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

Perspective

TCM is a valuable heritage of human experience. Therapeutic potential of these agents is supported by numerous animal studies. However, available clinical studies are small and well-designed randomized clinical trials are lacking to validate these therapies in patients with CKD. Although the therapeutic efficacy of herbs and herb-derived components has not been rigorously tested in large randomized controlled trials, the cumulative experience of treatment success supports more detailed examination of the therapeutic potential of herbal medications in complementing or expanding existing therapies for CKD. Currently, there is inadequate evidence to support the use of TCHMs in patients with CKD. The major challenges and the direction of future studies in this field are described below and summarized in Figure 1.

Figure 1.

Schematic outlining evidence-based investigation of traditional Chinese herbal medications (TCHMs). Future studies are required to identify active compounds from TCHMs and to determine their molecular mechanism of action. Well-designed animal studies and randomized clinical trials are needed to validate the physiological and pathological roles of these agents for treatment of patients with kidney disease. Complementary use of western and eastern medicines for treatment of kidney disease will also need to be further defined and proven.

Isolation of Active Components of Herbs

Naturally occurring compounds from plants/herbs are of interest to researchers both in their natural forms and as parent compounds for additional synthetic modification. More than 100 prescribed drugs in the United States are obtained from natural sources and represent one-fourth of the total drugs used.[100] Natural compounds currently used in medicine exhibit a wide chemical diversity. These compounds, together with their analogs, demonstrate the importance of compounds from natural sources in modern drug discovery efforts. Isolation of active compounds from herbs used in TCM and the study of their molecular mechanisms are highly important in the development of novel, clinically useful drugs for medical therapy including CKD. Many laboratories in China and other countries are actively involved in drug discovery efforts based on herbal medication used in TCM. For example, recent studies using capillary gas chromatography and gas chromatography–mass spectrometry have identified several active compounds with strong anti-oxidant and anti-inflammation activities from Bupleurum marginatum.[101] Another example is the identification of a water-soluble analog of triptolide, named Minnelide, which was recently shown to effectively reduce pancreatic tumor growth and spread, thus improving survival in patients.[102] The therapeutic effect of Minnelide has not been determined in patients with kidney disease. The structures of some commonly used compounds for CKD are shown in Figure 2.

Figure 2.

Chemical structures of active compounds in herbal medications used for treatment of kidney diseases in traditional Chinese medicine (TCM). Rhein and emodin are isolated from rhubarb. Saikosaponin a (SSa) and its epimer saikosaponin d (SSd) are major triterpenoid saponin derivatives from Radix bupleuri. Triptolide, a diterpene triepoxide, is one of the major active components isolated from the extracts of Tripterygium wilfordii Hook F.

Lack of High-quality Clinical Trials

Controlled randomized clinical studies of traditional Chinese herbal medications are difficult to design and execute for at least two reasons. First, there is a wide variation in the prescription of herbal medicine between physicians for the treatment of the same disease condition. This lack of standardization in prescription precludes direct comparison of treatment efficacy. Second, frequent adjustments of the herbal prescription are made based on patients' symptoms and signs, and these adjustments in prescription are not standardized practice. Although this practice reflects more personalized care, it also renders the application of the gold standard in assessment of therapeutic efficacy, randomized controlled trials, nearly impossible. The only solution is to standardize prescription pattern and dosage adjustment among physicians. At least in the context of a clinical trial, these standardized approaches should be taken during the study. Furthermore, a recommendation has been developed to improve the reporting of clinical trials using herbal medicine interventions.[103] This should help consolidate efforts and track available clinic studies. A well-designed prospective randomized clinical trial for TCM was published recently to compare the efficacy and safety of oseltamivir and maxingshigan–yinqiaosan in treating uncomplicated H1N1 influenza.[104] Recently, a multicenter, double-blinded, randomized controlled clinical trial was published to compare the effects of TCHMs (a mixed herbal decoction) with benazepril in 578 Chinese patients with CKD stage 3 caused by primary glomerulonephritis.[105] Patients were randomly assigned to three groups: patients received TCHMs, benazepril, or TCHMs combined with benazepril. After a 24-week follow-up, the authors reported that TCHMs combined with benazepril can ameliorate renal function and decrease proteinuria synergistically in these patients. Several well-designed prospective randomized clinical trials are currently ongoing in China to study TCHMs in patients with CKD.

Mechanistic Analysis of Active Compounds Using Modern Approaches

Experiences from TCM practices strongly suggest that single agents are less effective than multiple herbal formulas. The basic concept of TCM consists of multiple drug therapy including rule drug, minister drug, assistant drug, and messenger drug. It is believed that herbal medications target different pathways to restore the balance of the body between Yin and Yang. This concept is quite similar to the current concept of systems pharmacology, which views therapeutic targets of drugs as parts of cellular networks that control physiological responses. Systems pharmacology aims to link genome-wide measurements and biological networks with the effects of drugs on cells, tissues, and organisms.[106] In addition, the syndrome differentiation and treatment approach in TCM is an initial form of individualized treatment in modern medicine. Therefore, we believe that the modern systems biology concept might be inspired from TCM theory. However, the modern systems biology approach could be used to study the interactions among active compounds from herbal extracts in cells or tissues along with newly developed molecular biology technologies. A pioneer study in this field was published by Wang et al.,[107] in which they described the basic mechanism of Realgar–Indigo naturalis formula in treating human acute promyelocytic leukemia using systems biology and molecular biology approaches. They found that the main components of Realgar–Indigo naturalis formula are realgar, Indigo naturalis, and S. miltiorrhiza, and their major active ingredients are tetraarsenic tetrasulfide, indirubin, and tanshinone IIA. They reported that the combination of all three ingredients yields synergy in the treatment of a murine acute promyelocytic leukemia model in vivo and in the induction of acute promyelocytic leukemia cell differentiation in vitro. This combination causes increased ubiquitination/degradation of promyelocytic leukemia-retinoic acid receptor-α oncoprotein and enhanced G(1)/G(0) arrest in acute promyelocytic leukemia cells through hitting multiple targets compared with the effects of mono- or bi-agents. These data support the concept that tetraarsenic tetrasufide serves as the principal component of the formulas, whereas indirubin and tanshinone IIA serve as adjuvant ingredients. In addition, mechanistic studies of active compounds from herbal extracts should also be performed to identify the direct drug targets and downstream signaling pathways. The role of these compounds in renal physiology and pathology should also be examined using animal models. Together, these studies could improve our understanding of the mechanism of action for individual compounds and identify combinations of compounds that target different but complementary processes in the hope of developing a more effective therapy.

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