中国学者发现叶酸显著延缓轻中度慢性肾病进展
2016年10月1日，《美国医学会杂志内科学分册》正式发表南方医科大学南方医院侯凡凡、北京大学第一医院霍勇等学者的中国脑卒中一级预防试验（CSPPT）肾脏亚组研究报告，发现适量补充叶酸可显著延缓高血压患者肾病的进展，降低慢性肾病进展为尿毒症的风险。
该研究入组15104例估计肾小球滤过率≥30mL/min/1.73m²的成人高血压患者（其中包括1671例慢性肾病患者），平均年龄60（45～75）岁。患者被随机分配接受每天依那普利10mg＋叶酸0.8mg（7545例）或单用依那普利10mg（7559例），中位随访4.4年。
结果表明，依那普利＋叶酸与单用依那普利相比，估计肾小球滤过率减退速度显著较慢（每年1.28%比1.42%，P=0.02），肾病进展风险降低21%。
尤其在治疗前已有慢性肾病的患者，补充叶酸使肾病进展风险降低56%，肾功能快速减退速度降低33%，复合事件（肾病进展和全因死亡）风险降低38%，肾功能减退风险降低44%（0.96%比1.72%，P＜0.001）。
治疗前无慢性肾病的患者，肾病进展风险无组间差异。
因此，该研究表明，依那普利＋叶酸与单用依那普利相比，可显著延缓轻中度慢性肾病患者的慢性肾病进展。
对此，美国康奈尔大学、美国疾病控制预防中心的学者发表同期述评《考虑慢性疾病营养素需求》，指出叶酸通常被用于治疗高同型半胱氨酸血症，但是同型半胱氨酸降低对其相关慢性疾病预防和治疗的益处尚未得到证实。高同型半胱氨酸血症在慢性肾病患者中常见，然而叶酸诱导的血清同型半胱甘酸水平降低在其他研究中对肾功能并无影响。既往维生素补充对肾功能影响的研究入组了包括维生素B12在内的其他B族维生素，而这可能为上述差异产生的原因。
叶酸是人体必须的一种营养素，我国人群叶酸缺乏十分常见，平均血清水平显著低于西方人群，原因可能与饮食习惯和遗传基因不同有关。
天然叶酸在绿叶蔬菜中含量最高，与西方人喜好生吃蔬菜不同，中国人习惯熟食蔬菜，蔬菜中的叶酸可能因高温烹饪而被破坏。叶酸代谢需要亚甲基四氢叶酸还原酶，该酶有三种基因多态性，其中TT基因型叶酸水平最低。中国人TT基因型的频率为25%，而白种人为12%。
由于叶酸对人体健康的重要性，1998年起美国和加拿大等国家通过在面粉等谷物中添加叶酸强制补充叶酸，而中国尚未执行强制补充叶酸的政策，可能也是我国人群叶酸缺乏常见的原因。
前期流行病学调查显示，叶酸缺乏是中国农村社区人群肾病进展的危险因素。针对这一特点，该研究开展了上述补充叶酸延缓肾功能减退的随机对照研究。前期研究还证实，补充叶酸能有效降低高血压患者首发脑卒中的风险。
由于人口老龄化和糖尿病、高血压发病率增加等原因，慢性肾病已成为殃及我国1.2亿人群的公共健康问题。慢性肾病具有进展至尿毒症的高度风险，尿毒症患者目前只能终生依赖透析或肾移植生存，耗费巨大医疗资源。慢性肾病患者并具有并发脑卒中等心脑血管事件的高度风险。因此，如何有效延缓慢性肾病进展、预防心脑血管事件发生，一直都是医学界和医疗卫生部门关注的重点。
该研究首次证实，叶酸缺乏人群适量补充叶酸能有效延缓慢性肾病进展。叶酸价格低廉、服用方便且十分安全，适于作为高危人群的防治手段。这一发现也为针对我国人群特点开展重大慢性疾病防治提供了重要借鉴。
JAMA Intern Med. 2016 Oct 1;176(10):1443-1450.
Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial.
Xu X, Qin X, Li Y, Sun D, Wang J, Liang M, Wang B, Huo Y, Hou FF; investigators of the Renal Substudy of the China Stroke Primary Prevention Trial (CSPPT).
Nanfang Hospital, Southern Medical University, Guangzhou, China; Peking University First Hospital, Beijing, China.
IMPORTANCE: The efficacy of folic acid therapy on renal outcomes has not been previously investigated in populations without folic acid fortification.
OBJECTIVE: To test whether treatment with enalapril and folic acid is more effective in slowing renal function decline than enalapril alone across a spectrum of renal function at baseline from normal to moderate chronic kidney disease (CKD) among Chinese adults with hypertension.
DESIGN, SETTING, AND PARTICIPANTS: In this substudy of eligible China Stroke Primary Prevention Trial (CSPPT), 15,104 participants with an estimated glomerular filtration rate (eGFR) 30 mL/min/1.73 m2 or greater, including 1671 patients with CKD, were recruited from 20 communities in Jiangsu province in China.
INTERVENTIONS: Participants were randomized to receive a single tablet daily containing 10 mg enalapril and 0.8 mg folic acid (n = 7545) or 10 mg enalapril alone (n = 7559).
MAIN OUTCOMES AND MEASURES: The primary outcome was the progression of CKD, defined as a decrease in eGFR of 30% or more and to a level of less than 60 mL/min/1.73 m2 if the baseline eGFR was 60 mL/min/1.73 m2 or more, or a decrease in eGFR of 50% or more if the baseline eGFR was less than 60 mL/min/1.73 m2; or end-stage renal disease. Secondary outcomes included a composite of the primary outcome and all-cause death, rapid decline in renal function, and rate of eGFR decline.
RESULTS: Overall, 15,104 Chinese adults with a mean (range) age of 60 (45-75) years were recruited; median follow-up was 4.4 years. There were 164 and 132 primary events in the enalapril group and the enalapril-folic acid group, respectively. Compared with the enalapril group, the enalapril-folic acid group had a 21% reduction in the odds of the primary event (odds ratio [OR], 0.79; 95% CI, 0.62-1.00) and a slower rate of eGFR decline (1.28% vs 1.42% per year; P = .02). Among the participants with CKD at baseline, folic acid therapy resulted in a significant reduction in the risks for the primary event (OR, 0.44; 95% CI, 0.26-0.75), rapid decline in renal function (OR, 0.67; 95% CI, 0.47-0.96) and the composite event (OR, 0.62; 95% CI, 0.43-0.90), and a 44% slower decline in renal function (0.96% vs 1.72% per year, P < .001). Among those without CKD at baseline, there was no between-group difference in the primary end point.
CONCLUSIONS AND RELEVANCE: Enalapril-folic acid therapy, compared with enalapril alone, can significantly delay the progression of CKD among patients with mild-to-moderate CKD.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00794885.
PMID: 27548766
DOI: 10.1001/jamainternmed.2016.4687
JAMA Intern Med. 2016 Oct 1;176(10):1451-1452.
Time to Think About Nutrient Needs in Chronic Disease.
Stover PJ, Berry RJ, Field MS.
Cornell University, Ithaca, New York; National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, Georgia.
PMID: 27548386
PMCID: PMC5094357
DOI: 10.1001/jamainternmed.2016.4699
