Chinese Herbal Medicine Tangshen Qushi Formula for Patients with Stage 2–4 Diabetic Kidney Disease: Clinical Evidence and Natural Product Development

Background The global burden of diabetic kidney disease (DKD) continues to rise, with a significant proportion of patients progressing to end-stage kidney disease despite advancements in conventional pharmacotherapy such as renin-angiotensin system blockers, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. These treatments, while beneficial, offer only modest slowing of disease progression and are associated with residual risks and adverse effects, highlighting a clear need for new and/or complementary therapeutic options, particularly in early-stage DKD. Chinese herbal medicine is widely used in clinical practice for DKD management in China, yet high-quality evidence from rigorous, placebo-controlled trials within contemporary guideline-recommended care is scarce. Guided by the evidence-based practice paradigm, which integrates the current best research evidence, clinical expertise, and patient values, this thesis investigates the Tangshen Qushi Formula (TQF), a standardised Astragalus-based granule formulation developed from long-term clinical observation and research with an objective to address the Chinese medicine syndrome of qi deficiency and dampness, which is central to DKD pathology from the Chinese medicine theoretical framework. Aims, objectives, and research questions The overarching aim of this project was to evaluate the preclinical evidence, clinical feasibility, efficacy, safety, and patient acceptability of TQF granules for patients with stage 2–4 DKD. This was operationalised through 4 specific research questions: 1) What are the therapeutic effects and plausible mechanistic actions of TQF and its components in animal models of DKD? 2) To what extent is it feasible to conduct a rigorously designed clinical trial of TQF granules? 3) What are the effects of TQF granules on kidney function and safety outcomes in patients with stage 2–4 DKD? 4) What are participants' expectations, experiences, and adherence behaviours in a pilot trial of TQF granules? Methods and results A multi-method approach was employed, comprising 3 integrated studies as outlined below: 1.Systematic review of preclinical evidence A PROSPERO-registered, PRISMA-compliant systematic review and meta-analysis synthesised evidence from 45 animal studies on TQF's principal herbal components (Astragali Radix, Isaria Cicadae and Cordyceps Cicadae, and Centella Herba). The review identified a mechanistic foundation, demonstrating that Astragali Radix consistently improved kidney function (reducing serum creatinine, blood urea nitrogen, and proteinuria) and ameliorated histopathological injury via anti-fibrotic, antioxidant, and anti-inflammatory pathways. The other components provided complementary antioxidant and anti-inflammatory actions. Despite heterogeneity and a predominance of type 1 diabetes models, the review revealed biological plausibility and informed the formulation for clinical evaluation. 2.Placebo-controlled pilot RCT A double-blind, placebo-controlled pilot randomised controlled trial (RCT) was conducted with 60 Chinese adults with stage 2–4 DKD. Participants were randomly assigned to either TQF granules or indistinguishable placebo for 48 weeks, with a 12-week follow-up. The primary, intention-to-treat analysis demonstrated a statistically significant preservation of estimated glomerular filtration rate (eGFR) in the TQF group compared to placebo at the end of the intervention period (48 weeks), a benefit that was sustained through follow-up. A significant reduction in serum uric acid was also observed at Week 48. In the per-protocol analysis, TQF also led to a significant reduction in albuminuria, suggesting that adherence may be important for this effect. TQF exhibited an acceptable safety profile, with no significant differences in adverse events versus placebo and no evidence of organ toxicity or metabolic disturbance. 3.Embedded qualitative study Semi-structured interviews were conducted with 22 participants from TQF and placebo groups from the pilot RCT to explore patient perspectives. Thematic analysis revealed that participation was motivated by trust in physicians, prior positive Chinese herbal medicine experience, and altruism. TQF granules were generally acceptable, overcoming traditional decoction barriers, although taste and solubility were noted for improvement. Adherence was influenced by perceived renal and metabolic benefits and by clear, responsive communication from the research team. Placebo recipients reported lower satisfaction and were more likely to withdraw. The study identified optimisations for future trials, including sensory enhancements, remote monitoring options, and logistical support. Conclusion This thesis provides a coherent, multi-tiered evidence base demonstrating feasibility of further clinical evaluation of TQF granules in a clinical setting subject to minor improvements identified from the pilot study. The systematic review helped to elucidate biological plausibility through multi-target renoprotective mechanisms. The pilot RCT translated this into a clinically relevant efficacy evaluation based on preserving renal function, with an acceptable safety profile. The qualitative study completed the evidence-based practice cycle by confirming real-world acceptability and providing a patient-centred roadmap for optimising future trials and implementation. While limitations exist—such as the preclinical model focus, the pilot's small sample size, and the single-site design—the convergent findings from these integrated methodologies support the advancement of TQF to an adequately powered, multi-centre trial to determine the clinical benefits of TQF for DKD patients. This work exemplifies a comprehensive translational pathway for evaluating complex herbal interventions and underscores the potential of integrating Chinese medicine with conventional care to address unmet clinical needs in DKD management.