Summary of findings
Description of the condition
Primary nephrotic syndrome (NS) is a relatively rare, but important kidney disease in children and adults (Eddy 2003; Hull 2008). It has an annual incidence of 2 to 7/100,000 children (Eddy 2003) and 3/100,000 adults (Hull 2008). There are five main distinct histological variants of primary NS: minimal change nephropathy (MCN); focal segmental glomerulosclerosis (FSGS); membranous nephropathy (MN); mesangioproliferative glomerulonephritis (MsPGN) (immunoglobulin A (IgA) nephropathy and non-IgA nephropathy); and membranoproliferative glomerulonephritis (MPGN). Acute complications related to primary NS include thromboembolism, infection, and acute kidney injury (AKI). Deep and renal vein thromboses could lead to pulmonary embolism. Bacterial and viral infections such as pneumonia and cellulitis are an ongoing threat to the health of immunocompromised patients. Long-term sequelae of primary NS relate mainly to adverse events of immunosuppressive treatments on bones, growth and the cardiovascular system (Eddy 2003; Hull 2008).
Description of the intervention
Tripterygium wilfordii Hook F (TwHF) has been used widely in traditional Chinese medicine to treat rheumatoid arthritis and other autoimmune and inflammatory diseases. Results from studies in Chinese patients (Tao 1987; Tao 1989) stimulated further investigation of TwHF for rheumatoid arthritis in western countries (Goldbach-Mansky 2009; Tao 2001; Tao 2002). TwHF has been prescribed as an immunosuppressive agent for primary NS in China for more than 20 years (Chen 1985; Jiang 1994). Preliminary observations suggested that remission was achieved in 8/13 (62%) children with primary NS and maintained in four children (31%) for up to three years (Jiang 1994). A meta-analysis of three studies enrolling 150 adult patients with primary refractory NS indicated that TwHF were associated with a higher complete remission (Odds ratio (OR) 2.81, 95% CI 1.26 to 6.30) and complete or partial remission (OR 3.25, 95% CI 1.20 to 8.76) (Xu 2009a).
Non-standardised TwHF preparations have been reported as causing serious adverse events and death (Wen 1999). A search of the Chinese Biological Medicine (CBM) Database (from 1982 to 1996) identified 38 patients who experienced adverse events related to non-standardised TwHF preparations (Wen 1999). The adverse events included leukopenia (9/38, 24%), aplastic anaemia (5/38, 13%), gastrointestinal tract disturbances (10/38, 26%), liver dysfunction (4/38, 11%), skin lesions such as erythema and papules (5/38, 13%) and other rare complications. Serious adverse events were primarily related to haematological system, and 8/38 (21%) died (leukopenia (4/8, 50%); aplastic anaemia (2/8, 25%); severe liver dysfunction (2/8, 25%)) (Wen 1999). Toxicities caused by non-standardised TwHF preparations which were reported before 1996 were difficult to compare with adverse events reported for standardised TwHF preparations such as ethanol-ethyl acetate and chloroform-methanol extracts of TwHF (Goldbach-Mansky 2009). Peeling the roots of this plant and using a standardised extraction method can fundamentally reduce toxicity and increase tolerability (Tao 2002). More recently, the most common adverse events of standardised TwHF preparations were gastrointestinal tract disturbances, leukopenia, thrombocytopenia, rash, skin pigmentation, and malfunction of reproductive system (Bao 2011). Most of these could be resolved by dose adjustment or drug discontinuation (Bao 2011; Goldbach-Mansky 2009).
How the intervention might work
Kupchan 1972 first demonstrated that triptolide and tripdiolide, two diterpenoid triepoxides from TwHF, possess antileukaemic properties. More recently, triptolide and tripdiolide were considered to be the principal active components of TwHF (Tao 1995). Two preparations of TwHF have been used extensively in experimental and clinical studies because of their lower toxicity profiles: chloroform-methanol extract (T2 or TwHF multiglycoside) and ethanol-ethyl acetate extract (Goldbach-Mansky 2009; Sharma 1997; Tao 1998; Tao 2001; Tao 2002; Wan 2010).
Sharma 1997 demonstrated the in vitro inhibitory effect of chloroform-methanol extract on increased glomerular albumin permeability in isolated glomeruli. The protective effect of chloroform-methanol extract on glomerular filtration barriers may be independent from anti-inflammatory and immunosuppressive properties of TwHF (Sharma 1997). Hong 2002 showed that in vitro triptolide could effectively inhibit the pro-inflammatory and immunoregulatory potential of TNF-α activated human renal proximal tubular epithelial cells by inhibiting C3, B7h, and CD40 expression. The chloroform-methanol extract, presumably through reducing production of injurious cytokines, ameliorated proteinuria and acute mesangial injury in Thy1.1 glomerulonephritis rat model (Wan 2005). Triptolide displayed a prominent in vivo anti-proteinuric effect in puromycin aminonucleoside (PAN)-induced nephrosis rat model characterised by improvement of foot process effacement, decrease of podocyte injury marker (desmin) and restoration of nephrin and podocin expression and distribution (Zheng 2008). This in vitro study further confirmed the protective effect of triptolide on immortalised mouse podocytes from PAN-induced disruption of actin cytoskeleton and microfilament-associated synaptopodin and abnormality of nephrin and podocin expression (Zheng 2008). The effects of triptolide may be attributed to the suppression of reactive oxygen species generation and subsequent p38 mitogen-activated protein kinase pathway activation, and restoration of RhoA activity (Zheng 2008).
Why it is important to do this review
Although TwHF has been used widely as an immunosuppressive agent for primary NS in China for more than 20 years, the efficacy and safety of TwHF have not been systematically reviewed.
This review aimed to assess the benefits and harms of TwHF for the treatment of primary NS in adults and children, either as a sole agent or combined with other drug therapies.
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) investigating the efficacy and safety of TwHF administered to patients with primary NS were considered for inclusion. Quasi-RCTs (studies in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) were excluded. All the included RCTs had a follow-up of at least three months.
Types of participants
Adult and children diagnosed with primary NS were included. The diagnosis of NS were defined by the authors in each single study. In absence of an explicit definition of primary NS, proteinuria above 3.5 g/24 h was used as the cut-off value for adults, and in children urine protein-creatinine ratio above 200 mg/mmol, proteinuria above 300mg/dL, or protein on urine dipstick above 3+ was used (KDIGO 2012).
Patients with secondary NS were excluded.
Types of interventions
- Two preparations of TwHF extracts (ethanol-ethyl acetate extract and chloroform-methanol extract) have been investigated in clinical studies and reported to carry lower toxicity profiles compared with other TwHF preparations. This review considered only ethanol-ethyl acetate extract and chloroform-methanol extract of TwHF. Other TwHF preparations were excluded because of their less favourable toxicity profiles (Tao 2002; Wen 1999).
- TwHF versus placebo, no treatment, non-immunosuppressive agents (such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, anticoagulants, antiplatelet agents, or fish oil), or immunosuppressive drugs (glucocorticoids, alkylating agents, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, or leflunomide).
- TwHF in addition to the listed immunosuppressive and non-immunosuppressive agents versus the same drugs. Co-interventions were permitted where all study arm patients received the same co-interventions.
- Various doses, frequencies of administration, and therapeutic durations of the same TwHF preparation were included.
- Any preparations of other traditional Chinese herbal medicines, including single herb, compound herbs, extracts, raw materials, Chinese proprietary medicines, and practitioner-prescribed herbal formulae (individualised treatment) according to the study report, were excluded.
Types of outcome measures
Complete remission, partial remission, and complete or partial remission at the last follow-up. Complete and partial remission were assessed according to the definition provided in each single study. In the absence of an explicit definition of remission, we applied the following parameters (KDIGO 2012).
- In children
- Complete remission was defined as urine protein-creatinine ratio < 20 mg/mmol or < 1+ of protein on urine dipstick for three consecutive days.
- Partial remission was defined as proteinuria reduction of ≥ 50% from the presenting value and absolute urine protein-creatinine ratio of 20 to 200 mg/mmol.
- In adults
- Complete remission was defined as proteinuria < 0.3 g/24 h, accompanied by a normal serum albumin concentration and normal serum creatinine.
- Partial remission was defined as reduction of proteinuria to 0.3 to 3.5 g/24 h and a decrease > 50% from baseline, accompanied by an improvement or normalisation of the serum albumin concentration and stable serum creatinine (change in creatinine < 25%)
- Urinary protein excretion at last follow-up
- Serum albumin at last follow-up
- Serum creatinine at last follow-up
- Adverse events of TwHF
Search methods for identification of studies
- Cochrane Renal Group's specialised register were searched by the Trial Search Coordinator of Cochrane Renal Group in August 2012
- Cochrane Register of Controlled Trials (CENTRAL) in The Cochrane Library (2012 Issue 8)
- PUBMED (1966 to August 2012)
- EMBASE (1966 to August 2012)
- CBM (Chinese Biological Medical Database) (1978 to November 2010)
- CNKI (Chinese National Knowledge Infrastructure) (1979 to November 2010)
- VIP (ChongQing WeiPu Chinese Science and Technology Periodical Database) (1989 to November 2010)
- WanFang Database (1980 to November 2010)
See Appendix 1 for search strategies used.
Searching other resources
We searched the reference lists of relevant studies and related Chinese journals (6 November 2010).
Data collection and analysis
Selection of studies
The search strategy was applied to obtain titles and abstracts of relevant studies. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable; however studies and reviews that may have included relevant data or information were retained initially. Two authors independently assessed retrieved abstracts and, if necessary the full text, to determine which satisfied the inclusion criteria. Disagreements were resolved by consultation with a third author.
Data extraction and management
Data extraction was conducted independently by two authors using standard data extraction forms. Studies reported in non-English language journals were translated before assessment. Where more than one publication of one study existed, the publication with the most complete data was included. Where relevant outcomes were published only in earlier versions, these data were included in the analyses. Any discrepancies between published versions were to be highlighted. Any further information required from the original investigators was requested by phone or written correspondence and any relevant information obtained was included in this review. Disagreements were resolved by consultation with a third author.
Assessment of risk of bias in included studies
The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011). For each item, the judgement (low risk of bias, high risk of bias, or unclear risk of bias) was followed by a description of the design, conduct or observations underlying the judgement (see Appendix 2).
- Was there adequate sequence generation (selection bias)?
- Was allocation adequately concealed (selection bias)?
- Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
- Participants and personnel
- Outcome assessors
- Were incomplete outcome data adequately addressed (attrition bias)?
- Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
- Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For dichotomous outcomes (e.g. remission) results were expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (e.g. urinary protein excretion, serum albumin, serum creatinine), the mean difference (MD) were used, or the standardised mean difference (SMD) if different scales have been used. If possible, we also aimed to determine the applicability of the results to individual patients, such as calculation of absolute risk reductions with therapy in relation to different baseline risk of the event with no therapy or a different therapy. Adverse events were tabulated and assessed using descriptive techniques. Where possible, risk difference with 95% CI was to be calculated for each adverse event, compared with either no treatment or another agent.
Unit of analysis issues
Studies with multiple intervention arms were analysed by entering each pair-wise comparison separately. For dichotomous outcomes, both the number of events and the total number of patients were halved. For continuous outcomes, only the total number of participants were halved, while the means and standard deviations were left unchanged (Higgins 2011).
Dealing with missing data
Data such as numbers of participants screened, randomised, intention-to-treat, and as-treated and per-protocol populations were evaluated and analysed. Attrition rates (drop-outs, losses to follow-up and withdrawals) were investigated. Issues of missing data and imputation methods (such as last-observation-carried-forward) were critically appraised (Higgins 2011). Participant results missing due to drop-out, intention-to-treat analysis was performed and compared with per-protocol analysis for the dichotomous data; while the continuous data remained unchanged due to the difficulty of application of ITT for this type of data (Moher 2010). For missing statistics such as standard deviations, these studies were not considered in the meta-analysis unless the missing data could be appropriately imputed using methods recommended by the Cochrane Collaboration (Higgins 2011). We also contacted principal investigators to request the missing data.
Assessment of heterogeneity
Heterogeneity was analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.10 used for statistical significance (Higgins 2011). I² values of 25%, 50% and 75% corresponded to low, medium and high levels of heterogeneity.
Assessment of reporting biases
Assessment of publication bias was not conducted because of the small numbers of included studies in the three comparisons.
Data were pooled using the random-effects model but the fixed-effect model was also used to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
The following subgroup analyses were planned.
- Type of NS (steroid-resistant NS (SRNS) or frequently relapsing NS (FRNS)).
- NS pathology.
- Age of participants (e.g. children or elderly patients).
- We conducted sensitivity analyses to explore the influence of diagnostic criteria of NS on the treatment effect.
Description of studies
Results of the search
The search strategy identified 2938 citations (6 November 2010) (Figure 1). Of these, 50 studies were considered as potentially eligible. All were conducted in China and reported in Chinese language. A total of 30/50 studies were excluded after further evaluation. We attempted to contact the investigators from the remaining 20 studies to obtain missing data. The authors of two studies could not be contacted and subsequently excluded (10%). We were successful in eliciting responses from 18 studies (90%). Eight of these studies were further excluded after contact with the investigators.
|Figure 1. Flow diagram of study selection|
Age and gender appeared to be balanced in all included studies. Three studies did not report if proteinuria and serum creatinine were comparable at baseline (Li 2000; Wen 1993; Yuan 2003); and seven studies reported comparability at baseline (A-Da 2008; Chen 2003; Han 1999; Song 1998; Zhang 2007a; Zhao 1997; Zhao 2009).
The 10 included studies randomised a total of 630 patients (345 in the experimental group and 285 in the control group). The median sample sizes was 64 patients (range from 36 to 92).
Eight studies only enrolled patients with primary NS. We contacted the investigators of the remaining two studies and confirmed that all enrolled patients had been diagnosed with primary NS (Li 2000; Zhao 1997). Sensitivity analyses for diagnostic criteria were conducted to detect the potential impact of unpublished information (Li 2000; Zhao 1997).
Common pathologic diagnoses reported in nine included studies were MCN, FSGS, MsPGN (including IgA nephropathy), MN, and MPGN. One study included only adults with primary IgA nephropathy-induced primary NS (A-Da 2008).
Initial doses of TwHF ranged from 0.5 mg/kg/d (Wen 1993) to 2.0 mg/kg/d (Song 1998; Zhao 2009), and were administered for four (Chen 2003; Zhao 2009) and eight weeks (A-Da 2008; Song 1998; Zhao 1997).
The median follow-up was 12 months (range: 3 to 18 months).
A presentation of comparisons in these 10 included studies was presented in additional Table 1. Nine studies featured two-arm design. Zhao 1997 conducted a three-armed study that compared 34 patients receiving TwHF plus prednisone (0.6 mg/kg/d), 26 patients receiving TwHF, and 26 patients receiving prednisone (1.0 mg/kg/d). The prednisone group (1.0 mg/kg/d) was split into two equal-sized subgroups. Two comparisons were conducted: (A) TwHF plus prednisone (0.6 mg/kg/d) (N = 34) versus prednisone (1.0 mg/kg/d) (N = 13) and (B) TwHF (N = 26) versus prednisone (1.0 mg/kg/d) (N = 13). We conducted primary analyses according to experimental and control interventions:
We excluded 40 studies from this review.
- One study was only followed for two months (Xiao 2007).
Risk of bias in included studies
|Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies|
|Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study|
Although all included studies were RCTs, explicit methods of randomised sequence generation was described in only one. A-Da 2008 used a random number table for sequencing. We determined that drawing of lots was used in nine studies by contacting study investigators.
None of the included studies described allocation sequence concealment methods after contact with study investigators.
None of the included studies reported blinding methods.
Incomplete outcome data
None of the studies described losses to follow-up or treatment withdrawals.
The primary outcome (remission) was reported in all included studies. Secondary outcome data on urinary protein excretion, serum albumin, serum creatinine, and drug-related adverse events were presented in two (20%), two (20%), three (30%), and five studies (50%), respectively.
Other potential sources of bias
There was insufficient information to determine other potential sources of bias.
Effects of interventions
See: Summary of findings for the main comparison Summary of findings: Tripterygium wilfordii Hook F (TwHF) versus no TwHF; Summary of findings 2 Summary of findings: Tripterygium wilfordii Hook F versus prednisone; Summary of findings 3 Summary of findings: Comparison of TwHF and CPA
Results are presented in Summary of findings for the main comparison, Summary of findings 2 and Summary of findings 3. Subgroup and sensitivity analyses are presented in Table 2 (TwHF versus non-TwHF) and Table 3 (TwHF versus prednisone).
TwHF versus non-TwHF
TwHF significantly increased complete remission ( Analysis 1.1 (4 studies, 293 participants): RR 1.46, 95% CI 1.18 to 1.80; I² = 3%) and complete or partial remission ( Analysis 1.3 (4 studies, 293 participants): RR 1.26, 95% CI 1.10 to 1.44; I² = 0%). The effect of TwHF on partial remission did not reach statistical significance ( Analysis 1.2 (4 studies, 293 participants): RR 0.77, 95% CI 0.49 to 1.21; I² = 0%).
One study (Zhang 2007a) reported no significant difference in urinary protein excretion ( Analysis 1.4 (1 study, 78 participants: MD -0.03 g/24 h, 95% CI -0.21 to 0.15) and serum albumin ( Analysis 1.5 (1 study, 78 participants: MD 0.66 g/L, 95% CI -2.82 to 4.14). Two studies (Song 1998; Zhang 2007a) reported a significant decrease in serum creatinine; however heterogeneity was high (93%) and therefore we did not pool these studies ( Analysis 1.6).
One study (Song 1998) reported three types of adverse events of TwHF: infection, liver transaminase elevation, and leukopenia/bone marrow suppression. There were no significant differences in these adverse events ( Analysis 1.7).
We were unable to perform subgroup analyses for pathological diagnosis of NS and age of participants due to lack of data.
SRNS or FRNS
Song 1998 included patients with SRNS or FRNS. There were no statistically significant subgroup differences in complete remission (P = 0.37), partial remission (P = 0.81) and complete or partial remission (P = 0.62) ( Table 2).
Wen 1993 and Zhang 2007a compared TwHF + prednisone versus prednisone; Li 2000 and Song 1998 compared TwHF + prednisone + CPA versus prednisone + CPA. There were no statistically significant subgroup differences in complete remission (P = 0.62), partial remission (P = 0.53), and complete or partial remission (P = 0.72).
Sensitivity analyses for diagnostic criteria
The diagnosis of primary NS was not confirmed until we contacted the principal investigator in one study (Li 2000). This study was excluded from the sensitivity analysis. There were no significant changes of complete, partial, and complete or partial remission (additional Table 2).
TwHF versus prednisone
There were no significant differences in complete remission ( Analysis 2.1 (4 studies, 223 participants): RR 1.09, 95% CI 0.83 to 1.43, I² = 0%), partial remission ( Analysis 2.2 (4 studies, 223 participants): RR 1.07, 95% CI 0.69 to 1.65, I² = 0%), or complete or partial remission ( Analysis 2.3 (4 studies, 223 participants): RR 1.06, 95% CI 0.92 to 1.22, I² = 14%).
Urinary protein excretion, serum albumin, and serum creatinine were not reported.
Two studies (Han 1999; Yuan 2003) showed no significant difference in liver transaminase elevation ( Analysis 2.4.1 (2 studies 101 participants): RR 1.51, 95% CI 0.16 to 14.22; I² = 47%). Yuan 2003 reported no significant difference for leukopenia or bone marrow suppression, elevated blood pressure, elevated blood glucose, femoral head necrosis, and infection. One study (Yuan 2003) reported the risk of psychosis was significantly lower in the TwHF group compared to the prednisone group ( Analysis 2.4.7 (1 study, 37 participants): RR 0.11, 95% CI 0.01 to 0.75).
SRNS or FRNS
Han 1999 only enrolled patients with SRNS or FRNS. There were no statistically significant subgroup differences in complete remission (P = 0.17), partial remission (P = 0.82) and complete or partial remission (P = 0.06) (additional Table 3).
Pathological diagnosis of NS
A-Da 2008 included only patients with IgA nephropathy-induced primary NS. There were no significant subgroup differences in complete remission (P = 0.53), partial remission (P = 0.51), and complete or partial remission (P = 0.94).
Yuan 2003 only enrolled elderly patients. There were no significant subgroup differences in complete remission (P = 0.91), partial remission (P = 0.53), and complete or partial remission (P = 0.60)
A-Da 2008, Yuan 2003 and Zhao 1997 compared TwHF and prednisone; and Han 1999 compared TwHF + cyclosporine versus prednisone + cyclosporine. There were no statistically significant subgroup differences in complete remission (P = 0.17), partial remission (P = 0.82) and complete or partial remission (P = 0.06).
Sensitivity analyses for diagnostic criteria
The diagnosis of primary NS was not confirmed until we contacted the principal investigator in one study (Zhao 1997). This study was excluded from the sensitivity analysis. There were no significant changes of complete, partial, and complete or partial remission (additional Table 3).
TwHF versus CPA
There were no significant differences in complete remission ( Analysis 3.1 (2 studies, 114 participants): RR 1.06, 95% CI 0.82 to 1.37; I² = 0%), partial remission ( Analysis 3.2 (2 studies, 114 participants): RR 1.02, 95% CI 0.46 to 2.29; I² = 0%), and complete or partial remission ( Analysis 3.3 (2 studies, 114 participants); RR 1.05, 95% CI 0.90 to 1.23; I² = 0%).
One study reported no significant differences in urinary protein excretion ( Analysis 3.4 (1 study, 46 participants): MD -0.30 g/24 h, 95% CI -1.34 to 0.74) and serum albumin ( Analysis 3.5 (1 study, 46 participants): MD 1.00 g/L, 95% CI -1.91 to 3.91). This study reported TwHF was associated with a significant decrease in serum creatinine ( Analysis 3.6 (1 study, 46 participants): MD -14.00 μmol/L, 95% CI -26.43 to -1.57).
There were no significant differences in the following adverse events: gastrointestinal discomfort, liver transaminase elevation, menstrual disorders, leukopenia and haemorrhagic cystitis. The risk of hair loss was significantly lower for the TwHF group compared to the CPA group ( Analysis 3.7.5 (2 studies, 114 participants): RR 0.11, 95% CI 0.02 to 0.59; I² = 0%). Subgroup and sensitivity analyses were not performed due to the lack of data.
Summary of main results
This systematic review provides some support for the effectiveness of TwHF for the treatment of primary NS; however the quality of evidence was suboptimal because of the small number of included studies enrolling small numbers of participants; short follow-up in each study; only a few studies in each comparison category; and major concerns with methodological bias. TwHF could significantly increase complete remission by 46% (18% to 80%) and complete or partial remission by 26% (10% to 44%). In a population with an expected rate of complete remission of 436/1000, TwHF could increase the number of patients achieving complete remission to 637/1000 (514 to 785). Complete or partial remission could be increased from 664 to 837/1000 (730 to 956). Meta-analyses of head-to-head comparisons demonstrated that there were no significant differences in the primary outcomes when TwHF was compared with either prednisone or CPA. Few studies reported data on secondary outcomes - proteinuria, serum albumin and serum creatinine; one study reported TwHF could significantly decrease serum creatinine compared with CPA. Issues of safety varied considerably and still remain unclear due to the poor reporting of adverse events and the variety of toxicity profiles. Compared to prednisone, TwHF was associated with a lower risk of psychosis. Patients treated with TwHF had a lower risk of hair loss when compared with CPA. However there were no significant differences in other adverse events, including reversible amenorrhoea, leukopenia, liver transaminase elevation, and gastrointestinal discomfort. A double-blind, placebo-controlled study examined the safety and efficacy of TwHF in the treatment of rheumatoid arthritis (Tao 2002). Although the dose in Tao 2002 was 180 mg/d to 360 mg/d for 20 weeks - higher than in any of the 10 included studies (0.5 to 2.0 mg/kg/d for 4 to 8 weeks as initial therapy) - no serious adverse events were observed, and no patients withdrew because of adverse events.
Overall completeness and applicability of evidence
All included studies were conducted in Chinese patients and published in Chinese language journals. Evidence is still needed to examine the effects of TwHF for other ethnicities. There was little evidence related to the use of TwHF in children with NS. In Chinese clinical practice many physicians were reluctant to use TwHF for children to avoid reproductive system complications (Li 2000). Pathological variations may differ in response to TwHF treatment; however due to the paucity of evidence we unable to use subgroup analyses to determine whether those variations could convey different responses to TwHF treatment. Although four studies enrolled patients with SRNS or FRNS, heterogeneity in the interventions among these four studies did not allow us to examine the effect of TwHF on patients with SRNS or FRNS.
Quality of the evidence
This review included 10 studies (630 participants). Assessment according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group indicated that the results could be considered as low quality level. The suboptimal methodological quality of the included studies was the major contributing factor. No study demonstrated adequate allocation concealment. Effect estimates from studies with inadequate concealment of allocation have been shown to overestimate beneficial effects by 18% (95% CI 5% to 29%) than that from studies with adequate concealment of allocation (Pildal 2007). Blinding was not reported in any study. The outcome measurements were all objective and were not likely to be influenced by lack of blinding; however lack of blinding could introduce potential bias in clinical studies (Higgins 2011). Although primary outcome completeness rates were 100%, this was remarkably lower for secondary outcomes (20% to 50%). Consequently, selective outcome reporting bias should be considered when interpreting the results.
Both the numbers of included studies and participants were relatively small, and all tested comparisons involved no more than four studies. Follow-up duration was no more than 18 months. The paucity of evidence did not allow us to perform subgroup analyses to explore modification effects by age, pathological variations, clinical conditions, and co-interventions. Such modification effects may potentially influence the efficacy of TwHF and should be investigated in the future. None of the included studies were designed to evaluate the efficacy of within intervention differences, such as dose and duration variation. More and better evidence is needed to explore benefits that may be conferred by different doses and durations of TwHF treatment.
Potential biases in the review process
Assessment of publication bias was not conducted because of the small number of included studies in the three comparisons. All studies were reported in Chinese language journals. Therefore, publication bias and language bias should be carefully considered when interpreting these results.
Agreements and disagreements with other studies or reviews
Xu 2009a meta-analysed results from three studies enrolling 150 adult patients with primary refractory NS. TwHF significantly increased complete remission (OR 2.81, 95% CI 1.26 to 6.30) and complete or partial remission (OR 3.25, 95% CI 1.20 to 8.76). The efficacy of TwHF on primary IgA nephropathy was examined in another meta-analysis of four studies with 188 patients (Chen 2010a). TwHF significantly increased complete remission (RR 1.53, 95% CI 1.09 to 2.16) and complete or partial remission (RR 1.27, 95% CI 1.08 to 1.48).
Implications for practice
Overall, the quality of evidence was suboptimal due to the small number of included studies enrolling small numbers of participants; short follow-up in each study; only a few studies in each comparison category; and major concerns with methodological bias. This review has highlighted the fact that no well-designed RCT has been performed to test the efficacy and safety of TwHF for primary NS. In the majority of the included studies TwHF was used in conjunction with other immunosuppressive agents such as prednisone and CPA. Therefore, the individual effect of TwHF is still unclear. TwHF may have an add-on effect on remission in patients with primary NS. There was insufficient evidence to assess if TwHF was as effective as prednisone or CPA.
Implications for research
There is need for more methodologically sound studies with an emphasis on adequate sample size and follow-up. Furthermore, priority should be given to the choice of definite endpoints (all-cause mortality, risk of end-stage kidney disease) rather than surrogate outcomes (decline in kidney function). Recording and reporting adverse events should also be improved in future clinical studies. TwHF should be further directly compared with other widely used immunosuppressive agents after the superiority over placebo or no treatment has been clearly established. Ideally, optimal doses and durations of TwHF treatment that are most beneficial and least harmful to patients of different races, ages, and clinical and pathological severity still remain to be clarified.
We would like to thank the referees for their comments and feedback on this review. We would also like to acknowledge the contribution of Ribao Wei and JIanhui Zhou who helped to prepare this systematic review.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. Electronic search strategies
Appendix 2. Risk of bias assessment tool
Last assessed as up-to-date: 13 August 2012.
Contributions of authors
- Draft the protocol: Yizhi Chen, Qing Yuan
- Study selection: Yizhi Chen, Zhixiang Gong
- Extract data from studies: Yizhi Chen, Zhixiang Gong
- Enter data into RevMan: Yizhi Chen, Zhixiang Gong
- Carry out the analysis: Yizhi Chen
- Interpret the analysis: Yizhi Chen, Guangyan Cai, Xiangmei Chen, Xuezhi Zhao, Li Tang, Qing Yuan
- Draft the final review: Yizhi Chen, Guangyan Cai, Xiangmei Chen, Xuezhi Zhao, Li Tang, Qing Yuan
- Disagreement resolution: Xiangmei Chen
- Update the review: Yizhi Chen
Declarations of interest
Sources of support
- No sources of support provided, Not specified.
- This work was partially supported by the National Science and Technology Department 863 Project (2012AA02A512), the National Key New Drug Innovation Project (2013ZX09104-003), the Beijing Science and Technology Project (D13110700470000), and the National Science and Technology Support Program (2011BAI10B00, 2011BAI10B03), China.The sponsors had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.
Medical Subject Headings (MeSH)
*Tripterygium [adverse effects]; Cyclophosphamide [therapeutic use]; Drugs, Chinese Herbal [adverse effects; *therapeutic use]; Immunosuppressive Agents [adverse effects; *therapeutic use]; Nephrotic Syndrome [*drug therapy]; Phytotherapy [*methods]; Prednisone [adverse effects; therapeutic use]; Randomized Controlled Trials as Topic; Remission Induction [methods]
MeSH check words
* Indicates the major publication for the study