Therapeutic Use of Traditional Chinese Herbal Medications for Chronic Kidney Diseases

Yifei Zhong; Yueyi Deng; Yiping Chen; Peter Y. Chuang; John Cijiang He

Disclosures

Kidney Int. 2013;84(6):1108-1118. 

In This Article

Treatment of Kidney Disease With TCHMs

The therapeutic principles of TCM for CKD include 'replenishing vital energy and nourishing blood,' 'clearing heat and eliminating dampness,' and 'coordinating Yin and Yang in the body.'[6] Hundreds of herbs used in prescriptions of a single herb, decoctions of multiple herbs, or patent medicines have been used to treat patients with CKD. These prescriptions have effects including promotion of diuresis, reduction of proteinuria, and improvement of renal function.[2,7] Mechanisms of action have been studied for some herbs. Their effects are mainly related to anti-inflammation, antioxidation, antifibrosis, regulation of immune system, anticoagulation, and improvement of metabolic disturbance.[2,3] Active ingredients purified from herbs that have been studied in CKD include saikosaponin a and d (SSa and SSd) and triptolide. However, the active compounds in many decoctions or patent medications are still unknown, and clinical trials demonstrating their efficacy for treatment of CKD are limited. We have summarized current evidence supporting TCHMs in the treatment of CKD. Key findings from in vitro studies, animal models, and human trials are included in Table 2 .

Astragalus and Decoction of Astragalus With Angelica Sinensis

The medicinal herb Astragalus is derived from the root of Leguminosae plant Astragalus membranaceus or Astragalus mongholicus. It contains more than 60 components including polysaccharides, saponins (astragalosides I–VII), flavonoids, amino acids, and trace elements.[8]Astragalus is traditionally used either alone or in conjunction with another Chinese herb, A. sinensis, to treat patients with CKD.[2]

Mechanisms of Action. Pharmacological studies have shown that several compounds from Astragalus exhibit multiple effects including stimulation of the immune system, diuresis, antioxidation, and anti-inflammation.[9–11] In addition, A. membranaceus has been shown to attenuate podocyte injury induced by complement membranous attack complex.[12] In a recent study, the effects of astragaloside IV were analyzed systemically using a computer-assisted target identification program, which identified 39 putative targets including calcium influx inhibition, vasodilatation, antithrombosis, antioxidation, anti-inflammation, and immune regulation.[13]

Animal Studies. The biological effects of Astragalus have been investigated in several animal models of kidney disease including 5/6 nephrectomy,[14] doxorubicin-induced nephropathy,[15] unilateral ureteral obstruction,[16] glomerulonephritis,[17] and streptozotocin-induced diabetic nephropathy.[18] The results from these studies suggest that Astragalus treatment reduces proteinuria and attenuates kidney injury. These effects are associated with inactivation of free radicals, inhibition of nitric oxide synthesis, and reduction of tumor necrosis factor-α production.[15,17,18] A decoction of Astragalus with A. sinensis has also been shown to attenuate renal interstitial fibrosis in rats with chronic puromycin aminonucleoside nephrosis and obstructive uropathy by suppressing transforming growth factor-β1 expression, macrophage infiltration, and reactive oxygen species production, as well as promoting extracellular matrix degradation.[14,19,20,21]

Clinical Studies.Astragalus has been used by itself or as one of the 'ruler drugs' in decoctions to treat CKD. Several small clinical studies published in Chinese language journals suggest that Astragalus decreases proteinuria and improves the plasma levels of total cholesterol and albumin in patients with nephrotic syndrome. In a systematical review of randomized and semirandomized trials using Astragalus for the treatment of diabetic nephropathy, 21 randomized controlled and 4 case–controlled studies with a total of 1804 patients (945 in the treatment group and 859 in the control group) were included. The authors of the systematic review concluded that Astragalus is able to improve renal function and reduce proteinuria in patients with diabetic nephropathy.[22] In another meta-analysis of patients with diabetic nephropathy, significant beneficial effects on glomerular filtration rate, urinary albumin excretion rate, and thickness of the glomerular basement membrane were observed in the Astragalus-treated group as compared with the control group.[23] Unfortunately, in these two studies, the authors could not carry out a systematic review on adverse effects owing to the lack of report on severe side effects in all the clinical trials involved. Successful treatment of patients with nephrotic syndrome using Astragalus has also been reported. For example, a 77-year-old woman with idiopathic membranous nephropathy and nephrotic syndrome, who had developed treatment failure with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, cyclosporine A, and mycophenolate mofetil, responded to A. membranaceus at a dose of 15 g/day with remission of proteinuria.[24] No side effects were reported in this patient.

Side Effects.Astragalus is generally considered safe for most adults. The side effects that can be exclusively ascribed to Astragalus, however, are not well characterized because it is generally used in combination with other herbs. Astragalus is known to inhibit CYP3A4 and can affect the metabolism of certain drugs metabolized by this enzyme.[25] For example, Astragalus was reported to reduce cyclophosphamide-induced immunosuppression.[26] From the above meta-analysis, it is important to note that the adverse effects of TCHMs have been underreported in clinical trials, and this should be corrected in future studies.

Rheum Palmatum L and its Components: Emodin and Rhein

The medicinal herb rhubarb is derived from the root of the Rheum palmatum L plant. Studies of inorganic elements in rootstocks of Rheum australe by atomic absorption spectrophotometry identified 19 elements including more than 20 types of anthraquinones, in which emodin (3-methyl-1,6,8-carboxyl-anthraquinone), rhein, and aloe-emodin have been studied extensively.[27,28]

Mechanisms of Action. The strong cathartic actions of rhubarb are thought to increase the excretion of waste products, including nitrogenous waste accumulated in patients with renal failure, through the intestines.[29] Hence, rhubarb has been used to treat patients with renal failure. Recently, emodin, an active compound of rhubarb, has been shown to inhibit the lipopolysaccharide-induced expression of Toll-like receptor 4 and downregulate tumor necrosis factor-α and interleukin-6 synthesis in renal tubular epithelial cells.[30] Emodin has also been shown to inhibit the differentiation and maturation of dendritic cells and increase the number of regulatory T cells.[31] These studies suggest that emodin has a major role in the regulation of inflammation and immune response. Rhein, another active compound of rhubarb, has been shown to improve cell metabolism through glucose transporter 1 and it decreases mesangial cell hypertrophy and extracellular matrix synthesis.[32] These results indicate that the active ingredients in rhubarb have multiple mechanisms of action that could improve CKD.

Animal Studies. Zhang and el Nahas[33] examined the effect of a rhubarb extract on the development of renal failure in Wistar rats with 5/6 nephrectomy. Rhubarb extract treatment decreased proteinuria and glomerulosclerosis as compared with no treatment. Treatment of db/db diabetic mice using rhein, an active compound of rhubarb, has been shown to decrease the levels of extracellular matrix and expression of transforming growth factor-β1 and fibronectin in the kidney.[34] In addition, combination therapy with rhein and an angiotensin-converting enzyme inhibitor in db/db mice provided additional renal protection that was more than either therapy by itself, as reflected in the reduction of urinary albumin excretion and improvement of renal function and histology.[35]

Clinical Studies. Clinical studies on the effects of rhubarb in patients with CKD have been reported in Chinese medical journals and summarized in an English review article.[27] These studies suggest that rhubarb is able to reduce proteinuria and improve renal function by itself and may also cause further reduction of proteinuria and improvement of renal function when used together with angiotensin-converting enzyme inhibitors. A recent meta-analysis of clinical studies of rhubarb, which included seven studies that compared Rheum officinale (rhubarb root) against no treatment and two studies that compared rhubarb against captopril, found that R. officinale had a beneficial effect on renal function compared with no treatment, but it was not superior to captopril treatment.[36] The effect of treatment on all-cause mortality was not available from those studies. Only minor adverse events were reported in association with R. officinale. Diarrhea was reported in two-thirds of patients when the initial dose of R. officinale was >3 g/day, but was resolved when the dose was reduced. Standardized monitoring or voluntary self-reporting was not undertaken. The authors of the meta-analysis concluded that all nine studies were of low quality, and available evidence supporting the use of R. officinale in patients with CKD was scant.

Side Effects. The major side effects of Rheum include nausea, vomiting, diarrhea, and abdominal pain. Long-term use of Rheum could cause electrolyte disorders and liver toxicity.[37]

Decoctions of Radix Bupleuri and Components of R. Bupleuri (Saikosaponin a and d)

Saireito is a combination of 12 herbs, of which R. bupleuri is a major component. Saireito has been used in China and Japan for treatment of kidney diseases. Saikosaponin a (SSa) and its epimer saikosaponin d (SSd) are major triterpenoid saponin derivatives found in R. bupleuri, which has been used for the treatment of various inflammation-related diseases.[38] The phytochemistry and pharmacology of R. bupleuri has been reviewed previously.[39]

Mechanism of Action. Saireito suppresses inflammation[40] and proliferation of mesangial cells.[41] Both SSa and SSd have been shown to inhibit the expression of inducible nitric-oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-6 in lipopolysaccharide-stimulated RAW264.7 cells.[42] SSd inhibited mesangial cell proliferation and matrix synthesis.[43] Saikosaponins also suppressed the proliferation of human T cells by inhibiting nuclear factor-κB, nuclear factor of activated T cell, and activator protein 1 (c-Fos) signaling pathways.[44] In addition, both in vivo and in vitro studies confirmed that saikosaponins exhibit potent anti-inflammatory and immune-modulatory activities.[39]

Animal Studies. Saireito prevented mesangial cell proliferation in a rat model of mesangioproliferative glomerulonephritis.[45] Saireito also decreased urinary protein excretion in a rat model of subtotal nephrectomy.[46,47] However, saireito did not provide any additional benefit when added to enalapril for renal protection in rats with subtotal nephrectomy.[48] Saireito has also been shown to reduce gentamicin-induced nephrotoxicity in rats[49] and in MRL/lpr mice.[50] In a rat model of mesangioproliferative glomerulonephritis induced by anti-Thy1 monoclonal antibody, SSd attenuated the amount of proteinuria, increase in systolic blood pressure, accumulation of extracellular matrix, formation of glomerular crescents, and infiltration of macrophages and CD8+ T lymphocytes.[51] SSd was also able to reduce proteinuria in a rat model of aminonucleoside-induced nephropathy.[52]

Clinical Studies. In a randomized controlled study investigating the efficacy of saireito in a pediatric population with IgA nephropathy, 101 patients received either saireito or no treatment for 2 years.[53] Urinary protein excretion and hematuria were significantly reduced in the saireito group, but remained unchanged in those who did not receive saireito. Proteinuria normalized in 46% of the patients in the saireito group compared with 10% in those in the untreated group. So far, no clinical study of SSa or SSd for treatment of CKD has been published.

Side Effects. The use of R. bupleuri is known to cause interstitial pneumonia, elevated liver function tests and jaundice, edema and hypertension, cystitis, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea. However, these symptoms are often associated with overdose and prolonged use of R. bupleuri.[54] It has also been reported that saireito occasionally causes side effects such as immunodeficiency, gastroduodenal ulcer, and osteoporosis that are often associated with long-term administration of corticosteroids.[55] Drug-induced pneumonitis and drug-induced acute hepatitis have also been reported with saireito treatment.[56,57] However, the side effects of these TCHMs are usually underreported in clinical trials. Saireito is a combination of 12 herbs, which immediately raises the question of pharmacological interactions among them and toxicity induced by each of them. Therefore, this drug will be difficult to be approved by the current regulation of drug administration.

Cordyceps Sinensis and its Component H1-A

C. sinensis (Cs) is a blade-shaped fungus that derives its nutrients from larvae of Lepidoptera.[58] Its secondary metabolites are cyclic peptides and H1-A.[59] Cs was described in the old Chinese TCM textbook to treat patients suffering from urinary disturbance and edema 2000 years ago. Although kidney disease was not described at that time, these symptoms are considered to be kidney specific based on the TCM theory.

Mechanism of Action.In vitro studies showed that both aqueous extracts of the whole fruiting body of Cs and purified polysaccharides from Cs have potent antioxidant activity.[60] Cs extracts also inhibited proliferation of cultured mesangial cell.[61–63]

Animal Studies. Shahed et al.[64] examined the renal protective effects of a hot-water extract of the powdered Cs in a rat model of kidney ischemia/reperfusion injury. Intraperitoneal injection of the Cs extract before surgery significantly mitigated the rise in serum creatinine and the increase in mRNA transcripts of inflammatory cytokines, monocyte chemoattractant protein-1, and tumor necrosis factor-α associated with ischemia/reperfusion kidney injury. In a separate study, Cs treatment improved the renal function of a murine model for immunocomplex glomerulonephritis (MRL lpr/lpr).[65] In an IgA nephropathy model, a fractionated crude methanolic extract of the fruiting bodies of Cs significantly reduced hematuria and proteinuria, and improved kidney histology. Compound H1-A of Cs, purified by silica gel column chromatography and high-performance liquid chromatography, also demonstrated renal protection against IgA nephropathy.[61] The mechanism of renal protection of Cs in the rat 5/6 nephrectomy model of renal injury was examined using nuclear magnetic resonance spectral analysis of the kidneys. Cs treatment attenuated glomerulosclerosis and urinary albumin/creatinine ratio in 5/6 nephrectomized rats. Metabolic analysis of kidney tissues from 5/6 nephrectomized rats showed changes in the levels of tricarboxylic acid cycle intermediates (fumarate, succinate, and malate) and suppression of branched-chain amino acid (valine, leucine, and isoleucine) metabolism, which were reversed by Cs treatment.[66]

Clinical Studies. In a study of 69 renal allograft recipients, Cs reversed cyclosporine nephrotoxicity.[67] In another study of 202 patients receiving standard immunosuppressive medications who were treated with or without Cs, the incidences of chronic allograph nephropathy and total urinary protein excretion were significantly lower in the Cs group as compared with the group without Cs treatment.[68] Others have also reported the beneficial effects of Cs in chronic allograph nephropathy.[69] Several studies in the Chinese medical literature have reported that Cs treatment of patients with acute kidney injury or CKD improved kidney function. However, these studies have major methodological flaws, including inadequate information on patient follow-up, lack of a control group with standardized care, and small number of patients.

Side Effects. There are very few reports of adverse reactions in human to Cs, which is available as a dietary supplement. Some patients have reported nausea, dry mouth, and stomach discomfort with Cs.[70,71] However, these adverse reactions are extremely rare.

Triptolide (PG490)

Extracts of Tripterygium wilfordii Hook F have been used to treat glomerulonephritis for more than 30 years in China with remarkable antiproteinuric effects. Triptolide, a diterpene triepoxide, is one of the major active components of these extracts. Structural modifications, structure–activity relationships, pharmacology, and clinical development of triptolide have been recently reviewed.[72]

Mechanism of Action. Triptolide has potent immunosuppressive, immunomodulatory, and anti-inflammatory effects. The molecular and cellular effects of triptolide have been reviewed.[73–75]

Animal Studies. Triptolide effectively reduced proteinuria in rats with puromycin-induced nephropathy without affecting the glomerular filtration rate.[76] The antiproteinuric effect was associated with improvement in foot process effacement, a decrease in the podocyte injury marker desmin, as well as the restoration of nephrin and podocin expression and distribution. In addition, generation of reactive oxygen species and activation of p38 mitogen-activated protein kinase were suppressed by tripolide in podocytes.[76] Triptolide has also been shown to attenuate kidney injury in an experimental rat model of passive Heymann nephritis.[77] Triptolide also improved renal function by inhibition of cyst growth in kidney-specific Pkd1(flox−/−); Ksp-Cre mouse model of autosomal dominant polycystic kidney disease.[78] It is hypothesized that triptolide arrests cellular proliferation and attenuates overall cyst formation by restoring Ca2+ signaling in these cells.[79] In db/db diabetic mice, albuminuria was markedly attenuated by triptolide treatment, accompanied by alleviation of glomerular hypertrophy and podocyte injury.[80] In addition, inflammation and oxidative stress in the kidneys were also attenuated. The effect of triptolide on glomerular hypertrophy was similar to valsartan, but the effects of triptolide on renal inflammation and oxidative stress were more profound than those of valsartan.[80] In addition, triptolide significantly ameliorated lupus nephritis in (NZB × NZW) F1 mice through suppression of cytokine and chemokine production.[81]

Clinical Studies. Although extracts of T. wilfordii Hook F and triptolide have been used to treat patients with CKD for many years, and multiple successful case reports and small clinical studies have been published in Chinese medical journals, no randomized clinical trials have been ever published in English peer-reviewed journals.

Side Effects. The major side effects of T. wilfordii Hook F include gastrointestinal disorders, liver toxicity, infertility, and hematopoietic disorder.[82,83] Animal studies suggest that triptolide treatment is associated with nephrotoxicity.[84] However, in two clinical studies to examine the effects of T. wilfordii Hook F in kidney transplant patients, no significant side effects were observed including nephrotoxicity.[85,57] These data suggest that T. wilfordii Hook F, when administered at a therapeutic dose, is relatively safe. There are currently no data on the adverse events in patients treated with triptolide.

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