Traditional Chinese medicine composition for treating diabetic kidney disease as well as pharmaceutical preparation and application of traditional Chinese medicine composition

Abstract

The invention relates to the field of traditional Chinese medicines, in particular to a traditional Chinese medicine composition for treating diabetic kidney diseases and a preparation method and application thereof. The traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 10 to 60 parts of raw radix astragali seu hedysari, 5 to 30 parts of rhizoma polygonati, 5 to 30 parts of rhizoma dioscoreae, 5 to 30 parts of fructus corni, 3 to 15 parts of rhizoma coptidis, 5 to 30 parts of ramuli euonymi, 5 to 30 parts of fructus arctii and 3 to 15 parts of leech. The traditional Chinese medicine composition preferably selects the raw material medicines and compatibility thereof, focuses on strengthening spleen and middle warmer, tonifying spleen and kidney, strengthening spleen and reinforcing kidney, clearing heat and removing toxicity, gives full play to the treatment characteristics of multi-component, multi-path and multi-target synergistic effect of traditional Chinese medicines, and can obviously improve clinical healing of patients with diabetic kidney diseases. The early-stage small-scale clinical observation shows that the prescription for invigorating spleen, tonifying kidney, clearing heat and harmonizing collaterals can effectively improve clinical symptoms and traditional Chinese medicine syndromes of patients with diabetic kidney diseases, reduces UACR values, and has good popularization and application values.

Description

Technical Field

[0001] The present invention relates to the field of Chinese medicine compositions, and in particular to a Chinese medicine composition for treating diabetic nephropathy, and a pharmaceutical preparation and application thereof. Background Art

[0002] Diabetic nephropathy (DKD) is a chronic kidney disease (CKD) caused by diabetes mellitus (DM). It is one of the main microvascular complications of DM, with varying degrees of proteinuria and progressive renal function impairment as the main manifestations. Foreign studies have found that 20%-40% of DM patients have DKD, and about 50% of DKD patients develop end-stage renal disease (ESRD) as their disease progresses, requiring dialysis or kidney transplantation. Meta-analysis shows that the prevalence of DKD in T2DM patients in my country is 21.8%. DKD has become the main cause of CKD in hospitalized patients in my country, and has become the main cause of ESRD after chronic nephritis (CGN), placing a great economic burden on society and families.

[0003] Proteinuria is the most important clinical manifestation and pathological product of DKD, and is also a key factor in promoting the occurrence and development of the disease. The initial process of proteinuria formation involves glomerular and tubular damage, which is considered to be the result of glomerular filtration barrier or tubulointerstitial damage. Proteinuria is not only an indicator of kidney damage, but also closely related to the progression of DKD. Persistent proteinuria and leakage of plasma proteins accumulated in the glomeruli are independent risk factors for aggravating glomerular sclerosis. In addition, urinary protein itself has toxic effects that cause tubulointerstitial damage, which can stimulate renal tubular epithelial cells (PTECs) to induce the production of inflammatory factors, leading to inflammation and fibrosis, which is one of the main reasons for the development of DKD into ESRD. Therefore, clinical intervention for DKD proteinuria can help delay the progression of DKD to ESRD, which has high economic value and social significance.

[0004] With the development of medicine, renal replacement therapies such as dialysis and kidney transplantation have been continuously improved, and the efficacy of ESRD has been significantly improved. However, there has been no breakthrough in the medical community on how to reduce DKD proteinuria, delay the progression of DKD, and prevent it from developing into ESRD. Early intervention of DKD patients, reducing proteinuria, and avoiding ESRD have become important issues currently faced by DKD researchers. Traditional Chinese medicine has the characteristics of multi-target and multi-pathway treatment. The use of traditional Chinese medicine to treat DKD not only has the characteristics of wide application and few side effects, but also has irreplaceable advantages over Western medicine in improving the clinical symptoms of DKD patients and delaying the progression of DKD.

[0005] Although the name "diabetic nephropathy" is not recorded in ancient Chinese medical books, DKD can be classified into the categories of "kidney consumption", "kidney consumption", "lower consumption", "edema", "turbid urine" and other symptoms in Chinese medicine according to its clinical manifestations. Chinese medicine emphasizes "adhering to the pathogenesis". Contemporary doctors generally believe that DKD is caused by spleen and kidney deficiency, insufficient qi and yin, stasis of blood, dampness, turbidity and evil toxins. Its pathogenesis can be summarized as deficiency of the root and excess of the symptoms. The root deficiency is mainly spleen and kidney deficiency in terms of internal organs, and the qi, blood, yin and yang are mainly qi deficiency, yin deficiency and yang deficiency. The excess of the symptoms includes stasis, dampness, phlegm, fluid, toxicity, heat and wind.

[0006] The spleen is responsible for transportation and transformation, ascending the clear, and controlling. When the spleen is full, the physiological function of the spleen to consolidate water, moisture, and essence is normal. If the spleen is deficient, unable to ascend, and unable to control, the essence and fine substances leak from the bottom, and proteinuria occurs; the kidney is responsible for receiving qi, consolidating, controlling water, and governing the two yin, receiving the essence of the five internal organs and storing it. The kidney does not receive qi, the qi does not hold the essence, the kidney gate is not solid, and the essence and fine substances leak from the bottom, which is also the cause of proteinuria in DKD. The spleen and kidney are the foundation of the acquired and the foundation of the innate, and there is a mutually supportive relationship. The healthy operation of the spleen depends on the warmth of the kidney, and the essence and qi in the kidney also rely on the spleen to transport and transform the essence of water and grain to maintain fullness. When the spleen and kidney qi are full, the body's function of consolidating water, moisture, and essence is normal. Therefore, spleen and kidney qi deficiency is the key to the occurrence of DKD proteinuria, and "strengthening the spleen and replenishing qi" has become the main method for clinical treatment of DKD proteinuria.

[0007] The Medical Prescriptions states: "Diseases in the lower part of the body are caused by dampness and heat." The retention of dampness and heat leading to prolonged and difficult-to-heal proteinuria is a major feature of DKD. Dampness is a yin evil, and it is sticky and stubborn when it causes disease. It is easy to block the rise and fall of the qi mechanism, and it is easy to attack the yin position and injure the lower part of the body. Heat is a yang evil, and it is easy to injure the body fluid and consume qi. The spleen and kidney are deficient in qi, and the body fluid metabolism is unbalanced. Over time, the water and dampness stagnate and become heat. The dampness and heat are stalemate, and the dampness tends to go down, burning the lower part of the body, disturbing the sperm chamber, and the kidney loses its sealing and storage, resulting in the leakage of fine substances with urine. "If the blood is not good, it will become water." Blood stasis is also of great significance to the progression of DKD. The spleen and kidney qi deficiency is unable to circulate blood, resulting in blood stasis, long-term illness into the collaterals, kidney collaterals are affected by blood stasis, further blocking the rise and fall of qi, leading to unfavorable qi transformation, and blood stasis is easy to turn into heat and burn the true yin, further aggravating kidney deficiency. Meta-analysis suggests that the method of replenishing qi, nourishing yin and activating blood circulation can be used as an effective supplement and alternative therapy for the treatment of DKD, especially for improving DKDUAER, Scr, and FPG. Based on the importance of dampness, heat, and stasis to the pathogenesis of DKD, it is of great significance to pay attention to clearing dampness and heat, removing stasis and collaterals in the treatment of DKD.

[0008] In the course of DKD, the deficiency of the original cause and the excess of the pathogen are mutually causal and reciprocating. The spleen and kidney qi deficiency and the three evils of dampness, heat and blood stasis are combined to cause the protracted course of DKD and frequent changes. "Strengthening the spleen and kidney, clearing away the excess of the pathogen" has become the key to the treatment of DKD. Therefore, a Chinese medicine composition with more diversified ingredients, more reasonable dosage optimization and modern pharmacological mechanism support is needed to improve the treatment effect. Summary of the invention

[0009] The object of the present invention is to provide a Chinese medicine composition (Jianpi Yishen Qinghua Heluo prescription) for treating diabetic nephropathy and a preparation method thereof, as well as the use of the Chinese medicine composition or pharmaceutical preparation in preparing drugs for treating diabetic nephropathy.

[0010] The "Jianpi Yishen Qinghua Heluo Recipe" is based on the pathological characteristics of DKD, which is characterized by deficiency of spleen and kidney qi and damp-heat stasis. It is adapted from the "Jianpi Qinghua Recipe" of Professor Cai Gan, a famous Chinese medicine doctor in China, for the treatment of DM. It is composed of raw astragalus, polygonatum, yam, cornus officinalis, coptis root, euphorbia obesa, arctium barbata, and leech. This Chinese medicine composition gives full play to the therapeutic characteristics of Chinese medicine with multiple components, multiple pathways, and multiple targets. It focuses on strengthening the spleen and replenishing qi, tonifying the kidney and consolidating essence, clearing away heat and detoxifying, dispelling wind and dampness, and promoting blood circulation and removing blood stasis. It can significantly improve the clinical efficacy of DKD patients and delay the progression of DKD. Early small-scale clinical observations have found that Jianpi Yishen Qinghua Heluo Recipe can effectively improve the clinical symptoms and TCM syndromes of DKD patients and reduce UACR values.

[0011] The first aspect of the present invention provides a traditional Chinese medicine composition for treating DKD, wherein the traditional Chinese medicine composition is composed of the following raw materials in parts by weight:

[0012] 10-60 weight parts of raw astragalus, 5-30 weight parts of polygonatum, 5-30 weight parts of yam, 5-30 weight parts of cornus, 3-15 weight parts of coptis, 5-30 weight parts of euphorbia pulex, 5-30 weight parts of burdock seeds, and 3-15 weight parts of leech.

[0013] Furthermore, the preferred traditional Chinese medicine composition of the present invention is composed of the following raw medicines in parts by weight: 30 parts by weight of raw astragalus, 15 parts by weight of polygonatum, 15 parts by weight of yam, 15 parts by weight of cornus officinalis, 6 parts by weight of coptis chinensis, 15 parts by weight of parsley, 15 parts by weight of burdock seeds, and 6 parts by weight of leech.

[0014] This Chinese medicine composition is based on the three methods of tonifying, clearing and unblocking. In the formula, "Astragalus" strengthens the spleen and tonifies the middle, raises yang and lifts the sunken, "Polygonatum" strengthens the spleen and benefits the kidney, replenishes qi and nourishes yin, "Chinese yam" strengthens the spleen and strengthens the kidney, replenishes deficiency and benefits essence, "Cornus" nourishes the kidney, astringes essence and consolidates loss, "Coptis" clears away heat, detoxifies and strengthens yin, "Gallus" promotes blood circulation, removes blood stasis and dredges the collaterals, "Arctium" dispels wind, detoxifies and eliminates dampness and turbidity, and "Leech" breaks blood, removes blood stasis and dredges the kidney collaterals. The whole formula uses Astragalus as the main ingredient, Polygonatum, Chinese yam and Cornus as the ministers, Coptis and Gallus as the assistants, and Arctium and Leech as the messengers, which together play the effects of strengthening the spleen, benefiting the kidney, clearing and harmonizing the collaterals. See the formula diagram for details. Figure 1 .

[0015] Astragalus is sweet and slightly warm in nature. It ranks first in the most frequently used Chinese medicine formula for the treatment of DKD and has a clear therapeutic effect on DKD. Modern research has found that astragalus polysaccharides and astragalus total saponins can inhibit the over-activation of RAS, reduce glomerular pressure, and reduce the production of urinary mAlb.

[0016] Polygonatum sibiricum is sweet and mild in nature, and has the effects of tonifying the spleen and replenishing qi, nourishing the kidney and replenishing essence. Polygonatum sibiricum polysaccharide is the main active ingredient of Polygonatum sibiricum. Studies have found that Polygonatum sibiricum polysaccharide has hypoglycemic and antioxidant effects. Its protective mechanism on the kidneys of DM rats may be related to its control of blood sugar and anti-fibrosis factors.

[0017] Chinese yam is sweet and mild in nature. It has the effects of strengthening the spleen and kidney, nourishing essence and replenishing deficiency. It is one of the most commonly used Chinese medicines for the treatment of DKD. Mr. Shi Jinmo believes that the combination of astragalus and Chinese yam in the treatment of DKD can take into account the regulation of spleen yang and spleen yin, and have the effects of strengthening the spleen and promoting transportation, and concentrating essence and stopping leakage.

[0018] Cornus officinalis tastes sour and astringent and is slightly warm in nature. It is beneficial to the liver and kidney, astringent and replenishes the essence, and stops collapse. A large number of in vivo and in vitro experimental studies have found that Cornus officinalis not only has multiple pharmacological effects such as lowering blood sugar, anti-oxidation, and inhibiting inflammatory response, but can also improve renal fibrosis in DKD rats, reduce inflammatory cell infiltration, and alleviate renal pathological changes.

[0019] Coptis chinensis is bitter and cold in nature, and has the effects of clearing away heat and dampness, purging fire and detoxifying. Network pharmacology studies have found that Coptis chinensis can regulate DKD renal tissue inflammation by affecting the AGEs-RAGE signaling pathway. Meta-analysis found that berberine has multiple effects such as improving insulin resistance, lowering blood sugar, regulating lipids, lowering blood pressure, reducing urinary Alb, anti-inflammatory, anti-oxidative stress, and antibacterial. In addition, studies have found that berberine has a protective effect on high-glucose-induced podocyte injury, can increase podocyte survival rate in high-glucose environment, reduce podocyte migration rate, maintain glomerular filtration barrier function, and can activate autophagy through AMPK and its downstream signaling pathway to reduce podocyte injury.

[0020] The taste of Herba Lycopodii is bitter and pungent, and it is cold in nature. It is good at expelling old blood stasis and septicemia, and it can remove dampness and wind, detoxify and clear heat. Modern research has found that Herba Lycopodii has pharmacological effects such as lowering blood sugar, regulating blood lipids, inhibiting allergic reactions, and resisting hypoxia. Network pharmacology and molecular docking studies have found that Herba Lycopodii can participate in the regulation of multiple signal pathways, inhibiting inflammatory responses, resisting oxidative stress, resisting hypoxia, resisting cell apoptosis, and improving renal hemodynamics to delay the progression of DKD.

[0021] Burdock seeds are bitter and cold in nature, and have the effects of dispelling wind and heat, detoxifying and removing dampness and turbidity. Network pharmacology and molecular docking studies have found that burdock seeds can treat DKD by playing anti-inflammatory and reducing oxidative stress through signaling pathways such as AGEs-RAGE. Modern pharmacological studies have confirmed that burdock seeds and their extracts have unique advantages in the treatment of DKD. Single or compound burdock seed preparations can effectively reduce DKD proteinuria, reduce edema, and have the effects of lowering blood sugar, lowering blood pressure, regulating lipid metabolism, improving microcirculation, and regulating immunity.

[0022] Leeches are bitter and salty in nature, and have the effects of breaking blood and removing blood stasis, promoting menstruation and eliminating symptoms. Zhang Xichun said that "the salty taste specifically enters the blood, breaking blood stasis without hurting new blood, and not damaging the qi at all." Many clinical and experimental studies have shown that leeches and their extracts can prevent and treat DKD by inhibiting inflammatory responses and oxidative stress, protecting podocytes, improving endothelial function and blood rheology, lowering lipids, resisting fibrosis, resisting cell apoptosis, and regulating metabolic disorders.

[0023] The second aspect of the present invention provides a pharmaceutical preparation with the above-mentioned traditional Chinese medicine composition for treating DKD as an active ingredient. The pharmaceutical preparation is prepared by conventional preparation methods in the art into commonly used dosage forms in pharmacy, such as decoctions, granules, tablets, capsules, oral liquids, mixtures or syrups.

[0024] Furthermore, the pharmaceutical preparation of the present invention can be prepared by the following method:

[0025] (A) The water decoction of Jianpi Yishen Qinghua Heluo Fang was prepared by the traditional water decoction method: the Chinese medicine pieces were weighed according to the formula ratio, drinking water was added until the water surface exceeded the pieces by 2 cm, and the pieces were soaked for 30 minutes, and the medicine liquid was poured out, and the residue was added with water again, and the medicine liquid was poured out after decoction (the decoction method was the same as before), and the two medicine liquids were combined, filtered and further concentrated to obtain the water extract of the Chinese medicine composition;

[0026] (B) A pharmaceutically acceptable carrier is added to the water extract and prepared by a conventional preparation method in the art.

[0027] The third aspect of the present invention provides the use of the above-mentioned Chinese medicine composition and pharmaceutical preparation in the preparation of drugs for treating DKD.

[0028] The dosage of the present invention is a therapeutically effective amount, for example, about 2 g / kg body weight to about 5.5 g / kg body weight per day, and a preferred dosage is about 3 g / kg body weight to about 4 g / kg body weight. The general medication period is 6-24 months, preferably 6-18 months, and more preferably 12-18 months. Of course, the medication period also needs to consider the route of administration and the patient's health status, which are all within the skill range of skilled physicians.

[0029] In addition, the Chinese medicine composition of the present invention can be used as the sole active ingredient for the treatment of DKD, and can also be used together with other therapeutic agents (such as empagliflozin).

[0030] Functions and Effects of the Invention

[0031] The spleen-strengthening, kidney-benefiting, clearing and harmonizing prescription of the present invention is safe and effective in treating patients with spleen-kidney qi deficiency and damp-heat stasis type DKD (stage G1-G3a), can reduce the patients' urine protein, improve the patients' glucose and lipid metabolism imbalance and inflammatory state, reduce the risk factors of renal vascular disease, protect renal function, and can reduce the patients' fatigue, shortness of breath, laziness, frequent urination, soreness of waist and knees, edema, heavy limbs, dark complexion, and skin and nail discoloration symptoms, thereby improving their quality of life. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is the solution to the spleen-tonifying, kidney-benefiting, clearing and harmonizing prescription of the present invention. DETAILED DESCRIPTION

[0033] The present invention is now described in detail with reference to embodiments, but the implementation of the present invention is not limited thereto.

[0034] The experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. The medicinal materials used in the examples of the present invention can be obtained from Chinese medicinal material sales companies unless otherwise specified. The medicinal materials obtained are Chinese medicinal material slices unless otherwise specified. The slices can be obtained from sales companies or processed after being obtained.

[0035] The embodiment of the present invention provides a traditional Chinese medicine composition for treating diabetic nephropathy. The traditional Chinese medicine composition is prepared from the following raw materials: 10-60 weight parts of raw astragalus, 5-30 weight parts of polygonatum, 5-30 weight parts of yam, 5-30 weight parts of cornus, 3-15 weight parts of coptis, 5-30 weight parts of euphorbia pulex, 5-30 weight parts of burdock seeds, and 3-15 weight parts of leeches.

[0036] Preferably, 20-50 parts by weight of raw astragalus, 5-25 parts by weight of polygonatum, 5-25 parts by weight of yam, 5-25 parts by weight of cornus, 3-12 parts by weight of coptis root, 5-25 parts by weight of euphorbia pulex, 5-25 parts by weight of arctium, and 3-12 parts by weight of leech;

[0037] More preferably, 30-40 parts by weight of raw astragalus, 10-20 parts by weight of polygonatum, 10-20 parts by weight of yam, 10-20 parts by weight of cornus, 3-9 parts by weight of coptis root, 10-20 parts by weight of ghost arrow feather, 10-20 parts by weight of burdock fruit, 3-9 parts by weight of leech

[0038] Most preferably, 30 parts by weight of raw astragalus, 15 parts by weight of polygonatum, 15 parts by weight of yam, 15 parts by weight of cornus officinalis, 6 parts by weight of coptis chinensis, 15 parts by weight of euphorbia pulex, 15 parts by weight of arctium, and 6 parts by weight of leech.

[0039] The preparation method of the traditional Chinese medicine composition for treating diabetic nephropathy comprises:

[0040] (A) A water decoction of Jianpi Yishen Qinghua Heluo Fang was prepared by a traditional decoction method: Chinese herbal medicine slices were weighed according to the formula ratio, drinking water was added until the water surface exceeded the slices by 2 cm, and the slices were soaked for 30 minutes, heated over high heat until the liquid medicine boiled, then lowered to low heat, and continued to boil for 30 minutes while maintaining a slight boiling state, the liquid medicine was poured out, the residue was added with water again, and the liquid medicine was poured out after decoction in the same way, the two liquid medicines were combined, filtered, and further concentrated to obtain a water extract of the Chinese herbal medicine composition;

[0041] (B) Adding a pharmaceutically acceptable carrier to the water extract and preparing tablets, granules, oral preparations, etc. by conventional preparation methods in the art, as follows:

[0042] Example 1: Preparation of decoction of Chinese medicine composition

[0043] Weigh 30 parts by weight of raw astragalus, 15 parts by weight of polygonatum, 15 parts by weight of yam, 15 parts by weight of cornus officinalis, 6 parts by weight of coptis chinensis, 15 parts by weight of euphorbia pulex, 15 parts by weight of arctium, and 6 parts by weight of leech.

[0044] Weigh the above-mentioned Chinese medicines according to the formula ratio, rinse with water and soak them in a container for more than 30 minutes, heat over high heat until the medicine liquid boils, then reduce the heat and continue to cook at a slight boiling state for 30 minutes, pour out the medicine liquid, add water to the residue again, boil in the same way and pour out the medicine liquid, combine the two medicine liquids, filter and further concentrate to obtain a water decoction of the Chinese medicine composition.

[0045] Example 2: Preparation of granules of Chinese medicine composition

[0046] Weigh 30 parts by weight of raw astragalus, 15 parts by weight of polygonatum, 15 parts by weight of yam, 15 parts by weight of cornus officinalis, 6 parts by weight of coptis chinensis, 15 parts by weight of euphorbia pulex, 15 parts by weight of arctium, and 6 parts by weight of leech.

[0047] Weigh the above Chinese medicines according to the formula ratio, rinse with water and soak in a container for more than 30 minutes, heat the medicine liquid until it boils, then turn to low heat, continue to keep it in a slightly boiling state for 30 minutes, pour out the medicine liquid, add water to the residue again, decoct it in the same way and pour out the medicine liquid, combine the two medicine liquids, filter and further concentrate, filter and set aside. Finally, take the extract and dextrin according to the ratio and suck them into the boiling granulator container to complete the mixing and granulation, dry at 50℃ for 2 hours, pass the dried granules through a 12-14 mesh sieve, and package them.

[0048] Example 3: Preparation of tablets of Chinese medicine composition

[0049] Weigh 30 parts by weight of raw astragalus, 15 parts by weight of polygonatum, 15 parts by weight of yam, 15 parts by weight of cornus officinalis, 6 parts by weight of coptis chinensis, 15 parts by weight of euphorbia pulex, 15 parts by weight of arctium, and 6 parts by weight of leech.

[0050] Weigh the above Chinese medicines according to the formula ratio, rinse with water and soak in a container for more than 30 minutes, heat over high heat until the liquid medicine boils, then turn to low heat, continue to keep it in a slightly boiling state for 30 minutes, pour out the liquid medicine, add water to the residue again, decoct in the same way and pour out the liquid medicine, combine the two liquid medicines, further concentrate after filtering, filter and set aside. Finally, take the extract and dextrin according to the ratio and suck them into the boiling granulator container to complete the mixed granulation, dry at 50℃ for 2 hours, pass the dried granules through a 12-14 mesh sieve, add magnesium stearate, mix well, and press into tablets.

[0051] Example 4 Clinical efficacy of Jianpi Yishen Qinghua Heluo prescription in treating DKD and efficacy of TCM syndromes

[0052] 1. Clinical data

[0053] 1.1 Case source

[0054] This trial uses patients with DKD (stage G1-G3a) diagnosed as spleen and kidney qi deficiency and damp-heat and blood stasis as the research subjects. The included cases are patients treated in the outpatient clinics and wards of the Nephrology Department, Traditional Medicine Department, and Endocrinology Department of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from March 2023 to October 2023, and those who met the inclusion and exclusion criteria were screened and qualified.

[0055] 1.2 Diagnostic criteria

[0056] 1.2.1 Western medicine DKD diagnosis and staging standards: formulated based on the "Chinese Guidelines for Clinical Diagnosis and Treatment of Diabetic Kidney Disease" and the "Chinese Guidelines for the Prevention and Treatment of Diabetic Kidney Disease (2021 Edition)".

[0057] 1.2.2 Diagnostic criteria for DKD in Traditional Chinese Medicine: The diagnostic criteria for DKD spleen and kidney qi deficiency and damp-heat stasis syndrome were formulated with reference to the "Guiding Principles for Clinical Research of New Chinese Medicines (Trial)" and the "Diagnosis, Syndrome Differentiation and Efficacy Evaluation Criteria for Diabetic Nephropathy (Trial Scheme)".

[0058] 1.3 Inclusion criteria: aged 18-80 years, regardless of gender; meet the diagnostic criteria of DKD G1-G3a, A2-A3; stable non-dialysis patients; TCM syndrome of spleen and kidney qi deficiency, damp-heat stasis; blood pressure ≤ 130 / 80 mmHg, diastolic blood pressure ≥ 70 mmHg; no mental illness, clear consciousness, and independent judgment ability; included cases have not participated in clinical trials of other drugs 3 months before enrollment; understand the entire trial process, voluntarily accept treatment, and sign the "Informed Consent Form". (Note: All of the above items must be met before enrollment.)

[0059] 1.4 Exclusion criteria: Patients with proteinuria caused by DM combined with NDKD (primary kidney disease or other secondary kidney diseases except DKD); patients with T1DM, kidney disease caused by gestational DM, and kidney disease caused by secondary DM; patients with acute complications of DM, such as DKA, or stressful situations such as surgery and trauma in the past month; patients with serious primary diseases or complications such as cardiovascular, respiratory, liver and hematopoietic systems; patients with consumptive diseases such as malignant tumors, tuberculosis and other acute and chronic infectious diseases; patients with urinary tract infections; patients with large amounts of proteinuria (24hUP>3.5g); patients who are allergic or intolerant to any component of the drugs used in this project; patients who have used nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and iodine contrast agents in the past 3 months; patients who have newly used ARB or ACEI in the past 3 months; patients who are pregnant, breastfeeding or preparing for pregnancy in the near future. Note: Anyone with any of the above items should be excluded.

[0060] 1.5 Exclusion criteria: patients with incomplete data collection; patients who participated in other clinical trials during treatment.

[0061] 1.6 Criteria for termination of the trial: severe adverse reactions during the trial or allergies to the trial drugs; failure to follow the treatment prescribed in the trial protocol and inability to comply with the doctor's instructions; eGFR < 30 ml / min / 1.73 m 2 ; Scr doubles or enters dialysis treatment; patients request to withdraw from the trial; serious cardiovascular and cerebrovascular diseases occur during the trial.

[0062] 2. Research Methods

[0063] 2.1 Sample size calculation, randomization and grouping methods

[0064] With UACR as the primary endpoint, the sample size estimation method of superiority test was adopted. According to the results of pre-experimental data of previous clinical observations, the mean decrease of UACR after treatment was used as the basis for sample size estimation. The sample size was calculated using PASS15.0 software. Considering that there were about 10% of missing cases, the total sample size of the two groups was 104. SPSS28.0 statistical software generated a random number table, and the patients were randomly assigned to the control group and the treatment group in a 1:1 ratio according to the number table. The treatment allocation table corresponding to the serial number 1-104 was listed. Patients who met the inclusion criteria were assigned to the control group and the treatment group according to the serial number in the order of visit, with 52 cases in each group.

[0065] 2.2 Treatment methods

[0066] 2.2.1 Basic treatment plan

[0067] 1. General treatment: 1) Diet control: control calorie intake, daily protein intake is about 0.6-0.8g / kg / d, sodium intake is 1.5-2.0g / d (equivalent to sodium chloride 3.75-5.00g / d); 2) Lifestyle adjustment: moderate exercise, weight control, quit smoking or reduce smoking.

[0068] 2. Control blood sugar: Maintain the original blood sugar-lowering plan. For the patients in this study, the blood sugar control target is HbAlc ≤ 7%. The HbA1c control target for elderly patients can be appropriately relaxed to 8.5%. The HbA1c control target for those at risk of hypoglycemia can be further relaxed, but should not exceed 9%. Those whose blood sugar control is not up to standard can add insulin treatment. Monitor blood sugar during treatment and be alert to the occurrence of hypoglycemia. If hypoglycemia occurs, adjust the blood sugar-lowering plan in time.

[0069] 3. Control blood pressure: Maintain the original antihypertensive regimen (losartan potassium tablets are the preferred antihypertensive drug). ARB or ACEI antihypertensive drugs must be taken orally for more than 3 months when enrolled. The blood pressure target value is controlled below 130 / 80 mmHg, and the diastolic blood pressure should not be lower than 70 mmHg. For those whose blood pressure does not meet the target after taking antihypertensive drugs, antihypertensive drugs that do not affect the urine protein excretion rate can be added.

[0070] 4. Control blood lipids: Maintain the original lipid-lowering regimen, control the LDL target value below 2.6mmol / L, and use statins as the first choice of lipid-lowering drugs. The dosage of pravastatin should be reduced for patients in stage G3.

[0071] 5. Correct electrolyte imbalance and regulate water metabolism: For patients with combined electrolyte imbalance or obvious edema, timely correction of electrolyte imbalance and diuretic treatment should be given.

[0072] 6. Other treatments: If other symptoms occur during the trial, give symptomatic treatment in a timely manner and keep good trial records.

[0073] 2.2.2 Treatment plan for the control group: basic treatment plus empagliflozin (manufacturer: Boehringer IngelheimPharma GmbH&CO.KG, approval number: National Medicine Standard HJ20201008), 10 mg / tablet, once a day, 1 tablet each time, orally.

[0074] 2.2.3 Treatment plan for the treatment group: The control group's treatment plan was supplemented with Jianpi Yishen Qinghua Heluo recipe (raw astragalus 30g, polygonatum 15g, yam 15g, cornus 15g, coptis 6g, herba ophiopogonis 15g, burdock seeds 15g, leech 6g), one dose per day, decocted in water twice, combined the liquid medicine, taken warm in the morning and evening.

[0075] 2.2.4 Treatment course: The treatment course for both groups was 12 weeks.

[0076] 2.3 Evaluation indicators

[0077] 2.3.1 TCM Syndrome Score: Drafted with reference to the "Guidelines for Clinical Research of New Chinese Medicines (Trial)". The main symptoms observed are: fatigue, shortness of breath, frequent urination, soreness of waist and knees, edema, heaviness of limbs, dark complexion, and skin and nails. The above symptoms are divided into 4 levels according to severity, with no symptoms 0 points, mild 1 point, moderate 2 points, and severe 3 points. The score is counted once before and after treatment.

[0078] 2.3.2 Laboratory indicators

[0079] The following indicators were tested and recorded before and after treatment in the two groups of patients:

[0080] A. Efficacy indicators

[0081] 1) Primary endpoint: UACR.

[0082] 2) Secondary endpoint: eGFR.

[0083] 3) Other efficacy indicators: 24hUP, Uα1-MG, UNAG, FPG, 2hPG, HbA1c, TC, TG, HDL, LDL, NLR, hs-CRP, PA, Alb, and Hcy.

[0084] B. Safety indicators: routine blood test, routine urine test, routine stool test, liver function test, blood electrolytes, and electrocardiogram.

[0085] 2.3.3 Clinical efficacy

[0086] The clinical efficacy was observed with UACR as the primary endpoint and eGFR as the secondary endpoint. Refer to the "Standards for Diagnosis, Syndrome Differentiation and Efficacy Evaluation of Diabetic Nephropathy (Trial Scheme)"

[18] The following clinical efficacy criteria were formulated: markedly effective: UACR decreased by more than 1 / 2 or decreased to normal; effective: UACR decreased by less than 1 / 2 compared with before treatment; ineffective: UACR remained unchanged or increased compared with before treatment.

[0087] 2.3.4 TCM Syndrome Efficacy

[0088] Refer to the "Guidelines for Clinical Research of New Chinese Medicines (Trial)"

[17] Proposed: Clinical control: TCM clinical symptoms and signs disappear or basically disappear, syndrome efficacy rate ≥ 90%; markedly effective: TCM clinical symptoms and signs are significantly improved, syndrome efficacy rate ≥ 70% (< 90%); effective: TCM clinical symptoms and signs are improved, syndrome efficacy rate ≥ 30% (< 70%); ineffective: TCM clinical symptoms and signs are not significantly improved, or even aggravated, syndrome efficacy rate < 30%. (Syndrome efficacy rate (nimodipine method) = [(total score before treatment - total score after treatment) ÷ total score before treatment] × 100%.)

[0089] 2.4 Statistical methods

[0090] SPSS 28.0 software was used for data statistical processing. The measurement data that conformed to the normal distribution were expressed as mean ± standard deviation. The data that do not conform to normal distribution are expressed as median (interquartile range) (M (IQR)), and the count data are expressed as rate. The measurement data that conform to normal distribution are statistically analyzed by t test, the independent sample t test is used for comparison between groups, the paired t test is used for comparison before and after treatment within the group, the measurement data with non-normal distribution or uneven variance are statistically analyzed by rank sum test, and the two-way analysis of variance of measurement data with non-normal distribution or uneven variance is implemented by rank-based Scheirer-Ray-Hare test, the count data are statistically analyzed by chi-square test, and the rank data are statistically analyzed by non-parametric statistical methods (rank sum test). P ≤ 0.05 indicates that the difference is statistically significant.

[0091] 3. Results

[0092] 3.1 Analysis of the balance of baseline data

[0093] A total of 104 patients were enrolled in this study and divided into a treatment group (n=52) and a control group (n=52) according to the random number table method. There were 29 males and 23 females in the treatment group, aged 24-79 years, DM duration 3-33 years, DKD duration 4 months-10 years, 33 cases in G1 stage, 11 cases in G2 stage, 8 cases in G3a stage, 39 cases in A2 stage, 13 cases in A3 stage, UACR 30.74-2894.99mg / g, UACR 30.74-281.10mg / g in A2 stage, UACR 309.50-2894.99mg / g in A3 stage, 24hUP 0.02-2.48g, 24hUP 0.02-0.57g in A2 stage, 24hUP0.11-2.48g in A3 stage, eGFR 49.97-134.16ml / min / 1.73m 2 , HbA1c5.5-7.6%, total score of TCM syndrome 9-19 points.

[0094] In the control group, there were 30 males and 22 females, aged 29-79 years, with DM duration of 2-32 years, DKD duration of 3 months-10 years, 32 cases in G1 stage, 15 cases in G2 stage, 5 cases in G3a stage, 41 cases in A2 stage, and 11 cases in A3 stage. UACR was 31.17-3122.02 mg / g, UACR in A2 stage was 31.17-229.74 mg / g, UACR in A3 stage was 373.17-3122.02 mg / g, 24hUP was 0.01-2.54 g, 24hUP in A2 stage was 0.01-0.61 g, 24hUP in A3 stage was 0.26-2.54 g, and eGFR was 47.81-156.93 ml / min / 1.73 m 2 , HbA1c5.5-7.4%, total score of TCM syndrome 8-18 points.

[0095] There was no significant difference in the general conditions of the two groups of patients, including gender, age, duration of DM, duration of DKD, CKD stage, albuminuria stage, UACR, 24hUP, eGFR, HbA1c, and total score of TCM syndrome (P>0.05), indicating that the baseline data of the two groups were well balanced and comparable.

[0096] 3.2 Efficacy analysis

[0097] 3.2.1 Analysis of efficacy of primary endpoints

[0098] Before the intervention, there was no statistical difference in UACR between the two groups (P>0.05), which was comparable. After the intervention, the UACR of the treatment group was significantly decreased compared with that before treatment (P<0.001), and the UACR of the control group was decreased compared with that before treatment (P<0.05). The UACR of the two groups did not obey the normal distribution after the normality test. The Scheirer-Ray-Hare test was implemented in R language instead of the two-way ANOVA nonparametric test. The results showed that there was a statistically significant difference in the main effect of UACR between the two groups (P<0.01), indicating that the UACR efficacy of the treatment group was better than that of the control group.

[0099] Patients were counted according to albuminuria stages. Before the intervention, there was no statistical difference in UACR between the two groups of patients with stage A2 (P>0.05), which was comparable. After the intervention, the UACR of patients with stage A2 in the treatment group decreased significantly compared with before treatment (P<0.001), and the UACR of patients with stage A2 in the control group decreased compared with before treatment (P<0.05). At 4 weeks and 8 weeks of intervention, the UACR of patients with stage A2 in the treatment group was significantly lower than that in the control group (P<0.05). The results of the Scheirer-Ray-Hare test showed that there were statistically significant differences in the main effect of UACR time and the main effect between groups between the two groups of patients with stage A2 (P<0.05, P<0.001), indicating that the UACR efficacy of patients with stage A2 was related to the treatment time period, and the UACR efficacy of patients with stage A2 in the treatment group was better than that in the control group. Before the intervention, there was no statistical difference in UACR between the two groups of patients with stage A3 (P>0.05), which was comparable. After the intervention treatment, the UACR of stage A3 patients in the treatment group decreased significantly compared with that before treatment (P<0.01), and the UACR of stage A3 patients in the control group decreased compared with that before treatment (P<0.05). The results of the Scheirer-Ray-Hare test showed that there was a statistically significant difference in the main effect of UACR between the two groups of stage A3 patients (P<0.05), indicating that the UACR efficacy of stage A3 patients in the treatment group was better than that in the control group.

[0100] The above results suggest that the efficacy of UACR in patients with DKD stage 2 is related to the treatment period, and the spleen-tonifying, kidney-benefiting, and meridian-clearing formula can optimize the therapeutic effect of empagliflozin on UACR in patients with DKD. The results are shown in Tables 1, 2, 3, 4, 5, and 6.

[0101] Table 1 Comparison of UACR (mg / g) between the two groups of patients before and after treatment (M (IQR))

[0102]

[0103] Note: *P<0.05 for intra-group comparison, ***P<0.001 for intra-group comparison, UACR normal reference value: 0-30mg / g

[0104] Table 2 Comparison of UACR (mg / g) between the two groups according to grouping and treatment cycle (M (IQR))

[0105]

[0106] Note: ▲▲P<0.01 for comparison between groups, normal reference value of UACR: 0-30mg / g

[0107] Table 3 Comparison of UACR (mg / g) in the two groups of patients in stage A2 before and after treatment ( M(IQR)

[0108]

[0109] Note: *P<0.05 for intra-group comparison, ***P<0.001 for intra-group comparison, UACR normal reference value: 0-30m

[0110] Table 4 Comparison of the intervention effects of grouping and treatment cycle on UACR (mg / g) in two groups of patients in stage A2 M(IQR)

[0111]

[0112]

[0113] Note: ▲P<0.05 for comparison between groups, ▲▲▲P<0.001 for comparison between groups, #P<0.05 for comparison between time, UACR normal reference value: 0-30mg / g Table 5 Comparison of UACR (mg / g) between the two groups of patients with stage A3 before and after treatment ( M(IQR)

[0114]

[0115] Note: *P<0.05 for intra-group comparison, **P<0.01 for intra-group comparison, UACR normal reference value: 0-30mg / g

[0116] Table 6 Comparison of intervention effects of grouping and treatment cycle on UACR (mg / g) in two groups of patients with stage A3 ( M(IQR)

[0117]

[0118] Note: ▲P<0.05 for comparison between groups, normal reference value of UACR: 0-30mg / g

[0119] 3.2.2 Clinical efficacy analysis

[0120] The clinical efficacy was evaluated with UACR as the main endpoint. After the intervention treatment, 19 patients in the treatment group showed marked effect, 15 were effective, and the total clinical effective rate was 69.39%. There were 9 patients in the control group who showed marked effect, 17 were effective, and the total clinical effective rate was 55.32%. The clinical efficacy of the treatment group was better than that of the control group (P < 0.05). The results are shown in Table 7:

[0121] Table 7 Comparison of clinical efficacy between the two groups of patients after treatment (cases, %)

[0122]

[0123] Note: Total effective rate = (markedly effective + effective) / total number of cases, ▲ Inter-group comparison P < 0.05

[0124] 3.2.3 Efficacy analysis of secondary endpoints

[0125] Before the intervention, there was no statistical difference in eGFR between the two groups (P>0.05), which was comparable. After the intervention, the eGFR of the treatment group was higher than that before treatment (P<0.05), while there was no statistical difference in the eGFR of the control group (P>0.05), indicating that Jianpi Yishen Qinghua Heluo Fang can effectively improve the renal function of DKD patients. The results are shown in Table 8:

[0126] Table 8 eGFR (ml / min / 1.73m 2 )Compare

[0127]

[0128] Note: *P<0.05 for intra-group comparison, normal reference value of eGFR:>90ml / min / 1.73m 2

[0129] 3.2.4 Analysis of other efficacy indicators

[0130] 1.24hUP efficacy analysis

[0131] Before the intervention, there was no statistical difference in 24hUP between the two groups (P>0.05), which was comparable. After the intervention, the 24hUP of the treatment group was significantly lower than that before treatment (P<0.001), and the 24hUP of the control group was lower than that before treatment (P<0.05).

[0132] Patients were statistically analyzed according to albuminuria stages. Before the intervention, there was no statistical difference in 24hUP between the two groups of patients with stage A2 (P>0.05), which was comparable. After the intervention, the 24hUP of patients with stage A2 in the treatment group was significantly lower than that before treatment (P<0.01), and there was no statistical difference in 24hUP of patients with stage A2 in the control group (P>0.05). Before the intervention, there was no statistical difference in 24hUP between the two groups of patients with stage A3 (P>0.05), which was comparable. After the intervention, the 24hUP of patients with stage A3 in the treatment group was significantly lower than that before treatment (P<0.01), and there was a decrease in 24hUP of patients with stage A3 in the control group (P<0.05).

[0133] It is suggested that Jianpi Yishen Qinghua Heluo prescription combined with empagliflozin can effectively reduce the 24hUP of DKD patients, and Jianpi Yishen Qinghua Heluo prescription can enhance the effect of empagliflozin in reducing the 24hUP of DKD stage 2 patients. The results are shown in Tables 9 and 10:

[0134] Table 9 Comparison of 24hUP (g) between the two groups of patients before and after treatment (M (IQR))

[0135]

[0136] Note: *P<0.05 for intra-group comparison, ***P<0.001 for intra-group comparison, 24hUP normal reference value: 0-0.15g

[0137] Table 10 Comparison of 24hUP(g) stages between the two groups before and after treatment ( M(IQR)

[0138]

[0139] Note: *P<0.05 for intra-group comparison, **P<0.01 for intra-group comparison, 24hUP normal reference value: 0-0.15g

[0140] 2. Analysis of the efficacy of renal tubular function (Uα1-MG, UNAG)

[0141] 1) Analysis of the efficacy of Uα1-MG

[0142] Before the intervention, there was no statistical difference in Uα1-MG between the two groups (P>0.05), which was comparable. After the intervention, the Uα1-MG of the treatment group was significantly lower than that before treatment (P<0.01), while there was no statistical difference in the Uα1-MG of the control group (P>0.05), indicating that Jianpi Yishen Qinghua Heluo Fang can effectively reduce Uα1-MG in DKD patients and improve renal tubular function. The results are shown in Table 11.

[0143] Table 11 Comparison of Uα1-MG (mg / L) between the two groups of patients before and after treatment

[0144]

[0145]

[0146] Note: **P<0.01 for intra-group comparison, Uα1-MG normal reference value: 0-12.0mg / L

[0147] 2) Analysis of UNAG efficacy

[0148] Before the intervention, there was no statistical difference in UNAG between the two groups (P>0.05), which was comparable. After the intervention, the UNAG of the treatment group was significantly lower than that before treatment (P<0.01), while there was no statistical difference in UNAG of the control group (P>0.05), indicating that Jianpi Yishen Qinghua Heluo Fang can effectively reduce UNAG in DKD patients and improve renal tubular function. The results are shown in Table 12.

[0149] Table 12 Comparison of UNAG (mg / L) between the two groups of patients before and after treatment

[0150]

[0151] Note: **P<0.01 for intra-group comparison, normal reference value of UNAG: 0-11.5mg / L

[0152] 3. Analysis of efficacy of glucose metabolism (FPG, 2hPG, HbA1c)

[0153] Before the intervention treatment, there was no statistical difference in FPG, 2hPG, and HbA1c between the two groups (P>0.05), which was comparable. After the intervention treatment, the FPG, 2hPG, and HbA1c of the patients in the treatment group were significantly lower than those before treatment (P<0.001), and the FPG of the patients in the control group was significantly lower than that before treatment (P<0.01), and the 2hPG and HbA1c were significantly lower than those before treatment (P<0.001). The FPG, 2hPG, and HbA1c of the patients in the treatment group were lower than those in the control group during the same period (P<0.05), indicating that Jianpi Yishen Qinghua Heluo Fang can effectively improve the glucose metabolism of DKD patients. The results are shown in Table 13:

[0154] Table 13 Comparison of FPG, 2hPG and HbA1c between the two groups of patients before and after treatment ( M(IQR)

[0155]

[0156]

[0157] Note: **P<0.01 for intra-group comparison, ***P<0.001 for intra-group comparison, ▲P<0.05 for inter-group comparison, FPG normal reference value:

[0158] 4.3-5.9mmol / L, 2hPG normal reference value: <7.8mmol / L, HbA1c normal reference value: 3.6-6.0%

[0159] 4. Analysis of the efficacy of lipid metabolism (TC, TG, HDL, LDL)

[0160] Before the intervention, there was no statistical difference in TC, TG, HDL, and LDL between the two groups (P>0.05), which was comparable. After the intervention, TC, TG, and LDL of the treatment group were significantly lower than those before treatment (P<0.001), and HDL was not significantly different from that before treatment (P>0.05). TC and LDL of the control group were lower than those before treatment (P<0.05), and TG and HDL were not significantly different from those before treatment (P>0.05), indicating that Jianpi Yishen Qinghua Heluo Fang has a positive effect on improving lipid metabolism in patients with DKD. Jianpi Yishen Qinghua Heluo Fang can effectively improve the efficacy of empagliflozin in reducing TG in patients with DKD. The results are shown in Table 14.

[0161] Table 14 Comparison of TC, TG, HDL, and LDL in the two groups of patients before and after treatment ( M(IQR)

[0162]

[0163]

[0164] Note: *P<0.05 for intra-group comparison, ***P<0.001 for intra-group comparison, TC normal reference value: 0-5.18mmol / L, TG normal reference value: 0-1.70mmol / L, HDL normal reference value: 1.16-1.42mmol / L, LDL normal reference value: 0-3.37mmol / L

[0165] 5. Analysis of efficacy of inflammatory indicators (NLR, hs-CRP)

[0166] Before the intervention, there was no statistical difference in NLR and hs-CRP between the two groups (P>0.05), which was comparable. After the intervention, the NLR and hs-CRP of the treatment group were lower than those before treatment (P<0.05), and there was no statistical difference in NLR and hs-CRP of the control group (P>0.05), indicating that Jianpi Yishen Qinghua Heluo Fang can effectively improve the inflammatory state in DKD patients. The results are shown in Table 15.

[0167] Table 15 Comparison of NLR and hs-CRP between the two groups of patients before and after treatment ( M(IQR)

[0168]

[0169]

[0170] Note: *P<0.05 for intra-group comparison, normal reference value of hs-CRP: 0-0.6mg / dl

[0171] 6. Analysis of the efficacy of serum proteins (PA, Alb)

[0172] Before the intervention treatment, there was no statistical difference in serum PA and Alb between the two groups (P>0.05), which was comparable. After the intervention treatment, PA and Alb of the patients in the treatment group were significantly increased compared with those before treatment (P<0.001), while there was no statistical difference in PA and Alb of the patients in the control group compared with those before treatment (P>0.05). Alb of the patients in the treatment group was higher than that of the control group during the same period (P<0.05), indicating that Jianpi Yishen Qinghua Heluo Fang can effectively improve the serum PA and Alb levels of DKD patients, and the intervention effect on Alb is more obvious. The results are shown in Table 16.

[0173] Table 16 Comparison of PA and Alb between the two groups of patients before and after treatment

[0174]

[0175] Note: ***P<0.001 for intra-group comparison, ▲P<0.05 for inter-group comparison, normal reference value of PA: 200-400 mg / L, normal reference value of Alb: 40.0-55.0 g / L

[0176] 7. Analysis of Hcy efficacy

[0177] Before the intervention treatment, there was no statistical difference in serum Hcy between the two groups (P>0.05), which was comparable. After the intervention treatment, the serum Hcy of the patients in the treatment group decreased compared with that before treatment (P<0.05), and there was no statistical difference in serum Hcy of the patients in the control group compared with that before treatment (P>0.05), indicating that Jianpi Yishen Qinghua Heluo Fang can effectively reduce the serum Hcy level of DKD patients. The results are shown in Table 17.

[0178] Table 17 Comparison of Hcy (μmol / L) between the two groups of patients before and after treatment (M (IQR))

[0179]

[0180] Note: *P<0.05 for intra-group comparison, normal reference value of Hcy: 0-15.0μmol / L

[0181] 5.2.5 Analysis of the efficacy of traditional Chinese medicine

[0182] 1. Analysis of TCM syndrome efficacy

[0183] After the intervention treatment, 1 case of TCM syndrome in the treatment group was clinically controlled, 13 cases were markedly effective, 30 cases were effective, and the total effective rate was 89.80%. 0 case of clinical control, 0 case of markedly effective, 18 cases were effective, and the total effective rate was 38.30%. The TCM syndrome efficacy of the treatment group was significantly better than that of the control group (P < 0.001). The results are shown in Table 18.

[0184] Table 18 Comparison of TCM syndrome efficacy between the two groups of patients after treatment (cases, %)

[0185]

[0186] Note: Total effective rate = (clinical control + marked effect + effective) / total number of cases, ▲▲▲Inter-group comparison P < 0.001

[0187] 2. Analysis of the efficacy of single TCM syndrome

[0188] After the intervention treatment, the efficacy of each TCM syndrome in the treatment group was significantly better than that in the control group (P < 0.001), indicating that Jianpi Yishen Qinghua Heluo prescription has significant efficacy in improving the clinical TCM syndrome of patients with spleen and kidney qi deficiency and damp-heat stasis type DKD, and can comprehensively improve the symptoms of fatigue, shortness of breath, laziness, frequent urination, soreness of waist and knees, edema, heaviness of limbs, dark complexion, and skin and nail disorder in patients with spleen and kidney qi deficiency and damp-heat stasis type DKD, and improve the quality of life of DKD patients. The results are shown in Table 19.

[0189] Table 19 Comparison of the efficacy of single TCM syndromes in the two groups of patients after treatment (cases, %)

[0190]

[0191]

[0192]

[0193] Note: Total effective rate = (clinical control + marked effect + effective) / total number of cases, ▲▲▲Inter-group comparison P < 0.001

[0194] 3.2.6 Security Analysis

[0195] No serious adverse events occurred during the treatment in both groups. One patient in the treatment group and three patients in the control group withdrew from the trial due to urinary tract infection, which was considered to be related to the adverse reactions of empagliflozin. The results of this study showed that Jianpi Yishen Qinghua Heluo prescription had no adverse effects on the liver and kidney function, electrolytes, and blood routine of patients.

[0196] Example 5 Animal model experiment

[0197] 1. Experimental methods: 40 SFP healthy male SD rats were randomly divided into normal group, model group, empagliflozin group, Jianpi Yishen Qinghua Heluo Fang group, and Jianpi Yishen Qinghua Heluo Fang combined with empagliflozin group, with 8 rats in each group. A high-sugar and high-fat diet (20.0% sucrose, 10.0% lard, 2.5% cholesterol, 1.0% bile salt, 66.5% conventional feed) combined with low-dose (35 mg / kg) STZ injection was used to establish the DKD rat model. The normal group and the model group were gavaged with distilled water once a day, and the other three groups were gavaged with the corresponding drugs (6.3 times the equivalent dose of humans) once a day, with a gavage volume of 4 ml / kg / day, for 8 weeks. 24h urine was collected in metabolic cage to detect 24hUP, UACR, Uα1-MG, Uβ2-MG, and UNAG of rats in each group; blood was collected from abdominal aorta to detect SCysC, Scr, BUN, SUA, NLR, hs-CRP, FPG, TC, TG, HDL, LDL, and Hcy of rats in each group. Kidney specimens were stained with HE, PAS, and Masson to observe the pathological changes of renal tissues of rats in each group. qRT-PCR was used to detect the gene expressions of NF-κB, TNF-α, IL-8, and MCP-1 in renal tissues of rats in each group. WB was used to detect the protein expressions of AGEs, RAGE, NF-κB, TNF-α, IL-8, MCP-1, and VEGF in renal tissues of rats in each group.

[0198] 2. Experimental results

[0199] In terms of body weight and kidney coefficient, Jianpi Yishen Qinghua Heluo formula can increase the body weight of DKD rats (compared with the model group, P < 0.05) and reduce the kidney coefficient of DKD rats (compared with the model group, P < 0.01). The efficacy of the combination with empagliflozin is better than that of the two drugs alone (compared with the single drug group, P < 0.05 or P < 0.001). In terms of 24-h urine volume, both empagliflozin and Jianpi Yishen Qinghua Heluo formula are effective in improving the polyuria symptoms of DKD rats (compared with the model group, P < 0.001 or P < 0.01). The efficacy of the combination of the two drugs is better than that of the two drugs alone (compared with the single drug group, P < 0.05).

[0200] In terms of proteinuria, empagliflozin alone or in combination with Jianpi Yishen Qinghua Heluo Fang can reduce UACR (compared with the model group, P < 0.05 or P < 0.01) and 24hUP (compared with the model group, P < 0.01 or P < 0.001). The combination of the two drugs is more effective in reducing UACR and 24hUP than the two drugs alone (UACR: the combination of the two drugs group compared with the Jianpi Yishen Qinghua Heluo Fang group, P < 0.05, the empagliflozin group compared with the Jianpi Yishen Qinghua Heluo Fang group, P > 0.05; 24hUP: the combination of the two drugs group compared with the Jianpi Yishen Qinghua Heluo Fang group, P < 0.001, and the empagliflozin group compared with the empagliflozin group, P < 0.05). The combination of the two drugs can reduce UNAG in DKD rats (compared with the normal group, P < 0.05, compared with the model group, P < 0.05). See Table 20 for details:

[0201] Table 20 Comparison of UACR (mg / g), 24hUP (mg), and UNAG (mg / L) in rats of each group after intervention ( M(IQR)

[0202]

[0203] Note: *Compared with the normal group, P<0.05; **Compared with the normal group, P<0.01; ***Compared with the normal group, P<0.001; ▲Compared with the model group, P<0.05; ▲▲Compared with the model group, P<0.01; ▲▲▲Compared with the model group, P<0.001; #Compared with the empagliflozin group, P<0.05; ##Compared with the empagliflozin group, P<0.01; △Compared with the Jianpi Yishen Qinghua Heluo Fang group, P<0.05; △△△Compared with the Jianpi Yishen Qinghua Heluo Fang group, P<0.001

[0204] In terms of renal function, Jianpi Yishen Qinghua Heluo formula can reduce Scr, BUN, and SUA in DKD rats (compared with the model group, P < 0.05), and the combination of the two drugs can reduce SCysc in DKD rats (compared with the model group, P < 0.05), and the efficacy is better than that of empagliflozin alone (compared with the empagliflozin group, P < 0.05); in terms of inflammation, empagliflozin and Jianpi Yishen Qinghua Heluo formula can reduce hs-CRP in DKD rats (compared with the normal group, P > 0.05), and the combination of the two drugs can reduce NLR in DKD rats better than the two drugs alone (compared with the model group, P < 0.01); in terms of glucose metabolism, Jianpi Yishen Qinghua Heluo formula can reduce FPG in DKD rats (compared with the model group, P < 0.05). Compared with the model group, P<0.05); in terms of lipid metabolism, Jianpi Yishen Qinghua Heluo formula can reduce TC, TG, and LDL in DKD rats (compared with the model group, P<0.05 or P<0.01 or P<0.001), and its efficacy in reducing TG and LDL is better than that of empagliflozin (compared with the empagliflozin group, P<0.05). When used in combination with empagliflozin, it can enhance the efficacy of empagliflozin in reducing TC, TG, and LDL (compared with the empagliflozin group, P<0.05 or P<0.01); in terms of risk factors, Jianpi Yishen Qinghua Heluo formula can reduce Hcy in DKD rats (compared with the model group, P<0.05), and the combination of the two drugs can enhance the efficacy of empagliflozin in reducing Hcy (compared with the empagliflozin group, P<0.05). Pathological staining results showed that Jianpi Yishen Qinghua Heluo formula could reduce the proliferation of glomerular basement membrane and mesangial matrix, reduce renal interstitial inflammatory cell infiltration, tubular lesions and renal interstitial fibrosis in DKD rats (PAS positive rate and Masson positive rate compared with the model group P < 0.001). qRT-PCR results showed that Jianpi Yishen Qinghua Heluo formula could down-regulate the gene expression of NF-κB, TNF-α, IL-8 and MCP-1 in the renal tissue of DKD rats (compared with the model group P < 0.01), and the combination of the two drugs could enhance the effect of Jianpi Yishen Qinghua Heluo formula on down-regulating the gene expression of NF-κB, TNF-α, IL-8 and MCP-1 (compared with Jianpi Yishen Qinghua Heluo formula group P < 0.001 or P < 0.01), and enhance the effect of Empagliflozin on down-regulating the gene expression of IL-8 and MCP-1 in the renal tissue of DKD rats (compared with the normal group P > 0.05). WB results showed that Jianpi Yishen Qinghua Heluo prescription could down-regulate the protein expression of AGEs, RAGE, NF-κB, TNF-α, IL-8 and VEGF in the renal tissue of DKD rats (P<0.001 or P<0.01 compared with the model group); combined with empagliflozin, it could down-regulate the protein expression of MCP-1 in the renal tissue of DKD rats (P<0.01 compared with the model group); the combination of the two drugs was more effective in down-regulating the protein expression of AGEs, RAGE, NF-κB, TNF-α, IL-8 and VEGF than the single drug group (P<0.001 or P<0.01 compared with the single drug group).

[0205] 3. Experimental conclusion

[0206] Jianpi Yishen Qinghua Heluo formula can effectively alleviate the morbid symptoms of DKD rats such as emaciation and polyuria, improve the inflammation and glucose and lipid metabolism imbalance of DKD rats, reduce the risk factors of DKD renal vascular lesions, protect renal function, and enhance the effect of empagliflozin on reducing urine protein. One of its kidney protection mechanisms may be to regulate related inflammatory factors through the AGEs-RAGE signaling pathway, inhibit DKD inflammatory response, improve renal vascular endothelial function, reduce renal lesions, and reduce DKD proteinuria.

[0207] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. The present invention may be subject to various changes and improvements without departing from the spirit and scope of the present invention. These changes and improvements fall within the scope of the present invention. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A Chinese medicine composition for treating diabetic nephropathy, characterized in that: The traditional Chinese medicine composition is composed of the following raw materials in parts by weight: 10-60 parts by weight of raw astragalus, 5-30 parts by weight of polygonatum, 5-30 parts by weight of yam, 5-30 parts by weight of cornus, 3-15 parts by weight of coptis root, 5-30 parts by weight of euphorbia pulex, 5-30 parts by weight of burdock fruit and 3-15 parts by weight of leech.

2. The Chinese medicine composition for treating diabetic nephropathy according to claim 1, characterized in that: The traditional Chinese medicine composition is composed of the following raw materials in parts by weight: 30 parts of raw astragalus, 15 parts of polygonatum, 15 parts of yam, 15 parts of cornus officinalis, 6 parts of coptis root, 15 parts of euphorbia pulex, 15 parts of arctium barbatae, and 6 parts of leech.

3. The Chinese medicine composition for treating diabetic nephropathy according to claim 1, characterized in that: Raw Astragalus is the main medicine, Polygonatum sibiricum, Chinese yam, and Cornus officinalis are the auxiliary medicines, Coptis chinensis and Psoralea corylifolia are the adjuvant medicines, and Arctium lappa and Leech are the guiding medicines.

4. A pharmaceutical preparation comprising the Chinese medicine composition as claimed in any one of claims 1 to 3 as an active ingredient, characterized in that: The drug preparation is prepared into a common dosage form in pharmacy by a conventional preparation method in the art.

5. The pharmaceutical preparation according to claim 4, characterized in that The pharmaceutical preparation is in the form of decoction, granules, tablets, capsules, oral liquid, mixture or syrup.

6. The method for preparing the pharmaceutical preparation for treating diabetic nephropathy according to claim 4, characterized in that: The steps include: (A) A water decoction of Jianpi Yishen Qinghua Heluo Fang was prepared by a traditional decoction method: Chinese herbal medicine slices were weighed according to the formula ratio, drinking water was added until the water surface exceeded the slices by 2 cm, and the slices were soaked for 30 minutes, heated over high heat until the liquid medicine boiled, then lowered to low heat, and continued to boil for 30 minutes while maintaining a slight boiling state, the liquid medicine was poured out, the residue was added with water again, and the liquid medicine was poured out after decoction in the same way, the two liquid medicines were combined, filtered, and further concentrated to obtain a water extract of the Chinese herbal medicine composition; (B) A pharmaceutically acceptable carrier is added to the water extract and prepared by a conventional preparation method in the art.

7. Use of the Chinese medicine composition according to claim 1 or 2 in the preparation of a drug for treating diabetic nephropathy.

8. The use according to claim 7, characterized in that: This medicine is used in combination with other therapeutic agents.

9. The use according to claim 8, characterized in that: The other therapeutic agent is empagliflozin.

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