Systematic Review To Evaluate Drug Treatment For IgA Nephropathy

IntroductionIgAN was first reported in 1968 by Dr J.Berger. It is now generally known to be the most common type of primary glomerulonephritis throughout the world. IgAN was initially thought to be a rare and benign cause of recurrent hematuria, however, it is neither rare nor benign. It has been demonstrated that IgAN is a worldwide disease that causes ESRD in up to 15-20%of affected patients within 10 years from the apparent onset of disease and in up to 30-40% of individuals within 20 years from diagnosis.Clinical observations of IgA nephropathy patients show over 35 percent of patients who have undergone renal transplantation have recurrent IgA nephropathy. This Clinical manifestations provided strong support for the idea that IgA nephropathy is a systemic disease. The mechanisms involved in the pathogenesis of this disease have remained unclear. Therefore many treatments approaches have been attempted in the past 2 decades, however, no specific treatment has been established, there are wide variations in current practice.The most commonly used regimens include immunosuppressive agents such as glucocorticoids, cyclosporin A or cyclophosphamide, and nonimmunosuppressive medications including fish oils, anticoagulants, antihypertensive agents and surgical tonsillectomy,which have been tested in a variety of studies including RCTs.The mechanisms of this disease have remained unclear. Our published meta-analysis show ACEI or steroids alone have statistically significant effects on protecting renal function and reduction of proteinuria in IgA nephropathy patients. Over the past decade or so, many studies from around the world, involving large cohorts of patients,have reported combination therapy RCTs studies for IgAN.Maybe combination therapy of nonimmunosuppressive treatment and/or immunosuppressive agents would have shown a benefit for slowing the deterioration of renal function, as well as a reduction in daily proteinuria, however, published reports examining the efficacy for preserving renal function and reduction proteinuria in IgAN have yielded conflicting results.Therefore, we present results of a systematic review summarizing currently available evidence from RCTs pertaining to the effect of combination treatment for IgA nephropathy.PartⅠ:Systematic review to evaluate nonimmunosuppressive agents for IgA nephropathyObjective:Published reports examining the efficacy of nonimmunosuppressive agents:RAS blockers, fish oils and statins agents for preserving renal function in IgA nephropathy (IgAN) have yielded conflicting results. To evaluate systematically the effects of nonimmunosuppressive agents on IgAN,we conducted a meta analysis of published randomised controlled trials (RCTs). Methods:MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that compared nonimmunosuppressive agents with placebo and any other antihypertensive agents or non-immunosuppressive agents for treating IgAN. The quality of the studies was evaluated with the method of intention to treat analysis and allocation concealment, as well as with the Jadad method. Meta analyses were performed on the outcomes of proteinuria and renal function in patients with IgAN. Results:1 nineteen RCTs were included in the review.eleven RCTS about RASI vs other nonimmunosuppressive agents;five RCTS about fish oils;three RCTs about statins. 2 about RASI vs other nonimmunosuppressive agents:Eleven RCTs involving 585 patients were included in the review.Seven trials used placebo/no treatment as controls. Four trials used other antihypertensive agents as controls. Overall, ACEI/ARB agents had statistically significant effects on protecting renal function(p＜0.00001) and reduction of proteinuria (p＜0.00001) when compared with control group. Tests for heterogeneity showed no difference in effect among the studies. Systolic and diastolic blood pressure,glomerular filtration rate and age did not influence treatment response.ACEI/ARB agents were well tolerated.3 about fish oils:Five RCTs involving 266 patients were included in the review. Overall, fish oils agents had not statistically significant effects on protecting renal function(p＞0.05) and reduction of proteinuria (p＞0.05) when compared with control group.4 about statins:Three RCTs involving 66 patients were included in the review. Overall, fish oils agents had statistically significant effects on protecting renal function(p＜0.05) and reduction of proteinuria (p＜0.05) when compared with control group. Conclusions:The current cumulative evidence suggests that ACEI/ARB agents had statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN when compared with control groups. But for fish oil, The current cumulative evidence suggests patients with IgAN cannot get benfit from it;For statins, we need more RCTs for its effects on protecting renal function and reduction of proteinuria in patients with IgAN. So we conclude ACEI/ARB agents are a promising medication and evidence-based recommendations for IgAN.PartⅡ:Systematic review to evaluate immunosuppressive agents for IgA nephropathyObjective:Published reports have examined the efficacy of immunosuppressive agents. To evaluate systematically the effects of immunosuppressive agents on IgAN,we conducted a meta analysis of published randomised controlled trials (RCTs).Methods:MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that compared immunosuppressive agents with placebo and any other antihypertensive agents or non-immunosuppressive agents for treating IgAN. RCTs for two or more immunosuppressive agents were excluded.The quality of the studies was evaluated with the method of intention to treat analysis and allocation concealment, as well as with the Jadad method. Meta analyses were performed on the outcomes of proteinuria and renal function in patients with IgAN.Results:1 six RCTs about Glucocorticoids were included in the review.Because a meta analysis about MMF have be published in 2009,so we do not evaluate it for IgAN again.2 about Glucocorticoids vs other nonimmunosuppressive agents:six RCTs involving 585 patients were included in the review. glucocorticoid agents had statistically significant effects on improved renal survival (HR 0.20,95%CI 0.20 to 0.39) and reduction of proteinuria when compared with the con trol group. Tests for heterogeneity showed no difference in effect among the studies. In general, glucocorticoid agents were well tolerated. Patients receiving glucocorticoids therapy did not have an increased risk of development of type 2 diabetes mellitus, hypertension or Cushingoid adverse effects, while glucocorticoids were associated with a significant increase in the risk of gastrointestinal tract adverse events.Conclusions:The current cumulative evidence suggests that glucocorticoids have statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN, but we should be careful for its gastrointestinal tract reaction.In general, glucocorticoids agents are a promising medication and should be investigated further.PartⅢ:Systematic review to evaluate combined treatment modality for IgA nephropathy Objective:To evaluate systematically the effects of combined treatment modality on IgAN,we conducted a meta analysis of published randomised controlled trials (RCTs).Methods:MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that Studies with a combination therapy with nonimmunosuppressive medications and/or immunosuppressive agents, in only one arm, were included.The quality of the studies was evaluated with the method of intention to treat analysis and allocation concealment, as well as with the Jadad method. Meta analyses were performed on the outcomes of proteinuria and renal function in patients with IgAN.Results:1 sixteen RCTs were included in the review. RCTs were divided into five sub-groups according to the administered therapy. The first group includes 8 studies evaluating the effect of RASI plus nonimmunosuppressive agents therapy on renal function and daily proteinuria in patients with IgA nephropathy. The second group includes three studies on the effect of steroids plus RASB agents, and the third group includes two studies relating to the effect of CTX+W+D; the fourth group includes one studies relating to the effect of Steroids plus CTX plus AZA;the fifth group includes two studies relating to the effect of STEROIDS+ARC+W+D on these same outcomes.2 RASB plus non-immunosuppressive agents for IgA nephropathy:according to our meta-analysis, in which the weight of individual studies has been taken into account, combined treatment with ACEI plus ARB and RASB and fish oil or UK was more effective than with RASB alone for a reduction in daily proteinuria; The GFR at the end of treatment was significantly higher in patients receiving combined with non-immunosuppressive agents therapy compared to patients in the control groups receiving RASI alone.There was no significant heterogeneity between these trials3 steroids and RASB agents for IgA nephropathyour meta-analysis indicates that combined treatment with steroids and RASB agents had significant effects on protecting renal function when compared with control group,as well as a reduction in daily proteinuria.4 Trials of combined cyclophosphamide and dipyridamole and warfarin treatmentaccording to our meta-analysis,The results indicate that combined treatment with cyclophosphamide and dipyridamole and warfarin agents seem not to be beneficial for stabilizing kidney function in patients with IgA nephropathy, as well as a reduction in daily proteinuria.5 Trials of combined cyclophosphamide and steroids and azathioprine treatmentThis therapy has an acceptably low risk of side effects and seem to be beneficial for both reducing proteinuria and protecting kidney function in patients with IgA nephropathy.6 Trials of combined steroids and azathioprine and warfarin,and dipyridamole treatmentAccording to this analysis, combined treatment induced a stronger reduction in proteinuria when compared with control group, but not give benefit to the outcome of renal functionin.Conclusions:In conclusion, At present, The pathogenesis of IgAN is still unknown. causal therapy is not available. The best treatment for IgAN remains poorly defined. our analysis provides recommendations for IgAN treatment especially for Severe IgA Nephropathy that "A cocktail therapy" about combination Therapy with RASB and steroids as fundamental combination would have shown a benefit for renoprotective effect; Of course, this treatment still need a large sample, multi-center, well-designed RCT to confirm.Part IV Evidence-based recommendations for IgANEvidence-based recommendations for the management of IgAN were published since 1999. Most of the evidence-based recommendations are about immunosuppressive treatments for IgAN. However, the results are paradoxical, and these recommendations should be partly criticized for methodology. The main criticism of meta-analysis by Samuels was that they were based on a variety of sources, including non-randomized controlled trial data and quasi-randomized controlled trials. More importantly, no recommendations or meta-analysis commented on combintion treatment for IgAN in protecting renal function and reducing proteinuria.1 recommendationsnonimmunosuppressive agents and immunosuppressive agents can get benefit for IgA nephropathy.we pay attention to RASI for nonimmunosuppressive agents and steroids for immunosuppressive agents.2 recommendationscombination therapy of nonimmunosuppressive treatment and/or immunosuppressive agents for IgAN would have shown benefits.3 recommendationswe can recommended combination therapy with RASB and steroids as fundamental combination.4 recommendationswe can use such a"cocktail therapy" for severe IgAN patientst and adjust dose or species by glomerular histopathological scores,hypertension,persistent microscopic hematuria and proteinuria, and impaired renal function.In conclusion, At present, The pathogenesis of IgAN is still unknown. causal therapy is not available. The best treatment for IgAN remains poorly defined. our analysis provides recommendations for IgAN treatment especially for Severe IgA Nephropathy that"A cocktail therapy"about combination Therapy with RASB and steroids as fundamental combination would have shown a benefit for renoprotective effect; Of course, this treatment still need a large sample, multi-center, well-designed RCT to confirm.