Background
Diabetic nephropathy (DN) is one of the primary causes of end-stage renal disease (ESRD) and accounts for more than 40% of hemodialysis patients [
1]. Among all patients with diabetes mellitus (DM), about 25–40% of patients may develop DN 20–25 years after the diagnosis of DM, and about one-third of patients with DN may suffer from ESRD [
2]. Because of its high prevalence and severe consequences, DN has been a significant healthcare problem and has resulted in an enormous financial burden [
3‐
5]. In Taiwan, about 6%–8% of adults over 40 years of age have DM, and DN can be found in 40% of adults with DM [
6]. This burden may be the primary reason why Taiwan’s healthcare system was ranked 45th out of 195 countries, which is much lower than other developed countries [
7]. For this reason, how to provide care that is more comprehensive for patients with DN has become such a vital issue.
Traditional Chinese medicine (TCM) is commonly used by the Chinese population, with prevalence ranging from 45.3% among patients with chronic kidney disease (CKD) [
8] to 77.9% among patients with DM in Taiwan [
9]. Some TCM treatments may have therapeutic benefits in CKD in clinical studies or DN in animal studies [
10‐
13]. However, studies on ESRD and mortality rates of incident DN in patients with TCM treatments are still lacking since most clinical trials on TCM only reported improvements in renal function. The influence TCM treatments have on ESRD and mortality can only be inferred from the few studies conducted previously in CKD patients but did not differentiate etiology or patients with DM. Nevertheless, the clinical course of incident DN, DM, and CKD may be entirely different in TCM users. Among patients with DM, the risk of DN seemed higher among patients with incident type 2 DM who used TCM [
14], but the occurrence of ESRD may be lower among TCM users [
15]. However, the mortality rate was not assessed among patients with DM. The mortality rate is not only the most concerned outcome of patients with DN, but the rate of ESRD would also be estimated more accurately when considering mortality [
16].
On the other hand, for patients with CKD with undifferentiated etiology, the influence of TCM is somewhat controversial. An early questionnaire-based study revealed that only 10% of patients with CKD ever used TCM, and ESRD risk increased by 20% among TCM users [
17]. Some studies showed that certain TCM herbs with aristolochic acid or non-prescribed herbs might be related to renal failure [
18‐
20]. In contrast, a study with data collected from 2000 to 2008, showed that patients with CKD taking aristolochic acid-free TCM herbs had lower risks of mortality [
21]. Lin et al. reported that the risk of ESRD was lower among patients with CKD who received TCM herbs during a similar study period without excluding aristolochic acid-containing herbs [
8]. However, aristolochic acid-containing TCM treatments may still be a potential confounding factor since only after 2003; all aristolochic acid-containing TCM treatments became strictly prohibited in Taiwan. DN-specific studies aimed to clarify the ESRD and mortality rate of TCM users among patients with DN requires studies to be conducted with a more extensive population and follow-up durations that are free of aristolochic acid-containing herbs [
22].
This study aims to explore the mortality and ESRD rates of patients with DN using TCM treatments by studying the entire incident DN cohort from 2004 to 2006, with follow-up until the end of 2012, instead of the sampled dataset used in earlier studies. This information is crucial for both TCM and western medicine (WM) doctors when treating patients with DN.
Discussion
This study is the first and most extensive cohort study about mortality and ESRD rates of TCM users who are patients with incident DN. Although observational studies are not as rigorous as randomized clinical trials for assessing effectiveness and causality, this study shows that lower ESRD and mortality rates highly correlated with the use of TCM. Both of these long-term outcomes are consistent with the short-term outcomes mentioned in previous clinical and cohort studies [
12,
15,
39]. The use of a cohort from 2004 enabled us to both remove any potential adverse effects of aristolochic acid-containing herbs and estimate the outcomes of patients with DN who used TCM more accurately than previous studies [
8,
21]. The TCM treatment is unlikely the primary factor contributing to patients with DN who were unsatisfied with their healthcare mentioned recently [
7], nor the precipitating factor reported previously among patients with all-cause CKD [
17‐
19,
40]. Instead, reduced ESRD and mortality rates among TCM users showed the potential of TCM treatments to be considered as a part of the integrative care system for patients with DN. Also, the results provide crucial information about using TCM for DN, since previous clinical studies still lack data regarding changes in ESRD or mortality rates because of the limited duration of follow-ups [
12,
39].
The potential renoprotective effect may be the reason why the all-cause mortality rate was lower among TCM users since the ESRD rate was also lower and the time to ESRD was about one year later than among TCM nonusers. These results closely correspond to several clinical trials that examined the efficacy of TCM treatments on DN, in which proteinuria and the glomerular filtration rate improved by integrating TCM treatments into standard WM treatments [
39]. Renoprotection may come from direct effects, such as
Astragalus membranaceus (Fisch.) Bge.
, Huang Qi in Chinese, for improving proteinuria [
12], or decreasing the use of nephrotoxic WM medications [
41,
42].
Nevertheless, renoprotection may be only one reason that TCM users had a lower mortality rate since the risks of mortality decreased much more than the risks of ESRD. Because DN may solely increase the risks of cardiovascular diseases [
43], cerebrovascular diseases [
44], and even various kinds of cancer [
45], both the clinical courses and treatment effects among patients with DN with these complications may be different [
43]. For this reason, the potential of TCM treatments for reducing the risk of these complications and mortality rates among patients with DN is worthy of further study, especially when TCM users were associated with better outcomes among patients with stroke or malignancies [
46,
47]. Furthermore, we also found that the occurrence of ESRD might compromise the lower mortality rate among TCM users. Patients with ESRD or even pre-ESRD were thought to have less residual renal function, which may cause a higher mortality rate than patients without ESRD. Since studies about TCM use among patients with ESRD are limited and only certain TCM treatments seemed beneficial among patients with ESRD [
48,
49], further studies about long-term outcomes of TCM users among patients with pre-ESRD or ESRD patients are needed.
In addition, the influence of the time of initiating TCM treatments implies that TCM doctors need to consider DN earlier, even before it occurs. TCM users who started the TCM treatment only after DN diagnosis, namely new TCM users, had the best survival rate, while the mortality of former TCM users was the highest among all patients with DN. The different outcomes of patients with various initiation times suggest that TCM doctors may consider protecting renal function even before the diagnosis of DN as the currently recommended management for DN [
50]. The lower risks of mortality among new TCM users implies that some TCM treatments might have secondary protective effects as a part of the integrative management of patients with DN since some TCM treatments may improve renal function and proteinuria when combined with conventional WM treatments [
12,
51]. On the contrary, some TCM treatments should be used cautiously in patients with DM even before DN occurs, as former TCM users showed in our study. For example, TCM treatments intended to remove excess body fluid may cause fluid imbalance or even dehydration, which may potentially damage renal function [
8].
Moreover, as the initial report about the risks of ESRD and mortality among patients with incident DN in the Chinese population (the main ethnic group in Taiwan), we found that the results were entirely different from risks assessed among patients with CKD of undifferentiated etiology. The ESRD rate among DN was twice as high as in patients with general CKD in Taiwan (IR: 20.2 per 1000 PY for DN versus 11.1 per 1000 PY for all CKD re-calculated according to Lin et al.’s report [
8]). For TCM users, the risk of ESRD reduced less among patients with DN (aCSHR: 0.81 for DN versus 0.47 for all CKD [
8]), but the risk of mortality seemed comparable (aHR: 0.48 versus 0.6 for all CKD [
21]). Since CKD may have various causes, the influence of TCM treatments would vary widely depending on the causes, and therefore, the outcomes of TCM users should be estimated accordingly.
Through this study, we demonstrated that TCM users had lower ESRD and mortality rates among patients with incident DN. For this reason, the use of TCM should be assessed when visiting patients with DM, and it also should be taken into consideration when conducting cohort studies about DN. However, there are some limitations to this study. First, since only reimbursed TCM treatments were included in this study, we may have underestimated the use of TCM because of the lack of data regarding self-paid TCM and folk medicines. Since TCM treatments are reimbursed and readily accessible (the medication fee is about 1 USD/per day), the influence caused by the self-paid TCM and folk medicine would be minimal. Besides, the efficacy of specific TCM treatment was not assessed in this study since it is unlikely to use all kinds of TCM treatments as a therapeutic regimen for DN. In this study, we included all kinds of TCM treatments under the consideration that the guideline or consensus of TCM treatments for DN are still lacking, and TCM prescriptions are somewhat complicated in the real world due to the TCM treatment theory “bian-zheng-lun-zhi,” which means that treatments should be personalized according to the individuals’ conditions. Therefore, the feasibility of using TCM treatments among patients with DN assessed in this study would be helpful when intending to explore the effectiveness of specific TCM treatments by conducting clinical trials or bench studies. Second, although PSM was used to decrease the differences between TCM users and nonusers, it is impossible to assess all potential confounding factors for ESRD or mortality. For example, TCM users are usually associated with higher socioeconomic status (as the unmatched cohort in our study), and therefore the lower risk may be relevant to both TCM use and socioeconomic status. In addition to choosing a matched cohort by using the geolocation and insured level as the proxy for socioeconomic status [
8,
25], we also found former TCM users had an inconsistent outcome with other TCM users (Table
3), which may imply that bias from socioeconomic status may be minimal. Third, since the information about stopping treatment is not available in this database, we do not know the exact reason why former TCM users discontinued TCM treatment before DN diagnosis. One possible reason is deteriorating renal function, and discontinuation of treatment may be suggested at that time. Because the average treatment effect of TCM seems beneficial in this study, and the causative nephrotoxic agents have been prohibited since 2003, TCM treatments are unlikely the leading cause of poor outcomes. Instead, late diagnosis of DN may be one crucial possible factor since the overall outcome of patients with incident DN seemed poorer than western countries. Another concern is that the poorer outcomes of former TCM users may indicate that nephrologists may stop some TCM treatments because of deteriorating renal function. However, this reason for discontinuation could not be verified because it was not accessible, and the lab data was not available in this database. Theoretically, this condition may confound the outcome analysis, but since the HR was only 0.01 higher than patients who never used TCM and the HR was much lower among new TCM users, we proposed positive correlations between TCM use and a better survival rate.
Nevertheless, we still suggest that TCM doctors should be cautious about patients’ renal function and choose TCM treatments carefully even before a definite diagnosis of DN is made. Fourth, the actual quality of control in DM and hypertension is crucial to patients with DN, but the relevant laboratory data is absent in this database. Extensive consideration of potential confounding medications (e.g., medications for hypertension and DM), the severity of DN-related complications (e.g., DCSI and CCI), the CKD-related complications (e.g., hyperuricemia, and cardiovascular disease), and renoprotective agents, may enable this limitation to be overcome for the most part. Finally, some newly approved anti-diabetes medications are not included in this study, such as the sodium-glucose cotransporter-2 inhibitors. This medication can lower cardiovascular risk among patients with DM and may decrease the mortality rate. However, it was not possible to include this medicine in the analysis since it was only approved in Taiwan in 2014.