The current study demonstrated that one-fifth of patients with CKD have been prescribed harmonizing formulas, which were associated with risk reduction of ESRD in our previous study (10). Symptoms, signs, and ill-defined conditions; diseases of the digestive system; and diseases of the musculoskeletal system were the three most frequent disease classifications for prescribing harmonizing formulas. Patients with CKD who were young, female, had high premiums, lived in central or southern Taiwan or urban areas, did not have comorbidities (acute coronary syndrome, diabetes, hypertension, or cerebrovascular disease), had lower disease severity, and used NSAIDs and analgesic drugs other than NSAIDs were more likely to have harmonizing formulas prescriptions.
Nearly half of incident CKD patients used conventional CHM. Harmonizing formulas accounted for 46.1% of prescriptions. Although the efficacy of harmonizing formulas in reducing depression and improving survival in patients with liver cancers and systemic lupus erythematosus have been reported in studies (14, 17), few studies have paid attention to prescription patterns and outcomes in treating patients with CKD (18, 19). Combined with the results of Yang et al. (2014), Chen et al. (2018), and our previous findings, the current study indicated that one harmonizing formula, Jia Wei Xiao Yao San, is the main prescription for patients with late CKD. This formula potentially improves patient renal function after short- or long-term observation (10, 19). Jia Wei Xiao Yao San is traditionally used to relieve stagnation in liver qi, reduce depression symptoms, and improve spleen qi deficiency. Although the mechanisms of delaying ESRD are complex and worthy of further study, Jia Wei Xiao Yao San may affect renal clinical outcome by improving depressive symptoms, which are a novel predictor of accelerated eGFR decrease, dialysis therapy initiation, death, or hospitalization (10, 20). We are unsure of the effect harmonizing formulas have in relieving uremic symptoms or slowing renal progression.
We attempted to use the ICD-9-CM to as a reference for the indications of harmonizing formula prescription in CKD patients. CHM has its own historical and systematic philosophy of symptom differentiation (Bian Zheng) to assess, explicate, diagnose, and treat patient symptoms. Numerous symptoms in CKD patients not requiring dialysis are either unrecognized or suboptimally managed by clinical care workers (21, 22). assessed 283 patients with stage 1–5 CKD and reported that tiredness (81%; 95% CI: 76.0–85.6), sleep disturbance (70%; 64.3–75.3), and pain in bones or joints (69%; 63.4–74.6) were the most common symptoms regardless of CKD stage. Loss of appetite, nausea, vomiting, fatigue, and edema are common symptoms in late-stage CKD, which are similar to “spleen deficiency syndrome” in CHM and tend to involve the digestive system. In addition, local pain, weakness in the loin and knee, and calf cramps are frequently encountered CKD symptoms, which are similar to “liver–kidney insufficiency syndromes” in CHM and tend to involve the musculoskeletal system. Shao Yao Gan Cao Tang, a frequently prescribed harmonizing formula in CKD, is used to relieve muscle pain or skeletal muscle tremors in Japan and China (23). However, additional beneficial effects of Shao Yao Gan Cao Tang on renal health remain unknown and warrant further investigation.
Female sex, low prevalence of comorbidity, and high use of analgesic drugs were associated with higher prescription frequency for harmonizing formulas in CKD. Although the causal relationships are difficult to establish in this study, a possible explanation is that prevalence of pain for females is high, and they are more likely to be aware of pain and receive relevant treatments (24, 25). NSAIDs are commonly used for pain control in clinical practice, but caution should be exercised when they are applied in CKD because they can induce more severe renal injuries (26). How harmonizing formulas interact with NSAIDs for pain control in patients with CKD remains unclear. Thus, more research is required on this combination therapy to study its efficacy in pain control in CKD and preventing further renal injury.
Our study has some advantages. First, assessments of Chinese herbal formulas in the study were drawn from a nationwide health insurance database with highly comprehensive records of CHM prescriptions. Second, CHM in this study was prescribed by quality assurance physicians who were educated in the same system and accredited by Taiwan’s government; this strengthens the reliability of symptomatic differentiation and accuracy of disease diagnostic coding. Third, Taiwan’s NHI is one of the few national insurance programs that reimburses both Western medicine and CHM, providing an opportunity to explore the foundational philosophies of these two different modes for treating certain diseases. However, some limitations must be declared. First, the lack of laboratory and patient-reported data in the claims database prevents us from exploring the possible mechanisms of harmonizing formulas on health outcomes such as emotion, pain, and renal function. In addition, using the ICD-9-CM diagnosis system to identify disease classification of CHM prescriptions may not have accurately reflected the indications of CHM formulas. However, we believe that using the main categories of diseases partially represented the CHM diagnostic system. Finally, our results were from the NHI program having high accessibility, which may limit their generalizability.