Systematic Evaluation and Meta-analysis of Traditional Chinese Medicine in the Treatment of Diabetic Nephropathy

The Chinese Society of Traditional Chinese Medicine has issued the “Guidelines for Prevention and Treatment of Diabetic Nephropathy in Traditional Chinese Medicine”, in which diabetic nephropathy is divided into main evidence, part-evidence and changeable evidence, in which the main evidence is deficiency of qi and yin, deficiency of yin in liver and kidney, deficiency of qi and blood, deficiency of yang in spleen and kidney, respectively, the main evidence is used to use the Senqi Dihuang Tang with addition or subtraction, Qiji Chrysanthemum Dihuang Pill with addition or subtraction, Danggui Blood Replenishing Tang with Kidney Qi-wan with addition or subtraction, Pianzi Lizhong Wan with Zhenwu Tang with addition or subtraction. For blood stasis, dampness-heat and phlegm-drinking, in addition to the main formula, add peach kernel, safflower and danshen to activate blood circulation and eliminate blood stasis; for dampness-heat, add Huanglian, Poria and rhubarb to clear away heat and promote dampness; for phlegm-drinking, add ErChen Tang or WuLingShan to add or subtract. Variations of the syndrome are turbid toxin violating the stomach, drowning toxin in the brain, watery qi lingering in the heart, turbid toxin stasis, all of which are caused by the pathological products of renal deficiency and powerlessness.

In the “Diabetic Nephropathy Combined Diagnosis and Treatment Guidelines” issued by the Chinese and Western Medicine Association of Chinese Physicians Association in 2021, the degree of proteinuria is graded by the degree of urine turbidity for typing and treatment. Mild proteinuria (0.5g ≤ UTP ≤ 1g in 24h urine) is accompanied by bitter taste in mouth and dryness in mouth, and the urine is red and astringent, which belongs to the injection of dampness and heat, and treatment is to use Cheng’s Dioscoreopsis Dioxide Drink with subtractions. Moderate proteinuria (1g < UTP ≤ 3.5g) with abdominal distension, fatigue, is a deficiency of the spleen and qi trap, the treatment should be used to replenish the middle and benefit qi soup, severe proteinuria (UTP ≥ 3.5g) and accompanied by dizziness, tinnitus, lumbar and knee soreness and weakness, is the evidence of renal qi is not solid, this time, we need to pay attention to differentiate between the yin and yang bias, bias Yin, it is appropriate to Zhi Bo Dihuang Tang combined with the Er Zhi Pill plus or minus, and biased in yang, it is appropriate to antler antlers to replenish the astringent Pill plus or minus.

Diabetic nephropathy prevention and treatment guidelines for Chinese medicine will be diabetic nephropathy staging and evolution of the law is summarized as the onset of the early stage, the progression of lesions, lesions, early due to diabetes mellitus for a long period of time caused by qi and yin deficiency gradually to the liver and kidney due to the kidney qi deficiency, opening and closing of the loss, open and close the less frequent urination, open and close the less and close the less urinary edema. In the advanced stage of the disease, the deficiency is more serious, mainly due to the deficiency of spleen and kidney yang, water and dampness retention, overflowing skin, and yang deficiency can not warm the four end, then cold limbs. In the advanced stage of the disease, the change of the evidence is mainly bee rise, the water and drink Lingxin shot lungs, turbid evil congestion Sanjiao, to the upper and lower grid refusal, or even drowning poison human brain.

Diabetic nephropathy is characterized by proteinuria, generalized weakness, and edema in the late stage [20]. In Chinese medicine, the pathogenesis of the disease is that the kidney qi is weak and has no power to regulate, leading to the leakage of essence and micro-substances, and Astragalus is “the most qi tonic medicine”, and its sweet and warm nature also helps to transform the qi effect of yang. Thirsty kidney disease patients are often accompanied by symptoms of edema, and astragalus has the function of diuresis and swelling, can play the role of assisting the spleen to transport water and dampness, through the channels to facilitate the waterway, improve the role of fluid dispersion, in modern pharmacology, astragalus contains astragali saponin, there is protection of the inner wall of the blood vessels, which can restore the function of microvessels in the glomerulus, thus strengthening the filtration of urinary protein to improve the patient’s renal function, and to slow down the development of the disease.The frequency of the use of yam is second only to astragalus, yam is sweet and flat, can supplement the lungs, spleen and kidneys of the three organs of the qi, but also need to medicinal drugs on the patient’s body almost no negative impact, and yam has a tonic kidney filling essence, astringent and diarrhea stopping function, can be nourished in the innate qi, fill the essence of the innate, fixing the essence of the subtle to prevent the leakage of the body. The polysaccharide in yam can significantly reduce blood glucose in the body, as well as urea nitrogen and creatinine in the blood, which can effectively alleviate some of the inflammatory reactions caused by diabetic nephropathy and protect the organs of the body. Poria, the holy medicine of dehumidification, Qing tonic good, sweet and bland in nature, with the spleen and kidney, diuresis and seepage of dampness, and thirst disease nephropathy patients with weak spleen and qi, for the dampness of the evil trapped, the earth can not be weak to cure water, so the water and dampness gathered into edema.Poria is good at tonifying qi and promoting water circulation, strengthening the spleen and seeping dampness, which can effectively reduce the symptoms of edema without harming the fluid. The active ingredients in Poria are Poria polysaccharide and Poria ethanol, which can effectively treat proteinuria and edema caused by renal insufficiency, and can slow down the development of the disease towards end-stage renal failure. Danshen is bitter and slightly cold in nature, with the effect of activating blood circulation, removing blood stasis, tonifying blood and nourishing blood. In patients with thirst-quenching kidney disease, blood stasis obstructs collaterals and hinders the operation of qi, resulting in abnormal circulation of water and liquid, which is transformed into oedema, which can be seen as stagnant blood running through the whole course of the disease. Salvia divinorum can break the blood stasis and generate new blood, which not only can reduce edema caused by blood stasis, but also can prevent the symptoms of water and drink overriding the heart in the late stage of the disease of thirst-quenching nephropathy. In modern pharmacology, Salvia miltiorrhiza also has the ability to reduce capillary permeability, reduce inflammatory exudation, and achieve anti-inflammatory effect, so as to achieve the treatment of diabetic nephropathy early inflammatory reaction, and protect the kidneys.Cornus officinalis is sour and astringent and warm in nature, with the effect of tonifying the kidney and filling in the essence, astringent and solidifying the kidney, it can supplement the kidney qi and astringent essence and micro-substances and thus protect the organs. In modern pharmacology, Cornus officinalis has obvious hypoglycemic effect and is one of the main medicines for the treatment of diabetes.

In modern research, Astragalus has outstanding therapeutic effect on DKD, as a commonly used additive and subtractive drug in diabetes mellitus and diabetic nephropathy Chinese formula. Its main active substances are astragali polysaccharides, astragali saponins and flavonoids, which can effectively improve the symptoms of DKD, and its mechanism of action may be related to the inhibition of PI3K/Akt/FoxO1 signaling pathway, increase the autophagy activity of renal tissue cells, reduce the damage of renal tissue, thus slowing down the development process of DKD. And some related studies have shown that the combined application of Astragalus injection in the conventional treatment of DKD can play a synergistic role and improve the therapeutic effect, which has a better effect on reducing proteinuria, regulating microcirculation, lowering blood lipids, and improving the renal function of patients, and it is one of the ideal methods to effectively prevent and delay the progression of DKD.The Chinese medicine Cordyceps sinensis is a well-known medicinal fungus in China, which belongs to Cordyceps sinensis of the ergot family, and has the effects of preserving the lungs and benefiting the kidneys, replenishing the deficiency and filling the essence. Clinically, it has significant anti-fibrosis, immune regulation, antioxidant, hypoglycemic and other effects, and has a better clinical protective effect on the lungs, kidneys, immune system and so on. In clinical research we found that on the basis of conventional treatment, the addition of Cordyceps preparation can reduce the excretion of urinary micro-protein in DKD patients, reduce the interstitial damage of renal tubules in DKD patients, and delay the progression of renal fibrosis. A medicinal fungus similar to Cordyceps sinensis, Cicadellia sinensis, is also getting more and more clinical attention.

RCTs of Chinese medicine for DN, with or without blinding.

For patients diagnosed with DN, the diagnosis of DN was referred to the DN diagnostic criteria piloted by the Nephrology Branch of the Chinese Society of Traditional Chinese Medicine in 2007.

Along with the basic treatment, the treatment group was intervened with TCM techniques including Chinese herbs, proprietary Chinese medicines, TCM extracts, and TCM injections, with or without ACEI/ARB drugs. The control group was treated with placebo or ACEI/ARB drugs alone, with unlimited dosage and duration of administration.

Clinical efficacy, urinary microalbumin excretion rate (UAER), blood creatinine (SCr), blood urea nitrogen (BUN), glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), postprandial 2h blood glucose (2hPG), cholesterol (TC), and triglycerides (TG) [21].

(1) Duplicate publications, and (2) literature with incomplete data information or questionable data.

We searched PubMed, China Knowledge Network Database (CNKI), Wanfang Data Knowledge Service, and Wipro to collect relevant RCTs of Chinese medicine interventions in DN, and the search period was set as January 2006-October 2023.The search was conducted by combining free words and subject terms, and the search strategy was adjusted according to the characteristics of different databases in a timely manner for multiple searches, to improve the search rate. The search terms included: diabetic nephropathy, traditional Chinese medicine, traditional Chinese medicine, Chinese herbal medicine, Chinese medicine, randomized controlled, clinical research.

Two evaluators independently cross-checked, and in case of disagreement, discussed or consulted with a third party to reach agreement. The extraction of basic information mainly included: (1) the basic information of the included literature, such as the title, the first author, and the time of publication. (2) Baseline characteristics of the study population, including sample size, age, gender, etc. of each group. (3) Specific details of the interventions, including the type of drug administered, the dose of drug administered, the frequency of drug administration, and the duration of treatment. (4) Key elements of risk of bias evaluation. (5) The outcome indicators and outcome measures of interest. The risk of bias of the included studies was evaluated by 2 evaluators using the Cochrane Handbook for Systematic Evaluators’ Risk of Bias Assessment Tool for RCTs.

Meta-analysis was performed using RevMan 5.3 software provided by Cochrane. Relative risk (RR) was used as the effect indicator for counting data, and mean difference (MD) was used as the effect indicator for measuring data, and point estimates and 95% confidence intervals (CIs) were given for each effect. Heterogeneity test was performed before combining the results (P=0.05 as the level of significance), and the magnitude of heterogeneity was quantitatively determined by combining with the I². If there was no statistical heterogeneity among the results, a fixed-effects model was used for meta-analysis, and if there was statistical heterogeneity, a random-effects model was used for meta-analysis. The magnitude of heterogeneity was quantitatively determined. If there was no statistical heterogeneity among the results of each study, Meta-analysis was performed using a fixed-effects model. If there was statistical heterogeneity, Meta-analysis was performed using a random-effects model.

Table 1 and Figure 1 show the results of the effect of UAER, 9 studies reported UAER, 437 patients in the experimental group and 446 patients in the control group, the heterogeneity test showed that I²=94.36%, suggesting that there was a large heterogeneity among the studies. After the sensitivity analysis of each study by excluding each study, and the analysis of different subgroups of the study subjects with respect to the duration of the disease, the drug dosage form, and the evidence, the source of heterogeneity still could not be found. According to P<0.00001, I²=94.36%>50%, a randomized controlled model was chosen for the combined analysis. The meta result showed that the diamond was located on the side favoring the experimental group, SMD=-1.92, 95%CI [-2.59,-1.33], P<0.00001, the difference was statistically significant, which indicated that the experimental group was superior to the experimental group in improving UAER in diabetic nephropathy. The results showed that the experimental group was better than the experimental group in improving UAER in diabetic nephropathy. Nephropathy UAER better than the control group.

Figure 1.

UAER affects the result

Table 2 and Figure 2 show the results of the effect of BUN. 15 studies reported 788 patients in the test group and 788 patients in the control group, and the results of the heterogeneity test showed that I²=96.85%, suggesting that there was a large heterogeneity among the studies. After the sensitivity analysis by excluding each study one by one and analyzing different subgroups of the study subjects with regard to the duration of the disease, the drug dosage form, and the diagnostic symptoms, the source of heterogeneity still could not be found. According to P<0.00001, I²=96.85%>50%, the randomized controlled model was chosen for the combined analysis. The meta result showed that the diamond was located on the side favoring the experimental group, MD=-1.78, 95C [-2.18,-1.23], P<0.00001, the difference was statistically significant, which indicated that the experimental group was better than the control group in improving the BUN in diabetic nephropathy. Better than the control group.

Figure 2.

The effect of BUN

Table 3 and Figure 3 show the results of SCr effects, respectively. 18 studies reported 904 patients in the Scr test group and 903 patients in the control group, and the results of the heterogeneity test showed that I²=98.56%, suggesting that there was a large degree of heterogeneity among the studies. After sensitivity analysis of each study by eliminating each study, and different subgroups of the study subjects with regard to the duration of the disease, the drug dosage form, and the symptoms of the disease, the source of the heterogeneity could not be found. According to P<0.00001, I²=98.56%>50%, the random effect model was chosen for the analysis, and the meta-analysis showed that the diamond was located on the side favoring the experimental group, MD=-15.26, 95%CI [-23.25,-8.15], P<0.0001, the difference was statistically significant, which indicated that the experimental group was superior to the experimental group in terms of improving the Scr of diabetic nephropathy. The results showed that the experimental group was better than the experimental group in terms of improving the Scr of diabetic nephropathy. Scr in diabetic nephropathy was better than the control group.

Figure 3.

SCR impact results

Table 4 and Figure 4 showed the results of the effect of FBG, 12 studies reported FBG, 709 patients in the test group and 704 patients in the control group, the results of the heterogeneity test showed that: I²=96.23%, suggesting that there was a large heterogeneity between the studies, and according to the P<0.00001, I²=96.23%>50%, so a random-effects model was chosen for the analysis. The results of the Meta-analysis showed that: the rhombus located on the side favoring the experimental group, MD=-0.79, 95%CI [-1.08,-0.39], P<0.0001, the difference was statistically significant, indicating that the experimental group was better than the control group in improving FBG in diabetic nephropathy.

Figure 4.

FBG effect

Table 5 and Figure 5 show the results of the effect of 2hPG.A total of 5 studies described 2 hours postprandial glucose, and a total of 754 patients were included. The combined results showed that: there was a large heterogeneity among the studies(I²=82%). After the sensitivity analysis by excluding each study one by one, and different subgroups of analysis targeting the study’s intervention period, drug dosage form, and evidence, the source of heterogeneity still couldn’t be found. A random effect model, MD=-0.58, 95%CI [-0.89,-0.15], P=0.01<0.05, P=0.01<0.15, was used for the study. Random effect model, MD= -0.58, 95%CI [-0.89,-0.15], P=0.01<0.05, the difference was statistically significant, which indicated that the trial group was better than the control group in improving the 2-hour postprandial blood glucose.

Figure 5.

The effects of 2hPG

Table 6 and Figure 6 show the results of the effect of glycated hemoglobin. A total of 9 studies described glycated hemoglobin, a total of 1,070 patients were included,535 patients in each of the control and experimental groups. The combined results showed that: there was a high degree of heterogeneity among the studies(I²=98.56%). After sensitivity analysis by excluding each study one by one and different subgroups of the studies targeting the intervention period, drug dosage form and the diagnostic profile. The random effect model was chosen, the diamond was located on the side favoring the experimental group, MD=-0.69, 95%CI [-1.29, -0.29], Z=3.25, P=0.00005, and the difference was statistically significant, indicating that the experimental group was better than the control group in improving glycated hemoglobin.

Figure 6.

Effects of glycosylated hemoglobin

Table 7 and Figure 7 shows the results of cholesterol effects. Among the included RCTs, a total of 7 studies described cholesterol, and a total of 534 patients were included. The combined results showed: P<0.00001 for heterogeneity test, I²=49%, moderate heterogeneity among studies. Fixed effect model was chosen. Meta-analysis showed that: the test group was more effective in lowering cholesterol than the control group, with an MD: -0.58, 95%CI [-0.67, -0.34].

Figure 7.

Cholesterol effect

Table 8 and Figure 8 show the results of the effect of triglycerides. Among the included RCTs, a total of 7 studies described triglycerides and a total of 534 patients were enrolled. The combined results showed: Heterogeneity test P=0.29, I²=23%, moderate heterogeneity among studies. Fixed effect model was chosen. Meta-analysis showed that: the test group had a better effect on lowering triglycerides than the control group. MD: -0.37, 95%CI: [-0.48, -0.29].

Figure 8.

Effects of triglycerides