Li-Bei Zhan, Xiao-Dong Xiong, Kai Zhao

Department of Endocrinology, Shenyang Second Hospital of Traditional Chinese Medicine, Shenyang 110101, Liaoning, China

Keywords:

ABSTRACT

1. Introduction

Diabetic kidney disease (DKD) is one of the most important microvascular complications of diabetes mellitus (DM). It is a unique renal complication of DM and has become the main cause of chronic kidney disease and end-stage renal disease [1]. The pathogenesis of DKD is not clear, and it has been shown that it is related to hemodynamics, glycolipid metabolism disorder, inflammatory response, cytokines and other factors for a longterm comprehensive effect [2-3]. At present, the main clinical measures are to control blood glucose, blood pressure, blood lipid, exercise nutrition intervention and reduce urine protein to delay the sustained renal damage, but the effect is not good [4]. In recent years, traditional Chinese medicine (TCM) has shown its unique advantages in the treatment of DKD due to its comprehensive effect of multi-channel and multi-target. This study was to observe the clinical effect of warming yang, descending turbidity and dredging collaterals on DKD patients with yin-yang deficiency and blood stasis syndrome.

2. Data and methods

2.1 Case selection and grouping

76 cases of DKD with deficiency of yin-yang deficiency and blood stasis syndrome were randomly divided into observation group and control group. The trial met the requirements of medical ethics and was approved by the hospital ethics committee.

2.2 Case diagnosis and acceptance criteria

2.2.1 Case diagnosis criteria

The diagnosis standard of T2DM was established according to the relevant standards of Chinese guidelines for the prevention and treatment of type 2 diabetes (2017 version) [5], that is, the patients with typical diabetes symptoms and random blood glucose≥11.1mmol/L, or FBG ≥7.0mmol/L, or 2hPG ≥11.1mmol/L at OGTT.

The diagnosis standard of DKD was established in accordance with the relevant standards of the expert consensus on the prevention and treatment of diabetic nephropathy (2014 Edition) [6]. The diagnosis was early DKD (phase III): continuous microalbuminuria, UAE was 20-200 μ g / min or 30-300mg / 24h. The glomerular basement membrane was thickened and the mesangium was further widened by pathological examination.

The diagnosis standard of DKD with deficiency of yin-yang deficiency and blood stasis syndrome conforms to the guidelines for the prevention and treatment of diabetic nephropathy in traditional Chinese medicine [7], the diagnosis, syndrome differentiation and classification of diabetic nephropathy and the evaluation standard of curative effect (Trial Scheme) [8], the symptoms are mental depression, cold limbs, diarrhea, impotence, and spermatorrhea; the secondary symptoms are pale, listless, listless, puffy, acid and tinnitus; the tongue pulse is light, white, and pulse Later or thin and weak, or dark tongue color, tortuous sublingual vein, ecchymosis and ecchymosis, and astringent pulse.

2.2.2 Case inclusion criteria

①M(fèi)eet the above diagnostic criteria of traditional Chinese and Western medicine; ②The age range is 40-70 years; ③Voluntarily participate in the test and sign the informed consent.

2.2.3 Case exclusion criteria

①T1DM or those with diabetic ketoacidosis and other acute complications in the near future; ②those with other kidney diseases and taking history of nephrotoxic drugs; ③Those with serious organ dysfunction such as heart, lung, liver and brain; ④Those who are allergic or intolerant to the test drug.

2.3 Treatment

Control group: give western medicine conventional treatment [5-6], including appropriate exercise, diet regulation, health education, smoking and alcohol cessation, body quality control, blood sugar control, blood pressure control, correction of lipid metabolism disorders. Observation group: on the basis of the control group, the herbs (Astragalus, euryale, plantain, yam, Poria, epimedium, polygonatum, rehmannia, Yizhiren, Danshen, Zelan, cinnamon, Morinda officinalis, Radix Polygoni Multiflori, scorpion, rhubarb, roasted licorice root) were given by the warm yang and turbidity reducing method, one dose per day, three times in the morning, the middle and the evening. The course of treatment in both groups was one month, and adverse reactions were recorded.

2.4 Observation indicators

2.4.1 Clinical efficacy and TCM syndrome score

The TCM syndrome score and efficacy evaluation criteria are all formulated according to the guiding principles for clinical research of new Chinese medicine [9]. According to the severity of symptoms, 0 point, 1 point, 2 point and 3 point shall be calculated respectively according to no, light, medium and heavy symptoms, and 0 point and 1 point shall be calculated according to the presence of tongue pulse. Evaluation criteria of curative effect: ①Significant effective: clinical symptoms and signs basically disappeared, TCM syndrome integral curative effect index≥70%, blood sugar decreased by more than 1 / 3, UAER decreased by more than 1 / 2; ②Effective: clinical symptoms and signs improved, TCM syndrome integral curative effect index≥30%, blood sugar decreased by less than 1 / 3, UAER decreased by less than 1 / 2; ③Ineffective: clinical symptoms and signs did not improve or even worsen significantly The integral therapeutic index of TCM syndromes was less than 30%, and there was no change or aggravation of blood glucose and UAER. TCM syndrome integral efficacy index = (total score before treatment - total score after treatment) / total score before treatment ×100%.

2.4.2 Biochemical indexes of blood

FPG, 2hPG, SCR, bun, mAlb, HbA1c, Cys-C and CRP were measured by automatic biochemical analyzer, HbA1c and immunoturbidimetry. The changes of blood biochemical indexes were observed before and after treatment.

2.4.3 Hemorheology index

PV, Par and FIB were measured by automatic blood flow meter. The changes of hemorheology indexes were observed before and after treatment.

2.5 Statistical methods

SPSS 22.0 was used for data statistical analysis. The mean standard deviation (x±s) was used as the measurement data, the t-test was used as the comparison between groups, the rate (%) was used as the count data, and the χ2test was used as the comparison between groups. P < 0.05 was statistically significant.

3. Results

3.1 Comparison of baseline characteristics of two groups of patients

Among the 38 patients in the control group, 24 were male and 14 were female; the age was 42-67 years, the average age was (59.75±8.14) years; the course of DM was 6-15 years, the average course of DM was (7.53±1.49) years; the course of DKD was 10-18 months, the average course of DKD was (14.58±2.02) months; the body mass index (BMI) was (25.94±3.71) kg/m2. Among the 38 patients in the observation group, 28 were male and 10 were female, the age was 45-68 years, the average age was (60.37±8.42) years; the course of DM was 6-18 years, the average course of DM was (8.05±1.58) years; the course of DKD was 12-19 months, the average course of DKD was (14.76±2.18) months; the body mass index (BMI) was (26.46±3.73) kg/m2. During the observation period, there were no cases of abscission or withdrawal.

3.2 Two comparison of the clinical effect before and after treatment

Results as shown in Table 1, the total clinical effective rate of the observation group was significantly higher than that of the control group (P<0.05).

Table 1 Comparison of clinical effects of two groups before and after treatment

3.3 Comparison of TCM syndrome scores before and after treatment in two groups

Results as shown in Table 2, after treatment, the TCM syndrome score of the two groups was significantly lower than that before treatment, the difference was statistically significant (P<0.01); and the degree of decline in the observation group was more significant than that in the control group, the difference was statistically significant (P<0.01).

Table 2 Comparison of TCM syndrome scores between the two groups before and after treatment

3.4 Comparison of renal function indexes between two groups before and after treatment

Results as shown in Table 3, after treatment, the indexes of SCR, bun, mAlb and other renal functions in the two groups were significantly lower than those before treatment, the difference was statistically significant (P<0.05 or P<0.01); and the degree of decline in the observation group was more significant than that in the control group, the difference was statistically significant (P<0.05).

Table 3 Comparison of renal function indexes between the two groups before and after treatment

3.5 Comparison of glucose metabolism indexes between two groups before and after treatment

Results as shown in Table 4, after treatment, FPG, 2hPG, HbAlc and other indicators of glucose metabolism in the two groups were significantly lower than before treatment, the difference was statistically significant (P<0.05 or P<0.01); and the degree of decline in the observation group was more significant than that in the control group, the difference was statistically significant (P<0.05 or P<0.01).

Table 4 Comparison of glucose metabolism indexes between the two groups before and after treatment

3.6 Comparison of hemorheology indexes of two groups before and after treatment

Results as shown in Table 5, the hemorheological indexes of PV, Par and Fib in the two groups after treatment were significantly lower than those before treatment, and the difference was statistically significant (P<0.05 or P<0.01); the degree of decline in the observation group was more significant than that in the control group, and the difference was statistically significant (P<0.05 or P<0.01).

Table 5 Comparison of hemorheology indexes between the two groups before and after treatment

3.7 Comparison of Cys-C and CRP before and after treatment in two groups

Results as shown in Table 6, Cys-C and CRP in the two groups after treatment were significantly lower than those before treatment, the difference was statistically significant (P<0.05 or P<0.01); and the degree of decline in the observation group was more significant than that in the control group, the difference was statistically significant (P<0.05 or P<0.01).

Table 6 Comparison of inflammatory factors between the two groups before and after treatment

4. Discussion

The mechanism of DKD development is not clear, which may involve many factors such as glycolipid metabolism disorder, inflammatory response, endothelial cell damage, hemodynamic and hemorheological abnormalities, advanced glycation end products accumulation [10]. In recent years, the research on micro inflammatory state, microcirculation disorder and pathogenesis of DKD has become one of the hot issues in clinical research. Therefore, it is of great significance to study the effects of traditional Chinese medicine treatment on microcirculation disorders, micro inflammatory state and biochemical indexes of DKD with deficiency of yin-yang deficiency and blood stasis syndrome.

There is no record of DKD in the ancient books of traditional Chinese medicine. In traditional Chinese medicine, it is classified as "thirst quenching", "fatigue", "urine turbidity" and "edema". At present, the name of DKD has been unified as "diabetes nephropathy", and the pathogenesis evolution of DKD can be understood from the perspective of the pathogenesis of diabetes in traditional Chinese medicine [11-12]. Therefore, the pathogenesis of DKD is based on the deficiency of Qi and Yin, and the heat is the standard. If the disease is not prolonged, there will be pathological changes of deficiency of yin and Yang, blood stasis and internal resistance, which is suitable for the treatment of Warming Yang, reducing turbidity and dredging collaterals. In the traditional Chinese medicine composition of Warming Yang, reducing turbidity and dredging collaterals, Astragalus membranaceus, epimedium, Morinda officinalis, Yizhiren, cinnamon invigorating spleen and kidney, benefiting qi and warming Yang, yam, rehmannia root, Huangjing, making Polygonum multiflorum, Euryale ferox, nourishing yin and kidney, filling essence and consolidating the essence, Cheqianzi and poria cocos infiltrate into water, Zelan, Salvia miltiorrhiza and rhubarb activate blood and remove stasis, scorpion disperses and dredges collaterals, baked licorice and reconcile various drugs. It is suitable for the pathogenesis of deficiency of both yin and Yang and blood stasis in DKD. Modern pharmacological research shows that Astragalus can significantly reduce the fasting blood glucose level in DKD rats to regulate the disorder of glycolipid metabolism, reduce the excretion of renal proteinuria to protect the basement membrane of glomerulus, and the specific mechanism of action is closely related to the inhibition of oxidative stress level, the reduction of adiponectin protein and endothelin level in renal tissue, and the reduction of TGF - β / Smads signal transduction pathway expression [13]. Epimedium can protect renal function by inhibiting the expression of inflammatory factors and apoptosis factors, reducing the level of oxidative stress and extracellular matrix deposition in DKD rats [14]. Yizhiren can reduce the level of blood glucose and urinary albumin in DKD mice, protect the renal function and achieve the purpose of DKD treatment. The mechanism of action is closely related to the regulation of intestinal microbial function, the inhibition of oxidative stress level, and the down regulation of AQP2 and p27kip1Protein expression [15-16]. Chinese yam polysaccharide can reduce the level of blood glucose and lipid and improve the renal function in DKD mice. The mechanism may be related to the inhibition of AR/p38MAPK/CREB signal pathway [17]. Polygonatum Polysaccharide plays a renal protective role in DKD by reducing blood glucose and inhibiting the expression of fibrosis factors, while Polygonatum saponin plays a renal protective role in inhibiting Wnt/β-Catenin signal transduction pathway and tubulointerstitial fibrosis [18]. Euryale can regulate the expression of TIMP-1 and MMP-9, inhibit the deposition of extracellular matrix, reduce the excretion of proteinuria, and protect the renal function to delay the progress of DKD [19]. Zeylang can reduce the urinary protein level of early DKD mice by inhibiting the expression of PKCα, PKCβⅠ, AGEs-MCP-1-TGF-β1, so as to play a renal protective role [20]. Sodium tanshinone Ⅱ A sulfonate and Danshen injection have significant effect in the clinical treatment of patients with DKD, and can regulate the blood lipid, hemorheological state, and the expression of inflammatory factors to play a therapeutic role [21]. The effective components of rhubarb are rhein and rhein, which can significantly reduce the excretion of DKD urinary protein, improve glomerulosclerosis, reduce mesangial expansion and renal hypertrophy [22]. In recent years, it has been found that DKD is closely related to hemorheology. Patients with DKD are more likely to have hypercoagulable state, decreased RBC deformation and microthrombosis. The results of this study showed that traditional Chinese medicine can significantly reduce the syndrome integral of DKD patients with deficiency of yin-yang deficiency and blood stasis syndrome (P<0.01), renal function indexes such as SCR, BUN and MALB (P<0.05 or P<0.01), glucose metabolism indexes such as FPG, 2hPG and HbAlc (P<0.05 or P<0.01), hemorheology indexes such as PV, Par and FIB (P<0.05 or P<0.01), suggesting that traditional Chinese medicine can significantly reduce the syndrome integral of DKD patients with deficiency of yin-yang deficiency and blood stasis syndrome (P<0.01) It can effectively alleviate the clinical symptoms of DKD patients with deficiency of yin-yang deficiency and blood stasis syndrome, improve glucose metabolism, renal function and microcirculation disorders, and improve the clinical treatment effect.

The essence of microinflammatory state lies in the systemic chronic slight inflammatory reaction centered on the release of acute phase reaction proteins such as CRP and cytokines such as TNF-α, IL-1 and IL-6, which can directly aggravate renal injury [23-24]. CRP is essentially a non glycosylated polymer protein, and its synthesis site is mainly in the liver. It can bind to the specific surface receptor of the kidney, so as to activate the inflammatory response of the human body, leading to the thickening of mesangial membrane and the impairment of renal function. Therefore, CRP can be used as a sensitive and objective indicator to evaluate the micro inflammatory state of DKD, and also a target marker for the activation of inflammatory cytokines in the body. Studies have shown that CRP can cause abnormal proliferation of DKD glomerular cells and destroy the permeability of endothelial cells. The increase of CRP level is also closely related to urinary protein excretion [25-26]. Cys-C is the sulfur-containing amino acid metabolite of the body, the synthesis site is mainly in the body nuclear cells, the elimination of metabolism process is mainly carried out in the kidney, when the level is too high, it indicates that the renal function is damaged, which is an important indicator to measure the glomerular filtration rate, and the level change degree and glomerular filtration rate show a significant negative correlation trend [27]. Therefore, the monitoring of Cys-C and CRP has an important guiding value for the condition, treatment and prognosis of DKD. The results of this study suggest that the method of Warming Yang, reducing turbidity and dredging collaterals can reduce the micro inflammatory state of DKD patients with deficiency of yin-yang deficiency and blood stasis syndrome, and avoid further damage to renal tissue.

In conclusion, compound of warming yang, descending turbidity and dredging collaterals has remarkable efficacy in treating of diabetic kidney disease patients with yin-yang deficiency and blood stasis syndrome by alleviating clinical symptoms, glucose metabolism, renal function and microcirculatory disturbance, and the mechanism related to alleviation of microinflammation.