通过整合基于网络的生化数据库和真实世界临床数据解读中药治疗糖尿病肾病的疗效及机制：回顾性队列研究

Deciphering the Efficacy and Mechanisms of Chinese Herbal Medicine for Diabetic Kidney Disease by Integrating Web-Based Biochemical Databases and Real-World Clinical Data: Retrospective Cohort Study.

作者信息

Wu Chien-Wei, Chen Hsing-Yu, Yang Ching-Wei, Chen Yu-Chun

机构信息

Division of Chinese Internal and Pediatric Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

出版信息

JMIR Med Inform. 2021 May 11;9(5):e27614. doi: 10.2196/27614.

DOI:10.2196/27614

PMID:33973855

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8150407/

Abstract

BACKGROUND

Diabetic kidney disease (DKD) is one of the most crucial causes of chronic kidney disease (CKD). However, the efficacy and biomedical mechanisms of Chinese herbal medicine (CHM) for DKD in clinical settings remain unclear.

OBJECTIVE

This study aimed to analyze the outcomes of DKD patients with CHM-only management and the possible molecular pathways of CHM by integrating web-based biomedical databases and real-world clinical data.

METHODS

A total of 152,357 patients with incident DKD from 2004 to 2012 were identified from the National Health Insurance Research Database (NHIRD) in Taiwan. The risk of mortality was estimated with the Kaplan-Meier method and Cox regression considering demographic covariates. The inverse probability of treatment weighting was used for confounding bias between CHM users and nonusers. Furthermore, to decipher the CHM used for DKD, we analyzed all CHM prescriptions using the Chinese Herbal Medicine Network (CMN), which combined association rule mining and social network analysis for all CHM prescriptions. Further, web-based biomedical databases, including STITCH, STRING, BindingDB, TCMSP, TCM@Taiwan, and DisGeNET, were integrated with the CMN and commonly used Western medicine (WM) to explore the differences in possible target proteins and molecular pathways between CHM and WM. An application programming interface was used to assess these online databases to obtain the latest biomedical information.

RESULTS

About 13.7% (20,947/131,410) of patients were classified as CHM users among eligible DKD patients. The median follow-up duration of all patients was 2.49 years. The cumulative mortality rate in the CHM cohort was significantly lower than that in the WM cohort (28% vs 48%, P<.001). The risk of mortality was 0.41 in the CHM cohort with covariate adjustment (99% CI 0.38-0.43; P<.001). A total of 173,525 CHM prescriptions were used to construct the CMN with 11 CHM clusters. CHM covered more DKD-related proteins and pathways than WM; nevertheless, WM aimed at managing DKD more specifically. From the overrepresentation tests carried out by the online website Reactome, the molecular pathways covered by the CHM clusters in the CMN and WM seemed distinctive but complementary. Complementary effects were also found among DKD patients with concurrent WM and CHM use. The risk of mortality for CHM users under renin-angiotensin-aldosterone system (RAAS) inhibition therapy was lower than that for CHM nonusers among DKD patients with hypertension (adjusted hazard ratio [aHR] 0.47, 99% CI 0.45-0.51; P<.001), chronic heart failure (aHR 0.43, 99% CI 0.37-0.51; P<.001), and ischemic heart disease (aHR 0.46, 99% CI 0.41-0.51; P<.001).

CONCLUSIONS

CHM users among DKD patients seemed to have a lower risk of mortality, which may benefit from potentially synergistic renoprotection effects. The framework of integrating real-world clinical databases and web-based biomedical databases could help in exploring the roles of treatments for diseases.

摘要

背景

糖尿病肾病（DKD）是慢性肾脏病（CKD）的最关键病因之一。然而，中药（CHM）治疗DKD在临床环境中的疗效和生物医学机制仍不清楚。

目的

本研究旨在通过整合基于网络的生物医学数据库和真实世界临床数据，分析仅接受中药治疗的DKD患者的结局以及中药可能的分子途径。

方法

从台湾国民健康保险研究数据库（NHIRD）中识别出2004年至2012年期间共152357例新发DKD患者。采用Kaplan-Meier法和Cox回归模型，并考虑人口统计学协变量来估计死亡风险。使用治疗权重的逆概率来处理中药使用者和非使用者之间的混杂偏倚。此外，为了解用于DKD的中药，我们使用中药网络（CMN）分析所有中药处方，该网络结合了关联规则挖掘和所有中药处方的社会网络分析。此外，将基于网络的生物医学数据库，包括STITCH、STRING、BindingDB、TCMSP、TCM@Taiwan和DisGeNET，与CMN和常用西药（WM）整合，以探索中药和西药在可能的靶蛋白和分子途径上的差异。使用应用程序编程接口评估这些在线数据库以获取最新的生物医学信息。

结果

在符合条件的DKD患者中，约13.7%（20947/131410）的患者被归类为中药使用者。所有患者的中位随访时间为2.49年。中药队列的累积死亡率显著低于西药队列（28%对48%，P<.001）。经协变量调整后，中药队列的死亡风险为0.41（99%CI 0.38 - 0.43；P<.001）。共使用173525份中药处方构建了具有11个中药簇的CMN。中药覆盖了比西药更多的与DKD相关的蛋白质和途径；然而，西药在治疗DKD方面更具针对性。通过在线网站Reactome进行的过表达测试表明，CMN中的中药簇和西药所覆盖的分子途径似乎不同但具有互补性。在同时使用西药和中药的DKD患者中也发现了互补效应。在患有高血压的DKD患者中，接受肾素 - 血管紧张素 - 醛固酮系统（RAAS）抑制治疗的中药使用者的死亡风险低于未使用者（调整后风险比[aHR] 0.47，99%CI 0.45 - 0.51；P<.001），在慢性心力衰竭患者中（aHR 0.43，99%CI 0.37 - 0.51；P<.001）以及缺血性心脏病患者中（aHR 0.46，99%CI 0.41 - 0.51；P<.001）。