Chinese herbal medicine for diabetic kidney disease: historical perspective, clinical evidence and new therapeutic development
Creators: name: Zhang, La
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 420803
subject: Traditional Chinese medicine and treatments

description: Diabetic kidney disease (DKD) is the foremost microvascular complication of diabetes mellitus, which is characterised as persistent albuminuria and progressive loss of kidney function induced by diabetes. The health burden of DKD is substantial and continues to grow in parallel with the escalating prevalence of diabetes. Despite current pharmacotherapies including hypoglycaemic agents, hypotensive drugs and reninangiotensin system (RAS) inhibitors, substantial residual risk of DKD initiation and progression remains. Considering the increasing prevalence of DKD, novel renal protective therapeutics are in great need. Chinese herbal medicine (CHM) has been used since antiquity in some countries and regions, and is still being used to treat kidney diseases in combination with contemporary medicine. Guided by traditional knowledge and contemporary practice of herbal application, existing and potentially novel therapeutics for DKD may be evaluated and further developed from CHM. To-date, the development of therapeutics from CHM has been impeded by general lack of clinical evidence, complex chemical profiles and unclear mechanisms of action. Moreover, the conventional drug application of the “one target, one drug” approach has been a limitation when it comes to complex and multi-factorial clinical presentations such as DKD. CHM is a complex intervention that commonly involves a number of herbal ingredients clinically for treating individual patients with DKD.<br><br>Objectives<br><br>Guided by a “whole evidence” framework, the aims of this research are to:<br><br>- Evaluate the classical literature evidence of CHM as a treatment for DKD<br>- Evaluate the clinical trial evidence of CHM as adjunctive therapy for DKD<br>- Explore and propose the bioactive compounds and pharmacological mechanisms of promising CHM for DKD<br><br>Review of classical literature<br><br>A search of the classical Chinese medicine literature was conducted in the Zhong Hua Yi Dian (ZHYD, 5th Edition, 2014). A total of 278 DKD-relevant classical citations with treatment information were identified and analysed. These citations were derived from 68 classical Chinese medicine books spanning from AD 583 to AD 1895. Based on the rating results, there were 23 citations that were most likely DKD. Ba wei wan, Liu wei di huang wan and Hui xiang san were the most frequently cited formulae for DKD. The herbs frequently used were huang qi (Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao), ren shen (Panax ginseng C. A. Mey.), wu wei zi (Schisandra chinensis (Turcz.) Baill.), tian hua fen (Trichosanthes kirilowii Maxim.) and huang lian (Coptis chinensis Franch.). It was found that citations with positive turbid urine symptoms used huang qi more often than other high-frequency herbs.<br><br>Systematic reviews of randomised controlled trials <br><br>The Cochrane handbook of systematic reviews of interventions (version 5.1.0) guided the methods of the systematic reviews. The first systematic review included 20 randomised controlled trials (RCT) with 2719 DKD patients comparing CHM with placebo. Meta-analysis suggested that CHM reduced greater albuminuria than placebo, regardless of whether RAS inhibitors were concurrently administered. When CHM was used as an adjunct to RAS inhibitors, estimated glomerular filtration rate (eGFR) was improved in the CHM group compared with the placebo group. The adverse events (AE) rates were low and similar between CHM and placebo groups. Huang qi was used most frequently among included RCTs.<br><br>Accroding to the results of the first systematic review and classical literature review, the herb huang qi was selected as a subject for further study. The second systematic review included 66 RCTs employing sole huang qi preparations with 4785 DKD participants. Overall, the included studies have substantial risk of bias due to methodological shortfalls. The meta-analysis showed that additional use of huang qi injection reduced albuminuria, proteinuria and serum creatinine concentration compared to conventional therapy alone. An anti-albuminuria effect was also reported in the oral huang qi preparation group. The safety of huang qi prepareations was uncertain because AEs were only reported in one third of included studies. More detailed safety evaluation particularly for huang qi injections are needed due to severe allergic reactions after injections have been observed. <br><br>Network pharmacology study<br><br>Network pharmacology is a novel drug discovery approach that uses data from highthroughput experiments, omics studies and other biological research and integrates and analyses them as a whole. It was applied to visualise and predict the complex<br>relationships underlying the numerous DKD targets and multiple herbal compounds. <br><br>The herb huang qi was selected for the network pharmacology study based on the results reported above. Searching retrieved 103 distinct human targets related to DKD. Thirty-eight (38) bioactive compounds from huang qi were identified, with a<br>corresponding 327 targets. The huang qi–DKD PPI network contained 2269 shared targets, and 127 of these were considered to play central communication roles. These key targets were enriched in 174 biological pathways and the most significant pathways were integrin-linked kinase (ILK) signalling, tumour necrosis factor-related apoptosisinducing ligand (TRAIL) signalling, transforming growth factor beta (TGFβ)/Smad2/3 signalling, vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) signalling network and glypican/glypican-1 pathway. Further analysis of the herbal compounds-key targets-pathways network revealed that quercetin, calycosin, formononetin, kaempferol, isorhamnetin, betulinic acid, gamma-sitosterol, (24S)-24-Propylcholesta-5-ene-3beta-ol and bifendate were directly associated with 21 key targets enriched in the top 10 pathways.<br><br>Conclusion<br><br>By employing a whole evidence strategy, this research systematically evaluated the current best available evidence about CHM as adjunctive therapy for DKD, from both historical and contemporary perspectives. Classical literature evidence indicated that huang qi was commonly used in DKD-like disorders, particularly for those presenting with turbid urine (cloudy or foamy urine). With moderate to low quality evidence from RCTs, CHM may have beneficial effects on renal function and albuminuria beyond those reported by conventional treatment alone in adults with DKD. Moreover, adjunctive use of sole huang qi preparations with RAS inhibitors appeared to lowering albuminuria/proteinuria, as well as reducing serum creatinine concentration in the short<br>term. The pharmacological actions of huang qi could be mediated by ILK signalling, TGF-β/Smad signalling, NF-κB pathway and glypican/glypican-1 pathway. Eight compounds with direct potential to regulate key targets are provided as new therapeutic<br>development candidates for DKD. Hence, further research is warranted to determine their clinical benefit.