- Email: [email protected]
Safety and Efficacy of a Quinolone-Based Regimen for Treatment of Tuberculosis in Renal Transplant Recipients
Safety and Efficacy of a Quinolone-Based Regimen for Treatment of Tuberculosis in Renal Transplant Recipients H.E. Yoon, Y.J. Jeon, H.W. Chung, S.J. Shin, H.S. Hwang, S.J. Lee, Y.K. Chang, B.S. Choi, C.W. Park, Y.S. Kim, S.Y. Kim, and C.W. Yang ABSTRACT Background. Rifampin (RFP) is a first-line antituberculosis drug, but it increases the risk of acute rejection (AR) in transplant recipients. This study evaluated whether quinolone (QNL) can replace RFP in renal transplant recipients with tuberculosis. Methods. One hundred nine patients with active tuberculosis were included. Patients consisted of RFP (n ⫽ 91) and QNL (n ⫽ 18) groups based on the initial treatment regimen. Patients with RFP-associated adverse effects were subdivided into RFP-maintenance (RFP-M; n ⫽ 18) and QNL-conversion (QNL-C; n ⫽ 8) groups. Clinical outcomes were compared between groups. Results. The incidence of AR was higher in the RFP group than in the QNL group (24.2% vs 5.6%). The QNL group showed significantly higher 10-year graft survival rates than the RFP group (88.1% vs 66.5%; P ⫽ .022). The QNL-C group showed significantly higher 10-year graft survival rates than the RFP-M group (87.5% vs 27.8%; P ⫽ .011). The rate of complete functional recovery after AR was higher in the QNL-C group than in the RFP-M group (50% vs 22.2%). Conclusions. A QNL-based regimen may be safe and effective for treatment of tuberculosis and may lower the risk of graft failure in renal transplant recipients. uberculosis (TB) is a serious opportunistic infection in renal transplant recipients. According to the Korean National Tuberculosis Association, the new TB case notification rate in Korea was 73 per 100,000 people in 2009, which is much higher than in Western countries.1–3 The incidence among renal transplant recipients is also higher, ranging from 2.9% to 7.8%.4 – 6 The first-line anti-TB drugs are isoniazid, rifampin (RFP), pyrazinamide, and ethambutol (or streptomycin), which generally result in ⬎95% cure in uncomplicated TB infection.7–9 However, because RFP is an inducer of the cytochrome P450 3A4 microsomal enzymes, it reduces blood levels of calcineurin inhibitors (CNIs).10,11 As a result, the incidence of acute rejection (AR) and graft loss is increased in transplant patients using RFP.1,3 Quinolones (QNLs) are commonly used for treatment of TB, especially in patients with multidrug-resistant TB or those with adverse effects from first-line drugs.12,13 The successful treatment of TB with QNL in place of RFP was previously reported in renal transplant recipients.14,15 However, there is no report comparing the outcomes between an RFP-based regimen and a QNL-based regimen.
T
0041-1345/12/$–see front matter doi:10.1016/j.transproceed.2011.12.065 730
In the present study, clinical outcomes and adverse effects were compared between an RFP-based regimen and a QNL-based regimen, and the effect of QNL on allograft outcomes was evaluated in renal transplant recipients.
From the Division of Nephrology, Department of Internal Medicine, Incheon St. Mary’s Hospital, Catholic University of Korea, Incheon, Korea (H.E.Y., H.W.C., S.J.S.), Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, Catholic University of Korea, Seoul, Korea (Y.J.J., B.S.C., C.W.P., Y.S.K., C.W.Y.), and Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary’s Hospital (H.S.H., S.J.L., Y.K.C., S.Y.K.), Catholic University of Korea, Daejeon, Korea. Supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A102065). Address reprint requests to Chul Woo Yang, MD, PhD, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, Catholic University of Korea, 505, Banpodong, Seocho-gu, Seoul, Korea, 137-040. E-mail: yangch@ catholic.ac.kr © 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 730 –733 (2012)
QUINOLONE TO TREAT TUBERCULOSIS IN RENAL TRANSPLANT PATIENTS
731
METHODS
RESULTS
Between January 1984 and April 2009, 1,787 patients underwent renal transplantation at Seoul St Mary’s Hospital and Daejeon St Mary’s Hospital. Of these, 109 developed active TB during the study period. We retrospectively reviewed the medical records of these patients. The RFP-based regimen was a daily oral regimen including RFP (450 – 600 mg), isoniazid (300 – 400 mg), ethambutol (800 mg), and pyrazinamide (1,000 –1,500 mg). The QNL-based regimen included levofloxacin (500 –1,000 mg) instead of RFP. Levofloxacin was chosen because of a long-term safety profile.16 Treatment was continued for at least 6 months using the RFP-based regimen and at least 12 months using the QNL-based regimen, because regimens not including RFP should be continued for 12–18 months.3,15 In the RFP-based regimen, the dose of CNI was increased 2–5-fold to maintain stable trough levels.17–19 According to the initial treatment regimen, patients consisted of an RFP-based group (n ⫽ 91) and a QNL-based group (n ⫽ 18). Each group was further divided into an AR group and a non-AR group depending on the development of AR during anti-TB treatment. In addition, patients with RFP-associated adverse effects were subdivided into 2 groups: patients who developed AR but continued RFP (RFP-maintenance [RFP-M]; n ⫽ 18) or those who replaced RFP with QNL (QNL-conversion [QNL-C]; n ⫽ 8). Clinical outcomes were compared the between RFP and QNL groups and between the RFP-M and QNL-C groups. The study was approved by our Institutional Review Board (KC11RISI0117). Continuous data are presented as mean ⫾ SD and were compared by Student t test or paired t test. Statistical analysis was performed using SPSS software. Categoric data were compared by chi-square tests or Fisher exact tests. Kaplan-Meier curves and log-rank tests were used to describe and compare the survival rates for allografts. A P value of ⬍.05 was taken to indicate significance.
Patient characteristics did not differ between the RFP and QNL groups, except that the average duration of anti-TB treatment was significantly longer in the QNL group than in the RFP group (Table 1). The incidence of AR during anti-TB treatment was 4 times higher in the RFP group than in the QNL group (24.2% vs 5.6%). The overall graft survival rates for the QNL group were significantly higher than those for the RFP group (94.4% at 5 years and 88.1% at 10 years vs 79.8% at 5 years and 66.5% at 10 years; P ⫽ .022). Graft failure developed in 43 patients (47.3%) in the RFP group and in 2 patients (11.1%) in the QNL group. Eight cases of graft failure (18.6%) in the RFP group were due to AR during anti-TB treatment. RFP was replaced by QNL in 4 patients in the AR group and in 4 patients in the non-AR group because of other adverse effects: hepatotoxicity (n ⫽ 2); arthralgia and decreased visual acuity (n ⫽ 1); and RFP resistance (n ⫽ 1). The graft survival rates for the QNL-C group were significantly higher than those for the RFP-M group (87.5% at both 5 years and 10 years vs 50.0% at 5 years and 27.8% at 10 years; P ⫽ .011). In the RFP-M group, graft function deteriorated after AR in 10 patients (55.6%), and complete functional recovery, defined as the antirejection treatment recovering graft function to within 10% of the baseline value, was noted in only 4 patients (22.2%). In contrast, in the QNL-C group, graft function deteriorated in 1 patient (25%) and complete functional recovery was noted in 2 patients (50%).
Table 1. Comparison of Patient Characteristics Between the RFP and QNL Groups
Age, y Female sex, n (%) Pre-Tx Diabetes, n (%) Pre-Tx Dialysis modality, n (%), HD:PD:none Deceased donor, n (%) Donor age, y Donor sex female, n (%) HLA mismatch no. Retransplant, n (%) Pre-Tx transfusion, n (%) Pre-Tx maximum PRA, % Current PRA, % Serum creatinine, mg/dL Months from Tx to Dx of TB Prior history of TB, n (%) Site of infection, n (%) Pulmonary Extrapulmonary Combined Months on anti-TB medication Follow-up years after Dx of TB
RFP (n ⫽ 91)
QNL (n ⫽ 18)
P Value
41 ⫾ 11 30 (33.0) 31 (34.1) 83 (91.2):6 (6.6):2 (2.2) 15 (16.5) 38 ⫾ 13 32 (35.2) 3.1 ⫾ 1.4 7 (7.7) 76 (83.5) 0⫾0 8.0 ⫾ 16.0 2.0 ⫾ 1.4 50 ⫾ 56 2 (2.2)
43 ⫾ 12 6 (33.3) 5 (27.8) 15 (83.3):3 (16.7):0 (0) 4 (22.2) 40 ⫾ 12 7 (38.9) 4.7 ⫾ 1.5 1 (5.6) 14 (77.8) 6.7 ⫾ 11.5 6.7 ⫾ 11.5 1.6 ⫾ 0.8 55 ⫾ 61 1 (5.6)
.490 .976 .604 .310 .514 .517 .763 .057 1.000 .514 .629 .948 .283 .728 .421
45 (49.5) 31 (34.1) 15 (16.5) 10 ⫾ 5 8⫾6
11 (61.1) 7 (38.9) 0 (0) 12 ⫾ 1 8⫾4
.053 ⬍.001 .808
Abbreviations: RFP, rifampin; QNL, quinolone; Tx, transplantation; HD, hemodialysis; PD, peritoneal dialysis; PRA, panel reactive antibody; Dx, diagnosis; TB, tuberculosis.
732
In the RFP group, cyclosporine (CsA) doses were increased 2.9 ⫾ 0.5–fold during anti-TB treatment (range 2– 4-fold). The average increase in CsA dose did not differ between the AR (3.1 ⫾ 0.6 –fold, range 2– 4-fold) and non-AR (2.9 ⫾ 0.5–fold, range 2– 4-fold) groups (P ⫽ .077). However, the CsA trough levels significantly decreased at the time of AR (30.4 ⫾ 12.6 ng/mL, range 12– 60) compared with those before AR (148.5 ⫾ 27.4 ng/mL, range 106 –193) in the AR group (P ⬍ .001). In the QNL group, the CsA doses during anti-TB treatment did not differ from those before anti-TB treatment. In the RFP group, the rate of resistance or relapse of TB was 11.0% (n ⫽ 10), total mortality rate was 18.7% (n ⫽ 17), and TB-related mortality rate was 6.6% (n ⫽ 6). In contrast, there were no cases of TB resistance or relapse, TB-related death, or other deaths in the QNL group.
DISCUSSION
The present study demonstrates that a QNL-based regimen may be safe and effective for treatment of active TB in renal transplant recipients and may lower the risk of graft failure. Until now, no report has compared the allograft outcomes between RFP-based and QNL-based regimens. Our experience suggests that a QNL-based regimen may be recommended as the primary treatment for TB in renal transplant recipients. It is still controversial whether an RFP-based regimen is effective and safe in transplant recipients. Some reports show favorable graft outcomes,15,17,19,20 but others show a high incidence of AR and graft loss.1,3,21 The discrepancy seems to be related to regional differences and the number of patients.20,21 In the present study, TB developed in 109 of 1,787 patients, and most patients were initially treated with RFP. However, they experienced a high incidence of AR (22.4%) and graft failure because of AR (18.6%). The main reason for the high incidence of AR in the RFP-based regimen is the drug interaction between CNIs and RFP. In the present study, the doses of CsA were increased in the RFP group 2– 4-fold, but we saw a significant decrease in CsA trough levels. One could argue that the increment in the CsA dose was insufficient to prevent AR, but the average increase in the CsA dose did not differ between the AR and non-AR groups. This finding suggests that an increment of CsA dose alone is insufficient to lower the risk of AR, and the CsA levels were unpredictable. For this reason, another drug with less interaction with CNIs, QNL, was needed. In this study, there was no significant change in CsA dose during anti-TB treatment in the QNL group. After we started to use QNL instead of RFP as an initial drug, we obtained a dramatically lower rate of AR (5.6%), which was one-fourth that with the RFP-based regimen. Thereafter, no graft failure because of AR occurred during the anti-TB medication. Based on our data, we suggest that a QNL-based regimen could be used as an initial regimen for treatment of TB in renal transplant recipients.
YOON, JEON, CHUNG ET AL
In this study, the overall 10-year graft survival rates for the RFP group were significantly lower than those for the QNL group. The beneficial effect of conversion from RFP to QNL on graft survival and function also was apparent. The 10-year graft survival rates for the QNL-C group were significantly higher than those for the RFP-M group. In addition, the complete functional recovery after AR was more often achieved in the QNL-C group than in the RFP-M group, and the deterioration of graft function was less. This finding suggests that both the initial use of QNL and conversion to QNL are better than the use of RFP in treating TB in renal transplant recipients. In conclusion, a QNL-based regimen may be as effective and safe for the treatment of TB and may lower the risk of graft failure in renal transplant recipients compared with an RFP-based regimen. We cautiously suggest that a QNLbased regimen could be considered as the primary treatment of TB in patients receiving CsA. REFERENCES 1. Aguado JM, Herrero JA, Gavalda J, et al: Spanish Transplantation Infection Study Group, Gesitra: Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in spain. Transplantation 63:1278, 1997 2. Ram R, Swarnalatha G, Prasad N, et al: Tuberculosis in renal transplant recipients. Transpl Infect Dis 9:97, 2007 3. Singh N, Paterson DL: Mycobacterium tuberculosis infection in solid-organ transplant recipients: Impact and implications for management. Clin Infect Dis 27:1266, 1998 4. Park JS, Kim MS, Lee JH, et al: Mycobacterial infection after kidney transplantation—single center experience. J Korean Soc Transplant 15:39, 2001 5. Sung JY, Kim CW, Lee HH, et al: Clinical manifestations of Mycobacterium tuberculosis infection after renal transplantation. J Korean Soc Transplant 22:58, 2008 6. Hong T, Lee CH, Kim GH, et al: Clinical characteristics of tuberculosis in kidney transplantation patients. J Korean Soc Transplant 19:42, 2005 7. European best practice guidelines for renal transplantation. Section iv: Long-term management of the transplant recipient. Iv.7.2. Late infections. Tuberculosis. Nephrol Dial Transplant 17(Suppl 4):39, 2002 8. Horsburgh CR Jr, Feldman S, Ridzon R: Practice guidelines for the treatment of tuberculosis. Clin Infect Dis 31:633, 2000 9. Kdigo clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 9(Suppl 3):S1, 2009 10. Cassidy MJ, van Zyl–Smit R, Pascoe MD, et al: Effect of rifampicin on cyclosporin a blood levels in a renal transplant recipient. Nephron 41:207, 1985 11. Offermann G, Keller F, Molzahn M: Low cyclosporine A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment. Am J Nephrol 5:385, 1985 12. Jacobs MR: Fluoroquinolones as chemotherapeutics against mycobacterial infections. Curr Pharm Des 10:3213, 2004 13. Tomioka H, Sato K, Shimizu T, et al: Anti–Mycobacterium tuberculosis activities of new fluoroquinolones in combination with other antituberculous drugs. J Infect 44:160, 2002 14. Jha V, Sakhuja V, Gupta D, et al: Successful management of pulmonary tuberculosis in renal allograft recipients in a single center. Kidney Int 56:1944, 1999 15. Sakhuja V, Jha V, Varma PP, et al: The high incidence of tuberculosis among renal transplant recipients in india. Transplantation 61:211, 1996
QUINOLONE TO TREAT TUBERCULOSIS IN RENAL TRANSPLANT PATIENTS 16. Treatment of tuberculosis. MMWR Recomm Rep 52:1, 2003 17. al-Sulaiman MH, Dhar JM, al-Khader AA: Successful use of rifampicin in the treatment of tuberculosis in renal transplant patients immunosuppressed with cyclosporine. Transplantation 50:597, 1990 18. Peschke B, Ernst W, Gossmann J, et al: Antituberculous drugs in kidney transplant recipients treated with cyclosporine. Transplantation 56:236, 1993
733
19. Sayiner A, Ece T, Duman S, et al: Tuberculosis in renal transplant recipients. Transplantation 68:1268, 1999 20. Park YS, Choi JY, Cho CH, et al: Clinical outcomes of tuberculosis in renal transplant recipients. Yonsei Med J 45:865, 2004 21. el-Agroudy AE, Refaie AF, Moussa OM, et al: Tuberculosis in egyptian kidney transplant recipients: study of clinical course and outcome. J Nephrol 16:404, 2003
T
0041-1345/12/$–see front matter doi:10.1016/j.transproceed.2011.12.065 730
In the present study, clinical outcomes and adverse effects were compared between an RFP-based regimen and a QNL-based regimen, and the effect of QNL on allograft outcomes was evaluated in renal transplant recipients.
From the Division of Nephrology, Department of Internal Medicine, Incheon St. Mary’s Hospital, Catholic University of Korea, Incheon, Korea (H.E.Y., H.W.C., S.J.S.), Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, Catholic University of Korea, Seoul, Korea (Y.J.J., B.S.C., C.W.P., Y.S.K., C.W.Y.), and Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary’s Hospital (H.S.H., S.J.L., Y.K.C., S.Y.K.), Catholic University of Korea, Daejeon, Korea. Supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A102065). Address reprint requests to Chul Woo Yang, MD, PhD, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, Catholic University of Korea, 505, Banpodong, Seocho-gu, Seoul, Korea, 137-040. E-mail: yangch@ catholic.ac.kr © 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 730 –733 (2012)
QUINOLONE TO TREAT TUBERCULOSIS IN RENAL TRANSPLANT PATIENTS
731
METHODS
RESULTS
Between January 1984 and April 2009, 1,787 patients underwent renal transplantation at Seoul St Mary’s Hospital and Daejeon St Mary’s Hospital. Of these, 109 developed active TB during the study period. We retrospectively reviewed the medical records of these patients. The RFP-based regimen was a daily oral regimen including RFP (450 – 600 mg), isoniazid (300 – 400 mg), ethambutol (800 mg), and pyrazinamide (1,000 –1,500 mg). The QNL-based regimen included levofloxacin (500 –1,000 mg) instead of RFP. Levofloxacin was chosen because of a long-term safety profile.16 Treatment was continued for at least 6 months using the RFP-based regimen and at least 12 months using the QNL-based regimen, because regimens not including RFP should be continued for 12–18 months.3,15 In the RFP-based regimen, the dose of CNI was increased 2–5-fold to maintain stable trough levels.17–19 According to the initial treatment regimen, patients consisted of an RFP-based group (n ⫽ 91) and a QNL-based group (n ⫽ 18). Each group was further divided into an AR group and a non-AR group depending on the development of AR during anti-TB treatment. In addition, patients with RFP-associated adverse effects were subdivided into 2 groups: patients who developed AR but continued RFP (RFP-maintenance [RFP-M]; n ⫽ 18) or those who replaced RFP with QNL (QNL-conversion [QNL-C]; n ⫽ 8). Clinical outcomes were compared the between RFP and QNL groups and between the RFP-M and QNL-C groups. The study was approved by our Institutional Review Board (KC11RISI0117). Continuous data are presented as mean ⫾ SD and were compared by Student t test or paired t test. Statistical analysis was performed using SPSS software. Categoric data were compared by chi-square tests or Fisher exact tests. Kaplan-Meier curves and log-rank tests were used to describe and compare the survival rates for allografts. A P value of ⬍.05 was taken to indicate significance.
Patient characteristics did not differ between the RFP and QNL groups, except that the average duration of anti-TB treatment was significantly longer in the QNL group than in the RFP group (Table 1). The incidence of AR during anti-TB treatment was 4 times higher in the RFP group than in the QNL group (24.2% vs 5.6%). The overall graft survival rates for the QNL group were significantly higher than those for the RFP group (94.4% at 5 years and 88.1% at 10 years vs 79.8% at 5 years and 66.5% at 10 years; P ⫽ .022). Graft failure developed in 43 patients (47.3%) in the RFP group and in 2 patients (11.1%) in the QNL group. Eight cases of graft failure (18.6%) in the RFP group were due to AR during anti-TB treatment. RFP was replaced by QNL in 4 patients in the AR group and in 4 patients in the non-AR group because of other adverse effects: hepatotoxicity (n ⫽ 2); arthralgia and decreased visual acuity (n ⫽ 1); and RFP resistance (n ⫽ 1). The graft survival rates for the QNL-C group were significantly higher than those for the RFP-M group (87.5% at both 5 years and 10 years vs 50.0% at 5 years and 27.8% at 10 years; P ⫽ .011). In the RFP-M group, graft function deteriorated after AR in 10 patients (55.6%), and complete functional recovery, defined as the antirejection treatment recovering graft function to within 10% of the baseline value, was noted in only 4 patients (22.2%). In contrast, in the QNL-C group, graft function deteriorated in 1 patient (25%) and complete functional recovery was noted in 2 patients (50%).
Table 1. Comparison of Patient Characteristics Between the RFP and QNL Groups
Age, y Female sex, n (%) Pre-Tx Diabetes, n (%) Pre-Tx Dialysis modality, n (%), HD:PD:none Deceased donor, n (%) Donor age, y Donor sex female, n (%) HLA mismatch no. Retransplant, n (%) Pre-Tx transfusion, n (%) Pre-Tx maximum PRA, % Current PRA, % Serum creatinine, mg/dL Months from Tx to Dx of TB Prior history of TB, n (%) Site of infection, n (%) Pulmonary Extrapulmonary Combined Months on anti-TB medication Follow-up years after Dx of TB
RFP (n ⫽ 91)
QNL (n ⫽ 18)
P Value
41 ⫾ 11 30 (33.0) 31 (34.1) 83 (91.2):6 (6.6):2 (2.2) 15 (16.5) 38 ⫾ 13 32 (35.2) 3.1 ⫾ 1.4 7 (7.7) 76 (83.5) 0⫾0 8.0 ⫾ 16.0 2.0 ⫾ 1.4 50 ⫾ 56 2 (2.2)
43 ⫾ 12 6 (33.3) 5 (27.8) 15 (83.3):3 (16.7):0 (0) 4 (22.2) 40 ⫾ 12 7 (38.9) 4.7 ⫾ 1.5 1 (5.6) 14 (77.8) 6.7 ⫾ 11.5 6.7 ⫾ 11.5 1.6 ⫾ 0.8 55 ⫾ 61 1 (5.6)
.490 .976 .604 .310 .514 .517 .763 .057 1.000 .514 .629 .948 .283 .728 .421
45 (49.5) 31 (34.1) 15 (16.5) 10 ⫾ 5 8⫾6
11 (61.1) 7 (38.9) 0 (0) 12 ⫾ 1 8⫾4
.053 ⬍.001 .808
Abbreviations: RFP, rifampin; QNL, quinolone; Tx, transplantation; HD, hemodialysis; PD, peritoneal dialysis; PRA, panel reactive antibody; Dx, diagnosis; TB, tuberculosis.
732
In the RFP group, cyclosporine (CsA) doses were increased 2.9 ⫾ 0.5–fold during anti-TB treatment (range 2– 4-fold). The average increase in CsA dose did not differ between the AR (3.1 ⫾ 0.6 –fold, range 2– 4-fold) and non-AR (2.9 ⫾ 0.5–fold, range 2– 4-fold) groups (P ⫽ .077). However, the CsA trough levels significantly decreased at the time of AR (30.4 ⫾ 12.6 ng/mL, range 12– 60) compared with those before AR (148.5 ⫾ 27.4 ng/mL, range 106 –193) in the AR group (P ⬍ .001). In the QNL group, the CsA doses during anti-TB treatment did not differ from those before anti-TB treatment. In the RFP group, the rate of resistance or relapse of TB was 11.0% (n ⫽ 10), total mortality rate was 18.7% (n ⫽ 17), and TB-related mortality rate was 6.6% (n ⫽ 6). In contrast, there were no cases of TB resistance or relapse, TB-related death, or other deaths in the QNL group.
DISCUSSION
The present study demonstrates that a QNL-based regimen may be safe and effective for treatment of active TB in renal transplant recipients and may lower the risk of graft failure. Until now, no report has compared the allograft outcomes between RFP-based and QNL-based regimens. Our experience suggests that a QNL-based regimen may be recommended as the primary treatment for TB in renal transplant recipients. It is still controversial whether an RFP-based regimen is effective and safe in transplant recipients. Some reports show favorable graft outcomes,15,17,19,20 but others show a high incidence of AR and graft loss.1,3,21 The discrepancy seems to be related to regional differences and the number of patients.20,21 In the present study, TB developed in 109 of 1,787 patients, and most patients were initially treated with RFP. However, they experienced a high incidence of AR (22.4%) and graft failure because of AR (18.6%). The main reason for the high incidence of AR in the RFP-based regimen is the drug interaction between CNIs and RFP. In the present study, the doses of CsA were increased in the RFP group 2– 4-fold, but we saw a significant decrease in CsA trough levels. One could argue that the increment in the CsA dose was insufficient to prevent AR, but the average increase in the CsA dose did not differ between the AR and non-AR groups. This finding suggests that an increment of CsA dose alone is insufficient to lower the risk of AR, and the CsA levels were unpredictable. For this reason, another drug with less interaction with CNIs, QNL, was needed. In this study, there was no significant change in CsA dose during anti-TB treatment in the QNL group. After we started to use QNL instead of RFP as an initial drug, we obtained a dramatically lower rate of AR (5.6%), which was one-fourth that with the RFP-based regimen. Thereafter, no graft failure because of AR occurred during the anti-TB medication. Based on our data, we suggest that a QNL-based regimen could be used as an initial regimen for treatment of TB in renal transplant recipients.
YOON, JEON, CHUNG ET AL
In this study, the overall 10-year graft survival rates for the RFP group were significantly lower than those for the QNL group. The beneficial effect of conversion from RFP to QNL on graft survival and function also was apparent. The 10-year graft survival rates for the QNL-C group were significantly higher than those for the RFP-M group. In addition, the complete functional recovery after AR was more often achieved in the QNL-C group than in the RFP-M group, and the deterioration of graft function was less. This finding suggests that both the initial use of QNL and conversion to QNL are better than the use of RFP in treating TB in renal transplant recipients. In conclusion, a QNL-based regimen may be as effective and safe for the treatment of TB and may lower the risk of graft failure in renal transplant recipients compared with an RFP-based regimen. We cautiously suggest that a QNLbased regimen could be considered as the primary treatment of TB in patients receiving CsA. REFERENCES 1. Aguado JM, Herrero JA, Gavalda J, et al: Spanish Transplantation Infection Study Group, Gesitra: Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in spain. Transplantation 63:1278, 1997 2. Ram R, Swarnalatha G, Prasad N, et al: Tuberculosis in renal transplant recipients. Transpl Infect Dis 9:97, 2007 3. Singh N, Paterson DL: Mycobacterium tuberculosis infection in solid-organ transplant recipients: Impact and implications for management. Clin Infect Dis 27:1266, 1998 4. Park JS, Kim MS, Lee JH, et al: Mycobacterial infection after kidney transplantation—single center experience. J Korean Soc Transplant 15:39, 2001 5. Sung JY, Kim CW, Lee HH, et al: Clinical manifestations of Mycobacterium tuberculosis infection after renal transplantation. J Korean Soc Transplant 22:58, 2008 6. Hong T, Lee CH, Kim GH, et al: Clinical characteristics of tuberculosis in kidney transplantation patients. J Korean Soc Transplant 19:42, 2005 7. European best practice guidelines for renal transplantation. Section iv: Long-term management of the transplant recipient. Iv.7.2. Late infections. Tuberculosis. Nephrol Dial Transplant 17(Suppl 4):39, 2002 8. Horsburgh CR Jr, Feldman S, Ridzon R: Practice guidelines for the treatment of tuberculosis. Clin Infect Dis 31:633, 2000 9. Kdigo clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 9(Suppl 3):S1, 2009 10. Cassidy MJ, van Zyl–Smit R, Pascoe MD, et al: Effect of rifampicin on cyclosporin a blood levels in a renal transplant recipient. Nephron 41:207, 1985 11. Offermann G, Keller F, Molzahn M: Low cyclosporine A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment. Am J Nephrol 5:385, 1985 12. Jacobs MR: Fluoroquinolones as chemotherapeutics against mycobacterial infections. Curr Pharm Des 10:3213, 2004 13. Tomioka H, Sato K, Shimizu T, et al: Anti–Mycobacterium tuberculosis activities of new fluoroquinolones in combination with other antituberculous drugs. J Infect 44:160, 2002 14. Jha V, Sakhuja V, Gupta D, et al: Successful management of pulmonary tuberculosis in renal allograft recipients in a single center. Kidney Int 56:1944, 1999 15. Sakhuja V, Jha V, Varma PP, et al: The high incidence of tuberculosis among renal transplant recipients in india. Transplantation 61:211, 1996
QUINOLONE TO TREAT TUBERCULOSIS IN RENAL TRANSPLANT PATIENTS 16. Treatment of tuberculosis. MMWR Recomm Rep 52:1, 2003 17. al-Sulaiman MH, Dhar JM, al-Khader AA: Successful use of rifampicin in the treatment of tuberculosis in renal transplant patients immunosuppressed with cyclosporine. Transplantation 50:597, 1990 18. Peschke B, Ernst W, Gossmann J, et al: Antituberculous drugs in kidney transplant recipients treated with cyclosporine. Transplantation 56:236, 1993
733
19. Sayiner A, Ece T, Duman S, et al: Tuberculosis in renal transplant recipients. Transplantation 68:1268, 1999 20. Park YS, Choi JY, Cho CH, et al: Clinical outcomes of tuberculosis in renal transplant recipients. Yonsei Med J 45:865, 2004 21. el-Agroudy AE, Refaie AF, Moussa OM, et al: Tuberculosis in egyptian kidney transplant recipients: study of clinical course and outcome. J Nephrol 16:404, 2003