Editorial Shenqi Particle: A Novel Therapy for Idiopathic Membranous Nephropathy Related Article, p. 1068
M
embranous nephropathy is among the most common causes of nephrotic syndrome in nondiabetic adults. Three-fourths of all cases are idiopathic (IMN), meaning they have no detectable clinical, serologic, or histologic evidence of secondary causes. It is recognized that supportive treatment alone leads to complete remission in 5%-30% and partial remission in 25%-40% of patients with IMN 5 years after diagnosis.1-3 However, 35%-40% of patients with IMN treated with supportive treatment alone reach end-stage renal disease within 10 years, while adding immunosuppressive treatment reduces this rate to 8%-11%.1,2,4,5 An immunosuppressive regimen for treating IMN typically includes alternating monthly courses of alkylating agents (cyclophosphamide or chlorambucil) and steroids, or calcineurin inhibitor–steroid combinations (Table 1). Steroids alone have been ineffective in IMN with the exception of favorable findings reported in one Japanese cohort.6 Meanwhile, both cyclosporine and tacrolimus demonstrated efficacy in earlier IMN trials, but there was a high risk of relapse when the drugs were discontinued.7,8 A recent randomized trial in patients with IMN in the United Kingdom found no benefit of cyclosporine over supportive treatment in reducing the primary outcome, defined as a 20% decline in kidney function.9 Serious adverse effects, such as sterility, that are encountered with alkylating agents prohibit their use in certain patient populations.10 Although recent prospective cohort studies have reported success in treating IMN with rituximab therapy as first- and second-line strategies, no large-scale controlled trials have been published to date.11,12 Therefore, the need to pursue newer and safer drugs and regimens for IMN persists. Traditional Chinese medicine (TCM) is practiced based on the accumulated experiential evidence of its practitioners and has been used to treat patients with kidney disease for thousands of years. Although many patients with kidney disease have been treated successfully with TCM, clinical trials examining its clinical efficacy are lacking. Designing adequately powered randomized clinical trials that test TCM is challenging due to the large variation in treatment prescription even for the same disease condition, as well as the need for frequent dose adjustment at follow-up visits. In addition, the formulas that TCM practitioners prescribe typically involve mixtures of herbs in different proportions prepared in decoctions. The active components of these herbal mixtures and their molecular mechanisms of action are largely unknown. However, in the last decade, Am J Kidney Dis. 2013;62(6):1027-1029
experimental and small-scale clinical studies have provided some evidence and mechanisms of action for TCM in the treatment of kidney disease.13 In this issue of AJKD, Chen et al14 report results of a randomized trial comparing Shenqi particle—a specific mixture of 13 TCM remedies—to conventional immunosuppression with cyclophosphamide-prednisone in 190 patients with biopsy-confirmed IMN. Individuals in the experimental arm received 9.6 g of the Shenqi particle 3 times a day, while in the standard therapy arm, cyclophosphamide was given monthly for 6 months, followed by doses every third month up to a cumulative dose of 9-12 g/m2 along with a tapering course of prednisone. In order to avoid constituent variations, the Shenqi particle was prepared and mixed in a standardized manner at a single pharmaceutical firm and dispensed from there. Initially patients were followed up every 2 weeks, then monthly, then bimonthly. At 48 weeks, among 132 participants remaining in the per-protocol analysis, the primary outcomes of complete or partial remission occurred at a similar rate in the 2 groups: complete remission was reached by 11 of the 63 (17.5%) Shenqi particle participants versus 20 of the 69 (29%) standard therapy patients, and partial remission was reached by 35 of the 63 (55.6%) patients in the Shenqi particle group versus 34 of 69 (49.3%) in standard therapy. Remission rates were similar to previously reported IMN trials with similar defined end points (Table 1). Remission rates also were similar between the 2 arms when participants with severe (protein excretion ⬎ 8 g/d) and moderate (3.5-8 g/d) proteinuria were analyzed separately. Mean reductions in proteinuria in the 2 arms over the duration of the study also were similar. Other secondary outcomes, including serum albumin levels and end-stage renal disease and death rates, also were not significantly different between the 2 groups. Importantly, there were fewer serious adverse events reported in the Shenqi particle group than in the standard therapy group. These data suggest both that Shenqi particle is a safe and effec-
Address correspondence to John Cijiang He, MD, Division of Nephrology, Box 1243, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Pl, New York, NY 10029. E-mail: cijiang. [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386/$0.00 http://dx.doi.org/10.1053/j.ajkd.2013.08.005 1027
Menon, Chuang, and He Table 1. Trials in Treatment of Idiopathic Membranous Nephropathy
Reference
Primary Outcome
Study Period (mo)
Ponticelli et al4 (1989)
CR ⫹ PR
24a
Ponticelli et al10 (1998)
CR ⫹ PR
12a
Cattran et al7 (2001)
CR ⫹ PR
6a
Praga et al8 (2007)
CR ⫹ PR
18
Jha et al2 (2007)
CR ⫹ PR
120
Howman et al9 (2012)
20% decline in creatinine-based eGFR
36
Ruggenenti et al11 (2012)c Chen et al14 (2013)d
NA CR ⫹ PR
29 12
Immunosuppression
Sample Size
Combined CR and PR (%)
Chlorambucil/steroid Supportive therapy Chlorambucil/steroid Cyclophosphamide/steroid Cyclosporine/steroid Placebo/steroid
42 39 44 43 28 23
28 (66.7) 9 (23.0) 36 (81.8) 40 (93.0) 21 (75.0) 5 (21.7)
Tacrolimus Supportive therapy Cyclophosphamide/steroid Supportive therapy Chlorambucil/steroid Cyclosporine Supportive therapy Rituximab Shenqi particle Cyclophosphamide/Steroid
25 23 47 46 33 36 37 68 63 69
19 (76.0) 6 (26.1) 34 (72.3) 16 (34.8) NRb
47 (69.1) 46 (73.0) 54 (78.3)
Abbreviations: CR, complete remission; eGFR, estimated glomerular filtration rate; NA, not applicable; NR, not reported; PR, partial remission. a These trials have reported longer term outcomes. b Cyclosporine was the supportive therapy in the primary outcome. c Prospective single-center observational experience with rituximab in IMN. d Present study.
tive therapy for IMN and that it has a more favorable side-effect profile. However, there are some concerns. Notably, a substantial percentage of patients were lost to follow-up in both study arms (27% and 32% in the Shenqi particle and standard therapy groups, respectively), albeit at similar rates. Neither group received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Also, as acknowledged by the authors, the study did not include a run-in period to allow for spontaneous remissions to occur in participants prior to assignment to specific treatment groups. Although spontaneous remissions in IMN increase with duration of disease,1 a higher proportion occurs within 1-2 years,15 which is the timeline of this study and could be a potential confounder in the outcome. Most importantly, as with other TCM remedy mixtures, exact mechanisms of action and interaction of multiple active components in Shenqi particle remain undefined. Nonetheless, this study in Chinese patients suggests the short-term efficacy of Shenqi particle for treating IMN. Implicit in this inference is the simultaneous need to rigorously and uniformly decoct and dispense the medication to patients, as was done in the study. The study also raises exciting avenues for future research. First, another combination of these herbs in a different proportion could have similar or greater efficacy. For instance, 2 previous AJKD reports16,17 suggested that Astragalus membranaceus 1028
alone is associated with remission of proteinuria in IMN. Hence, the ideal TCM combination for IMN remains to be determined. While the exact active components of Shenqi particle are uncertain, multiple individual components in this mixture have been reported in clinical and experimental settings to have anti-inflammatory (nuclear factor-B antagonism),18 immunomodulatory,19 antiproliferative,20-22 antiatherogenic,23 and antiproteinuric effects.13,24,25 The efficacy of Shenqi particle in the present study suggests that the optimal therapeutic approach for treating IMN might require simultaneously targeting multiple injury mechanisms. Interestingly, patients in the Shenqi particle group had creatinine-based estimated glomerular filtration rates (GFRs) that were substantially better (by 15 mL/min/1.73 m2) compared to standard therapy at 48 weeks of follow-up. Descriptions of medications that result in GFR improvements of this magnitude within 1 year in other glomerular disease settings are rare. However, it is possible that estimating GFR using creatinine-based equations could overestimate the actual GFR in this study of proteinuric patients; the lack of reported weight and muscle mass changes, which can result in differences in creatinine generation, are both caveats to the observed effects on creatininebased estimated GFR.26 From a pathogenetic perspective, considering the identification of the antibodies against the M-type phospholipase A2 receptor (PLA2R) Am J Kidney Dis. 2013;62(6):1027-1029
Editorial
in IMN and its relation to successful treatment, it may be of considerable interest to determine whether Shenqi particle treatment affects the levels of this antibody.27,28 Because Shenqi particle also demonstrated excellent safety and tolerability in this study, its application in the treatment of other glomerular diseases also should be investigated. Finally, it remains to be determined whether Shenqi particle is efficacious as an adjunctive or supportive therapy in patients with IMN who may not be candidates for aggressive immunosuppression due to low risk of disease progression or high risk of complications. In summary, from this study, Shenqi particle holds promise as an agent in IMN treatment. Although the efficacy of Shenqi particle on disease relapse and its efficacy in other ethnic groups need to be elucidated further, this study demonstrates that it is feasible to carry out a randomized trial of TCM in patients with kidney disease. Madhav C. Menon, MD Peter Y. Chuang, MD John Cijiang He, MD, PhD Icahn School of Medicine Mount Sinai, New York
ACKNOWLEDGEMENTS Support: Dr Menon is supported by an American Society of Nephrology fellowship grant. Dr Chuang is supported by National Institutes of Health (NIH) 5K08DK082760. Dr He is supported by NIH 1R01DK088541, Veterans Affairs Merit Award, and Chinese 973 fund 2012CB51760. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Schieppati A, Mosconi L, Perna A, et al. Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med. 1993;329:85-89. 2. Jha V, Ganguli A, Saha TK, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007;18:1899-1904. 3. Hogan SL, Muller KE, Jennette JC, Falk RJ. A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis. 1995;25:862-875. 4. Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med. 1989;320:8-13. 5. Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. 1995;48:1600-1604. 6. Shiiki H, Saito T, Nishitani Y, et al. Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan. Kidney Int. 2004;65:1400-1407. 7. Cattran DC, Appel GB, Hebert LA, et al. Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial. Kidney Int. 2001;59:1484-1490. 8. Praga M, Barrio V, Juarez GF, Luno J, Grupo Espanol de Estudio de la Nefropatia Membranosa. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int. 2007;71:924-930. Am J Kidney Dis. 2013;62(6):1027-1029
9. Howman A, Chapman TL, Langdon MM, et al. Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial. Lancet. 2013;381:744-751. 10. Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol. 1998;9:444-450. 11. Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol. 2012;23: 1416-1425. 12. Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 2008;73:117-125. 13. Peng A, Gu Y, Lin SY. Herbal treatment for renal diseases. Ann Acad Med Singapore. 2005;34:44-51. 14. Chen Y, Deng Y, Ni Z, et al. Efficacy and safety of traditional Chinese medicine (Shenqi particle) for patients with idiopathic membranous nephropathy: a multicenter randomized controlled clinical trial. Am J Kidney Dis. 2013:62:1068-1076. 15. Polanco N, Gutierrez E, Covarsi A, et al. Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol. 2010;21:697-704. 16. Ahmed MS, Hou SH, Battaglia MC, Picken MM, Leehey DJ. Treatment of idiopathic membranous nephropathy with the herb Astragalus membranaceus. Am J Kidney Dis. 2007;50:10281032. 17. Leehey DJ, Casini T, Massey D. Remission of membranous nephropathy after therapy with Astragalus membranaceus. Am J Kidney Dis. 2010;55:772. 18. Gui D, Huang J, Guo Y, et al. Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-kappaB-mediated inflammatory genes expression. Cytokine. 2013;61:970-977. 19. Wang ZT, Ng TB, Yeung HW, Xu GJ. Immunomodulatory effect of a polysaccharide-enriched preparation of Codonopsis pilosula roots. Gen Pharmacol. 1996;27:1347-1350. 20. Yoon JJ, Lee YJ, Lee SM, Jin SN, Kang DG, Lee HS. Poria cocos inhibits high glucose-induced proliferation of rat mesangial cells. Am J Chin Med. 2013;41:71-83. 21. Lu Y, Zhang BY, Jia ZX, Wu WJ, Lu ZQ. Hepatocellular carcinoma HepG2 cell apoptosis and caspase-8 and Bcl-2 expression induced by injectable seed extract of Coix lacryma-jobi. Hepatobiliary Pancreat Dis Int. 2011;10:303-307. 22. Cai Q, Lin J, Wei L, et al. Hedyotis diffusa willd inhibits colorectal cancer growth in vivo via inhibition of STAT3 signaling pathway. Int J Mol Sci. 2012;13:6117-6128. 23. Woo KS, Yip TW, Chook P, et al. Cardiovascular protective effects of adjunctive alternative medicine (Salvia miltiorrhiza and Pueraria lobata) in high-risk hypertension. Evid Based Complement Alternat Med. 2013;2013:132912. 24. Tong Y, Wang Q, Hou H. Protection by Chinese herbs against doxorubicin-induced focal and segmental glomerulosclerosis in rats. Drug Dev Ind Pharm. 2008;34:663-667. 25. Ge X, Zhang Y, Jiang J, et al. Identification of microRNAs in Helicoverpa armigera and Spodoptera litura based on deep sequencing and homology analysis. Int J Biol Sci. 2013;9:1-15. 26. Branten AJ, Vervoort G, Wetzels JF. Serum creatinine is a poor marker of GFR in nephrotic syndrome. Nephrol Dial Transplant. 2005;20:707-711. 27. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11-21. 28. Beck LH Jr, Fervenza FC, Beck DM, et al. Rituximabinduced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol. 2011;22: 1543-1550. 1029
M
embranous nephropathy is among the most common causes of nephrotic syndrome in nondiabetic adults. Three-fourths of all cases are idiopathic (IMN), meaning they have no detectable clinical, serologic, or histologic evidence of secondary causes. It is recognized that supportive treatment alone leads to complete remission in 5%-30% and partial remission in 25%-40% of patients with IMN 5 years after diagnosis.1-3 However, 35%-40% of patients with IMN treated with supportive treatment alone reach end-stage renal disease within 10 years, while adding immunosuppressive treatment reduces this rate to 8%-11%.1,2,4,5 An immunosuppressive regimen for treating IMN typically includes alternating monthly courses of alkylating agents (cyclophosphamide or chlorambucil) and steroids, or calcineurin inhibitor–steroid combinations (Table 1). Steroids alone have been ineffective in IMN with the exception of favorable findings reported in one Japanese cohort.6 Meanwhile, both cyclosporine and tacrolimus demonstrated efficacy in earlier IMN trials, but there was a high risk of relapse when the drugs were discontinued.7,8 A recent randomized trial in patients with IMN in the United Kingdom found no benefit of cyclosporine over supportive treatment in reducing the primary outcome, defined as a 20% decline in kidney function.9 Serious adverse effects, such as sterility, that are encountered with alkylating agents prohibit their use in certain patient populations.10 Although recent prospective cohort studies have reported success in treating IMN with rituximab therapy as first- and second-line strategies, no large-scale controlled trials have been published to date.11,12 Therefore, the need to pursue newer and safer drugs and regimens for IMN persists. Traditional Chinese medicine (TCM) is practiced based on the accumulated experiential evidence of its practitioners and has been used to treat patients with kidney disease for thousands of years. Although many patients with kidney disease have been treated successfully with TCM, clinical trials examining its clinical efficacy are lacking. Designing adequately powered randomized clinical trials that test TCM is challenging due to the large variation in treatment prescription even for the same disease condition, as well as the need for frequent dose adjustment at follow-up visits. In addition, the formulas that TCM practitioners prescribe typically involve mixtures of herbs in different proportions prepared in decoctions. The active components of these herbal mixtures and their molecular mechanisms of action are largely unknown. However, in the last decade, Am J Kidney Dis. 2013;62(6):1027-1029
experimental and small-scale clinical studies have provided some evidence and mechanisms of action for TCM in the treatment of kidney disease.13 In this issue of AJKD, Chen et al14 report results of a randomized trial comparing Shenqi particle—a specific mixture of 13 TCM remedies—to conventional immunosuppression with cyclophosphamide-prednisone in 190 patients with biopsy-confirmed IMN. Individuals in the experimental arm received 9.6 g of the Shenqi particle 3 times a day, while in the standard therapy arm, cyclophosphamide was given monthly for 6 months, followed by doses every third month up to a cumulative dose of 9-12 g/m2 along with a tapering course of prednisone. In order to avoid constituent variations, the Shenqi particle was prepared and mixed in a standardized manner at a single pharmaceutical firm and dispensed from there. Initially patients were followed up every 2 weeks, then monthly, then bimonthly. At 48 weeks, among 132 participants remaining in the per-protocol analysis, the primary outcomes of complete or partial remission occurred at a similar rate in the 2 groups: complete remission was reached by 11 of the 63 (17.5%) Shenqi particle participants versus 20 of the 69 (29%) standard therapy patients, and partial remission was reached by 35 of the 63 (55.6%) patients in the Shenqi particle group versus 34 of 69 (49.3%) in standard therapy. Remission rates were similar to previously reported IMN trials with similar defined end points (Table 1). Remission rates also were similar between the 2 arms when participants with severe (protein excretion ⬎ 8 g/d) and moderate (3.5-8 g/d) proteinuria were analyzed separately. Mean reductions in proteinuria in the 2 arms over the duration of the study also were similar. Other secondary outcomes, including serum albumin levels and end-stage renal disease and death rates, also were not significantly different between the 2 groups. Importantly, there were fewer serious adverse events reported in the Shenqi particle group than in the standard therapy group. These data suggest both that Shenqi particle is a safe and effec-
Address correspondence to John Cijiang He, MD, Division of Nephrology, Box 1243, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Pl, New York, NY 10029. E-mail: cijiang. [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386/$0.00 http://dx.doi.org/10.1053/j.ajkd.2013.08.005 1027
Menon, Chuang, and He Table 1. Trials in Treatment of Idiopathic Membranous Nephropathy
Reference
Primary Outcome
Study Period (mo)
Ponticelli et al4 (1989)
CR ⫹ PR
24a
Ponticelli et al10 (1998)
CR ⫹ PR
12a
Cattran et al7 (2001)
CR ⫹ PR
6a
Praga et al8 (2007)
CR ⫹ PR
18
Jha et al2 (2007)
CR ⫹ PR
120
Howman et al9 (2012)
20% decline in creatinine-based eGFR
36
Ruggenenti et al11 (2012)c Chen et al14 (2013)d
NA CR ⫹ PR
29 12
Immunosuppression
Sample Size
Combined CR and PR (%)
Chlorambucil/steroid Supportive therapy Chlorambucil/steroid Cyclophosphamide/steroid Cyclosporine/steroid Placebo/steroid
42 39 44 43 28 23
28 (66.7) 9 (23.0) 36 (81.8) 40 (93.0) 21 (75.0) 5 (21.7)
Tacrolimus Supportive therapy Cyclophosphamide/steroid Supportive therapy Chlorambucil/steroid Cyclosporine Supportive therapy Rituximab Shenqi particle Cyclophosphamide/Steroid
25 23 47 46 33 36 37 68 63 69
19 (76.0) 6 (26.1) 34 (72.3) 16 (34.8) NRb
47 (69.1) 46 (73.0) 54 (78.3)
Abbreviations: CR, complete remission; eGFR, estimated glomerular filtration rate; NA, not applicable; NR, not reported; PR, partial remission. a These trials have reported longer term outcomes. b Cyclosporine was the supportive therapy in the primary outcome. c Prospective single-center observational experience with rituximab in IMN. d Present study.
tive therapy for IMN and that it has a more favorable side-effect profile. However, there are some concerns. Notably, a substantial percentage of patients were lost to follow-up in both study arms (27% and 32% in the Shenqi particle and standard therapy groups, respectively), albeit at similar rates. Neither group received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Also, as acknowledged by the authors, the study did not include a run-in period to allow for spontaneous remissions to occur in participants prior to assignment to specific treatment groups. Although spontaneous remissions in IMN increase with duration of disease,1 a higher proportion occurs within 1-2 years,15 which is the timeline of this study and could be a potential confounder in the outcome. Most importantly, as with other TCM remedy mixtures, exact mechanisms of action and interaction of multiple active components in Shenqi particle remain undefined. Nonetheless, this study in Chinese patients suggests the short-term efficacy of Shenqi particle for treating IMN. Implicit in this inference is the simultaneous need to rigorously and uniformly decoct and dispense the medication to patients, as was done in the study. The study also raises exciting avenues for future research. First, another combination of these herbs in a different proportion could have similar or greater efficacy. For instance, 2 previous AJKD reports16,17 suggested that Astragalus membranaceus 1028
alone is associated with remission of proteinuria in IMN. Hence, the ideal TCM combination for IMN remains to be determined. While the exact active components of Shenqi particle are uncertain, multiple individual components in this mixture have been reported in clinical and experimental settings to have anti-inflammatory (nuclear factor-B antagonism),18 immunomodulatory,19 antiproliferative,20-22 antiatherogenic,23 and antiproteinuric effects.13,24,25 The efficacy of Shenqi particle in the present study suggests that the optimal therapeutic approach for treating IMN might require simultaneously targeting multiple injury mechanisms. Interestingly, patients in the Shenqi particle group had creatinine-based estimated glomerular filtration rates (GFRs) that were substantially better (by 15 mL/min/1.73 m2) compared to standard therapy at 48 weeks of follow-up. Descriptions of medications that result in GFR improvements of this magnitude within 1 year in other glomerular disease settings are rare. However, it is possible that estimating GFR using creatinine-based equations could overestimate the actual GFR in this study of proteinuric patients; the lack of reported weight and muscle mass changes, which can result in differences in creatinine generation, are both caveats to the observed effects on creatininebased estimated GFR.26 From a pathogenetic perspective, considering the identification of the antibodies against the M-type phospholipase A2 receptor (PLA2R) Am J Kidney Dis. 2013;62(6):1027-1029
Editorial
in IMN and its relation to successful treatment, it may be of considerable interest to determine whether Shenqi particle treatment affects the levels of this antibody.27,28 Because Shenqi particle also demonstrated excellent safety and tolerability in this study, its application in the treatment of other glomerular diseases also should be investigated. Finally, it remains to be determined whether Shenqi particle is efficacious as an adjunctive or supportive therapy in patients with IMN who may not be candidates for aggressive immunosuppression due to low risk of disease progression or high risk of complications. In summary, from this study, Shenqi particle holds promise as an agent in IMN treatment. Although the efficacy of Shenqi particle on disease relapse and its efficacy in other ethnic groups need to be elucidated further, this study demonstrates that it is feasible to carry out a randomized trial of TCM in patients with kidney disease. Madhav C. Menon, MD Peter Y. Chuang, MD John Cijiang He, MD, PhD Icahn School of Medicine Mount Sinai, New York
ACKNOWLEDGEMENTS Support: Dr Menon is supported by an American Society of Nephrology fellowship grant. Dr Chuang is supported by National Institutes of Health (NIH) 5K08DK082760. Dr He is supported by NIH 1R01DK088541, Veterans Affairs Merit Award, and Chinese 973 fund 2012CB51760. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Schieppati A, Mosconi L, Perna A, et al. Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med. 1993;329:85-89. 2. Jha V, Ganguli A, Saha TK, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007;18:1899-1904. 3. Hogan SL, Muller KE, Jennette JC, Falk RJ. A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis. 1995;25:862-875. 4. Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med. 1989;320:8-13. 5. Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. 1995;48:1600-1604. 6. Shiiki H, Saito T, Nishitani Y, et al. Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan. Kidney Int. 2004;65:1400-1407. 7. Cattran DC, Appel GB, Hebert LA, et al. Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial. Kidney Int. 2001;59:1484-1490. 8. Praga M, Barrio V, Juarez GF, Luno J, Grupo Espanol de Estudio de la Nefropatia Membranosa. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int. 2007;71:924-930. Am J Kidney Dis. 2013;62(6):1027-1029
9. Howman A, Chapman TL, Langdon MM, et al. Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial. Lancet. 2013;381:744-751. 10. Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol. 1998;9:444-450. 11. Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol. 2012;23: 1416-1425. 12. Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 2008;73:117-125. 13. Peng A, Gu Y, Lin SY. Herbal treatment for renal diseases. Ann Acad Med Singapore. 2005;34:44-51. 14. Chen Y, Deng Y, Ni Z, et al. Efficacy and safety of traditional Chinese medicine (Shenqi particle) for patients with idiopathic membranous nephropathy: a multicenter randomized controlled clinical trial. Am J Kidney Dis. 2013:62:1068-1076. 15. Polanco N, Gutierrez E, Covarsi A, et al. Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol. 2010;21:697-704. 16. Ahmed MS, Hou SH, Battaglia MC, Picken MM, Leehey DJ. Treatment of idiopathic membranous nephropathy with the herb Astragalus membranaceus. Am J Kidney Dis. 2007;50:10281032. 17. Leehey DJ, Casini T, Massey D. Remission of membranous nephropathy after therapy with Astragalus membranaceus. Am J Kidney Dis. 2010;55:772. 18. Gui D, Huang J, Guo Y, et al. Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-kappaB-mediated inflammatory genes expression. Cytokine. 2013;61:970-977. 19. Wang ZT, Ng TB, Yeung HW, Xu GJ. Immunomodulatory effect of a polysaccharide-enriched preparation of Codonopsis pilosula roots. Gen Pharmacol. 1996;27:1347-1350. 20. Yoon JJ, Lee YJ, Lee SM, Jin SN, Kang DG, Lee HS. Poria cocos inhibits high glucose-induced proliferation of rat mesangial cells. Am J Chin Med. 2013;41:71-83. 21. Lu Y, Zhang BY, Jia ZX, Wu WJ, Lu ZQ. Hepatocellular carcinoma HepG2 cell apoptosis and caspase-8 and Bcl-2 expression induced by injectable seed extract of Coix lacryma-jobi. Hepatobiliary Pancreat Dis Int. 2011;10:303-307. 22. Cai Q, Lin J, Wei L, et al. Hedyotis diffusa willd inhibits colorectal cancer growth in vivo via inhibition of STAT3 signaling pathway. Int J Mol Sci. 2012;13:6117-6128. 23. Woo KS, Yip TW, Chook P, et al. Cardiovascular protective effects of adjunctive alternative medicine (Salvia miltiorrhiza and Pueraria lobata) in high-risk hypertension. Evid Based Complement Alternat Med. 2013;2013:132912. 24. Tong Y, Wang Q, Hou H. Protection by Chinese herbs against doxorubicin-induced focal and segmental glomerulosclerosis in rats. Drug Dev Ind Pharm. 2008;34:663-667. 25. Ge X, Zhang Y, Jiang J, et al. Identification of microRNAs in Helicoverpa armigera and Spodoptera litura based on deep sequencing and homology analysis. Int J Biol Sci. 2013;9:1-15. 26. Branten AJ, Vervoort G, Wetzels JF. Serum creatinine is a poor marker of GFR in nephrotic syndrome. Nephrol Dial Transplant. 2005;20:707-711. 27. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11-21. 28. Beck LH Jr, Fervenza FC, Beck DM, et al. Rituximabinduced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol. 2011;22: 1543-1550. 1029
