Conversion to Combined Therapy with Sirolimus and Mycophenolate Mofetil Improved Renal Function in Stable Renal Transplant Recipients

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Long-term treatment with a calcineurin inhibi-tor (CNI) has been shown to cause renal toxic-ity and chronic renal allograft dysfunction.1,2 Sirolimus (SRL), a new immunosuppressant without nephrotoxicity has provided a great opportunity to improve long-term graft sur-vival in renal transplantation.3,4 The Rapamune Maintenance Regimen Study Group recently

reported that early withdrawal of cyclosporine from a cyclosporine/SRL/steroid regimen im-proved 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 pres-sure.7Therefore, CNI-free SRL-based maintenance

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transplant recipients who had CNI withdrawn and received combined SRL and MMF therapy.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

pa-tient survival rates were both 100% at 12 months, though one of the 30 papa-tients (3.33%, 1/30) had biopsy-proven 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

trans-plant 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)

©2007 Elsevier & Formosan Medical Association

. . . .

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

*Correspondence to: Dr Po-Huang Lee, Department of Surgery, National Taiwan University Hospital,

7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: pohuang1115@ntu.edu.tw

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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 low-dose 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.12Early clinical studies have doc-umented that MMF, as compared with azathio-prine, decreased the incidence of acute rejection in cyclosporine-based regimens.13Moreover, pharma-cokinetic studies suggested a 12-hour area under the concentration curve (AUC) of 30–60 mg/L· hour or a trough mycophenolic acid (MPA) con-centration of 1–3.5 mg/L for reduction of acute rejection episodes in the early post-transplant period.14Continued 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 elimina-tion of CNIs and conversion to maintenance SRL and MMF therapy could provide adequate im-munosuppression.16 However, the pharmacoki-netic 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 mon-itoring 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

elimination of CNI and conversion to combined SRL and MMF therapy in stable Taiwanese renal transplant recipients. The study protocol was ap-proved by the National Taiwan University Hospital Research Ethics Committee and patients gave their consent to receive the CNI-free immunosuppres-sive therapy. Adult renal transplant recipients on de novo cyclosporine- (Sandimmune Neoral, Novartis, Basel, Switzerland) or tacrolimus-based (Prograf, Fujisawa, London, UK) immunosuppres-sive 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, bio-chemistry tests, abdominal and renal sonography, chest X-ray, urinalysis and fasting blood sugar. Patients with steroid withdrawal, obstructive uropa-thy, multiple organ transplants, malignancy, hepa-titis B, hepahepa-titis 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 minimiza-tion in combinaminimiza-tion with SRL/MMF/steroids be-fore cyclosporine or tacrolimus was completely withdrawn. For those on primary CNI/MMF/ steroids therapy, 2 mg of SRL was added to the im-munosuppression regimen with 50% dose re-duction 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 dur-ing 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

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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 pharmaco-kinetic monitoring of MMF was conducted at least 6 months after CNI withdrawal when a steady state of immunosuppression was achieved. The enzyme-multiplied immunoassay technique was employed and validated by the Proficiency Testing Program.17 A three-sample method (C0, C0.5and C2) by Shaw et al18was used to calculate the abbreviated AUC of MPA.18The abbreviated AUC0–12hof 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 inci-dence of acute rejection and renal function after CNI elimination. The secondary endpoints were graft and patient survival, side effects and infec-tious complications. Patients with significant de-terioration of renal function (> 30%) underwent graft renal biopsy, and biopsy-proven acute re-jection was treated with corticosteroids. The glo-merular filtration rate (GFR) immediately before and after CNI withdrawal was estimated by the Cockcroft–Gault formula, with a correction fac-tor of 0.85 for women and compared by paired

t test. History taking, physical examination,

com-plete blood count, platelet counts, urinalysis and fasting blood chemistries, including blood urea nitrogen, serum creatinine, glucose, serum aspar-tate aminotransferase and alanine aminotrans-ferase, triglycerides, cholesterol, alkaline phosphate and lactate dehydrogenase were regularly checked for identification of side effects. If hypertriglyc-eridemia (> 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

original CNIs when SRL or MMF dose was signif-icantly 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 en-rolled 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 immunosup-pressive 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 elimina-tion 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 pe-riod and the 12-month study pepe-riod, two patients resumed cyclosporine because of elevation of liver enzymes and two resumed tacrolimus, one be-cause 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 ad-dition 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

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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 nephropa-thy. The GFR from 4 to 12 months after with-drawal 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

GFR upon CNI elimination) of patients who would be predicted to benefit from combined SRL and MMF therapy. Details of patient demo-graphics 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±0.35mg/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 0 10 20 30 40 50 60 –6 –3 0 3 6 9 12 GFR (mL/min) ‡ † ‡ ‡ † † † * sCre x 10 (mg/dL)

Months post-CNI elimination

0 10 20 30 40 50 60 –6 –3 0 3 6 9 12 GFR (mL/min) sCre x 10 (mg/dL) § § ‡ § § § * * ‡ † * † * * ‡

Months post-CNI elimination

A * * * B * * * * * † ‡

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 mycophe-nolate 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) 43.5± 12.4 19–67

Graft age (months post-transplant) 31.7± 18.6 9–72

Gender (male/female) 17/13 –

Primary CNI (cyclosporine/tacrolimus) 23/7 –

Baseline sCre (mg/dL) 1.48± 0.42 1.0–2.8

Baseline estimated GFR (mL/min) 49.45± 19.40 24.6–116.4

sCre at 12 mo (mg/dL) 1.41± 0.60 0.9–4.0 Estimated GFR at 12 mo (mL/min) 54.02± 20.34 17.3–98.5 Acute rejection at 12 mo 3.33% (1/30) – Graft survival at 12 mo 100% (30/30) – Leukopenia (< 4000/mm3) 3.33% (1/30) Anemia (Hb< 10 g/dL) 3.33% (1/30) – Hyperlipidemia (> 200 mg/dL) 33.33% (10/30) – Hypercholesterolemia (> 240 mg/dL) 30.00% (9/30) – Major infections 16.67% (5/30) –

*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.

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(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 re-mained on the combined SRL/MMF/steroid regi-men agreed to undergo the pharmacokinetic study of MPA. Their albumin levels ranged from 3.9 to 5.0 g/dL. The average MPA C0was 3.21± 2.55 mg/L, average C0.5 21.81± 13.67 mg/L and average C2 8.10±6.28mg/L. The abbreviated AUC0-12hof MPA ranged from 26.0 to 150.3 mg/L·hour, and the average AUC0–12hof MPA was 64.86±36.62mg/L· hour at an average MMF dose of 1.56±0.45g/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/mm3except 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

12.7±1.6g/dL (range, 9.6–16.3g/dL). As for hyper-lipidemia, 10 patients (33.3%, 10/30) received fi-brates 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, re-spectively. The average on-therapy cholesterol lev-els 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 infec-tion and sepsis. The pathogens were found to be

Escherichia coli in two patients and Enterococcus

species in the other. Based on sensitivity tests, an-tibiotics were given and the infections were con-trolled. Another two patients, Patient 3 and Patient 22, had severe productive cough and weight loss at 4 and 3 months, respectively, after CNI 0 2 4 6 8 10 0 3 6 9 12 SRL level (ng/mL) SRL dose (mg/day) MMF (g/day)

Months post-CNI elimination

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.

0 2000 4000 6000 8000 10,000 0 3 6 9 12 0 200 400 600 800 1000 WBC/μL PLT/1000μL

Months post-CNI elimination

Figure 3. Average platelet (PLT) and white blood cell

(WBC) counts for renal transplant recipients on combined sirolimus and mycophenolate mofetil therapy. CNI= cal-cineurin inhibitors. 0 100 200 300 400 500 0 3 6 9 12 CHO (mg/dL) TG (mg/dL)

Months post-CNI elimination

Figure 4. Average triglyceride (TG) and cholesterol (CHO)

levels for renal transplant recipients on combined siroli-mus and mycophenolate mofetil therapy. CNI= calcineurin inhibitors.

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withdrawal. Both patients had chest films showing interstitial infiltration and cavitations over bilat-eral upper lung fields. Representative chest X-ray films of Patient 3 before and after CNI withdrawal are shown in Figure 5. Expectorated sputum cul-tures and sensitivity tests in the two patients both yielded Mycobacterium tuberculosis with suscepti-bility to isoniazid, rifampin, ethambutol and streptomycin. Both patients primarily received a four-drug combination which included isoni-azid, 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 ther-apy and recovered very well. No evidence of re-lapse was detected after the anti-TB therapy was stopped. To differentiate the causes of TB infec-tion 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 fibro-calcified change in the upper lung fields on the screening chest films, which was suggestive of in-active pulmonary TB before our study. The other

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 transplan-tation.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 nephro-toxic to renal transplants. Withdrawal of CNIs and conversion to a CNI-free regimen amelio-rated the detrimental effects of CNIs and hope-fully can promote long-term graft survival in stable renal transplant patients. However, we introduced MMF to our CNI-free regimen in order to lessen

A B

Figure 5. Representative chest films of Patient 3 (A) before and (B) 4 months after calcineurin inhibitor withdrawal and

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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 im-munoassay) 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 nor-malize 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.5,21,22Our results showed that conversion to a combined SRL and MMF reg-imen provides good renal function with minimal dyslipidemia.

While combined therapy of SRL and MMF less-ened 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/mm3with 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 com-bined SRL and MMF therapy. The active TB infec-tions in the two patients seemed to be caused by reactivation of old pulmonary foci, which were ev-ident 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.23Even though there is a noticeable drug interaction between SRL and ri-fampin, 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 in-crease the risk of TB infection in long-term im-munosuppressed 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

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 sat-isfactory MPA AUC0–12h of 64.86± 36.62 mg/L· hour, which was higher than the average AUC0–12h (48.70± 19.01mg/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.12While 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 im-munosuppressive agents such as MMF and SRL. Reactivation has been noted to be the most com-mon 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 con-ventional therapy.25,26Additionally, 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 fi-brocalcified lesions on chest films carried a very high risk of TB reactivation (50%, 2/4) when re-ceiving 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 tar-geting 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 with-drawal of CNIs and conversion to combined SRL and MMF therapy improved renal function in stable renal transplant patients, although there was

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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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