| Summary: | 博士 === 國立陽明大學 === 環境與職業衛生研究所 === 102 === Background:Taiwan is one of the highest incidence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) countries worldwide. Previous studies have reported a positive association between Chinese herbal medicines (CHMs) and CKD/ESRD. However, they neither defined CHMs specifically nor evaluated the sources/types of CHMs used by the study subjects and the association between the use of CHMs and the disease progression of CKD/ESRD remains unclear. We conducted three studies to clarify the above-mentioned issues including: (1)Risk of chronic kidney disease among users of non-prescribed CHMs; (2)Non-aristolochic acid prescribed CHMs and the risk of mortality in patients with CKD; (3)Impact of prescribed renoprotective CHMs on the mortality of CKD patients.
Materials and methods:In the first study entitled “Risk of chronic kidney disease among users of non-prescribed CHMs”; we used matched case-control study design. The cases were consecutive outpatients that presented to the Nephrology Division of Landseed Hospital with a first-time diagnosis of CKD, and the controls were randomly selected from the outpatients that presented to Landseed Hospital that did not have CKD/ESRD. One control was matched to each case for age (5-year interval), gender, and date of the outpatient visit (index date; within a week). We then used a structured questionnaire to collect subjects’ demographic data, personal medical history, family history of CKD/ESRD, use of prescription and over-thecounter (OTC) drugs, and consumption of CHM prior to the index date. Conditional logistic regression analyses were used to explore the association between various predictors and the risk of CKD. Subgroup analyses were also performed by stratifying on age, gender, education level, stage of CKD, as well as diabetes mellitus and hypertension to determine whether the association between CHM use and CKD persisted across different subgroups. In the second study entitled “Non-aristolochic acid prescribed CHMs and the risk of mortality in patients with CKD”; we employed the longitudinal data of one million subjects randomly sampled from the National Health Insurance Research Database (NHIRD) in 2000 in Taiwan. This database contained follow-up medical information, spanning from 1997 to 2008, for the above-mentioned subjects. We identified patients with CKD by searching CKD related ICD-9-CM codes from the outpatients in the database. Only subjects who had a first-time diagnosis of CKD on or after January 1st, 2000 were included. We excluded subjects who had taken any AA-containing medications before the diagnosis of CKD, diagnosed with cancer prior to the diagnosis of CKD, had human immunodeficiency virus (HIV) infection, were not Taiwanese citizens and died within one month after the diagnosis of CKD. All eligible subjects were then followed from the time of incident diagnosis of CKD till death or December 31st, 2008, whichever came first. The outcome of interest was the risk of all-cause mortality in patients with CKD during the follow-up period. We performed Cox proportional hazard regression to assess the association between various predictors and study subjects’ survival status. In the third study entitled“Impact of prescribed renoprotective CHMs on the mortality of CKD patients”; we also employed the NHIRD database as described in the previous study. The study protocol, follow-up period, and main inclusion/exclusion criteria of the study subjects were the same as the second study. The outcome of interest was the risk of all-cause mortality and CKD-related mortality in patients with CKD during the follow-up period. We classify CKD subjects into three groups including (a). nonuse of renoprotective CHMs (reference group), (b). use of other renoprotective CHMs (Other RPCHM group), and (c). use of renoprotective CHMs that contain Angelica sinensis (Angelica group) to study whether Angelica and other RPCHM was beneficial in ameliorating the mortality of CKD patients. We performed Cox proportional hazard regression to assess the association between various predictors and study subjects’ survival status. We also performed subgroup analyses to determine whether the association between renoprotective CHM use and survival status persisted across different subgroups. All study protocols were approved by the Institutional Review Board of Landseed Hospital (IRB-08-08S for study 1 and IRB-12-23 for study 2 and 3). All statistical analyses were performed using the SAS statistical package version 9.1.3 (SAS Institute, Inc., Cary, NC, USA).
Results:In the first study entitled “Risk of chronic kidney disease among users of non-prescribed CHMs”; a total of 424 participants, including 212 cases and 212 controls, were eligible for the final analysis. There were 23.6% of cases who consumed non-prescribed CHM, whereas only 6.6% of the controls received non-prescribed CHM (p<0.001). In the multivariate analysis, we found that illiteracy (odds ratio (OR) 6.3, 95% confidence interval (CI) 2.4–16.6), hypertension (OR 5.4, 95% CI 2.9–9.8) and occasional use of non-prescribed CHMs (OR 6.2, 95% CI 1.8–21.6) were positively correlated with the risk of CKD; whereas having a habit of regular exercise was inversely correlated with CKD (OR 0.5, 95% CI 0.3–0.9). In the second study entitled “Non-aristolochic acid prescribed CHMs and the risk of mortality in patients with CKD”; a total 47,876 patients with CKD were identified. Among them, 13,864 subjects were eligible for final analyses. After controlling for potential confounders, we found that subjects who started to receive non-AA prescribed CHMs after the diagnosis of CKD had a lower risk of mortality as compared to nonusers of non-AA prescribed CHMs [adjusted hazard ratio (aHR) 0.6; 95% CI 0.4-0.7, p<0.001]. Moreover, subjects who had used non-AA prescribed CHMs both prior to and after the diagnosis of CKD also had a lower risk of mortality than nonusers (aHR 0.6; 95% CI 0.5-0.8, p<0.001). In subgroup analyses, we found that such an inverse association was present only among patients whose CKD was not severe enough to warrant erythropoietin therapy. In the third study entitled “Impact of prescribed renoprotective CHMs on the mortality of CKD patients”; a total 11,625 CKD subjects met the inclusion criteria and were eligible for final analyses. A total of 848 patients died during the follow-up period, of which, 33% (n= 279) were attributable to CKD-related mortality. After controlling for other variables, the use of renoprotective CHMs was associated with a lower all-cause mortality (other RPCHM group (≧median): aHR 0.5, 95% CI 0.3-0.8, p= 0.008 ; Angelica group(<median): aHR 0.6, 95% CI 0.4-0.9, p= 0.14; Angelica group (≧median): aHR 0.6, 95% CI 0.4-0.8, p= 0.002). Use of higher amount of Angelica sinensis also had a beneficial effect on CKD-related mortality (Angelica group (≧median): aHR 0.3, 95% CI 0.2-0.8, p= 0.010). However we did not find any statistical association between patients who received less amount of Angelica sinensis and CKD-related mortality (aHR 0.9, 95% CI 0.5-1.7, p= 0.706). In subgroup analyses, we found that the inverse association between the use of renoprotective CHMs and the risk of mortality was only present among those whose CKD was not severe enough to warrant erythropoietin therapy.
Conclusions:Occasional use of non-prescribed CHMs was associated with the risk of CKD in Taiwan. Moreover, patients who received non-AA prescribed CHMs after the diagnosis of CKD yet before the commencement of erythropoietin therapy had a lower risk of all-cause mortality than those who did not. Notably, the receipt of prescribed renoprotective CHMs, particularly Angelica sinensis, after the diagnosis of CKD seemed to be associated with a low risk of all-cause and CKD-related mortality among CKD patients whose disease was not severe enough to warrant erythropoietin therapy.
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