| Membranous nephropathy(MN), a common cause of adult nephrotic syndrome worldwide, can be idiopathic, or secondary to various clinical conditions, including neoplasia, hepatitis B, systemic autoimmune disease, drug or toxicant exposure. The diagnosis and treatment of MN always attract much attention in the field of chronic kidney disease(CKD).In recent years, the study which identified M-type phospholipase A2 receptor(PLA2R) as a major antigen in idiopathic MN supported the hypothesis that immune deposits formed by circulating antibodies and auto-antigen in podocytes play the key pathogenic role in the mechanisms of MN. Circulating PLA2 R antibodies were found in a majority 75% of serum samples from patients with idiopathic MN, but absent in patients with secondary MN and other glomerulopathy or autoimmune diseases, so these antibodies were suggested to not only play a direct pathogenic role but also be a promising marker for the differential diagnosis. PLA2 R antigen staining were assessed in the renal biopsies and showed a good correlation with the serological test of PLA2 R antibodies. However, with accumulating evidence, conflicting results have raised concerns about the clinical performance of serological anti-PLA2 R and histological PLA2 R staining tests for the diagnosis of idiopathic MN across various clinical situations. How to analysis the diagnostic false positive or false negative result of circulating PLA2 R antibodies? How to evaluate the diagnostic value of PLA2 R antibodies and glomerular PLA2 R antigen detection for the differentiation of idiopathic and secondary MN? Which potential factors or conditions may affect the accuracy of diagnostic result? These questions are urgent to be answered.The treatment of idiopathic MN also remains controversial. Some recommend that idiopathic MN patients with good long-term prognosis should avoid any type of immunosuppressants because of the serious adverse effects of aggressive immunosuppressive therapeutic approaches, as well as the fact that a considerable percentage of idiopathic MN patients achieve spontaneous remission during the clinical course.In KDIGO clinical practice guidelines for MN, it is suggested that patients at medium or high risk for progression are candidates for immunosuppressive therapy. For the application of immunosuppressant, KDIQO clinical practice guidelines recommend glucocorticoids(GC) combined with cyclophosphamide(CTX) as the first option. GC combined with cyclosporin A(Cs A) or tacrolimus(TAC) is advised to be used when patients have contraindication or no response to CTX. However, Cs A has the adverse effects of damaging renal functions and inducement of malignancies, and TAC is too expensive for most patients to receive a long-term therapy. Seeking for an alternative immunosuppressant with low cost and less adverse effects is helpful for patients and clinicians.1eflunomide(LEF) is a commonly used immunosuppressant in autoimmune disease, and it has been widely applied in kidney disease during recent years. However, clinical trials of LEF in the treatment of idiopathic MN are not much up to now, and none clinical evidence-based research has been conducted to evaluate its efficacy and safety.In order to answer the question above, we attempt to perform meta-analysis based on the publications about the two topics:I. Meta analysis of the diagnostic accuracy of serum PLA2 R autoantibodies and glomerular PLA2 R antigen staining for the differentiation of idiopathic and secondary membranous nephropathyWith increasing number of studies, the efficiencies of the circulating antibodies and antigen renal tissue diagnosis detection among the reports worldwide are not consistent.In this part, we aimed to evaluate the diagnostic value of serum PLA2 R autoantibodies and glomerular PLA2 R antigen staining for the differentiation of idiopathic and secondary membranous nephropathy comprehensively, and try to analysis the potential factors having impact on the accuracy of PLA2 R antibodies, provide evidence to assist physicians in clinical.Methods:Systematically computerized searches were performed among commonly used Chinese and English database, including Pubmed, Embase, Web of Knowledge, Cochrane library, Wanfang and CNKI. The case-control studies about serum PLA2 R autoantibodies and glomerular PLA2 R antigen staining in the diagnosis of idiopathic and secondary MN were included. Characteristics of included studies and data of 2 × 2 contingency tables were extracted. The Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Review(QUADAS) assessment tool which contains 14 items was applied for the quality assessment of the included studies. All data analysis were conducted by the software STATA 12.0.The pooled specificity, sensitivity, diagnostic odds ratio, area under curve and likehood ratios were took to evaluate the diagnostic efficiency. To explore the potential source of heterogeneity, we stratified the studies into several subgroups according to characteristics of studies and patients. Publication bias was investigated by Deek’s plot.Results:1. Our search initially yielded 432 publications in total, and after screening of them, 19 studies were finally included in this analysis. 13 of them only investigated the diagnostic value of circulating PLA2 R antibodies detection, 3 studies only provided complete data for PLA2 R glomerular deposits in the discernment between idiopathic MN and secondary MN, and 3 studies contained both serological and histological tests. the quality of the included studies were moderate;2. Serum PLA2 R antibodies in the differential diagnosis of idiopathic and secondary MN showed the pooled sensitivity of 0.68(95%CI,0.61–0.74), the pooled specificity of 0.97(95%CI, 0.85–1.00), DOR 73.75(95%CI, 12.56–432.96), positive LR 24.48(95%CI, 4.21–142.43) negative LR 0.33(95%CI, 0.28–0.40), AUC 0.82(95%CI, 0.78–0.85) with significant heterogeneity; PLA2 R staining in biopsies showed a DOR(34.70, 95% CI, 9.93–121.30), a sensitivity of 0.78(95%CI, 0.72–0.83), a specificity of 0.91(95%CI, 0.75–0.97) and AUC of 0.84(95%CI, 0.81–0.87) without heterogeneity across studies(I2=0.00%).3. Subgroup analysis revealed that study design, detection methods, types of publications, race, types of secondary MN, levels of proteinuria, use of immunosuppressor and interval between biopsy and serum sampling are potential factors resulting in the diagnostic heterogeneity of circulating PLA2 R antibodies.Limitations:1. Among included studies, only a few were prospective;2. The methods used for the detection of circulating PLA2 R antibodies in included studies were not uniform, Western blot and indirect immunofluorescence can only be qualitative, there is no standard to determine quantitatively using an optimal cutoff value;3. Other factors which we have not taken into consideration in our analysis may also be the source of significant heterogeneity across studies4. Only 6 studies provided complete data for PLA2 R glomerular deposits in the discernment between idiopathic MN and secondary MN, we failed to conduct further analysis based on available clinical information.Conclusions:1. According to the evidence provided by those publications, PLA2 R staining in biopsies may have a better performance than the detection of circulating PLA2 R antibodies in the differential diagnosis of idiopathic and secondary MN;2. The detection of circulating PLA2 R antibodies may be affected by so many factors, therefore their conclusion for diagnosis should be considered with caution, especially for the possible false positive result, we advised to further validate the diagnosis in combined with detection of glomerular PLA2 R in biopsiesII. Meta analysis of leflunomide in treatment of idiopathic MNLEF is an inhibitor of dihydroorotate dehydrogenase, which is the key enzyme in pyrimidine synthesis, leading to a decrease of T cell and B cell and presents an anti-proliferative effect. LEF play multiple roles in immunoregulation, it can also inhibit the activities of tyrosine protein kinase and NF-κB to exert the anti-inflammatory effect. After oral administration,following catabolism caused by digestive system make LEF turn into its bioactive metabolite—A771726, which mainly distributes in liver and kidney and the half-life period of A771726 can be as long as 15~18 days. Till now, LEF in treatment of henoch schonlein purpura nephritis, lupus nephritis and refractory nephropathy syndrome had been widely studied but the efficacy of LEF in treatment of idiopathic MN was not consistent among studies, and it is also be controversial about the occurrence of adverse effects of LEF.In order to evaluate the efficacy and safety of LEF in treatment of idiopathic MN, in this part, we also collected the relevant publications and conducted a meta analysis about this topic, we aimed to update the understanding of LEF in applications and offer evidence of LEF in treatment of idiopathic MN.Methods:Systematically computerized literature search was initially performed among commonly used Chinese and English database, including Pubmed, Embase, Web of Knowledge, Cochrane library, Wanfang and CNKI, and the latest search was till to Feb, 2015. The case-control studies about LEF in treatment of idiopathic MN were included in our analysis. Manual searches were conducted following reviews of the reference lists of all selected articles to identify any missing studies. We used Cochrane reviewers’ handbook 4.2 combined with Jadad scale to evaluate the quality assessment of the included studies. The following information were extracted: first author, publication date, course of follow up, sample size, age, sex, intervention in treatment group and control group, number of complete remission cases, number of partial remission cases, number of invalid cases, number of death cases, types and number of adverse effects. In this part, main outcome indexes were complete remission, partial remission and total remission rate at the end of follow up, and secondary outcome index was the occurrence of adverse effects. The software STATA 12.0 was used to calculate relative risk(RR) of each index.Results:1. Our search initially yielded 231 publications in total, and after screening of them, 9 studies were finally included in this analysis. All of them were single-center clinical case control trials, and none of them report the death cases. Patients in control group of 2 studies did not receive any immunosuppressor before, and only use the ACEI as support treatment. Other 7 studies use CTX combined with GCs as control.2. In total, when compared to control group which did not use LEF, there was no statistical significance in complete(RR=1.113; 95% CI, 0.791-1.567; P=0.538), partial(RR=1.315; 95% CI, 0.925-1.868; P=0.127) and total remission rate(RR=1.113; 95% CI, 0.791-1.567; P=0.538) at follow up of 6 months. However, when follow up turn to 12 months, the complete(RR=1.946; 95% CI, 0.941-4.024; P=0.026) and total remission rate(RR=2.320; 95% CI, 1.078-4.993; P=0.031) between two groups were significant different;3. When compared to the control group which used CTX combined with GCs, there was no statistical significance in complete(RR=1.039; 95% CI, 0.736-1.469; P=0.827), partial(RR=1.197; 95% CI, 0.831-1.698; P=0.364) and total remission rate(RR=1.111; 95% CI, 0.945-1.308; P=0.203) at follow up of both 6 months and 12 months(P>0.05). However,In the comparison of adverse effects, the difference between groups was significant(RR=0.461; 95% CI, 0.321-0.663; P=0.000);4. When compared to the group which did not receive any immunosuppressor, the complete(RR=3.761; 95% CI, 1.258-11.242; P=0.018), partial(RR=3.456; 95% CI, 1.181-10.109; P=0.024) and total remission rate(RR=4.025; 95% CI, 1.991-8.136; P=0.000) at follow up of 12 months were significant higher.Limitations:1. All included studies were conducted in China, and it might objectively result in bias of selection;2. The quality of included studies was low, the main reason was no detailed description of the methodology, such as whether assign patients into groups using a random and double blind methods. It is possible that there are quite some difficulties in the proceed of clinical research based on the Cochranes’ standard;3. The sample size was small;4.The definition of outcome were not absolutely consistent, for example, some studies announced the level of proteinuria in complete remission was below 0.3g/d, but in other studies, this threshold value could be 0.4 or 0.5 g/d. Apparently, it may have more or less impact on our results of analysis.Conclusions:1. Based on those publications, we could concluded that compared to CTX combined with GCs, the efficacy of LEF combined with GCs did not show a significant difference but the occurrence of adverse effects was much lower than CTX combined with GCs. Thus, LEF could be considered as an alternative drug in treatment of idiopathic MN;2. The result that the efficacy of LEF combined with GCs in treatment of idiopathic MN was better than nonuse of immunosuppressor need further evaluation and observation, because the increasing incidence of adverse effects might have negative impact on prognosis. |
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