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Supplementary appendix

Title:-converting enzyme inhibitors Benefit to Kidney and Cardiovascular Outcomes for Patients with non-dialysisCKD stages 3-5: A Network Meta-analysis of Randomized Clinical Trials.

Supplementary appendix Concents Tables Table S1: Risk of bias assessments for included trials.

Table S2: Baseline characteristics according to randomized treatment.

Table S3a-d: Subgroup analysis for primary outcomes for each treatment versus placebo in the network meta-analysis framework. Results are presented as odds ratios (95% CI). All odds ratios use placebo as referenced agent. Ranks are obtained according to SUCRAs (surface under the cumulative ranking curve measure). Significant results are in bold.DKD,Diabetic Kidny Disease; ACEIs, angiotensin-converting-enzyme inhibitors; ARBs, angiotensin-II receptor blockers.CCBs, Calcium Channel Blockers

Table S4: Subgroup analyses for hyperkalemia for each treatment versus placebo.

Table S5: Subgroup analyses for studies with low bias risk of each item in the Cochrane risk of bias tool (including Sequence generation, Allocation concealment, Blinding, Incomplete outcome data, Selective outcome reporting, and Other source of bias) for each treatment versus placebo.

Figures Figure S1. Loop-specific inconsistency approach for of primary outcomes: (a) kidney failure, (b) cardiovascular events, (c) cardiovascular death, and (d) Total mortality. Loop(s) [Control -β-blocker-ARBI] for cardiovascular events and [CCB-β-blocker-ACEI] for death are formed only by multi-arm trial(s) - Consistent by definition

Figure S2. Loop-specific inconsistency approach for of adverse events comparisons:(a) hyperkalemia (b) cough (c) hypotension (d) edema. Loop(s) [control- β-blocker-ACEI] for hyperkalemia are formed only by multi-arm trial(s) - Consistent by definition

Figure S3. Summary of results from network meta-analysis (on the upper triangle) onadverse events comparisons:(a) hyperkalemia (b) cough (c) edema (d) hypotension. On the lower triangle and upper triangle, the row-defining treatment is compared with the column-defining treatment, and ORs of >1 favor the row-defining treatment. Significant results are shown in boldface type

Figure S4.Comparison-adjusted funnel plot for the network of primary outcomes: (a) kidney failure, (b) cardiovascular events, (c) cardiovascular death, and (d) total mortality withblood pressure lowering therapy in advanced non-dialysis CKD patients. A: placebo; B:diuretic;C:control;D:CCB;E: β-blocker;F:ARB+ACEI;G:ARB;H:ACEI.

Figure S5.Comparison-adjusted funnel plot for the network of adverse events comparisons:(a) hyperkalemia (b) cough (c) hypotension (d) edemawithblood pressure lowering therapy in advanced non-dialysis CKD patients. A: placebo; B:diuretic;C:control;D:CCB;E: β-blocker;F:ARB+ACEI;G:ARB;H:ACEI.

Figure S6. Forest plot for results of primary outcomes: (a) kidney events, (b) cardiovascular death, (c) cardiovascular events and(d) all-cause death in studies with low bias risk of each item in the Cochrane risk of bias tool (including Sequence generation, Allocation concealment, Blending, Incomplete outcome data, Selective outcome reporting, and Other source of bias.

Appendix References

Search/MESH terms

Table S1. Quality assessment for included trials Blinding Incomplete Selective Other Sequence Allocation Trial outcome outcome outcome source of generation concealment participants personnel assessors data reporting bias ACE-Is vs. placebo SOLVD 2013[1] LOW UNCLEAR LOW LOW UNCLEAR LOW LOW LOW ADVANCE 2010[2] LOW LOW LOW LOW LOW LOW LOW LOW EUROPA 2007[3] LOW LOW LOW LOW LOW LOW LOW LOW PROGRESS 2007[4] LOW LOW LOW LOW LOW LOW LOW LOW PEACE 2006[5] LOW LOW LOW LOW LOW LOW LOW LOW Hou 2006[6] LOW LOW LOW LOW LOW LOW LOW LOW Tong 2006[7] UNCLEAR LOW LOW LOW UNCLEAR LOW LOW LOW SAVE 2004[8] LOW LOW LOW LOW LOW LOW LOW LOW HOPE 2001[9] LOW LOW LOW LOW LOW LOW LOW LOW REIN-1 1999[10] LOW LOW LOW LOW LOW LOW UNCLEAR UNCLEAR REIN-2 1997[11] LOW LOW LOW LOW LOW LOW LOW LOW AIPRI 1996[12, 13] LOW LOW LOW LOW LOW LOW UNCLEAR UNCLEAR Ihle 1996[14] UNCLEAR UNCLEAR LOW LOW UNCLEAR LOW LOW LOW ARBs vs. placebo ORIENT 2011[15] LOW LOW LOW LOW LOW LOW LOW LOW TRANSCEND 2011 [16] LOW LOW LOW LOW LOW LOW LOW LOW RENAAL 2001[17] LOW LOW LOW LOW LOW LOW LOW LOW ACE-Is vs. active control AVER 2008[18] LOW UNCLEAR LOW LOW LOW LOW LOW LOW AASK 2006[19] LOW LOW HIGH HIGH HIGH LOW LOW LOW Hou 2005[20] UNCLEAR UNCLEAR HIGH HIGH HIGH LOW LOW LOW MacGregor 2005[21] LOW LOW HIGH HIGH HIGH LOW LOW LOW Marin 2001[22] UNCLEAR UNCLEAR HIGH HIGH HIGH LOW LOW LOW Nephros 2001[23] LOW LOW HIGH HIGH HIGH LOW UNCLEAR UNCLEAR Cinotti2001[12] UNCLEAR UNCLEAR HIGH HIGH HIGH LOW LOW LOW Petersen 2001[24] UNCLEAR UNCLEAR LOW LOW UNCLEAR LOW HIGH UNCLEAR Kumagai 2000[25] UNCLEAR LOW HIGH HIGH UNCLEAR HIGH LOW LOW Thannedouche 1994[26] LOW UNCLEAR HIGH HIGH HIGH UNCLEAR UNCLEAR UNCLEAR Bjorck 1992[27] UNCLEAR UNCLEAR HIGH HIGH HIGH UNCLEAR LOW LOW Kamper 1992[28] LOW LOW HIGH HIGH HIGH UNCLEAR LOW LOW Zucchelli 1992[29] UNCLEAR UNCLEAR HIGH HIGH HIGH LOW LOW LOW Fogari 1999[30] UNCLEAR UNCLEAR HIGH HIGH HIGH LOW LOW LOW ARBs vs. active control KVT 2013[31] LOW LOW HIGH HIGH UNCLEAR LOW LOW LOW HIJ-CREATE 2010[32] LOW LOW HIGH HIGH LOW LOW LOW LOW CASE-J 2009[33] LOW LOW HIGH HIGH LOW LOW LOW LOW E-COST 2005[34] LOW LOW HIGH HIGH LOW LOW LOW LOW ACE-Is vs. ARBs ROAD 2007[35] LOW LOW HIGH HIGH LOW LOW LOW LOW Shoda 2005[36] LOW LOW HIGH HIGH HIGH LOW LOW LOW Dual blockade vs. Monotherapy ONTARGET 2011[37] LOW LOW LOW LOW LOW LOW LOW LOW Kanno 2006[38] LOW LOW HIGH HIGH HIGH LOW LOW LOW Study used with three arms PRONEDI 2013[39] LOW LOW HIGH HIGH HIGH LOW LOW LOW ALLHAT 2006[40] LOW LOW LOW LOW LOW LOW LOW LOW COPE 2013[41] LOW LOW HIGH HIGH LOW LOW LOW LOW Bakris 1996[42] UNCLEAR UNCLEAR HIGH HIGH LOW LOW LOW LOW IDNT 2003/2001[43] LOW LOW LOW LOW LOW LOW LOW LOW RASI vs. active control or ACE-I vs.

no_treatment Mimura 2008[44] LOW LOW HIGH HIGH HIGH LOW LOW LOW

Assessment of risk bias according to the Cochrane collaboration tool, low risk of bias were represented as “LOW” and high risk of were “HIGH”

Table S2: Baseline characteristics according to randomized treatment. Blood pressure Arm and simple size Age (years) Creatinine (umol)L) Follow-up Trials (mmHg) DKD/total arm 1(DKD/ total) arm 2 (DKD /total)) arm1 arm2 arm1 arm2 arm1 arm2 (years) ACE-Is vs. placebo SOLVD 2013[1] 308/1036 ACE-I (150/498) Placebo (158/538) 64.1 64.5 127 126 132.6 131.7 3.45 ADVANCE 2010[2] 4518/4518 ACE-I (2253/2253) Placebo (2265/2265) 66 66 145 145 87 87 4·3 EUROPA2007[3] † 308/1917 ACE-I (NPS/978) Placebo (NPS/939) 65.4 139.8 NA NA 4·2 PROGRESS 2007[4] † 11/1757 ACE-I (NPS/895) Placebo (NPS/862) 70 147 102 5 PEACE 2006[5] † 262/1355 ACE-I (NPS/698) Placebo (NPS/657) 68.3 133 118 4·8 Hou 2006[6] 0/224 ACE-I (0/112) Placebo (0/112) 44·4 45 153·2 151·6 353·6 344·8 3·4 Tong 2006[7] 38/38 ACE-I (18/18) Placebo (20/20) 65·9 65·7 160 160 183 199 2 SAVE 2004[8] † 194/719 ACE-I (NPS/359) Placebo (NPS/360) 64.2 NA NA 133.7 3·5 HOPE 2001[9] 663/980 ACE-I (351/509) Placebo (312/471) 68·1 68·8 139·4 141·3 NA NA 4·5 REIN-1 1999[10] 0/196 ACE-I (0/99) Placebo (0/87) 49·1 50·3 142 144·9 168 185·6 2·8 REIN-2 1997[11] 0/166 ACE-I (0/78) Placebo (0/88) 48·9 49·7 149·8 148 212 212 3 AIPRI 1996[12, 13] NM ACE-I (NM /300) Placebo (NM /283) 51 51 142 144 185·6 185·6 3 Ihle 1996[14] 0/70 ACE-I (0/36) Placebo (0/34) 41·3 47·7 147 154 459·7 389 2 ARBs vs. placebo

ORIEN T 2011[15] 566/566 ARB (282 /282) Placebo ( 284/284) 59.1 59.2 141.7 140.8 143.21 143.21 3.2 TRANSCEND 551/1480 ARB (NPS /729) Placebo (NPS/751) 69.5 142 117.7 4.7 2011[16] † RENAAL 2001[17] 1513/1513 ARB (751 /751) Placebo (762/762) 60 60 152 153 168 168 3.4 ACE-Is vs. active control AVER 2008[18] 0/263 ACE-I (0/131) CCB (0/132) 57.5 58.3 165.2 165.1 181.2 176.8 3 AASK 2006[19] 0/877 ACE-I (0/436) beta blocker (0/441) 54.4 54.9 151 150 176.8 176.8 4.1 Hou 2005[20] 0/92 ACE-I (0/47) Control (0/45) 46.8 49.5 151.5 147.93 374.8 383.7 2 MacGregor 2005[21] 0/56 ACE-I (0/28) CCB (0/28) 49.7 50.3 151 146 335 338 4 Marin 2001[22]Rafael 2001 0/241 ACE-I (0/129) CCB (0/112) 53 56 155 157.5 247.5 256.4 3 Nephros 2001[23] ‡ 0/107 ACE-I (0/53) CCB (0/54) 52 55.5 159 160 171.9 163.6 1.83 Giulio 2001[12] 0/131 ACE-I (0/66) Control (0/65) 49.6 52.1 140 142.2 200.7 210.4 1.875 Petersen 2001[24] 8/40 ACE-I (5/20) CCB (3/20) 62 54 151.2 158.4 257 247 1.75 Kumagai 2000[25] 0/49 ACE-I (0/27) CCB (0/22) 58.6 58.5 162 166 185.6 185.6 1 Thanneduche 1994[26] 0/100 ACE-I (0/52) beta blocker (0/48) 52 50 167 166 264 265 3 Bjorck 1992[27] 40/40 ACE-I (22/22) beta blocker (18/18) 42 42 163 161 NA NA 2.2 Kamper 1992[28] 13/70 ACE-I (6/35) Control (7/35) 49 49.5 160.8 147.7 450.8 431.5 2 Zucchelli 1992[29] 0/121 ACE-I (0/60) CCB (0/61) 55 55 166 164 256.4 265.2 3 Fogari 1999[30] 107/107 ACE-I (54/54) CCB (53/53) 56.3 56.4 165.7 165.3 176.8 185.6 2 ARBs vs. active control KVT 2013[] 119/293 ARB (60/149) Control (59/144) 64.1 64.2 143.6 142.2 282 283 3 HIJ-CREATE 2010[32] 386/1022 ARB (185/509) Control (201/513) 70 70 136 137 NA NA 3 CASE-J 2009[33] 1154/2720 ARB (585/1376) CCB (569/1344) 65.6 65.3 163.3 163.4 NA NA 3.2 E-COST 2005[34] 0/141 ARB (0/69) Control (0/72) 67.1 66.7 144.7 144.6 129.4 130.9 3.1 ACEIs vs. ARBs

ROAD 2007[35] NM/360 ACE-I (NM/180) ARB (NM/180) 50.5 51.3 149.9 150.7 243 252 3.7 Shoda 2005[36] 0/68 ACE-I (0/36) ARB (0/32) 50.4 49.3 138.9 140 205.1 251.1 5 Dual blockade vs.Monotherapy ONTARGET 2011[37] 2452/5623 ACE-I/ARB ARB+ACE-I 69.3 142.9 122.9 4.7 *† (NPS/1871) (NPS/3752) Kanno 2006[38] NM/90 ARB (NM/45) ACE-I+ARB (NM/45) 59.9 60.3 135 140 265.2 265.2 3.1 Study used with three arm1 arm2/arm3 arm1 arm2/arm3 arm1 arm2/arm3 arm1 arm2/arm3 Follow-up arms 1888/5662 CCB/diuretic ALLHAT 2006[40] * ACE-I (501/1533) 70.6 70.8 146.9 146.7 NA NA 4.9 ((506/1516)/( 881/2613)) 143/834 beta blocker/diuretics COPE 2013[41] ARB (50/287) 55 54.6 153 153 NA NA 3.6 ((52/283)/(41/264)) 63/63 ARB/ACE-I+ARB PRONEDI 2013[39] ACE-I (35/35) 68.7 67.9/63 153 154/152 132.6 137.9/131.7 2.7 ((28/28)/(70/70)) 52/52 CCB/beta blocker Bakris 1996[42] ACE-I (18/18) 62 62.1 155 158.4 141 163.8 5.3 ((18/18)/(16/16)) 1715/1715 CCB/placebo IDNT 20032001[43] ARB (579/579) 59.3 59.1/58.3 160 159/158 148 146/150 2.6 ((567/567)/(569/569)) RASIvs. active control or ACE-I vs.

no_treatment 0/75 ACE-I or ARB conventional agents Mimura 2008[44] 57 58 129 130 132.6 123.8 4 (0/38) (0/37) DKD,diabetic kidney disease; ACEIs,angiotensin-converting-enzyme inhibitors; ARBs,angiotensin-II receptor blockers; CCBs, Calcium Channel Blockers; ACEI+ARB, dual blockade ; † represents the mean measurements of the two arms; ‡ represents median of the measurements.* represents trials with three-arms, and combined the active controls when analyzed;NM:not mentioned;NPS:not provided separately(only provided total number of diabetics); Dual blockade, treatment with dual blockade of the -angiotensin system;monotherapy, treatment with one of the renin-angiotensin system inhibitors. Table S3a: Subgroup analyses for the primary outcome of kidney events for each treatment versus placebo.Ranking indicates the probability that the drug class is “best,” second-“best,” etc. Odds ratios and 95%CI treatment strategies vs. placebo for kidney events, and ranks according to SUCRAs

The average Follow-up Rank DKD patients Rank Treatme The average serum Standard Rank Trials with sample Rank Rank serum creatinine Rank (>3ys ) (SUCRA) nt creatinine was less analysis (SUCRA) size more than 100 (SUCRA) (SUCRA) was greater than (SUCRA) (SUCRA) strategies than 200umol/l 200umol/l 0.54 0.53 0.65 2 0.45 1 0.54 1 0.86 ACEIs 1 1 2 (0.41,0.73) (0.38,0.73) (0.43,0.99) (0.30,0.68) (0.41,0.73) (0.37,2.01) 0.76 0.74 0.78 4 0.52 2 0.76 4 0.82 ARBs 4 3 1 (0.58,1.00) (0.56,0.99) (0.58,1.04) (0.26,1.03) (0.58,1.00) (0.72,0.95) ACEI+A 0.65 0.53 0.55 1 2.41 7 0.65 2 2 2 —— —— RB (0.35,1.22) (0.28,1.01) (0.28,1.07) (0.46,12.69) (0.35,1.22) β-blocke 0.91 0.80 1.01 6 1.03 5 0.91 6 1.09 6 5 4 r (0.53,1.57) (0.45,1.44) (0.52,1.98) (0.37,2.86) (0.53,1.57) (0.16,7.52) 0.81 0.85 0.78 5 0.90 4 0.81 5 1.13 CCB 5 6 5 (0.58,1.14) (0.60,1.20) (0.52,1.16) (0.49,1.64) (0.58,1.14) (0.91,1.41) 1.01 1.25 ------0.77 3 1.01 7 control 8 8 —— —— (0.60,1.70) (0.66,2.38) (0.41,1.45) (0.60,1.70) 0.71 0.72 0.77 3 —— —— 0.71 3 diuretic 3 3 —— —— (0.41,1.24) (0.41,1.25) (0.42,1.40) (0.41,1.24)

Placebo Reference 7 Reference 7 Reference 7 Reference 6 Reference 8 Reference 3

Number 13 33 21 17 16 7 of trials

Table S3b: Subgroup analyses for the primary outcome of cardiovascular enents for each treatment versus placebo. Ranking indicates the probability that the drug class is “best,” second-“best,” etc. Odds ratios and 95%CI treatment strategies vs. placebo for cardiovascular events, and ranks according to SUCRAs

The average Follow-up Rank Rank Treatme The average serum Standard Rank Trials with sample Rank Rank serum creatinine Rank (>3ys ) (SUCRA) DKD nt creatinine was less than analysis (SUCRA) size more than 100 (SUCRA) (SUCRA) was greater than (SUCRA) patients (SUCRA) strategies 200umol/l 200umol/l 0.73 0.72 0.73 1 0.70 (0.33,1.49) 2 0.72 1 0.89 ACEIs 1 2 3 (0.64,0.84) (0.63,0.82) (0.63,0.83) (0.62,0.84) (0.74,1.07) 0.83 0.84 0.83 5 0.55 (0.17,1.73) 1 0.82 6 0.87 ARBs 5 5 2 (0.70,0.98) (0.72,0.99) (0.70,0.99) (0.66,1.01) (0.75,1.01) ACEI+A 0.84 0.86 0.85 6 —— —— 0.83 5 6 6 —— —— RB (0.61,1.17) (0.63,1.17) (0.61,1.18) (0.56,1.23) 0.77 0.78 0.79 4 2.31 (0.08,63.49) 6 0.76 4 0.20 β-blocker 4 4 1 (0.51,1.17) (0.51,1.17) (0.49,1.26) (0.49,1.20) (0.01,4.41) 0.74 0.78 0.73 2 1.13 (0.31,4.22) 5 0.72 2 CCB 2 3 —— —— (0.59,0.92) (0.63,0.97) (0.58,0.92) (0.54,0.95) 1.11 1.12 2.24 7 1.18 (0.28,5.07) 4 —— —— control 8 8 —— —— (0.75,1.63) (0.76,1.65) (0.09,56.81) 0.76 0.68 0.76 3 —— —— 0.75 3 diuretic 3 1 —— —— (0.58,1.01) (0.52,0.89) (0.56,1.02) (0.54,1.04) Placebo Reference 7 Reference 7 Reference 8 Reference 3 Reference 7 Reference 4

Number 30 23 21 10 6 of trials 17

Table S3c: Subgroup analyses for the primary outcome of cardiovasculardeathfor each treatment versus placebo. Odds ratios and 95%CI treatment strategies vs. placebo for cardiovascular death, and ranks according to SUCRAs

The average Follow-up Rank Treatme The average serum Standard Rank Trials with sample Rank Rank serum creatinine Rank (>3ys ) (SUCRA) nt creatinine was less analysis (SUCRA) size more than 100 (SUCRA) (SUCRA) was greater than (SUCRA) strategies than 200umol/l 200umol/l 0.73 1.65 0.73 1 ACEIs 1 0.73 (0.62,0.86) 1 0.73 (0.62,0.86) 1 2 (0.63,0.86) (0.20,13.70) (0.61,0.87) 1.16 1.16 6 ARBs 6 1.18 (0.88,1.58) 7 1.16 (0.88,1.54) 6 —— —— (0.88,1.53) (0.79,1.70) ACEI+A 1.17 1.17 5 5 1.19 (0.80,1.76) 6 1.17 (0.80,1.70) 7 —— —— RB (0.80,1.70) (0.72,1.90) β-blocke 0.72 —— —— 0.72 2 2 0.72 (0.31,1.70) 2 0.72 (0.31,1.68) 2 r (0.31,1.69) (0.30,1.71) 0.90 1.78 1.38 7 CCB 3 1.00 (0.60,1.68) 4 0.80 (0.47,1.38) 3 3 (0.60,1.34) (0.15,21.30) (0.57,3.35) 1.48 12.61 1.11 4 control 7 1.13 (0.26,4.91) 5 1.11 (0.26,4.80) 5 4 (0.40,5.53) (0.32,496.20) (0.25,4.97) diuretic —— —— —— —— —— —— —— —— —— ——

Placebo Reference 4 Reference 3 Reference 4 Reference 1 Reference 3

Number 12 19 16 14 5 of trials Ranking indicates the probability that the drug class is “best,” second-“best,” etc.Subgroup analyses by DKD or NDKD were not performed because of few available data..

Table S3d: Subgroup analyses for the primary outcome of all-cause mortality for each treatment versus placebo. Odds ratios and 95%CI treatment strategies vs. placebo for all-cause death, and ranks according to SUCRAs

The average Follow-up Rank Rank Treatme The average serum Standard Rank Trials with sample Rank Rank serum creatinine Rank (>3ys ) (SUCRA) DKD nt creatinine was less than analysis (SUCRA) size more than 100 (SUCRA) (SUCRA) was greater than (SUCRA) patients (SUCRA strategies 200umol/l 200umol/l ) 0.77 0.76 0.77 1.98 0.76 1 0.88 ACEIs 1 1 1 2 1 (0.66,0.91) (0.65,0.90) (0.65,0.91) (0.48,8.27) (0.64,0.90) (0.73,1.06) 1.01 1.02 1.01 1.04 4 0.98 ARBs 4 3 5 —— —— 3 (0.82,1.25) (0.82,1.27) (0.80,1.27) (0.80,1.35) (0.81,1.18) ACEI+A 1.09 1.08 1.09 1.10 5 5 4 6 —— —— —— —— RB (0.75,1.59) (0.72,1.61) (0.73,1.62) (0.70,1.71) 1.49 1.41 1.42 8 diuretic 8 7 —— 7 —— —— —— —— (0.60,3.75) (0.56,3.57) (0.55,3.64) 1.00 1.49 0.93 2.18 1.17 6 0.95(0.66,1. CCB 2 8 2 3 2 (0.67,1.49) (0.68,3.28) (0.57,1.52) (0.39,12.18) (0.52,2.66) 38) β-blocke 1.28 1.14 1.29 1.14 7 5.19(0.83,32 7 5 6 —— —— 5 r (0.79,2.07) (0.69,1.90) (0.75,2.24) (0.68,1.92) .1) 1.44 1.59 0.96 6.16 0.99 3 control 6 6 3 4 —— —— (0.48,4.34) (0.14,18.22) (0.22,4.24) (0.70,54.29) (0.22，4.39)

Placebo Reference 3 Reference 2 Reference 4 Reference 1 Reference 2 Reference 4

Number 17 30 18 20 9 7 of trials Ranking indicates the probability that the drug class is “best,” second-“best,” etc.

Table S4: Subgroup analyses for hyperkalemia for each treatment versus placebo. Odds ratios and 95%CI treatment strategies vs. placebo for hyperkalemia, and ranks of according to SUCRAs

The average Follow-up Rank Rank Treatme The average serum Standard Rank Trials with sample Rank Rank serum creatinine Rank (>3ys ) (SUCRA) DKD nt creatinine was less than analysis (SUCRA) size more than 100 (SUCRA) (SUCRA) was greater than (SUCRA) patients (SUCRA strategies 200umol/l 200umol/l ) 1.55 2.08 1.41 1.20 2.11 4 2.08 ACEIs 6 5 4 5 4 (0.93,2.59) (1.08,3.99) (0.72,2.74) (0.39,3.65) (0.99,4.5) (0.68,6.33) 2.08 2.20 2.18 1.25 2.09 2.15 ARBs 7 6 5 6 5 (1.44,2.99) (1.51,3.20) (1.50,3.18) (0.28,5.47) (1.41,3.10) (1.25,3.69) ACEI+A 9.97 10.56 10.46 8 8 6 —— —— —— —— RB (6.67,14.92) (6.98,15.95) (6.92,15.83) —— 0.56 1.76 1.57 3 diuretic 2 4 —— —— —— —— —— (0.15,2.13) (0.56,5.48) (0.51,4.84) 0.41 053 0.48 0.12 0.28 1 0.63 CCB 1 1 1 1 1 (0.16,1.02) (0.20,1.46) (0.17,1.32) (0.01,1.31) (0.04,1.78) (0.18,2.22) β-blocke 0.83 2.76 0.71 0.25 2.37 1.46 3 7 2 2 3 r (0.27,2.57) (1.06,7.20) (0.14,3.71) (0.01,6.49) (0.95,5.89) (0.15,14.45) 0.80 0.75 0.64 control 4 3 —— 3 —— —— (0.13,4.79) (0.03,19.06) (0.08,5.28) —— Placebo Reference 5 Reference 2 Reference 3 Reference 4 Reference 2 Reference 2

Number 9 22 13 12 9 5 of trials Ranking indicates the probability that the drug class is “best,” second-“best,” etc.

Table S5: Subgroup analyses for studies with low bias risk of each item in the Cochrane risk of bias tool (including Sequence generation, Allocation concealment, Blinding, Incomplete outcome data, Selective outcome reporting, and Other source of bias) for each treatment versus placebo. Odds ratios and 95%CI treatment strategies vs. placebo for primaryevents, and ranks according to SUCRAs Treatment Kidney Rank cardiovascula Rank cardiovascular Rank all-cause Rank strategies events (SUCRA) r events (SUCRA) death (SUCRA) death (SUCRA) 0.63 0.83 0.77 1 0.81 1 ACEIs 1 2 (0.49,0.80) (0.77,0.89) (0.63,0.95) (0.69,0.96) 0.92 0.91 1.19 4 1.06 4 ARBs 3 4 (0.83,1.01) (0.83,0.99) (0.80,1.78) (0.84,1.34) 0.66 1.19 3 2.41 2 ACEI+ARB 2 - - (0.47,0.91) (0.72,1.96) (0.46,12.69) - - - β-blocker - - - - - 0.80 - - - - CCB - - 1 (0.72,0.88) control ------

0.84 - - - - diuretic - - 3 (0.75,0.94) Placebo Reference 4 Reference 5 Reference 2 Reference 3

Number of 6 11 8 11 trials Ranking indicates the probability that the drug class is “best,” second-“best,” etc; “-”: no available data

Figure S1. Loop-specific inconsistency approach for of primary outcomes: (a) kidney failure, (b) cardiovascular events, (c) cardiovascular death, and (d) total mortality.Loop(s) [Control -β-blocker-ARBI] for cardiovascular events and [CCB-β-blocker-ACEI] for death are formed only by multi-arm trial(s) - Consistent by definition. If the lower limit of 95%CI of the ROR reaches one in each closed loops, it indicates that there is no significant disagreement.

Figure S2. Loop-specific inconsistency approach for of adverse events comparisons:(a) hyperkalemia (b) cough (c) hypotension (d) edema.Loop(s) [control- β-blocker-ACEI] for hyperkalemia are formed only by multi-arm trial(s) - Consistent by definition. If the lower limit of 95%CI of the ROR reaches one in each closed loops, it indicates that there is no significant disagreement.

a hyperkalemia b cough

cedema d hypotension

Figure S3 Summary of results from network meta-analysis (on the upper triangle) onadverse events comparisons:(a) hyperkalemia (b) cough (c) edema (d) hypotension. On the lower triangle and upper triangle, the row-defining treatment is compared with the column-defining treatment, and ORs of >1 favor the row-defining treatment.

a b

d c

Figure S4.Comparison-adjusted funnel plot for the network of primary outcomes: (a) kidney failure, (b) cardiovascular events, (c) cardiovascular death, and (d) total mortality withblood pressure lowering therapy in advanced non-dialysis CKD patients. A: placebo; B:diuretic;C:control;D:CCB;E: β-blocker;F:ARB+ACEI;G:ARB;H:ACEI.

Figure S5.Comparison-adjusted funnel plot for the network of adverse events comparisons:(a) hyperkalemia (b) cough (c) hypotension (d) edemawithblood pressure lowering therapy in advanced non-dialysis CKD patients. A: placebo; B:diuretic;C:control;D:CCB;E: β-blocker;F:ARB+ACEI;G:ARB;H:ACEI.

Figure S6. Forest plot for results of primary outcomes: (a) kidney events, (b) cardiovascular events, (c) cardiovascular deathand(d) all-cause death in studies with low bias risk of each item in the Cochrane risk of bias tool (including Sequence generation, Allocation concealment, Blinding, Incomplete outcome data, Selective outcome reporting, and Other source of bias). AppendixReferences

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Search/MESH terms MEDLINE (OVID) 1. exp Angiotensin-Converting Enzyme Inhibitors/ 2. angiotensin converting enzyme inhibit$.tw. 3. (ace and inhibit$).tw. 4. (ACE or ACE1 or ACEI or ACE-I or ACEs). 5..tw. 6.benazepril.tw. 7.benazeprila.tw. 8. captopril.tw. 9. enalapril.tw. 10. .tw. 11. .tw. 12. fosinopril.tw. 13. lisinopril.tw. 14. perindopril.tw. 15. ramipril.tw. 16. benazeprilat.tw. 17. ceranapril.tw. 18. cilazaprilat.tw. 19. .tw. 20 .fosinoprilic acid.tw. 21. .tw. 22. libenzapril.tw. 23. .tw. 24. ramiprilat.tw. 25. .tw. 26. .tw. 27. .tw. 28. hydrochloride 29. teprotide.tw. 30. .tw. 31. .tw. 32.quinapril.tw. 33..tw. 34..tw. 35. deacetylalacepril.tw. 36.fosinopril$. 37.losartan.tw. 38..tw. 39.elisartan.tw 40.embusartan.tw. 41.forasartan.tw. 42.saprisartan.tw. 43..tw. 44.vasvalsartan.tw. 45.zolasartan.tw. 46.miardis.tw. 47.cozaar.tw. 48.atacand.tw. 49.teveten.tw. 50.avapro.tw. 51.micardis.tw. 52.avalide.tw. 53.aprovel.tw. 5 54.amias.tw. 55.diovan.tw. 56.olmetec.tw. 57. irbesartan.tw. 58. candesartan.tw. 59. .tw. 60. .tw. 61. olmesartan.tw. 62. telmisartan.tw. 63. (ace adj2 inhibitor$).tw. 64. (angiotensin adj2 receptor antagonist$).tw. 65.ARB.tw. 66.Angiotensin 2 Receptor Antagonist.tw. 67.Angiotensin Receptor Antagonist.tw. 68.Angiotensin II Antagonist.tw. 69.AT 2 receptor blocker.tw. 70.AT 2 receptor antagonist.tw. 71. .tw. 72. or/1-71 73. (kidney disease or renal disease).tw. 74. Kidney Failure, Chronic/ 75. Kidney Failure/ 76. (chronic kidney or chronic renal).tw. 77. Renal Insufficiency, Chronic/ or Kidney Failure, Chronic/ 78. Uremia/ 79.(CKD or CKF or CRF or ESRD or ESKF or ESRF or ESKD or CRD).tw. 80. (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw. 81. renal replacement therapy/ or exp renal dialysis/ or exp hemofiltration/ 82. (predialysis or dialysis).tw. 83. (haemodialysis or haemodialysis).tw. 84. (hemofiltration or haemofiltration).tw. 85. (hemodiafiltration or haemodiafiltration).tw. 86. (CAPD or CCPD or APD or PD).tw. 87. exp Proteinuria/ 88. proteinuria.tw. 89.albuminuria.tw. 90.macroalbuminuria.tw. 91.microalbuminuria.tw. 92.(urin$ adj6 (protein$ or albumin$ or microalbumin$)).tw. 93. or/73-92 94. Randomized controlled trial.pt. 95.Controlled clinical trial.pt 96. Randomized.tw. 97. Placebo.tw. 6 98.Drug therapy/ 99.Randomly.tw. 100.Trial.tw. 101.Groups.tw. 102.(random$ adj5 trial$).tw. 103. (random$ adj5 allocation$).tw. 104.(Blind$ adj5 method$).tw. 105.or/94-104 106. 72 and 93 and 105 EMBASE 1.exp Angiotensin-Converting Enzyme Inhibitors 2. angiotensin adj2 receptor antagonist$ 3. Angiotensin 2 Receptor Antagonist 4. Angiotensin Receptor Antagonist 5 .Angiotensin II Antagonist 6.AT 2 receptor blocker 7.AT 2 receptor antagonist 8.fosinopril$ 9.losartan 10.azilsartan 11.elisartan 12.embusartan 13.forasartan 14.saprisartan 15.tasosartan 16.vasvalsartan 17.zolasartan 18.miardis 19.cozaar 20.atacand 21.teveten 22.avapro 23.micardis 24.avalide 25.aprovel 26.amias 27.diovan 28.olmetec 29. irbesartan 30. candesartan 31. eprosartan 32. valsartan 33. olmesartan 7 34. telmisartan 35. ace adj2 inhibitor$ 36. angiotensin converting enzyme inhibit$ 37. ace adj2 inhibit$ 38. ACE or ACE1 or ACEI or ACE-I or ACE 39.alacepril 40.benazepril 41.benazeprila 42.captopril 43. enalapril 44. cilazapril 45. enalaprilat 46. fosinopril 47. lisinopril 48. perindopril 49. ramipril 50. benazeprilat 51. ceranapril 52. cilazaprilat 53. delapril 54. fosinoprilic acid 55. imidapril 56. libenzapril 57. quinaprilat 58. ramiprilat 59. rentiapril 60. saralasin 61. spirapril 62.temocapril hydrochloride 63. teprotide 64. zofenopril 65. trandolapril 66.quinapril 67.moexipril 68.ceronapril 69. deacetylalacepril 70. aliskiren 71 .or/1-70 72. kidney disease or renal disease 73. Kidney Failure, Chronic 74.Kidney Failure 75.chronic kidney or chronic renal 76. Uremia 77.CKD or CKF or CRF or ESRD or ESKF or ESRF or ESKD or CRD 8 78.end-stage renal or end-stage kidney or endstage renal or endstage kidney 79. predialysis or dialysis 80. haemodialysis or haemodialysis 81. hemodiafiltration or haemodiafiltration 82. CAPD or CCPD or APD or PD 83.exp Proteinuria 84. proteinuria 85. macroalbuminuria 86. microalbuminuria 87. albuminuria 88. or/72-87 89. Randomized controlled trial 90.Controlled clinical trial 91.blind and method 92. randomized and controlled and trial 93. random and allocation 94. or/89-93 95. 71 and 88 and 94 COCHRANE CONTROLLED TRIALS 1. (kidney disease or renal disease).tw. 2. Kidney Failure, Chronic/ 3. Kidney Failure/ 4. (chronic kidney or chronic renal).tw. 5. Renal Insufficiency, Chronic/ or Kidney Failure, Chronic/ 6. Uremia/ 7.(CKD or CKF or CRF or ESRD or ESKF or ESRF or ESKD or CRD).tw. 8. (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw. 9. renal replacement therapy/ or exp renal dialysis/ or exp hemofiltration/ 10. (predialysis or dialysis).tw. 11. (haemodialysis or haemodialysis).tw. 12. (hemofiltration or haemofiltration).tw. 13. (hemodiafiltration or haemodiafiltration).tw. 14. (CAPD or CCPD or APD or PD).tw. 15. exp Proteinuria/ 16. proteinuria.tw. 17. albuminuria.tw. 18. macroalbuminuria.tw. 19. microalbuminuria.tw. 20. (urin$ adj6 (protein$ or albumin$ or microalbumin$)).tw. 21. or/1-20 22. exp Angiotensin-Converting Enzyme Inhibitors/ 23. angiotensin converting enzyme inhibit$.tw. 24. (ace adj2 inhibit$).tw. 9 25.(ACE or ACE1 or ACEI or ACE-I or ACEs).tw. 26. alacepril.tw. 27. benazepril.tw. 28. benazeprila.tw. 29. captopril.tw. 30. enalapril.tw. 31. cilazapril.tw. 32. enalaprilat.tw. 33. fosinopril.tw. 34. lisinopril.tw. 35. perindopril.tw. 36. ramipril.tw. 37. benazeprilat.tw. 38. ceranapril.tw. 39. cilazaprilat.tw. 40. delapril.tw. 41 .fosinoprilic acid.tw. 42. imidapril.tw. 43. libenzapril.tw. 44. quinaprilat.tw. 45. ramiprilat.tw. 46. rentiapril.tw. 47. saralasin.tw. 48. spirapril.tw. 49.temocapril hydrochloride 50. teprotide.tw. 51. zofenopril.tw. 52. trandolapril.tw 53. quinapril.tw. 54. moexipril.tw. 55. ceronapril 56. deacetylalacepril.tw. 57. fosinopril$. 58. losartan.tw. 59. azilsartan.tw. 60. elisartan.tw 61. embusartan.tw. 62. forasartan.tw. 63. saprisartan.tw. 64. tasosartan.tw. 65. vasvalsartan.tw. 66. zolasartan.tw. 67. miardis.tw. 68. cozaar.tw. 10 69. atacand.tw. 70. teveten.tw. 71. avapro.tw. 72. micardis.tw. 73. avalide.tw. 74. aprovel.tw. 75. amias.tw. 76. diovan.tw. 77. olmetec.tw. 78. irbesartan.tw. 79. candesartan.tw. 80. eprosartan.tw. 81. valsartan.tw. 82. olmesartan.tw. 83. telmisartan.tw. 84. (ace adj2 inhibitor$).tw. 85. (angiotensin adj2 receptor antagonist$).tw. 86. ARB.tw. 87. Angiotensin 2 Receptor Antagonist.tw. 88. Angiotensin Receptor Antagonist.tw. 89. Angiotensin II Antagonist.tw. 90. AT 2 receptor blocker.tw. 91.AT 2 receptor antagonist.tw. 92. aliskiren.tw. 93. or/22-92 94. Randomized controlled trial.pt. 95. Controlled clinical trial.pt 96. Randomized.tw. 97. Placebo.tw. 98. Drug therapy/ 99. Randomly.tw. 100.Trial.tw. 101. Groups.tw. 102. (random$ adj5 trial$).tw. 103. (random$ adj5 allocation$).tw. 104. (Blind$ adj5 method$).tw. 105. or/94-104 106. 21 and 93 and 105