A traditional Chinese medicine composition for treating chronic kidney disease and its application

Abstract

This invention belongs to the field of traditional Chinese medicine, specifically relating to a traditional Chinese medicine composition for treating chronic kidney disease and its application. Its main active ingredients, by weight, include: Astragalus membranaceus 20-35 parts, Cuscuta chinensis 10-25 parts, Codonopsis pilosula 10-25 parts, Atractylodes macrocephala 10-20 parts, Poria cocos 10-25 parts, Dioscorea opposita 10-25 parts, Salvia miltiorrhiza 10-25 parts, and Coix lacryma-jobi 10-30 parts. Real-world cohort studies have shown that this traditional Chinese medicine composition for treating chronic kidney disease can significantly improve the survival rate of patients with chronic kidney disease, delay the decline in glomerular filtration rate, effectively reduce the risk of kidney disease progression, and has good safety.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for treating chronic kidney disease and application thereof. BACKGROUND

[0002] Chronic kidney disease (CKD) is a disease that affects the health of the kidney structure or function abnormality for more than 3 months, and the main manifestations are the decrease of estimated glomerular filtration rate (eGFR), the retention of metabolic products, the imbalance of water, electrolyte and acid-base. In terms of traditional Chinese medicine, there is no word of "chronic kidney failure" or "chronic kidney disease" in ancient books, but the disease can be attributed to "guan ge", "long closed", "edema", "drowning poison", "kidney labor" and other categories. Modern traditional Chinese medicine unifies it as chronic kidney failure, which refers to the gradual decline of kidney qi, the failure of qi transformation, the abnormality of opening and closing, the retention of dampness and poison, and the main symptoms of the disease are oliguria or anuria, or the main symptoms are mental debilitation, pale complexion, nausea, poor appetite, and edema of limbs. With the aging of the population and the change of disease spectrum, the prevalence of CKD is increasing year by year, and the disease is insidious and continuously progresses, with high mortality and disability, which has become a global public health problem that seriously endangers human health.

[0003] At present, the western medicine treatment of CKD includes controlling the primary disease, changing the lifestyle (including low salt, low fat, limiting protein diet), controlling the risk factors such as hypertension and hyperglycemia, inhibiting the overactivation of renin-angiotensin system, and preventing and treating complications. However, these measures cannot completely control the progression of renal insufficiency, especially for patients with CKD 3-5, there is still lack of effective measures to delay the deterioration of renal function. Traditional Chinese medicine emphasizes syndrome differentiation and treatment, and the past clinical practice shows that traditional Chinese medicine has unique advantages in improving the clinical symptoms of CKD patients, improving renal function, preventing and delaying the progression of CKD.

[0004] The applicant previously developed a traditional Chinese medicine preparation for treating chronic kidney disease (publication number: CN102579894A), and the weight ratio of the raw materials is: 20-35 parts of radix notoginseng, 13-25 parts of radix codonopsis, 8-20 parts of rhizoma atractylodis, 10-25 parts of poria cocos, 10-25 parts of radix rehmanniae, 10-25 parts of radix falcaliae, 10-25 parts of semen lagenariae, 10-30 parts of radix salviae miltiorrhizae, and 8-25 parts of radix salviae miltiorrhizae. The traditional Chinese medicine preparation has the effects of tonifying the spleen and nourishing the kidney, and has certain therapeutic effect on chronic kidney disease. However, the traditional Chinese medicine preparation is heavy in tonifying the spleen and light in nourishing the kidney, and emphasizes the entry of the spleen into the kidney, and the therapeutic effect in delaying the decrease of eGFR of patients with chronic kidney disease, delaying the progression of kidney disease and improving the survival rate of patients still needs to be further improved. SUMMARY

[0005] The first objective of this invention is to provide a traditional Chinese medicine composition for treating chronic kidney disease, and the second objective of this invention is to provide the application of this traditional Chinese medicine composition.

[0006] According to a first aspect of the present invention, a traditional Chinese medicine composition for treating chronic kidney disease is provided, the main active ingredients comprising, by weight: 20-35 parts of Astragalus membranaceus, 10-25 parts of Cuscuta chinensis, 10-25 parts of Codonopsis pilosula, 10-20 parts of Atractylodes macrocephala, 10-25 parts of Poria cocos, 10-25 parts of Dioscorea opposita, 10-25 parts of Salvia miltiorrhiza, and 10-30 parts of Coix lacryma-jobi.

[0007] This invention posits that chronic kidney disease (CKD) is characterized by involvement of both the spleen and kidneys, with spleen and kidney deficiency being the fundamental pathogenesis of CKD stages 3-5. The spleen and kidneys pathologically influence each other, manifesting as: ① Spleen deficiency leading to water retention. Weak spleen qi fails to properly transport fluids from the stomach, resulting in water retention. Over time, this can damage kidney yang, leading to insufficient kidney yang and inability to warm the middle jiao (middle burner), further damaging spleen yang. The two mutually exacerbate each other; spleen and kidney yang deficiency, along with impaired qi transformation, manifests as edema, lower back pain, and pale complexion. ② Spleen deficiency leading to impaired control. The spleen plays a crucial role in controlling and storing essence, supporting the kidney's essence storage. ③ Spleen deficiency leading to weakened exterior defense. Spleen deficiency results in insufficient production of defensive qi, loose pores, and weakened resistance to pathogens, making the body susceptible to external pathogens. From the perspective of the pathogenesis of kidney diseases, most are immune-mediated diseases, meaning that spleen qi deficiency and loose pores lead to immune dysfunction, inducing abnormal immune responses and further contributing to disease development. ④ Spleen deficiency leading to impaired blood control. Spleen deficiency primarily means the spleen is unable to properly control the flow of blood within the meridians, resulting in blood spilling outside the vessels. Clinically, this can manifest as hematuria in kidney disease. ⑤ Spleen deficiency leading to essence depletion. Spleen deficiency impairs its function of transporting and transforming nutrients, failing to replenish kidney essence, leading to kidney essence deficiency. Clinically, this manifests as proteinuria, edema, renal anemia, renal osteodystrophy, and many other symptoms associated with kidney disease, often accompanied by fatigue, weakness in the lower back and knees, hair loss, loose teeth, decreased libido, abdominal distension, poor appetite, and loose stools.

[0008] This invention utilizes the principles of tonifying the spleen and kidneys, eliminating dampness and turbidity, and promoting blood circulation and unblocking collaterals as treatment methods. In the herbal composition for treating chronic kidney disease, Astragalus membranaceus and Cuscuta chinensis are the principal herbs, tonifying spleen qi, warming spleen yang, and tonifying kidney qi; Codonopsis pilosula, Atractylodes macrocephala, Poria cocos, and Dioscorea opposita are the assistant herbs, tonifying the spleen and kidneys; Coix lacryma-jobi strengthens the spleen, eliminates dampness and turbidity, and Salvia miltiorrhiza promotes blood circulation and unblocks collaterals as adjuvant herbs. The entire formula works synergistically to tonify the spleen and kidneys, eliminate dampness and turbidity, and promote blood circulation and unblock collaterals, primarily supporting the body's vital energy while also addressing pathogenic factors. This invention emphasizes treating the kidneys through the spleen and benefiting the spleen through the kidneys, forming a complete and virtuous cycle of qi movement, thus exhibiting excellent therapeutic effects in delaying the progression of chronic kidney disease. This invention is applicable to stages 3-5 of chronic kidney disease, characterized by fatigue, shortness of breath, reluctance to speak, lower back and knee pain, heaviness in the limbs, poor appetite, loose stools, nausea and vomiting, and a pale, swollen, or dark tongue, diagnosed by traditional Chinese medicine as spleen and kidney qi deficiency with dampness and turbidity obstruction.

[0009] The raw materials for this formula come from the following sources:

[0010] Astragalus: The dried root of *Astragalus membranaceus* (Fisch.) Bge. var. *mongholicus* (Bge.) Hsiao or *Astragalus membranaceus* (Fisch.) Bge. (Fabaceae family). It enters the Lung and Spleen meridians. It is sweet and warm in nature.

[0011] Cuscuta seed: The dried, mature seed of Cuscuta chinensis Lam., a plant in the Convolvulaceae family. It enters the liver, kidney, and spleen meridians. It is sweet and warm in nature.

[0012] Codonopsis pilosula: The dried root of Codonopsis pilosula (Franch.) Nannf., Codonopsis pilosula Nannf. var. modesta (Nannf.) L. Shen, or Codonopsis tangshen Oliv., all belonging to the Campanulaceae family. It enters the Spleen and Lung meridians. It is sweet and neutral in nature.

[0013] Atractylodes macrocephala: The dried rhizome of Atractylodes macrocephala Koidz., a plant in the Asteraceae family. It enters the spleen and stomach meridians. It is bitter, sweet, and warm in nature.

[0014] Poria: The dried sclerotium of the fungus *Poria cocos* (Schw.) Wolf (family Polyporaceae). It enters the heart, lung, spleen, and kidney meridians. It is sweet, bland, and neutral in nature.

[0015] Yam: The dried rhizome of Dioscorea opposita Thunb., a plant in the Dioscoreaceae family. It enters the spleen, lung, and kidney meridians. It is sweet and neutral in nature.

[0016] Danshen: The dried root and rhizome of *Salvia miltiorrhiza* Bunge., a plant in the Lamiaceae family. It enters the Heart and Liver meridians. It is bitter and slightly cold in nature.

[0017] Job's tears: The dried, mature seed kernel of *Coix lacryma-jobi* L. var. *ma-yuen* (Roman.) Stapf, a plant of the Poaceae family. It enters the spleen, stomach, and lung meridians. It is sweet, bland, and cool in nature.

[0018] In some embodiments, the main active ingredients, by weight, include: 30 parts Astragalus membranaceus, 25 parts Cuscuta chinensis, 15 parts Codonopsis pilosula, 15 parts Atractylodes macrocephala, 15 parts Poria cocos, 15 parts Dioscorea opposita, 10 parts Salvia miltiorrhiza, and 10 parts Coix lacryma-jobi.

[0019] In some implementations, the yam is Huai yam. Huai yam is a specialty of Jiaozuo City, Henan Province, and is a Chinese national geographical indication product. Huai yam is listed as a superior-grade medicine in the "Shennong's Classic of Materia Medica," indicating its higher medicinal value.

[0020] In some embodiments, medically acceptable excipients are also included. Specifically, the excipients used are carriers or excipients commonly used in the art, including but not limited to starch, lactose, glucose, sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose, malt, gelatin, polyols (such as propylene glycol, glycerol, mannitol), tablets, etc., to help improve the stability or activity of the drug, or to produce an acceptable taste or odor when taken orally.

[0021] In some embodiments, the dosage form of the traditional Chinese medicine composition is an oral liquid, tablet, ointment, granule, capsule, decoction, powder, or pill. This facilitates clinical administration.

[0022] According to a second aspect of the present invention, the use of the above-described traditional Chinese medicine composition for treating chronic kidney disease in the preparation of a medicament for treating chronic kidney disease is provided.

[0023] In some implementations, chronic kidney disease is stage 3-5 chronic kidney disease.

[0024] According to a third aspect of the present invention, the above-described traditional Chinese medicine composition for treating chronic kidney disease is provided for use in the preparation of a medicament for delaying the progression of chronic kidney disease and / or delaying the decline in glomerular filtration rate and / or improving the survival rate of patients with chronic kidney disease.

[0025] In some implementations, chronic kidney disease is stage 3-5 chronic kidney disease.

[0026] When the traditional Chinese medicine composition for treating chronic kidney disease of the present invention is a decoction, the dosage of one dose is approximately 100-150 mL, with 150 mL being the usual dosage and 100 mL for patients with edema. One dose refers to the volume of filtrate obtained after decocting the raw materials of the traditional Chinese medicine composition for treating chronic kidney disease in the prescribed dosage for one use (e.g., 30g Astragalus membranaceus, 25g Cuscuta chinensis, 15g Codonopsis pilosula, 15g Atractylodes macrocephala, 15g Poria cocos, 15g Dioscorea opposita, 10g Salvia miltiorrhiza, and 10g Coix lacryma-jobi).

[0027] Compared with the prior art, the beneficial effects of the present invention include:

[0028] Real-world cohort studies have shown that the traditional Chinese medicine composition for treating chronic kidney disease of the present invention can significantly improve the survival rate of patients with chronic kidney disease, delay the decline in glomerular filtration rate, effectively reduce the risk of kidney disease progression, and has good safety. Attached Figure Description

[0029] Figure 1This is a flowchart of case screening in a real-world cohort study according to the present invention.

[0030] Figure 2 These are the Kaplan-Meier curves of the spleen-tonifying and kidney-benefiting group and the astragalus-sugar spleen-tonifying and kidney-strengthening group in the real-world cohort study of this invention. Detailed Implementation

[0031] The present invention will be further described in detail below with reference to specific embodiments. Unless otherwise specified, all raw materials used in the present invention are commercially available.

[0032] Example 1

[0033] The traditional Chinese medicine decoction for treating chronic kidney disease in this embodiment is prepared from the following components: Astragalus membranaceus 30g, Cuscuta chinensis 25g, Codonopsis pilosula 15g, Atractylodes macrocephala 15g, Poria cocos 15g, Dioscorea opposita 15g, Salvia miltiorrhiza 10g, and Coix lacryma-jobi 10g.

[0034] Its preparation method includes the following steps:

[0035] After crushing each raw material separately, mix them together and add 300 parts by weight of water. Soak for 30 minutes, boil and then simmer for 30 minutes. Filter to obtain the first filtrate and the residue. Add 250 parts by weight of water to the residue, continue to boil and simmer for 30 minutes. Filter to obtain the second filtrate. Mix the first filtrate and the second filtrate to obtain the final product.

[0036] The traditional Chinese medicine decoction prepared in this embodiment is a single dose, which is approximately 150 mL.

[0037] Example 2

[0038] The traditional Chinese medicine decoction for treating chronic kidney disease in this embodiment is prepared from the following components: Astragalus membranaceus 30g, Cuscuta chinensis 25g, Codonopsis pilosula 10g, Atractylodes macrocephala 10g, Poria cocos 10g, Dioscorea opposita 10g, Salvia miltiorrhiza 15g, and Coix lacryma-jobi 15g.

[0039] Its preparation method is the same as that of Example 1.

[0040] Example 3

[0041] The traditional Chinese medicine decoction for treating chronic kidney disease in this embodiment is prepared from the following components: Astragalus membranaceus 20g, Cuscuta chinensis 10g, Codonopsis pilosula 10g, Atractylodes macrocephala 10g, Poria cocos 10g, Dioscorea opposita 10g, Salvia miltiorrhiza 10g, and Coix lacryma-jobi 10g.

[0042] Its preparation method is the same as that of Example 1.

[0043] Example 4

[0044] The traditional Chinese medicine decoction for treating chronic kidney disease in this embodiment is prepared from the following components: Astragalus membranaceus 35g, Cuscuta chinensis 25g, Codonopsis pilosula 25g, Atractylodes macrocephala 20g, Poria cocos 25g, Dioscorea opposita 25g, Salvia miltiorrhiza 25g, and Coix lacryma-jobi 30g.

[0045] Its preparation method is the same as that of Example 1.

[0046] Comparative Example 1

[0047] The traditional Chinese medicine preparation for treating chronic kidney disease in this comparative example (hereinafter referred to as the "Spleen-Tonifying and Kidney-Nourishing Formula") is prepared from the following components: Astragalus membranaceus 30g, Codonopsis pilosula 20g, Atractylodes macrocephala 15g, Poria cocos 15g, Dioscorea opposita 15g, Polygonum multiflorum 15g, Cuscuta chinensis 15g, Coix lacryma-jobi 20g, and Salvia miltiorrhiza 15g.

[0048] The preparation method is the same as that disclosed in Example 1 of the prior application (publication number: CN102579894A).

[0049] To illustrate the therapeutic effect of the traditional Chinese medicine composition for treating chronic kidney disease (hereinafter referred to as Qi Tu Bu Pi Gu Shen Fang) of the present invention on chronic kidney disease, a real-world cohort study was conducted.

[0050] I. Relevant Standards

[0051] 1. Based on the 2012 KDIGO Clinical Practice Guidelines for the Clinical Management of Chronic Kidney Disease diagnostic criteria, at least one of the following indicators must be met for more than 3 months:

[0052] (1) Kidney damage lasting ≥3 months, with or without a decrease in glomerular filtration rate (eGFR). Kidney damage refers to structural or functional abnormalities of the kidney, manifested as one of the following: abnormal kidney pathological morphology; or presence of indicators of kidney damage, including abnormal blood or urine components or abnormal kidney imaging examinations.

[0053] (2) eGFR < 60 mL / min / 1.73 m for 3 consecutive months 2 There may be or may not be signs of kidney damage.

[0054] 2. Glomerular filtration rate was estimated using the CKD-EPI formula, and staging was performed according to the staging definitions in the 2012 KDIGO Clinical Practice Guidelines for the Management of Chronic Kidney Disease:

[0055] Stage 1: Kidney injury markers (+), normal or increased eGFR, eGFR ≥ 90 mL / min;

[0056] Stage 2: Kidney injury markers (+), mild decrease in eGFR, eGFR 60–89.9 mL / min;

[0057] Phase 3: Moderate decrease in eGFR, eGFR 30–59.9 mL / min;

[0058] Phase 4: eGFR severely decreased, eGFR 15–29.9 mL / min;

[0059] Stage 5: Renal failure, eGFR < 15 mL / min (or dialysis).

[0060] 3. Inclusion criteria:

[0061] (1) Patients who received treatment at Guangdong Provincial Hospital of Traditional Chinese Medicine between 2016 and 2023;

[0062] (2) Baseline Scr levels were estimated using the CKD-EPI equation, and patients were diagnosed with CKD stage 3-5 according to the KDIGO guidelines.

[0063] (3) Age 18 to 80 years old.

[0064] 4. Exclusion criteria:

[0065] The patient has already undergone renal replacement therapy (dialysis or kidney transplantation); survival time is less than 3 months.

[0066] II. Source of Cases:

[0067] The Guangdong Provincial Hospital of Traditional Chinese Medicine's case database and chronic disease management nephrology database were searched using keywords such as "kidney disease," "kidney failure," "nephritis," "proteinuria," or "hematuria." Patients diagnosed with CKD stages 3-5 who visited the hospital between 2016 and September 2023 were included (calculated using the CKD-EPI formula).

[0068] III. Grouping:

[0069] Patients were grouped according to the Chinese medicine prescriptions they took: patients who received conventional Western medicine treatment combined with the Chinese medicine decoction for treating chronic kidney disease in Example 1 were included in the Qi Tu Bu Pi Gu Shen Fang group (hereinafter referred to as the Qi Tu Bu Pi Gu Shen group), and patients who received conventional Western medicine treatment combined with the Chinese medicine preparation for treating chronic kidney disease in Comparative Example 1 were included in the Bu Pi Yi Shen Fang group (hereinafter referred to as the Bu Pi Yi Shen group).

[0070] IV. Data Collection

[0071] Data collection includes demographic data, disease diagnosis and medication data, and laboratory indicators, specifically:

[0072] Demographic data includes gender and age.

[0073] Disease diagnosis and medication information includes the diagnosis of the primary disease, whether the patient has hypertension, diabetes, hyperlipidemia, hyperuricemia, anemia, and whether sodium bicarbonate, ketoacid tablets, calcium supplements, traditional Chinese medicine for clearing turbidity, traditional Chinese medicine for tonifying, and other specialized traditional Chinese medicines. The diagnosis of the primary disease includes primary glomerular diseases, hypertensive nephropathy, diabetic nephropathy, other secondary kidney diseases (including infectious or autoimmune-related nephropathy, obstructive nephropathy, uric acid-related nephropathy, pyelonephritis), and diseases of unknown primary origin. Traditional Chinese medicine for clearing turbidity includes Shen Shuai Ning tablets, Hai Kun Shen Xi capsules, Uremic Kang granules, and Rhubarb Turbidity-Clearing Capsules. Traditional Chinese medicine for tonifying includes Jin Shui Bao, Bai Ling capsules, and San Qi oral liquid. Other traditional Chinese medicines include Compound Nephritis Tablets, Nephritis Recovery Tablets, Huang Kui Capsules, Nephritis Relief Tablets, and Yi Shen Hua Shi Granules.

[0074] Laboratory parameters include creatinine (SCr), hemoglobin (Hb), albumin (ALB), blood urea nitrogen (Urea), total carbon dioxide (TCO2), and potassium ions (K). + ), calcium ions (Ca 2+ Phosphate (P) ions, sodium (Na) ions + The following parameters were measured: low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (Glu), and urine protein-to-creatinine ratio (PCR). The patient's eGFR was then calculated using the EPI formula.

[0075] V. Statistical Methods:

[0076] Statistical analysis was performed using RStudio 4.3.0. Normally distributed continuous data were described using mean ± standard deviation (Mean ± SD), and the two-sample t-test was used for comparisons between groups. Non-normally distributed continuous data were described using median (1 / 4 digit, 3 / 4 digit) (M(P25,P75)), and the rank-sum test was used for comparisons between groups. Categorical data were described using proportions or percentages (%), and the chi-square test was used for comparisons between groups. Baseline data preprocessing was performed first, removing variables with a missing value rate greater than 40% and samples with a missing value rate greater than 20%. Outliers in continuous variables were truncated, and missing values ​​were imputed using the K-nearest neighbor algorithm. A 1:1 nearest neighbor propensity score was used to balance covariates between groups to reduce selection bias. Kaplan-Meier curves using the Log-rank test were used to compare the survival rates of the two groups upon reaching the endpoint event. Using the occurrence of a composite outcome and patient survival time as dependent variables and other potential factors as independent variables, univariate Cox regression was performed. Factors with p < 0.05 were included to construct a multivariate Cox regression model using a backward stepwise regression method. The optimal model was selected based on the Akaike Information Criterion (AIC). The Schoenfeld residual trend test was used to examine whether the variable and survival time in each model met the PH hypothesis. Results are expressed as hazard ratios (HR) and 95% confidence intervals (95% CI). All tests were two-tailed, and p < 0.05 was considered statistically significant.

[0077] VI. Results

[0078] 1. Case screening

[0079] As of September 2023, the Guangdong Provincial Hospital of Traditional Chinese Medicine's Chronic Kidney Disease Database contained 28,932 kidney disease patients, of whom 16,395 met the criteria for treatment between 2016 and 2023. After excluding 15,860 patients who did not meet the inclusion and exclusion criteria, 535 patients were selected, including 439 in the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Group and 96 in the Spleen-Tonifying and Kidney-Benefiting Group. The Guangdong Provincial Hospital of Traditional Chinese Medicine's SMP-CKD Database contained 2,577 kidney disease patients, of whom 1,372 met the criteria for treatment between 2016 and 2023. After excluding 1,239 patients who did not meet the inclusion and exclusion criteria, 133 patients were selected, including 125 in the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Group and 8 in the Spleen-Tonifying and Kidney-Benefiting Group. Finally, 668 patients were included in the analysis, including 564 in the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Group and 104 in the Spleen-Tonifying and Kidney-Benefiting Group. The case screening flowchart is shown below. Figure 1 As shown.

[0080] 2. Baseline characteristics

[0081] From the final 668 included patients, PCR variables with a deletion rate >40% were removed, and samples with a deletion rate >20% were also removed, leaving 640 patients. Among them, 542 patients were in the Qi Tu Bu Pi Gu Shen group, and 98 patients were in the Bu Pi Yi Shen group. Baseline characteristics before matching are shown in Table 1:

[0082] Table 1 Baseline features before matching

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] As can be seen from Table 1, the baseline characteristics of the two groups were balanced before matching. However, since the ratio of the number of people in the spleen-tonifying and kidney-benefiting group to the number of people in the astragalus-sugar spleen-tonifying and kidney-strengthening group was 1:5, a 1:1 propensity score matching was used to balance the two groups of samples.

[0089] After 1:1 propensity score matching, a total of 196 patients were identified. The baseline characteristics after matching are shown in Table 2.

[0090] Table 2 Baseline features after matching

[0091]

[0092]

[0093]

[0094]

[0095] As shown in Table 2, the median age of the matched patients was 57.54 (47.57, 65.34) years, with 104 males (53.06%) and 92 females (46.94%). There were 26 (13.27%) patients with CKD stages 3, 31 (15.82%) with CKD stages 4, and 139 (70.92%) with CKD stages 5, respectively. Among the primary disease diagnoses, 54 (27.55%) cases were primary glomerular diseases, 4 (2.04%) were hypertensive nephropathy, 7 (3.57%) were diabetic nephropathy, 10 (5.10%) were other secondary glomerular diseases, and 121 (61.73%) had unknown primary causes. Of the 180 (91.84%) patients, 123 (62.76%) were using ACEI / ARB antihypertensive drugs, 67 (34.18%) had diabetes, 86 (43.88%) had hyperlipidemia, 90 (45.92%) had hyperuricemia, and 156 (79.59%) had anemia. The overall median follow-up time was 26.46 (9.79, 42.60) months, with the median follow-up time for the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Group being 27.26 (11.19, 42.48) months and the median follow-up time for the Spleen-Tonifying and Kidney-Benefiting Group being 25.74 (8.86, 43.02) months.

[0096] 3. Survival Analysis

[0097] Of the 196 patients who underwent 1:1 propensity score matching, 54 (27.55%) experienced an overall decrease in eGFR ≥30% from baseline. Specifically, 34 (34.69%) of these events occurred in the spleen-tonifying and kidney-nourishing group, while 20 (20.41%) occurred in the astragalus-sugar-codone spleen-tonifying and kidney-strengthening group. The Kaplan-Meier curves for the two groups are shown below. Figure 2 As shown, from Figure 2 It can be seen that the median survival time of the spleen-tonifying and kidney-benefiting group was 56.6 months, due to... Figure 2 The horizontal dashed line drawn at 0.50 on the vertical axis does not intersect with the Kaplan-Meier curve of the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Group. Therefore, the median survival time of the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Group is not shown in the figure, indicating that the median survival time of the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Group is longer than that of the Spleen-Tonifying and Kidney-Benefiting Group. Moreover, during the follow-up period, the survival rate of the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Group was consistently significantly higher than that of the Spleen-Tonifying and Kidney-Benefiting Group, which was statistically significant (P = 0.03), indicating that the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Formula can significantly improve the survival rate of patients with chronic kidney disease.

[0098] 4. Cox Regression

[0099] The two univariate Cox regressions are shown in Table 3:

[0100] Table 3 Univariate Cox Regression

[0101]

[0102]

[0103]

[0104] As shown in Table 3, compared with the spleen-tonifying and kidney-nourishing group, the HR (95% CI) of the Qi Tu spleen-tonifying and kidney-nourishing group was 0.547 (0.315, 0.951) (P = 0.032), suggesting that the application of Qi Tu spleen-tonifying and kidney-nourishing formula is a potential protective factor for patients with CKD stage 3-5 to have an eGFR decrease of ≥30% from baseline. Other significant factors included comorbid diabetes (HR(95% CI): 2.120 (1.243, 3.619), P = 0.006), use of sodium bicarbonate (HR(95% CI): 1.995 (1.151, 3.456), P = 0.014), use of diuretics (HR(95% CI): 2.045 (1.198, 3.493), P = 0.009), and use of traditional Chinese medicine for clearing heat and dampness (HR(95% CI): 2.139 (1.231, 3.718), P = 0.007). These were all potential risk factors for a ≥30% decrease in eGFR from baseline in patients with CKD stages 3-5, and will be further adjusted in the multivariate Cox regression model 3.

[0105] The two sets of multivariate Cox regressions are shown in Table 4:

[0106] Table 4 Multifactor Cox Regression

[0107]

[0108]

[0109] Table 4 shows the univariate Cox regression results for Model 1, comparing the Spleen-Tonifying and Kidney-Benefiting group with the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening group. The univariate Cox regression results indicate that, with the Spleen-Tonifying and Kidney-Benefiting group as the reference, the HR value for the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening group was 0.547 (95% CI: 0.315–0.951), which was statistically significant (P = 0.032). Model 2, based on Model 1, further corrected for imbalanced covariates between groups. Model 3, based on Model 2, further corrected for significant variables with univariate P < 0.05. Adjusted for multivariate results, the use of Qi Tu Bu Pi Gu Shen Fang was an independent protective factor against a ≥30% decrease in eGFR from baseline in CKD stage 3-5 patients (Model 2: HR: 0.560, 95% CI: 0.320-0.982, P = 0.043; Model 3: HR: 0.450, 95% CI: 0.254-0.798, P = 0.006). The use of Qi Tu Bu Pi Gu Shen Fang can reduce the risk of a ≥30% decrease in eGFR from baseline by approximately 55.0%.

[0110] 5. Conclusion

[0111] No liver damage events have occurred in the clinical application of the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Formula of the present invention, indicating its good safety. Compared with the Spleen-Tonifying and Kidney-Benefiting Formula, the Astragalus and Cuscuta Spleen-Tonifying and Kidney-Strengthening Formula of the present invention reduces the amount of Polygonum multiflorum, which not only reduces potential hepatotoxicity and nephrotoxicity, but also effectively reduces the risk of kidney disease progression.

Claims

1. A traditional Chinese medicine composition for treating chronic kidney disease in stages 3-5, characterized in that, It is prepared from the following raw materials by mass parts: Radix Astragali 20-35 parts, Semen Nelumbinis 10-25 parts, Codonopsis 10-25 parts, Atractylodes 10-20 parts, Poria 10-25 parts, Dioscorea 10-25 parts, Salvia miltiorrhiza 10-25 parts, and Coix 10-30 parts.

2. The traditional Chinese medicine composition for treating stage 3-5 chronic kidney disease according to claim 1, characterized in that, It is prepared from the following raw materials by mass parts: Radix Astragali 30 parts, Semen Nelumbinis 25 parts, Codonopsis 15 parts, Atractylodes 15 parts, Poria 15 parts, Dioscorea 15 parts, Salvia miltiorrhiza 10 parts, and Coix 10 parts.

3. The traditional Chinese medicine composition for treating stage 3-5 chronic kidney disease according to claim 1 or 2, characterized in that, The Dioscorea is Dioscorea opposita.

4. The traditional Chinese medicine composition for treating stage 3-5 chronic kidney disease according to claim 1 or 2, characterized in that, It also includes a medically acceptable adjuvant.

5. The traditional Chinese medicine composition for treating stage 3-5 chronic kidney disease according to claim 1 or 2, characterized in that, The dosage form of the traditional Chinese medicine composition is oral liquid, tablet, ointment, granule, capsule, decoction, powder or pill.

6. Use of the traditional Chinese medicine composition for treating stage 3-5 chronic kidney disease according to any one of claims 1-5 in the preparation of a medicament for treating stage 3-5 chronic kidney disease.

7. Use of the traditional Chinese medicine composition for treating stage 3-5 chronic kidney disease according to any one of claims 1-5 in the preparation of a medicament for delaying the progression of stage 3-5 chronic kidney disease and / or delaying the decline of glomerular filtration rate and / or improving the survival rate of patients with stage 3-5 chronic kidney disease.

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