Astragali Radix (AR, Huangqi) is derived from the dry roots of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. In the clinical practice of TCM, AR is mainly used to invigorate Qi, manifested in two aspects, supplementing the Defense-Qi (which has the physiological functions of defending exogenous pathogenic factors, warming and nourishing the whole body) and replenishing the Middle-Qi (which is the function motivity of spleen and stomach) (Chen Z. et al., 2020). Therefore, as recorded in “Compendium of Materia Medica,” AR is known as the key CMM of tonics. The chemical studies of its ingredients are relatively clear, mainly including triterpenoid saponins (mostly cycloartane-type), flavonoids, and polysaccharides (Su et al., 2021).

The effects of AR on the reduction of proteinuria and serum creatinine have been studied in patients. After treatment with AR injection in 30 patients with chronic glomerulonephritis, the content of urine protein decreased obviously from 2328 ± 3157 to 1017 ± 765 mg/24 h (Shi et al., 2002). The effect of AR on reducing total cholesterol, triglyceride, and low-density lipoprotein (LDL) and increasing plasma total protein and albumin has also been confirmed in patients with CKD (Zhang et al., 2005). In addition to small clinical trials, a systematic review of 66 studies involving 4,785 diabetic kidney disease participants also demonstrated the benefits of AR injection or preparation in reducing albuminuria, proteinuria, and serum creatinine levels (Zhang L. et al., 2019). Furthermore, AR-containing preparations are effective in improving eGFR in patients with mild to moderate CKD (Yoshino et al., 2022).

In recent years, the immunomodulatory effect of AR has been gradually developed (Wang YP. et al., 2002; Chen Z. et al., 2020). A previous study has shown that AR significantly downregulated CD₄ and upregulated CD₈ in patients with chronic glomerulonephritis, suggesting that it has a regulatory effect on cellular immunology (Shi et al., 2002). Several pieces of evidence have accumulated showing the potential of AR in reducing water retention (Ma et al., 1996; Wang H. Y. et al., 2002). The therapeutic effect of AR on nephrotic syndrome (NS) may be demonstrated by reducing the expressions of arginine vasopressin (AVP) mRNA, AVP V2 receptor mRNA, and AVP-dependent aquaporin-2 (AQP2) mRNA, thereby eliminating edema. In addition, AR has the effect of ameliorating the blunted renal response to the atrial natriuretic peptide (Ma et al., 1999). It suggested that AR is different from diuretics in the treatment of edema. AR protects against oxidative stress-induced damage in proximal tubular epithelial cells via antiapoptotic and antiinflammatory mechanisms (Shahzad et al., 2016). It was demonstrated by the downregulation of pro-apoptotic Bax and upregulation of Bcl-XL, a decrease in nuclear factor kappa B (NF-κB, p65, p50), a decrease in tumor necrosis factor (TNF)-α, and an increase in transforming growth factor (TGF) β1.

As the main active ingredient of AR, astragaloside significantly improved the state of oxidative stress in podocytes cultured with adriamycin (ADR) and suppressed the cytoskeletal rearrangement, improving the migration ability of podocytes via upregulating the expression of matrix metalloproteinase 2 (MMP-2) and MMP-9 (Sai et al., 2018). The most studied astragaloside IV can inhibit high glucose-induced cell apoptosis through increasing hepatocyte growth factor production via its specific receptor c-met and inhibiting the phospho-p38 mitogen-activated protein kinase (MAPK) signal pathway (Mou et al., 2008; Wang Q. et al., 2014). Calycosin is another component of AR that can inhibit the phosphorylation of IKBα and NF-κB p65 in db/db mice and cultured mouse tubular epithelial cells (Zhang YY. et al., 2019).

Rhei Radix et Rhizoma (RRR, Dahuang), the dried roots and rhizomes of Rheum palmatum L., Rheum tanguticum Maxim. Ex Balf., or Rheum officinale Baill, is widely used as a laxative for many years. Pharmacological studies have confirmed its multiple activities, such as antibacterial, purgative, antifibrosis, regulating gastrointestinal, antiinflammatory, and antitumor activities (Xiang et al., 2020). In a systemic review of 18 randomized or quasirandomized trials including 1,322 patients with CKD, RRR showed significant positive effects on relieving symptoms, lowering serum creatinine, and adjusting disturbance of lipid metabolism (Li et al., 2004). In addition, in a prospective clinical trial of 151 patients with chronic renal failure (CRF), the frequency of end-stage renal failure in the RRR group was 52% lower than that in the ACE inhibitor group. Besides, a slope of progression as the progressive rate of decline in renal function was found to be more horizontal in the RRR-treated group (Li, 1996).

As shown by Zhang et al., treatment with the extracts of RRR reversed the abnormalities of the urinary metabolites in adenine-induced CKD animals and reduced the expression of histopathological inflammatory markers such as collagen (Col) I, Col III, and pro-fibrosis marker TGF-β1 (Zhang et al., 2015). Research on network pharmacology suggested that RRR could target multiple targets involved in the accumulation of extracellular matrix (ECM), the release of inflammatory factors, the balance of coagulation, and fibrinolysis, which showed a synergistic therapeutic effect (Xiang et al., 2015). Regarding the mechanism of RRR against renal fibrosis, some studies have shown that its nephroprotective effect was to reduce the expressions of TGF-β1, TGF-β receptor I (TGF-β RI), TGF-β RII, Smad2, p-Smad2, Smad3, p-Smad3, and Smad4, meanwhile increasing Smad7 (Zhang ZH. et al., 2018). In addition to improving renal fibrosis, RRR could also improve the intestinal barrier function in 5/6 nephrectomy (5/6Nx) rats by regulating systemic inflammation, intestinal barrier markers, and toll-like receptor 4-myeloid differential protein-88-NF-κB inflammatory response (Ji et al., 2020).

Rhein is the main active component of RRR. Recent studies have shown that in adenine mice or unilateral ureteral obstruction (UUO) mice, rhein effectively recovered Klotho promoter hypermethylation via reversing aberrant DNA methyltransferases expression, thus upregulating the expression of Klotho protein (Zhang et al., 2016; Zhang et al., 2017). Besides, the renal protective mechanism of rhein was also related to the activation of the sirtuin 3-forkhead box O3α signaling pathway to exert antioxidant capacity and the regulation of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathways to inhibit autophagy (Tu et al., 2017; Wu et al., 2020).

Abelmoschi Corolla (AC, Huangshukui), the flower of Abelmoschus manihot (L.) Medic., a single medicament of TCM for eliminating heat and dampness, has been widely used for the treatment of CKD in China. As a modern preparation extracted from AC, the Huangkui capsule has been approved by the China National Medical Products Administration (Z19990040). As reviewed by Sun et al., in approximately 2,000 CKD patients, AC showed to decrease proteinuria with stable kidney function during follow-up (Sun X. et al., 2022). Besides, after a comprehensive evaluation, the clinical value of the Huangkui capsule in treating CKD is class B and that for diabetic nephropathy (DN) and chronic nephritis is class A (Wang et al., 2022).

For the mechanistic studies, the Huangkui capsule has been shown to improve kidney inflammation and glomerular injury in ADR-induced nephropathy through inhibition of the p38 MAPK signaling pathway and AC inhibits ROS-ERK1/2-mediated NLRP3 inflammasome activation (Tu Y. et al., 2013; Li W. et al., 2019b). Recent research demonstrated that Huangkui capsule protection against renal fibrosis is dependent on the transient receptor potential channel 6 (TRPC6) pathway (Gu et al., 2020). In detail, the Huangkui capsule inhibited the expressions of a plethora of pro-inflammatory mediators in UUO mice by suppressing both canonical (Smad2/3) and noncanonical (MAPK) signaling pathways and the TRPC6/calcineurin A/nuclear factor of the activated T-cells signaling axis, which were possible through direct inhibition of TRPC6 activity in a heterologous expression system and indirect suppression of TRPC6 expression in both WT and TRPC6 knockout mice. Flavonoids, such as quercetin, isoquercitrin, hyperoside, gossypetin-8-O-β-D-glucuronide, and quercetin-3-O-glucoside, can inhibit the epithelial to mesenchymal transition in HK-2 cells (Cai et al., 2017). An et al. indicated that hyperoside pretreatment could significantly decrease albuminuria and prevent glomerular basement membrane (GBM) damage and oxidative stress in diabetes mellitus mice by decreasing podocyte heparanase expression (An et al., 2017). Liu et al. have revealed that quercetin ameliorated pyroptosis and injury in podocytes under HG conditions via adjusting METTL3-dependent m⁶A modification and regulating NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling (Liu et al., 2021).

Salviae Miltiorrhizae Radix et Rhizoma (SM, Danshen) is a CMM derived from the root of Salvia miltiorrhiza Bunge. It exhibits various pharmacological activities, such as antioxidant activities, inhibiting the expression of adhesion molecules, antiplatelet aggregation, inhibiting mast cell degranulation, and inhibiting apoptosis and is commonly used for promoting blood circulation and removing stasis (Han et al., 2008). Previous studies have demonstrated that the injection of SM preparation could significantly reduce blood urea nitrogen and creatinine and improve renal function, probably by its antioxidant effects (You et al., 2012; Lu et al., 2015).

In the study of metabonomics in rats with CRF, 54 metabolites could be regulated by SM ethanol extract and water extract (Cai et al., 2018). Moreover, the extract of SM mentioned above significantly regulates the expressions of alpha-smooth muscle actin (α-SMA), FN, E-cadherin, p-ERK, NADPH1 oxidase 1 (NOX1), NOX2, NOX4, TGF-β, TGF-βRI, TGF-βRII, Smad2, Smad3, and Smad7 in HK-2 cells, that is, modulating the NADPH oxidase/ROS/ERK and TGF-β/Smad signaling pathways. A recent study also showed that SM can significantly regulate intestinal bacteria in CRF rats.

Several components isolated from SM have been used to treat kidney disease. The pharmacodynamic effects of salvianolic acid A on 5/6Nx rats showed that it could reduce proteinuria, improve renal function, and reduce renal tubulointerstitial fibrosis. The mechanism is closely related to its antiinflammatory activities through inhibition of the activation of the NF-κB and p38 MAPK signaling pathways (Zhang HF. et al., 2018). In addition, salvianolic acid A treatment improved glucocorticoid resistance of podocytes, partly by modulating the soluble urokinase plasminogen activator receptor (suPAR)/uPAR-αvβ3 signaling pathway (Li X. et al., 2021).

In general, the effect of SM on promoting blood circulation and removing stasis may be related to the increase in renal blood flow, the decrease of the expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF), and the recovery of expression of neuronal nitric oxide synthase (nNOS) by magnesium lithospermate B (Lin et al., 2019). On the other hand, the effects of magnesium lithospermate B on attenuating renal function, renal fibrosis, and inflammation were investigated in 5/6Nx rats, showing a reduction in the expressions of FN, Col III, Col IV, TNF-α, and monocyte chemoattractant protein-1 (MCP-1), which are associated with inhibition of TF activation (Wang et al., 2019). In addition, other studies have shown that inhibition of the mitochondrial apoptosis pathway, i.e., inhibition of mitochondrial Bax accumulation and release of cytochrome c, may also be the renal protective mechanism of magnesium lithospermate B.

Poria (Fuling) is the dry sclerotium derived from Poria cocos (Schw.) Wolf (Polyporaceae). The inner parts of Poria are commonly known as “Fuling” in Chinese. Triterpenoids are the main components of Poria, and it exhibits a variety of biological activities such as antiinflammatory, immunomodulatory, antitumor, antioxidant, and antibacterial activities (Ríos, 2011; Miao et al., 2016; Li X. et al., 2019). In TCM, Poria has the effects of strengthening the spleen, promoting diuresis, and eliminating edema and is mainly used to treat the disorder of fluid metabolism. In the ADR-induced NS rat model, Poria extract could significantly improve the levels of urine protein, creatinine, serum total cholesterol, and IL-4 cytokine and attenuate kidney injury (Zan et al., 2017). Likewise, Poria treatment significantly improves the disturbance of water metabolism in puromycin aminonucleoside (PAN)-induced NS rats by inhibiting the expression of the epithelial sodium channel and AQP2 (Lee et al., 2014). An in vitro study also revealed that Poria treatment inhibited the activation of Sgk1 and decreased the expression of TonEBP mRNA (Lee et al., 2012). Its effect on AQP2 might be related to the inhibition of PKA and the decrease of the cAMP content.

Because of the obvious diuretic effect of ethanol extract from the surface layer of Poria, Zhao et al. focused on the protective effect of triterpenoids from the surface layer of Poria on CKD (Zhao et al., 2012). Several studies have demonstrated that triterpenoids isolated from the surface layer of Poria have beneficial renal protective effects on renal fibrosis. Poricoic acid A is the main triterpenoid in the surface layer of Poria. It exhibited the suppression of fibrosis by stimulating AMPK and inhibiting Smad3, preventing abnormal ECM accumulation and remodeling, and promoting the deactivation of fibroblasts (Chen D. Q. et al., 2020). Poricoic acid A combined with melatonin has a protective effect on acute kidney injury (AKI)-to-CKD transition. On the 14th day of renal ischemia-reperfusion injury in rats, poricoic acid A and melatonin treatment significantly inhibited the expressions of α-SMA, Col I, and FN. Inhibition of the TGF-β/Smad, Wnt/β-catenin, and NF-κB/Nrf2 pathways may be the mechanisms of poricoic acid A against renal fibrosis (Chen D. Q. et al., 2019a; Chen D. Q. et al., 2019b). Interestingly, poricoic acid A and melatonin could upregulate growth arrest-specific 6 (Gas6)/Axl signaling to reduce oxidative stress and inflammation in the AKI disease status and further downregulate Gas6/Axl signaling to attenuate renal fibrosis in the CKD disease status (Chen D. Q. et al., 2019b). This may reveal the bidirectional regulation of TCM to some extent. As reported previously, some new poricoic acids such as poricoic acid ZC, poricoic acid ZD, poricoic acid ZE, poricoic acid ZG, poricoic acid ZH, poricoic acid ZI, poricoic acid ZM, and poricoic acid ZP significantly attenuated renal fibrosis though the same mechanisms as poricoic acid A in vivo and in vitro (Wang et al., 2018a; Wang et al., 2018b; Chen L. et al., 2019; Wang M. et al., 2020a).

AR and Angelicae Sinensis Radix (AS, Danggui, the root of Angelica sinensis (Oliv.) Diels) are a common CMM pair used to treat kidney disease for years. The combination of the two CMMs is also known as Danggui Buxue Tang (DBT) with a weight ratio of 5:1. When the two CMMs are decocted together, it can help a better dissolution of effective components and the generation of new components. For example, with the increase in the ratio of AR, the dissolution of ferulic acid and ligustilide increased (Gao et al., 2007). Moreover, the results indicated that immunomodulatory, oesteotropic, and estrogenic effects were best exerted at the AR to AS ratio of 5:1.

According to what has been mentioned before, blood stasis always accompanies CKD. Studies have shown that the AR–AS pair also could promote recovery of blood flow, improve the microstructure dysfunction, enhance NO production via activating eNOS, and induce erythropoietin (EPO) mRNA expression and secretion of EPO protein (Meng et al., 2007; Gao et al., 2008). The mechanism acting on EPO might be related to increasing the expression of HIF-1α mRNA and promoting the protein translation of HIF-1α via a Raf/MEK/ERK-dependent signaling pathway (Zheng et al., 2010). However, some studies reported that the CMM pair could not reduce urinary protein (Lu et al., 1997; Li et al., 2000). It was suggested that the effect of the pair on preventing and treating glomerulosclerosis might not directly affect hemodynamics or filtration membrane permeability but is related to regulating lipid metabolism by upregulating the expression of hepatic LDL receptor gene and increasing the activities of serum lipoprotein and lecithin-cholesterol acyltransferase.

The immunomodulatory effect of DBT is reflected in the immune activation in human T-lymphocytes and macrophages. Specifically, DBT could significantly induce the proliferation of cultured T-lymphocytes and the secretion of IL-2 and p-ERK and increase the phagocytosis of cultured macrophages (Gao et al., 2006). This is consistent with the view of the TCM theory that TCM with beneficial Qi participates in improving the defense ability of the immune system.

The antirenal fibrosis effect of the AR–AS pair has been extensively studied, and its mechanism mainly includes downregulating the expressions of TGF-β1 and connective tissue growth factor (CTGF), preventing the activation of c-Jun N-terminal kinase (JNK)-MAPK, and inhibiting the expression of NLRP3 inflammasomes (Huang et al., 2003; Wang et al., 2003; Wang et al., 2016). Integrated lipidomics, transcriptomics, and network pharmacology techniques were also used to reveal the mechanisms of DBT (Sun L. et al., 2022). Just as the AR–AS pair, astragaloside IV and ferulic acid have been proved to improve renal tubulointerstitial fibrosis and protect the function of vascular endothelium, which may be the pharmacological material basis of the pairs (Meng et al., 2011; Yin et al., 2014).

Sanqi oral solution (SQ), composed of AR and Notoginseng Radix et Rhizoma (Sanqi, the roots and rhizomes of Panax notoginseng (Burk.) F.H.Chen), is a patented hospital preparation, which was designed and developed by the famous nephrologist Nizhi Yang (Tian et al., 2019). Notoginseng Radix et Rhizoma is an important CMM related to Blood, with the features of promoting blood circulation, removing blood stasis, inducing blood clotting, and alleviating pain (Lei and Chiou, 1986; Cicero et al., 2003). Based on the efficacy of AR in invigorating healthy Qi and Notoginseng Radix et Rhizoma in eliminating pathogenic factors, the combination has been used for clinically treating CKD for over 20 years with good curative effect. In a rat model of membranous nephropathy, SQ successfully reduced proteinuria, increased serum albumin, and restored podocyte injury, which was associated with the inhibition of the NF-κB signaling pathway (Tian et al., 2019). Moreover, SQ could also exert renoprotective effects on renal I/R injury by inhibiting apoptosis and enhancing autophagy, combined with regulating ERK/mTOR pathways (Tian et al., 2020).

Since both have a distinct ability to regulate T-lymphocyte subsets (Yang Z. et al., 2007; Wan et al., 2013), SQ indicated regulation of lymphocyte subsets and reduction of macrophages infiltration in renal tissues (Wei et al., 2013). In vitro experiments showed that inhibition of mesangial cell proliferation by SQ may be related to inhibition of IL-β1 secretion and gene expression and promotion of IL-10 secretion and gene expression (Yang N. Z. et al., 2007). Thus, it was considered that mesangial cells were important target cells of SQ in preventing and treating chronic nephritis and delaying CKD progression.

Zhenwu Tang (ZWT) is a classical CMM formula originally from an ancient medicinal book “Treatise on Febrile Diseases.” It is composed of Aconiti Lateralis Radix Praeparata (Fuzi), Poria, Atractylodis Macrocephalae Rhizoma (Baizhu), Paeoniae Radix Alba (Baishao), and Zingiberis Rhizoma Recens (Shengjiang). ZWT has been widely used as a remedy for CKD, relieving the clinical manifestations of edema, dyuria, and oliguria through warming Kidney/Spleen Yang to promote diuresis. Clinical studies have indicated that ZWT improved the clinical curative effect, alleviated the scores of symptoms such as the limb chills, decreased proteinuria, and blood lipids, improved renal function, and alleviated serum levels of IL-8, IL-13, CTGF, and hepatocyte growth factor (Tian et al., 2017).

The warming Yang effect of ZWT is related to antiinflammation and antifibrosis. In improving the inflammatory response, ZWT significantly reduced the serum levels of AGEs and decreased the release of inflammatory mediators (TNF-α, IL-1β, and IL-6) (Wu J. et al., 2016). The mechanism is closely related to upregulating the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein and IκB mRNA, downregulating the expressions of RAGE1, p-p65, and p-IκBα, and inhibiting the activation of the NF-κB/NLRP3 pathway (Wu J. et al., 2016; Liu et al., 2018; Liu et al., 2019; Li H. et al., 2020). Interestingly, ZWT blocked the activation of NLRP3 inflammasome and inhibited IL-1β and caspase-1, which is closely related to dramatically promoting the secretion of exosomes in renal tissues (Li H. et al., 2020). In ameliorating renal fibrosis, ZWT significantly inhibited renal mRNA and protein expression of Wnt4 and its downstream genes β-catenin and Axin (La et al., 2018). In addition, ZWT could ameliorate streptozotocin-induced proteinuria and podocyte injury by suppressing the hyperactivity of the renal renin–angiotensin system and modulating the slit diaphragm (Cai et al., 2010).

The diuretic effect of ZWT was tested in NS rats and kidney-Yang-deficient rats. It turns out that ZWT could attenuate ADR-induced renal edema, which was related to the downregulation of miR-92b expression and upregulation of AQP2 expression (Liang et al., 2019). The rat model of kidney-Yang deficiency was made by injecting hydrocortisone acetate. The results showed that ZWT could adjust the osmotic pressure set point, increase the secretion of plasma aldosterone, and reduce the secretion of antidiuretic hormone, thereby promoting the excretion of Na⁺ and K⁺ and keeping the balance of water and the electrolyte content (Liang et al., 1999).

According to the characteristics of chronic nephritis patients, such as kidney deficiency, spontaneous sweating, and susceptibility to exogenous evil, Zhan and Dai put forward the treatment of invigorating Qi and consolidating the superficial resistance (supportive treatment); on the other hand, patients with chronic nephritis are often combined with the exogenous wind-heat syndromes, damp-heat syndromes, and blood stasis syndromes, which should be treated by clearing heat and removing dampness, as well as promoting blood circulation and removing blood stasis (Zhan et al., 2003). Therefore, YiQi QingRe Gao (YQQRG), a CMM formula, was developed and has been applied in Guang’anmen Hospital for more than two decades.

As an empirical formula, YQQRG is composed of 12 CMMs. The prescription takes AR as the monarch medicine, combined with Atractylodis Macrocephalae Rhizoma and Saposhnikoviae Radix (Fangfeng), which is the composition of Yupingfeng San, to invigorate Qi, consolidate the superficial resistance, and eliminate evil or toxin in the outside; Lonicerae Japonicae Flos (Jinyinhua), Forsythiae Fructus (Lianqiao), Duchesneae Indicae (Shemei), Hedyotis Diffusa (Baihuasheshecao), and Imperatae Rhizoma (Baimaogen) can clear heat and remove dampness in the inside; Poria, Alismatis Rhizoma (Zexie), Leonuri Herba (Yimucao), and Dioscoreae Nipponica Rhizoma (Chuanshanlong) can promote blood circulation and diuresis and guide the evil of dampness, heat, and turbid to go out. In a previous clinical study, it was found that YQQRG could significantly reduce TCM symptom scores of patients with chronic glomerulonephritis, effectively decrease 24 h urine protein, and improve plasma albumin and immunoglobulin (Ig) G, IgA levels, and the effective rate of treatment was 90% (Zhan and Dai, 2003).

Animal experiments have shown that the formula inhibits the expression levels of inflammatory factors such as TNF-α, TNFR1, IL-1β, and MCP-1 in renal tubulointerstitium, downregulates the expression level of caspase-3 in the renal tissues, and upregulates the expression level of Bcl-2 to exert an antiapoptotic effect (Wen et al., 2015). In maintaining the glomerular filtration barrier, YQQRG could upregulate the expressions of podocyte-related proteins such as nephrin, podocin, and CD2AP in kidney tissues of rats with PAN nephropathy and inhibit their mRNA level in feedback (Zhan et al., 2014). Moreover, the main molecular chaperones of endoplasmic reticulum stress, such as glucose-regulated protein 78 (GRP78) and GRP94, and cytoskeletal regulatory proteins, such as α-actin-4, synaptopodin, desmin, and uPAR, were all inhibited by YQQRG (Yang et al., 2016a). An in vitro experiment indicated that treatment with serum-containing YQQRG inhibited LPS-induced rat mesangial cell proliferation, downregulated mRNA and protein levels of Wnt4 and TGF-β1, and reduced the aggregation of the mesangial matrix (Yang et al., 2016b). Dioscin might be the key component in YQQRG to exert the above effects.

Sun et al. consider that the pathogenesis of CKD is the deficiency of kidney collaterals caused by wind pathogen, mixed with blood stasis and dampness heat (Sun et al., 2008). Therefore, Qufeng Tongluo Recipe (QTR) was developed as an empirical formula. This prescription selects Zaocys (Wushaoshe) as the monarch medicine and Sinomenii Caulis (Qingfengteng) and Piperis Kadsurae Caulis (Haifengteng) as the minister medicines, and it takes the properties of insects’ moving and dredging collaterals (dredging the channel) and vines’ winding and spreading to achieve the effects of dispelling wind, eliminating dampness, and dredging collaterals. This is assisted by AR to invigorate Qi, dredge collaterals, promote diuresis, and reduce swelling and Taxilli Herba (Sangjisheng) to nourish the liver and kidneys and dispel wind and dampness. Rehmanniae Radix (Dihuang) is used as the courier to nourish Yin and generate fluid, which not only prevents the dryness of the herbs but also leads the herbs straight into the kidney meridian. All the CMMs are combined to achieve the effects of expelling wind, dredging collaterals, invigorating Qi, and tonifying the kidneys. In the clinical treatment of DN-complicated CRF, QTR showed the effect of reducing blood lipid, improving renal function, and reducing serum TGF-β1 level (Sun et al., 2004).

Animal experiments showed that QTR could improve kidney injury by regulating the expressions of cytoskeletal proteins (synaptopodin, α-actinin-4, and desmin) and slit diaphragm proteins (CD2AP) (Wang Z. et al., 2014a; Wang Z. et al., 2014b), increasing the anion site and HSPG expression in the GBM to protect the basement membrane damage (Sun et al., 2010; Ma et al., 2011). In addition to improving the glomerular filtration function, QTR could also inhibit the accumulation of ECM by reducing the expressions of Col IV, fibronectin, and laminin in kidney tissues and downregulate the expression of renal fibrosis-related proteins α-SMA and vimentin, thus playing an antifibrosis role (Wu et al., 2008; Ma et al., 2019). The results in vitro indicated that the inhibition of QTR on the proliferation of mesangial cells was related to the regulation of the cell cycle process and the inhibition of TGF expression (Sun et al., 2008; Wu et al., 2013). The regulation of cell cycle progression is reflected in the reduction of the protein and mRNA expression levels of cylinD1, cyclin-dependent kinase 2 (CDK2), and p21 and the increase of p27.

Uremic clearance granule (UCG) is the first CMM preparation in the field of treating early and mid-stage CRF. It contains 16 kinds of CMMs and exerts the effects of removing turbidity by catharsis, invigorating the spleen, dispelling dampness, promoting blood circulation, and removing blood stasis in TCM. In some small-scale clinical trials, UCG is effective in reducing serum creatinine levels, improving renal blood flow, and improving the state of microinflammation (Wu et al., 2004). In a multicenter clinical trial involving 300 patients with stage 3b-4 CKD, UCG significantly reduced serum creatinine, delayed the reduction of estimated GFR, and delayed the progression of CKD at 24 and 48 weeks after administration (Zheng et al., 2017; Zheng et al., 2019). Subsequently, it was recommended in the clinical application guide of Chinese patent medicine in the treatment of CKD stage 3–5 (nondialysis), version 2020 (The Standardization Project Team of The Clinical Application Guide of Chinese Patent Medicine in The Treatment of Dominant Diseases, 2021).

In the clinical application of UCG in the recent 30 years, its mechanism of action has been comprehensively studied. In terms of inhibiting the tubular epithelial to mesenchymal transition, UCG could significantly increase E-cadherin expression and suppress vimentin and α-SMA expression both in vivo and in vitro (Lu et al., 2013). On the effect of oxidative stress, UCG showed the effect of restoring mitochondrial regeneration (shown as restoring the expression of mitochondrial transcription factor A and peroxisome proliferator-activated receptor γ co-activator-1α), improving mitochondrial structure and function, and further inhibiting the apoptosis of tubular epithelial cells, which is related to the inhibition of the TGF-β1-ROS-MAPK pathway (Xu et al., 2015). Focusing on the role of TGF-β1 expression in renal fibrosis, it was proved that UCG downregulated the protein expressions of TGF-β1, TGF-β receptor I, receptor II and Smad2/3, and upregulated the protein expressions of SnoN and Smad7 (Huang et al., 2014; Wu W. et al., 2016). Further experiments revealed that regulation of TGF-β1 transcription and translation by UCG was due to induction of remethylation of the TGF-β1 promoter in CRF rats (Miao et al., 2010). In addition, the effect of UCG in correcting the imbalance of MMP-2/TIMP-1 in model rats has also been elucidated (Huang et al., 2014).

With the continuous research on UCG, the original prescription was simplified and recombined, and finally the second-generation product Huang Gan formula (HGF) was formed. HGF is composed of RRR, Zingiberis Rhizoma, Bupleuri Radix, Glycyrrhizae Radix et Rhizoma, and Aconiti Lateralis Radix Preparata. It can significantly improve the renal function of rats in CRF models, reduce oxidative stress injury, and delay the development of renal fibrosis (Xiao et al., 2014). At present, the mechanism of HGF is relatively limited. Mo et al. showed that HGF plays an antiinterstitial fibrosis role by inhibiting the Wnt/β-catenin pathway through depressing protein and mRNA expressions of Wnt1, β-catenin, transcription factor 4, and FN (Mo et al., 2015). Similar to UCG, HGF also shows the effect of antioxidative stress. The research indicated that the effect of HGF in advanced oxidation protein products-induced human mesangial cells was related to the inhibition of the JAK2/STAT3 pathway and the regulation of the balance of the advanced glycation end products receptor (Deng et al., 2017).

The above systematically summarizes the research strategies and mechanisms of TCM in treating CKD (the relevant mechanisms are summarized in Figure 2). At present, many small clinical studies have been published in Chinese journals to support the kidney protective effect of TCM on CKD, and there are many systematic reviews and meta-analyses. With the gradual deepening of research, more and more large-scale well-designed randomized controlled trials have been carried out. Table 2 summarizes the large-sample clinical trials on the prevention and treatment of various CKD with TCM in recent years, which further supports the effectiveness of TCM.