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Original Research |

Multitarget Therapy for Induction Treatment of Lupus Nephritis: A Randomized TrialMultitarget Therapy for Induction Treatment of Lupus Nephritis

Zhihong Liu, MD; Haitao Zhang, MD; Zhangsuo Liu, MD; Changying Xing, PhD; Ping Fu, MD; Zhaohui Ni, MD; Jianghua Chen, MD; Hongli Lin, MD; Fuyou Liu, MD; Yongcheng He, MD; Yani He, MD; Lining Miao, MD; Nan Chen, MD; Ying Li, MD; Yong Gu, MD; Wei Shi, MD; Weixin Hu, MD; Zhengzhao Liu, MD; Hao Bao, MD; Caihong Zeng, PhD; and Minlin Zhou, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 11 November 2014.


From Jinling Hospital, Nanjing University School of Medicine and The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; West China Hospital, Chengdu, China; Renji Hospital, Ruijin Hospital, and Huashan Hospital, Shanghai, China; The First Affiliated Hospital of Zhejiang University, Hangzhou, China; The First Affiliated Hospital of Dalian Medical University, Dalian, China; The Second Xiangya Hospital of Central South University, Changsha, China; Shenzhen Second People's Hospital, Shenzhen, China; Daping Hospital, Chongqing, China; The Second Affiliated Hospital of Jilin University, Changchun, China; The Third Hospital of Hebei Medical University, Hebei, China; and Guangdong General Hospital, Guangdong, China.

Grant Support: By the National Basic Research Program of China (973 Program, No. 2012CB517600, No. 2012CB517606), National Key Technology R&D Program (2011BA I10B04, 2013BAI09B04).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1030.

Reproducible Research Statement:Study protocol: Available at www.annals.org. Statistical code: Available from Dr. Zhang at htzhang163@163.com. Data set: not available.

Requests for Single Reprints: Zhihong Liu, MD, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210016, China; e-mail, liuzhihong@nju.edu.cn.

Current Author Addresses: Drs. Zhihong Liu, Zhang, Hu, Zhengzhao Liu, Bao, Zeng, and Zhou: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, China, 210016.

Dr. Zhangsuo Liu: The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan, China, 450052.

Dr. Xing: The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China, 210029.

Dr. Fu: West China Hospital, 37 Guoxue Xiang, Wuhou District, Chengdu, China, 610041.

Dr. Ni: Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, China, 200127.

Dr. Jianghua Chen: The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang, China, 310003.

Dr. Lin: The First Affiliated Hospital of Dalian Medical University, NO 222, Zhongshan Road, Dalian, China, 116011.

Dr. Fuyou Liu: The Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha, Hunan, China, 410011.

Dr. Yongcheng He: Shenzhen Second People's Hospital, 3002 West Sungang Road, Futian District, Shenzhen, China, 518035.

Dr. Yani He: Daping Hospital, Third Military Medical University, 10 Changjiangzhilu Daping, Yuzhong District, Chongqing, China, 400042.

Dr. Miao: The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, China, 130041.

Dr. Nan Chen: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 RuiJin Er Lu, Shanghai, China, 200025.

Dr. Li: The Third Hospital of Hebei Medical University, 102 Youyi North Street, Shijiazhuang, Hebei Province, China, 050081.

Dr. Gu: Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040.

Dr. Shi: Guangdong General Hospital, Guangdong Academy of Medical Science, 106 Zhongshan Er Road, Guangzhou, China, 510080.

Author Contributions: Conception and design: Zhihong Liu, H. Zhang, Zhangsuo Liu. P. Fu.

Analysis and interpretation of the data: Zhihong Liu, H. Zhang, Zhangsuo Liu, P. Fu, Zhengzhao Liu, H. Bao, C. Zeng.

Drafting of the article: Zhihong Liu, H. Zhang, P. Fu, H. Bao, C. Zeng.

Critical revision of the article for important intellectual content: Zhihong Liu, H. Zhang, Zhangsuo Liu, P. Fu, Zhengzhao Liu, H. Bao, C. Zeng, M. Zhou.

Final approval of the article: Zhihong Liu, H. Zhang, Zhangsuo Liu, C. Xing, P. Fu, Z. Ni, J. Chen, H. Lin, F. Liu, Yani He, L. Miao, N. Chen, Y. Gu, W. Shi, W. Hu, H. Bao, C. Zeng, M. Zhou.

Provision of study materials or patients: Zhihong Liu, H. Zhang, C. Xing, P. Fu, Z. Ni, J. Chen, H. Lin, F. Liu, Yongcheng He, Yani He, L. Miao, N. Chen, Y. Li, Y. Gu, W. Shi, W. Hu, Zhengzhao Liu, C. Zeng.

Statistical expertise: P. Fu, M. Zhou.

Obtaining of funding: Zhihong Liu, H. Zhang, P. Fu.

Administrative, technical, or logistic support: Zhihong Liu, H. Zhang, Zhengzhao Liu.

Collection and assembly of data: Zhihong Liu, H. Zhang, Zhangsuo Liu, C. Xing, P. Fu, J. Chen, H. Lin, F. Liu, Yongcheng He, N. Chen, W. Hu, Zhengzhao Liu, C. Zeng.


Ann Intern Med. 2015;162(1):18-26. doi:10.7326/M14-1030
Text Size: A A A

Background: Treatment of lupus nephritis (LN) remains challenging.

Objective: To assess the efficacy and safety of a multitarget therapy consisting of tacrolimus, mycophenolate mofetil, and steroid compared with intravenous cyclophosphamide and steroid as induction therapy for LN.

Design: 24-week randomized, open-label, multicenter study. (ClinicalTrials.gov: NCT00876616)

Setting: 26 renal centers in China.

Patients: Adults (aged 18 to 65 years) with biopsy-proven LN.

Intervention: Tacrolimus, 4 mg/d, and mycophenolate mofetil, 1.0 g/d, versus intravenous cyclophosphamide with a starting dose of 0.75 (adjusted to 0.5 to 1.0) g/m2 of body surface area every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy.

Measurements: The primary end point was complete remission at 24 weeks. Secondary end points included overall response (complete and partial remission), time to overall response, and adverse events.

Results: After 24 weeks of therapy, more patients in the multitarget group (45.9%) than in the intravenous cyclophosphamide group (25.6%) showed complete remission (difference, 20.3 percentage points [95% CI, 10.0 to 30.6 percentage points]; P < 0.001). The overall response incidence was higher in the multitarget group than in the intravenous cyclophosphamide group (83.5% vs. 63.0%; difference, 20.4 percentage points [CI, 10.3 to 30.6 percentage points]; P < 0.001), and the median time to overall response was shorter in the multitarget group (difference, −4.1 weeks [CI, −7.9 to −2.1 weeks]). Incidence of adverse events did not differ between the multitarget and intravenous cyclophosphamide groups (50.3% [91 of 181] vs. 52.5% [95 of 181]).

Limitation: The study was limited to 24 weeks of follow-up.

Conclusion: Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy for LN.

Primary Funding Source: National Basic Research Program of China, National Key Technology R&D Program.

Figures

Grahic Jump Location
Figure 1.

Study flow diagram.

IVCY = intravenous cyclophosphamide.

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Grahic Jump Location
Figure 2.

Complete remission incidence at 24 weeks in all patients with LN and per pathologic class subgroup, by treatment (MT regimen or IVCY).

Bars represent 95% CIs. LN = lupus nephritis; MT = multitarget; IVCY = intravenous cyclophosphamide.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Probability of achieving overall remission (complete remission and partial remission) in patients treated with the MT regimen or IVCY.

MT = multitarget; IVCY = intravenous cyclophosphamide.

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Appendix Figure.

Histologic changes in a patient who achieved complete remission after induction therapy with multitarget regimen.

The initial kidney biopsy revealed that the glomeruli showed diffuse and massive immune complex deposits in the mesangial and subendothelial areas, with thrombi in the capillary lumens. A. Periodic acid-Schiff; original magnification, ×400. B. Masson trichrome; original magnification, ×400. C. Periodic acid-Schiff methenamine silver Masson; original magnification, ×400. D. Immunofluorescent labeling of IgG; original magnification, ×400. E. Electron microscope image. A repeated biopsy indicated that glomerular mesangial and subendothelial deposits were significantly decreased and that “wire loops” and thrombi disappeared with remaining mild mesangial expansion and occasional endothelial cell proliferation. The intensity of staining for IgG also decreased. F. Periodic acid-Schiff; original magnification, ×400. G. Masson trichrome; original magnification, ×400. H. Periodic acid-Schiff methenamine silver Masson; original magnification, ×400. I. Immunofluorescent labeling of IgG; original magnification, ×400. J. Electron microscope image.

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Comments

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Comment
Posted on December 5, 2014
Alexandre Braga Libório, Dulce Maria Silva Barreto
Universidade Federal do Ceará
Conflict of Interest: None Declared
We read with interest the article by Liu et al. [1] evaluating a multitarget therapy for induction treatment of lupus nephritis. In this article, the authors conclude that patients receiving triple therapy (prednisone, mycophenolate and tacrolimus) achieved more complete remission than patients receiving prednisone and cyclophosphamide alone. Complete remission criteria utilized by the authors include renal function, urine sediment, serum albumin and 24h-proteinuria. At appendix table 5, it is clear that multitarget therapy was better regarding proteinuria reduction, but not in relation to renal function. In fact, there was a greater renal function improvement in the cyclophosphamide-treated group (although non-statistically significant). Some questions remain about the results: (1) taking into consideration only nephritic remission criteria (renal function and urinary sediment), was there any difference between the groups?; (2) if only proteinuria remission was responsible for the difference between the groups, how many patients received angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-II receptor blocker (ARB)? Moreover, we believe that systematic use of ACEI/ARB must be part of a treatment protocol when evaluating a drug with possible immunosuppressive-independent antiproteinuric action such as calcineurin inhibitor.
The authors declare no potential conflict of interest.

1. Liu, Z., Zhang, H., Liu, Z., Xing, C., Fu, P., Ni, Z., Chen, J., Lin, H., Liu, F., He, Y., He, Y., Miao, L., Chen, N., Li, Y., Gu, Y., Shi, W., Hu, W., Liu, Z., Bao, H., Zeng, C. & Zhou, M., 2014, Multitarget Therapy for Induction Treatment of Lupus Nephritis: A Randomized, Controlled Trial, Annals of internal medicine.

Alexandre Braga Libório*
Dulce Maria Silva Barreto#
* Professor, Clinical Medicine Department, Universidade Federal do Ceará,
# Chief of Glomerulopathy Section, Nephrology service, Hospital Geral de Fortaleza.
Comment on Multitarget therapy in Lupus Nephritis
Posted on December 19, 2014
Y.K.O. Teng, T.W.J. Huizinga, A.J. Rabelink
Dept. of Nephrology & Rheumatology, Leiden University Medical Center, The Netherlands
Conflict of Interest: None Declared
We read with interest the article of Zhihong et al. in which they compared triple therapy with cellcept, tacrolimus and steroids to monthly cyclophosphamide. The authors included patients of Asian origin with new-onset lupus nephritis or a flare while on azathioprine maintenance therapy. Patients were included from 2009-2011 and the 24-weeks results are described which are in favor of triple therapy.
As this study stopped including patients 3,5 years ago, it is of highly interest for the practicing clinician to know what maintenance therapy was given. We know from kidney transplantation literature that calcineurin-induced (CNI) nephrotoxicity was found in 25% of patients after 24 weeks, 33% after 1 year and almost 100% after 10 year (NEJM 2003;349:2326). Because the authors were able to analyse 23 repeat biopsies, it would be interesting to establish microscopic signs of CNI nephrotoxicity which would explain the lower eGFR in the multitarget treatment group.
Whether multitarget therapy is really superior to high dose cyclophosphamide will need to be proven when further follow-up of the study is shared. The present study was designed as a non-superiority trial with an estimated power of 80% and the hypothetical power of superiority of multitarget therapy was not calculated. From a statistical point of view, there was a 14% drop-out in each group which was not reflected in the statistical non-responder analysis. Despite this, the present study shows very promising results and definitely warrants further study in a general (non-Asian) lupus nephritis population. Because the follow-up was short, and, as with any successful induction therapy in lupus nephritis, two questions remain unsolved: how long and how intense should this therapy be given in order to achieve long-term remission without cumulative side-effects?
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Summary for Patients

Multitarget Therapy for Induction Treatment of Lupus Nephritis

The full report is titled “Multitarget Therapy for Induction Treatment of Lupus Nephritis. A Randomized Trial.” It is in the 6 January 2015 issue of Annals of Internal Medicine (volume 162, pages 18-26). The authors are Zhihong Liu, H. Zhang, Zhangsuo Liu, C. Xing, P. Fu, Z. Ni, J. Chen, H. Lin, F. Liu, Yongcheng He, Yani He, L. Miao, N. Chen, Y. Li, Y. Gu, W. Shi, W. Hu, Zhengzhao Liu, H. Bao, C. Zeng, and M. Zhou.

This article was published online first at www.annals.org on 11 November 2014.

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