Narrative Review Recent Advances in Traditional Chinese Medicine for Kidney Disease Yifei Zhong, MD, PhD,1 Madhav C. Menon, MD,2 Yueyi Deng, MD,1 Yiping Chen, MD,1 and John Cijiang He, MD, PhD2 Because current treatment options for chronic kidney disease (CKD) are limited, many patients seek out alternative therapies such as traditional Chinese medicine. However, there is a lack of evidence from large clinical trials to support the use of traditional medicines in patients with CKD. Many active components of traditional medicine formulas are undetermined and their toxicities are unknown. Therefore, there is a need for research to identify active compounds from traditional medicines and understand the mechanisms of action of these compounds, as well as their potential toxicity, and subsequently perform well-designed, randomized, controlled, clinical trials to study the efficacy and safety of their use in patients with CKD. Significant progress has been made in this field within the last several years. Many active compounds have been identified by applying sophisticated techniques such as mass spectrometry, and more mechanistic studies of these compounds have been performed using both in vitro and in vivo models. In addition, several well-designed, large, randomized, clinical trials have recently been published. We summarize these recent advances in the field of traditional medicines as they apply to CKD. In addition, current barriers for further research are also discussed. Due to the ongoing research in this field, we believe that stronger evidence to support the use of traditional medicines for CKD will emerge in the near future. Am J Kidney Dis. -(-):---. ª 2015 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic kidney disease (CKD); renal disease; traditional Chinese medicine (TCM); herbal medicine; alternative medicine; glomerular disease; inflammation; anti-inflammatory; anti-oxidant; antifibrotic; immunomodulation; animal models; clinical trials; review.

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urrent therapy for chronic kidney disease (CKD) remains limited. Renin-angiotensin system blockade is the mainstay, but many patients on treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers continue to progress to end-stage renal disease (ESRD).1 Treatment of glomerular disease with steroid and immunosuppressive medications is often associated with significant adverse effects. Patients experiencing recurrence or resistance to therapy are difficult to manage. Therefore, there is a need to develop more potent and safe therapies for this patient population. Because of the lack of effective therapy, many patients with CKD in China and other countries in Asia seek alternative treatments, such as traditional medicines. The practice of traditional medicine is based on the cumulative empirical experience of previous practitioners, summarized in historical textbooks. The main principle of traditional medicines is to regulate the natural balance of the yin and yang by focusing on the individualized care plan for each patient. Accumulated experience from the practice of traditional medicines suggests that combination herbal medications have greater efficacy than herbal agents in isolation. As a result, prescriptions of traditional medicines usually combine several herbs to produce a formula. The percentage of each component in the formulas varies based on the symptoms and signs of individual patients. Individual components in each herbal prescription are then adjusted at Am J Kidney Dis. 2015;-(-):---

each follow-up visit to achieve the maximal effects. This reflects the concept of personalized medicine, but also causes difficulty in clinical studies. Most traditional medicine practitioners use 3 principles to treat patients with CKD: “replenishing vital energy and nourishing blood,” “clearing heat and eliminating dampness,” and “coordinating Yin and Yang in the body.”2 Experiences from practitioners suggest that these principles could help improve symptoms, increase diuresis, reduce proteinuria, and preserve kidney function.3,4 Scientists in the field of traditional medicines have made efforts to understand the cellular and molecular mechanisms of these principles by using modern scientific techniques. However,

From the 1Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; and 2Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY. Received January 6, 2015. Accepted in revised form April 5, 2015. Address correspondence to Yifei Zhong, MD, PhD, Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, People’s Republic of China 200032 (e-mail: [email protected]) or John Cijiang He, MD, PhD, Division of Nephrology, Box 1243, Mount Sinai School of Medicine, One Gustave L Levy Pl, New York, NY 10029 (e-mail: [email protected]).  2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.04.013 1

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interpretation of these principles by Western medicine remains a challenge. Recently, research funding in the field of traditional medicines has increased in China. Peer-reviewed articles published in this field have also dramatically increased based on data from PubMed (Fig 1). For this review, we searched PubMed using the search terms traditional Chinese medicines, herbal medicine, alternative treatment, and kidney, with a time frame between 2005 and 2015. We selected only articles published in peer-reviewed English-language journals. Although we briefly summarize all relevant studies in this field over the last decade that were located by our search, we emphasize the new mechanistic studies and clinical trials that have been published since our last review article in 2013.5 Whereas our previous review provided a broader discussion of the potential effects of traditional medicines, the current review focuses on the anti-inflammatory, antioxidative, and antifibrotic effects of traditional medicines commonly used in kidney disease. We also discuss the strengths and weakness of recently published clinical trials and meta-analyses in this field. We hope that our review will not only update clinical nephrologists’ knowledge of traditional medicines, but also help researchers in this field design and perform better clinical trials in the future.

RECENT BASIC SCIENCE RESEARCH ADVANCES Overview Mechanistic studies applying traditional medicines to the treatment of kidney disease that were reported before 2013 are reviewed in our prior publication.5 While those mechanistic studies were performed with mixed herbal formulas, recent studies have focused more on active compounds purified from herbal medicines. These data could help us understand structurefunction relationships and the molecular mechanisms

Figure 1. The number of articles on traditional Chinese medicines published in English from 1995 through 2014. This information was obtained from PubMed by searching “Chinese herbal medicine” as a key word. 2

of these traditional medicines and represent important progress in this field. These studies suggest that the major effects of traditional medicines are related to anti-inflammatory, antioxidative, antifibrotic, and immunomodulatory pathways4,6 (Table 1). Anti-inflammatory and Antioxidative Effects of Traditional Medicines Inflammation and oxidative stress are 2 closely linked disease processes. Many traditional medicines have been shown to have both anti-inflammatory and antioxidative effects. For Astragalus membranaceus, the anti-inflammatory effects have been reported not only in kidney disease,7 but also in lung inflammation8 and myocardial injury.9 Astragalus has been shown to have strong anti-inflammatory and antioxidative stress effects in different cell types, including kidney cells, through regulation of Nrf2/HO-1 (nuclear factor [erythroidderived 2]-like 2)/heme oxygenase 1) signaling, suppression of p38 MAPK (mitogen-activated protein kinase), NF-kB (nuclear factor kB), and Toll-like receptor–mediated pathways.7,10-13 Astragalus has been shown to reduce proteinuria and attenuate kidney injury in several animal models of kidney disease.5 Free radical inactivation, inhibition of nitric oxide synthesis, and reduced TNF-a (tumor necrosis factor a) production have been observed in conjunction with these observed beneficial effects.5 Tripterygium wilfordii Hook F (TWHF) and its active component, triptolide, have been extensively used in China to treat glomerulonephritis. Triptolide has been shown to possess potent anti-inflammatory and antioxidative effects in many diseases.14-17 Triptolide has been reported to reduce proteinuria in animal models of glomerular disease.5 Recently, Lu et al18 identified TAB1 (transforming growth factor b [TGFb] activated kinase 1, also known as MAP3K7 binding protein 1) as the binding target of triptolide in macrophages. Triptolide inhibits TAK1 kinase (MAPK kinase kinase 7) activity by interfering with the formation of the TAK1-TAB1 complex, and the binding affinity of triptolide to TAB1 correlates highly with the inhibitory activity of triptolide against MAPK pathway activation in macrophages. These studies provide a potential molecular mechanism for the anti-inflammatory effects of triptolide.18 Saikosaponin a and its epimer saikosaponin d are obtained from radix bupleuri (the dried root of Bupleurum falcatum L), and their anti-inflammatory effects were discussed in our recent review.5 Antioxidative effects of saikosaponin have also been reported in kidney cells.19 In China, radix puerariae (kudzu root) has been used in the treatment of patients with early stages of diabetic nephropathy. We examined the effects of puerarin, one Am J Kidney Dis. 2015;-(-):---

Mechanismsa Herbal Name

Main Active Compounds

Anti-inflammatory

Antioxidative

Antifibrotic

Immunomodulation

Astragalus membranaceus

Astragalosides I-VII, flavonoids, etc69

111

111

111

11

Tripterygium wilfordii Hook F

Triptolide71

111

1

111

111

Radix bupleuri

Saikosaponin a & d55

11

11

11

1

Radix puerariae Abelmoschus manihot Ophiocordyceps sinensis

Puerarin Myricetin, cannabiscitrin, etc77 Cyclic peptides & H1-A79

Rheum palmatum L

Emodin or rhein26

Cortex Moutan

Paeonol84

11 11

111 111

1 11

11

11 11

1

Indications

Side Effects

Primary glomerular disease,65 No significant side effects reported membranous nephropathy,70 diabetic nephropathy66 Primary glomerular disease,63,64 GI disorders, liver toxicity, infertility, PKD,61 Henoch-Scho¨nlein hematopoietic disorders72,73 62 purpura IgA nephropathy74 Interstitial pneumonia, liver toxicity, edema, hypertension, cystitis, GI disorders, immunodeficiency75,76 20 Early diabetic nephropathy No significant side effects reported Primary glomerular disease,59 Upper respiratory tract infection, diabetic nephropathy78 hyperlipidemia, liver toxicity59 Chronic kidney injury,67 chronic Overall only a few side effects allograft nephropathy80 reported (dry mouth, nausea, stomach discomfort)81,82 To improve kidney function in GI disorders; long-term use causes CKD patients68 electrolyte disorders and liver toxicity83 CKDb May affect clotting85

Abbreviations: CKD, chronic kidney disease; GI, gastrointestinal; IgA, immunioglobulin A; PKD, polycystic kidney disease. a Biological effects were confirmed by multiple in vitro and in vivo studies, 111; effects were shown only in 2-4 (1-2 in vitro and 1-2 in vivo studies), 11; and effects were shown only in one study (either in vitro or in vivo study), 1. b Used by traditional medicines practitioners without clinical studies.

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Table 1. Summary of the Mechanism of Action for Commonly Used Traditional Medicines

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of its active compounds, in streptozocin-induced diabetic rats and found that it attenuated kidney hypertrophy, mesangial expansion, proteinuria, and podocyte footprocess effacement to a similar degree as losartan.20 Puerarin treatment also suppressed oxidative stress in diabetic kidneys to a greater extent than losartan. Abelmoschus manihot (L) medic (AM) is commonly used to treat inflammatory diseases in China. AM is used to make Huangkui capsule, which has been shown to improve kidney inflammation and glomerular injury in rats with doxorubicin-induced nephropathy through inhibition of the p38 MAPK signaling pathway and TGFb1 protein expression.21 In vitro studies have suggested that both aqueous extracts and purified polysaccharides from Ophiocordyceps sinensis (formerly known as Cordyceps sinesis) have potent antioxidant activity.22 In addition, these compounds have been shown to have an anti-inflammatory effect through suppression of MCP-1 (monocyte chemoattractant protein 1) and TNF-a expression in the ischemia-reperfusion kidney injury model. Cortex Moutan (root bark of Paeonia suffruticosa Andr) is a well-known traditional medicine that has been observed to have protective effects against inflammation in several animal models, including high-fat-diet– and streptozocin-induced diabetic rats, and in vitro in rat mesangial cells treated with advanced glycation end products.23,24 Antifibrotic Effects of Traditional Medicines Kidney fibrosis is the final common pathway by which earlier stages of CKD progress to ESRD. Antifibrotic therapy is an attractive approach to treat patients with CKD. Recent studies suggest that many traditional medicines have antifibrotic effects. Astragalus has been found to have antifibrotic effects through inhibition of the TGFb1 pathway in several cell types and tissues.25-28 A decoction of Astragalus with Angelica sinensis has been shown to have renal antifibrotic effects in rats by suppressing TGFb1 expression and promoting degradation of the extracellular matrix.29-32 Astragaloside IV—believed to be the active ingredient of the dried root of Astragalus membranaceus—also has been reported to inhibit hyperglycemia-induced expression of TGFb1 in kidney tubular cells.33 TWHF has been found to ameliorate glomerulosclerosis in an doxorubicin-induced nephropathy model via reduction of extracellular matrix synthesis, suppression of TGFb1 level, and inhibition of the TGFb1/Smad signaling pathway.34 Triptolide has been shown to attenuate kidney fibrosis in a rat unilateral ureteric obstruction model.35 Saikosaponins have been reported to have antifibrotic effects in liver disease and to inhibit mesangial 4

cell proliferation and matrix synthesis.36-38 Rhein (an acidic compound derived from rhubarb) has been observed to decrease levels of kidney extracellular matrix and TGFb1/fibronectin in diabetic db/db mice.39 Huangkui capsule, the AM extract, has been shown to have antifibrotic effects (through inhibition of TGFb1 protein expression) in rats with doxorubicininduced nephropathy.21 Immunomodulation Effects of Traditional Medicines Several traditional medicines are known to regulate the immune system (reviewed in Zhong et al5). Therefore, these traditional medicines have been used as alternatives to immunosuppressive medications for the treatment of primary glomerular disease. They have been also considered as antirejection medications for transplantation. Astragalus is considered a natural immunomodulator.40-43 Astragalus membranaceus has been shown to mitigate podocyte injury induced by complement membrane attack complex.44 Systems biology analysis also indicates that the immune system is a major target of astragaloside IV.9 Recent studies suggest that Astragalus membranaceus can reverse immunoglobulin A (IgA) dysglycosylation in IgA nephropathy.45 Triptolide has shown potent immunosuppressive and immunomodulatory effects in experimental models.15,46,47 It has been reported to attenuate rheumatoid arthritis by regulating the RANKL (receptor-activated NF-kB ligand)/RANK/OPG (osteoprotegerin) signaling pathway.48 Triptolide treatment has been found to reduce the incidence of diabetes in NOD (nonobese diabetic) mice, an autoimmune diabetic model.49 In addition, triptolideconditioned dendritic cells have been shown to induce allo-specific T-cell regulation and prolong kidney transplant survival.50 PG27, a refined extract from TWHF (the traditional medicine for which triptolide is the active ingredient), is effective in extending survival of cardiac xenografts through inhibition of IKKa (IkB kinase catalytic subunit)/ IkBa/NF-kB and MAPK/AP-1 signaling pathways.51 Because of its potent immunomodulatory effects, TWHF has been used to treat primary glomerular disease in China for many years. Triptolide has also been shown to attenuate kidney injury in experimental models of immune injury such as Heymann nephritis52 and lupus nephritis.53 Saikosaponins have immunomodulatory activities and have been shown to suppress the proliferation of human T cells by inhibiting NF-kB, NFAT (nuclear factor of activated T cells), and AP-1 (c-Fos) signaling pathways.54,55 Emodin, from Rheum emodi, or Himalayan rhubarb) has also been shown to inhibit dendritic cell maturation and increase the number of regulatory T cells.56 Am J Kidney Dis. 2015;-(-):---

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RECENT ADVANCES IN CLINICAL EVIDENCE Overview Although many small clinical studies published in Chinese journals support a kidney protective effect of traditional medicine for CKD, large and welldesigned randomized controlled trials (RCTs) are still lacking. However, progress has been made recently in this field. We outline the recent large relatively well-designed RCTs, then briefly discuss smaller studies and describe relevant systematic reviews and meta-analyses. Most studies published in Chinese journals have been included in these systematic reviews and meta-analyses and therefore have not been separately reviewed here. Key aspects of recent studies of traditional medicine in different kidney diseases are summarized in Table 2. Large Randomized Clinical Trials of Traditional Medicines in Kidney Disease In a recent study,57 we compared the safety and efficacy of the traditional Chinese medicine Shenqi particle with a control group receiving the standard therapy of prednisone and cyclophosphamide in adult patients with idiopathic membranous nephropathy. To our knowledge, this was the first open-label, multicenter, randomized, controlled trial in the field of traditional medicines in kidney disease. We recruited 190 patients with biopsy-proven idiopathic membranous nephropathy from 7 hospitals in China. All patients had nephrotic syndrome with estimated glomerular filtration rate (eGFR) . 30 mL/min/1.73 m2. Patients received either Shenqi particle or prednisone and cyclophosphamide for a total of 48 weeks. The primary

outcomes were complete and partial remission of proteinuria; secondary outcomes included serum albumin level, eGFR, doubling of serum creatinine level, ESRD, and death. Reduction of urinary protein excretion was similar in the Shenqi particle and control groups. However, eGFRs declined less in the Shenqi particle group than in controls. In addition, patients in the Shenqi particle group had fewer side effects than those in the control group. These findings suggested that Shenqi particle could be an alternative therapy for patients with idiopathic membranous nephropathy, particularly in patients who do not tolerate standard therapy. Some of the limitations of the study were the high rate of loss to follow-up, short study duration, and lack of an observation period prior to initiation of the study to exclude patients with spontaneous remission.58 Recently, another well-designed, prospective, multicenter, open-label RCT was published that assessed the efficacy and safety of AM in patients with biopsy-proven primary glomerular disease.59 A total of 417 patients from 27 hospitals in China were enrolled in the study. Patients were randomly divided into an AM group, a losartan group, or an AM plus losartan group. After 12 or 24 weeks of treatment, patients treated with AM or AM plus losartan had significantly less proteinuria than those treated with losartan alone. However, there were no differences in serum creatinine levels and eGFRs among these groups after 12 or 24 weeks of treatment. Moreover, there were no significant differences in adverse events between these groups. Similar results were observed when the subgroup of patients with IgA nephropathy was specifically analyzed. However, there was no

Table 2. Recent Trials Studying Use of Traditional Medicines in Kidney Disease

Study

N

Disease

Therapeutic Arms

Wang et al60 573 Primary glomerulonephritis Traditional medicinesa/ placebo vs benazepril/ (2012) with CKD stage 3 placebo vs traditional medicines/benazepril Chen et al57 190 Membranous nephropathy Shenqi particle vs (2013) cyclophosphamide/ steroid Wu et al62 58 Henoch-Scho¨nlein purpura Triptolide/prednisone vs prednisone (2013)b Zhang 417 Primary glomerular AM vs losartan vs AM/ et al59 disease losartan combination (2014) Chen et al61 9 ADPKD with proteinuria Tripterygium . 1 g/d (2014)c

Primary Outcome

Mean eGFR

Study Period (mo)

6

CR 1 PR

11

CR 1 PR

6

Mean change in proteinuria

6

Reduction in proteinuria

12

Outcome

48.5 6 15.9 vs 43.0 6 12.4 vs 48.3 6 17.5 mL/min (P , 0.05) 46/63 (73.0%) vs 54/69 (78.3%); P 5 0.5 40/42 (95%) vs 10/14 (72%); P 5 0.029 2508 vs 2376 mg/d (P 5 0.003) vs 2545 mg/d (P , 0.001) 6/9 patients to ,0.5 g/d

Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; AM, Abohelmus manicot; CKD, chronic kidney disease; CR, complete remission; eGFR, estimated glomerular filtration rate; PR, partial remission. a Traditional Chinese medicine mixture that was formulated and titrated according to symptoms. b Pediatric patients (this study reported longer term outcomes). c Prospective single-center observational experience; all patients had experienced treatment failure with losartan. Am J Kidney Dis. 2015;-(-):---

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additional benefit when AM was combined with losartan to treat these patients with primary glomerular disease. The mechanism of renoprotective effects of AM is likely related to its antioxidative and antiinflammatory effects, as discussed previously. The authors concluded that AM is a promising alternative therapy for patients with CKD with moderate proteinuria. Because most of these patients had IgA nephropathy, AM could be an alternative therapy for patients with IgA nephropathy who may not tolerate losartan. However, there are a few concerns. First, the effects of AM on commonly accepted outcomes, such as doubling of serum creatinine level, initiation of ESRD, and mortality, remain unclear. Second, effects of AM in patients with advanced glomerular disease such as nephrotic syndrome or severely decreased kidney function were not determined. Because angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may not be well tolerated in this patient population due to further declines in GFR or hyperkalemia, it would be important to determine the effects of AM in these patients. The long-term side effects of AM also need to be determined. Another study recruited 578 patients with CKD secondary to primary glomerulonephritis.60 These patients received either traditional medicines, benazepril, or a combination of the 2. A composite primary end point of 50% increase in serum creatinine level, ESRD, or death was used. After a 24-week follow-up, patients receiving either traditional medicines alone or in combination with benazepril had improved kidney function, whereas eGFRs worsened in patients treated only with benazepril. Patients receiving combination therapy had a higher cumulative survival rate than those treated with either traditional medicines or benazepril alone (P 5 0.044). Patients in the traditional medicine group reported fewer adverse events than those in the other 2 groups. Interestingly, patients using benazepril alone or together with traditional medicines had reduced 24hour urinary protein excretion rates and urinary albumin-creatinine ratios, whereas proteinuria was increased in patients receiving only traditional medicines. The authors concluded that combination therapy with traditional medicines and renin-angiotensin system blockade provided better kidney protection in patients with proteinuric CKD than monotherapy with either one. The major concern of this study is that the traditional medicines prescribed here were not well defined and were made by 4 different decoctions. Small Clinical Trials of Traditional Medicines in Kidney Disease In an uncontrolled trial, Chen et al61 examined the effects of TWHF in 9 patients with polycystic kidney disease and proteinuria. They found that 6 months of 6

treatment with TWHF reduced proteinuria, preserved kidney function, and diminished total kidney volume in these patients, suggesting multiple effects of TWHF. However, there are several limitations of the study. First, the authors did not use patients with proteinuric CKD as controls. Second, they did not test whether TWHF also improves kidney function and reduces kidney volume in patients with nonproteinuric polycystic kidney disease. In addition, patients with polycystic kidney disease likely require more than 6 months of therapy and therefore longer term side effects may arise with continued treatment. Another study looked at the clinical efficacy of triptolide in children with moderately severe Henoch-Schönlein purpura.62 Fifty-six children with Henoch-Schönlein purpura who had nephrotic-range proteinuria, normal kidney function, and ,50% crescents or sclerosing lesions on biopsy were enrolled. They were divided into a treatment group (n 5 42; triptolide at 1 mg/kg daily, combined with prednisone at 2 mg/kg daily for 6-9 months) and a control group (n 5 14; prednisone alone, with the same protocol). Short-term remission was observed in 95% of the treatment group and 72% of the control group (P 5 0.029). However, no significant differences in proteinuria, hematuria, hypertension, or eGFR decline were observed between the 2 groups in long-term follow-up. The authors concluded that triptolide is effective in relieving short-term symptoms in children with moderately severe Henoch-Schönlein purpura. Systematic Reviews and Meta-analyses of Traditional Medicines in Kidney Disease A recent systematic review and meta-analysis was performed on RCTs using different Tripterygium preparations versus placebo, standard care, or other immunosuppressive treatment in patients with CKD.63 The study included 75 trials with 4,386 participants and compared the outcomes, including changes in serum creatinine level and creatinine clearance, proteinuria, remission and relapse rate, and drug-related adverse events. Overall, Tripterygium therapy significantly reduced protein excretion by a mean of 628 (95% confidence interval [CI], 521-736) mg/d and reduced serum creatinine level by 0.12 (95% CI, 0.060.17) mg/dL compared with controls (both P , 0.001). In addition, Tripterygium boosted the rate of complete remission by 56% while reducing relapse by 58% (P , 0.05). However, increased rates of abnormal liver function test results and altered menstruation were seen with Tripterygium preparations. The concerns noted in this meta-analysis included the significant heterogeneity in the primary outcome and the suboptimal study quality of included trials. A recent Cochrane systematic review assessed the effects of TWHF in patients with primary nephrotic Am J Kidney Dis. 2015;-(-):---

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syndrome.64 A total of 10 randomized controlled trials with 630 participants and a minimum follow-up of 3 months were included. Four studies involving 293 participants compared TWHF versus non-TWHF groups and showed increased complete remission with TWHF (relative risk, 1.46; 95% CI, 1.18-1.80) without increased adverse events at 12 to 16 months. Four studies with 223 participants compared TWHF to prednisone and found no significant differences in the remission rate. Two studies comprising 114 participants that compared the effects of TWHF versus cyclophosphamide also found no significant differences in remission rates. No serious adverse events related to TWHF were noted. The quality of evidence was suboptimal on account of the small sample size, short follow-up, and concerns for methodologic bias. Therefore, the evidence was not sufficient to conclude whether TWHF was as effective as prednisone or cyclophosphamide. The same approach was used to assess the therapeutic effects of astragalus in patients with CKD in a meta-analysis including 22 studies with 1,323 participants.65 Overall, these studies were low quality, and commonly accepted primary outcomes were not reported. The effects of astragalus on kidney function were inconsistent. Astragalus significantly increased creatinine clearance at end of treatment in 4 studies and decreased serum creatinine levels in 13 studies. Astragalus decreased 24-hour proteinuria in 10 studies. In 6 of the 22 studies, no adverse effects were noted; the other 16 studies did not report adverse effects. Therefore, there is insufficient evidence to conclude that astragalus has kidney protective effects; moreover, its adverse effects remain under-reported. Li et al66 performed a systematic review of randomized and semi-randomized controlled trials to assess the kidney protective effect of astragalus in diabetic nephropathy. Twenty-five studies comprising 21 randomized and 4 semi-randomized trials including 1,804 patients were analyzed; the authors concluded that astragalus-treated patients had better kidney outcomes than controls. Though the findings are encouraging, most of these studies had suboptimal design with small numbers of patients. Large RCTs are required to confirm these findings. Zhang et al67 reviewed clinical trials related to the therapeutic effects of Ophiocordyceps sinensis in patients with CKD. They included 22 studies with 1,746 participants and found that cordyceps preparations significantly decreased serum creatinine levels in 14 studies, increased creatinine clearance in 6, and reduced 24-hour proteinuria in 4. However, they also noticed significant problems related to suboptimal reporting and flawed methodologic approaches. Therefore, results from these clinical trials need to be interpreted with caution. Am J Kidney Dis. 2015;-(-):---

Another meta-analysis studied Rheum officinale (a type of rhubarb) in kidney disease.68 The authors concluded that this traditional medicine had a beneficial effect on kidney function compared with no treatment, but was not superior to captopril treatment (reviewed in Zhong et al5).

BARRIERS AND FUTURE DIRECTIONS The preceding review of recently published studies reflects the concerns and barriers in traditional medicines research (summarized in Box 1). In the past, the quality of most clinical studies in this field has been suboptimal and they have been published only in Chinese-language journals. However, the quality of studies has improved as reflected by several recent large clinical trials in this field. Numerous limitations pertaining to these trials arise from the nature of practice of traditional Chinese medicine, such as wide variations in prescriptions and unstandardized dose adjustments of the parent compound mixtures based on patients’ subjective symptoms and signs. There is also inadequate reporting of adverse events in many studies. To overcome these barriers, first, we need to identify the active moieties from traditional medicine mixtures using modern technologies, including highthroughput mass spectrometry. Next, we need to test the biological activity and toxicity profile of these compounds using both in vitro techniques and animal models of kidney disease. The detailed mechanisms

Box 1. Limitations and Barriers of Clinical Trials With Traditional Medicines for Kidney Disease 1. Traditional medicine often is a mixed formula and the active components are unknown. 2. The percentage of each component in traditional medicine formulas varies from prescription to prescription and from provider to provider. 3. The percentage of each component in the traditional medicine formulas changes at each follow-up visit based on changes in patients’ symptoms and signs. 4. Extensive experience from traditional medicine practice suggests that formulas with mixed compounds work better than single agents. Therefore, clinical trials with single agents may not be as effective as the formulas. 5. Interactions among traditional medicine components and between traditional medicine and Western medicine remain largely unknown. 6. Adverse effects of traditional medicine are often underreported and data for long-term follow-up of patients treated by traditional medicines are lacking. 7. Most patients with CKD seek traditional medicines when Western medicine failed to help them. Patients on traditional medicines may be more resistant to therapy. 8. Most previous clinical studies of traditional medicines for kidney disease have issues, including small size, suboptimal reporting, and flawed methodologic approaches. Abbreviation: CKD, chronic kidney disease. 7

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of action of these compounds should also be determined by applying modern molecular and cell biology techniques. We could then obtain the most effective and structurally well-characterized moieties from traditional medicine compounds for use in clinical trials in patients with different kinds of kidney disease. However, experiences from the practice of traditional medicines suggest that the formulas consisting of multiple herbal medicines are more effective than single agents. Therefore, it might be necessary to combine several active moieties from traditional medicine formulas to obtain maximal benefits. The interactions among active compounds isolated from the same formula also need to be determined in order to identify potential synergistic effects. Modern systems biology approaches can help us achieve these goals. Importantly, those conducting clinical trials must, prior to study initiation, use information on the identified and tested active moieties to standardize prescriptions and decide the dosage adjustment patterns that participating physicians may use. Finally, we need to develop a better system to report longer term side effects of traditional medicines associated with clinical trials and practice.

CONCLUSIONS In summary, major progress has been made in traditional medicines research for kidney disease. More active compounds have been identified recently from traditional medicines formulas that have the potential to treat kidney disease. Our understanding of the mechanisms of action of traditional medicines in kidney disease has improved due to recent mechanistic studies in vitro and in animal models of kidney disease. In addition, more clinical data, including several welldesigned prospective controlled randomized trials, have been published. However, the current evidence, even from pooled meta-analyses, is insufficient to support clinical uses of traditional medicines in kidney disease. Further efforts are required to improve our understanding of the mechanisms of traditional medicines, identify new traditional medicines compounds as potential drugs, and perform well-designed RCTs to confirm their efficacy and safety before traditional medicines can emerge as a viable therapeutic alternative for patients with kidney diseases.

ACKNOWLEDGEMENTS Support: Dr Zhong is supported by the National Natural Science Foundation of China for Young Investigators (1999-30901944), the Shanghai Bureau of Health for Young Investigators (2011XYQ2011059), Shanghai Pujiang Program (14PJ1408000); Dr He is supported by National Institutes of Health (NIH) 1R01DK078897, NIH 1R01DK088541, Chinese 973 fund 2012CB517601, and a VA Merit Award. Financial Disclosure: The authors declare that they have no relevant financial interests.

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