Efficacy and safety of Abelmoschus manihot for IgA nephropathy: A multicenter randomized clinical trial.

RATIONALE AND OBJECTIVE: IgA nephropathy (IgAN) is an important cause for end-stage renal disease worldwide. The treatment for IgAN remains challenging, and few randomized and controlled clinical trials have been conducted to evaluate new therapies. The present study assesses the efficacy and safety of Abelmoschus manihot (AM) in IgAN patients. STUDY DESIGN: Randomized, non-inferiority, double-blind, double-dummy multicenter trial. SETTING AND PARTICIPANTS: This trial was designed to recruit 1,600 biopsy-proven IgAN patients (proteinuria between 0.5-3.0 g/d and estimated glomerular filtration rate [eGFR] of ≥ 45 ml/min/1.73 m2) across China. INTERVENTIONS: The participants were randomized at 1:1 to AM (2.5 g for three times per day) or losartan potassium (100 mg per day) for 48 weeks. OUTCOMES: The primary outcome was the change in 24-hour proteinuria from baseline to week 48. The secondary outcomes were the change in eGFR from baseline to week 48, and the incidents of endpoint events (proteinuria ≥ 3.5 g/24 h, doubling of serum creatinine, or receiving renal replacement treatment). RESULTS: Among 1,470 randomized patients (mean age, 37.4 [SD, 10.6] years old; 777 [52.9%] were female; mean eGFR, 95.0 [SD, 24.3] mL/min/1.73 m2; mean 24-hour proteinuria, 1.2 [SD, 0.7] g/d), the mean decline in 24-h proteinuria at week 48 was 230 mg and 253 mg in the AM and losartan potassium groups, respectively (P = 0.676). The mean difference in the change in 24-h proteinuria between these two groups was -23.32 mg (95% confident interval: -123.2 to 76.6, p = 0.647). The mean decline in eGFR was 0.41 ml/min/1.73 m2 and 0.76 ml/min/1.73 m2 in the AM and losartan potassium groups, respectively (p = 0.661). The mean difference in the change in eGFR between these two groups was -0.43 ml/min/1.73 m2 (95% confident interval: -1.99 to 1.13, p = 0.589). The incidence of endpoint events was 8.6% in the AM group and 8.2% in the losartan group (p = 0.851). LIMITATIONS: The results of the trial may not be generalized to IgAN patients with a proteinuria of > 3.0 g/d and an eGFR of < 45 ml/min/1.73 m2. The long-term benefits of AM in reducing the risk of progressive renal dysfunction remains unclear, based on this 48-week observation. CONCLUSION: AM can be recommended as a promising treatment for IgAN patients.

Abelmoschus manihot - a traditional Chinese medicine versus losartan potassium for treating IgA nephropathy: study protocol for a randomized controlled trial.

BACKGROUND: IgA nephropathy (IgAN) is one of the most common primary glomerular diseases worldwide, but effective therapy remains limited and many patients progress to end-stage renal disease (ESRD). Only angiotensin-converting enzyme inhibitors (ACE-I)/angiotensin-receptor blockers (ARB) show a high level of evidence (1B level) of being of value in the treatment for IgAN according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. However, traditional Chinese medicine has raised attention in kidney disease research. Abelmoschus manihot, a single medicament of traditional Chinese medicine has shown therapeutic effects in primary glomerular disease according to the randomized controlled clinical trial that we have completed. Here, we conduct a new study to assess the efficacy and safety of Abelmoschus manihot in IgAN. Also, this study is currently the largest double-blind, randomized controlled registered clinical research for the treatment of IgAN. METHODS: We will conduct a multicenter, prospective, double-blind, double-dummy randomized controlled study. The study is designed as a noninferiority clinical trial. Approximately 1600 biopsy-proven IgAN patients will be enrolled at 100 centers in China and followed up for as long as 48 weeks. IgAN patients will be randomized assigned to the Abelmoschus manihot group (in the form of a huangkui capsule, 2.5 g, three times per day) and the losartan potassium group (losartan potassium, 100 mg/d). The primary outcome is the change in 24-h proteinuria from baseline after 48 weeks of treatment. Change in estimated glomerular filtration rate (eGFR) from baseline after 48 weeks of treatment, the incidence of endpoint events (proteinuria ≥3.5 g/24 h, the doubling of serum creatinine, or receiving blood purification treatment) are the secondary outcomes. Twenty-four-hour proteinuria and eGFR are measured at 0, 4, 12, 24, 36 and 48 weeks. DISCUSSION: This study will be of sufficient size and scope to evaluate the efficacy and safety of Abelmoschus manihot compared to losartan potassium in treating patients with IgAN. The results of this study may provide a new, effective and safe treatment strategy for IgAN. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02231125 . Registered on 30 August 2014.

Treatment of chronic kidney disease using a traditional Chinese medicine, Flos Abelmoschus manihot (Linnaeus) Medicus (Malvaceae).

The flowers of Abelmoschus manihot (Linnaeus) Medicus (Malvaceae; Flos A. manihot) have been used in China for many centuries as a traditional Chinese medicine for the treatment of chronic kidney disease. The Huangkui capsule is a single-plant drug extracted from the dry corolla of Flos A. manihot that has been approved by China's State Food and Drug Administration for the treatment of chronic glomerulonephritis. The purpose of this paper is to review briefly some of the past experiences in rapid filtration and to present more fully a few facts brought out in recent studies. The primary chemical constituents of Flos A. manihot are flavonoids. In vivo, the flavonoids can be transformed into glucuronide-sulphate conjugates, which are the major metabolites of Flos A. manihot and could contribute to the renoprotective effects in vivo. Flos A. manihot can ameliorate proteinuria, podocyte apoptosis, glomerulosclerosis and mesangial proliferation. The renoprotective effects of Flos A. manihot are related to inhibition of caspase-3 and caspase-8 overexpression, reduction of the infiltration of ED1(+) and ED3(+) macrophages, downregulation of oxidative stress, inhibition of the p38 mitogen-activated protein kinase and serine/threonine kinase pathways and suppression of transforming growth factor-ß1 and tumour necrosis factor-α expression. Recently, a multicentre randomized controlled trial demonstrated that Flos A. manihot was more effective than the angiotensin-receptor blocker losartan in reducing proteinuria in patients with primary glomerular disease. Because Flos A. manihot is generally preferred by Chinese patients and clinicians, high-quality trials to test the efficacy and safety of Flos A. manihot are urgently needed.

Efficacy and safety of Flos Abelmoschus manihot (Malvaceae) on type 2 diabetic nephropathy: A systematic review.

OBJECTIVE: To evaluate the efficacy and safety of Flos Abelmoschus manihot (Malvaceae) on type 2 diabetic nephropathy (DN). METHODS: The Cochrane Library, PubMed/MEDLINE, Excerpta Medical Database, Chinese electronic literature databases, and the references of relevant articles were searched in March 2012 for randomized controlled trials (RCTs) that reported the effects of Flos A. manihot on type 2 DN patients with overt but subnephrotic-range proteinuria (500-3,500 mg/24 h). The quality of trials was evaluated using the Cochrane-recommended method. The results were summarized as risk ratios (RRs) for dichotomous outcomes or mean differences (MDs) for continuous outcomes. RESULTS: Seven trials (531 patients) were included. Flos A. manihot significantly decreased proteinuria [MD -317.32 mg/24 h, 95% confidence interval (CI) [-470.48, -164.17],P<0.01]. After excluding a trial that only included patients with well-preserved renal function, Flos A. manihot was associated with a significant decrease in serum creatinine (MD -11.99 µmol/L, 95% CI [-16.95, -7.04],P<0.01). Serious adverse events were not observed. The most common adverse event was mild to moderate gastrointestinal discomfort; however, patients receiving this herb did not have an increased risk for tolerated gastrointestinal discomfort (RR 1.48, 95% CI [0.39, 5.68],P=0.57). CONCLUSIONS: Flos A. manihot may be considered as an important adjunctive therapy with the first-line and indispensable therapeutic strategies for type 2 DN. High-quality RCTs are urgently needed to confirm the effect of Flos A. manihot on definite endpoints such as end-stage renal disease.

L-Carnitine supplementation for adults with end-stage kidney disease requiring maintenance hemodialysis: a systematic review and meta-analysis.

BACKGROUND: A previous meta-analysis indicated that l-carnitine significantly increased hemoglobin and decreased the required erythropoietin dose in maintenance hemodialysis patients. OBJECTIVE: An updated systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to reevaluate effects of l-carnitine. DESIGN: The Cochrane Library, PubMed, and EMBASE databases (31 December 2012) were searched to identify RCTs that investigated effects of l-carnitine in adults with end-stage kidney disease that required maintenance hemodialysis. RESULTS: Forty-nine RCTs (1734 participants) were included. l-Carnitine significantly decreased serum low-density lipoprotein (LDL) (mean difference: -5.82 mg/dL; 95% CI: -11.61, -0.04 mg/dL) and C-reactive protein (CRP) (-3.65 mg/L; -6.19, -1.12 mg/L). There were no significant differences in triglycerides (-0.89 mg/dL; -29.32, 27.53 mg/dL), cholesterol (0.14 mg/dL; -6.15, 6.42 mg/dL), high-density lipoprotein (1.13 mg/dL; -2.44, 4.70 mg/dL), hemoglobin (0.68 g/dL; 0.14, 1.50 g/dL), hematocrit (2.04%; -1.39, 5.48%), albumin (1.65 g/L; -0.22, 3.51 g/L), or the required erythropoietin dose (-0.76 KU/wk; -1.75, 0.23 KU/wk). No adverse effects were reported. CONCLUSIONS: This meta-analysis failed to confirm the previous findings regarding the effects of l-carnitine on hemoglobin and the erythropoietin dose but showed that l-carnitine significantly decreased serum LDL and CRP. The extent of the decrease in LDL was not clinically relevant, whereas the significant decrease in CRP was both statistically and clinically relevant. However, the relevance of decrease in CRP with hard endpoints such as all-cause mortality and cardiovascular complications still remains to be clarified.

Tripterygium wilfordii Hook F (a traditional Chinese medicine) for primary nephrotic syndrome.

BACKGROUND: Tripterygium wilfordii Hook F (TwHF), a traditional Chinese herbal medicine used as an immunosuppressive agent, has been prescribed in China for patients with primary nephrotic syndrome (NS) for more than two decades. Although patients with primary NS in China have benefited from TwHF treatment, its properties have not yet been fully understood. OBJECTIVES: To assess the benefits and harms of TwHF for patients with primary NS. SEARCH METHODS: We searched the Cochrane Renal Group's specialised register (August 2012), Cochrane Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 8), EMBASE (1966 to August 2012), and MEDLINE (1966 to August 2012). We also searched 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), and reference lists of articles (6 November 2010). SELECTION CRITERIA: Only randomised controlled trials (RCTs) were included. Two standardised preparations of TwHF were investigated: ethanol-ethyl acetate extract and chloroform-methanol extract. All other TwHF preparations were excluded because of reported toxicities. Other traditional Chinese herbal medicines were also excluded. All included RCTs had a follow-up of at least three months. DATA COLLECTION AND ANALYSIS: Data extraction and risk of bias assessment were undertaken independently by two authors. Where details of randomised sequence generation and allocation concealment were absent or inadequately reported, we contacted original study investigators for verification and details of the procedure. For dichotomous outcomes (remission and drug-related adverse events) we used risk ratio (RR) with 95% confidence intervals (95% CI) and mean difference (MD) for continuous outcomes (urinary protein excretion, serum albumin and serum creatinine). MAIN RESULTS: Ten studies enrolling 630 participants were included. 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. Four studies (293 participants) contributed to the comparison of TwHF versus non-TwHF. TwHF significantly increased complete remission (RR 1.46, 95% CI 1.18 to 1.80) and complete or partial remission (RR 1.26, 95% CI 1.10 to 1.44) without escalating the adverse events profile at the last follow-up (12 to 16 months). Four studies (223 participants) compared TwHF with prednisone. There were no statistically significant differences between complete remission, partial remission, and complete or partial remission. Two studies (114 participants) contributed to the comparison of TwHF versus cyclophosphamide (CPA) at the last follow-up (3 to 12 months). There were no statistically significant differences between complete, partial, or complete or partial remission. One study (46 participants) reported TwHF was associated with a significantly lower serum creatinine compared with CPA (MD -14.00 µmol/L, 95% CI -26.43 to -1.57). No serious adverse events of TwHF were observed. One study (37 participants) reported TwHF was associated with a significantly lower risk of psychosis when compared to prednisone (RR 0.11, 95% CI 0.01 to 0.75), and two studies showed a significantly lower risk of hair loss with TwHF when compared to CPA ((2 studies, 114 participants): RR 0.11, 95% CI 0.02 to 0.59). AUTHORS' CONCLUSIONS: 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. More methodologically sound and sufficiently powered studies, with adequate follow-up would help to better inform management options for the use of TwHF for primary NS. TwHF should be further directly compared with other widely used immunosuppressive agents after the superiority over placebo or no treatment has been clearly established.

Meta-analysis of Tripterygium wilfordii Hook F in the immunosuppressive treatment of IgA nephropathy.

OBJECTIVE: Numerous Chinese patients with IgA nephropathy (IgAN) have benefited from Tripterygium wilfordii Hook F (TwHF) from two decades ago. However, to date there is no systematic evaluation of this remedy for IgAN. METHODS: We conducted a meta-analysis of all eligible randomized clinical trials (RCTs) to assess the effect of TwHF on IgAN for the first time. In August 2009 a systematic search was performed among eight electronic databases. Review Manager (RevMan) version 5.0 was used. RESULTS: (i) Four eligible RCTs with 188 participants were included; (ii) The validities of included RCTs were generally acceptable; (iii) TwHF brought about a favorable increase in complete remission (CR) (RR 1.53, 95%CI 1.09 to 2.16, I(2)=12%) and total remission (TR) (RR 1.27, 95%CI 1.08 to 1.48, I(2)=0%) compared with non-TwHF treatment; and this result was further confirmed by intention-to-treat analysis; (iv) Exploiting subgroup meta-analysis, TwHF led to significantly greater improvements of IgAN with non-nephrotic proteinuria with regard to the increase of CR (RR 1.80, 95%CI 1.21 to 2.68, I(2)=0%) and TR (RR 1.32, 95%CI 1.11 to 1.57, I(2)=0%), and decrease of urinary proteinuria excretion (UPE) (MD -467.41 mg/24h, 95%CI -633.99 to -300.82, I(2)=0%). Meanwhile, the renal function was well preserved (MD -2.66 µmol/L, 95%CI -9.26 to 3.94, I(2)=0%). Conclusion Although the results of this meta-analysis should be interpreted with caution and warrant further investigation, TwHF was certainly a valuable and promising immunosuppressive remedy for IgAN, which was in accordance with the accruing evidence from numerous large clinical and experimental studies.

[Protective effects of beta-asarone on cultured rat cortical neurons damage induced by glutamate].

OBJECTIVE: To study the protective effects of beta-asarone on cultured rat cortical neurons damage induced by glutamate. METHODS: The protective effects of beta-asarone on cultured rat cortical neurons after glutamate intoxication were observed with morphology, extent of damage, livability, Intracellular calcium concentration and apoptosis ratio. RESULTS: Morphological changes, LDH leakage and intracellular calcium concentration increasing, cell survival decreasing were observed in cultured rat cortical neurons exposured to glutamate; 7.5, 15, 30 microg/ml beta-asarone could increase cell survival, decrease LDH leakage and apoptosis ratio; 15, 30 microg/ml beta-asarone could reduce intracellular calcium concentration. CONCLUSION: The results suggest that beta-asarone prevents the toxicity of glutamate, and it maybe attribute to its effect of anticalcium.