Li-Chang Liu,Xin Liu,Qi Huang,Wei-Hong Hong,Min-Jian Feng,Yu-Yan Jin,Xue-Fei Du

1Zhuhai Hospital,Guangdong Traditional Chinese Medicine Hospital,Zhuhai 519015,China.

Abstract Objective: Our goal was to examine the impact of Zhuangshen Gujing decoction on proteinuria associated with chronic nephritis. Methods: 72 patients with chronic nephritis proteinuria were divided randomly into two groups;one group was treated with Zhuangshen Gujing (n=36;treatment group) and the other group was treated with irbesartan (n=36;control group).After 6 months’ treatment,urine protein and renal function were evaluated.Results: Proteinuria resolved completely in four patients in the treatment group;complete disease resolution was observed only among three individuals in the control group.Of the 32 cases remaining in the treatment group,15 had substantial responses to Zhuangshen Gujing decoction,9 had partial responses,and 8 had no response to treatment;the overall the response rate was 73.33%.Among the 33 cases remaining in the control group,12 had a substantial response to irbesartan,5 had a partial response,and 16 had no response to treatment;the overall response rate among the controls was 57.67% (P=0.031).We also observed statistically significant differences with respect to quantitative comparisons of urinary protein at 24 days after a single course of treatment(P=0.001).Conclusion:Zhuangshen Gujing decoction is effective in treating chronic nephritis proteinuria.

Keywords:Zhuangshen Gujing decoction,Chronic nephritis,Proteinuria,Clinical observation

Background

Chronic nephritis is a leading cause of chronic renal failure in China,currently accounting for 54.4% of all cases [1].Proteinuria is one of the main symptoms of chronic nephritis.Given the recent improvements with respect to our understanding of renal disease,urinary protein is now recognized not only as an important indicator of renal damage,but also as a critical independent risk factor associated with poor prognosis in cases of nephropathy[2].At present,a large number of studies have been performed in an effort to delineate the relationship of proteinuria and renal toxicity.Among the most significant are its impact on mesangial and tubular cytotoxicity and its capacity to promote glomerular and tubulointerstitial fibrosis;both of these mechanisms can lead to a decline in renal function,and may eventually develop into end-stage renal disease.As such,effective control of proteinuria is an important treatment goal with respect to efforts to delay renal insufficiency in patients with chronic nephritis with proteinuria as the main manifestation.Basic countermeasures of modern medicine for chronic nephritis proteinuria patients include the use of angiotensin converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) drugs,glucocorticoids,cytotoxic drugs,and immunosuppressants.However,long-term use of these drugs may be associated with significant side effects and decreased sensitivity.Therefore,these conventional methods used for the treatment of chronic nephritis proteinuria have some limitations,and there are many problems to be solved with respect to their clinical application.

Traditional Chinese medicine (TCM)-based diagnosis and treatment may be used to promote significant reductions in proteinuria in patients with chronic nephritis,this strategy may also result in resolution of clinical symptoms with few adverse effects,using straightforward and inexpensive formulations.At present,TCM-based formulations are in extensive clinical use throughout China.As one example,Zhuangshen Gujing decoction has been prescribed for many years by chief physician,Dr.Liu Xin;this formulation has been found to be effective for reducing proteinuria [3].The prescription of Chinese medicine Zhuangshen Gujing decoction is comprised of Huangjing (Rhizoma Polygonati),Huangqi (Radix Astragali),Tusizi (Semen Cuscutae),Jinyingzi(Fructus Rosae Leavigatae),Fupenzi (Fructus Rubi),Sangpiaoxiao (Otheca Mantidis),Yeqiaomaigen(Rhizoma Fagopyri Cymosi),Ciweipi (Corium Erinacei seu Hemiechanus),Shuizhi (Hirudo),and other bioactive compounds.This formulation serves to improve kidney and spleen function.Clinical observations have suggested that it can effectively reduce or even eliminate proteinuria without apparent adverse reactions.The aim of this study was to evaluate the impact of Zhuangshen Gujing decoction on proteinuria associated with glomerulonephritis.

Materials and methods

Clinical data

From February 2017 to June 2019,72 patients with chronic nephritis proteinuria were enrolled.The study was approved by the Institutional Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine(B2017-049-01).Patients were divided randomly using a random number table method into the treatment group (n=36) that received Zhuangshen Gujing and the control group (n=36) that were treated with the ARB drug,irbesartan.The treatment group included 20 males and 16 females with an age range of 18-65 years(average age,35.5 ± 2.5 years).The shortest course of therapy was 9 months,and the longest was 5 years,with an average duration of therapy at 3.2 ± 0.3 years.Among those in the control group,17 were males and 19 were females with an age range of 17-62 years(average age,34.5 ± 2.3 years).Most of the patients were treated for 7 months,with some treated up to 6 years;the average duration of therapy was 3.4 ± 0.5 years.Clinical manifestations of disease among members of both groups included lumbar pain,fatigue,edema,and hypertension.Findings on urinalysis included mainly proteinuria,with 24 h urine protein quantification tests detecting 0.3-1 g total protein.Urine samples from some patients included both red and white blood cells;blood urea nitrogen and serum creatinine (Cr) were within the normal range.A comparison of baseline characteristics revealed no statistically significant differences(P＞0.05).

Diagnostic criteria

Patients were diagnosed with moderate chronic nephritis according to Western medicine diagnostic criteria as described [4].TCM Diagnostic and Symptom Scoring Criteria included those provided by the Guiding Principles of Clinical Research on New Chinese Medicines [5].The standard of deficiency of spleen and kidney Qi in chronic nephritis were diagnosed by more than two attending physicians.The main symptoms associated with this diagnosis include lumbar spine pain,fatigue,swelling,and/or epigastric distention;other symptoms include loose stool,frequent urination,or nocturia,light red coloration of the tongue,teeth marks,and thin veins.

Inclusion criteria

Chronic nephritis patients included were those aged 18-70 years of age with 24 h urine protein at 0.3-1 g,and no history of glucocorticoid,cytotoxic,or other immunosuppressive therapies during the previous six months.

Table 1 Gender composition of the treatment and control groups

Table 2 Ages of patients in treatment and control groups

Table 3 Comparison of disease duration

Table 4 Clinical outcomes

Table 5 Comparison of 24 hours urine protein(g)before and after treatment

Exclusion criteria

Exclusion criteria included (1) secondary chronic kidney disease due to systemic lupus erythematosus,diabetic nephropathy,hypertensive nephropathy,gouty nephropathy or drug-induced renal damage;(2)comorbidities including serious conditions associated with the heart,brain,lung,liver,and/or hematopoietic system,malignant tumors,tuberculosis other respiratory infections,and liver function abnormalities.Other exclusion criteria included allergy to the study drugs,mentally illness,and general inability to cooperate with the study protocol.

Treatment methods

Both groups received general medical support,including low-salt,low-fat,high quality low-protein diets and anti-hypertensive medication function and other basic treatments designed to protect renal function.Patients were advised to avoid overwork and physical labor,as well as to avoid nephrotoxic drugs such as seafood,shrimp,crab,and other potentially nephrotoxic foods.They were asked to avoid situations associated with colds and upper respiratory infections,and to seek active management of complications and complications.The treatment group received the following:Zhuangshen Gujing decoction (Huangjing(Rhizoma Polygonati)10 g,Huangqi (Radix Astragali)10 g,Tusizi(Semen Cuscutae)10 g,Jinyingzi(Fructus Rosae Leavigatae) 10 g,Fupenzi (Fructus Rubi) 10 g,Sangpiaoxiao (Otheca Mantidis) 10 g,Yeqiaomaigen(Rhizoma Fagopyri Cymosi) 10 g,Ciweipi (Corium Erinacei seu Hemiechanus) 10 g,Shuizhi (Hirudo) 10 g) prepared by Jiangsu Jiangyin Pharmaceutical Factory,Production Lot No.090113),three times per day.Patients in the control group were treated with irbesartan tablets (0.15 mg tablets,Shanxi Jianmin Pharmaceutical Co.,Ltd.,production lot number 1108032),one tablet orally per day.Both groups underwent treatment for 6 months;the impact of drug therapy was determined after a single course of treatment.

Observation indicators

Twenty-four-hour urine collections were performed for quantification of total urinary protein quantification from patients in both groups.

Evaluation criteria

Standards were as described in Guiding Principles of Clinical Research on New Chinese Medicines [4].Endpoints included:complete remission,with 24h urine protein quantitatively within normal limits,implying normal renal function;substantial effect,with 24h urine protein quantitatively assessed as a 50%reduction compared to levels determined at the start of the experiment and normal renal function;partially effective,with 24h urinary protein quantitatively assessed as more than 25%but less than 50%reduction compared to levels determined at the start of the experiment and stable renal function was stable (i.e.,no more than 25% decrease of serum creatinine from base value);and ineffective,in which none of the aforementioned criteria were met.

Statistical methods

SPSS13.0 analytical software was used to evaluate findings for rank ordered classification variables using rank sum test and for the comparison of rates using chi-square test.Data were presented as mean ±standard deviation (SD);values with normal distribution were evaluated with t-tests,and those without normal distribution,via a signed-rank sum test(Wilcoxon pairing method).P＜0.05 was considered as statistically significant.

Results

Demographic data

The two groups were compared with a chi-square test;the differences were not statistically significant in Table 1(P=0.510).Data are presented as mean±SD;statistical significance was as shown.The age composition of the two groups was evaluated byt-test;no significant differences were observed between the two groups in Table 2 (P=0.729).Data were presented as mean ± SD;statistical significance was as shown.The average duration of disease was evaluated by t-test;no statistically significant differences were detected in Table 3(P=0.433).

Comparison of therapeutic impact

The differences between the two groups was statistically significant with respect to differential outcome after Ridit analysis in Table 4(P=0.031).

Values for 24 h urine protein quantification before and after treatment

There were no significant differences in 24 hours urine protein levels before treatment.After 6 months of treatment,proteinuria decreased in all groups,with statistically significant differences as shown in Table 5(P＜0.01).

Discussion

A prospective clinical trial performed in the United States [6,7]confirmed that the severity of proteinuria has predictive value for the incidence and the development of chronic renal failure;control of proteinuria can reduce the rate of deterioration associated with chronic renal failure.As such,reducing or even eliminating proteinuria is an extremely important goal with respect to ongoing protection of renal function and if one hopes to delay the progress of the disease.These points are in accordance with the concepts of "early disease prevention" and "both disease prevention and prevention of change" that are the hallmarks of TCM.Basic countermeasures used in Western medicine for the treatment of proteinuria associated with chronic nephritis include the use of ACEI/ARBs,glucocorticoids,cytotoxins,and immunosuppressants.However,long-term use of these drugs is often associated with significant side effects;patients can become tolerant and thus less sensitive to the therapeutic impact of these modalities.Therefore,there are some significant limitations to the conventional methods used to treat proteinuria associated with chronic nephritis and many problems that remain to be solved with respect to their clinical application.

Proteinuria is evaluated by standard urinalysis and using a 24 hours total urine collection test.Principles of TCM suggest that urinary protein is the result of kidney dysfunction.Improving kidney health is the the fundamental solutions to prevent it happening.Zhuangshen Gujing decoction,which has been proved to tonify Qi and lift Yang,is a good choice to reducing proteinuria [9-11].In this study,we found that Zhuangshen Gujing decoction results in substantial clinical improvement with respect to proteinuria.After 6 months of treatment,proteinuria decreased compared the control group (P＜0.001);and more patients in the Zhuangshen Gujing decoction group get more benefit than the control group,as the effective rate was 73.33% for the Zhuangshen Gujing decoction group while that was 57.67% in the control group (P=0.031).

There are some several limitations to this study.First,the patient populations that met the inclusion criteria were relatively small;as such,there are limitations with respect to the strength of the statistical analysis.We hope to have the opportunity to carry out a larger study in the near future.Second,proteinuria associated with chronic nephritis develops over a long period of time and as such is a rather complex process;the disease changes over time and outcomes often need longer periods of study.Unfortunately,this study included only several weeks of observation;as such,the long-term efficacy and adverse reactions that might be attributed to these drugs cannot be fully evaluated.

We hope to be able to extend the observation period and to include regular follow-up in the future.Additional studies will provide a more comprehensive dataset for analysis and will provide a more reliable reference for ongoing clinical use.