Integrative management for diabetic kidney disease : patients' and clinicians' perspectives, clinical effectiveness and possible mechanisms

Abstract

Diabetic kidney disease (DKD) is a chronic and progressive complication of diabetes occurs in one-third of diabetic patients. It affects 2 percent of the population globally with higher incidence in Asia. DKD is the leading cause of end-stage kidney disease (ESKD) in Hong Kong that increases annual direct medical costs by 5 folds. There is a significant residual risk of ESKD despite conventional strategies including the renin-angiotensin-aldosterone system blockade, control of blood glucose and blood pressure. Previous big data studies showed that Chinese Medicine (CM) reduced the risk of ESKD and mortality among chronic kidney disease (CKD) patients. However, there is no evidence-based clinical practice guideline integrating CM to DKD management. This project aims to generate evidence for a DKD integrative Chinese-western Medicine (IM) management strategy through mixed methodologies from a clinical efficacy-driven approach. Previously, a clinical service programme was conducted for diabetic CKD patients based on an IM clinical protocol developed by literature review and expert consensus. Retrospective evaluation of the programme showed improved symptoms, renal function and albuminuria after 48 weeks of add-on CM. Following this initiative, we conducted a focus group interview series to identify the concerns and expectations among patients and clinicians regarding DKD IM service. Seven high-level themes, for instance, barriers towards IM service, motivation to seek CM service, experience of CM service and preferred model of IM service delivery were identified with 25 subthemes. Results showed that retarding renal progression and minimising treatment-related complications and side effects are the shared goals among patients and clinicians. The convenience of access to IM affected patients’ compliance and the lack of supportive and communicable clinical evidence hindered collaborative practice among clinicians. Subsequently, SCHEMATIC, an add-on randomised controlled pragmatic clinical trial, was conducted to evaluate an adapted IM treatment protocol for DKD patients with CKD stage 2 to 3 and macroalbuminuria. In the nested analysis, add-on CM contributed to a significant increase in estimated glomerular filtration rate of 3.90 ml/min/1.73m^2 (95% CI: 0.02 to 7.78, P=0.05) after adjusting for confounders. The effect was independent of blood pressure, blood glucose and albuminuria control. The intervention did not increase risk of adverse events. Subgroup analyses from SCHEMATIC indicated that astragalus is likely to play a key role in the add-on effect of SCHEMATIC. Finally, the physiobiochemical and histological effect of combined astragaloside IV (AS-IV) and captopril was studied using uninephrectomised db/db mice to delineate the mechanisms of renoprotection provided by add-on CM. In vivo data suggested that AS-IV attenuated glomerulosclerosis, mesangial expansion and hyalinosis, and synergistically reduced tubulointerstitial fibrosis and tubular atrophy when co-administrated with captopril. The combined therapy abrogated the downstream expression of fibrotic markers but an opposite effect on TGF-ẞ suggested that other signaling pathways of fibrosis were targeted. In conclusion, our qualitative and quantitative evidence unraveled the concerns and expectations among patients and clinicians, provided evidence on an effective clinical management protocol and evaluated plausible mechanisms for DKD IM treatment. It formed the backbone of evidence-based IM clinical practice guideline for future health services provision and research.