The Efficacy Of Paricalcitol On EGFR And Proteinuria In Non-dialysis CKD Patients:A Meta-analysis

BackgroundSecondary hyperparathyroidism(SHPT)is a common complication of chronic kidney disease(CKD),represented with serum 1,25(OH)2D3(active vitamin D)levels dropped and calcium,phosphorus and other mineral and bone metabolism disorder(MBD),resulting in parathyroid hyperplasia and secretion of parathyroid hormone(PTH).Vitamin D receptor activators(VDRAs)as the classical drugs for CKD-SHPT and CKD-MBD,increase the plasma level of vitamin D or its analogues,which combined with the vitamin Drecept or(VDR),correct hypo-calcemia and inhibit the secretion of parathyroid hormone.Paricalcitol is a selective VDRA,which can highly selectively combine with body VDR.So it keeps the curative effect of traditional vitamin D drugs.At the same time,some studies also found that it can inhibit the expression of renin,renin receptor,transforming growth factor β,angiotensin Ⅱ type 1 receptor(ATIR)on kidney.So it brings extra benefits to down-regulation of the renal renin-angiotensin system(RAAS),further it can reduce the proteinuria and delay the process of renal fibrosis.The above studies suggest paricalcitol may have the function of delaying progression of CKD.However several studies have shown that vitamin D analogue may have the risk of declining eGFR in non-dialysis CKD patients.The authors speculated that the possible pathogenesis is that because paricalcitol affects the muscle metabolism(the vit amin D receptor widely exists in muscle),increases the metabolites.So it is controversy that whether there is any influence of pariclacitol administration renal function of non-dialysis patients.No systematic reviews talked about the effect on eGFR of pariclacitol.Thus we performed a systematic review and meta-analysis of all available RCTs to address the effect of paricalcitol on eGFR and proteinuria in non-dialysis CKD patients,aiming to provide safe and effective evidence-based basis for the application of the drug in the non-dialys is patients.Methods:1.Setting out exclusion and inclusion criteria according to the system of evaluation methods formulate,including the characteristics of the objective of study,intervention measures and outcome indicators of measurement,etc.2.According to the collaborative search strategy,PubMed,the clinical control test database of Cochrane Library,Embase,Chinese Wanfang database,CN KI,VIP database(-2014.3),Published and unpublished literature and abstracts in academic meetings(ASN、WCN,CSN)were also searched by hand.The index words are "paricalcitol,chronic kidney diseases,CKD".3.Selecting the RCTs concerning the effect of paricalcitol on eGFR and proteinuria in non-dialysis patients,according to the exclusion and inclusion criteria which we set out before.4.Using the Cochrane Library system evaluation guidelines to evaluate the quality of literatures included,and extracting the literatures’ basic information(author,publication time,characteristics of study population),the number of cases,follow-up time,the dose of paricalcitol and changes in eGFR,albuminuria,incidence of adverse events,etc.5.Review Manager Software 5.2 was used for statistical analysis.Standardized mean difference(SMD)was used to evaluating variation of eGFR after treatment,meanwhile odds ratio(OR)to evaluating relation-ship between decrease in albuminuria and paricalcitol.The effect was expressed in 95%confidence interval(CI)(inspection level α= 0.05).The heterogeneity between the studies was detected using the statistic Pvalues and 12 of chi-square test(x2).If no heterogeneity between included studies(P>0.10,I2<50.0%),a fixed effects model was used to perform meta-analysis.If there is statistical hetero geneity between studies(P<0.10,12>50.0%),analys sources of heterogeneity.If there was obvious clinical heterogeneity,a subgroup analysis was used.If the clinical heterogeneity is not obvious,use the random effects model to perform meta-analysis.If the heterogeneity still couldn’t eliminate(12>50.0%),descriptive system evaluation or Meta regression method was used to explore sources of heterogeneity.Result:1.Search ResultsThe combined search of "PubMed,the clinical control test database of Cochrane Library,Embase,Chinese Wanfang database,CNKI,VIP database",also included some hand-searching of published and unpublished literature and abstracts in academic meetings(ASN、WCN,CSN),retrieved 547 citations(302 in Chinese,245 in English).After discarding a number of duplicates retrieved by individual searches and reviewing all titles and abstracts,many studieswere excluded because they were not RCTs,or their investigated objective is for hemodialysis,peritoneal dialysis or renal transplant patients,or the follow-up time is shorter and the document of eGFR or proteinuria data information is not complete.About the quality of studies selected,there are two for grade A,and 5 for B.Overall,this analysis included seventrials and enrolled a total of 834 patients(508 in experimental group,326 in control group).2.Meta analysis result(1)Effects of Paricalcitol on eGFR to non-dialysis CKD patients:The six RCTs studies were undertaken to prospectively test the changes of eGFR a fter paricalcitol treatment,in which two trials were compared the changes sep arately between paricalcitol lug/d.2 ug/d and the placebo group.Considering obvious clinical heterogeneity(different doses),six studies were divided into lower dose group(<2 ug/d)and higher dose groups(2 ug/d)for eliminating heterogeneity,then respectively compared with control group.Results indicate that the lower dose group(<2 ug/d)had no significant effect on patients’ eGFR compared with placebo,[SMD = 0.10,95%CI(0.28～0.28),P = 0.26),while eGFR significantly decline in higher dose groups(2 ug/d)compared with placebo group[SMD = 0.45,95%CI(0.63～0.27),P<0.0001](2)Effects of Paricalcitol on on Proteinuria to non-dialysis CKD patients:The six RCTs studies showed that a number of patients had a reduction in proteinuria(>10%or15%).There was no statistical heterogeneity(P=0.22,I2 =27.0%),so a fixed effects model was used.The result is:Compared with pla cebo,paricalcitol reduced proteinuria significantly[OR(95%CI)= 2.09(1.52～2.58),P<0.00001],and there was no difference between different dose groups[OR(95%CI)= 1.09(0.62～1.91),P=0.77].(3)Adverse events of Treatment:For paricalcitol treatments groups versus control groups,six studies reported treatment-related adverse events of treat ment,included "hypercalcemia,hyperp-hosphatemia,respiratory infection,fever,cough,abdominal pain,constipation,heart failure and death etc.The statistical heterogeneity was significant(P=0.22,12 =27.0%).Because of clinical het erogeneity(different doses),six studies were divided into lower dose group(<2 ug/d)and high dose group(2 ug/d)for eliminating heterogeneity,and then respectively compared with control group.Neither lower dose group nor hign er dose group had statistical difference with the incidence of adverse events,compared with the placebo group([OR(95%CI)= 0.93(0.51一1.52),P=0.76],[OR(95%CI)= 2.08(0.70～6.81),P=0.19]).There was also no differ ence between different dose groups of the incidence of adverse events[OR(95%CI)= 1.09(0.62～1.91),P=0.77].(4)Publication Bias and Sensitivity Analyses:Funnel figure of seven studies were roughly symmetric,prompting no significant publication bias.One trial had less samples.The appeal results without essential change after removing the trial.Sensitivity analyses prompt a stabled result.Conclusion:The effect of paricalcitol on eGFR in non-dialysis CKD patients may be associated with the dose.Lower dose paricalcitol(<2ug/d)has no effect on eGFR in non-dialysis CKD patients meanwhile reduceing proteinuria.The hig her dose(2ug/d)may reduce eGFR without farther reduction in proteinuria.There is no significant difference between different doses for reduction in prote inuria.But our study has certain limitations.First of all,the literatures and number of patients in which we included are relatively less.Secondly,"eGFR"or "proteinuria" are not the primary end points in most trials.In addition,there is also lacked of observation for hard endpoints,just like incidence of end-stage renal disease(ESRD),mortality,etc.The major limitations of this meta-analysis outlined above must be stressed when evaluating our results in a clinical setting.So well-designed and large samples of randomized trials are needed to valuate the effective dose and safety of paricalcitol used in non-dialysis CKD patients.