Diabetic nephropathy is one of the most serious complications in patients with diabetes. It is now the major leading cause of end-stage renal failure throughout the world [
The natural history of diabetic nephropathy includes five stages, starting with initial hyperfunction and hypertrophy at diagnosis, followed by increased glomerular filtration rate (GFR) with normal albumin excretion, incipient diabetic nephropathy (characterised by microalbuminuria), then overt clinical nephropathy leading to progressive renal failure, followed by end-stage renal disease (ESRD) with uremia [
Throughout the process, the relentless decline in renal function that starts at stage 4 (overt clinical nephropathy) with a mean GFR fall rate of approximately 1 mL/min2 is a prominent feature in patients with diabetic nephropathy. When diabetic nephropathy develops into ESRD, renal replacement therapy (RRT) is required for survival. This has a major societal impact because of the enormous financial burden on patients and governments. Moreover, the survival of patients with diabetes undergoing dialysis is much worse than that of nondiabetic patients [
The use of an ACEi or an angiotensin II receptor blocker (ARB) is now a component of standard therapy for patients with diabetic nephropathy, along with the control of glucose, lipids, and blood pressure. However, many patients continue to show progressive kidney damage. One study [
At present, many botanical medicines are applied as complementary therapy for diabetic nephropathy.
Reduced GFR and increased albuminuria are independent risk factors for diabetic nephropathy [
Many clinical trials have been conducted to assess the effectiveness and safety of
The aim of this paper was to summarise the evidence on the effectiveness and safety of
We included all RCTs conducted on adults (≥18 years) with early diabetic nephropathy, according to Mogensen stage III [
The primary outcome measurement was the incipient urinary albumin excretion rate (UAER) at the end of the study. Secondary outcomes were SCR, BUN, FBG, postprandial blood glucose (PBG), hemorrheology indices, and adverse reactions.
Our search process included two steps. First, we searched all clinical trials and reviews regarding complementary and alternative treatment for diabetic nephropathy. Then we screened the clinical trials or reviews that only considered the effect of
We searched the following databases: PubMed (from January 1966 to September 2010), EMBASE (from January 1985 to September 2010), Cochrane library, ClinicalTrials.gov, the Chinese Biomedical Medical Database (CBM) (from 1979 to September 2010), VIP medicine information system (VMIS) (from 1989 to September 2010), China National Knowledge Infrastructure (CNKI) Database (from 1994 to September 2010), Wanfang Medicine Online (from 1998 to September 2010), and Traditional Chinese Medicine (TCM) online. More details on the search strategy are described in the Appendix.
We checked the reference lists of all acquired articles and called authors to ask for unpublished studies. In addition, we contacted manufacturers of
Two authors (L. Zhang and W. Mao) independently assessed the title or abstract of each record to select potential eligible studies. Full articles were retrieved for further assessment if they were graded as included or unclear. Then they independently assessed the full articles to decide which ones were to be included. Differences were resolved by a third author ( Z. H. Wen).
Two authors (L. Zhang and Z. Z. Liu) independently extracted the data using a self-developed data-extraction form, which included the following data. General information: first author, published/unpublished, publication year, and location. Trial design: comparison groups, method of randomisation, allocation concealment, and blinding (participants, intervention administrators, and outcome assessors). Participants: disease or condition, diagnostic criteria, inclusion and exclusion criteria, total number and number in comparison groups, and baseline characteristics. Interventions: treatment duration, the name and form of medication, the composition or ingredients, manufacture and quality control, and dose and administration. Outcomes: outcome measures used, adverse events, author conclusions. Followup: length of follow-up, any results of follow-up, reason and number of dropouts and withdrawals, and method of analysis.
Two authors (L. Zhang and W. Mao) independently assessed the selected trials for methodological quality using the Cochrane Collaboration tool for assessing risk of bias [
We resolved discrepancies by discussion. Sometimes we consulted authors Z. H. Wen and X. F. Guo to make the final decision.
To measure the effects of treatments, we considered the primary and secondary outcomes detailed above. For continuous data, weighted mean differences between groups and its 95% confidence intervals were calculated when the same measurement scale was used [
Not all of the trials provided difference of means and its standard deviation (SD) before and after treatment in both groups. The SD was calculated using the following formula [
We used a chi-square test to test heterogeneity and set the significance level at 0.1, in view of its low power. We also used the
We investigated publication biases of studies that included more than five trials [
Data analysis was conducted using Review Manager 5.0 software, and STATA 11.0 SE. A meta-analysis was conducted on the primary and secondary outcomes mentioned above to summarise and to compare the efficacy of treatment with
A total of 16 RCTs, all published trials that were conducted in China, were included. For details of studies selection and included studies see Figure
Flowchart detailing study selection.
The 16 included trials involved 1099 participants. Five of these studies compared ACEi/ARB alone to
Patients in all 16 trials had early diabetic nephropathy in Mogensen stage III [
The exclusion criteria were slightly variable among trials. In all studies, patients with other reasons for microalbuminuria, such as urinary infection, heart failure, primary hypertension, diabetic ketoacidosis, or cancer, were excluded.
No dose-related restrictions were included in the trials in this paper. One [
The primary outcome measurement, UAER, was mentioned in 15 trials. Regarding the secondary outcomes, 11 trials included FBG data [
Initially, 105 trials were prepared to be included in our study. However, after we read the articles and called the authors, 89 trials were excluded due to the following reasons. Twenty-eight trials did not conform to the literature inclusion criteria after reading the entire article and examining the data. Outcome measure data were missing or unclear in eight articles. Two articles had been published in different journals with the same data. Three trials were retrospective studies, and one trial used improper statistical methods. Finally, 48 trials were excluded after we called the authors and confirmed that randomisation was not used.
All 16 trials were randomised trials; however, explicit generation of the allocation sequence was described in 6 trials or (by their authors during telephone calls) [
None of the included trials were confirmed to use blinding. This may have been due to the difficulty in preparing of placebo, which is similar to
After we telephoned authors, a bias of incomplete outcome data was reported in 4 trials [
We analysed the effect of
For Group 1, the UAER data were available in 10 trials with a total sample size of 661 participants. At the end of the study, UAER decreased with an overall effect size of 34.64
Comparison 1. Urinary albumin excretion ratio (UAER): (a)
Subgroup 1.1.1 (Figure
The role of different baseline UAER levels was tested by metaregression using STATA 11.0 SE. The results showed a significant influence of the covariables (Table
Result of the metaregression.
Number of studies | Coefficient |
|
|
Tau2 |
|
Adjusted |
|
---|---|---|---|---|---|---|---|
Urea baseline | 10 | −50.74 (−63.32, −38.16) | −9.30 | <0.001 | 0.00 | 0.00 | 100.00 |
Characteristics of the included studies.
Author, year | Study design | Duration | No. of participants, treatment |
Treatment group: |
Control group: |
Total group: Age (yrs) |
Treatment group: Medication, |
Control group: Medication, |
Adverse |
---|---|---|---|---|---|---|---|---|---|
Chen, 2010 |
RCT, Ginkgo + ACEi/ARB versus ACEi/ARB | 21 days | 34/34 | 44, 6 | 43, 8 | Unclear |
|
Erbesartan oral 150 mg qd | Not noted |
| |||||||||
Chu, 2010 |
RCT, Ginkgo + ACEi/ARB versus ACEi/ARB | 56 days | 58/54 | 56.1, 14.4 | 56.2, 15.6 | Unclear |
|
Valsartan 80 mg qd | Not noted |
| |||||||||
Han, |
RCT, Ginkgo + ACEi/ARB versus ACEi/ARB | 42 days | 35/30 | Unclear | Unclear | 50.6, 12.5 |
|
Lotensin 10–20 mg qd | Not noted |
| |||||||||
Huang et al., 2006 [ |
RCT, Ginkgo + conventional treatment versus conventional treatment | 14 days | 23/22 | 54, 9 | 54, 9 | Unclear |
|
Conventional treatment | Not noted |
| |||||||||
Li and Han, |
RCT, Ginkgo + ACEi/ARB versus ACEi/ARB | 28 days | 36/32 | Unclear | Unclear | 46–74 |
|
Fosinopril oral 10 mg qd | Mild cough three in treatment group, two in control group |
| |||||||||
Li et al., |
RCT, Ginkgo + conventional treatment versus conventional treatment | 60 days | 34/29 | 66.19, 7.13 | 68.2, 71.7 | Unclear |
|
Conventional treatment | Not noted |
| |||||||||
P. Y. Lu, 2005 |
RCT, Ginkgo + conventional treatment versus conventional treatment | 28 days | 34/30 | 41–78 | 45–72 | Unclear |
|
Conventional treatment | Not noted |
| |||||||||
J. Lu, 2005 |
RCT, Ginkgo + conventional treatment versus conventional treatment | 28 days | 30/30 | 58.9, 8.5 | 57.1, 7.9 | Unclear |
|
Conventional treatment | No adverse effect was found |
| |||||||||
Qiu, 2006 |
RCT, Ginkgo + conventional treatment versus conventional treatment | 14 days | 32/28 | Unclear | Unclear | 51, 9 |
|
Conventional treatment | No adverse effect was found |
| |||||||||
Quan, 2003 |
RCT, Ginkgo + conventional treatment versus conventional treatment | 28 days | 50/50 | Unclear | Unclear | 50.5, 12.5 |
|
Conventional treatment | Not noted |
| |||||||||
Tian, 2009 |
RCT, Ginkgo + conventional treatment versus conventional treatment | 28 days | 30/30 | 59.8, 6.4 | 60.3, 5.7 | Unclear |
|
Conventional treatment | Not noted |
| |||||||||
Wang, 2003 [ |
RCT, Ginkgo + conventional treatment versus conventional treatment | 28 days | 30/30 | 54.3, 5.2 | 56.0, 6.5 | Unclear |
|
Conventional treatment | Not noted |
| |||||||||
Wang, 2005 |
RCT, Ginkgo + conventional treatment versus conventional treatment | 28 days | 30/30 | 36.7, 11.3 | 37.1, 10.9 | Unclear |
|
Conventional treatment | Not noted |
| |||||||||
Zhang, 2009 |
RCT, Ginkgo + ACEi/ARB versus ACEi/ARB | 28 days | 35/30 | Unclear | Unclear | 50.2, 8.5 |
|
Benazepril 10 mg qd | Not noted |
| |||||||||
Zhang, 2007 |
RCT, Ginkgo + conventional treatment versus conventional treatment | 21 days | 42/42 | 58.2, 3.6 | 59.5, 3.4 | Unclear |
|
Conventional treatment | Not noted |
| |||||||||
Zhang et al., 2006 [ |
RCT, Ginkgo + conventional treatment versus conventional treatment | 20 days | 30/30 | Unclear | Unclear | 51.2, 2.3 |
|
Conventional treatment | Not noted |
RCT: random control trial; ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blockers.
Numerical data of outcomes of the included studies.
Outcomes measured | |
---|---|
Author, year | Numerical data of outcomes (difference before and after treatment; mean, SD) |
Treatment group/control group | |
Chen, 2010 |
Outcomes measured: UAER, FBG, SCR |
Chu, 2010 [ |
Outcomes measured: UAER, FBG, BUN, SCR |
Han, 2008 [ |
Outcomes measured: UAER, SCR, BUN |
Huang et al., 2006 [ |
Outcomes measured: UAER, FBG |
Li and Han, 2010 [ |
Outcomes measured: UAER, SCR |
Li et al., 2007 [ |
Outcomes measured: UAER, SCR, FBG |
P. Y. Lu, 2005 [ |
Outcomes measured: UAER, SCR, BUN, FBG, PBG |
J. Lu, 2005 [ |
Outcomes measured: UAER, FBG, high shear viscosity, low shear viscosity, plasma viscosity |
Qiu, 2006 [ |
Outcomes measured: UAER, SCR, BUN, FBG, PBG, plasma viscosity |
Quan, 2003 [ |
Outcomes measured: UAER, SCR, BUN, FBG, PBG, low shear viscosity, high shear viscosity |
Tian, 2009 [ |
Outcome measured: UAER |
Wang, 2005 [ |
Outcomes measured: UAER, SCR, BUN, FBG, PBG |
Wang, 2004 [ |
Outcomes measured: UAER, FBG |
Zhang, 2009 [ |
Outcomes measured: UAER, SCR, BUN, FBG |
Zhang, 2007 [ |
Outcomes measured: UAER, FBG |
Zhang et al., 2006 [ |
Outcomes measured: low shear viscosity, high shear viscosity, plasma viscosity |
UAER: urinary albumin excretion ratio; SCR: serum creatinine; BUN: blood urea nitrogen; FBG: fasting blood-glucose; PBG: postprandial blood gluco.
Methodological quality of analysed studies.
Author, year | Random sequence |
Allocation |
Blinding | Incomplete outcome |
Selective |
Other bias |
---|---|---|---|---|---|---|
Chen, 2010 |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
Chu, 2010 [ |
Low risk | Low risk | High risk | Unclear | Low risk | Unclear |
Han, 2008 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
Huang et al., 2006 [ |
Low risk | Low risk | High risk | High risk | Low risk | Unclear |
Li and Han, 2010 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
Li et al., 2007 [ |
Low risk | Unclear | High risk | Unclear | Unclear | Unclear |
P. Y. Lu, 2005 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
J. Lu, 2005 [ |
Low risk | Low risk | High risk | Low risk | Low risk | Unclear |
Qiu, 2006 [ |
Low risk | Low risk | High risk | Low risk | Low risk | Unclear |
Quan, 2003 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
Tian, 2009 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
Wang, 2005 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
Wang, 2004 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
Zhang, 2009 [ |
Low risk | Unclear | High risk | Low risk | Unclear | Unclear |
Zhang, 2007 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
Zhang et al., 2006 [ |
Unclear | Unclear | High risk | Unclear | Unclear | Unclear |
For Group 2, three trials including 376 participants reported urea levels, which decreased with an overall effect size of 27.95
Data for FBG were presented in 11 trials with a total of 762 participants (Figure
Comparison 2. Blood glucose: (a) fasting blood-glucose (FBG), (b) postprandial blood glucose (PBG).
PBG was presented in four trials with a total of 284 participants (Figure
SCR data were presented in 10 trials with a total of 728 participants (Figure
Comparison 3. Kidney function: (a) serum creatinine (SCR), (b) blood urea nitrogen (BUN).
Seven trials including 526 participants were analysed. BUN decreased by 0.68 mmol/L compared to the control group (from 0.36 to 1.01,
In three trials with 220 participants, high shear viscosity and low shear viscosity were presented. The former decreased with an overall effect size of 1.17 mPa
Comparison 6. Hemorrheology: (a) high-cut whole blood viscosity, (b) low-cut whole blood viscosity, and (c) plasma viscosity.
High shear viscosity
Low shear viscosity
Plasma viscosity
No study reported serious adverse effects such as bleeding [
The funnel plots of FBG and BUN (Figure
Funnel plot comparison. (a) Urinary albumin excretion rate (UAER) with ginkgo add-on conventional treatment versus conventional treatment alone, (b) fasting blood glucose (FBG), (c) serum creatinine (SCR), (d) blood urea nitrogen (BUN).
The principal finding of this paper is that
Microalbuminuria is associated with an increased likelihood of progression of generic chronic kidney disease (CKD) to more advanced stages or even to ESRD [
ACEi and ARB reduce urinary albumin excretion and slow the progression of CKD [
Our paper showed that
Abnormal hemodynamic indexes, such as increase in whole blood viscosity and plasma viscosity, are risk factors for development of diabetic nephropathy [
In all trials included in our paper, kidney function was reported as SCR and BUN. Well-controlled UAER and improved haemodynamics play important roles in kidney protection. However, the effects of extract on SCR and BUN found in our subgroup analysis were not statistically significant, although the pooled effect size of the entire group had statistical significance. It was possibly due to the short course (from 14 to 60 days) of treatment in the included trials.
As some studies reported,
In addition, several clinical studies observed herb drug interactions between
Our findings are generalisable to the majority of patients with early diabetic nephropathy being treated with
Although 16 trials were included in our paper, randomisation methods were elaborated in 6 trials. We confirmed that none of the trials were blinded, which could have affected the results. Some doctors might pay more attention to patients in a treatment group than those in a control group. In addition, some of the studies were conducted several years ago, and the authors may have forgotten the details of some incomplete outcomes, which could have resulted in selective reporting.
Variation among trials was apparent in terms of sample size, treatment course, dosage, and forms of
Conventional therapy including control of glucose, lipid, and BP is necessary as a general intervention according to the guidelines. However, this conventional therapy was not be well reported in the included studies, and we were unable to adjust for potential influences in our analyses.
The statistical heterogeneity among trials in this study was apparently substantial. Heterogeneity in UAER, FBG, and BUN mainly originates from subgroups allocated according to different baseline values or interventions. Heterogeneity in hemorrheology may be explained by differences in baseline characteristics among participants.
Although a series of comprehensive search strategies were conducted, the results of our paper were based on published studies. The funnel plots of FBG and BUN appear asymmetric, suggesting evidence of publication bias in the literature. But poor methodological quality in smaller studies and heterogeneity due to different interventions should also be considered as possible reasons for asymmetry.
#1 Nephropathy, Diabetic OR Nephropathies, Diabetic OR Diabetic Nephropathy OR Diabetic Kidney Diseases OR Kidney Disease, Diabetic OR Kidney Diseases, Diabetic OR Diabetic Glomerulosclerosis OR Kimmelstiel-Wilson Syndrome OR Kimmelstiel Wilson Syndrome OR Syndrome, Kimmelstiel-Wilson OR Kimmelstiel-Wilson Disease OR Kimmelstiel Wilson Disease OR Nodular Glomerulosclerosis OR Glomerulosclerosis, Nodular OR Glomerulosclerosis, Diabetic OR Intracapillary Glomerulosclerosis
#2 Traditional Chinese Medicine OR Chinese Traditional Medicine OR Chinese Herbal Drugs OR Chinese Drugs, Plant OR Medicine, Traditional OR Ethnopharmacology OR Ethnomedicine OR Ethnobotany OR Medicine, Kampo OR Kanpo OR TCM OR T.C.M. OR Medicine, Ayurvedic OR Alternative Medicine OR Complementary Medicine OR Phytotherapy OR Herbology OR Plants, Medicinal OR Plant Preparations OR Plant Extracts OR Plants, Medicine OR Materia Medica OR Single Prescription OR Acupuncture OR Meridians OR Electroacupuncture OR Moxibustion OR Auriculotherapy OR Catgut embedding OR Herbs OR Chinese Medicine Herb OR Herbal Medicine.
#3 Clinical Trial OR clinical study OR Controlled Trial OR Controlled study OR random* control* Trial OR random* control* study OR Multicenter Study OR Meta-Analysis OR placebo control OR dummy control OR blinding OR clinical research OR medical trial
#4 #1 AND #2 AND #3
#5 Search “
#6 Search “Egb 761”
#7 Search “Tavonin”
#8 Search “tavonin”
#9 Search “tebonin”
#10 Search “Rokan”
#11 Search “tanakan”
#12 Search “LI 1370”
#13 Search “EGB”
#14 Search “bilobalid”
#15 Search “kaveri”
#16 Search ginkgo$ OR gingko$ OR gingko OR ginko$ OR gingko OR gincosan
#17 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16
#18 #1 and #17 Limits: Humans, Clinical Trial, Meta-Analysis, Randomised Controlled Trial, Review
#19 #4 OR #18
#2 Diabetes nephropathy OR diabetic glomerulopathy OR diabetic glomerulosclerosis OR diabetic intercapillary glomerulosclerosis OR diabetic nephropathies OR diabetic nephrosclerosis OR glomerulonecrosis, intercapillary; glomerulosclerosis, diabetic OR glomerulosclerosis, intercapillary; intercapillary glomerulosclerosis OR Kimmelstiel Wilson syndrome OR kimmelstiel wilson disease OR kimmelstiel wilson nephropathy OR kimmelstiel wilson syndrome OR nephropathy, diabetic
#3 Traditional Chinese Medicine OR Chinese Traditional Medicine OR Chinese Herbal Drugs OR Chinese Drugs, Plant OR Medicine, Traditional OR Ethnopharmacology OR Ethnomedicine OR Ethnobotany OR Medicine, Kampo OR Kanpo OR TCM OR T.C.M. OR Medicine, Ayurvedic OR Alternative Medicine OR Complementary Medicine OR Phytotherapy OR Herbology OR Plants, Medicinal OR Plant Preparations OR Plant Extracts OR Plants, Medicine OR Materia Medica OR Single Prescription OR Acupuncture OR Meridians OR Electroacupuncture OR Moxibustion OR Auriculotherapy OR Catgut embedding OR Herbs OR Chinese Medicine Herb OR Herbal Medicine
#4 #1 or #2
#5 #4 and #3 Quick limits “humans,” limit “MJ,” advanced limits “RCT,” “CT”
#6 “
#7 #4 and #6 Quick limits “humans,” limit “MJ,” advanced limits “RCT,” “CT”
#8 #5 OR #7
#9 # 3 OR #6
Subject: diabetic nephropathy
Subheading:
Disease management
Drug therapy
Prevention
Rehabilitation
Therapy
Quick limits “humans” Advanced limits “RCT,” “CT”.
There are no conflict of interests for any of the authors of this study.
This research was supported by grants from “Scientific Research Project of Public Welfare Industry, State Administration of Traditional Chinese Medicine of P. R. of China (No. 201007005)” and “the United Project of Guangdong Provincial Department of Science and Technology and Guangdong Provincial Academy of Chinese Medical Science (No. 2011B032200011)”.