Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial | Cerebrovascular Disease | JAMA Internal Medicine | JAMA Network
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1.
Collins  AJ, Foley  RN, Chavers  B,  et al.  US Renal Data System 2013 Annual Data Report.  Am J Kidney Dis. 2014;63(1)(suppl):A7.PubMedGoogle ScholarCrossref
2.
Peralta  CA, Shlipak  MG, Judd  S,  et al.  Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality.  JAMA. 2011;305(15):1545-1552.PubMedGoogle ScholarCrossref
3.
Sarnak  MJ, Levey  AS, Schoolwerth  AC,  et al; American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.  Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.  Hypertension. 2003;42(5):1050-1065.PubMedGoogle ScholarCrossref
4.
Zhang  L, Wang  F, Wang  L,  et al.  Prevalence of chronic kidney disease in China: a cross-sectional survey.  Lancet. 2012;379(9818):815-822.PubMedGoogle ScholarCrossref
5.
Drawz  PE, Rosenberg  ME.  Slowing progression of chronic kidney disease.  Kidney Int Suppl (2011). 2013;3(4):372-376.PubMedGoogle ScholarCrossref
6.
Meguid El Nahas  A, Bello  AK.  Chronic kidney disease: the global challenge.  Lancet. 2005;365(9456):331-340.PubMedGoogle ScholarCrossref
7.
Mills  KT, Xu  Y, Zhang  W,  et al.  A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010.  Kidney Int. 2015;88(5):950-957.PubMedGoogle ScholarCrossref
8.
Marti  F, Vollenweider  P, Marques-Vidal  PM,  et al.  Hyperhomocysteinemia is independently associated with albuminuria in the population-based CoLaus study.  BMC Public Health. 2011;11:733.PubMedGoogle ScholarCrossref
9.
Ponte  B, Pruijm  M, Marques-Vidal  P,  et al.  Determinants and burden of chronic kidney disease in the population-based CoLaus study: a cross-sectional analysis.  Nephrol Dial Transplant. 2013;28(9):2329-2339.PubMedGoogle ScholarCrossref
10.
Jager  A, Kostense  PJ, Nijpels  G,  et al.  Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study.  Arterioscler Thromb Vasc Biol. 2001;21(1):74-81.PubMedGoogle ScholarCrossref
11.
Ninomiya  T, Kiyohara  Y, Kubo  M,  et al.  Hyperhomocysteinemia and the development of chronic kidney disease in a general population: the Hisayama study.  Am J Kidney Dis. 2004;44(3):437-445.PubMedGoogle ScholarCrossref
12.
House  AA, Eliasziw  M, Cattran  DC,  et al.  Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial.  JAMA. 2010;303(16):1603-1609.PubMedGoogle ScholarCrossref
13.
Jamison  RL, Hartigan  P, Kaufman  JS,  et al; Veterans Affairs Site Investigators.  Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial.  JAMA. 2007;298(10):1163-1170.PubMedGoogle ScholarCrossref
14.
Qin  X, Huo  Y, Langman  CB,  et al.  Folic acid therapy and cardiovascular disease in ESRD or advanced chronic kidney disease: a meta-analysis.  Clin J Am Soc Nephrol. 2011;6(3):482-488.PubMedGoogle ScholarCrossref
15.
Qin  X, Huo  Y, Xie  D, Hou  F, Xu  X, Wang  X.  Homocysteine-lowering therapy with folic acid is effective in cardiovascular disease prevention in patients with kidney disease: a meta-analysis of randomized controlled trials.  Clin Nutr. 2013;32(5):722-727.PubMedGoogle ScholarCrossref
16.
Huo  Y, Li  J, Qin  X,  et al; CSPPT Investigators.  Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial.  JAMA. 2015;313(13):1325-1335.PubMedGoogle ScholarCrossref
17.
Jardine  MJ, Kang  A, Zoungas  S,  et al.  The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis.  BMJ. 2012;344:e3533.PubMedGoogle ScholarCrossref
18.
Myung  SK, Ju  W, Cho  B,  et al; Korean Meta-Analysis Study Group.  Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials.  BMJ. 2013;346:f10.PubMedGoogle ScholarCrossref
19.
Levey  AS, Stevens  LA, Schmid  CH,  et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).  A new equation to estimate glomerular filtration rate.  Ann Intern Med. 2009;150(9):604-612.PubMedGoogle ScholarCrossref
20.
Systolic Blood Pressure Intervention Trial (SPRINT) protocol. November 1, 2012 (https://www.sprinttrial.org/public/Protocol_Current.pdf).
21.
Lv  J, Ehteshami  P, Sarnak  MJ,  et al.  Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis.  CMAJ. 2013;185(11):949-957.PubMedGoogle ScholarCrossref
22.
Sarnak  MJ, Greene  T, Wang  X,  et al.  The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study.  Ann Intern Med. 2005;142(5):342-351.PubMedGoogle ScholarCrossref
23.
Hou  W, Lv  J, Perkovic  V,  et al.  Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis.  Eur Heart J. 2013;34(24):1807-1817.PubMedGoogle ScholarCrossref
24.
Shurraw  S, Hemmelgarn  B, Lin  M,  et al; Alberta Kidney Disease Network.  Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease: a population-based cohort study.  Arch Intern Med. 2011;171(21):1920-1927.PubMedGoogle ScholarCrossref
25.
Pfeiffer  CM, Sternberg  MR, Fazili  Z,  et al.  Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults.  J Nutr. 2015;145(3):520-531.PubMedGoogle ScholarCrossref
26.
Spence  JD, Eliasziw  M, House  AA.  B-vitamin therapy for diabetic Nephropathy  [Reply].  JAMA. 2010;304:636-637.Google ScholarCrossref
27.
Spence  JD.  Metabolic B12 deficiency: a missed opportunity to prevent dementia and stroke.  Nutr Res. 2016;36(2):109-116. doi:10.1016/j.nutres.2015.10.003.PubMedGoogle ScholarCrossref
Original Investigation
October 2016

Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial

Author Affiliations
  • 1National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 2State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 3Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 4Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 5Department of Cardiology, Peking University First Hospital, Beijing, China
JAMA Intern Med. 2016;176(10):1443-1450. doi:10.1001/jamainternmed.2016.4687
Abstract

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

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