Chronic kidney disease (CKD) is a common and progressive disease that has become a major public health problem on a global scale. Renal fibrosis is a common feature in the pathogenesis of CKD, which is mainly related to the excessive accumulation and deposition of extracellular matrix caused by various inflammatory factors. No ideal treatment has yet been established. In recent years, based on the traditional Chinese medicine (TCM) theory of CKD and its molecular mechanism, clinical evidence or experimental studies have confirmed that a variety of Chinese materia medica (CMM) and their effective components can delay the progress of CKD. TCM believes that the pathogenesis of CKD is the deficiency in the root and excess in the branch, and the deficiency and excess are always accompanied by the disease. The strategies of TCM in treating CKD are mainly based on invigorating Qi, tonifying the kidneys, promoting blood circulation, removing stasis, eliminating heat and dampness, removing turbidity, and eliminating edema, and these effects are multitargeted and multifunctional. This review attempts to summarize the theories and treatment strategies of TCM in the treatment of CKD and presents the efficacy and mechanisms of several CMMs supported by clinical evidence or experimental studies. In addition, the relationship between the macroscopic of TCM and the microscopic of modern medicine and the problems faced in further research were also discussed.
In recent years, research on the mechanism and intervention strategies of chronic kidney disease (CKD) has become a hot spot in the nephrology field. CKD is defined by the Kidney Disease Outcomes Quality Initiative in terms of either kidney damage or decreased glomerular filtration rate (GFR, <60 ml/min per 1.73 m
) with or without evidence of kidney damage, for three or more months, regardless of the cause (National Kidney Foundation, 2002; Steven and Levin, 2013). It is characterized by increased inflammatory cell infiltration, tubular atrophy, tubulointerstitial fibrosis, and glomerulosclerosis, finally leading to some forms of end-stage renal disease (ESRD) or renal failure (Boor et al., 2010). However, in ESRD, the survival of patients depends on the renal replacement therapy or dialysis because of lack of kidney donors. The global burden of CKD study in 2017 showed that the global prevalence of CKD has exceeded 9%, accounting for 18.97% of CKD patients worldwide living in China (GBD Chronic Kidney Disease Collaboration, 2020). In 2017, CKD resulted in 1.2 million deaths, and the number has been projected to rise to 2.2 million (best-case scenario) and up to 4.0 million (worst-case scenario) by 2040 (Foreman et al., 2018). Therefore, CKD has become a major public health problem on a global scale. Delaying or preventing the progress of CKD has become an important challenge facing the clinical medicine community and the health departments of various countries.
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Current therapy for CKD includes angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which act by decreasing proteinuria, lowering blood pressure, and thus retarding CKD progression (Levey and Coresh, 2012; Ruggenenti et al., 2012). However, the treatments are not sufficient for all patients and long-term medication may lead to a number of adverse effects such as hyperkalemia and acute kidney injury (Kidney Disease Outcomes Quality Initiative (K/DOQI), 2004). As an important branch of complementary and alternative medicine, traditional Chinese medicine (TCM) has been proved to protect people’s health for thousands of years. Preclinical studies or clinical trials have shown that Chinese materia medica (CMM), a form of TCM treatment, is promising in treating CKD, especially in the aspects of reducing proteinuria and adverse effects of western drugs, and reduces ESRD risk by 60% (Wojcikowski et al., 2006; Lin et al., 2015). As a large number of people use herbs for medicinal purposes, the safety of CMM has been questioned. The most well-known adverse effect is nephropathy induced by aristolochic acid, which resulted in ESRD and urothelial malignancy. The mechanism of nephrotoxicity induced by aristolochic acid has been clarified as mainly related to the induction of tubular cell apoptosis, the formation of aristolochic acid-DNA adducts, and the inhibition of mitochondrial ATP synthesis (Nortier and Vanherweghem, 2007; Han et al., 2019). Some studies suggest that nephrotoxic effects may be caused by incorrect use of CMMs or toxic CMMs or potentially toxic CMMs (Jha et al., 2013; Jha and Rathi, 2018). It is important to point out that the use of CMMs by physicians practicing TCM is based on the theory of TCM and they prescribe formulas on the basis of syndrome differentiation and treatment approach (Li L. et al., 2019). According to the ancient compatibility rule of “Jun-Chen-Zuo-Shi” (“monarch-minister-assistant-courier”), making a prescription with two or more CMMs can increase the medicinal effects and restrain the CMM’s toxic properties (Wei and Zheng, 2008). Therefore, the syndrome differentiation and treatment approach and compatibility theory ensure the efficacy and safety of CMMs.
To date, the pathophysiological mechanism of CKD has been reviewed in some studies (Chen et al., 2018; Lv et al., 2018; Rinschen and Saez-Rodriguez, 2021). Some evidence has shown that single CMM and CMM formulas possess a range of important pharmacological properties in improving CKD. In this review, we attempt to discuss the current knowledge of TCM for the treatment of CKD and its possible interventional mechanisms.
The advantages of TCM in the treatment of CKD are mainly reflected in the overall concept and syndrome differentiation. The concept of organs in TCM is different from that in modern medicine. As recorded in the “Yellow Emperor’s Canon of Internal Medicine, ” the kidney is the place of true Yin and true Yang and the base of hiding and the place for storing the essence. In the TCM theory, the essence transforms Qi (the vital energy) and produces Blood (the body circulation) (Tu X. et al., 2013). Therefore, abnormalities of the kidney are believed to cause the disorder of the body. TCM classifies CKD into the categories of “edema, ” “retention of urine, ” and “kidney fatigue.” As CKD is characterized by severe proteinuria, the lesions are mainly in the spleen and kidneys. Proteinuria is the pathological product of human essence substance flowing down and leakage of the essence. A basic substance that constitutes the human body and sustains life activities is similar to “vital essence” in TCM, which emphasizes that these essences should be stored in the human body and should not be released. Damage to the kidney leads to a loss of vital substances, resulting in the deficiency of Qi and Yang. Furthermore, the kidney is called the viscera of water, and it is responsible for the body fluid. If the water is stagnant, dampness and heat will occur (Ding et al., 2014). Moreover, with the damage to the kidney essence, Qi cannot consolidate the Blood, resulting in unfavorable blood circulation and blood stasis (anticoagulation) formation (Li X. et al., 2019a).
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Besides, the vital substances stored in the kidneys depend on the transportation and distribution of the spleen. The disorder of spleen transport is usually caused by improper diet, deficiency of endowment, and excessive fatigue, which lead to spleen Qi deficiency. Furthermore, with the development of spleen Qi deficiency, the development of disease, the decline of fire in the vital gate, and the loss of warm spleen, it will further lead to the deficiency of spleen Yang. The spleen cannot warm the grain and liquid, and then the transport of liquid and water is abnormal, which leads to water dampness. As mentioned in “Plain Questions, ” with Yin and Yang in relative balance, the spirit can be cured. Thus, TCM believes that “spleen-kidney deficiency” is an internal condition; blood stasis, internal dampness, and heat are inextricably linked to the patient’s viscera (Shi and Shen, 1982; Nie, 2008; Wu and Ma, 2011; Su et al., 2013). The treatment principle for CKD is reinforcing deficiency and purging excess, and simultaneous treatment of the branch and the root to achieve “Yin and Yang in relative balance” (stabilization status).
The pathogen of CKD is mainly manifested as blood stasis, dampness heat (hygropyrexia), and turbid toxin (retained hazardous substances). Blood stasis syndrome is one of the most common CM syndromes among patients with primary glomerular disease (Li et al., 2009). “Blood stasis” in TCM covers glomerulosclerosis, an increase of the extraglomerular matrix, thickening of the basement membrane, adhesion of balloon, microthrombosis in the glomerulus, collapse or stenosis of the capillary lumen, compression and occlusion of vascular loops, and tubulointerstitial fibrosis and atrophy (Wu and Ma, 2011; Guo et al., 2019). TCM has the viewpoint that by removing excessive patterns of stagnated blood, the Blood and Qi can be invigorated, and then they promote blood circulation. This condition is suitable for promoting blood circulation and removing blood stasis, invigorating Qi to reduce swelling.
When the spleen and kidneys are deficient, water dampness is endogenous. Pathogenic dampness resides in the body, leading to heat from Yang, or heat from dietary intake, and eventually pathogenic dampness changes to heat from dampness. As the famous medical scientist Lingtai Xu inferred, there must be heat when there is dampness. In microscopic differentiation of syndromes, dampness heat in renal pathology often shows swelling of endothelial cells, formation of microthrombus,
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