still able to apply the combined SRL and MMF therapy to patients on anti-TB treatment by increasing the daily dose of SRL and maintaining the same target trough level. Combined SRL and MMF therapy might increase the risk of TB infection in long-term immunosuppressed transplant recipients, as SRL and MMF both suppress T-cell proliferation, which is important for immunity against mycobacterium.24 Therapeutic drug monitoring of SRL and MMF should be employed because it is crucial for the 378
success of this CNI-free regimen. We found that MMF at an average daily dose of 1.56 ± 0.45 g/day, when combined with SRL, could achieve a satisfactory MPA AUC0–12h of 64.86 ± 36.62 mg/L· hour, which was higher than the average AUC0–12h (48.70 ± 19.01 mg/L·hour, n = 5) in our other study which employed similar doses of MMF (1.60 ± 0.55 g/day) in combination with cyclosporine (FDCC [Fixed Dose vs. Concentration Controlled study], data exposure approved by Roche). Our findings support Render’s suggestion that there might be a pharmacokinetic interaction between SRL and MMF.12 While adequate MPA exposure significantly decreased the risk of acute rejection, dosage of SRL should be reduced to avoid overt T-cell suppression, especially in Asian countries where TB is prevalent. Renal transplant recipients should be screened for latent TB infection before receiving potent immunosuppressive agents such as MMF and SRL. Reactivation has been noted to be the most common form of TB in renal transplant recipients, and Ataserver et al showed that MMF was associated with the development of TB at a younger age and at a higher frequency when compared with conventional therapy.25,26 Additionally, SRL has been found to be frequently associated with pulmonary complications, including TB and pneumonitis.9–11 While the tuberculin skin test is not relevant to screening latent TB infection in Taiwan, we found that chest films provide valuable information. In this study, we showed that patients with apical fibrocalcified lesions on chest films carried a very high risk of TB reactivation (50%, 2/4) when receiving combined MMF and SRL therapy. On the contrary, there was little risk of primary pulmonary TB (0%, 0/26) for patients without latent infection. To receive potent immunosuppressive therapy targeting T-cell proliferation, such as SRL and MMF, transplant patients should be screened for latent TB infection. Isoniazid chemoprophylaxis might be necessary in countries where TB is endemic.27 In conclusion, we demonstrated that withdrawal of CNIs and conversion to combined SRL and MMF therapy improved renal function in stable renal transplant patients, although there was J Formos Med Assoc | 2007 • Vol 106 • No 5
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a risk of TB reactivation for those with latent TB infection.
Acknowledgments The authors would like to thank Professor Sir Roy Calne for his critical review of the manuscript.
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