Research progress on non-drug treatment of diabetic kidney disease

Bei-Liang Miao,Li Yu,Jing Li,Hong-Tao Yang＊

1First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin,China.2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion,Tianjin,China.

Abstract Diabetic kidney disease is one of the most serious and common chronic complications of diabetes and one of the leading causes of death in diabetic patients.In the case of diabetic kidney disease,sustained proteinuria is irreversible until it develops into end-stage renal disease.Drug treatment of diabetic kidney disease is relatively limited.More and more evidences into the effectiveness and safety that related non-drug treatments not only have the characteristics of simple operation and high safety,but also can improve the clinical symptoms of patients with diabetic kidney disease,reduce laboratory indicators,and delay disease progression.This article summarizes the recent literature on non-drug treatment of diabetic kidney disease such as exercise therapy,acupuncture therapy,acupoint application,auricular acupoint pressing pill therapy,moxibustion therapy,in order to provide reference for clinical treatment.

Keywords:Diabetic kidney disease,External therapy,Modern rehabilitation treatment methods,Traditional non-drug therapy,Acupuncture

Background

Diabetic kidney disease(DKD)refers to glomerular sclerosis caused by abnormal metabolism of diabetes mellitus,which is a typical diabetic microvascular disease and a common complication of diabetes[1].The incidence of DKD has increased sharply in recent years.Studies have shown that about 21.8%of diabetic patients in China developed DKD from 1980 to 2019[2].Once patients with DKD develop into dominant nephropathy,they will continue to progress and eventually become end-stage renal disease,which is the second most common cause of end-stage renal disease in China after glomerular disease[3].At present,angiotensin converting enzyme inhibitor and angiotensin II receptor blocker are the main drugs to delay the progression of DKD.The latest drugs,sodium glucose co-transporter 2 inhibitors,can effectively reduce blood glucose,control the occurrence of proteinuria,and reduce the incidence of renal failure and cardiovascular events has good treatment effect,but there are still a small part of the patients in the use of the drug in mycotic genital infections,urinary tract infections and diabetic ketoacidosis adverse reactions[4,5].Therefore,in order to effectively control the development of DKD and prevent the process of DKD,it is necessary to cooperate with more efficient and safe external therapy,including modern rehabilitation treatment methods and traditional Chinese medicine treatment methods.Therefore,the author now summarizes the research progress on treatment of DKD with external therapy as follows.

Exercise therapy

Exercise plays an important part in diabetes prevention and management[6].Expert Consensus on MultidisciplinaryDiagnosis,Treatmentand Management of Diabetic Kidney Diseaseattaches importance to the multidisciplinary diagnosis,treatment and management of patients with DKD,and emphasizes the role of exercise therapy[7].It is recommended that patients with DKD do at least 150 minutes of moderate-intensity aerobic exercise(such as brisk walking)per week for at least 5 days per week,divided into periods of at least 30 minutes each time.For patients at risk for cardiovascular disease,an exercise tolerance assessment should be performed before moderate intensity exercise.Proper exercise is not only conducive to weight loss and physical improvement[8],but also can improve the body’s sensitivity to insulin and reduce the level of HbA1c,thus reducing the risk of diabetic patients complicated with DKD[9].Bai et al.[10]on the basis of routine treatment combined with ballroom dancing,tai chi,walking and other exercise therapy,after 3 months of treatment,the levels of fasting plasma glucose,postprandial plasma blood glucose,hemoglobin A1c(HbA1c),total cholesterol,triglyceride,low-density lipoprotein cholesterol,urinary microalbuminuria,blood urea nitrogen,and serum creatinine in the experimental group were lower than those in the control group.It is suggested that non-high-intensity rational exercise therapy can relax the muscles and the whole body.At the same time,through non intensive exercise can put the brain in a protective inhibition state,which can reduce sympathetic nervous system activity,reduce the levels of norepinephrine and epinephrine,improve the level of renal function of patients,and play a role in protecting the patient’s kidney.A meta-study abroad found that aerobic exercise reduced HbA1c by 0.6%[11].Yu et al.[12]to explore whether reasonable exercise is beneficial to patients with DKD.They observed 1,232 patients with type 2 diabetes mellitus(age 18–75 years)who were followed up regularly for more than 1 year from 2008 to 2010 at Chia-Yi Christian Hospital were enrolled.They are divided to sedentary group,low physical activity group and adequate physical activity group according to their metabolic equivalent.The results showed that males were more likely to engage in physical activity.Waist circumference,body weight,blood glucose and triglyceride,microalbuminuria,and the estimated glomerular filtration rate were significantly lower in the adequate physical activity group.Physical activity displayed borderline significance in reducing urine protein levels by>50%in the macroalbuminuria group.It is suggested that appropriate exercise is helpful to improve the prognosis of patients with DKD.

The role of exercise in diabetic kidney disease is not well known.In animal studies,exercise reduced advanced glycosylation end products(AGEs)and oxidative stress and reduced proteinuria and preserved renal podocyte[13,14].

Acupuncture therapy

Effectiveness of acupuncture in the treatment of diabetic kidney disease

Acupuncture is one of the important means of non-drug treatment,which has two-way adjustment and overall adjustment.It is good at dredging the meridians,promoting blood circulation and removing blood stasis,making Qi and blood flow and harmonizing Yin and Yang.Many meta-analysis suggest that acupuncture for the treatment of diabetic kidney disease can not only be used as an adjuvant therapy to increase the efficacy,but also can fundamentally solve and relieve the clinical symptoms and indicators of DKD.Zhao et al.[15]explored the clinical efficacy of acupuncture in the adjuvant treatment of diabetic renal disease through meta-analysis and found that acupuncture in the adjuvant treatment of DKD could significantly reduce the levels of Urinary albumin excretion,serum creatinine,blood urea nitrogen,triglyceride,improve renal function and improve the clinical effective rate of DKD treatment.At the same time,it was found that the most commonly used acupoints of DKD were Shenshu(BL23),Guanyuan(CV4),Zusanli(ST36),Taixi(KI3),Sanyinjiao(SP6),Pishu(BL20)and Yinlingquan(SP6).Wang et al.[16]also conducted a meta-analysis on the treatment of diabetic kidney disease with acupuncture and moxibustion,and found that acupuncture can reduce the level of urinary albumin excretion,delay the deterioration of renal function and improve backache,edema,limb numbness,frequent urination and other symptoms in patients with DKD.

Different angles of acupuncture treatment of diabetic kidney disease

Treat from the“spleen”

This method believes that spleen deficiency is the basic pathogenesis of diabetic kidney disease,so harmonizing spleen-stomach acupoints are often used for treatment.Zhang et al.[17]used the method of harmonizing spleen-stomach for early intervention of diabetic kidney disease.They used multi-central,randomized and blind methods,130 cases of diabetic kidney disease were divided into an observation group and a control group,65 cases in each group.They were treated by routine diabetic therapy,and in the observation group,acupuncture at Quchi(LI11),Zhigou(TE6),Hegu(LI4),Xuehai(SP10),Zusanli(ST36),Yinlingquan(SP9),Fenglong(ST40),Diji(SP8),Sanyinjiao(SP6),Taichong(LR3),Tianshu(ST25),Gaohuang(BL43),Shenshu(BL23),Zhongwan(CV12),Zhongji(CV3)were added with needling method of harmonizing spleen-stomach,apply the uniform reinforcing-reducing method for 30 minutes,twice a day,1 week was a course of treatment,and a total of 6 courses of treatment were observed.The results showed that the needling method of harmonizing spleen-stomach is an effective method for diabetic kidney disease.This method can improve progressive renal lesion induced by abnormal metabolism of blood sugar and lipids,improve renal blood flow and glomerular filtration rate(GFR),decrease urinary albumin secretion,inhibit over expression of membrane cofactor protein 1,protect glomerulus and renal tubules,so as to improve renal function and delay renal lesion.

Treat from the“kidney”

This method believes that diabetic kidney disease is mostly middle-aged and elderly patients,so kidney Qi deficiency is the basic cause of the disease.Shenshu(BL23),Taixi(KI3),Sanyinjiao(SP6),Guanyuan(CV4)and Mingmen(GV4)are often used as the main acupoints to replenish kidney qi.Chen et al.[18]treated 30 diabetic kidney disease patients with acupuncture on Shenshu(BL23),Taixi(KI3),Sanyinjiao(SP6)and related points on the basis of conventional western medicine.The results showed that the levels of HbA1c,urinary microalbuminuria,serum creatinine and blood urea nitrogen in the treatment group were significantly decreased,the difference was significant(P<0.05).The effective rate of the treatment group was 83.3%,and that of the control group was 70%.This study shows that acupuncture has obvious protective effect on renal function of diabetic kidney disease.

Treat from the“spleen and kidney”

Geng et al.[19]believes that the deficiency of spleen and kidney is the basic pathogenesis of this disease,so the back acupoints such as Weiwanxiashu(EX-B3),Shenshu(BL23),Pishu(BL20)and Geshu(BL17)were selected,and the acupoints such as Guanyuan(CV4),Zusanli(ST36),Sanyinjiao(SP6),Taixi(KI3)and Xuehai(SP10)were selected to strengthen the spleen,invigorate the kidney and promote blood circulation,which has a good intervention effect in the treatment of early diabetic kidney disease.Chu et al.[20]in order to explore the curative effect of acupuncture in the treatment of DKD,30 patients in the experimental group were treated with a twisting tonic method at Guanyuan(CV4),Pishu(BL20),Shenshu(BL23),Zusanli(ST36),and Taixi(KI3)points on the basis of diet control and conventional hypoglycemic drug treatment.In Ganshu(BL18),Weiwanxiashu (EX-B3), Yinlingquan (SP9),Sanyinjiao(SP6)and other acupoints,small amplitude flattening,replenishing,relieving and twisting maneuvers were performed for 30 days,and the needle was retained for 20 minutes,once a day,compared with 24 patients who received conventional treatment.The results showed that the total effective rate of the acupuncture group was 93.3% and that of the control group was 66.7%,the difference was statistically significant(P<0.05).Xing et al.[21]divided 120 patients into a treatment group and a control group.The control group was treated with conventional western medicine.The treatment group was given traditional Chinese medicine decoction and acupuncture treatment on the basis of conventional western medicine.Fengchi(GB20),Pishu(BL20),Weishu(BL21),Shenshu(BL23),Sanyinjiao(SP6),Taixi(KI3),Zusanli(ST36)and other acupoints were selected to apply the uniform reinforcing-reducing method for 30 minutes.The results showed that urinary albumin excretion,urinary microalbuminuria and HbA1c in the treatment group were significantly reduced compared to before treatment.The effective rate of the treatment group was 93.33%,and the control group was 73.33%.Comparing the two groups,the curative effect of the treatment group was significantly better than that of the control group,which was statistically significant(P<0.05),suggesting that acupuncture combined with traditional Chinese medicine combined with western medicine has a better effect on early diabetic kidney disease than western medicine alone.

Treat from the“blood stasis”

The key to pathogenesis of diabetic kidney disease due to blood stasis damage of kidney collaterals.Acupuncture is often used to enrich qi,activate blood circulation and remove collaterals.The commonly used acupoints are Xuehai(SP10),Diji(SP8),Sanyinjiao(SP6),Dadun(LR1)and Zusanli(ST36).Yang[22]observed the clinical effect of acupuncture acupoints with the method of replenishing Qi and activating blood on the basis of western medicine treatment for diabetic kidney disease.The results showed that the trace levels of blood glucose,Scr,urinary albumin excretion rate and 24 h urine protein in the treatment group decreased significantly compared with the control group.It is suggested that the acupuncture method for replenishing qi and activating blood can enhance the microcirculation by stimulating the acupoints related to the pathological changes,so as to relax the channels,change or eliminate the blood stasis barrier of blood circulation,and produce the effects of removing blood stasis and regenerating new energy,replenishing qi and nourishing Yin,strengthening the spleen and kidney,reduce urine protein excretion,reduce blood interleukin 1,endothelin 1 and other glomerular sclerosis-related factors to achieve the purpose of treat diabetic kidney disease.

In conclusion,acupuncture is often used to treat DKD by invigorating spleen and kidney,invigorating qi and promoting blood circulation,and at the same time,combining the differentiation of meridians and collaterals and selecting points for treatment.Many studies have shown that[23]the mainly selected acupoints are Shenshu(BL23),Pishu(BL20),Zusanli(ST36),Taixi(KI3),Sanyinjiao(SP6),Xuehai(SP10),Guanyuan(CV4)and the most frequently used the extra point is Weiwanxiashu(EX-B3).The main meridian and collateral of the selected acupoints are spleen meridian of foot-taiyin(SP),bladder meridian of-taiyang(BL),kidney meridian of foot-shaoyin(KI)and stomach meridian of-yangming(ST).The sites of the acupoints are mainly the lower extremities and the lumber-back.

Mechanism of acupuncture in treating diabetic kidney disease

Research on the mechanism of acupuncture treatment of DKD has also been intensified.Studies showed that acupuncture treatment can slow down the pathological changes of diabetic kidney disease by improving glucose metabolism disturbance,lipid metabolic disorders,affecting hemodynamic,and oxidative stress.

Improve glucose and lipid metabolic disorders

Modern studies have shown that DKD is a glomerular disease dominated by microvascular damage,and its occurrence and development are closely related to glucose metabolic disorders[24,25].Animal experiments found that acupuncture Weiwanxiashu(EX-B3)can significantly reduce the blood sugar and urine sugar content of experimental diabetic rabbits,improve glucose metabolic disorders,and significantly improve the morphology and function of pancreatic islets[26].DKD patients often have lipid metabolic disorders.Recent studies have found that blood cholesterol levels and serum low density lipoprotein levels are positively correlated with the decline of renal function[27,28].Liu et al.[29]found that electro-acupuncture therapy can effectively reduce the levels of total cholesterol and triglyceride in the experimental group of rats,improve the fat metabolism disorder of DKD rats,and help improve the kidney damage of DKD rats.

Improve renal hemodynamics

The high osmotic pressure caused by hyperglycemia can increase the glomerular filtration rate,cause hyperperfusion,hypertension,and hyperfiltration in the renal blood flow,expand the extracellular matrix and thicken glomerular basement membrane,leading to glomerulus sclerosis[30,31].Pan et al.[32]found through clinical trials that acupuncture at Taixi(KI3)and Yingu(KI10)points can significantly improve the blood flow of the renal seg-mental artery of the kidneys,increase the blood perfusion of the kidneys,and improve the ischemic state of the kidneys.Thereby it may play a role in protecting the nephron and promoting the excretion of metabolic toxins.At the same time,studies have shown that acupuncture can reduce the level of angiotensin II,thereby expanding efferent vessel,improving the state of hyperperfusion,hypertension,and hyperfiltration in the glomerulus[33].At the same time,it reduces the proportion of non-selective filtration pores on the filtration membrane,so that large molecules substance filtration is reduced,the permeability of the basement membrane is reduced,the urine protein is reduced,and it plays a role in kidney protection.

Antioxidant stress

Studies have found that[34,35]oxidative stress can change renal hemodynamics,damage glomerular endothelial cells,cause matrix deposition outside the mesangial cells and thicken the glomerular basement membrane,which is closely related to the occurrence and development of DKD.Wang et al.[36]found that the spleen-stomach needling acupuncture method can significantly reduce plasma malondialdehyde,carbonyl group,and 8-hydroxyguanine levels than before treatment.At the same time,The level of 8-hydroxydeoxyguanine was significantly lower than before treatment.It is suggested that acupuncture can improve the ability of patients with DKD to resist oxidative stress,thereby improving renal function and delaying renal damage.

Other therapies

Acupoint application

Acupoint application refers to the penetration of traditional Chinese medicine to specific acupoints or areas through the skin.At present,most acupuncture points for diabetic kidney disease are Shenshu(BL23)or the kidney area.Wu et al.[37]selected 114 patients with early diabetic kidney disease,the control group received conventional treatment,and the treatment group was treated with Ziyin Tongluo decoction combined with acupoint application of Chinese medicine on the basis of conventional treatment.The improvements of renal function of the two groups were observed after treatment.After 3 months of treatment,renal function indexes of the observation group(including aspartate transaminase, alanine aminotransferase,serum albumin,serum creatinine and 24 h urinary protein quantitative)better than those of the control group,and difference was statistically significant(P<0.05).This research showed that use Ziyin Tongluo decoction combined with acupoint application of Chinese medicine in the treatment of early diabetic kidney disease,the improvement of renal function of the patients was good,curative effect was obvious,and was worthy of clinical promotion.Huang[38]selected 13 patients with diabetic kidney disease.The control group was given basic nursing care,western medicine treatment and Chinese medicine decoction(Ziyin Bushen decoction)treatment.The experimental group was combined with acupoint application treatment on this basis,and both groups were treated 3 months.Compare the relevant indicators of the two groups of laboratories.The results showed that the levels of urinary albumin excretion rate,HbA1c and Scr in the experimental group were lower than those in the control group,and glomerular filtration rate was higher than that in the control group,with significant differences(P<0.05).It is suggested that acupoint application combined with oral administration of traditional Chinese medicine can improve the blood sugar level and renal function of patients with diabetic kidney disease.

Auricula acupoint pressing pill therapy

Auricular acupoint pressing pill therapy is a simple physical noninvasive pressure on acupoints.This method is closer to acupuncture.Guo et al.[39]divided 84 patients into treatment group and control group and observed for 12 weeks.The control group was given conventional treatment,and the treatment group was given wangbuliuxing auricular acupoint pressing pill on the basis of the control group.Select acupuncture points for endocrine,triple energizer,kidney,adrenal gland,pancreas,gallbladder,liver,insomnia point,and er mi gen acupoint.The results showed that compared with the control group,the symptoms and signs improved significantly after treatment in the treatment group and the 24 h urine microalbumin level could be significantly reduced.Wang et al.[40]randomly divided 62 patients diagnosed into the treatment group and the control group,with 31 patients in each group.The control group was given basic diabetes drugs to control blood sugar,and the treatment group was additively treated withSemen Vaccariae(a kind of cowherb seed,called Wang Bu Liu Xing in Chinese)auricular acupoint sticking on the basis of the control group.The acupoints were selected as pancreas,gallbladder,endocrine,spleen,kidney,and bladder acupoints.The treatment group had obvious advantage over the control group.Although the drug absorption of auricular acupoint pressing pill therapy is worse than that of oral and enema,it is still an effective and safe treatment and can be used as an adjuvant treatment for diabetic kidney disease.

Moxibustion therapy

Moxibustion at acupoints can regulate the vasomotion and contraction of blood vessels through the thermal action of moxibustion and the conduction of acupoints through the channels and collaterals,greatly accelerating the blood flow velocity of local tissues,reducing blood flow resistance,increasing local circulating blood flow,and stimulating and improving the body’s immune function.To achieve the function of improving patient symptoms and improving biochemical indicators.Tan et al.[41]have found that moxibustion adjuvant therapy can increase the plasma albumin level of patients with diabetic kidney disease,reduce the urine protein level,and improve clinical efficacy.Fei et al.[42]used moxibustion on Shenshu(BL23)and Geshu(BL17)for 4 weeks on the basis of routine hypoglycemia.The results showed that the moxibustion group can effectively reduce the level of nitric oxide and correct renal hemodynamics in patients with early diabetic kidney disease.Song et al.[43]used traditional Chinese medicine combined with gentle moxibustion at Guanyuan(CV4)and Shenshu(BL23)acupoint.Studies have shown that this program can effectively reduce urine protein and delay the progression of diabetic kidney disease.

Conclusion

With the continuous progress of technology,people pay more and more attention to external therapy that are safe and have low side effects.Through our review,we obtained the following summarized results based on the available relevant studies that we searched through literature.(1)Practice has proved that some external treatments have significant effects on improving the clinical symptoms of diabetic kidney disease patients,reducing various biochemical indicators,protecting the kidneys,delaying the progression of diabetic kidney disease,and improving the quality of life of patients.(2)Proper aerobic exercise is helpful to improve the prognosis of diabetic kidney disease patients.(3)Acupuncture points such as Shenshu(BL23),Pishu(BL20),Zusanli(ST36),Taixi(KI3),Sanyinjiao(SP6)is most commonly used and the most frequently used the extra point is Weiwanxiashu(EX-B3).The main meridian and collateral of the selected acupoints are bladder meridian of-taiyin,spleen meridian of foot-taiyin,and stomach meridian of-yangming.(4)The possible mechanism of acupuncture in the treatment of diabetic kidney disease is to improve glucose metabolism disorder,lipid metabolism disorder,influence hemodynamics and oxidative stress.

However,the current research on non-drug treatment of diabetic kidney disease has obvious shortcomings,such as the small number of samples,short observation time,and the lack of multi-center large-sample research.It is expected that these problems can be solved step by step in the future.To establish objective,standardized and universal clinical protocol,so that external therapy will have a broader prospect in the prevention and treatment of diabetic kidney disease.