| BackgroundHypertension is prevalent in China.Chronic kidney disease(CKD)is both a cause and a consequence of hypertension.Hyperuricemia is not just closely assocated with gout,but is a risk factor for hypertension,CKD and cardiovascular diseases.The numbers of patients with hypertension,CKD and hyperuricemia were approximately 300,120 and 170 million,respectively,in China.Therefore,a better understanding of the modifiable risk factors of CKD and hyperuricemia in China,leading to early detection and effective prevention is helpful in clinical decision-making and timely management,and might alleviate the future burden of CKD,hyperuricemia and the associated complications.In China,about 75%hypertensive patients had elevated homocysteine concentrations(?10 ?mol/L)due to the inadequate folate intake.Previous studies had reported that elevated homocysteine concentrations were significantly associated with the risk of hyperuricemia,albuminuria/proteinuria and renal function decline.In addition to homocysteine lowering,folic acid has direct antioxidant effects,and may improve or restore endothelial function.Folic acid and its derivatives have been reported to offer a potent inhibition of xanthine oxidase.Therefore,we speculated that folic acid therapy may have a positive effect on serum uric acid(UA)levels,new-onset proteinuria and renal function,as well as all-cause mortality associated with CKD.However,no previous studies have confirmed these hypotheses.MethodsThis paper included one substudy and two post-hoc analyses of the China Stroke Primary Prevention Trial(CSPPT).The CSPPT was a randomized,double-blind,actively controlled trial that was conducted from May 2008 to August 2013 in 32 communities in the Anhui and Jiangsu provinces of China.The study enrolled a total of 20,702 hypertensive adults who were aged 45-75 years and did not have a history of major cardiovascular diseases.Part 1:This substudy of the CSPPT excluded individuals who used UA-lowering drugs or had missing UA concentrations at baseline.A total of 15,364 CSPPT patients were randomly assigned to a double-blind daily treatment with a single tablet that contained 10 mg enalapril and 0.8 mg folic acid(n = 7,685)or 10 mg enalapril alone(n = 7,679).The main outcome was the change in serum UA,which was defined as UA at the exit visit minus that at baseline.Secondary outcomes were as follows:1)controlled hyperuricemia and 2)new-onset hyperuricemia.Part 2:This post-hoc analysis of the CSPPT renal substudy excluded individuls with proteinuria at baseline.A total of 13,071 CSPPT patients were randomly assigned to a double-blind daily treatment with a single tablet that contained 10 mg enalapril and 0.8 mg folic acid(n = 6,511)or 10 mg enalapril alone(n = 6,560).The primary outcome was new-onset proteinuria,defined as a urine dipstick reading of?1+at the exit visit.Secondary outcomes included a composite of the primary outcome and all-cause death,as well as the annual rate of eGFR decline.Part 3:This post-hoc analysis of the CSPPT excluded individuls with missing data for eGFR or proteinuria at baseline.A total of 19,349 CSPPT patients were randomly assigned to a double-blind daily treatment with a single tablet that contained 10 mg enalapril and 0.8 mg folic acid(n = 9,674)or 10 mg enalapril alone(n = 9,675).Dipstick proteinuria was categorized into absent(urine dipstick reading negative),mild(urine dipstick reading trace or 1+),and heavy(urine dipstick reading>2+).Baseline eGFR levels was categorized into<60,60-89,?90 ml/min/1.73m2.The primary outcome was all-cause mortality.ResultsPart 1:After a median length of 4.4 years of treatment,the mean ± SD UA concentration increased by 34.7±72.5 ?mol/L in the enalapril alone group and by 30.7 ± 71.8 ?mol/L in the enalapril-folic acid group,which resulted in a mean group difference of-4.0 ?mol/L(95%CI:-6.5,-1.6 ?mol/L;P =0.001).Furthermore,compared with enalapril alone,enalapril-folic acid treatment showed a significant 31%increase in the controlled hyperuricemia(30.3%compared with 25.6%;OR:1.31;95%CI:1.01-1.70)and a significant 11%decrease in the adjusted odds of new-onset hyperuricemia(15.0%compared with 16.3%;OR:0.89;95%CI:0.79-0.99).A greater beneficial effect was observed in subjects with hyperuricemia(P-interaction=0.07)or higher concentrations of total homocysteine(P-interaction =0.02)at baseline.Furthermore,there was a significant inverse relation(P<0.001)between the reduction of total homocysteine and the change in UA concentrations.Part 2:The primary event occurred in 213(3.9%)and 188(3.5%)participants,respectively,in the enalapril and the enalapril-folic acid group(OR,0.90;95%CI,0.74-1.11).However,among participants with diabetes at baseline,folic acid therapy resulted in a significant 52%reduction in the risk for the primary event(3.7%in the enalapril-folic acid group vs.7.4%in the enalapril group;OR,0.48;95%CI,0.29-0.81)and a 38%reduction in the the composite event(OR,0.62;95%CI,0.42-0.92),and a 55%slower annual rate of eGFR decline(0.5%vs.1.1%per year,P=0.002).Among those without diabetes at baseline,there was no between-group difference in the primary and secondary outcomes.Part 3:Both lower eGFR levels(<60 vs.?90 ml/min/1.73m2,13.0 vs.2.2%;HR,1.93;95%CI:1.19-3.12)and heavy proteinuria[vs.absent,10.8 vs,2.7%;hazard ratio(HR),3.30;95%CI:2.10-5.18]were significantly associated with increased risks of all-cause mortality.Folic acid supplementation significantly reduced the risk of all-cause mortality in patients with heavy proteinuria(6.4%in the enalapril-folic acid vs.10.8%in the enalapril alone group;HR,0.49;95%CI:0.26-0.94),but not in those with absent or mild proteinuria(2.8 vs.2.9%;HR,0.99;95%CI:0.84-1.17;P-interaction:0.040).However,eGFR levels did not significantly modify the effect of folic acid supplementation in reducing the risk of all-cause mortality.ConclusionsCompared with enalapril alone,enalapril-folic acid therapy can significantly reduce the magnitude of the increase of UA concentrations in hypertensive adults,reduce the new-onset proteinuria and slow down the renal function decline in hypertensive patients with diabetes,and reduce the mortality risk associated with heavy proteinuria in hypertensive patients. |
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