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1 Supplementary Online Content Xu X, Qin X, Li Y, et al. Efficacy of folic acid therapy on the progression of chronic kidney disease: the Renal Substudy of the China Stroke Primary Prevention Trial. JAMA Intern Med. Published online August 22, doi:11001/jamainternmed etable 1. Baseline Characteristics in the Participants Included in and Excluded from the Outcome Analysis etable 2. Concomitant Medication During Treatment efigure 1. The flow chart of the participants efigure 2. The mean blood pressures during treatment in (A all participants and (B those with CKD. efigure 3. The box-and-whisker plot of the serum total homocysteine levels at baseline and after treatment by MTHFR C677T genotype and treatment allocation. This supplementary material has been provided by the authors to give readers additional information about their work.

2 Appendix Table 1. Baseline Characteristics in the Participants Included in and Excluded from the Outcome Analysis Variables Participants excluded Participants included (n=1802 (n=13302 Age, yr 57.9 ( (7.5 Male, no.(% 721 ( (38.9 Self-reported diabetes, no.(% 64 ( (3.8 Self-reported hyperlipidemia, no.(% 56 ( (2.9 SBP, mmhg ( (21.0 DBP, mmhg 95.8 ( (12.0 BMI, kg/m ( (3.6 Current smoking, no.(% 431 ( (22.5 MTHFR C677T, no.(% CC 427 ( (23.4 CT 921 ( (49.8 TT 454 ( (26.8 Laboratory results Glucose, mmol/l 6.0 ( (1.8 TC, mmol/l 5.8 ( (1.2 TG, mmol/l 1.7 ( (1.3 HDL-C, mmol/l 1.4 (4 1.3 (4 egfr, ml/min/1.73m ( (12.8 Proteinuria, no.(% 177 ( (12

3 Medication use, no.(% RAAS inhibitors 153 ( (9.4 CCB 107 ( (7.2 Diuretics 52 ( (2.6 Glucose-lowering drugs 24 ( (1.9 Lipid-lowering drugs 11 (6 117 (9 Antiplatelet drugs 66 ( (3.9 For continuous variables, values are presented as mean (SD. Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; MTHFR, methylene tetrahydrofolate reductase; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; egfr, estimated glomerular filtration rate; RAAS, renin-angiotensin-aldosterone system; CCB, calcium channel blocker.

4 Appendix Table 2. Concomitant Medication During Treatment Medication All Participants with Participants without participants CKD CKD Enalap Enalapr P Enal Enalapr P Enal Enalapr P ril il-fa april il-fa april il-fa (n=75 (n=754 (n=8 (n=867 (n=6 (n= Calcium channel (78.7 ( (84.5 ( (78.0 ( blocker Diuretics (57.7 ( (63.3 ( (57.0 ( Lipid-lowerin 7 (1 11 (1 1 1 ( (1 g drugs 48 (1 00 (1 44 Glucose-lower ( (1.3 ing drugs (1.7 ( ( ( Antiplatelet (8 9 6 ( (8 drugs (9 48 ( (8 67 All values except P are presented as No. (%.

5 Appendix Figure 1. The flow chart of the participants randomized 7745 randomized to received enalapril 7741 randomized to received enalapril-folic acid Excluded n=186 (2.4% missing baseline egfr: 175 (2.3% baseline egfr<30 ml/min: 11 (1% Excluded n=196 (2.5% missing baseline egfr: 181(2.3% baseline egfr<30 ml/min: 15 (2% 7559 enrolled in the renal sub-study 804 with CKD 7545 enrolled in the renal sub-study 867 with CKD 883 (11.7% dropped due to alive with missing renal outcome 919 (12.2% dropped due to alive with missing renal outcome 6676 analyzed for the composite outcome 715 with CKD 6626 analyzed for the composite outcome 760 with CKD 196 (2.5% dropped due to dead with missing renal outcome 189 (2.5% dropped due to dead with missing renal outcome 6480 analyzed for the renal outcome 680 with CKD 6437 analyzed for the renal outcomes 724 with CKD

6 Appendix Figure S2. The mean blood pressures during treatment in (A all participants and (B those with CKD. (A (B Blood Pressure (mmhg SBP DBP Enalapril Enalapril FA Blood Pressure (mmhg SBP DBP Enalapril Enalapril FA Months from baseline Months from baseline

7 Appendix Figure S3. The box-and-whisker plot of the serum total homocysteine levels at baseline and after treatment by MTHFR C677T genotype and treatment allocation. Total Homocysteine, µmol/l Baseline Exit visit Enalapril Enalapril-FA CC CT TT CC CT TT The box indicates the interquartile range and the band inside the box indicates the median.

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