Kdigo BP GL Suppl Table Dec 2012

KDIGO CLINICAL PRACTICE GUIDELINE
FOR THE MANAGEMENT OF BLOOD PRESSURE

IN CHRONIC KIDNEY DISEASE
Supplementary Tables
December 2012
TABLE OF CONTENTS
Supplemental Table 1. General population RCTs comparing BP targets in CKD subgroups

Supplemental Table 2. Evidence profile of RCTs examining the effect of blood pressure target in patients with CKD without DM
Supplemental Table 3. RCTs examining the effect of blood pressure targets in patients with CKD without DM [categorical outcomes]
Supplemental Table 4. RCTs examining the effect of blood pressure targets in patients with CKD without DM [continuous outcomes]
Supplemental Table 5. General population RCTs comparing ARB vs. CCB in CKD subgroups with and without DM
Supplemental Table 6. General population RCTs comparing ACEI or ARB vs. control (active or placebo) in CKD subgroups with and without DM
Supplemental Table 7. Evidence profile of RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD without DM
Supplemental Table 8. RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD without DM [categorical outcomes]
Supplemental Table 9. RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD without DM [continuous outcomes]
Supplemental Table 10. Evidence profile of RCTs examining the effect of ACEI or ARB vs. CCB in patients with CKD without DM
Supplemental Table 11. RCTs examining the effect of ACEI or ARB vs. CCB in patients with CKD without DM [categorical outcomes]
Supplemental Table 12. RCTs examining the effect of ACEI or ARB vs. CCB in patients with CKD without DM [continuous outcomes]
Supplemental Table 13. Evidence profile of RCTs examining the effect of ACEI vs. ARB in patients with CKD without DM
Supplemental Table 14. RCTs examining the effect of ACEI vs. ARB in patient with CKD without DM [categorical outcomes]
Supplemental Table 15. RCTs examining the effect of ACEI vs. ARB in patient with CKD without DM [continuous outcomes]
Supplemental Table 16. Evidence profile of RCTs examining the effect of high vs. low dose ACEI in patients with CKD without DM
Supplemental Table 17. RCTs examining the effect of high dose ACEI vs. low dose ACEI in patient with CKD without DM [categorical outcomes]
Supplemental Table 18. RCTs examining the effect of high dose ACEI vs. low dose ACEI in patient with CKD without DM [continuous outcomes]
Supplemental Table 19. Evidence profile of RCTs examining the effect of high vs. low dose ARB in patients with CKD without DM
Supplemental Table 20. RCTs examining the effect of high dose ARB vs. low dose ARB in patient with CKD without DM [categorical outcomes]
Supplemental Table 21. RCTs examining the effect of high dose ARB vs. low dose ARB in patient with CKD without DM [continuous outcomes]
Supplemental Table 22. RCTs examining the effect of ACEI vs. ß-blocker in patients with CKD without DM [categorical outcomes]
Supplemental Table 23. RCTs examining the effect of ACEI vs. ß-blocker in patients with CKD without DM [continuous outcomes]
Supplemental Table 24. RCTs examining the effect of ACEI + CCB vs. ACEI in patients with CKD without DM [categorical outcomes]
Supplemental Table 25. RCTs examining the effect of ACEI + CCB vs. ACEI in patients with CKD without DM [continuous outcomes]
Supplemental Table 26. RCTs examining the effect of ACEI + CCB vs. CCB in patients with CKD without DM [categorical outcomes]
Supplemental Table 27. RCTs examining the effect of ACE + CCB vs. CCB in patients with CKD without DM [continuous outcomes]
Supplemental Table 28. RCTs examining the effect of CCB vs. CCB in patients with CKD without DM [categorical outcomes]
Supplemental Table 30. RCTs examining the effect of ß-blocker vs. CCB in patients with CKD without DM [categorical outcomes]
Supplemental Table 31. RCTs examining the effect of ß-blocker vs. CCB in patients with CKD without DM [continuous outcomes]
Supplemental Table 32. RCTs examining the effect of central-acting agent vs. CCB in patients with CKD without DM [continuous outcomes]
Supplemental Table 33. General population RCTs comparing ACEI + diuretic vs. placebo in CKD with DM subgroups [categorical outcomes]
Supplemental Table 34. General population RCTs comparing ACEI + diuretic vs. placebo in CKD with DM subgroups [continuous outcomes]
Supplemental Table 35. General population RCTs comparing ARB or (ACE + ARB) vs. ACE in CKD subgroups with and without DM
Supplemental Table 36. General population RCTs comparing CCB vs. active control in CKD subgroups with and without DM
Supplemental Table 37. Evidence profile of RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM
Supplemental Table 38. RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM [categorical outcomes]
Supplemental Table 39. RCTs examining the effect of ACEI or ARB vs. placebo in patient with CKD and DM [continuous outcomes]
Supplemental Table 40. Evidence profile of RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM
Supplemental Table 41. RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM [categorical outcomes]
Supplemental Table 42. RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM [continuous outcomes]
Supplemental Table 43. Evidence profile of RCTs examining the effect of ACEI vs. ARB in patients with Type 2 DKD
Supplemental Table 44. RCTs examining the effect of ACEI vs. ARB in microalbuminuric patients with CKD and Type 2 DM [categorical outcomes]
Supplemental Table 45. RCTs examining the effect of ACEI vs. ARB in microalbuminuric patients with CKD and Type 2 DM [continuous outcomes]
Supplemental Table 46. Evidence profile of RCTs examining the effect of ARB vs. ARB in patients with CKD and DM
Supplemental Table 47. RCTs examining the effect of ARB vs. ARB in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]
Supplemental Table 48. RCTs examining the effect of ARB vs. ARB in overtly albuminuric patients with CKD and Type 2 DM [continuous outcomes]
Supplemental Table 49. RCTs examining the effect of DRI + ARB vs. placebo+ ARB in microalbuminuric patients with CKD and Type 2 DM [continuous outcomes]
Supplemental Table 50. RCTs examining the effect of dihydropyridine CCB vs. placebo in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]
Supplemental Table 51. RCTs examining the effect of aldosterone antagonist + ACEI vs. placebo + ACEI in patients with CKD and Type 2 DM [continuous outcomes]
Supplemental Table 52. RCTs examining the effect of endothelin antagonist vs. endothelin antagonist in patients with CKD with Type 2 DM [categorical outcomes]
Supplemental Table 53. RCTs examining the effect of endothelin antagonist vs. endothelin antagonist in patients with CKD with Type 2 DM [continuous outcomes]
Supplemental Table 54. Evidence profile of RCTs examining the effect of ACEI or ARB vs. CCB in transplant recipients without DM
Supplemental Table 55. RCTs examining the effect of ACE or ARB vs. CCB in transplant recipients with CKD without DM [categorical outcomes]
Supplemental Table 56. RCTs examining the effect of ACE or ARB vs. CCB in transplant recipients with CKD without DM [continuous outcomes]
Supplemental Table 57. Evidence profile of RCTs examining the effect of CCB vs. placebo in transplant recipients without DM
Supplemental Table 58. RCTs examining the effect of CCB vs. placebo in transplant recipients [categorical outcome]
Supplemental Table 59. RCTs examining the effect of CCB vs. placebo in transplant recipients without DM [continuous outcome]
Supplemental Table 60. RCTs examining the effect of ACE vs. ARB in hypertensive transplant recipients without DM [continuous outcomes]
Supplemental Table 61. RCTs examining the effect of ARB vs. placebo in transplant recipients [categorical outcome]
Supplemental Table 62. RCTs examining the effect of ARB vs. placebo in transplant recipients without DM [continuous outcome]
Supplemental Table 63. RCTs examining the effect of intensified vs. conventional BP control on children with CKD without DM [categorical outcome]
Supplemental Table 64. RCTs examining the effect of intensified vs. conventional BP control on children with CKD without DM [continuous outcome]
Supplemental Table 65. Age restriction in all RCTs for DM CKD, non-DM CKD, Transplant and CKD subgroups
Supplemental Table 66. PICO criteria for blood pressure targets in elderly studies
Supplemental Table 67. Ages and BP targets in elderly studies
Supplemental Table 68. PICO criteria for blood pressure agents in elderly studies
ABBREVIATIONS AND ACRONYMS FOR SUPPLEMENTAL TABLES
∆ Change KDOQI Kidney Disease Outcomes Quality Initiative

↓ Decrease kg Kilogram
↑ Increase L Liter
ACEI Angiotensin-converting enzyme inhibitors LOCF Last observation carried forward
ACR Albumin-creatinine ratio LV Left ventricular
ARB Angiotensin receptor blockers μ Micro-
β Beta MAP Mean arterial pressure
BMI Body mass index mg Milligram
BP Blood pressure MI Myocardial infarction
CAD Coronary artery disease min Minute
CCB Calcium channel blockers mL Milliliter
CHD Coronary heart disease mmHg Millimeters of Mercury
CHF Chronic heart failure mmol Millimole
CI Confidence interval mo Month
CKD Chronic kidney disease mol Mole
CrCl Creatinine clearance nd Not documented
CV Cardiovascular NS Not significant
CVA Cerebrovascular accident NNT Number needed to treat
d day OR Odds ratio
DBP Diastolic blood pressure PCR Protein-creatinine ratio
dL Deciliter PKD Polycystic kidney disease
DM Diabetes mellitus pts Patients
DRI Direct rennin inhibitor RCT Randomized controlled trial
eCrCl Estimated creatinine clearance RR Relative risk
eGFR Estimated glomerular filtration rate RRT Renal replacement therapy
ERT Evidence review team SBP Systolic blood pressure
ESRD End stage renal disease SCr Serum creatinine
ESRF End stage renal failure SD Standard deviation
EU European union UACR Urinary albumin-creatinine ratio
g Gram UAE Urinary albumin excretion
GFR Glomerular filtration rate UAER Urinary albumin excretion rate
h Hour UK United Kingdom
HDL High-density lipoprotein UPCR Urinary protein-creatinine ratio
HR Hazards ratio UPE Urinary protein excretion
HTN Hypertension US United States
IQR Interquartile range y year
Supplemental Table 1. General population RCTs comparing BP targets in CKD subgroups
Description No analyzed / Enrolled Blood pressure Results
Study Duration Baseline Achieved
Baseline Baseline Events (%) P
Outcome Year Outcome SBP/DBP SBP/DBP RR/OR/HR
Intervention Control Intervention Control GFR or SCr Proteinuria Intervention value
Country (Treatment) Intervention Intervention (95% CI)
[Control]
(Control) (Control)
Mortality
Active
treatment
Placebo SCr 119.4-
All-cause Pahor 1998 5y [BP target: 216 177 172/77 140/70 37 (17%) HR 1.18
[No BP 212.2 nd NS
mortality US[72] (5 y) SBP<160 or (216) (177) (172/77) (154/75) [26 (15%)] (0.72; 1.95)
target] μmol/L
≤20 mm Hg
reduction]
CV Events
36 (17%) HR 0.59
Any CV event nd
[47 (27%)] (0.38; 0.91)
Active
treatment
Placebo SCr 119.4-
Pahor 1998 5y [BP target: 216 177 172/77 140/70 14 (7%)1 HR 0.51
Stroke [No BP 212.2 nd nd
US[72] (5 y) SBP<160 or (216) (177) (172/77) (154/75) [22 (12%)] (0.26; 1.00)
target] μmol/L
≤20 mm Hg
reduction]
Any coronary 16 (7%) HR 0.62

NS
event [21 (12%)] (0.32; 1.19)
1 Primary outcome
Supplemental Table 2. Evidence profile of RCTs examining the effect of blood pressure target in patients with CKD without DM
Directness of the Summary of findings
# of studies Methodological
Total N Consistency evidence Other
Outcome and quality of studies
(Treatment) across studies generalizability/ considerations Quality of evidence for Qualitative and quantitative description of Importance
study design per outcome outcome effect of outcome
applicability
Composite 2 RCTs No important
1934 No limitations Direct None
kidney [1˚ in 1 RCT] inconsistencies2 High No difference3 Critical
(972) (0) (0) (0)
outcomes (High) (0)
No important
3 RCTs 1929 Some limitations Direct Imprecision
Mortality inconsistencies Low Insufficient evidence Critical
(High) (980) (-1) (0) (-1)
(0)
No important
2 RCTs 1429 No limitations Direct Imprecision
CV mortality inconsistencies Moderate Insufficient evidence Critical
(High) (708) (0) (0) (-1)
(0)
1 RCT 1094 No limitations Direct Sparse
CV events NA Moderate Insufficient evidence Critical
(High) (540) (0) (0) (-1)
No important
2 RCTs 1927 Some limitations4 Direct None
ESRD inconsistencies5 Moderate Possible benefit for lower target Critical
(High) (980) (-1) (0) (0)
(0)
Kidney
function 0 RCT -- -- -- -- -- -- -- High
(categorical)
∆Kidney 3 RCTs No important Uncertainty about
1674 No limitation None
function [1˚ in 1 RCT] inconsistencies directness Moderate No difference6 Moderate
(833) (0) (0)
(continuous) (High) (0) (-1)
Proteinuria
0 RCT -- -- -- -- -- -- -- High
(categorical)
Uncertainty about
Proteinuria 1 RCT 754 No limitations Sparse
NA directness Low Benefit for low target Moderate
(continuous) (High) (380) (0) (-1)
(-1)
1094 Hyperkalemia: 0% for low BP target and 1%
Adverse events 1 RCT Moderate
(540) for usual BP target (from 1 RCT)
2269
Total 3 RCTs
(1140)
Balance of potential benefits and harms Quality of overall evidence
Possible benefit from lower target for kidney outcomes Moderate for kidney outcomes
Possibly greater benefit from lower target for kidney outcomes in higher proteinuria subgroups Moderate for CV outcomes
Insufficient evidence for CV outcomes
2 Trial period results were not significant. Follow up of AASK was not significant. Follow-up of MDRD showed benefit of lower target.
3 Possible benefit for individuals with proteinuria (UPCR >0.22g/g) in AASK Follow up
4 MDRD follow-up study was considered to be “fair” quality
5 Trial period results were not significant. Long-term follow-up of MDRD showed benefit of lower target.
6 Benefit for proteinuria subgroups in MDRD Study 1 and 2.
Supplemental Table 3. RCTs examining the effect of blood pressure targets in patients with CKD without DM [categorical outcomes]7
Study Duration Baseline Baseline Achieved Events
Baseline P
Outcome Year Outcome GFR or SBP/DBP SBP/DBP No (%) RR/OR/HR Quality
Intervention Control Intervention Control Proteinuria value
Country (Treatment) SCr Intervention Intervention Intervention (95% CI)
(Control) (Control) [Control]
Composite kidney outcomes
↓GFR 50%
or 25
Risk
mL/min/
reduction
1.73 m2, nd NS Good
2%
ESRD or
(-22; 21)9
death during
the trial
↓GFR 50%
or 25 380 374
Risk
mL/min/ (540) (554)
reduction
1.73 m2 or nd NS Good
Mean -2%
ESRD AASK 2002
Lower BP Usual BP GFR 46 Male (-31; 20)10
during the 2006 20108 4y 152/96 128/78
[Target MAP [Target MAP mL/min/1. 0.61g/24h
trial US[11;70;99 (4 y) (149/95) (141/85)
92] 102-107] 73 m2 Female
] Risk
ESRD or 0.36 g/24h
reduction
death during nd NS Good
12%
the trial
(-13; 32)11
First CV
hospitalizati
on and
death during 540 554 71 (13%) HR 0.8412
NS Fair13
the trial (540) (554) [78 (14%)] (0.61; 1.16)
[from post-
trial follow
up]
7 Shaded studies were included in previous KDOQI guideline

8 Study only included African American patients
9 Adjusted
10 Adjusted
11 Adjusted
12 Adjusted
13 From post-trial follow-up data
Baseline P
First CV
hospitalizati
on or ESRD
143 (26%) HR 0.9114
during the NS Fair15
[159 (29%)] (0.72; 1.15)
trial [from
post-trial
follow up]
Doubling of
SCr, ESRD,
or death
282 (52%) HR 0.91
both phases NS Fair16
[285 (51%)] (0.77; 1.08)
[from post-
trial follow
up]
Doubling of
SCr or ESRD
eGFR 48
during both Median
mL/min/1. 213 (39%) HR 0.95
phases UPCR 0.08 NS Fair17
73m2 [209 (38%)] (0.78; 1.15)
[from post-
Low BP Usual BP
trial follow
Range Target in Target in 131/78
up]
8.8-12.2 y trial, then BP trial, then (134/78)
ESRD or
<130/80 BP<130/80
death during
both phases 238 (44%) HR 0.85 NS
Fair18
[from post- [256 (46%)] (0.71; 1.02) (0.08)
trial follow
up]
Doubling of
SCr, ESRD,
or death in eGFR 52
357 376 Median 145 (41%) HR 1.18
UPCR ≤0.22 mL/min/1. NS Fair19
(540) (554) UPCR 0.04 [135 (36%)] (0.93; 1.50)
[from post- 73 m2
trial follow
up]
14 Adjusted
15 From post-trial follow up data
Baseline P
Doubling of
SCr or ESRD
in UPCR 98 (27%) HR 1.39
0.03 Fair20
≤0.22 [from [83 (22%)] (1.04; 1.87)
post-trial
follow up]
ESRD or
death in
UPCR ≤0.22 119 (33%) HR 1.12
NS Fair21
[from post- [112 (30%)] (0.87; 1.45)
trial follow
up]
Doubling of
SCr, ESRD,
or death in
136 (75%) HR 0.73
UPCR >0.22 0.01 Fair22
[149 (85%)] (0.58; 0.93)
[from post-
trial follow
up]
Doubling of
SCr or ESRD eGFR 41
181 176 Median
in UPCR mL/min/1. 114 (63%) HR 0.76
(540) (554) UPCR 0.58 0.04 Fair23
>0.22 [from 73 m2 [126 (72%)] (0.58; 0.99)
post-trial
follow up]
ESRD, or
death in
UPCR >0.22 118 (65%) HR 0.67
0.002 Fair24
[from post- [143 (81%)] (0.52; 0.87)
trial follow
up]

Baseline P
SCr 2.0
MDRD MAP 90
Lower BP Usual BP mg/dL
ESRD or Study 2 3y 132 123 133/81 [126/77]27 RR 0.85
[MAP ≤92 [MAP ≤107 GFR 19 0.89 g/d -- nd Good
death 1994 (2 y) (132) (123) (133/82) (MAP 94 (0.60; 1.22)
mmHg]25 mmHg]26 mL/min/1.
1995[46;79] [134/81])
73 m2
Kidney 312 (72%)28 HR 0.7729
0.0024 Fair
failure or all- [312 (76%)] (0.65; 0.91)
cause
mortality 4y
nd nd
during the (2 y) HR 0.7730
146 total NS Fair31
trial [from Lower BP Usual BP (0.54; 1.11)
post-trial [Target MAP [Target MAP GFR 33
MDRD 2005 130/80 126/77
follow up] <92 <107 mL/min/1. 0.39 g/d
US[86] (131/80) (134/81)
Kidney (<125/75) or (<140/90) or 73 m2
failure or all- <98] <113]
cause
6y 432 408 312 (72%)32 HR 0.7733
mortality 0.0024 Fair34
(2 y) (432) (408) [312 (76%)] (0.65; 0.91)
[from post-
trial follow
up]
Mortality
Male
AASK Lower BP Usual BP GFR 46
All cause 4y 380 374 0.61g/24h 152/96 128/78 2%
200235 [Target MAP [Target MAP mL/min/1. nd NS Good
mortality (4 y) (540) (554) Female (149/95) (141/85) [2%]
US[99] 92] 102-107] 73 m2
0.36 g/24h
25 For patients ≥61 y, target was ≤98 mmHg

26 For patients ≥61 y, target was ≤113 mmHg
27 The actual mean follow-up systolic and diastolic BP in the usual group were 132.7/80.2 mmHg and in the low BP group were 125.6/76.7 mmHg (Tom Greene, PhD, personal communication, October 2009)
28 Primary outcome
29 Adjusted
30 Adjusted
32 Primary outcome
33 Adjusted
Baseline P
Lower BP Usual BP
Death [from [Target MAP [Target MAP GFR 33
MDRD 2005 6y 432 408 130/80 126/77 10%
post-trial <92 <107 mL/min/1. 0.39 g/d nd nd36 Fair37
US[86] (2 y) (432) (408) (131/80) (134/81) [6%]
follow up] (<125/75) or (<140/90) or 73 m2
<98] <113]
SCr 2.7
REIN 2 Median 19 Conventiona Intensified μmol/L
168 167 136/84 134/82 3 (2%) RR 1.4938
Death 2005 mo l BP BP GFR 34 UPE 2.9 g/d nd Fair
(169) (169) (137/84) (130/80) [2 (1%)] (0.25; 8.81)
Italy[85] (36 y) [DBP <90] [<130/80] mL/min/1.
73 m2
CV mortality
6y 380 374 Male 1%
CV mortality AASK 2002 Lower BP Usual BP GFR 46 nd NS Good
(4 y) (540) (554) 0.61g/24h 152/96 128/78 [1%]
200639 [Target MAP [Target MAP mL/min/1.
4y 540 554 Female (149/95) (141/85) 16 (3%) HR 0.9840
CV death US[70;99] 92] 102-107] 73 m2 NS Good
(4 y) (540) (554) 0.36 g/24h [15 (3%)] (0.48; 2.01)
SCr 2.7
168 167 136/84 134/82 1 (1%) RR 0.9941
CV mortality 2005 mo l BP BP GFR 34 UPE 2.9 g/d nd Fair
(169) (169) (137/84) (130/80) [1 (1%)] (0.06; 15.76)
Italy[85] (36 y) [DBP <90] [<130/80] mL/min/1.
73 m2
CV events
CV events 380 374 2%
nd NS Good
(composite) (540) (554) [3%]
Male 108 (20%) HR 1.0643
CV events AASK 2002 Lower BP Usual BP GFR 46 NS Good
4y 0.61g/24h 152/96 128/78 [94 (17%)] (0.76; 1.49)
200642 [Target MAP [Target MAP mL/min/1.
Stroke (4 y) 540 554 Female (149/95) (141/85) 26 (5%) RR 0.9244
US[70;99] 92] 102-107] 73 m2 nd Good
events (540) (554) 0.36 g/24h [29 (5%)] (0.55; 1.54)
27 (5%) RR 1.2045
CHF events nd Good
[23 (4%)] (0.70; 2.07)
36 Noted as statistically significant in letter to Annals by Good, 2005

38 Calculated by ERT
40 Adjusted
43 Adjusted
Baseline P
19 (4%) RR 0.8546
CAD events nd Good
[23 (4%)] (0.47; 1.54)
ESRD
Male Risk
AASK Lower BP Usual BP GFR 46
ESRD 4y 380 374 0.61g/24h 152/96 128/78 reduction
200247 [Target MAP [Target MAP mL/min/1. nd NS Good
during trial (4 y) (540) (554) Female (149/95) (141/85) 6%
US[99] 92] 102-107] 73 m2
0.36 g/24h (-29; 31)48
ESRD
during the
4y Low BP Usual BP HR 0.76
trial [from nd nd 127 total NS Fair49
(2 y) [Target MAP [Target MAP GFR 33 (0.52; 1.10)
post-trial MDRD 2005 130/80 126/77
<92 <107 mL/min/1. 0.39 g/d
follow up] US[86] (131/80) (134/81)
(<125/75) or (<140/90) or 73 m2
ESRD [from
6y <98] <113] 432 408 268 (62%) HR 0.6850
post-trial <0.001 Fair51
(2 y) (432) (408) [286 (70%)] (0.57; 0.82)
follow up]
SCr 2.7
μmol/L
168 167 34 (20%) RR 0.8952
ESRD GFR 34 UPE 2.9 g/d NS Good
(169) (169) [38 (23%)] (0.59; 1.34)
mL/min/1.
73 m2
SCr 2.7
ESRD in pts
with 106 109 136/84 134/82 HR 0.94
2005 mo l BP BP GFR 36 UPE 1.8 g/d -- NS Fair
proteinuria (169) (169) (137/84) (130/80) (0.45; 1.96)
Italy[85] (36 mo) [DBP <90] [<130/80] mL/min/1.
<3g/24h
73 m2
SCr 2.7
ESRD in pts
μmol/L
with 62 58 HR 0.92
GFR 31 UPE 4.9 g/d -- NS Fair
proteinuria (169) (169) (0.45; 1.81)
mL/min/1.
≥3g/24h
73 m2
48 Adjusted
50 Adjusted
Supplemental Table 4. RCTs examining the effect of blood pressure targets in patients with CKD without DM [continuous outcomes] 53
Study Duration Baseline Baseline Achieved
Outcome Baseline Baseline ∆ P
Year Outcome GFR or SBP/DBP SBP/DBP Quality
(Units) Intervention Control Intervention Control Proteinuria Intervention Intervention value
Country (Treatment) SCr Intervention Intervention
(Control) [Control]
(Control) (Control)
Kidney function
Acute slope: Mean
∆GFR in difference
first 3 mo, (lower vs. <0.001 Good
mL/min/1.73 usual)
m2/y -1.82
Chronic
slope:
Male
∆GFR after AASK Lower BP Usual BP GFR 46 -2.11
4y 380 374 0.61g/24h 152/96 128/78 4655 NS Good
first 3 mo, 200254 [Target MAP [Target MAP mL/min/1. (-2.32)
(4 y) (540) (554) Female (149/95) (141/85) (45)
mL/min/1.73 US[99] 92] 102-107] 73 m2
0.36 g/24h
m2/y
Total
slope56:
∆GFR over -2.21
NS Good
4 y, (-1.95)
mL/min/1.73
m2/y
Acute slope,
↓GFR in
SCr 2.0
patients with MDRD MAP 90
Low BP Usual BP mg/dL
GFR 25-55 Study 1 4 mo 285 300 132/81 [126/77]59 38 -3.4
[MAP ≤92 [MAP ≤107 GFR 38 1.1 g/kg/d 0.01 Good
mL/min/1.73 1994 1995 (2 y) (285) (300) (132/82) (MAP 94 (39) (-1.9)
mmHg]57 mmHg]58 mL/min/1.
m2, US[46;79] [134/81])
73 m2
mL/min/4
mo

55 Primary outcome
56 The results of the blood pressure comparison differed significantly depending on the level of baseline proteinuria for the acute slope (P=0.008) and total slopes (P=0.004) but not for the chronic slope (P=0.16).
57 For patients ≥61, target was ≤98 mmHg
58 For patients ≥61, target was ≤113 mmHg
(Control) [Control]
(Control) (Control)
Chronic
slope, ↓GFR
in patients
with GFR 4 mo-3y -2.8
0.006 Good
25-55 (2 y) (-3.9)
mL/min/1.73
m2,
mL/min/y
Total slope,
↓GFR in
patients with
-10.7
GFR 25-55 NS Good
(-12.3)
mL/min/1.73
m2,
mL/min/3y
3y
Total slope,
(2 y)
↓GFR in
subgroup of
patients with Benefit of
nd nd nd nd nd nd -- 0.0260 Fair
GFR 25-55 lower BP
and
proteinuria
>0.25 g/d
Total slope,
↓GFR in SCr 2.0
MAP 90
patients with mg/dL
132 123 133/81 [126/77]61 19 -3.7
GFR 13-24 GFR 19 0.89 g/kd/d NS Good
(132) (123) (133/82) (MAP 94 (19) (-4.2)
mL/min/1.73 mL/min/1.
[134/81])
m2, 73 m2
MDRD
mL/min/y
Study 2 3y
Total slope,
1994 1995 (2 y)
↓GFR in
US[46;79]
subgroup of
patients with Benefit of
nd nd nd nd nd nd -- 0.0162 Fair
GFR 13-24 lower BP
and
proteinuria
>1 g/d
60 By interaction analysis
62 By interaction analysis
(Control) [Control]
(Control) (Control)
0.24 (IQR
Median rate
0.0001;
of ↓GFR, 34
0.56) NS Good
mL/min/1.73 SCr 2.7 (36)
[0.22 (IQR
m2/mo μmol/L
168 167 0.06; 0.55)]
GFR 34 UPE 2.9 g/d
(169) (169) 0.25
Median rate mL/min/1.
(0.0001;
of ↓CrCl, 73 m2 39
0.75) NS Good
mL/min/1.73 (39)
[0.26 (0.03;
m2/mo
0.53)]
Rate of
Median 19 Conventiona Intensified
↓GFR in pts REIN 2 2005 SCr 2.7 137/84 130/80
mo l BP BP 0.21 (-0.03;
with Italy[85] μmol/L (136/84) (134/82)
(36 y) [DBP <90] [<130/80] 106 109 36 0.40)
proteinuria GFR 36 UPE 1.8 g/d NS Fair
(169) (169) (33) [0.18 (0.03;
<3g/24h, mL/min/1.
0.49)]
mL/min/1.73 73 m2
m2/mo
Rate of
↓GFR in pts SCr 2.7
0.39 (0.03;
with μmol/L
62 58 31 0.98)
proteinuria GFR 31 UPE 4.9 g/d NS Fair
(62) (58) (42) [0.51 (0.16;
≥3g/24h, mL/min/1.
1.05)]
mL/min/1.73 73 m2
m2/mo
Proteinuria
%∆Proteinur Male 0.61;
Male
ia AASK Lower BP Usual BP GFR 46 Female 0.36
4y 380 374 0.61g/24h 152/96 128/78 -17%
(geometric 200263 [Target MAP [Target MAP mL/min/1. (Male 0.61; <0.001 Good
(4 y) (540) (554) Female 0.36 (149/95) (141/85) (+7%)
mean US[99] 92] 102-107] 73 m2 Female
g/24h
UPCR) 0.46)

Supplemental Table 5. General population RCTs comparing ARB vs. CCB in CKD subgroups with and without DM
Study Duration Baseline
Baseline Baseline Achieved P
Outcome Year Outcome SBP/DBP Events (%)
GFR or SCr Proteinuria SBP/DBP RR/OR/HR value
Country (Treatment) Intervention Control Intervention Control Interventio Intervention
Intervention (95% CI)
n [Control]
(Control)
(Control)
Mortality
CASE-J
3y 1376 1344 163/92 136/77 8 (1%) RR 0.6564
Sudden death 2009 Candesartan Amlodipine nd nd NS
(3 y) (1376) (1344) (163/92) (135/77) [12 (1%)] (0.27; 1.59)
Japan[87]
CV Events
Cerebrovascul 44 (3%) RR 1.0766
NS
ar events65 [40 (3%)] (0.70; 1.64)
1376 1344 99 (7%) HR 0.95
CV events NS
(1376) (1344) [102 (8%)] (0.73; 1.24)
Cardiac 30 (2%) RR 0.9268
NS
events67 [32 (2%)] (0.56; 1.50)
Cerebrovascul
ar events69 in 32 (3%) RR 1.0970
NS
patients with [29 (3%)] (0.66; 1.79)
CKD Stage 3 CASE-J
3y 163/92 136/77
CV events in 2009 Candesartan Amlodipine nd nd
(3 y) 1140 1125 (163/92) (135/77) 72 (6%) RR 1.0071
patients with Japan[87] NS
(1140) (1125) [71 (6%)] (0.73; 1.37)
CKD Stage 3
Cardiac
events72 in 26 (2%) RR 0.9573
NS
patients with [27 (2%)] (0.56; 1.62)
CKD Stage 3
Cerebrovascul
ar events74 in 64 61 1 (2%) RR 0.2475
NS
patients with (64) (61) [4 (7%)] (0.03; 2.07)
CKD Stage 4
65 New occurrence or reoccurrence of a stroke or transient ischemic attack
67 New occurrence, aggravation, or reoccurrence of heart failure, angina pectoris, or acute MI
Baseline Baseline Achieved P
Outcome Year Outcome SBP/DBP Events (%)
GFR or SCr Proteinuria SBP/DBP RR/OR/HR value
Country (Treatment) Intervention Control Intervention Control Interventio Intervention
Intervention (95% CI)
n [Control]
(Control)
(Control)
CV events in
9 (14%) RR 0.4876
patients with nd
[18 (30%)] (0.23; 0.98)
CKD Stage 4
Cardiac
events77 in 3 (5%) RR 2.8678
NS
patients with [1 (2%)] (0.31; 26.75)
CKD Stage 4
Kidney Function
1376 1344 19 (1%) RR 0.7180
Renal events79 NS
(1376) (1344) [26 (2%)] (0.40; 1.28)
Renal events81
CASE-J 1140 1125 14 (1%) RR 1.5482
in patients with 3y 163/92 136/77 NS
2009 Candesartan Amlodipine (1140) (1125) nd nd [9 (1%)] (0.67; 3.53)
CKD Stage 3 (3 y) (163/92) (135/77)
Japan[87]
Renal events83
64 61 3 (5%) RR 0.2084
in patients with nd
(64) (61) [14 (23%)] (0.06; 0.68)
CKD Stage 4
79 SCr ≥4.0 mg/dL, end stage renal disease, doubling of SCr
81 SCr ≥4.0 mg/dL, end stage renal disease, doubling of SCr
83 S ≥4.0 mg/dL, end stage renal disease, doubling of S
Cr Cr
Supplemental Table 6. General population RCTs comparing ACEI or ARB vs. control (active or placebo) in CKD subgroups with and without DM
[Control]
(Control) (Control)
Composite outcome
Kidney failure or
halving of GFR in GFR 50
1533 2613 106 (7%) RR 1.00
entire subgroup Lisinopril mL/min/1.73 nd nd nd NS
(1533) (2613) [180 (7%)] (0.78; 1.29)
with GFR <60 m2
mL/min/1.73 m2
Kidney failure or
halving of GFR in ALLHAT GFR 49
5y 501 881 61 (12%) RR 1.13
DM subgroup with 2006 Lisinopril Chlorthalidone mL/min/1.73 nd nd nd NS
(5 y) (501) (881) [96 (11%)] (0.81; 1.60)
GFR <60 Multi[50] m2
mL/min/1.73 m2
Kidney failure or
1032 1732 45 (4%) RR 0.89
non-DM subgroup Lisinopril mL/min/1.73 nd nd nd NS
(1032) (1732) [84 (5%)] (0.62; 1.30)
with GFR <60 m2
mL/min/1.73 m2
CV death, MI or
stroke in patients 509 471 19% HR 0.80
NS
with SCr ≥1.4 (509) (471) [26%] (0.59; 1.09)
HOPE 2001 4y UACR 0.73 139/79
mg/dL Ramipril Placebo nd nd
Multi [58] (4 y) mg/mmol (141/79)
CV death, MI or
3394 16% HR 0.75
stroke in patients nd
(3394) [21%] (0.64; 0.89)
CrCl ≤65 mL/min
CV mortality, MI
or
revascularization 157 SCr 1.6 25 (32%)
138/76 nd nd
in patients with (157) mg/dL [28 (36%)]
eGFR <45
PEACE Median
mL/min/m2
2006 2007 5y Trandolapril Placebo nd nd
CV mortality, MI
Multi[89;90] (5 y)
or
revascularization 1198 SCr 1.3 153 (25%)
135/77 nd nd
in patients with (1198) mg/dL [147 (25%)]
eGFR 45-59.9
mL/min/m2
[Control]
(Control) (Control)
Composite of CV
UACR 25-
death, nonfatal
SCr 1.05 177 μg/mg
MI, and coronary
332 310 mg/dL in women; 105 (32%) RR 1.1485
revascularization 139/79 NS
(1498) (1479) GFR 78 17-125 [86 (28%)] (0.90; 1.45)
in patients with
mL/min/m2 μg/mg in
low-medium
men
microalbuminuria
Composite of CV
death, nonfatal
UACR >177
MI, and coronary SCr 1.14
μg/mg in
revascularization 73 75 mg/dL 23 (32%) RR 1.0386
women; 147/82 nd
in patients with (1498) (1479) GFR 75 [23 (31%)] (0.64; 1.66)
>125 μg/mg
high mL/min/m2
in men
microalbuminuria-
macroalbuminuria
Dialysis, or
doubling of SCr in
RR 0.587
patients with 637 NS
(0.2; 1.2)
UACR ≥3.4
TRANSCEN
mg/mmol 5y
D, 2009 Telmisartan Placebo nd nd nd nd nd
Dialysis, or (5 y)
Multi[62]
doubling of SCr in
RR 0.688
patients with 1629 NS
(0.2; 1.3)
eGFR <60
mL/min/1.73 m2
First morbid event Val-HeFT Serum
89 with eGFR <60 2y 2890 GFR 47 499 (34%) HR 0.86
2009 Valsartan Placebo albumin 4.0 nd nd nd
(2 y) (2890) mL/min/m2 [549 (38%)] (0.74; 0.99)
mL/min/m2 Multi[10] g/dL
Mortality
All death in
509 471 13% HR 0.59
patients with SCr nd
(509) (471) [23%] (0.42; 0.83)
≥1.4 mg/dL HOPE 2001 4y UACR 0.73 139/79
Ramipril Placebo nd nd
All death in Multi [58] (4 y) mg/mmol (141/79)
3394 13% HR 0.80
patients CrCl ≤65 nd
(3394) [17%] (0.67; 0.96)
mL/min
87 Estimated from figure
89 Death sudden death with resuscitation, hospitalization for HF, administration of IV inotropic or vasodilator drugs for ≥4 h without hospitalization
[Control]
(Control) (Control)
Total mortality in
patients with 157 SCr 1.6 13 (17%)
138/76 nd nd
eGFR <45 (157) mg/dL [20 (26%)]
mL/min/m2
nd nd
Total mortality in
135/77 nd nd
eGFR 45-59.9 (1198) mg/dL [72 (12%)]
mL/min/m2
Total mortality in
patients with 1355 69 (nd) HR 0.7390
eGFR<60 nd nd nd 0.05
eGFR<60 PEACE Median (1355) [92 (nd)] (0.54; 1.00)
mL/min/m2 2006 2007 5y Trandolapril Placebo
Multi[89;90] (5 y) UACR 25-
All-cause mortality SCr 1.05 177 μg/mg
in patients with 332 310 mg/dL in women; 37 (11%) RR 0.8991
139/79 NS
low-medium (1498) (1479) GFR 78 17-125 [39 (13%)] (0.58; 1.35)
microalbuminuria mL/min/m2 μg/mg in
men nd
All-cause mortality UACR >177
SCr 1.14
in patients with μg/mg in
73 75 mg/dL 8 (11%) RR 0.6392
high women; 147/82 NS
(1498) (1479) GFR 75 [13 (17%)] (0.28; 1.44)
microalbuminuria- >125 μg/mg
mL/min/m2
macroalbuminuria in men
Death in patients Val-HeFT Serum

2y 2890 GFR 47 362 (25%) HR 1.01
with eGFR <60 2009 Valsartan Placebo albumin 4.0 nd nd NS
(2 y) (2890) mL/min/m2 [341 (24%)] (0.85; 1.20)
mL/min/m2 Multi[10] g/dL
CV Mortality
CV death in
509 471 9% HR 0.59
patients with SCr nd
(509) (471) [15%] (0.39; 0.91)
≥1.4 mg/dL HOPE 2001 4y UACR 0.73 139/79
Ramipril Placebo nd nd
CV death in Multi [58] (4 y) mg/mmol (141/79)
3394 8% HR 0.67
patients CrCl ≤65 nd
(3394) [11%] (0.53; 0.85)
mL/min
CV mortality in
PEACE Median
2006 2007 5y Trandolapril Placebo nd 138/76 nd -- nd
eGFR <45 (157) mg/dL [14 (8%)]
Multi[89;90] (5 y)
mL/min/m2
90 Adjusted
[Control]
(Control) (Control)
CV mortality in
135/77 -- nd
eGFR 45-59.9 (1198) mg/dL [36 (6%)]
mL/min/m2
UACR 25-
CV death in SCr 1.05 177 μg/mg
patients with low- 332 310 mg/dL in women; 17 (5%) RR 0.7293
139/79 NS
medium (1498) (1479) GFR 78 17-125 [22 (7%)] (0.39; 1.33)
microalbuminuria mL/min/m2 μg/mg in
men
UACR >177
CV death in SCr 1.14
μg/mg in
patients with high 73 75 mg/dL 3 (4%) RR 0.3994
women; 147/82 NS
microalbuminuria- (1498) (1479) GFR 75 [8 (11%)] (0.11; 1.40)
>125 μg/mg
macroalbuminuria mL/min/m2
in men
CV Events
CHD in entire
GFR 50
subgroup with 1533 2613 184 (12%) RR 1.00
Lisinopril mL/min/1.73 nd nd nd NS
GFR <60 (1533) (2613) [318 (12%)] (0.84; 1.20)
m2
mL/min/1.73 m2
CHD in DM ALLHAT
5y GFR 49
subgroup with 2006 Chlorthalidone 501 881 76 (15%) RR 1.03
(5 y) Lisinopril mL/min/1.73 nd nd nd NS
GFR <60 Multi[50] (501) (881) [132 (15%)] (0.78; 1.37)
m2
mL/min/1.73 m2
CHD in non-DM
GFR 49
subgroup with 1032 1732 108 (11%) RR 1.00
GFR <60 (1032) (1732) [186 (11%)] (0.79; 1.26)
m2
mL/min/1.73 m2
MI in patients with 509 471 14% HR 0.78
NS
SCr ≥1.4 mg/dL (509) (471) [19%] (0.54; 1.11)
MI in patients 3394 11% HR 0.74
nd
CrCl ≤65 mL/min (3394) [14%] (0.61; 0.91)
HOPE 2001 4y UACR 0.73 139/79
Stroke in patients Ramipril Placebo nd nd
Multi [58] (4 y) 509 471 mg/mmol (141/79) 4% HR 0.83
with SCr ≥1.4 NS
(509) (471) [6%] (0.44; 1.56)
mg/dL
Stroke in patients 3394 4% HR 0.69
nd
CrCl ≤65 mL/min (3394) [6%] (0.49; 0.91)
[Control]
(Control) (Control)
CV mortality or MI
in patients with 157 SCr 1.6 16 (20%)
138/76 nd nd
eGFR <45 (157) mg/dL [19 (24%)]
PEACE Median
mL/min/m2
2006 2007 5y Trandolapril Placebo nd nd
CV mortality or MI
Multi[89;90] (5 y)
in patients with 1198 SCr 1.3 67 (11%)
135/77 nd nd
eGFR 45-59.9 (1198) mg/dL [68 (11%)]
mL/min/m2
PREVEND
Relative risk
IT 2004 4y Albumin >50 5%
CV events Fosinopril Placebo nd nd nd nd nd reduction nd
Netherlands (4 y) mg/24h [13%]
60%
[12]
ESRD
Kidney failure in
GFR 50
entire subgroup 1533 2613 70 (5%) RR 0.98
with GFR <60 (1533) (2613) [124 (5%)] (0.73; 1.31)
m2
mL/min/1.73 m2
Kidney failure in
ALLHAT GFR 49
DM subgroup with 5y 501 881 41 (8%) RR 1.07
2006 Lisinopril Chlorthalidone mL/min/1.73 nd nd nd NS
GFR <60 (5 y) (501) (881) [68 (8%)] (0.73; 1.58)
Multi[50] m2
mL/min/1.73 m2
Kidney failure in
GFR 51
non-DM subgroup 1032 1732 29 (3%) RR 0.88
with GFR <60 (1032) (1732) [56 (3%)] (0.56; 1.38)
m2
mL/min/1.73 m2
In all
HOPE 2003 5y 333 SCr 1.578 2 (nd)
Dialysis Ramipril Placebo nd patients, nd -- nd
Multi[59] (5 y) (333) mg/dL [1 (nd)]
144/80
Kidney failure
Newly developed
renal insufficiency 3,238 231 (nd)
nd nd nd nd -- NS
defined as SCr (3,577) [243 (nd)]
≥1.4 mg/dL HOPE 2003 5y
Ramipril Placebo 3 (nd)
Doubling of Scr Multi[59] (5 y) -- nd
In all [2 (nd)]
333 SCr 1.578
nd patients, nd
(333) mg/dL 2 (nd)
Dialysis 144/80 -- nd
[3 (nd)]
Supplemental Table 7. Evidence profile of RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD without DM
applicability
kidney [1˚ in 2 RCTs] inconsistencies High Benefit for ACEI95 Critical
(539) (0) (0) (0)
outcomes (High) (0)
No important
Mortality inconsistencies Moderate Insufficient evidence for ACEI or ARB Critical
(High) (582) (0) (0) (-1)
(0)
CV mortality 0 RCTs -- -- -- -- -- -- -- Critical
No important
CV events inconsistencies Moderate Insufficient evidence for ACEI or ARB Critical
(High) (582) (0) (0) (-1)
(0)
No important
3 RCTs 483 No limitations Direct Sparse
ESRD inconsistencies Moderate Possible benefit for ACEI or ARB Critical
(High) (243) (0) (0) (-1)
(0)
Sparse
Kidney
1 RCT 131 Some limitations Direct (-1)
function N/A Very low Insufficient evidence for ACEI or ARB Critical
(High) (66) (-1) (0) Imprecision
(categorical)
(-1)
∆Kidney 5 RCTs Important Uncertainty about
803 No limitations None
function [1˚ in 1 RCT] inconsistencies directness Low Possible benefit for ACEI96 Moderate
(404) (0) (0)
(continuous) (High) (-1) (-1)
No important
Proteinuria 1 RCTs 179 Some limitations Direct Sparse
inconsistencies Moderate Benefit for ACEI High
(categorical) (High) (92) (-1) (0) (-1)
(0)
No important Uncertainty about
Proteinuria 4 RCTs 1069 No limitations None
inconsistencies directness Moderate Benefit for ACEI and ARB Moderate
(continuous) (High) (539) (0) (0)
(0) (-1)
Drug discontinuation: 1-17% for ACEI or ARB
and 1-14% for placebo (from 5 RCTs)
1458 Hyperkalemia: 0-2% for ACEI or ARB and 0-
Adverse events 6 RCTs Moderate
(746) 1% for Placebo (from 5 RCTs)
Early rise in creatinine: 0-6% in ACEI and
ARB and 0-4% in Placebo (from 4 RCTs)
1458
Total 6 RCTs
(746)
No benefit in individuals with no or little proteinuria from the lower target. High for no proteinuria
Possible benefit from lower target in individuals with proteinuria above 0.3-1 g/d. Moderate for proteinuria 0.3-1 g/d
Insufficient evidence for CV outcomes Moderate for CV outcomes
95 Insufficient evidence for ARB in the Li study in IgA nephropathy, but trend to benefit.
96 Insufficient evidence for ARB in the Li study in IgA nephropathy, but trend to benefit.
Supplemental Table 8. RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD without DM [categorical outcomes] 97
Baseline P
Outcome Year Outcome Proteinur SBP/DBP SBP/DBP No (%) RR/OR/HR Quality
Intervention Control Intervention Control GFR or SCr value
Country (Treatment) ia Intervention Intervention Intervention (95% CI)
Doubling of SCr Maschio
3y 300 283 SCr 2.1 UPE 1.8 142/87 137/85 31 (10%) RR 0.51100
or the need for 1996 Benazpril Placebo <0.001 Good
(3 y) (300) (283) mg/dL g/d (144/88) (145/87)98 [57 (20%)]99 (0.34; 0.77)
dialysis Multi[66]
GFR 26
Doubling of Benazepril mL/min/1.73
Hou 2006101 3y 112 112 UPE 1.6 153/87 126/75102 44 (41%)103 RR 0.68104
SCr, ESRD, or (SCr 3.0-5 Placebo m2 0.004 Good
China[43] (3 y) (112) (112) g/d (152/85) (126/75) [65 (60%)] (0.51; 0.89)
death mg/dL) SCr 4.0
mg/dL
GFR 40
Doubling of SCr GISEN 1997 3y 78 88 UPE 5.6 150/92 144/88 18 (23%) RR 0.51105
Ramipril Placebo mL/min/1.73 0.004 Good
or ESRD Italy[2] (3 y) (78) (88) g/24h (150/91) (145/90) [40 (45%)] (0.32; 0.81)
m2
HVKIN
GFR 78 MAP
ESRD & 2006106 2y 49 47 137/83 1 (2%)107 RR 0.24108
Valsartan Placebo mL/min/1.73 2.3 g/d 92.7 NS Good
doubling SCr Hong (2 y) (54) (55) (136/81) [4 (8%)] (0.03; 2.07)
m2 (100.9)
Kong[53]
Mortality
Maschio
3y 300 283 SCr 2.1 UPE 1.8 142/87 137/85 8 (3%) RR 7.55110
Death 1996 Benazpril Placebo nd111 Good
(3 y) (300) (283) mg/dL g/d (144/88) (145/87)109 [1 (0.4%)] (0.95; 59.96)
Multi[66]

98 Estimated from graph
99 Benefit of ramipril only statistically significant in people with 24 hour urine protein excretion ≥3g
101 All Chinese patients
103 Primary outcome
107 Primary outcome
111 The death rates in the benazepril group and placebo groups were 1 death per 93 patient-years and 1 per 656 patient-years, respectively (P=0.04).”
Baseline P
GFR 26
Benazepril mL/min/1.73
Hou 2006112 3y 112 112 UPE 1.6 153/87 126/75113 1 (1%)
Death (SCr 3.0-5 Placebo m2 -- nd Good
China[43] (3 y) (112) (112) g/d (152/85) (126/75) [0 (0%)]
mg/dL) SCr 4.0
mg/dL
Ruggenenti GFR 50
2.5 y 92 83 UPE 1.7 142/89 1 (0.01%)
Death 1999 Ramipril Placebo mL/min/1.73 nd -- nd Good
(2.5 y) (99) (87) g/d (145/90) [0 (0%)]
Italy[84] m2
GFR 40
GISEN 1997 3y 78 88 UPE 5.6 150/92 144/88 2 (3%) RR 2.26114
Death Ramipril Placebo mL/min/1.73 nd Good
Italy[2] (3 y) (78) (88) g/24h (150/91) (145/90) [1 (1%)] (0.21; 24.41)
m2
CV events
Non-fatal CV
9 (0.03%) RR 0.61116
events nd Good
[14 (0.05%)] (0.27; 1.38)
(Composite)
2 (1%) RR 0.94117
MI nd Good
[2 (1%)] (0.13; 6.65)
2 (1%) RR 0.63118
Stroke nd Good
Maschio [3 (1%)] (0.11; 3.74)
3y 300 283 SCr 2.1 UPE 1.8 142/87 137/85
Transient 1996 Benazpril Placebo 1 (0.3%) RR 0.94119
(3 y) (300) (283) mg/dL g/d (144/88) (145/87)115 nd Good
ischemic attack Multi[66] [1 (0.4%)] (0.06; 15.01)
1 (0.3%) RR 0.94120
Angina nd Good
[1 (0.4%)] (0.06; 15.01)
Hypertensive 0 (0%)
-- nd Good
crisis [4 (1%)]
Hypotension or 3 (1%) RR 0.94121
nd Good
dizziness [3 (1%)] (0.19; 4.64)

Baseline P
5 (4%) RR 0.63124
MI GFR 26 nd Good
[8 (7%)] (0.21; 1.85)
Benazepril mL/min/1.73
Hou 2006122 3y 112 112 UPE 1.6 153/87 126/75123 3 (3%) RR 0.60125
Heart failure (SCr 3.0-5 Placebo m2 nd Good
China[43] (3 y) (112) (112) g/d (152/85) (126/75) [5 (4%)] (0.15; 2.45)
mg/dL) SCr 4.0
2 (2%) RR 0.67126
Stroke mg/dL nd Good
[3 (3%)] (0.11; 3.91)
1 (0.01%)
Atrial fibrillation -- nd Good
[0 (0%)]
0 (0%)
Heart failure Ruggenenti Median GFR 50 -- nd Good
92 83 UPE 1.7 142/89 [2 (0.2%)]
1999 2.5 y Ramipril Placebo mL/min/1.73 nd
(99) (87) g/d (145/90) 1 (0.01%)
Stroke Italy[84] (2.5 y) m2 -- nd Good
[0 (0%)]
Uncontrolled 0 (0%)
-- nd Good
hypertension [1 (0.01%)]
Non-fatal CV
4 (5%) RR 1.50127
events nd Good
[3 (3%)] (0.35; 6.51)
(Composite)
GFR 40 1 (0.1%) RR 1.13128
MI GISEN 1997 3y 78 88 UPE 5.6 150/92 144/88 nd Good
Ramipril Placebo mL/min/1.73 [1 (0.01%)] (0.07; 17.74)
Italy[2] (3 y) (78) (88) g/24h (150/91) (145/90)
Aortic m2 1 (0.1%)
-- nd Good
aneurysm [0 (0%)]
Uncontrolled 2 (0.03%) RR 1.13129
nd Good
hypertension [2 (0.02%)] (0.16; 7.82)
ESRD
Ruggenenti Median GFR 50
Need for 99 87 UPE 1.7 142/89 9 (9%) RR 0.44130
1999 2.5 y Ramipril Placebo mL/min/1.73 nd 0.01 Good
dialysis (99) (87) g/d (145/90) [18 (20%)] (0.21; 0.93)
Italy[84] (2.5 y) m2

Baseline P
GFR 40
Need for GISEN 1997 3y 78 88 UPE 5.6 150/92 144/88 17 (21%) RR 0.66131
Ramipril Placebo mL/min/1.73 NS Good
dialysis Italy[2] (3 y) (78) (88) g/24h (150/91) (145/90) [29 (33%)] (0.40; 1.11)
m2
GFR 36
Conventio
mL/min/1.73
Need for Cinotti 2001 23 mo nal anti- 66 65 UPE 0.35 141/85 139/83132 2 (3%) RR 0.39133
Lisinopril m2 nd Fair
dialysis Italy[26] (24 mo) HTN (66) (65) mg/min (142/86) (137/82) [5 (8%)] (0.08; 1.96)
SCr 2.27
therapy
mg/dL
Kidney function
GFR 36
Conventio
mL/min/1.73
Cinotti 2001 23 mo nal anti- 66 65 UPE 0.35 141/85 139/83134 3 (5%) RR 0.42135
Halving of GFR Lisinopril m2 nd Fair
Italy[26] (24 mo) HTN (66) (65) mg/min (142/86) (137/82) [7 (11%)] (0.11; 1.56)
SCr 2.27
therapy
mg/dL
Proteinuria
Ruggenenti Median GFR 50
92 87 UPE 1.7 142/89 15 (15%) RR 0.53136
UPE ≥3g/24h 1999 2.5 y Ramipril Placebo mL/min/1.73 nd 0.005 Good
(99) (87) g/d (145/90) [27 (31%)] (0.30; 0.92)
Italy[84] (2.5 y) m2

Supplemental Table 9. RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD without DM [continuous outcomes] 137
Baseline Baseline ∆ P
Outcome Year Outcome GFR or SBP/DBP SBP/DBP Quality
Intervention Control Intervention Control Proteinuria Intervention Intervention value
(Control) [Control]
(Control) (Control)
Kidney function
Median slope
4.0 -0.09
of ↓1/SCr, GFR 26 0.02 Good
(3.9) (-0.11)
dL/mg/y Benazepril mL/min/1.
Hou 2006138 3y 112 112 153/87 126/75139
Median slope (SCr 3.0-5 Placebo 73m2 UPE 1.6 g/d
China[43] (3 y) (112) (112) (152/85) (126/75)
of ↓eGFR, mg/dL) SCr 4.0 26 6.8
0.006 Good
mL/min/1.73m2 mg/dL (26) (8.8)
/y
↓GFR, Ruggenenti GFR 50
2.5 y 99 87 142/89 50 -0.26
mL/min/1.73 1999 Ramipril Placebo mL/min/1. UPE 1.7 g/d nd NS Good
(2.5 y) (99) (87) (145/90) (43) (-0.29)
m2/mo Italy[84] 73 m2
Mean rate of GFR 40
GISEN 1997 3y 78 88 UPE 5.6 150/92 144/88 40 -0.53
↓GFR, Ramipril Placebo mL/min/1. 0.03 Good
Italy[2] (3 y) (78) (88) g/24h (150/91) (145/90) (37) (-0.88)
mL/min/month 73 m2
GFR 36
Conventio
GFR, ∆inulin mL/min/1.
Cinotti 2001 23 mo nal anti- 66 65 UPE 0.35 141/85 139/83140 36141 -1.31
clearance, Lisinopril 73m2 <0.04 Fair
Italy[26] (24 mo) HTN (66) (65) mg/min (142/86) (137/82) (35) (-6.71)
mL/min/1.73m2 SCr 2.27
therapy
mg/dL
HVKIN
GFR 78 MAP
Rate of ↓GFR, 2006142 2y 49 47 137/83 78 -13.54
Valsartan Placebo mL/min/1. 2.3 g/d 92.7 nd Good
mL/min/1.73m2 Hong (2 y) (54) (55) (136/81) (87) (-9.08)
73 m2 (100.9)
Kong[53]
Proteinuria
Maschio
3y 300 283 SCr 2.1 142/87 137/85 1.8 -29%
%∆UPE, g/24h 1996 Benazpril Placebo UPE 1.8 g/d nd Good
(3 y) (300) (283) mg/dL (144/88) (145/87)143 (1.8) (+9%)
Multi[66]

141 Primary outcome
(Control) [Control]
(Control) (Control)
GFR 26
Benazepril mL/min/1.
Hou 2006144 3y 112 112 153/87 126/75145 1.6 52%
Rate of ↓UPE (SCr 3.0-5 Placebo 73m2 UPE 1.6 g/d <0.001 Good
China[43] (3 y) (112) (112) (152/85) (126/75) (1.7) (20%)
mg/dL) SCr 4.0
mg/dL
GFR 40
GISEN 1997 3y 78 88 UPE 5.6 150/92 144/88 5.6 -55%
UPE, g/24h Ramipril Placebo mL/min/1. 0.002 Good
Italy[2] (3 y) (78) (88) g/24h (150/91) (145/90) (5.1) (nd)146
73 m2
ΔProteinuria, HVKIN -0.57
GFR 78 MAP nd Good
g/d 2006147 2y 49 47 137/83 2.3 (-0.38)
Valsartan Placebo mL/min/1. 2.3 g/d 92.7
%ΔProteinuria, Hong (2 y) (54) (55) (136/81) (1.8) -34
73 m2 (100.9) <0.001 Good
g/d Kong[53] (+15)

146 Placebo value not provided but stated as not being significantly different than baseline
Supplemental Table 10. Evidence profile of RCTs examining the effect of ACEI or ARB vs. CCB in patients with CKD without DM
applicability
Composite 3 RCTs148 No important
kidney [1˚ in 1 RCT] inconsistencies High Benefit for ACEI Critical
(646) (0) (0) (0)
outcomes (High) (0)
No important
Mortality inconsistencies Moderate Insufficient evidence for ACEI vs. CCB Critical
(High) (569) (0) (0) (-1)
(0)
No important
2 RCTs 801 Some limitations Direct Imprecision
CV mortality inconsistencies Low Insufficient evidence for ACEI vs. CCB Critical
(High) (516) (-1) (0) (-1)
(0)
Sparse
2 RCTs 801 No limitations Direct (-1)
CV events NA Low Insufficient evidence for ACEI vs. CCB Critical
(High) (516) (0) (0) Imprecision
(-1)
ESRD NA Moderate Benefit for ACEI Critical
(High) (436) (0) (0) (-1)
Kidney
function NA Moderate Benefit for ACEI High
(High) (309) (0) (0) (-1)
(categorical)
1356 Some limitations None No benefit for ACEI in overall slope. Possible
function [1˚ in 2 RCTs] inconsistencies directness Low Moderate
(798) (-1) (0) benefit after 3 months with ACEI.149
(continuous) (High) (0) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Proteinuria 7 RCTs 1463 Some limitations None
inconsistencies directness Low Benefit for ACEI or ARB Moderate
(continuous) (High) (851) (-1) (0)
(0) (-1)
Drug discontinuation: 16-38% for ACEI or
1343 ARB and 9-40% for CCB (from 4 RCTs)
(790) Hyperkalemia: 2-5% for ACEI or ARB and 0-
6% for CCB (from 3 RCTs)
7 RCTs 1463
Total
(High) (851)
Benefit for ACEI for kidney outcomes Moderate for kidney outcomes
Insufficient evidence for CV outcomes Low for CV outcomes
148 AASK study includes death in composite outcome.

149 Decision on chronic slope primarily based on AASK results.
Supplemental Table 11. RCTs examining the effect of ACEI or ARB vs. CCB in patients with CKD without DM [categorical outcomes]
Baseline P
↓GFR 50%
Risk
or 25
87 (27%) reduction
mL/min/1.73 0.005 Good
[56 (38%)] 38%
m2, ESRD or
(13; 56)151
death
↓GFR 50% Risk
or 25 70 (22%) reduction
0.01 Good
mL/min/1.73 [43 (29%)] 38%
m2 or ESRD (10; 58)152
GFR 46 UPCR Male
151/96 135/82 Risk
mL/min/1. 0.34
ESRD or (150/96) (133/81) 65 (20%) reduction
73 m2 Female 0.32 0.007 Good
death [45 (30%)] 41%
(14; 60)153
AASK 2001
First CV 4y 436 217
2006150 Ramipril Amlodipine
hospitalizati (≥3y) (436) (217) 61 (14%) HR 1.27
US[7;70] NS Good
on and [23 (11%)] (0.78; 2.06)
death
First CV
113 (26%) HR 0.73
hospitalizati 0.05 Good
[65 (30%)] (0.54; 1.00)
on or ESRD
↓GFR 50%
or 25
mL/min/1.73 Risk
m2, ESRD or reduction
nd UPCR>0.22 nd nd nd 0.003 Poor
death in 48%
sub-group (20; 66)
with
UPCR>0.22

151 Adjusted
152 Adjusted
153 Adjusted
Baseline P
RRT, D/C
due to
↓renal
function, SCr 2.05
↓50% GFR, mg/dL
AVER 2008 3y 130 128 UPE 1249 165/103 138/85 15%
doubling of Enalapril Amlodipine GFR 45 nd NS Good
EU[35] (3 y) (131) (132) mg/24h (165/102) (138/84) [21%]
SCr, or mL/min/1.
hospitalizati 73 m2
on for
transient
renal failure
Doubling SCr ESPIRAL
3y Nifedipine 80 68 SCr 2.8 155/96 135/83 27 (21%)154 OR 0.47
and/or 2001 Fosinipril 1.7 g/24h 0.01 Fair
(3 y) GITS (129) (112) mg/dL (158/96) (144/81) [40 (46%)] (0.26; 0.84)
dialysis Spain[64]
Mortality
Risk
AASK GFR 46 UPCR Male
4y 436 217 151/96 135/82 18 (4%) reduction
Death 2001155 Ramipril Amlodipine mL/min/1. 0.34 NS Good
(≥3y) (436) (217) (150/96) (133/81) [13 (6%)] 31%
US[7] 73 m2 Female 0.32
(-41; 66) 156
ESPIRAL
All cause 3y Nifedipine 80 68 SCr 2.8 155/96 135/83 4 (3%) RR 0.57157
2001 Fosinipril 1.7 g/24h nd Poor
mortality (3 y) GITS (129) (112) mg/dL (158/96) (144/81) [6 (5%)] (0.17; 1.93)
Spain[64]
GFR 44
Nephros mL/min/1.
2y 53 54 UA 506 154/99 134/85 0 (0%)
Death 2001 Ramipril Felodipine 73 m2 -- nd Fair
(nd) (53) (54) mg/24h (159/100) (139/88) [0 (0%)]
Multi[41] SCr 149
μmol/L
CV mortality
4y 436 217 151/96 135/82 12 (3%) HR 0.90
CV death 2006158 Ramipril Amlodipine mL/min/1. 0.34 NS Good
(≥3y) (436) (217) (150/96) (133/81) [7 (3%)] (0.35; 2.30)
US[70] 73 m2 Female 0.32
ESPIRAL
3y Nifedipine 80 68 SCr 2.8 155/96 135/83 2 (2%) RR 0.57159
CV mortality 2001 Fosinipril 1.7 g/24h nd Poor
(3 y) GITS (129) (112) mg/dL (158/96) (144/81) [3 (3%)] (0.10; 3.29)
Spain[64]
154 Primary outcome

156 Adjusted
Baseline P
CV events
89 (20%) HR 1.49
CV events NS Good
[28 (13%)] (0.90; 2.45)
Stroke 23 (5%) RR 1.27161
AASK GFR 46 UPCR Male nd Good
events 4y 436 217 151/96 135/82 [9 (4%)] (0.60; 2.70)
2006160 Ramipril Amlodipine mL/min/1. 0.34
(≥3y) (436) (217) (150/96) (133/81) 20 (5%) RR 1.24162
CHF events US[70] 73 m2 Female 0.32 nd Good
[8 (4%)] (0.56; 1.78)
19 (4%) RR 1.89163
CAD events nd Good
[5 (2%)] (0.72; 5.00)
ESPIRAL
3y Nifedipine 80 68 SCr 2.8 155/96 135/83 1 (1%)
CV events 2001 Fosinipril 1.7 g/24h -- nd Poor
(3 y) GITS (129) (112) mg/dL (158/96) (144/81) [0 (0%)]
Spain[64]
ESRD
Risk
4y 436 217 151/96 135/82 47 (15%) reduction
ESRD 2001164 Ramipril Amlodipine mL/min/1. 0.34 0.01 Good
(≥3y) (436) (217) (150/96) (133/81) [32 (21%)] 44%
US[7] 73 m2 Female 0.32
(13; 65)165
Kidney function
↓GFR 50% Risk
or 25 4y 309 145 151/96 135/82 44 (14%) reduction
2001166 Ramipril Amlodipine mL/min/1. 0.34 0.03 Good
mL/min/1.73 (≥3y) (436) (217) (150/96) (133/81) [29 (18%)] 41%
US[7] 73 m2 Female 0.32
m2 (5; 63)167

165 Adjusted
167 Adjusted
Supplemental Table 12. RCTs examining the effect of ACEI or ARB vs. CCB in patients with CKD without DM [continuous outcomes]
Baseline Baseline ∆
Outcome Year Outcome GFR or SBP/DBP SBP/DBP P value Quality
Intervention Control Intervention Control Proteinuria Intervention Intervention
(Control) [Control]
(Control) (Control)
Kidney function
Acute slope
– ΔGFR in
-0.16170
first 3 mo, <0.001 Good
(+4.03)
mL/min/1.73
m2/y
Chronic
slope –
ΔGFR after GFR 46 UPCR Male -2.07
4y 436 217 151/96 135/82 46169 0.002 Good
first 3 mo, mL/min/1. 0.34 (-3.22)
(≥3y) (436) (217) (150/96) (133/81) (46.8)
mL/min/1.73 73 m2 Female 0.32
m2/y
Difference in
total mean
GFR slope – 0.34171
NS Good
over 4 y, (0.41; 1.08)
mL/min/1.73 AASK 2001
m2/y 2002168 Ramipril Amlodipine
Chronic US[7;99]
slope –
ΔGFR after
first 3 mo, -1.22
0.21 Poor
mL/min/1.73 (-2.02)
m2/y in sub-
group with
UPCR≤0.22 3y
nd nd nd nd nd nd nd
Chronic (3 y)
slope –
ΔGFR after
first 3 mo, -3.55
0.003 Poor
mL/min/1.73 (-5.92)
m2/y in sub-
group with
UPCR>0.22

169 Primary outcome
170 Significant interactions of the treatment regimen with baseline proteinuria (P=0.001) and baseline GFR (P=0.006). Acute rise in GFR with amlodipine confined to people with UPCR ≤0.22.
171 Significant interactions of the treatment regimen with baseline proteinuria (P<0.001) and baseline GFR (P=0.003). Higher proteinuria = More beneficial effect of ramipril.
(Control) [Control]
(Control) (Control)
Total mean
slope over
-1.02
3y in sub- 0.006 Poor
(+0.20)
group with
UPCR≤0.22
Total mean
slope over
-3.60
3y in sub- 0.006 Poor
(-5.62)
group with
UPCR>0.22
∆GFR,
-4.44
mL/min/1.73 nd Good
(-2.63)
m2 45172
SCr 2.05
∆GFR, (47)
mg/dL -3.98
mL/min/1.73 130 128 UPE 1249 165/103 138/85 NS Good
GFR 45 (-4.92)
m2 (LOCF) (131) (132) mg/24h (165/102) (138/84)
mL/min/1.
+0.26
∆SCr, mg/dL 73 m2 nd Good
2.05 (+0.25)
∆SCr, mg/dL (2.00) +0.47
NS Good
(LOCF) (+0.57)
∆GFR in AVER 2008 3y
Enalapril Amlodipine
patients with EU[35] (3 y)
proteinuria 70 -12.41
nd nd nd nd nd NS Poor
>1g/d, (70) (-6.62)
mL/min/1.73
m2 (LOCF)
∆GFR in
patients with
proteinuria 70 -13.54
nd nd nd nd nd 0.04 Poor
>1g/d, (70) (-4.25)
mL/min/1.73
m2
ESPIRAL
3y Nifedipine 80 68 SCr 2.8 155/96 135/83 2.8 +0.75
∆SCr, mg/dL 2001 Fosinipril 1.7 g/24h 0.03 Fair
(3 y) GITS (129) (112) mg/dL (158/96) (144/81) (2.9) (+1.25)173
Spain[64]
172 Primary outcome

173 ERT estimated from graph
(Control) [Control]
(Control) (Control)
ΔGFR in
patients with
proteinuria GFR 51
61 59 150/95 126/76 51 +16.30
between 1- mL/min/1. 1.98 g/24h nd Poor
(61) (59) (151/95) (126/77) (51) (+15.5)
3g/24h, 73 m2
mL/min/1.73 Peng
1y
m2 2009174 Valsartan Benidipine
(1 y)
ΔGFR in China[76]
patients with
GFR 52
proteinuria 57 59 150/97 128/78 52 +16
mL/min/1. 0.61 g/24h nd Poor
>1g/24h, (57) (59) (157/96) (127/78) (50) (+17.8)
73 m2
mL/min/1.73
m2
2.04 +0.46
∆SCr, mg/dL JLIGHT nd Fair
12 mo 47 40 SCr 2.04 156/94 140/83 (1.97) (+0.33)176
2004175 Losartan Amlodipine 2.85 g/d
ΔCrCl, (12 mo) (58) (59) mg/dL (155/93) (134/80) 38 -6
Japan[44] nd Fair
mL/min (41) (-4)177
1.86 +0.13
∆SCr, mg/dL NS Poor
(2.00) (+0.09)
Slope of SCr 1.86 1.064
Del Vecchio -- NS Poor
1/SCr 48 wks 44 46 mg/dL 157/100 134/85 (0.720)
2004 Enalapril Manidipine 1.37 g/24h
∆CrCl, (48 wks) (69) (67) CrCl 46 (155/100) (138/86) 46.3 -1.9
Italy[30] NS Poor
mL/min mL/min (42.9) (-3.7)
Slope of -0.003
-- NS Poor
CrCl (-0.005)
Proteinuria
Male 34;
AASK GFR 46 UPCR Male Female 0.32
4y 436 217 151/96 135/82 -20%
ΔUPCR, (%) 2001178 Ramipril Amlodipine mL/min/1. 0.34 (Male 0.30; <0.001 Good
(≥3y) (436) (217) (150/96) (133/81) (+0.58%)
US[7] 73 m2 Female 0.32 Female
0.30)
∆UPE, SCr 2.05 -246
nd Fair
mg/24h mg/dL (-149)
AVER 2008 3y 130 128 UPE 1249 165/103 138/85 1249
∆UPE. Enalapril Amlodipine GFR 45
EU[35] (3 y) (131) (132) mg/24h (165/102) (138/84) (1296) -356
mg/24h mL/min/1. nd Fair
(-142)
(LOCF) 73 m2

175 All Japanese patients
(Control) [Control]
(Control) (Control)
ESPIRAL
ΔProteinuria 3y Nifedipine 80 68 SCr 2.8 155/96 135/83 1.7 -0.65
2001 Fosinipril 1.7 g/24h <0.05 Fair
, g/24h (3 y) GITS (129) (112) mg/dL (158/96) (144/81) (1.8) (0)179
Spain[64]
ΔProteinuria
in patients
with GFR 51
61 59 150/95 126/76 1.98 -1.19
proteinuria mL/min/1. 1.98 g/24h NS Poor
(61) (59) (151/95) (126/77) (2.01) (-0.82)
between 1- 73 m2
3g/24h, Peng
1y
g/24h 2009180 Valsartan Benidipine
(1 y)
ΔProteinuria China[76]
in patients
GFR 52
with 57 59 150/97 128/78 0.61 -0.43
mL/min/1. 0.61 g/24h <0.01 Poor
proteinuria (57) (59) (157/96) (127/78) (0.59) (-0.29)
73 m2
<1g/24h,
g/24h
UAE GFR 44
(statistical Nephros mL/min/1.
2y 53 54 UA 506 154/99 134/85 506 -0.103
analysis of 2001 Multi Ramipril Felodipine 73 m2 nd Fair
(nd) (53) (54) mg/24h (159/100) (139/88) (365) (+0.137)
transformed [41] SCr 149
values) μmol/L
SCr 1.86
Del Vecchio
∆Proteinuria 48 wks 44 46 mg/dL 157/100 134/85 1.37 -0.37
2004 Enalapril Manidipine 1.37 g/24h <0.05 Poor
, g/24h (48 wks) (69) (67) CrCl 46 (155/100) (138/86) (1.6) (+0.02)
Italy[30]
mL/min
%Δ JLIGHT
12 mo 47 40 SCr 2.04 156/94 140/83 2.85 -35.8%
Proteinuria, 2004181 Losartan Amlodipine 2.85 g/d nd Fair
(12 mo) (58) (59) mg/dL (155/93) (134/80) (2.50) (+1%)182
g/d Japan[44]

181 All Japanese patients
Supplemental Table 13. Evidence profile of RCTs examining the effect of ACEI vs. ARB in patients with CKD without DM
applicability
Sparse
Composite 1 RCT
343 No limitations Direct (-1)
kidney [1˚ in 1 RCT] NA Low Insufficient evidence Critical
(168) (0) (0) Imprecision
outcomes (High)
(-1)
Mortality 0 RCTs -- -- -- -- -- -- -- Critical
Sparse
1 RCT 343 No limitations Direct (-1)
CV events NA Low Insufficient evidence Critical
(-1)
Sparse
ESRD NA Very low Insufficient evidence Critical
(-1)
Kidney
function 0 RCTs -- -- -- -- -- -- -- High
(categorical)
∆Kidney
1 RCT 207 Some limitations Direct Sparse
function NA Very low No difference Moderate
(High) (101) (-1) (0) (-1)
(continuous)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
3 RCTs No important Uncertainty about
Proteinuria 632 No limitations None
[1˚ in 1 RCT] inconsistencies directness Moderate No difference Moderate
(continuous) (309) (0) (0)
(High) (0) (-1)
Drug discontinuation: 4-9% for ACE and 3-7%
for ARB (from 3 RCTs)
632 Hyperkalemia: 2-6% for ACEI and 2-6% for
(309) ARB (from 2 RCTs)
Early rise in creatinine: 2-3% in ACEI and 3%
in ARB (from 1 RCT)
632
Total 3 RCTs
(309)
Insufficient evidence for kidney and CV outcomes Low for kidney outcomes
Low for CV outcomes
Supplemental Table 14. RCTs examining the effect of ACEI vs. ARB in patient with CKD without DM [categorical outcomes]
Baseline P
Benazepril Losartan eGFR 31
84 87 150/86 124/76 15 (18%)185 RR 1.20186
[40 mg/d [200 mg/d mL/min/1. UPE 2.1 g/d NS Good
Doubling of (84) (87) (152/86) (124/76)184 [13 (16%)] (0.61; 2.36)
Hou 2007183 3y titrated] titrated] 73 m2
SCr, ESRD,
China[42] (3 y) Benazepril eGFR 31
or death Losartan 84 88 151/86 124/76 26 (31%)188 RR 1.05189
[10 mg/d mL/min/1. UPE 1.4 g/d NS Good
[50 mg/d fixed] (84) (88) (150/86) (124/76) 187 [26 (30%)] (0.67; 1.65)
fixed] 73 m2
CV events
84 87 150/86 124/76 10 (11%) RR 1.29192
[40 mg/d [200 mg/d mL/min/1. UPE 2.1 g/d nd Good
(84) (87) (152/86) (124/76)191 [8 (9%)] (0.54; 3.12)
Hou 2007190 3y titrated] titrated] 73 m2
CV events
China[42] (3 y) Benazepril eGFR 31
Losartan 84 88 151/86 124/76 [8 (9%)] RR 0.84194
[10 mg/d mL/min/1. UPE 1.4 g/d nd Good
[50 mg/d fixed] (84) (88) (150/86) (124/76) 193 [10 (11%)] (0.35; 2.02)
fixed] 73 m2
ESRD
Enalapril Losartan 61 eGFR 62 134/83 129/83 19 (31%) RR 2.08195
UPE 2.2 g/d nd Fair
20mg/d 200mg/d (69) 63 mL/min/y (132/84) (128/83) [7 (11%)] (1.27; 6.19)
Enalapril Losartan 40 (67) eGFR 61 132/86 130/84 9 (23%) RR 2.03196
Woo 2009 UPE 2.3 g/d NS Fair
6y 10mg/d 200mg/d (45) mL/min/y (132/84) (128/83) [7 (11%)] (0.82; 5.00)
ESRF Singapore
(6 y) Enalapril Losartan 61 eGFR 62 134/83 129/83 19 (31%) RR 1.49197
[98] UPE 2.2 g/d NS Fair
20mg/d 100mg/d (69) 43 mL/min/y (132/84) (128/84) [9 (20%)] (0.75; 42.97)
Enalapril Losartan 40 (45) eGFR 61 132/86 130/84 9 (25%) RR 1.08198
UPE 2.3 g/d NS Fair
10mg/d 100mg/d (45) mL/min/y (132/84) (128/84) [9 (20%)] (0.47; 2.43)

185 Primary outcome
188 Primary outcome
Supplemental Table 15. RCTs examining the effect of ACEI vs. ARB in patient with CKD without DM [continuous outcomes]
(Control) [Control]
(Control) (Control)
Kidney function
Enalapril 61 eGFR 62 134/83 129/83 62 -3.5
UPE 2.2 g/d nd Fair
20mg/d Losartan (69) 63 mL/min/y (132/84) (128/83) (64) (-0.7)
Enalapril 200mg/d 40 (67) eGFR 61 132/86 130/84 61 -3.2
Woo 2009 UPE 2.3 g/d nd Fair
ΔeGFR, 6y 10mg/d (45) mL/min/y (132/84) (128/83) (64) (-0.7)
Singapore
mL/min/y (6 y) Enalapril 61 eGFR 62 134/83 129/83 62 -3.5
[98] UPE 2.2 g/d nd Fair
20mg/d Losartan (69) 43 mL/min/y (132/84) (128/84) (61) (-3.5)
Enalapril 100mg/d 40 (45) eGFR 61 132/86 130/84 61 -3.2
UPE 2.3 g/d nd Fair
10mg/d (45) mL/min/y (132/84) (128/84) (61) (-3.5)
Proteinuria
84 87 150/86 124/76 2.1 50%
[40 mg/d [200 mg/d mL/min/1. UPE 2.1 g/d NS Good
(84) (87) (152/86) (124/76)200 (2.0) (53%)
titrated] titrated] 73 m2
%ΔProteinur Hou 2007199 3y
eGFR
ia, g/d China [42] (3 y) Benazepril Losartan
84 88 30.6 151/86 124/76 1.4 38%
[10 mg/d [50 mg/d UPE 1.4 g/d NS Good
(84) (88) mL/min/1. (150/86) (124/76) 201 (1.6) (41%)
fixed] fixed]
73 m2
Enalapril 61 eGFR 62 134/83 129/83 2.2 -0.5
UPE 2.2 g/d nd Fair
20mg/d Losartan (69) 63 mL/min/y (132/84) (128/83) (2.2) (-1)
Enalapril 200mg/d 40 (67) eGFR 61 132/86 130/84 2.3 -0.6
Woo 2009 UPE 2.3 g/d nd Fair
6y 10mg/d (45) mL/min/y (132/84) (128/83) (2.2) (-1)
ΔUPE, g/d Singapore
(6 y) Enalapril 61 eGFR 62 134/83 129/83 2.2 -0.5
[98] UPE 2.2 g/d nd Fair
20mg/d Losartan (69) 43 mL/min/y (132/84) (128/84) (2.0) (-0.4)
Enalapril 100mg/d 40 (45) eGFR 61 132/86 130/84 2.3 -0.6
UPE 2.3 g/d nd Fair
10mg/d (45) mL/min/y (132/84) (128/84) (2.0) (-0.4)
Geometric
↓UACR, Menne 2008 30 wks 40 42 CrCl 105 UACR 9.6 153/91 139/79 9.6202 mean
Lisinopril Valsartan NS Good
mg/mmol Multi[67] (30 wks) (43) (43) mg/mL mg/mmol (153/92) (137/81) (9.1) -41%
(-51%)

202 Primary outcome
Supplemental Table 16. Evidence profile of RCTs examining the effect of high vs. low dose ACEI in patients with CKD without DM
applicability
Composite 1 RCT
168 No limitations Direct Sparse
kidney [1˚ in 1 RCT] NA Moderate Benefit for high doses of ACEI Critical
(84) (0) (0) (-1)
outcomes (High)
Sparse
(-1)
Important
ESRD inconsistencies Low Possible benefit Critical
(High) (145) (0) (0) (-1)
(-1)
Kidney
function NA Moderate Benefit for higher doses of ACEI High
(High) (84) (0) (0) (-1)
(categorical)
∆Kidney No important Uncertainty about
2 RCTs 269 Some limitations Sparse
function inconsistencies directness Very low Possible benefit for higher dose ACEI Moderate
(High) (145) (-1) (-1)
(continuous) (0) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Proteinuria 2 RCTs 269 Some limitations Sparse
inconsistencies directness Very low Possible benefit for higher dose ACEI Moderate
(continuous) (High) (145) (-1) (-1)
(0) (-1)
Drug discontinuation: 6-7% vs. 4% for ACEI
(from 2 RCTs)
269 Hyperkalemia: 4% vs. 0% for ACEI (from 1
(145) RCT)
Early rise in creatinine: 3% vs. 2% in ACEI
(from 1 RCT)
269
Total 2 RCTs
(145)
Possible benefit for kidney outcomes in higher dose ACEI Low for kidney outcomes
Supplemental Table 17. RCTs examining the effect of high dose ACEI vs. low dose ACEI in patient with CKD without DM [categorical outcomes]
Baseline P
Risk
Doubling of Benazepril eGFR 31
Hou 2007203 3y Benazepril 84 84 149/86 124/76 15 (18%)205 reduction
SCr, ESRD, [40 mg/d mL/min/1. UPE 2.1 g/d 0.028 Good
China[42] (3 y) [10 mg/d fixed] (84) (84) (151/86) (124/76)204 [26 (31%)] 51%
or death titrated] 73 m2
(4.8; 73.3)
CV events
Benazepril eGFR 31
Hou 2007206 3y Benazepril 84 84 149/86 124/76 10 (11%) RR 1.25208
CV events [40 mg/d mL/min/1. UPE 2.1 g/d nd Good
China[42] (3 y) [10 mg/d fixed] (84) (84) (151/86) (124/76)207 [8 (9%)] (0.52; 3.01)
titrated] 73 m2
ESRD
Risk
Benazepril eGFR 31
Hou 2007209 3y Benazepril 84 84 149/86 124/76 reduction
ESRD [40 mg/d mL/min/1. UPE 2.1 g/d nd 0.04 Good
China[42] (3 y) [10 mg/d fixed] (84) (84) (151/86) (124/76)210 47%
titrated] 73 m2
(4.2; 72.1)
ESRD (CKD
Woo 2009211
Stage 5, 6y Enalapril Enalapril 61 40 eGFR 62 134/83 129/83 19 (31%) RR 1.38212 NS
Singapore UPE 2.2 g/d Fair
eGFR <15 (6 y) [20 mg/d] [10 mg/d] (69) (43) mL/min (132/86) (130/84) [9 (23%)] (0.70; 2.75) (0.09)
[98]
mL/min)
Kidney function
Benazepril eGFR 31 Risk
Doubling of Hou 2007213 3y Benazepril 84 84 149/86 124/76
[40 mg/d mL/min/1. UPE 2.1 g/d nd reduction 0.04 Good
SCr China[42] (3 y) [10 mg/d fixed] (84) (84) (151/86) (124/76)214
titrated] 73 m2 49%

205 Primary outcome
211 Patients with IgA nephropathy and moderate grade proteinuria (mean 2.2g/d)
Supplemental Table 18. RCTs examining the effect of high dose ACEI vs. low dose ACEI in patient with CKD without DM [continuous outcomes]
(Control) [Control]
(Control) (Control)
Kidney function
60%
Benazepril Benazepril eGFR 31
Hou 2007215 3y 84 84 149/86 124/76 35 reduction in
%↓CrCl [40 mg/d [10 mg/d mL/min/1. UPE 2.1 g/d 0.02 Fair
China[42] (3 y) (84) (84) (151/86) (124/76)216 (34) high vs. low
titrated] fixed] 73 m2
dose ACE
Woo 2009217
ΔeGFR, 6y Enalapril Enalapril 61 40 eGFR 62 134/83 129/83 62 -3.5
Singapore UPE 2.2 g/d nd Fair
mL/min (6 y) [20 mg/d] [10 mg/d] (69) (43) mL/min (132/86) (130/84) (61) (-3.2)
[98]
Proteinuria
Benazepril Benazepril eGFR 31
%ΔProteinur Hou 2007218 3y 84 84 149/86 124/76 2.1 50%
[40 mg/d [10 mg/d mL/min/1. UPE 2.1 g/d <0.05 Good
ia China[42] (3 y) (84) (84) (151/86) (124/76)219 (1.4) [38%)
Woo 2009220
6y Enalapril Enalapril 61 40 eGFR 62 134/83 129/83 2.2 -0.5
∆UPE, g/d Singapore UPE 2.2 g/d nd Fair
(6 y) [20 mg/d] [10 mg/d] (69) (43) mL/min (132/86) (130/84) (2.3) (-0.6)
[98]

Supplemental Table 19. Evidence profile of RCTs examining the effect of high vs. low dose ARB in patients with CKD without DM
applicability
Composite 1 RCT
kidney [1˚ in 1 RCT] NA Moderate Benefit in high doses of ARB Critical
(87) (0) (0) (-1)
outcomes (High)
Sparse
(-1)
No important
ESRD inconsistencies Moderate Possible benefit in high doses of ARB Critical
(High) (150) (0) (0) (-1)
(0)
Kidney
function NA Moderate Benefit in high doses of ARB High
(High) (87) (0) (0) (-1)
(categorical)
∆Kidney Important Uncertainty about
3 RCTs 608 No limitations None
function inconsistencies directness Low Possible benefit for higher dose ARB Moderate
(High) (317) (0) (0)
(continuous) (-1) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
[1˚ in 1 RCT] inconsistencies directness Moderate Benefit for higher dose ARB Moderate
(continuous) (317) (0) (0)
(High) (0) (-1)
Drug discontinuation: 3-11% vs. 3-15% for
ARB (from 3 RCTs)
608 Hyperkalemia: 6% vs. 3% for ARB (from 1
(317) RCT)
Early rise in creatinine: 3% vs. 3% for ARB
(from 1 RCT)
608
Total 3 RCTs
(317)
Possible benefit for kidney outcomes with higher dose ARB arm Moderate for kidney outcomes
Supplemental Table 20. RCTs examining the effect of high dose ARB vs. low dose ARB in patient with CKD without DM [categorical outcomes]
Baseline P
Risk
Doubling of Losartan eGFR 30
Hou 2007221 3y Losartan 87 88 152/86 124/76 13 (16%)223 reduction
SCr, ESRD, or [200 mg/d mL/min/1. UPE 2.0 g/d 0.022 Good
China[42] (3 y) [50 mg/d fixed] (87) (88) (149/86) (124/76)222 [26 (30%)] 53%
death titrated] 73 m2
(5.5; 74.1)
CV events
Losartan eGFR 30
Hou 2007224 3y Losartan 87 88 152/86 124/76 8 (9%) RR 0.81226
CV events [200 mg/d mL/min/1. UPE 2.0 g/d nd Good
China[42] (3 y) [50 mg/d fixed] (87) (88) (149/86) (124/76)225 [10 (11%)] (0.34; 1.95)
titrated] 73 m2
ESRD
Risk
Losartan eGFR 30
Hou 2007227 3y Losartan 87 88 152/86 124/76 reduction
ESRD [200 mg/d mL/min/1. UPE 2.0 g/d nd 0.05 Good
China[42] (3 y) [50 mg/d fixed] (87) (88) (149/86) (124/76)228 47%
titrated] 73 m2
(3.6; 76.9)
Woo 2009229
6y Losartan Losartan 63 43 eGFR 64 132/84 128/83 7 (11%) RR 0.53230
ESRD Singapore UPE 2.2 g/d nd Fair
(6 y) [200 mg/d] [100 mg/d] (67) (45) mL/min (132/85) (128/84) [9 (20%)] (0.21; 1.32)
[98]
Kidney function
Losartan eGFR 30 Risk
Hou 2007231 3y Losartan 87 88 152/86 124/76
Doubling of SCr [200 mg/d mL/min/1. UPE 2.0 g/d nd reduction 0.04 Good
China[42] (3 y) [50 mg/d fixed] (87) (88) (149/86) (124/76)232
titrated] 73 m2 50% (CI nd)

223 Primary outcome
Supplemental Table 21. RCTs examining the effect of high dose ARB vs. low dose ARB in patient with CKD without DM [continuous outcomes]
(Control) [Control]
(Control) (Control)
Kidney function
55%
reduction in
Losartan Losartan eGFR 30 intervention
Hou 2007233 3y 87 88 152/86 124/76 34
%↓CrCl [200 mg/d [50 mg/d mL/min/1. UPE 2.0 g/d group 0.04 Fair
China[42] (3 y) (87) (88) (149/86) (124/76)234 (34)
titrated] fixed] 73 m2 compared to
control
group
eGFR 55 24h urinary
Candesartan Candesartan 84 72 133/79 132/77 55 -10
mL/min/1. protein 2.83 NS Good
[64 mg] [16 mg] (90) (90) (133/77) (133/75) (52) (-9)
73 m2 g/d
%∆eGFR, eGFR 49 24h urine
mL/min/1.73 mL/min/1. protein 2.85 NS Good
[128 mg] [16 mg] (89) (90) (133/77) (133/75) (52) (-9)
m2 73 m2 g/d
eGFR 49 24h urine
mL/min/1. protein 2.85 nd Fair
SMART [128 mg] [64mg] (89) (90) (133/79) (132/77) (55) (-10)
30 wk 73 m2 g/d
2009
(30 wk) eGFR 55 24h urinary
Canada[22] Candesartan Candesartan 84 72 133/79 132/77 119 +9
[64 mg] [16 mg] (90) (90) (133/77) (133/75) (127) (+8)
73 m2 g/d
eGFR 49 24h urine
%∆SCr, Candesartan Candesartan 75 72 132/77 130/76 135 +7
µmol/L [128 mg] [16 mg] (89) (90) (133/77) (133/75) (127) (+8)
73 m2 g/d
eGFR 49 24h urine
Candesartan Candesartan 83 88 132/77 130/76 135 +7
[128 mg] [64mg] (89) (90) (133/79) (132/77) (119) (9)
73 m2 g/d
Woo 2009235
ΔeGFR, 6y Losartan Losartan 63 43 eGFR 64 132/84 128/83 64 -0.7
Singapore UPE 2.2 g/d nd Fair
mL/min/y (6 y) [200 mg/d] [100 mg/d] (67) (45) mL/min (132/85) (128/84) (61) (-3.5)
[98]
Proteinuria

(Control) [Control]
(Control) (Control)
Losartan Losartan eGFR 30
%ΔProteinur Hou 2007236 3y 87 88 152/86 124/76 2.0 53%
[200 mg/d [50 mg/d mL/min/1. UPE 2.0 g/d <0.05 Good
ia , g/d China[42] (3 y) (87) (88) (149/86) (124/76)237 (1.6) (41%)
eGFR 55 24h urinary
Candesartan Candesartan 84 72 133/79 132/77 2.83238 -22.23
mL/min/1. protein 2.83 0.0492 Good
[64 mg] [16 mg] (90) (90) (133/77) (133/75) (2.80) (-7.49)
73 m2 g/d
SMART eGFR 49 24h urine
∆24h urine 30 wk Candesartan Candesartan 75 72 132/77 130/76 2.85239 -36.95 <0.000
2009 mL/min/1. protein 2.85 Good
protein, g/d (30 wk) [128 mg] [16 mg] (89) (90) (133/77) (133/75) (2.80) (-7.49) 1
Canada[22] 73 m2 g/d
eGFR 49 24h urine
Candesartan Candesartan 83 88 132/77 130/76 2.85240 -36.95
[128 mg] [64mg] (89) (90) (133/79) (132/77) (2.83) (-22.23)
73 m2 g/d
Woo 2009241
6y Losartan Losartan 63 43 eGFR 64 132/84 128/83 2.2 -1
ΔUPE, g/d Singapore UPE 2.2 g/d nd Fair
(6 y) [200 mg/d] [100 mg/d] (67) (45) mL/min (132/85) (128/84) (2.0) (-0.4)
[98]

238 Primary outcome
239 Primary outcome
240 Primary outcome
Supplemental Table 22. RCTs examining the effect of ACEI vs. ß-blocker in patients with CKD without DM [categorical outcomes]
Baseline P
↓GFR 50%
or 25 Risk
mL/min/ reduction
0.04 Good
1.73 m2, 22%
ESRD or (1; 38) 243
death
↓GFR 50%
309 300 Risk
or 25 nd
(436) (441) reduction NS
mL/min/ Good
22% (0.07)
1.73 m2 or Male 0.61
AASK 2002 GFR 45 (-2; 41) 244
ESRD 4y g/24h 151/96 135/82
2006242 Ramipril Metoprolol mL/min/1.
(≥3 y) Female 0.41 (150/96) (133/81) Risk
US[70;99] 73 m2
ESRD or g/24h reduction
NS Good
death 21%
(-5; 40) 245
First CV
hospitalizati 61 (14%) HR 0.98246
NS Good
on and [65 (15%)] (0.69; 1.39)
436 441
death
(436) (441)
First CV
113 (30%) HR 0.87247
hospitalizati NS Good
[124 (28%)] (0.67; 1.13)
on or ESRD
Mortality
Male 0.61
AASK GFR 45
All cause 4y 309 300 g/24h 151/96 135/82 2%
2002248 Ramipril Metoprolol mL/min/1. nd NS Good
mortality (≥3 y) (436) (441) Female 0.41 (150/96) (135/81) (2%)
US[99] 73 m2
g/24h
CV mortality

243 Adjusted
244 Adjusted
245 Adjusted
246 Adjusted
247 Adjusted
Baseline P
309 300 Male 0.61 1%
CV mortality AASK 2002 GFR 45 nd NS Good
4y (436) (441) g/24h 151/96 135/82 (1%)
2006249 Ramipril Metoprolol mL/min/1.
(≥3 y) 436 441 Female 0.41 (150/96) (135/81) 12 (3%) HR 1.06250
CV death US[70;99] 73 m2 NS Good
(436) (441) g/24h [12 (3%)] (0.47; 2.39)
CV events
CV events 309 300 3%
nd NS Good
(composite) (436) (441) [3%]
89 (20%) HR 1.05†
CV events NS Good
Male 0.61 [85 (19%)] (0.72; 1.53)
AASK 2002 GFR 45
Stroke 4y g/24h 151/96 135/82 23 (5%) RR 1.01252
2006251 Ramipril Metoprolol mL/min/1. nd Good
events (≥3 y) 436 441 Female 0.41 (150/96) (135/81) [23 (5%)] (0.58; 1.78)
US[70;99] 73 m2
(436) (441) g/24h 20 (5%) RR 0.92253
CHF events nd Good
[22 (5%)] (0.51; 1.66)
19 (4%) RR 1.07254
CAD events nd Good
[18 (4%)] (0.57; 2.01)
ESRD
Male 0.61 Risk
AASK GFR 45
4y 309 300 g/24h 151/96 135/82 reduction
ESRD 2002255 Ramipril Metoprolol mL/min/1. nd NS Good
(≥3 y) (436) (441) Female 0.41 (150/96) (135/81) 22%
US[99] 73 m2
g/24h (-10; 45)256

250 Adjusted
256 Adjusted
Supplemental Table 23. RCTs examining the effect of ACEI vs. ß-blocker in patients with CKD without DM [continuous outcomes]
(Control) [Control]
(Control) (Control)
Kidney function
Acute slope
–∆GFR in
first 3 -0.23
0.01 Good
months, (-1.73)
mL/min/1.73
m2/y
Chronic
slope – Male 0.61
AASK GFR 45
∆GFR after 4y 309 300 g/24h 151/96 135/82 46258
2002257 Ramipril Metoprolol mL/min/1. -1.87
first 3 (≥3 y) (436) (441) Female 0.41 (150/96) (135/81) (46) NS Good
US[99] 73m2 (-2.12)
months, g/24h
mL/min/1.73
m2 /y
Total slope –
∆GFR over
-1.89
4 y, 0.007 Good
(-2.42)
mL/min/1.73
m2 /y

258 Primary outcome
Supplemental Table 24. RCTs examining the effect of ACEI + CCB vs. ACEI in patients with CKD without DM [categorical outcomes]
Baseline P
Mortality
GFR 43
Nephros mL/min/1.
2y Ramipril + 51 53 UAE 530 154/99 134/85 0 (0%)
Death 2001 Ramipril 73 m2 -- nd Fair
(nd) felodipine (51) (53) mg/24h (159/100) (139/88) [0 (0%)]
Multi[41] SCr 147
mol/L
Kidney function
Regression
coefficients
for overall
-3.2 (-6.8;
effect
0.4) 259
calculated -- NS Good
[-4.7 (-8.8;
from
-1.5)]
baseline
GFR
(mL/min/y)
GFR 43
Regression
Nephros mL/min/1.
coefficients 2y Ramipril + 51 53 UAE 530 154/99 134/85
2001 Ramipril 73 m2 -2.4260
for 1/SCr (nd) felodipine (51) (53) mg/24h (159/100) (139/88) -- NS Good
Multi[41] SCr 147 [-3.8]
(1/μmol/L/y)
mol/L
X 10 -3
Regression
coefficients
for long-term -3.8 (-6.8;
effect 0.9) 261
-- NS Good
calculated [-5.8 (-8.7;
from 3 0.3)]
month GFR
(mL/min/y)
259 Primary outcome

260 Primary outcome
261 Primary outcome
Baseline P
Regression
coefficients
-2.8262
for 1/SCr -- NS Good
[-2.1]
(1/μmol/L/y)
X 10-3
262 Primary outcome

Supplemental Table 25. RCTs examining the effect of ACEI + CCB vs. ACEI in patients with CKD without DM [continuous outcomes]
(Control) [Control]
(Control) (Control)
Proteinuria
UAE GFR 43
2y Ramipril + 51 53 UAE 530 154/99 134/85 530 -0.03
analysis of 2001 Ramipril 73 m2 NS Good
(nd) felodipine (51) (53) mg/24h (159/100) (139/88) (506) (-0.10)
transformed Multi[41] SCr 147
values) mol/L
Supplemental Table 26. RCTs examining the effect of ACEI + CCB vs. CCB in patients with CKD without DM [categorical outcomes]
Baseline P
Mortality
GFR 43
Nephros mL/min/1.
2y Ramipril + 51 54 UAE 530 154/99 134/85 0 (0%)
Death 2001 Felodipine 73 m2 -- nd Fair
(nd) felodipine (51) (54) mg/24h (159/100) (139/86) [1 (2%)]
Multi[41] SCr 147
mol/L
Kidney function
Regression
coefficients
for overall
-3.2 (-6.8;
effect
-0.4) 263
calculated -- NS Good
[-4.8 (-8.1;
from
-0.8)]
baseline
GFR
(mL/min/y)
GFR 43
Regression
Nephros mL/min/1.
coefficients 2y Ramipril + 51 54 UAE 530 154/99 134/85
2001 Felodipine 73 m2 -2.4264
for 1/SCr (nd) felodipine (51) (54) mg/24h (160/99) (139/86) -- NS Good
Multi[41] SCr 147 [-7.4]
(1/μmol/L/y)
mol/L
X 10 -3
Regression
coefficients
for long-term -3.8 (-6.8;
effect 0.9) 265
-- <0.05 Good
calculated [-6.0 (-11.0;
from 3 2.3)]
month GFR
(mL/min/y)
263 Primary outcome

264 Primary outcome
265 Primary outcome
Baseline P
Regression
coefficients
-2.8266
for 1/SCr -- NS Good
[-9.0]
(1/μmol/L/y)
X 10-3
266 Primary outcome

Supplemental Table 27. RCTs examining the effect of ACE + CCB vs. CCB in patients with CKD without DM [continuous outcomes]
(Control) [Control]
(Control) (Control)
Proteinuria
UAE GFR 43
2y Ramipril + 51 54 UAE 530 154/99 134/85 530 -0.03
analysis of 2001 Felodipine 73 m2 NS Good
(nd) felodipine (51) (54) mg/24h (159/100) (139/88) (365) (+0.14)
transformed Multi[41] SCr 147
values) mol/L
Baseline P
Mortality
CARTER
All-cause 12 mo 147 130 SCr 1.27 UPCR 1921 152/87 133/76 2 (1%) RR 0.59267
2007 Cilnidipine Amlodipine nd Good
mortality (12 mo) (179) (160) mg/dL mg/g (152/88) (135/78) [3 (2%)] (0.10; 3.47)
Japan[36]
CV mortality
CARTER
12 mo 147 130 SCr 1.27 UPCR 1921 152/87 133/76 0 (0%)
CV mortality 2007 Cilnidipine Amlodipine -- nd Good
(12 mo) (179) (160) mg/dL mg/g (152/88) (135/78) [2 (2%)]
Japan[36]
CV events
CVD events- 1 (1%) RR 0.29268
nd Good
all [3 (2%)] (0.03; 2.80)
Angina 1 (1%)
-- nd Good
pectoris [0 (0%)]
0 (0%)
MI -- nd Good
[1 (1%)]
Abdominal
0 (0%)
aortic -- nd Good
[1 (1%)]
rupture
CARTER
Sudden 12 mo 147 130 SCr 1.27 UPCR 1921 152/87 133/76 0 (0%)
2007 Cilnidipine Amlodipine -- nd Good
death (12 mo) (179) (160) mg/dL mg/g (152/88) (135/78) [1 (1%)]
Japan[36]
2 (1%) RR 0.44269
Stroke nd Good
[4 (3%)] (0.08; 2.37)
Stroke-
2 (1%) RR 0.59270
cerebral nd Good
[3 (2%)] (0.10; 3.47)
infarction
Stroke-
transient 0 (0%)
-- nd Good
ischemic [1 (1%)]
attack

(Control) [Control]
(Control) (Control)
Kidney function
CARTER
12 mo 147 130 SCr 1.27 UPCR 1921 152/87 133/76 1.27 +0.1
∆SCr, mg/dL 2007 Cilnidipine Amlodipine NS Good
(12 mo) (179) (160) mg/dL mg/g (152/88) (135/78) (1.29) (+0.16)
Japan[36]
Proteinuria
CARTER
∆UPCR, 12 mo 147 130 SCr 1.27 UPCR 1921 152/87 133/76 1921271 -612
2007 Cilnidipine Amlodipine <0.05 Good
mg/g (12 mo) (179) (160) mg/dL mg/g (152/88) (135/78) (1712) (+169)
Japan[36]
271 Primary outcome

Supplemental Table 30. RCTs examining the effect of ß-blocker vs. CCB in patients with CKD without DM [categorical outcomes]
Baseline P
↓GFR 50%
or 25 Risk
mL/min/ reduction
nd NS Good
1.73 m2, 20%
ESRD or (-10; 41)273
death
↓GFR 50%
300 145 Risk
or 25
(441) (217) reduction
mL/min/ nd NS Good
24%
1.73 m2 or Male
AASK 2002 46 (-9; 47) 274
ESRD 4y 0.63g/24h 150/95 135/81
2006272 Metoprolol Amlodipine mL/min/1.
(≥3 y) Female (150/96) (133/81) Risk
US[70;99] 73 m2
ESRD or 0.44 g/24h reduction
nd 0.003 Good
death 42%
(17; 60) 275
First CV
hospitalizati 65 (15%) HR 1.30276
NS Good
on and [23 (11%)] (0.81; 2.08)
441 217
death
(441) (217)
First CV
124 (28%) HR 0.85277
hospitalizati NS Good
[65 (30%)] (0.62; 1.14)
on or ESRD
Mortality
Male
46
All cause AASK 2002278 4y 300 145 0.63g/24h 150/95 135/81 2%
Metoprolol Amlodipine mL/min/1. nd NS Good
mortality US[99] (≥3 y) (441) (217) Female (150/96) (133/81) [2%]
73 m2
0.44 g/24h
CV mortality
AASK 2002 300 145 46 Male 150/95 135/81 1%
CV mortality 4y Metoprolol Amlodipine nd NS Good
2006279 (441) (217) mL/min/1. 0.63g/24h (150/96) (133/81) [1%]

273 Adjusted
274 Adjusted
275 Adjusted
276 Adjusted
277 Adjusted
Baseline P
US[70;99] (≥3 y) 441 217 73 m2 Female 12 (3%) HR 0.85280
CV death NS Good
(441) (217) 0.44 g/24h [7 (3%)] (0.33; 2.17)
CV events
Male
300 145 0.63g/24h 150/95 135/81 3%
CV events nd NS Good
(441) (217) Female (150/96) (133/81) [2%]
0.44 g/24h
85 (19%) HR 1.41282
CV events AASK 2002 46 NS) Good
4y [28 (13%)] (0.86; 2.32)
2006281 Metoprolol Amlodipine mL/min/1.
Stroke (≥3 y) Male 23 (5%) RR 1.26283
US[70;99] 73 m2 nd Good
events 441 217 0.57g/24h 150/96 133/81 [9 (4%)] (0.59; 2.67)
(441) (217) Female (150/95) (135/81) 22 (5%) RR 1.35284
CHF events nd Good
0.38g/24h [8 (4%)] (0.61; 2.99)
18 (4%) RR 1.77285
CAD events nd Good
[5 (2%)] (0.67; 4.71)
ESRD
Risk
Male
AASK 2002 46 reduction
4y 300 145 0.63g/24h 150/95 135/81 <0.00
ESRD 2006286 Metoprolol Amlodipine mL/min/1. nd 59% Good
(≥3 y) (441) (217) Female (150/96) (133/81) 1
US[70;99] 73 m2 (36;
0.44 g/24h
74%)287
280 Adjusted
282 Adjusted
287 Adjusted
Supplemental Table 31. RCTs examining the effect of ß-blocker vs. CCB in patients with CKD without DM [continuous outcomes]
Study Duration Baseline Baseline
Baseline Achieved Baseline ∆ P
Outcome Year Outcome GFR or SBP/DBP Quality
Intervention Control Intervention Control Proteinuria Intervention Intervention Intervention value
Country (Treatment) SCr Intervention
(Control)
Kidney function
Acute slope
– ∆ GFR in
first 3 -1.73
<0.001 Good
months, (+4.03)
mL/min/1.73
m2/y
Chronic
slope – Male
46
∆GFR after AASK 2002288 4y 300 145 0.63g/24h 150/95 135/81 46289
Metoprolol Amlodipine mL/min/1. -2.33
first 3 US[99] (≥3 y) (441) (217) Female (150/96) (133/81) (46) 0.02 Good
73 m2 (-3.22)
months, 0.44 g/24h
mL/min/
1.73 m2/y
Total slope –
∆GFR over
-2.68
4 y, 0.004 Good
(-1.60)
mL/min/1.73
m2/y
Proteinuria
%∆Proteinur Male 0.61;
Male
ia 46 Female 0.41
AASK 2002290 6 mo 300 145 0.63g/24h 150/95 135/81 -14%
(geometric Metoprolol Amlodipine mL/min/1. (Male 0.63; <0.001 Good
US[99] (6 mo) (441) (217) Female (150/96) (133/81) (+58%)
mean 73m2 Female
0.44 g/24h
UPCR) 0.44)

289 Primary outcome
Supplemental Table 32. RCTs examining the effect of central-acting agent vs. CCB in patients with CKD without DM [continuous outcomes]
(Control) [Control]
(Control) (Control)
Proteinuria
Vonend
Mean
2003 24 wk 89 82 SCr 285 Albuminuria 149/90 141/86291 1.3 +0.3
∆albuminuri Moxonidine Nitrendipine nd Good
Germany & (22 wk) (89) (82) μmol/L 1.3 g/24h (150/90) (137/80) (1.9) (+0.2)
a, g/24h
Hungary[96]

Supplemental Table 33. General population RCTs comparing ACEI + diuretic vs. placebo in CKD with DM subgroups [categorical outcomes]
Baseline Events (%) P
Outcome Year Outcome GFR or SBP/DBP SBP/DBP RR/OR/HR
Intervention Control Intervention Control Proteinuria Intervention value
Country (Treatment) SCr Intervention Intervention (95% CI)
[Control]
(Control) (Control)
Composite kidney outcome
New-onset
microalbuminuria292,
new onset
ADVANCE
nephropathy293, 4y Perindopril- 1063 1094 300 (28%) HR 0.87
2009 Placebo nd nd nd nd NS
doubling of SCr to (4 y) Indapamide (1063) (1094) [336 (31%)] (0.74; 1.02)
Multi[29]
>200 μmol/L or
ESRD in eGFR<60
mL/min/1.73 m2
Composite CV outcomes
Composite of major
eGFR 87
macrovascular 128 (10%) HR 0.89
2482 mL/min/1. UACR ≥30 148/82 nd NS
events294 in patients [142 11%)] (0.70; 1.13)
73 m2
with CKD 1 or 2
Composite of major
eGFR 51
macrovascular 126 (12%) HR 0.87
2033 mL/min/1. nd 147/80 nd NS
events295 in patients [143 (14%)] (0.68; 1.10)
73 m2
with CKD 3
Composite of major
ADVANCE
macrovascular 4y Perindopril- UACR 30- 133 (11%) HR 0.91
2010 Placebo nd NS
events296 in patients (4 y) Indapamide 150 mg/g [144 (12%)] (0.72; 1.15)
Multi[40]
with UACR 30-150
Composite of major
macrovascular UACR ≥150 61 (14%) HR 0.73
nd nd nd nd NS
events297 in patients mg/g [77 (18%)] (0.52; 1.02)
with UACR ≥150
Composite of major eGFR
macrovascular ≤60 130 (12%) HR 0.80
nd NS
events298 in patients mL/min/1. [163 (18%)] (0.63; 1.01)
with eGFR ≤60 73 m2
Relative risk MICRO- RRR 0.70
4y UACR ≥2
reduction of MI, HOPE 2000 Ramipril Placebo 814 326 nd nd nd nd (0.54; nd
(4 y) mg/mmol
stroke or CV death Multi[4] 0.90)299
292 UACR 30-300 μg/mg

293 New onset macroalbuminuria defined as UACR >300μg/mg, which required confirmation by a 2nd sample
294 CV death, non-fatal MI, or non-fatal stroke
[Control]
(Control) (Control)
Composite of
cardiovascular EUROPA GFR <75
4y HR 0.84
death, non-fatal MI 2007 Perindopril Placebo 6295 mL/min/1. nd 140/81 nd nd 0.023
(4 y) (0.72; 0.98)
and resuscitative Multi[19] 73 m2
cardiac arrest
Mortality
All-cause mortality in eGFR 87
114 (9%) HR 0.90
patients with CKD 1 2482 mL/min/1. UACR ≥30 148/82 nd NS
[126 (10%)] (0.70; 1.10)
or 2 73 m2
eGFR 51
All-cause mortality in 117 (12%) HR 0.87
2033 mL/min/1. nd 147/80 nd NS
patients with CKD 3 [135 (13%)] (0.67; 1.10)
73 m2
All-cause mortality in
ADVANCE UACR 30- 115 (12%) HR 0.84
patients with UACR 4y Perindopril- nd NS
2010 Placebo 150 mg/g [135 (14%)] (0.66; 1.08)
30-150 (4 y) Indapamide
Multi[40]
UACR ≥150 64 (12%) HR 0.87
patients with UACR nd NS
nd mg/g nd nd [69 (14%)] (0.62; 1.22)
≥150
eGFR
≤60 124 (12%) HR 0.80
patients with eGFR nd NS
mL/min/1. [155 (14%)] (0.64; 1.03)
≤60
73 m2
SCr 102 Risk
PROGRESS
Total death in CKD 4y Perindopril- μmol/L 153 reduction
2007 2008 Placebo 1757 nd 149/84 nd NS
patients (4 y) Indapamide CrCl 50 [138] -4%
Multi[69;77]
mL/min (-31; 17)
CV mortality
eGFR 87
CV death in patients 61 (5%) HR 0.77
2482 mL/min/1. UACR ≥30 148/82 nd NS
with CKD 1 or 2 [79 (6%)] (0.55; 1.07)
73 m2
eGFR 51
CV death in patients 66 (7%) HR 0.80
2033 mL/min/1. nd 147/80 nd NS
with CKD 3 [82 (8%)] (0.58; 1.11)
73 m2
ADVANCE
CV death in patients 4y Perindopril- UACR 30- 62 (5%) HR 0.79
2010 Placebo nd NS
with UACR 30-150 (4 y) Indapamide 150 mg/g [78 (7%)] (0.57; 1.10)
Multi[40]
CV death in patients UACR ≥150 40 (9%) HR 0.76
nd NS
with UACR ≥150 mg/g [49 (12%)] (0.50; 1.16)
nd nd nd
eGFR
CV death in patients ≤60 68 (6%) HR 0.73
nd nd
with eGFR ≤60 mL/min/1. [94 (9%)] (0.54; 1.00)
73 m2
[Control]
(Control) (Control)
SCr 102 Risk
PROGRESS
CV deaths in CKD 4y Perindopril- μmol/L 85 reduction
2007 2008 Placebo 1757 nd 149/84 nd NS
patients (4 y) Indapamide CrCl 50 [86] 7%
Multi[69;77]
mL/min (-24; 32)
CV events
Major coronary
69 (6%) HR 0.89
events in patients NS
[77 (6%)] (0.64; 1.23)
with CKD 1 or 2 eGFR 87
Major 2482 mL/min/1. UACR ≥30 148/82 nd
cerebrovascular 73 m2 56 (5%) HR 0.88
NS
events in patients [63 (5%)] (0.61; 1.26)
with CKD 1 or 2
Major coronary
75 (6%) HR 0.90
[82 (7%)] (0.66; 1.24)
with UACR 30-150
UACR 30-
Major nd nd nd nd
150 mg/g
cerebrovascular 58 (5%) HR 0.96
NS
with UACR 30-150
Major coronary
74 (7%) HR0.85
[86 (8%)] (0.62; 1.16)
with CKD 3 ADVANCE eGFR 51
4y Perindopril-
Major 2010 Placebo 2033 mL/min/1. nd 147/80 nd
(4 y) Indapamide
cerebrovascular Multi[40] 73 m2 51 (5%) HR 0.84
NS
with CKD 3
Major coronary
39 (9%) HR 0.95
[38 (9%)] (0.61; 1.49)
with UACR ≥150
UACR ≥150
Major nd nd nd nd
mg/g
NS
with UACR ≥150
Major coronary
77 (7%) HR 0.79
eGFR [98 (9%)] (0.59; 1.07)
with eGFR ≤60
≤60
Major nd nd nd nd
mL/min/1.
73 m2 NS
with eGFR ≤60
SCr 102 Risk
PROGRESS
Major CV event in 4y Perindopril- μmol/L 178 reduction
2007 2008 Placebo 1757 nd 149/84 nd nd
CKD patients (4 y) Indapamide CrCl 50 [222] 30%
Multi[69;77]
mL/min (14; 42)
[Control]
(Control) (Control)
Risk
Stroke in CKD 112 reduction
nd
patients [152] 35%
(17; 50)
Risk
46 reduction
Major CHD event NS
[52] 18%
(-22; 45)
Major vascular event
Incidence
in patients with CKD -- nd
rate 6.5
(per 100 person-y)
Relative risk
reduction of major RRR 30%
-- nd
vascular event in (14; 42)
patients with CKD
Major vascular event

ARR 8.8%
in patients with CKD -- nd
(4.2; 12.5)
over 5 y
Number needed to
treat for 5 y to
prevent one major NNT 11 nd nd
vascular event in
patients with CKD
Incidence rate of
stroke in patients
4.2 nd nd
with CKD (per 100
person-y)
Relative risk
RRR 35
reduction of stroke in nd nd
(17; 50)
patients with CKD
Absolute risk
reduction of stroke in ARR 7.1
nd nd
patients with CKD (3.5; 9.9)
over 5 y
Number needed to
treat for 5 y to
NNT 14 nd
prevent one stroke in
patients with CKD
Kidney Function
[Control]
(Control) (Control)
Progression of
nephropathy300 in 89 (6%) HR 0.69
0.0074
patient with [128 (9%)] (0.52; 0.91)
microalbuminuria
1441 1421
Regression of (1441) (1421)
nephropathy301 in ADVANCE 797 (55%) HR 1.15
4y Perindopril- 0.0067
patients with 2009 Placebo nd nd nd nd [698 (49%)] (1.04; 1.27)
(4 y) Indapamide
microalbuminuria Multi[29]
Regression of
nephropathy302 in 197 204 51 (26%) HR 1.08
NS
patients with (197) (204) [47 (23%)] (0.72; 1.60)
macroalbuminuria
New or worsening
eGFR 87
nephropathy303 in 75 (6%) HR 0.69
2482 mL/min/1. UACR ≥30 148/82 nd nd
patients with CKD 1 [105 (9%)] (0.51; 0.93)
73m2
or 2
New or worsening eGFR 51
64 (6%) HR 0.93
nephropathy304 in 2033 mL/min/1. nd 147/80 nd NS
[68 (7%)] (0.66; 1.31)
patients with CKD 3 73m2
New or worsening
nephropathy305 in ADVANCE UACR 30- 74 (6%) HR 0.75
4y Perindopril- nd NS
patients with UACR 2010 Placebo 150 mg/g [97 (8%)] (0.55; 1.01)
(4 y) Indapamide
30-150 Multi[40]
New or worsening
nephropathy306 in UACR ≥150 53 (12) HR 0.76
nd nd nd nd NS
patients with UACR mg/g [64 (15%)] (0.53; 1.09)
≥150
New or worsening eGFR
nephropathy307 in ≤60 72 (7%) HR 0.95
nd NS
patients with eGFR mL/min/1. [76 (7%)] (0.69; 1.32)
≤60 73m2
300 Worsening of at least on albuminuria stage (from normoalbuminuria or either micro- or macroalbuminuria or from micro- to macroalbuminuria)
301 Improvement of at least one albuminuria stage.
302 Improvement of at least one albuminuria stage.
303 Development of macroalbuminuria, doubling of serum creatinine to a level of at least 2.26 mg/dL, need for RRT or death due to renal disease
Supplemental Table 34. General population RCTs comparing ACEI + diuretic vs. placebo in CKD with DM subgroups [continuous outcomes]
Outcome Year Outcome GFR or SBP/DBP SBP/DBP
(Control) (Control)
(Control) (Control)
Kidney Function
∆eGFR in patients
with 1441 1421 1.1
nd NS
microalbuminuria, (1441) (1421) (1.4)
ADVANCE
mL/min 4y Perindopril-
2009 Placebo nd nd nd nd
∆eGFR in patients (4 y) Indapamide
Multi[29]
with 197 204 1.5
nd NS
macroalbuminuria, (197) (204) (2.7)
mL/min
Supplemental Table 35. General population RCTs comparing ARB or (ACE + ARB) vs. ACE in CKD subgroups with and without DM
[Control]
(Control) (Control)
Composite outcomes
Dialysis, 2673 RR 0.93308
Telmisartan NS
doubling of SCr (2673) (0.85; 1.15)
or death in
patients with
Ramipril
microalbuminur Ramipril + 2648 RR 0.99309
NS
ia or Telmisartan (2648) (0.87; 1.8)
macroalbuminu ONTARGET
4y
ria 2008 nd nd nd nd nd
(4 y)
Dialysis, Multi[63] 4046 RR 0.99 310
Telmisartan NS
doubling of SCr (4046) (0.85; 1.7)
or death in
patients with Ramipril
Ramipril + 3988 RR 1.17311
eGFR <60 NS
Telmisartan (3988) (0.97; 1.27)
mL/min/1.73
m2

Supplemental Table 36. General population RCTs comparing CCB vs. active control in CKD subgroups with and without DM
Study, Duration Baseline Achieved
Outcome Year, Outcome SBP/DBP SBP/DBP RR/OR/HR
[Control]
(Control) (Control)
Composite outcome
Kidney failure or
1516 2613 90 (6%) RR 0.85
entire subgroup Amlodipine mL/min/1.73 nd nd nd NS
(1516) (2613) [180 (7%)] (0.66; 1.11)
with GFR <60 m2
mL/min/1.73 m2
Kidney failure or
halving of GFR in ALLHAT GFR 50
5y 506 881 56 (11%) RR 1.02
DM subgroup with 2006 Amlodipine Chlorthalidone mL/min/1.73 nd nd nd NS
(5y) (506) (881) [96% (11%)] (0.72; 1.44)
GFR <60 Multi[50] m2
mL/min/1.73 m2
Kidney failure or
1010 1732 34 (3%) RR 0.68
non-DM subgroup Amlodipine mL/min/1.73 nd nd nd NS
(1010) (1732) [84 (5%)] (0.46; 1.03)
with GFR <60 m2
mL/min/1.73 m2
All-cause mortality In all CKD
and progression pts: SCr 140 In all CKD
ACCOMPLI Benazepril + In all CKD
of CKD312 in 3y Benazepril + 335 309 mol/L pts: UACR 28 (8%) HR 0.79
SH 2010 hydrochlorothia patients: nd NS
patients with (3 y) amlodipine (561) (532) eGFR 45 28.8 [30 (10%)] (0.47; 1.34)
Multi[15] zide 145/78
diabetic mL/min/1.73 mg/mmol
nephropathy m2
CV Events
CHD in entire
GFR 51
subgroup with 1516 2613 194 (13%) RR 1.06
Amlodipine mL/min/1.73 nd nd nd NS
GFR <60 (1516) (2613) [318 (12%)] (0.89; 1.27)
m2
mL/min/1.73 m2
ALLHAT
5y
2006 Chlorthalidone
(5 y)
Multi[50]
CHD in DM
GFR 50
subgroup with 506 881 83 (16%) RR 1.07
GFR <60 (506) (881) [132 (15%)] (0.81; 1.41)
m2
mL/min/1.73 m2
312 Time to first event of doubling of serum creatinine concentration or end-stage renal disease, defined as eGFR less than 15 mL/min/1·73 m² or need for chronic dialysis.
Study, Duration Baseline Achieved
Outcome Year, Outcome SBP/DBP SBP/DBP RR/OR/HR
[Control]
(Control) (Control)
CHD in non-DM
GFR 51
subgroup with 1010 1732 111 (11%) RR 1.05
GFR <60 (1010) (1732) [186 (11%)] (0.83; 1.33)
m2
mL/min/1.73 m2
ESRD
Kidney failure in
GFR 51
entire subgroup 1516 2613 65 (4%) RR 0.92
with GFR <60 (1516) (2613) [124 (5%)] (0.68; 1.24)
m2
mL/min/1.73 m2
Kidney failure in
ALLHAT GFR 50
DM subgroup with 5y 506 881 44 (9%) RR 1.11
2006 Amlodipine Chlorthalidone mL/min/1.73 nd nd nd NS
GFR <60 (5 y) (506) (881) [68 (8%)] (0.77; 1.63)
Multi[50] m2
mL/min/1.73 m2
Kidney failure in
GFR 51
non-DM subgroup 1010 1732 21 (2%) RR 0.66
with GFR <60 (1010) (1732) [56 (3%)] (0.40; 1.09)
m2
mL/min/1.73 m2
In all CKD
Progression of pts: SCr 140 In all CKD
ACCOMPLI Benazepril + In all CKD
CKD313 in patients 3y Benazepril + 335 309 mol/L pts: UACR 16 (5%) HR 0.78
SH 2010 hydrochlorothia patients: nd NS
with diabetic (3 y) amlodipine (561) (532) eGFR 45 28.8 [17 (6%)] (0.38; 1.56)
Multi[15] zide 145/78
nephropathy314 mL/min/1.73 mg/mmol
m2
313 Time to first event of doubling of serum creatinine concentration or end-stage renal disease, defined as eGFR less than 15 mL/min/1·73 m² or need for chronic dialysis.
314In all CKD patients, the progression of kidney disease (doubling of SCr or ESRD) was slower in the benazepril + amlodipine group (1.6 mL/min/1.73m2) vs. the benazepril + hydrochlorothiazide group (-2.3
mL/min/1.73m2) [p-0.001].
Supplemental Table 37. Evidence profile of RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM
(Treatment) across studies generalizability/ considerations Quality of evidence Qualitative and quantitative description of Importance
study design per outcome for outcome effect of outcome
applicability
kidney DM2 (High) inconsistencies High Benefit for ACEI or ARB Critical
(1330) (0) (0) (0)
outcomes [1˚ in 2 RCTs] (0)
No important
3 RCTs 3251 No limitations Direct None
DM2 inconsistencies High No difference
(High) (1719) (0) (0) (0)
(0) No difference of
Mortality Sparse ACEI or ARB vs. Critical
1 RCT 405 No limitations Direct (-1) Placebo
DM1 NA Low Insufficient evidence
(-1)
No important
CV mortality315 DM2 inconsistencies High No difference of ACEI or ARB vs. Placebo Critical
(High) (3768) (0) (0) (0)
(0)
6 RCTs No important
CV events DM2 (High) inconsistencies High No difference of ACEI or ARB vs. Placebo316 Critical
(4265) (0) (0) (0)
[1˚ in 1 RCT] (0)
Important
DM2 inconsistencies Moderate Possible benefit Possible benefit of
(High) (3773) (0) (0) (0)
ESRD (-1) ACEI or ARB vs. Critical
1 RCT 405 No limitations Direct Sparse Placebo
DM1 NA Moderate Possible benefit
(High) (206) (0) (0) (-1)
No important
DM2 inconsistencies High Benefit
Kidney (High) (3773) (0) (0) (0)
(0) Benefit of ACEI or
function High
1 RCT ARB vs. Placebo
(categorical) 405 No limitations Direct Sparse
DM1 (High) NA Moderate Benefit
(206) (0) (0) (-1)
[1˚ in 1 RCT]
2193 No limitations None
function DM2 (High) inconsistencies directness Moderate Possible benefit of ACEI or ARB vs. Placebo Moderate
(1188) (0) (0)
(continuous) [1˚ in 1 RCT] (0) (-1)
No important
Proteinuria 2 RCT 1104 No limitations Direct None
DM2 inconsistencies Moderate Benefit of ACEI or ARB vs. Placebo High
(categorical) (High) (729) (0) (0) (0)
(0)
3176 Some limitations None
DM2 (High) inconsistencies directness Low Benefit
(1772) (-1) (0)
Proteinuria [1˚ in 2 RCTs] (0) (-1) Benefit of ACEI or
Moderate
(continuous) 1 RCT Uncertainty about ARB vs. Placebo
137 No limitations Sparse
DM1 (High) NA directness Low Benefit
(67) (0) (-1)
[1˚ in 1 RCT] (-1)
315 Includes 1 study (Brenner 2001) with a composite outcome for CVD mortality and morbidity
316 The data is consistent with the use of ACEI or ARB in preventing congestive heart failure.
(Treatment) across studies generalizability/ considerations Quality of evidence Qualitative and quantitative description of Importance
study design per outcome for outcome effect of outcome
applicability
Drug discontinuation: 8-17% for ACEI or ARB
and 1-22% for placebo (from 4 RCTs)
8069 Hyperkalemia: 1-2% for ACEI or ARB and
(4196) 0.5-1% for placebo (from 2 RCTs)
Early rise in creatinine: 0.2-2% in ACEI and
ARB and 0-2% in Placebo (from 2 RCTs)
9240
DM2 7 RCTs
(4795)
Total
542
DM1 2 RCTs
(273)
Possible benefit for preventing ESRD, slowing loss of kidney function and reducing proteinuria. Moderate for kidney outcomes
No difference for CV outcomes317 High for CV outcomes
Supplemental Table 38. RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM [categorical outcomes] 318
Outcome Year Outcome GFR or SBP/DBP SBP/DBP RR/OR/HR Quality
[Control]
(Control) (Control)
Type 2 DM
Overt albuminuria
Risk
Composite of RENAAL
41 mo 751 762 SCr 1.9 UACR 1237 152/82 140/74 327 (44%)319 reduction
doubling of SCr, 2001 Losartan Placebo 0.02 Good
(41 mo) (751) (762) mg/dL mg/g (153/82) (142/74) [359 (47%)] 16%
ESRD or death Multi[20]
(2%; 28%)
Composite of RR 0.81
IDNT 2001 32 mo 579 569 SCr 1.7 UAE 2900 160/87 140/77 189 (33%)320
doubling of SCr, Irbesartan Placebo (0.67; 0.03 Good
Multi[52] (≥24 mo) (579) (569) mg/dL mg/24h (158/87) (144/80) [222 (39%)]
ESRD or death 0.99)321
Mortality
Type 2 DM
Overt albuminuria
Risk
RENAAL reduction
41 mo 751 762 SCr 1.9 UACR 1237 152/82 140/74 158 (21%)
Death 2001 Losartan Placebo -2% NS Good
(41 mo) (751) (762) mg/dL mg/g (153/82) (142/74) [155 (20%)]
Multi[20] (-27%;
19%)
RR 0.94
IDNT 2001 32 mo 579 569 SCr 1.7 UAE 2900 160/87 140/77 87 (15%)
Death Irbesartan Placebo (0.70; NS Good
Multi[52] (≥24 mo) (579) (569) mg/dL mg/24h (158/87) (144/80) [93 (16%)]
1.27)322
Microalbuminuria
RR 3.11323
Irbesartan 194 SCr 1.05 UAE 53.4 153/91 141/83 3 (2%)
(0.33; nd Fair
IRMA 2 300mg (194) mg/dL μg/min (153/90) (144/83) [1 (1%)]
All-cause 24 mo 201 29.63)
2001 Placebo
mortality (24 mo) (201) RR 1.03324
Multi[74] Irbesartan 195 SCr 1.0 UAE 58.3 153/90 143/83 0 (0%)
(0.02; nd Fair
150mg (195) mg/dL μg/min (153/90) (144/83) [1 (1%)]
51.69)
Type 1 DM
Overt albuminuria
CrCl 84
MAP
Lewis 1993 36 mo 206 199 mL/min UPE 2500 137/85 8 (4%) RR 0.55325
Death Captopril Placebo 96 nd Good
US[51] (36 mo) (207) (202) SCr 1.3 mg/24h (140/86) [14 (7%)] (0.24; 1.29)
(100)
mg/dL

319 Primary outcome
320 Primary outcome
321 Adjustment for base-line covariates was performed with the use of Cox proportional-hazards models with terms for the treatment assignment and the base-line covariates.
[Control]
(Control) (Control)
CV mortality
Type 2 DM
Overt albuminuria
DIABHYCA
47mo 2443 2469 SCr 89.2 145/82 142/80 141 (6%) RR 1.07
CV-mortality R 2004 Ramipril Placebo nd NS Good
(47mo) (2443) (2469) µmol/L (145/82) (142/80) [133 (5%)] (0.85; 1.35)
Multi[65]
RENAAL Risk
CV-mortality 41 mo 751 762 SCr 1.9 UACR 1237 152/82 140/74 158 (21%)
2001 Losartan Placebo reduction NS Good
and morbidity (41 mo) (751) (762) mg/dL mg/g (153/82) (142/74) [155 (20%)]
Multi[20] 10%
IDNT 2003 32 mo 574 565 SCr 1.67 160/87 140/77 37 (7%) HR 0.79
CV-mortality Irbesartan Placebo UPE 2.9 g/d NS Good
Multi[18] (≥24 mo) (579) (569) mg/dL (158/87) (144/80) [46 (8%)] (0.51; 1.22)
CV events
Type 2 DM
Overt albuminuria
Risk
50 (7%) NS
MI reduction Good
RENAAL [68 (9%)] (0.08)
41 mo 751 762 SCr 1.9 UACR 1237 152/82 140/74 28%
2001 Losartan Placebo
First (41 mo) (751) (762) mg/dL mg/g (153/82) (142/74) Risk
Multi[20] 89 (12%)
hospitalization reduction 0.005 Good
[127 (17%)]
for CHF 32%
RR 0.91
Composite of 138 (24%)
(0.72; NS Good
CVD [144 (25%)]
1.14)326
259 (in 30%
Composite CV of patients) HR 0.90
NS Good
events [284 (in 33% (0.74; 1.10)
of patients)]
80 (10% of
IDNT 2001 patients) HR 0.72
CHF 32 mo 579 569 SCr 1.7 160/87 140/77 0.048 Good
2003 Irbesartan Placebo UPE 2.9 g/d [113 (13% of (0.52; 1.00)
(≥24 mo) (579) (569) mg/dL (158/87) (144/80)
Multi[18;52] patients)]
48 (8% of
Myocardial patients) HR 0.90
NS Good
infarction [51 (9% of (0.60; 1.33)
patients)]
30 (5% of
patients) HR 1.01
CVA NS Good
[28 (5% of (0.61; 1.67)
patients)]
[Control]
(Control) (Control)
31 (5% of
Cardiac
patients) HR 0.80
revascularizatio NS Good
[39 (6% of (0.49; 1.30)
n
patients)]
Irbesartan 194 SCr 1.05 UAE 53.4 153/91 141/83 9 (5%) RR 0.52
IRMA 2 NS Fair
Composite CV 24 mo 300mg (194) 201 mg/dL μg/min (153/90) (144/83) [18 (9%)] (0.24; 1.12)
2001 Placebo
events (24 mo) Irbesartan 195 (201) SCr 1.0 UAE 58.3 153/90 143/83 nd
Multi[74] nd nd Fair
150mg (195) mg/dL μg/min (153/90) (144/83) [18 (9%)]
Microalbuminuria
Composite of DIABHYCA
47mo 2443 2469 SCr 89.2 145/82 142/80 362 (15%)327 RR 0.97
combined CV R 2004 Ramipril Placebo nd NS Good
(47mo) (2443) (2469) µmol/L (145/82) (142/80) [377 (15%)] (0.85; 1.11)
events Multi[65]
Trevisan RR 1.00
6 mo 54 54 SCr 1.0 UPE 89.3 147/90 142/87 1 (2%)
MI 1995 Ramipril Placebo (0.06; nd Good
(6 mo) (60) (62) mg/dL mg/24h (151/91) (149/87) [1 (2%)]
Italy[92] 15.58]
Normoalbuminuria
MAP MAP
Ravid 1993 84 mo 49 45 SCr 106.5 UAE 11.6 0 (0%) RR 0.31328
CV events Enalapril Placebo 98 100 nd Good
Israel[82] (84 mo) (nd) (nd) µmol/L mg/24h [1 (2%) (0.01; 7.33)
(nd) (102)
ESRD
Type 2 DM
Overt albuminuria
Risk
reduction
48 mo 751 762 SCr 1.9 UACR 1237 152/82 140/74 147 (20%)
ESRD 28% 0.002 Good
(48 mo) (751) (762) mg/dL mg/g (153/82) (142/74) [194 (26%)]
(11%;
42%)
ESRD in RENAAL SCr 2.1-
highest SCr 2001 2004 Losartan Placebo 248 263 3.6 mg/dL 154/82 89329 (36%) RR 0.80330
UACR 1737 <0.05
tertile (2.1-3.6 Multi[20;83] (248) (263) CrCl 28.9 (157/83) [118 (45%)] (0.65; 0.99)
mg//dL) 41 mo mL/min
nd Fair
ESRD in (41 mo) SCr 1.6-
middle SCr 264 244 2.0 mg/dL 152/83 45331 (17%) RR 0.77332
UACR 1045 NS
tertile (1.6-2.0 (264) (244) CrCl 39.1 (153/82) [54 (22%)] (0.54; 1.10)
mg//dL) mL/min
327 Primary outcome

329 No of events calculated by ERT
[Control]
(Control) (Control)
SCr 0.9-
ESRD in lowest
239 255 1.6 mg/dL 149/82 14333 (6%) RR 0.75334
SCr tertile (0.9- UACR 947 NS
(239) (255) CrCl 50.7 (149/83) [20 (8%)] (0.39; 1.44)
1.6 mg//dL)
mL/min
Risk
reduction:
1335 (3%)
ESRD in CKD2 95 82% NS
[6 (10%)]
(-64%;
98%)
Risk
SCr 1.9 UACR 1237 152/82 64336 (12%) reduction:
ESRD in CKD3 1030 0.02
mg/dL mg/g (153/82) [87 (17%)] 33%
(8%; 52%)
Risk
81337 (44%) reduction: NS
ESRD in CKD4 387
[101 (50%)] 23% (0.08)
(-4%; 43%)
RR 0.83
IDNT 2001 32 mo 579 569 SCr 1.7 UAE 2900 160/87 140/77 82 (14%)
ESRD Irbesartan Placebo (0.62; NS Good
Multi[52] (≥24 mo) (579) (569) mg/dL mg/24h (158/87) (144/80) [101 (18%)]
1.11)338
Microalbuminuria
DIABHYCA
47mo 2443 2469 SCr 89.2 145/82 142/80 4 (0.2%) RR 0.40
ESRD R 2004 Ramipril Placebo nd NS Good
(47mo) (2443) (2469) µmol/L (145/82) (142/80) [10 (0.4%)]] (0.13; 1.30)
Multi[65]
Type 1 DM
Overt albuminuria
CrCl 84
MAP
Dialysis or Lewis 1993 36 mo 206 199 mL/min UPE 2500 137/85 20 (10%) RR 0.62
Captopril Placebo 96 nd Good
transplantation US[51] (36 mo) (207) (202) SCr 1.3 mg/24h (140/86) [31 (15%)] (0.37; 1.06)
(100)
mg/dL
Kidney Function
Type 2 DM
Overt albuminuria

[Control]
(Control) (Control)
Risk
RENAAL
Doubling of SCr 41 mo 751 762 SCr 1.9 UACR 1237 152/82 140/74 162 (22%) reduction
2001 Losartan Placebo 0.006 Good
mg/dL (41 mo) (751) (762) mg/dL mg/g (153/82) (142/74) [198 (26%)] 25% (8%;
Multi[20]
39%)
RR 0.71
Doubling of SCr IDNT 2001 32 mo 579 569 SCr 1.7 UAE 2900 160/87 140/77 98 (17%)
Irbesartan Placebo (0.54; 0.009 Good
mg/dL Multi[52] (≥24 mo) (579) (569) mg/dL mg/24h (158/87) (144/80) [135 (24%)]
0.92)339
Microalbuminuria
DIABHYCA
Doubling SCr 47mo 2443 2469 SCr 89.2 145 /82 142/80 48 (2%) RR 0.81
R 2004 Ramipril Placebo nd NS Good
mg/dL (47mo) (2443) (2469) µmol/L (145/82) (142/80) [60 (2%)] (0.56; 1.12)
Multi[65]
Type 1 DM
Overt albuminuria
Risk
CrCl 84
MAP reduction
Doubling of Lewis 1993 36 mo 206 199 mL/min UPE 2500 137/85 25 (12%)340
Captopril Placebo 96 43% 0.014 Good
SCr, mg/dL US[51] (36 mo) (207) (202) SCr 1.3 mg/24h (140/86) [43 (21%)]
(100) (6%; 65%)
mg/dL 341
Proteinuria
Type 2 DM
Microalbuminuria
↑30% from Irbesartan 194 SCr 1.05 UAE 53.4 153/91 141/83 10 (5%)342 HR 0.32
IRMA 2 <0.001 Good
baseline and 24 mo 300mg (194) 201 mg/dL μg/min (153/90) (144/83) [30 (15%)] (0.15; 0.65)
2001 Placebo
UAE >200 (24 mo) Irbesartan 195 (201) SCr 1.0 UAE 58.3 153/90 143/83 19 (10%)343 HR 0.56
Multi[74] 0.05 Good
μg/min 150mg (195) mg/dL μg/min (153/90) (144/83) [30 (15%)] (0.31; 0.99
Transition rates 340 174 SCr 0.8 UACR 171 138/78 130/73 67 (20%) RR 0.39344 <0.000
Telmisartan Good
from incipient (nd) (nd) mg/dL mg/g (137/77) (132/74) [87 (50%)] (0.30; 0.51) 1
to overt Telmisartan 168 174 SCr 0.8 UACR 172 138/78 128/72 28 (17%) RR 0.33345 <0.000
nephropathy Good
INNOVATIO 80 mg (nd) (nd) mg/dL mg/g (137/77) (132/74) [87 (50%)] (0.23; 0.48) 1
16mo
(UACR >300 N 2007 Placebo
(≥12mo) Telmisartan 172 174 SCr 0.8 UACR 171 137/78 132/74 39 (23%) RR 0.45346 <0.000
mg/g and Japan[55] Good
↑≥30%) 40 mg (nd) (nd) mg/dL mg/g (137/77) (132/74) [87 (50%)] (0.33; 0.62) 1
Transition rate 109 54 SCr 0.8 UACR 171 132/77 12373 18 (17%) RR 0.37347
Telmisartan <0.01
in (nd) (nd) mg/dL mg/g (128/73) (128/75) [24 (44%)] (0.22; 0.62)
340 Primary outcome
341 Adjustments for differences in mean arterial pressure
342 Primary outcome
343 Primary outcome
[Control]
(Control) (Control)
normotensive Telmisartan 51 54 SCr 0.8 UACR 171 133/78 123/72 6 (11%) RR 0.26348
<0.01 Good
patients 80 mg (nd) (nd) mg/dL mg/g (128/73) (128/75) [24 (44%)] (0.12; 0.59)
Telmisartan 58 54 SCr 0.8 UACR 171 131/75 122/73 12 (21%) RR 0.47349
<0.01 Good
40 mg (nd) (nd) mg/dL mg/g (128/73) (128/75) [24 (44%)] (0.26; 0.84)
RR
340 174 SCr 0.8 UACR 171 138/78 130/73 58 (17%) 14.84350
Telmisartan <0.001 Good
(nd) (nd) mg/dL mg/g (137/77) (132/74) [2 (1%)] (3.67;
60.05)
RR
Micaroalbumin Telmisartan 168 174 SCr 0.8 UACR 172 138/78 128/72 36 (21%) 18.64351
<0.001 Good
uria remission 80 mg (nd) (nd) mg/dL mg/g (137/77) (132/74) [2 (1%)] (4.56;
76.21)
RR
Telmisartan 172 174 SCr 0.8 UACR 171 137/78 132/74 22 (13%) 11.13352
<0.001 Good
40 mg (nd) (nd) mg/dL mg/g (137/77) (132/74) [2 (1%)] (2.66;
46.60)

Supplemental Table 39. RCTs examining the effect of ACEI or ARB vs. placebo in patient with CKD and DM [continuous outcomes] 353
(Control) (Control)
(Control) (Control)
Kidney Function
Type 2 DM
Overt albuminuria
Median rate of
-4.4
↓GFR /CrCl, nd 0.01 Good
(-5.2)
ml/min/1.73 m RENAAL 41 mo 751 762 SCr 1.9 UACR 1237 152/82 140/74
Losartan Placebo
Change in 2001 Multi[20] (41 mo) (751) (762) mg/dL mg/g (153/82) (142/74)
-0.056
slope of 1/Scr , nd 0.01 Good
(-0.069)
dL/mg/y
Microalbuminuria
Irbesartan 194 SCr 1.05 153/91 141/83 108 -6354
UACR 53.4 NS Fair
ΔGFR /CrCl, IRMA 2 2001 24 mo 300 mg (194) 201 mg/dL (153/90) (144/83) (109) (-4)
Placebo
ml/min/1.73 m2 Multi[74] (24 mo) Irbesartan 195 (201) SCr 1.0 153/90 143/83 110 -5355
UACR 58.3 NS Fair
150 mg (195) mg/dL (153/90) (144/83) (109) (-4)
MAP MAP
Ravid 1993 60 mo 48 42 SCr 106.5 UAE 142.7 106.3356 2.0357
∆SCr, µmol/L Enalapril Placebo 98 100 nd Good
Israel[82] (60 mo) (nd) (nd) µmol/L mg/24h (101.6) (14.4)
(nd) (102)
Proteinuria
Type 2 DM
Overt albuminuria
RENAAL 41 mo 751 762 SCr 1.9 UACR 1237 152/82 140/74 1237mg/g -35%
%∆UACR Losartan Placebo <0.001 Good
2001 Multi[20] (41 mo) (751) (762) mg/dL mg/g (153/82) (142/74) (1261mg/g) (+20%)21
Microalbuminuria
Irbesartan 194 SCr 1.0 UAE 53.4 153/91 141/83 -47%
53.4 <0.001 Fair
%ΔProteinuria, IRMA 2 2001 24 mo 300 mg (194) 201 mg/dL μg/min (153/90) (144/83) (+10%)358
Placebo
µg/min Multi[74] (24 mo) Irbesartan 195 (201) SCr 1.0 UAE 58.3 153/90 143/83 -9%
58.3 <0.001 Fair
150 mg (195) mg/dL μg/min (153/90) (144/83) (+10%)359
Agha 2009 6mo 190 171 SCr 1.2 UAE 102 134/82 131/79 102360 54.4 <0.000
↓UACR, mg/dL Losartan Placebo Poor
Pakistan[6] (6mo) (193) (190 mg/dL mg/dL (136/83) (134/81) (105) (0.8) 1
∆Proteinuria, Trevisan 1995 6 mo 54 54 SCr 1.0 147/90 142/87 62 -9

Ramipril Placebo 62 µg/min <0.01 Good
µg/min Italy[92] (6 mo) (60) (62) mg/dL (151/91) (149/87) (65) (+18)

354 Calculated by ERT from graph
356 Primary outcome
360 Primary outcome
(Control) (Control)
(Control) (Control)
MAP MAP
∆Albuminuria, Ravid 1993 60 mo 48 42 SCr 106.5 UAE 142.7 142.7 -3.0
Enalapril Placebo 98 100 nd Good
mg/24h Israel[82] (60 mo) (nd) (nd) µmol/L mg/24h (123.1) (+189.3) 361
(nd) (102)
340 174 SCr 0.8 UACR 171 138/78 130/73 172 -48.3 <0.000
Telmisartan Good
(nd) (nd) mg/dL mg/g (137/77) (132/74) (171) (+40.9) 1
∆UACR after INNOVATION
16mo Telmisartan 168 174 SCr 0.8 UACR 172 138/78 128/72 172 -58.8 <0.000
adjustment for 2007 Placebo Good
(≥12mo) 80 mg (nd) (nd) mg/dL mg/g (137/77) (132/74) (171) (+40.9) 1
SBP, mg/g Japan[55]
Telmisartan 172 174 SCr 0.8 UACR 171 137/78 132/74 173 -37.9 <0.000
Good
40 mg (nd) (nd) mg/dL mg/g (137/77) (132/74) (171) (+40.9) 1
Type 1 DM
Microalbuminuia
CrCl 80
MAP
%∆Proteinuria, Laffel 1995 24 mo 67 70 mL/min UPE 89.3 118/78 62362 -42%363
Captopril Placebo 92 ≤0.05 Good
µg/min US[49] (24 mo) (70) (73) SCr 1.1 mg/24h (130/82) (62) (+14%)
(92)
mg/dL

362 Primary outcome
363 Primary outcome
Supplemental Table 40. Evidence profile of RCTs examining the effect of ACEI or ARB vs. Dihydropyridine CCB in patients with CKD and Type 2 DM
applicability
Composite 1 RCT
kidney (High) NA Moderate Benefit ACEI or ARB vs. CCB Critical
(579) (0) (0) (-1)
outcomes [1˚ in 1 RCT]
Mortality NA Moderate No difference for ACEI or ARB vs. CCB Critical
(High) (579) (0) (0) (-1)
No important
2 RCTs 1229 No limitations Direct Imprecision Insufficient evidence for ACEI or ARB vs.
CV mortality inconsistencies Moderate Critical
(High) (623) (0) (0) (-1) CCB
(0)
No important
CV events inconsistencies High No difference for ACEI or ARB vs. CCB364 Critical
(High) (782) (0) (0) (0)
(0)
ESRD NA Moderate Possible benefit for ACEI or ARB vs. CCB Critical
(High) (579) (0) (0) (-1)
Kidney
function NA Moderate Benefit for ACEI or ARB vs. CCB High
(High) (579) (0) (0) (-1)
(categorical)
∆Kidney
function 0 RCTs -- -- -- -- -- -- -- Moderate
(continuous)
Sparse
1 RCT
Proteinuria 117 Serious limitations Direct (-1) Insufficient evidence for ACEI or ARB vs.
(High) NA Very low High
(categorical) (53) (-2) (0) Imprecision CCB
[1˚ in 1 RCT]
(-1)
(High) inconsistencies directness Moderate Benefit for ACEI or ARB vs. CCB Moderate
(continuous) (449) (0) (0)
[1˚ in 4 RCTs] (0) (-1)
Drug discontinuation: 7-13% for ACEI (from 3
RCTs) and 6-9% in CCB (from 2 RCTs)
1978 Hyperkalemia: 2% for ACEI or ARB and 0.5%
(985) for CCB (from 1 RCT)
Early rise in creatinine: 0.2% in ACEI and 0%
in CCB (from 1 RCT)
3466
Total 7 RCTs
(1739)
Possible benefit for ACEI or ARB in preventing ESRD, slowing loss of kidney function and reducing Moderate for kidney outcomes
proteinuria Moderate for cardiovascular outcomes
No difference for CV Events365
Supplemental Table 41. RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM [categorical outcomes] 366
[Control]
(Control) (Control
Overt albuminuria
Composite
of doubling RR 0.76
IDNT 2001 32 mo 579 567 SCr 1.7 UAE 2900 160/87 140/77 189 (33%)367
of SCr, Irbesartan Amlodipine (0.63; 0.005 Good
Multi[52] (≥24 mo) (579) (567) mg/dL mg/24h (159/87) (141/77) [233 (41%)]
ESRD or 0.92)368
death
Mortality
Overt albuminuria
RR 1.05
IDNT 2001 32 mo 579 567 SCr 1.7 UAE 2900 160/87 140/77 87 (15%)
Death Irbesartan Amlodipine (0.78; 1.42) NS Good
Multi[52] (≥24 mo) (579) (567) mg/dL mg/24h (159/87) (141/77) [83 (15%)] 369
CV mortality
Overt albuminuria
IDNT 2003 32 mo 574 565 SCr 1.67 160/87 140/77 52 (9%) HR 1.36
CV mortality Irbesartan Amlodipine UPE 2.9 g/d NS Good
Multi[18] (≥24 mo) (579) (567) mg/dL (159/87) (141/77) [37 (7%)] (0.89; 2.07)
Microalbuminuria
Chan
MAP MAP RR 2.52
Death from 1992370 12 mo 49 41 CrCl 66 UAE 64.7 1 (2%)
Enalapril Nifedipine 120 99 (0.11; nd Poor
MI Hong (12 mo) (52) (50) mL/min mg/24h [0 (0%)]
(117) (97) 61.12) 371
Kong[24]
CV events
Overt albuminuria
RR 1.03
Composite 138 (24%)
(0.81; 1.32) NS Good
of CVD [128 (23%)] 372
259 in 30%
Composite IDNT 2001 of patients HR 0.90
32 mo 579 567 SCr 1.7 160/87 140/77 NS Good
CV events 2003 Irbesartan Amlodipine UPE 2.9 g/d [278 in 28% (0.74; 1.10)
(≥24 mo) (579) (567) mg/dL (159/87) (141/77)
Multi[18;52] of patients]
80 in 10% of
patients HR 0.65
CHF 0.004 Good
[143 in16% (0.48; 0.87)
of patients]

367 Primary outcome
370 All patients were Chinese
[Control]
(Control) (Control
48 in 8% of
patients HR 1.54 NS
MI Good
[29 in 5% of (0.97; 2.45) (0.068)
patients]
30 in 5% of
patients HR 1.55
CVA NS Good
[18 in 3% of (0.84; 2.87)
patients]
31 in 5% of
Cardiac
patients HR 0.93
revasculariz NS Good
[32 in 5% of (0.55; 1.55)
ation
patients]
Microalbumnuria
J-MIND RR 1.82
24 mo Nifedipine 137 156 CrCl 102 UAE 42 161/90 145/82374 8 (6%)
CV events 2001373 Enalapril (0.61; NS Poor
(24 mo) retard (208) (228) mL/min mg/d (162/90) (143/82) [5 (3%)]
Japan[13] 5.44)375
RR 0.39
Composite DIAL 2004 12 mo Lercanidipi 66 64 SCr 79.6 UAER 86.5 156/93 140/80 2 (3%)
Ramipril (0.08; nd Fair
of CV events Italy[28] (12 mo) ne (89) (91) µmol/L µg/min (155/92) (140/80) [5 (8%)]
1.93)376
ESRD
Overt albuminuria
RR 0.76
IDNT 2001 32 mo 579 567 SCr 1.7 UAE 2900 160/87 140/77 82 (14%) NS
ESRD Irbesartan Amlodipine (0.57; 1.02) Good
Multi[52] (≥24 mo) (579) (567) mg/dL mg/24h (159/87) (141/77) [104 (18%)] 377 (0.06)
Kidney function
Overt albuminuria
RR 0.61
Doubling of IDNT 2001 32 mo 579 567 SCr 1.7 UAE 2900 160/87 140/77 98 (17%)
Irbesartan Amlodipine (0.48; 0.79) <0.001 Good
SCr Multi[52] (≥24 mo) (579) (567) mg/dL mg/24h (159/87) (141/77) [144 (25%)] 378
Proteinuria
Microalbuminuria
373 The J-MIND contains both micro- and normo-albuminuric patients

[Control]
(Control) (Control
Progression
from
J-MIND RR 0.91
microalbumi 24 mo Nifedipine 53 64 CrCl 102 UAE 42 161/90 145/82381 6%382
2001379 Enalapril (0.21; 3.87) NS Poor
nuria to (24 mo) retard (nd) (nd) mL/min mg/d380 (162/90) (143/82) [6%]
Japan[13] 383
macroalbumi
nuria
379 The J-MIND contains both micro- and normo-albuminuric patients

380 Baseline UAE is reported for all patients enrolled some of whom are normoalbuminuric.
382 Primary outcome
Supplemental Table 42. RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM [continuous outcomes] 384
(Control) (Control)
(Control) (Control
Proteinuria
Microalbuminuria
CrCl
101.58
∆Median Agardh 1996 12 mo 168 167 UAE 94.3 163/99 147/88 65.5385 -26.5 0.000
Lisinopril Nifedipine mL.min Good
UAE UK[5] (12 mo) (168) (167) mg/24h (161/97) (150/88) (63) (-5) 6
SCr 94.0
µmol/L
3 mo 149 144 57.9 -16.3
nd Good
(6 mo) (169) (163) (55.4) (0)
5 mo 144 142 57.9 -21.3
nd Good
(6 mo) (169) (163) (55.4) (-3.4)
∆UAER 6 mo 142 136 57.9 -34.6
nd Good
(6 mo) (169) (163) (55.4) (-4.7)
MARVAL SCr 97.3 UAER 57.9 147/85 135/78
6 mo Valsartan Amlodipine
2002 UK[95] 163 158 μmol/L µg/min (148/86) (136/79) 57.9 -24.2
(6 mo) nd Good
(169) (163) (55.4) (-1.7)
[LOCF]
56% <0.00
%∆UAER --386 Good
6 mo 142 136 (92%) 1
(6 mo) (169) (163) 44% <0.00
%↓UAER -- Good
(8%) 1
-19.7
(-34.1 to 5.3)
ΔProteinuria DIAL 2004 12 mo Lercanidipi 66 64 SCr 79.6 UAER 86.5 156/93 141/80 66.9387
Ramipril (-17.4 <0.05 Fair
, µg/min Italy[28] (12 mo) ne (89) (91) µmol/L µg/min (155/92) (140/81) (86.5)
(-32.0 to
2.8))
Mean
albuminuria
Chan 2000 CrCl
value during 388 Hong 60 mo 52 50 UAE 73.4 172/93 137/72 73.7389 -12.2
Enalapril Nifedipine 73.7 <0.01 Good
treatment (60 mo) (52) (50) mg/24h (169/93) (132/72) (76.9) (-11.6)
Kong[25] mL/min
period,
mL/min

385 Primary outcome
386 Primary outcome
387 Primary outcome
388 All patients were Chinese
389 Primary outcome
Supplemental Table 43. Evidence profile of RCTs examining the effect of ACEI vs. ARB in patients with Type 2 DKD
applicability
Composite
kidney 0 RCTs -- -- -- -- -- -- -- Critical
outcomes
Sparse
1 RCT 250 Some limitations Direct (1)
Mortality NA Very low Insufficient evidence for ACEI and ARB. Critical
(-1)
Sparse
1 RCT 250 Some limitations Direct (1)
CV events NA Very low Insufficient evidence for ACEI and ARB. Critical
(-1)
ESRD 0 RCTs -- -- -- -- -- -- -- Critical
Kidney
function 0 RCTs -- -- -- -- -- -- -- High
(categorical)
348 Some limitations Sparse
function (High) inconsistencies directness Very low Insufficient evidence for ACEI and ARB. Moderate
(179) (-1) (-1)
(continuous) [1˚ in 1 RCT] (0) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Proteinuria 567 Serious limitations None
(High) inconsistencies directness Very low Insufficient evidence for ACEI and ARB. Moderate
(continuous) (289) (-2) (0)
[1˚ in 1 RCT] (0) (-1)
Drug discontinuation: 14% for ACEI and 18%
250 in CCB
Adverse events 1 RCT Moderate
(130) Early rise in creatinine: 0.02% in ACEI and
0.02% in CCB
567
Total 3 RCTs
(289)
Insufficient evidence for CV outcomes Very low for CV outcomes
Insufficient evidence for kidney outcomes Very low for kidney outcomes
Supplemental Table 44. RCTs examining the effect of ACEI vs. ARB in microalbuminuric patients with CKD and Type 2 DM [categorical outcomes]
[Control]
(Control) (Control)
Mortality
GFR 94.3
mL/min/1. Median RR 0.92
Barnett 2004 60 mo 130 120 152/86 149/79391 6 (5%)
Death Enalapril Telmisartan 73 m2 UAE 60 (0.31; nd Fair
Multi[16] (60 mo) (130) (120) (153/85)390 (146/80) [6 (5%)]
SCr 0.99 μg/min 2.78)392
mg/dL
CV events
CHF/Non- GFR 94.3 13 (10%) RR 0.67394
nd Fair
fatal MI mL/min/1. Median [18 (15%)] (0.34; 1.30)
Barnett 2004 60 mo 130 120 152/86 149/79393
Enalapril Telmisartan 73 m2 UAE 60 RR 0.92
Multi[16] (60 mo) (130) (120) (153/85) (146/80) 6 (5%)
Stroke SCr 0.99 μg/min (0.31; nd Fair
[6 (5%)]
mg/dL 2.78)395

Supplemental Table 45. RCTs examining the effect of ACEI vs. ARB in microalbuminuric patients with CKD and Type 2 DM [continuous outcomes]
(Control) (Control)
(Control) (Control)
Kidney function
∆GFR,
-14.9
ml/min/1.73
[-17.9]
m2
Difference in GFR 94.3
∆GFR, mL/min/1. 3.0
Barnett 2004 60 mo 130 120 Median UAE 152/86 149/79396 94.3397
ml/min/1.73 Enalapril Telmisartan 73 m2 (+7.6; -1.6)398 nd Fair
Multi[16] (60 mo) (130) (120) 60 µg/min (153/85) (146/80) (91.4)
m2 SCr 0.99
mg/dL 0.10
∆SCr, mg/dL
[0.10]
Difference in 0
∆SCr, mg/dL (-0.66; 0.65)
12 wk 95 -2399
nd Fair
Geometric (52 wk) (97) (-6)
Lacourciere
means of 28 wk 49 49 GFR 95 UAE 73.9 154/88 138/79 95 -5400
2000 Enalapril Losartan nd Fair
GFR, (52 wk) (52) (51) mL/min μg/min (158/90) (144/82) (97) (-10)
Canada[48]
mL/min 52 wk 95 -5401
nd Fair
(52 wk) (97) (-9)
Proteinuria
0.99
∆UAE rate GFR 94.3
[1.03]
mL/min/1.
∆UAE rate Barnett 2004 5y 130 120 Median UAE 152/86 149/79402 60
Enalapril Telmisartan 73 m2 nd Fair
(between- Multi[16] (5 y) (130) (120) 60 µg/min (153/85) (146/80) (46) 1.04
SCr 0.99
group mg/dL (0.71; 1.51)
difference)
Adjusted CrCl 96.4
reduction in Sengul 2006 24 wk 110 109 mL/min Median AER 151/88 140/82 264403 -98
Lisinopril Telmisartan NS Poor
AER, Turkey[88] (24 wk) (110) (119) SCr 85.4 264 mg/24h (150/90) (140/85) (256) (-80)404
mg/24h mmol/L

397 Primary outcome
398 Since upper level of 95% CI of the difference between the enalapril and telmisartan groups was greater than +10ml/min/1.73m2, in favor of enalapril, telmisartan is not inferior to enalapril.
403 Primary outcome
404 Adjusted mean difference 18 (95% CI 0; 37), Adjusted for treatment, baseline value, weight and change in DBP. Adjusted mean difference 18, (0; 37.0) p=0.12
(Control) (Control)
(Control) (Control)
85.4 -1.4
∆SCr, mmol/L
(85.6) (+0.4)
12 wk 73.9 -23.2
NS Fair
Geometric (52 wk) (64.1) (-9.0)
Lacourciere
means of 28 wk 49 49 GFR 95 UAE 73.9 154/88 138/79 73.9 -34.5
2000 Enalapril Losartan NS Fair
albuminuria, (52 wk) (52) (51) mL/min μg/min (158/90) (144/82) (64.1) (-27.3)
Canada[48]
μg/min 52 wk 73.9 -40.4
NS405 Fair
(52 wk) (64.1) (-22.6)
405 There was no significant difference between groups with respect to the change from baseline in log UAE after 12 and 28 weeks of treatment. At week 52, analyses showed a significant
quantitative treatment-by-center interaction characterized by a variation in the magnitude of treatment differences from center to center. The difference between groups with respect to the change
from baseline in log UAE is not significant when the interaction is taken into account and significant (P = 0.026) otherwise
Supplemental Table 46. Evidence profile of RCTs examining the effect of ARB vs. ARB in patients with CKD and DM
applicability
Composite Important
kidney inconsistency406 Moderate No difference Critical
(High) (835) (0) (0) (0)
outcomes (-1)
Important
Mortality inconsistency Low Possible benefit for Telmisartan Critical
(High) (835) (0) (0) (-1)
(-1)
Important
CV mortality 2 RCTs 1684 No limitations Direct None
inconsistency Moderate Possible benefit for Telmisartan Critical
and morbidity (High) (835) (0) (0) (0)
(-1)
Sparse
ESRD NA Low Insufficient evidence for Telimisartan Critical
(-1)
Sparse
Kidney
function NA Low Insufficient evidence for Telimisartan Critical
(categorical)
(-1)
∆Kidney Uncertainty about
1 RCT 857 No limitations Sparse Possible benefit for Valsartan on measured
function NA directness Low Moderate
(High) (428) (0) (-1) CrCl (but not for SCr or eGFR).
(continuous) (-1)
Proteinuria 1 RCT 340 No limitations Direct Sparse
NA Moderate No difference High
(categorical) (High) (168) (0) (0) (-1)
3 RCTs Important Uncertainty about
(High) inconsistency directness Low Possible benefit for Telmisartan Moderate
(continuous) (1003) (0) (0)
[1˚ in 2 RCTs] (-1) (-1)
Drug discontinuation: 1.4-2% for ARB and
2024 1.4-3% in ARB (from 2 RCTs)
(1003) Hyperkalemia: 2% for ARB and 3% for ARB
(from 1 RCT)
2024
Total 3 RCTs
(1003)
Possible benefit for telmisartan vs. losartan for CV outcomes but no difference between telmisartan vs. Moderate for CV outcomes
valsartan. Low for kidney outcomes
Insufficient evidence for kidney outcomes
406 For mortality, the AMADEO study showed statistically significant benefit and Galle study was not statistically significant
Supplemental Table 47. RCTs examining the effect of ARB vs. ARB in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]
[Control]
(Control) (Control)
Composite
eGFR
of doubling VIVALDI
12 mo 428 429 56.7 UPER 2.7 148/82 142/79 22 (5%) RR 1.23407
of SCr, 2008 Telmisartan Valsartan NS Good
(12 mo) (443) (442) ml/min/1. g/d (149/83) (142/78) [18 (4%)] (0.67; 2.25)
ESRD or all- Multi[37]
73 m2
cause death
eGFR
Composite
49.5
of doubling AMADEO
12 mo 407 420 mL/min/1. UPCR 1971 144/80 135/77 3% RR 0.5408 NS
of SCr, 2008 Telmisartan Losartan Good
(12 mo) (419) (441) 73 m2 mg/g (143/80) (136/77) [6%] (0.25; 0.97) (0.08)
ESRD and Multi[14]
SCr 1.54
death
mg/dL
Mortality
eGFR
VIVALDI
All cause 12 mo 428 429 56.7 UPER 2.7 148/82 142/79 15 (4%) RR 1.88409
2008 Telmisartan Valsartan NS Good
death (12 mo) (443) (442) ml/min/1. g/d (149/82) (142/78) [8 (2%)] (0.81; 4.39)
Multi[37]
73 m2
eGFR
49.5
AMADEO
All-cause 12 mo 407 420 mL/min/1. UPCR 1971 144/80 135/77 2 (0.5%) RR 0.16410
2008 Telmisartan Losartan 0.007 Good
mortality (12 mo) (419) (441) 73 m2 mg/g (143/80) (136/77) [13 (3%)] (0.04; 0.70)
Multi[14]
SCr 1.54
mg/dL
CV mortality
eGFR
Death from VIVALDI
12 mo 428 429 56.7 UPER 2.7 148/82 142/79 8 (2%) RR 1.34411
cardiovascul 2008 Telmisartan Valsartan nd Good
(12 mo) (443) (442) ml/min/1. g/d (149/82) (142/78) [6 (1%)] (0.47; 3.82)
ar cause Multi[37]
73 m2
CV mortality and morbidity
Composite
31 (7%) RR 0.94412
CV morbidity NS Good
eGFR [33 (8%)] (0.59; 1.51)
and mortality VIVALDI
12 mo 428 429 56.7 UPER 2.7 148/82 142/79
Myocardial 2008 Telmisartan Valsartan 4 (1%) RR 0.36413
(12 mo) (443) (442) ml/min/1. g/d (149/82) (142/78) nd Fair
infarction Multi[37] [11 (3%)] (0.12; 1.14)
73 m2
11 (3%) RR 2.21414
Stroke nd Fair
[5 (1%)] (0.77; 6.29)

[Control]
(Control) (Control)
eGFR
49.5
Cardiovascu AMADEO
12 mo 407 420 mL/min/1. UPCR 1971 144/80 135/77 21 (5%) RR 0.59415
lar morbidity 2008 Telmisartan Losartan 0.04 Good
(12 mo) (419) (441) 73 m2 mg/g (143/80) (136/77) [37 (9%)] (0.35; 0.98)
and mortality Multi[14]
SCr 1.54
mg/dL
ESRD
eGFR
VIVALDI
12 mo 428 429 56.7 UPER 2.7 148/82 142/79 7 (2%) RR 0.88416
ESRD 2008 Telmisartan Valsartan NS Good
(12 mo) (443) (442) ml/min/1. g/d (149/82) (142/78) [8 (2%)] (0.32; 2.40)
Multi[37]
73 m2
Kidney function
eGFR
VIVALDI RR 1.00
Doubling of 12 mo 428 429 56.7 UPER 2.7 148/82 142/79 3 (1%)
2008 Telmisartan Valsartan (0.20; NS Good
SCr (12 mo) (443) (442) ml/min/1. g/d (149/82) (142/78) [3 (1%)]
Multi[37] 4.94)417
73 m2
Proteinuria
Transition
rates from
incipient to
overt 28 (17%) RR 1.00418
nd Good
nephropathy [39 (23%)] (0.67; 1.48)
(UACR >300
mg/g and INNOVATIO
↑≥30%) 16mo Telmisartan Telmisartan 168 172 SCr 0.8 UACR 172 138/78 128/74
N 2007
(≥12mo) 80mg 40mg (nd) (nd) mg/dL mg/g (137/78) (132/74)
Transition Japan[55]
rate in 6 (11%) RR 0.51419
nd Good
normotensiv [12 (21%) (0.20; 1.33)
e patients
Micaroalbum
36 (21%) RR 1.68420
inuria nd Good
[22 (13%)] (1.03; 2.72)
remission

Supplemental Table 48. RCTs examining the effect of ARB vs. ARB in overtly albuminuric patients with CKD and Type 2 DM [continuous outcomes]
(Control) (Control)
(Control) (Control)
Kidney function
%ΔeGFR,
48.4 -6%
ml/min/1.73 NS Good
(48.6) (-5%)
m eGFR
VIVALDI
%ΔCrCl, 12 mo 428 429 56.7 UPER 2.7 148/82 142/79
2008 Telmisartan Valsartan 57.8 -21%
ml/min/1.73 (12 mo) (443) (442) ml/min/1. g/d (149/82) (142/78) 0.001 Good
Multi[37] (59.0) (-14%)
m2 73 m2
%ΔSCr, 2750 14%
NS Good
mg/24h (2890) (12%)
Proteinuria
%ΔUPER, eGFR 2750421 33%
VIVALDI NS Good
mg/24h 12 mo 428 429 56.7 UPER 2.7 148/82 142/79 (2890) (-33%)
2008 Telmisartan Valsartan
%ΔUAE, (12 mo) (443) (442) ml/min/1. g/d (149/82) (142/78) 2750 -39%
Multi[37] NS Good
mg/24h 73 m2 (2890) (-36%)
eGFR 29.8
UPCR NA 0.03 Good
49.5 (21.4)422
AMADEO
12 mo 407 420 mL/min/1. UPCR 1971 144/80 135/77
2008 Telmisartan Losartan
(12 mo) (419) (441) 73 m2 mg/g (143/80) (136/77) 1426423 35.5
↓UACR Multi[14] 0.04 Good
SCr 1.54 (1390) (27.0)
mg/dL
∆UACR
after INNOVATIO
16mo Telmisartan Telmisart 168 172 SCr 0.8 UACR 172 138/78 128/74 172 -58.8
adjustment N 2007 nd Good
(≥12mo) 80mg an 40mg (nd) (nd) mg/dL mg/g (137/78) (132/74) (173) (-37.9)
for SBP, Japan[55]
mg/g
421 Primary outcome

422 Adjustment made for an analysis of covariance that included treatment and pooled center as class effects, with baseline as a covariate, was performed on the log-transformed data
423 Primary outcome
Supplemental Table 49. RCTs examining the effect of DRI + ARB vs. placebo+ ARB in microalbuminuric patients with CKD and Type 2 DM [continuous outcomes]
(Control) (Control)
(Control) (Control)
Kidney function
eGFR
↓eGFR, 2.4 (1.1; 3.7)
259 265 68.5 UACR 135/78 133/78 68.5 NS
ml/min/1.73 (3.8 (2.5; Good
(301) (298) mL/min/1. 513 mg/g (134/77) (135/79)424 (66.8) (0.07)
m2 5.1))
73 m2
Δ eGFR in
eGFR
patients with
129 119 47.1 UACR 136/77 133/76 47.1 -1.7
GFR <60 NS Good
(129) (119) mL/min/1. 628 mg/g (135/75) (139/75) (44.7) (+0.25)
ml/min/1.73
73 m2
m2
AVOID 2008
Δ eGFR 6 mo Aliskiren + Placebo +
2010
>60-<90 in (6 mo) Losartan Losartan eGFR
Multi[75;78]
patients with 104 122 73.6 UACR 134/78 136/78 73.6 -2.7
NS Good
GFR 60-90 (104) (122) mL/min/1. 410 mg/g (133/78) (135/80) (72.4) (-4.8)
ml/min/1.73 73 m2
m2
Δ eGFR in
eGFR
patients with
64 51 102.5 UACR 135/80 134/79 102.5 -5.6
GFR >90 NS Good
(64) (51) mL/min/1. 530 mg/g (133/78) (134/79) (100.4) (-9.5)
ml/min/1.73
73 m2
m2
Proteinuria
Difference in 18% (7;
513426
%↓UACR, 28)427 0.002 Good
(553)
mg/g eGFR (N/A)
Difference in 259 265 68.5 UACR 135/78 133/78
%↓overnight (301) (298) mL/min/1. 513 mg/g (134/77) (135/79)425 17% (4; 29)
UAE rate 73 m2 N/A 428 0.02 Good
(geometric AVOID 2008 (N/A)
6 mo Aliskiren + Placebo +
mean) 2010
(6 mo) Losartan Losartan
ΔUACR at Multi[75;78]
24 wks (%)
eGFR
in patients
129 119 47.1 UACR 136/77 133/76 628 -9
with GFR 0.045 Good
(129) (119) mL/min/1. 628 mg/g (135/75) (139/75) (670) (+13)
<60
73 m2
ml/min/1.73
m2, mg/g

426 Primary outcome
427 Adjustment for the change from baseline in systolic blood pressure
428 Adjustment for the change from baseline in systolic blood pressure
ΔUACR at
24 wks (%)
eGFR
in patients
104 122 73.6 UACR 134/78 136/78 410 -23
with GFR 0.021 Good
(104) (122) mL/min/1. 410 mg/g (133/78) (135/80) (484) (-1)
>60-90
73 m2
ml/min/1.73
m2, mg/g
ΔUACR at
24 wks (%)
eGFR
in patients
64 51 102.5 UACR 135/80 134/79 530 -27
with GFR 0.202 Good
(64) (51) mL/min/1. 530 mg/g (133/78) (134/79) (405) (-11)
>90
73 m2
ml/min/1.73
m2, mg/g
UACR
reduction
eGFR
≥50 (%) in
129 119 47.1 UACR 136/77 133/76 628429 25/122
patients with 0.019 Good
(129) (119) mL/min/1. 628 mg/g (135/75) (139/75) (670) (11/115)
GFR <60
73 m2
ml/min/1.73
m2, mg/g
UACR
reduction
eGFR
≥50 (%) in
104 122 73.6 UACR 134/78 136/78 410430 28/101
patients with 0.012 Good
(104) (122) mL/min/1. 410 mg/g (133/78) (135/80) (484) (17/118)
GFR >60
73 m2
ml/min/1.73
m2, mg/g
UACR
reduction
eGFR
≥50 (%) in
64 51 102.5 UACR 135/80 134/79 530431 18/62
patients with NS Good
(64) (51) mL/min/1. 530 mg/g (133/78) (134/79) (405) (8/50)
GFR >90
73 m2
ml/min/1.73
m2, mg/g
429 Primary outcome

430 Primary outcome
431 Primary outcome
Supplemental Table 50. RCTs examining the effect of dihydropyridine CCB vs. placebo in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]
[Control]
(Control) (Control
CV mortality
IDNT 2003 30 mo 565 565 SCr 1.65 159/87 141/77 37 (7%) HR 0.79
CV mortality Amlodipine Placebo UPE 2.9 g/d NS Good
Multi[18] (≥24 mo) (567) (569) mg/dL (158/87) (144/80) [46 (8%)] (0.51; 1.22)
CV events
278 (in 28%
of patients)
Composite HR 1.00
432 NS Good
CV events (0.83; 1.21)
[284 (in 33%
of patients)]
143 (in 16%
of patients)
HR 1.11
CHF 433 NS Good
(0.83; 1.50)
[113 (in 13%
of patients)]
IDNT 2003 30 mo 565 565 SCr 1.65 159/87 141/77 29 (in 5% of
Amlodipine Placebo UPE 2.9 g/d
Myocardial Multi[18] (≥24 mo) (567) (569) mg/dL (158/87) (144/80) patients) 434 HR 0.58
0.021 Good
infarction [51 (in 9% of (0.37; 0.92)
patients)]
18 (in 3% of
patients) 435 HR 0.65
CVA NS Good
[28 (in 5% of (0.35; 1.22)
patients)]
32 (in 5% of
Cardiac
patients) 436 HR 0.86
revasculariz NS Good
[39 (in 6% of (0.54; 1.38)
ation
patients)]
432 Primary outcome

433 Primary outcome
434 Primary outcome
435 Primary outcome
436 Primary outcome
Supplemental Table 51. RCTs examining the effect of aldosterone antagonist + ACEI vs. placebo + ACEI in patients with CKD and Type 2 DM [continuous outcomes]
(Control) (Control)
(Control) (Control)
Proteinuria
Overt albuminuria
GFR 73
Epstein Eplerenone
3 mo Placebo + 83 80 mL/min UACR 422 140/83 422437 -43
%↓UACR 2006 50 + nd <0.001 Good
(3 mo) Enalapril (91) (91) SCr mg/g (146/88) (280) (-9)
Multi[33] Enalapril
80µmol/L
Microalbuminuria
GFR 75
Epstein Eplerenone
3 mo Placebo + 77 80 mL/min UACR 140/85 240438 -50
%↓UACR 2006 100 + nd <0.001 Good
(3 mo) Enalapril (86) (91) SCr 240 mg/g (146/88) (280) (-9)
Multi[33] Enalapril
80µmol/L
437 Primary outcome

438 Primary outcome
Supplemental Table 52. RCTs examining the effect of endothelin antagonist vs. endothelin antagonist in patients with CKD with Type 2 DM [categorical outcomes]
Baseline P
Death,
ASCEND eGFR 34 Median ACR
ESRD and 5 mo Avosentan Avosentan 455 478 137/78 131/74 37 (8%) RR 0.95439
2010 mL/min/1. 160.9 nd Fair
doubling of (4 mo) 25 mg/d 50 mg/d (455) (478) (137/78) (131/73) [41 (9%)] (0.62; 1.45)
Multi[60] 73 m2 mg/mmol
SCr
Mortality
5 mo Avosentan Avosentan 455 478 137/78 131/74 21 (5%) RR 1.30440
Death 2010 mL/min/1. 160.9 nd Fair
(4 mo) 25 mg/d 50 mg/d (455) (478) (137/78) (131/73) [17 (4%)] (0.69; 2.43)
CV events
68 (15%) RR 1.01441
CV event ASCEND eGFR 34 Median ACR nd Fair
5 mo Avosentan Avosentan 455 478 137/78 131/74 [71 (15%)] (0.74; 1.37)
2010 mL/min/1. 160.9
(4 mo) 25 mg/d 50 mg/d (455) (478) (137/78) (131/73) 27 (6%) RR 0.98442
CHF Multi[60] 73 m2 mg/mmol nd Fair
[29 (6%)] (0.59; 1.63)
ESRD
5 mo Avosentan Avosentan 455 478 137/78 131/74 20 (4%) RR 0.88443
ESRD 2010 mL/min/1. 160.9 nd Fair
(4 mo) 25 mg/d 50 mg/d (455) (478) (137/78) (131/73) [24 (5%)] (0.49; 1.56)
Kidney function
Doubling of 5 mo Avosentan Avosentan 455 478 137/78 131/74 2 (0.4%) RR 0.53444
2010 mL/min/1. 160.9 nd Fair
SCr (4 mo) 25 mg/d 50 mg/d (455) (478) (137/78) (131/73) [4 (1%)] (0.10; 2.85)

Supplemental Table 53. RCTs examining the effect of endothelin antagonist vs. endothelin antagonist in patients with CKD with Type 2 DM [continuous outcomes]
(Control) (Control)
(Control) (Control)
Kidney function
ΔeGFR, ASCEND eGFR 34 Median ACR
5 mo Avosentan Avosentan 455 478 137/78 131/74 34 -3.35
ml/min/1.73 2010 mL/min/1. 160.9 nd Good
(4 mo) 25 mg/d 50 mg/d (455) (478) (137/78) (131/73) (33) (-4.08)
m2 Multi[60] 73 m2 mg/mmol
Proteinuria
Median ASCEND eGFR 34 Median ACR
5 mo Avosentan Avosentan 455 478 137/78 131/74 160.9 -44.30
%ΔACR, 2010 mL/min/1. 160.9 nd Good
(4 mo) 25 mg/d 50 mg/d (455) (478) (137/78) (131/73) (166.5) (-49.30)
mg/mmol Multi[60] 73 m2 mg/mmol
Supplemental Table 54. Evidence profile of RCTs examining the effect of ACEI or ARB vs. CCB in transplant recipients without DM
applicability
Composite
outcomes
Sparse
Mortality NA Very low Insufficient evidence Critical
(-1)
CV events 0 RCTs -- -- -- -- -- -- -- Critical
Sparse
Kidney
function NA Very low Insufficient evidence High
(categorical)
(-1)
∆Kidney 2 RCTs Important Uncertainty about
256 Some limitations Sparse
function [1˚ in 1 RCT] inconsistencies directness Very low Insufficient evidence Moderate
(130) (-1) (-1)
(continuous) (High) (-1) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Proteinuria 2 RCTs 256 Some limitations Sparse
inconsistencies directness Very low No difference Moderate
(continuous) (High) (130) (-1) (-1)
(0) (-1)
256 Drug discontinuation: 0-5% for ACEI and 11%
(130) for CCB (from 2 RCTs)
256
Total 2 RCTs
(130)
Possible benefit for increase in eGFR but insufficient evidence for clinically relevant outcomes Very low for kidney outcomes
Supplemental Table 55. RCTs examining the effect of ACE or ARB vs. CCB in transplant recipients with CKD without DM [categorical outcomes]
Baseline Baseline Achieved Events P
Outcome Year Outcome GFR or Quality
Proteinuria SBP/DBP SBP/DBP No (%) RR/OR/HR value
Country (Treatment) Intervention Control Intervention Control SCr
Intervention Intervention Intervention (95% CI)
Mortality
SCr 146
Midtvedt
1y 76 78 μmol/L UPE 129 170/104 2 (3%)
Death 2001 Lisinopril Nifedipine nd -- nd Fair
(1 y) (76) (78) GFR 43 mg/L (169/104) [0 (0%)]
Norway[68]
mL/min
Kidney function
↑GFR >5 SCr 146 18 (23%) RR 0.38445
Midtvedt nd Fair
mL/min 1y 76 78 μmol/L UPE 129 170/104 [49 (64%)] (0.24; 0.58)
2001 Lisinopril Nifedipine nd
↓GFR >5 (1 y) (76) (78) GFR 43 mg/L (169/104) 3 (4%) RR 0.77446
Norway[68] nd Fair
mL/min mL/min [4 (5%)] (0.18; 3.33)

Supplemental Table 56. RCTs examining the effect of ACE or ARB vs. CCB in transplant recipients with CKD without DM [continuous outcomes]
Duration
Study Baseline Baseline Achieved
Outcome Year GFR or SBP/DBP SBP/DBP Quality
measurement Intervention Control Intervention Control Proteinuria Intervention Intervention value
Country SCr Intervention Intervention
(Treatment) (Control) [Control]
(Control) (Control)
Kidney function
∆GFR, 1y 43‡ +1 0.000
Fair
mL/min (1 y) SCr 146 (46) (+10) 1
Midtvedt
1y 76 78 μmol/L UPE 129 170/104 -2
2001 Lisinopril Nifedipine nd 0.013 Fair
(1 y) (76) (78) GFR 43 mg/L (169/104) 146 (-12)
∆SCr, μmol/L Norway[68]
2y mL/min (137) 0 NS
Fair
(1 y) (-14) (0.06)
MAP MAP
1.5 0.0
Losartan Amlodipine 0.8 g/d 108 95 NS Poor
el-Agroudy (1.4) (+0.1)
12 mo 54 48 SCr 1.5 (108) (95)
∆SCr, mg/dL 2003
(12 mo) (54) (54) mg/dL MAP MAP
Egypt[32] 1.5 0.0
Captopril Amlodipine 0.9 g/d 106 94 NS Poor
(1.4) (+0.1)
(108) (95)
Proteinuria
1y SCr 146 -49
Midtvedt NS Fair
(1 y) 76 78 μmol/L UPE 129 170/104 129 (+136)
∆UPE, mg/L 2001 Lisinopril Nifedipine nd
2y (76) (78) GFR 43 mg/L (169/104) (124) -24
Norway[68] NS Fair
(1 y) mL/min (+76)
MAP MAP
0.8 -0.4
Losartan Amlodipine 0.8 g/day 108 95 nd Poor
el-Agroudy (0.6) (+0.2)
∆Proteinuria 12 mo 54 48 SCr 1.5 (108) (95)
2003
, g/d (12 mo) (54) (54) mg/dL MAP MAP
Egypt[32] 0.9 -0.4
Captopril Amlodipine 0.9 g/d 106 94 nd Poor
(0.6) (+0.8)
(108) (95)
Supplemental Table 57. Evidence profile of RCTs examining the effect of CCB vs. placebo in transplant recipients without DM
applicability
Composite
outcomes
CV events 0 RCTs -- -- -- -- -- -- -- Critical
Kidney
1 RCT 253 Some limitations Direct Sparse
function NA Low Insufficient evidence High
(High) (130) (-1) (0) (-1)
(categorical)
∆Kidney No important Uncertainty about
3 RCTs 581 Some limitations None
function inconsistencies directness Low Benefit for CCB Moderate
(High) (287) (-1) (0)
(continuous) (0) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Proteinuria
0 RCTs -- -- -- -- -- -- -- Moderate
(continuous)
463 Drug discontinuation: 5% for CCB and 1-2%
(228) for placebo (from 2 RCTs)
581
Total 3 RCTs
(287)
Balance of potential benefits and harms: Quality of overall evidence:
Possible benefit for kidney function outcomes Low for kidney outcomes
Supplemental Table 58. RCTs examining the effect of CCB vs. placebo in transplant recipients [categorical outcome] 447
Baseline P
Kidney function
Rahn 1999
↑SCr >22.1 24 mo 130 123 SCr 146.7 141/88 138/86 26 (20%) RR 0.62448
Germany[81 Nitrendipine Placebo nd 0.026 Good
μmol/L (24 mo) (130) (123) μmol/L (143/88) (143/90) [40 (33%)] (0.40; 0.94)
]

Supplemental Table 59. RCTs examining the effect of CCB vs. placebo in transplant recipients without DM [continuous outcome] 449
Intervention Control Intervention Control Proteinuria Intervention Intervention) value
(Control) [Control]
(Control) (Control)
Kidney function
146.7 +1.8
↑SCr, μmol/L Rahn 1999 0.025 Good
24 mo 130 123 SCr 146.7 141/88 138/86 (137.0) (+23.4)
Germany[81 Nitrendipine Placebo nd
(24 mo) (130) (123) μmol/L (143/88) (143/90) +1.2
∆CrCl, mL/min ] nd 0.014 Good
(-4.1)
3 mo 185
nd 0.002 Poor
Final SCr, (12 mo) (220)
van
μmol/L 12 mo 141
Riemsdijk nd 0.021 Poor
(12 mo) 98 112 (158)
2000 Isradipine Placebo nd nd nd nd
3 mo (98) (112) 56
Netherlands[ nd 0.026 Poor
Final CrCl, (12 mo) (50)
94]
mL/min 12 mo 63
nd NS Poor
(12 mo) (58)
Graft function 1.8 -0.28
0.005
[SCr, mg/dL] (2.0) (-0.24)
Graft function SCr 1.8
52 +11.1 NS
[eCrCl, 59 59 mg/dL
(47) (+6.4) (0.09)
mL/min] Kuypers (66) (65) eGFR 52
24 mo 150/90 138/82
Graft function 2004 Lacidipine Placebo mL/min nd Poor
(24 mo) (150/90)450 (144/84) 451 61 +11.0
[calculated Multi[47] Calculate 0.03
(51) (+2.5)
CrCl, mL/min] d GFR 61
Graft function mL/min
53 53 50 -0.1
[mGFR, <0.05
(66) (65) (47) (-4.7)
mL/min]

Supplemental Table 60. RCTs examining the effect of ACE vs. ARB in hypertensive transplant recipients without DM [continuous outcomes]
Outcome Year Outcome GFR or MAP MAP Quality
(Control) [Control]
(Control) (Control)
Kidney function
el-Agroudy
12 mo 54 54 SCr 1.5 106 94 1.5 0.0
∆SCr, mg/dL 2003 Captopril Losartan 0.9 g/d nd Poor
(12 mo) (54) (54) mg/dL (108) (95) (1.5) (0.0)
Egypt[32]
Proteinuria
el-Agroudy
∆Proteinuria, 12 mo 54 54 SCr 1.5 106 94 0.8 -0.4
2003 Captopril Losartan 0.9 g/d nd Poor
g/d (12 mo) (54) (54) mg/dL (108) (95) (0.9) (-0.4)
Egypt[32]
Supplemental Table 61. RCTs examining the effect of ARB vs. placebo in transplant recipients [categorical outcome]
Baseline P
Composite of kidney and CV outcomes
Composite of
all-cause
mortality, CV
morbidity and SECRET452 20 mo 255 247 138/84 131/80 13 (5%)453 RR 0.97454
Candesartan Placebo nd 0.11 g/L nd Fair
all-cause graft 2010 EU[80] (37 mo) (255) (247) (138/85) (137/83) [13 (5%)] (0.46; 2.05)
failure
(CrCl<15mL/mi
n or dialysis)
Mortality
All-cause SECRET455 20 mo 255 247 138/84 131/80 3 (1%) RR 0.73456
mortality 2010 EU[80] (37 mo) (255) (247) (138/85) (137/83) [4 (2%)] (0.16; 3.21)
CV mortality
SECRET457 20 mo 255 247 138/84 131/80 9 (4%) RR 1.74458
CV mortality Candesartan Placebo nd 0.11 g/L nd Fair
2010 EU[80] (37 mo) (255) (247) (138/85) (137/83) [5 (2%)] (0.59; 5.13)
Proteinuria
Nephrotic
syndrome SECRET459 20 mo 255 247 138/84 131/80 2 (1%) RR 0.97460
(proteinuria 2010 EU[80] (37 mo) (255) (247) (138/85) (137/83) [2 (1%)] (0.14; 6.82)
>3.5g/24h)
452 A predefined interim analysis showed that there would be too few events to permit any conclusions about the effect of treatment on the primary efficacy variable within the planned time course of the study. The
trial was therefore terminated, and each patient made a final visit at the next scheduled time point.
453 Primary outcome
Supplemental Table 62. RCTs examining the effect of ARB vs. placebo in transplant recipients without DM [continuous outcome]
Intervention Control Intervention Control Proteinuria Intervention Intervention)
(Control) [Control]
(Control) (Control)
Proteinuria
∆Albumin
16.40 -1.80
concentration, 0.0001 Fair
(16.70) (+1.05)
mg/L
∆Protein
0.11 -0.01
concentration, SECRET461 20 mo 255 247 138/84 131/80 0.003 Fair
Candesartan Placebo nd 0.11 g/L (0.11) (0.00)
g/L 2010 EU[80] (37 mo) (255) (247) (138/85) (137/83)
∆UPE rate, 0.12 -0.01
<0.0001 Fair
g/24h (0.14) (+0.03)
Relative 0.01 -15.0
0.0003 Fair
∆UPCR, % (0.02) (+23.5)
Supplemental Table 63. RCTs examining the effect of intensified vs. conventional BP control on children with CKD without DM [categorical outcome]
Baseline P
Outcome) Year Outcome GFR or MAP MAP No (%) HR Quality
Composite kidney outcome
Intensified Conventional
↓50% GFR
BP control BP control GFR 46 HR 0.65
or ESCAPE 5y 182 190 90 Total cohort 46 (25%)
(Target MAP (Target MAP mL/min/1. UPCR 1.4 (0.44; 0.02 Good
progression 2009 EU[34] (5 y) (189) (196) (90) 82 [69 (36%)]
<50th 50th-95th 73 m2 0.94)
to ESRD
percentile) percentile)
Mortality
BP control BP control GFR 46
ESCAPE 5y 182 190 90 Total cohort 0 (0%)
Death (Target MAP (Target MAP mL/min/1. UPCR 1.4 -- nd Fair
2009 EU[34] (5 y) (189) (196) (90) 82 [1 (1%)]
<50th 50th-95th 73 m2
ESRD
Actuarial 5-y
rate of delay
in the ESCAPE 5y 182 190 90 Total cohort 70%
(Target MAP (Target MAP mL/min/1. UPCR 1.4 -- 0.02 Good
progression 2009 EU[34] (5 y) (189) (196) (90) 82 [58%]
<50th 50th-95th 73 m2
of renal
disease462
462 50% decline in the glomerular filtration rate or progression to end-stage renal disease
Supplemental Table 64. RCTs examining the effect of intensified vs. conventional BP control on children with CKD without DM [continuous outcome]
Outcome Year Outcome GFR or MAP MAP Quality
(Control) [Control]
(Control) (Control)
Kidney function
Annual
↓GFR rate, ESCAPE 5y 182 190 90 Total cohort 46 1.1
(Target MAP (Target MAP mL/min/1. UPCR 1.4 NS Good
mL/min/1.73 2009 EU[34] (5 y) (189) (196) (90) 82 (45) (2.5)
<50th 50th-95th 73 m2
m2
Proteinuria
Median ESCAPE 6 mo 372 90 Total cohort 0.82 (IQR 0.36 (IQR <0.000
(Target MAP (Target MAP mL/min/1. UPCR 1.4 Fair
UPE, g/g 2009 EU[34] (5 y) (385) (90) 82 0.27; 1.74) 0.11; 0.95) 1
<50th 50th-95th 73 m2
Supplemental Table 65. Age restriction in all RCTs for DM CKD, non-DM CKD, Transplant and CKD subgroups
Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6
Study, Year Inclusion Criteria
(mean age ± SD) (mean age ± SD) (mean age ± SD) (mean age ± SD) (mean age ± SD) (mean age ± SD)
DM
Males: 18-75y and
Lisinopril Nifedipine
Agardh 1996[5] Postmenopausal
(59 ± 9.0) (58 ± 8.9)
females: 40-75 y
Losartan Control
Agha 2009[6] nd
(53.9 ± 11.1) (54.7 ± 10.9)
Enalapril Nifedipine
J-MIND 2001[13] <75 y
(59.9 ± 8.6) (60.2 ± 8.9)
Telmisartan Losartan
AMADEO 2008[14] 21-80 y (60.0 ± 9.2) (60.5 ± 9.4)
66.8% <65y 62.1% <65 y
Enalapril Telmisartan
Barnett 2004[16] 35-80 y
(61.2 ± 8.5) (60.0 ± 9.1)
Irbesartan Amlodipine Placebo
IDNT 2003[18] 30-70 y
(59.3 ± 7.1) (59.1 ± 7.9) (58.3 ± 8.2)
Losartan Placebo
RENAAL 2001[20] 31-70 y
(60 ± 7) (60 ± 7)
Chan 1992[24] >18 y
(60.1 ± 9.2) (56.1 ± 9.9)
Chan 2000[25] nd
(60.0 ± 9.3) (56.2 ± 9.9)
Ramipril Lercanidipine
DIAL 2004[28] 40-70 y
(60 ± 7) (58 ± 7)
Eplerenone 100 mg Eplerenone 50 mg Placebo
[Median (25th-75th [Median (25th-75th [Median (25th-75th
Epstein 2006[33] nd
percentile)] percentile)] percentile)]
[58 (53; 66)] [58 (52; 66)] [60 (53; 66)]
Telmisartan Valsartan
VIVALDI 2008[37] 30-80 y
(60.9 ± 9.2) (61.4 ± 9.1)
Enalapril Losartan
Lacourciere 2000[48] nd
[57.8 (1.5)] [59.2 (9.2)]
Laffel 1995[49] 14-57 y
(32.0 ± 8.1) (33.4 ± 9.0)
Captopril Placebo
Lewis 1993[51] 18-49 y
(35 ± 7) (34 ± 8)
Irbesartan Amlodipine Placebo
IDNT 2001[52] 30-70 y
(59.3 ± 7.1) (59.1 ± 7.9) (58.3 ± 8.2)
Avosentan 50 mg Avosentan 25 mg Placebo
ASCEND 2010[60] 21-80 y
(61.0 ± 9.1) (61.2 ± 8.8) (60.8 ± 8.9)
Ramipril Placebo
DIABHYCAR 2004[65] >50 y
(65.2 ± 8.4) (65.0 ± 8.3)
Irbesartan 300 mg Irbesartan 150 mg Placebo
IRMA 2001[74] 30-70
(57.3 ± 7.9) (58.4 ± 8) (58.3 ± 8.7)
Aliskiren Placebo
AVOID 2008[75] 18-85 y
(58.9 ± 9.6) (61.8 ± 9.6)
Enalapril or Placebo
Ravid 1993[82] nd (44 ± 4)
[range 34; 49 y]
Lowest Tertile Losartan Lowest Tertile Placebo Middle Tertile Losartan Middle Tertile Placebo Highest Tertile Losartan Highest Tertile Placebo
RENAAL 2004[83] >30 y
(59.6 ± 7.4) (60.2 ± 7.5) (60.7 ± 7.2) (60.3 ± 7.6) (59.6 ± 7.4) (60.5 ± 7.4)
Lisinopril Telmisartan
Sengual 2006[88] 40-65
(56.7 ±8.3) (56.5 ±8.2)
Ramipril Placebo
Trevisan 1995[92] 18-65 y
(56 ± 7) (58 ± 7)
Valsartan Amlodipine
MARVAL 2002[95] 35-75 y (59) (57)
[range 36; 75] [range 35; 75]
Non-DM
Ramipril Amlodipine
AASK 2001[7] 18-70 y
(54.2 ± 10.9) (54.4 ± 10.7)
Candesartan 16mg Candesartan 64 mg Candesartan 128 mg
SMART 2009[22] 18-80 y
(56.5 ± 12.2) (58.4 ± 12.4) (54.6 ± 12.6)
Lisinopril Control
Cinotti 2001[26] 18-70 y
(49.6 ± 10.8) (52.1 ± 11.0)
Enalapril Mandipine
Del Vecchio 2004[30] 18-70 y
(52.9 ± 10.5) (56.4 ± 10.0)
Intensified BP Control Conventional BP Control
ESCAPE 2009[34] 3-18 y
(11.5 ± 4.1) (11.5 ± 4.0)
Enalapril Amlodipine
AVER 2008[35] 18-80 y
(58.3 ± 11.3) (57.5 ± 12.9)
Cilnidipine Amlodipine
CARTER 2007[36] 20-80 y
(59.9 ± 13.3) (59.3 ± 12.9)
Ramipril Placebo
GISEN 1997[2] nd
(48.9 ± 13.6) (49.7 ± 13.6)
Ramipril+Felodipine Ramipril Felodipine
[Median (25th-75th [Median (25th-75th [Median (25th-75th
Nephros 2001[41] 18-74 y
percentile)] percentile)] percentile)]
[52 (45; 60)] [53 (43; 61)] [54 (49; 62)]
Benazepril (SCr 1.5-3.0 Benazepril (SCr 3.1-5.0
Placebo
Hou 2006[43] 18-70 y mg/dL) mg/dL)
(45.0 ± 14.1)
(45.1 ± 13.0) (44.4 ± 16.8)
Benazepril (10 mg/d) Benazepril (40 mg/d) Losartan (50 mg/d) Losartan (200 mg/d)
Hou 2007[42] 18-70
(59.1 ± 12.6) (49.1 ± 14.3) (51.5 ± 13.3) (51.0 ± 13.5)
Losartan Amlodipine
J-LIGHT 2004[44] 20-74 y
(55.7 ± 13.6) (57.5 ± 11.9)
Telmisartan 40 mg, Telmisartan 80 mg, or Placebo
INNOVATION 2005[55] 30-74 y
(61.7 ± 7.9)
MDRD 1994[46] 18-70 y No ages given
Valsartan Placebo
HKVIN 2006[53] ≥18 y
(41 ± 9) (40 ± 10)
Fosinopril Nifedipine GTS
ESPIRAL 2001[64] 18-75 y
(53 ± 14) (56 ± 14)
Benazepril Placebo
Maschio 1996[66] 18-70 y
(51 ± 13) (51 ± 12)
Valsartan Lisinopril Valsartan+Lisinopril
VALERIA 2008[67] 18-75 y
(57.0 ± 11.4) (59.7 ± 9.5) (59.2 ± 11.4)
Ramipril or Amlodipine or Metroprolol
AASK 2006[70] 18-70 y
(55 ± 11)
Benidipine or Valsartan
Peng 2009[76] nd
(43.2 ± 9.5)
Low BP goal or Usual BP goal
MDRD 1995[79] 18-70 y
(325 pts <55y; 260 pts ≥55y)
Ramipril Control
Ruggenenti 1999[84] nd
(49.1 ± 1.3) (50.3 ± 1.5)
Intensified BP Control Conventional BP Control
REIN 2005[85] 18-70 y
(54.6 ± 14.7) (53.1 ± 15.8)
Low Target BP Usual Target BP
MDRD 2005[86] 18-70 y
(51.5 ± 12.6) (52.0 ± 12.2)
Monoxidine Nitrendipine
Vonend 2003[96] ≥18 y
(55.7 ± 14.0) (53.3 ± 13.4)
Normal dose ACE Low dose ACE Normal dose ARB Low dose ARB
Woo 2009[98] nd
(34 ± 10) (32 ± 12) (32 ± 10) (34 ± 11)
Ramipril Amlodipine Metroprolol Low BP target High BP target
AASK 2002[99] 18-70 y
(54.4 ± 10.9) (54.5 ± 10.7) (54.9 ± 10.4) (54.5 ± 10.9) (54.7 ± 10.4)
Txp
Losartan Captopril Amlodipine
el-Agroudy 2003[32] ≥18 y
(29.9 ± 8) (31.4 ± 8) (28.6 ± 7)
Lacidipine Placebo
Kuypers 2004[47] 18-65 y
(46.5 ± 12.6) (48.3 ± 12.6)
Nifedipine Lisinopril
Midvedt 2001[68] ≥18 y
(45.2 ± 8.4) (43.5 ± 13.1)
Candesartan Placebo
Philipp 2010[80] 30-69 y
(50.0 ± 11.6) (49.7 ± 10.9)
Nitrendipine Placebo
Rahn 1999[81] 18-60 y
(43 ± 1) (42 ± 1)
Isradipine Placebo
van Riemdijk 2000[94] 18-70 y (45) (46)
[range 21; 70] [range 25; 56]
General Population
Benazepril +
Benazepril + Amlodipine
Hydrochlorothalizide
ACCOMPLISH[15] ≥55 y (≥65: 77.2%; ≥75:
(≥65: 75.4%; ≥75:
35.7%)
28.9%)
CKD Stage 1/. CKD Stage 3
ADVANCE[29;40] ≥55 y
(65.0 ± 6.4) (68.3 ± 6.4)
ALLHAT[50] ≥55 y No ages given for CKD subgroup
CASE-J[87] 20-85 y No ages given
eGFR <75
EUROPA[19] ≥18 y
(65.2)
Candesartan Amlodipine
HOPE[57] ≥55 y
(65.6 ± 10.3) (65.3 ± 10.6)
MICRO-HOPE[4] ≥55 y No ages given for CKD subgroup
ONTARGET[63] ≥55 y No ages given
Active treatment Control
Pahor[72] ≥60 y
(73.9 ± 6.7) (74.1 ± 7.0)
eGFR<45: (70.2 ± 7.9)
PEACE[89;90] ≥50 y
eGFR 45.0-59.9: (68.0 ± 7.7)
Active Fosinopril Placebo
PREVEND IT[12] 28-95 y
(51.1 ± 12.2) (51.5 ± 12.2)
CKD Subgroup
PROGRESS[69] nd
(70 ± 8)
TRANSCEND[61] ≥55 y No ages given for CKD subgroup
CKD, No Proteinuria CKD, Proteinuria
Val-HeFT[10] nd
(66 ± 9) (65 ± 10)
Supplemental Table 66. PICO criteria for blood pressure targets in elderly studies
Baseline
Study Achieved BP mmHg
GFR or SCr Baseline
Author Population Duration Intervention Comparator Intervention Outcomes
Intervention Proteinuria
Year (Comparator)
(Control)
SCr ≤2.0 Primary outcome: Composite of cardiovascular
Moderate
Strict treatment (≤2.0) events: sudden death, fatal or non-fatal stroke,
VALISH[71] 70-85 years, stable seated treatment group
Median 3 group 137/75 mg/dL fatal or non-fatal MI, death due to heart failure,
Ogihara 2010 SBP of ≥160 to 199 mm Hg (SBP maintained nd
y (SBP<140 mm (142/77) (based on other cardiovascular death, hospitalization, and
UI20530299 N=3260 at ≥140 mm Hg
Hg) exclusion renal disorder
and <150 mm Hg)
criteria) HR 0.9 (0.6 to 1.34)
Primary outcome: Combined incidence of
Moderate SCr <1.5
Strict treatment cerebrovascular disease, cardiac and vascular
JATOS[45] Elderly (65-85) HTN patients treatment group (<1.5) mg/dL
group 136/75 disease and renal failure
Ishii 2008 SBP >160 mm Hg 2y (SBP maintained (based on nd
(SBP<140 mm (146/78) P=0.99
UI19139601 N=4508 at ≥140 mm Hg exclusion
Hg) (P value between the 2 treatment groups did not
and <150 mm Hg) criteria)
differ significantly)
Indapamide
Primary outcome: Fatal and non fatal stroke and
(slow release Placebo SCr 88.6
death
80+years, SBP ≥160 mm Hg 1.5 mg) (89.2)
51 events occurred in the active treatment group
HYVET[17] and <200 mm Hg sitting and Perindopril if Matching placebo μmol/L
Median 2 145/79 as compared with 69 events in the placebo
Beckett 2008 ≥140 mm Hg standing with a needed (Excluded nd
y (159/83) group. RR of fatal and non fatal stroke of 30% (-
UI18378519 sitting DBP of <110 mm Hg (SBP <150 mm (SBP <150 mm SCr >150
1 to 51; P=0.06)
N=3845 Hg Hg µmol/L or
RR of death from any cause of 21% (4 to 35;
DBP <80 mm DBP <80 mm Hg) 1.7 mg/dL)
P=0.02)
Hg)
Primary outcome: Clinical events and risk
modification.
77 events occurred in the placebo and 32 in the
Nifedipine Placebo
Patients 60-90 years, Nifedipine group. Significant reduction in relative
STONE[38] (SBP 140-159 (Safety level SBP
SBP≥160 mm Hg or DBP 147/85 risk was observed for strokes and severe
Gong 1996 30 mo mm Hg and ≥200 mm Hg or nd nd
≥96 mm Hg (156/92) arrhythmia with an overall decrease from 1.0 to
UI8906524 DBP 90 mm DBP ≥110 mm
N=1632 0.41 (CI 0.27 to 0.61). There was a significant
Hg) Hg)
decrease in RR in stages 2 and 3 HTN, which
corresponded to 28.8 and 16.1% with placebo
and Nifedipine.
Supplemental Table 67. Ages and BP targets in elderly studies
Entry age Mean age Entry SBP Entry DBP Target SBP Target DBP
Trial Year N Follow up (y)
(y) (y) (mm Hg) (mm Hg) (mm Hg) (mm Hg)
ALLHAT Old[73] 2003 5700 4.9 >75 NA ≤180 ≤110 <140 <90
<160 and <140 if <90 and <80 if
ANBP2[31] 2003 6083 4.1 65-84 71.9 ≥160 ≥90
tolerated tolerated
CASTEL[23] 1994 655 7.0 ≥65 73.7 ≥160 ≥95 NS NS
EWPHE[8] 1985 840 4.7 ≥60 72 160-239 90-119 NA <90
HEP[9] 1986 884 4.4 60-79 68.8 ≥170 ≥105 <170 <105
170-219 and
HYVET pilot[21] 2003 1283 1.1 ≥80 83.8 95-119 <150 <80
SBP≥140
≥160 -199 and
HYVET[17] 2008 3845 1.8 ≥80 83.6 90-110 <150 <80
≥140 standing
<140 (strict) or
JATOS[45] 2008 4418 2.0 65-85 NA ≥160 NS <160 but, at or NS
>140 (mild)
If ≥180, then ≤
MRC Older[93] 1992 4396 5.8 65-74 70.3 160-209 <114 160; if <180, then NA
≤150
NISC-EH[3] 1999 414 3.9-4.5 ≥60 69.8 160-220 <115 NA NA
SCOPE[54] 2003 4969 3.7 70-89 76.4 160-179 90-99 <160 <90
SHELL[56] 2003 1882 2.7 ≥60 72.4 ≥160 ≤95 ≤160 and >20 NA
If>180, then <160;
SHEP[1] 1991 4736 4.5 ≥60 71.6 160-219 <90 if 160-180, then - NA
20
STONE[38] 1996 1632 3.0 60-79 66.4 ≥160 >95 140-159 <90
180-230 and
STOP[27] 1991 1627 2.1 70-84 75.7 105-120 <160 <90
DBP≥90
STOP 2[39] 1999 6614 5.0 70-84 76 ≥180 ≥105 <160 <95
SYST China[97] 1998 2394 3.0 ≥60 66.5 160-219 <95 <150 and ≥20 NA
160-219 and
SYST Eur[91] 1997 4695 2.0 ≥60 70.3 <95 <150 and ≥20 NA
SBP≥140
Strict SBP<140
VALISH[71] 2010 3079 3.07 70-84 76.1 SBP 160-199 NS and moderate NS
≥140 to <150
Supplemental Table 68. PICO criteria for blood pressure agents in elderly studies
Achieved BP Baseline
Study
mmHg GFR or SCr Baseline
Author Population Duration Intervention Comparator Outcomes
Intervention Intervention Proteinuria
Year
(Comparator) (Control)
Primary outcome: Morbidity and mortality
Total cardiovascular mortality rate was
60 years old +, SBP significantly reduced (-38%, P=0.023)
between 160 and 239 Non-fatal morbid cardiovascular study-
EWPHE[8] HCTZ 25mg or
mmHg and between 90 148/85 terminating events occurred at a rate of 20/1000
Amery 1958 12 y Triamterene 50mg Placebo nd nd
and 119 mm Hg DBP (167/90) patients-years in the placebo group and 8/1000
UI2856778 (titrated)
sitting, consent patient-years in the actively treated group. This
N=840 reduction (-60%, P=0.0064) was mainly
accounted for by a 63% reduction in severe
CHF.
Primary outcome: Strokes, coronary events, and
death from all causes
Beta- Then number of strokes (fatal and non-fatal) was
Diuretic
blocker significantly reduced in people randomized to
Patients age 65-74, mean receive active treatment (101 v 134 placebo,
MRC[93]
SBP 160-209 mm Hg and 156/ 153/ 165/ P=0.04) with RR 25% (CI 3% to 42%). Coronary
Tuomilheto 1992 6y Placebo nd nd
mean DBP <115 mm Hg 77 75 84 events were less common in those allocated to
UI1352716
N=4396 active treatment (128 events) than in those
150 mm 160 mm receiving placebo (159; P=0.08) with RR of 19%
Hg Hg (-2% to 36%). All cause mortality was similar in
the treated and placebo groups (23.9 v 24.7 per
patient-years).
Primary outcome: Major cardiovascular events,
SCr 88.0
a composite of cardiovascular death, non-fatal
μmol/L
stroke and non-fatal MI.
Patients 70-89 years, SBP (89.0
A first major cardiovascular event occurred in
160-179 mm Hg, DBP 90- μmol/L)
SCOPE[54] 242 candesartan patients and in 268 placebo
99 mm Hg, mini mental 145/80 (Excluded
Lithell 2003 4y Candesartan Placebo nd patients: RR with candesartan was 10.9% (-6.0
state examination test (149/82) SCr >180
UI12714861 to 25.1, P=0.19). Candesartan treatment
score ≥24 μmol/L in
reduced non-fatal stroke by 27.8% (1.3 to 47.2,
N=4964 men and
P=0.04) and all stroke by 23.6% (-0.7 to 42.1,
>140 μmol/L
P=0.056). There were no significant differences
in women)
in MI and cardiovascular mortality.
Primary outcome: Composite of cardiovascular

SCr >2.0
Patients ≥60 years, sitting Prospective study with open design and cerebrovascular events.
SHELL[56] (>2.0) mg/dL
SBP ≥160 mm Hg with a 142/79 Overall incidence of the primary endpoint was
Malacco 2003 3y (based on nd
DBP ≤95 mm Hg (143/80) 9.3% with no significant between-group
UI12875478 exclusion
N=1882 difference. Total mortality was also similar
criteria)
between groups.
Lacidipine Chlorthalidone
Study
Year
SHEP[1]
Primary outcome: Non fatal and fatal stroke
SHEP 60+ years old, SBP from
Chlorthalidone The 5 year incidence of total stroke was 5.2 per
Cooperative 160-219 mm Hg and DBP 144/68
5y (step 1) Placebo nd nd 100 participants for active treatment and 8.2 per
Research Group <90 mm Hg (155/71
Atenolol (step 2) 100 for placebo. RR by proportional hazards
1991 N=4736
regression analysis was 0.64 (P=.0003)
UI2046107
Primary outcome: Clinical events and risk
modification.
77 events occurred in the placebo and 32 in the
Placebo
Patients 60-90 years, Nifedipine Nifedipine group. Significant reduction in relative
STONE[38] (Safety level
SBP≥160 mm Hg or DBP (SBP 140-159 147/85 risk was observed for strokes and severe
Gong 1996 3y SBP ≥200 nd nd
≥96 mm Hg mmHg and DBP 90 (156/92) arrhythmia with an overall decrease from 1.0 to
UI8906524 mmHg or DBP
N=1632 mm Hg) 0.41 (CI 0.27 to 0.61). There was a significant
≥110 mm Hg)
decrease in RR in stages 2 and 3 HTN, which
corresponded to 28.8 and 16.1% with placebo
and Nifedipine.
Primary outcome: Fatal and non fatal stroke and
Patients 70-84 years, SBP
MI and other cardiovascular death.
between 180-230 mm Hg
Active treatment significantly reduced the
STOP[27] and DBP of at least 90 Atenolol, HCTZ plus
166/85 number of primary endpoints (94 v 58;
Dahlof 1991 mm Hg or DBP between 5y Amiloride, or Placebo nd nd
(193/95) P=0.0031) and stroke morbidity and mortality
UI1682683 105 and 120 mm Hg Prindolol
(53 v 29; P=0.0081). There was also a
irrespective of the SBP.
significant reduced number of deaths in the
N=1627
active treatment group (63 v 36; P=0.0079)
Primary outcome: The composite of fatal and
non fatal stroke and MI and other cardiovascular
Conventiona disease.
Patients 70-84 years, SBP l drugs: The primary combined endpoint occurred in 221
between 180-230 mm Hg Atenolol, Enalapril Felodipin of 2213 patients in the conventional drugs group
STOP 2[39] and DBP of at least 90 HCTZ plus or e or (19.8 events per 1000 patient-years) and in 438
158/ 159/ 159/
Hansson 1999 mmHg or DBP between 5y Amiloride, Lisinopril Isradipine nd nd of 4401 in the newer drugs group (19.8 per
81 81 80
UI10577635 105 and 120 mm Hg Prindolol or (<160/95 (<160/95 1000; relative risk 0.99 (CI 0.84 to 1.16),
irrespective of the SBP. Metoprolol mmHg) mmHg) P=0.89). The combined endpoint of fatal and
N=6617 (<160/95 non fatal stroke and MI and other cardiovascular
mmHg) mortality occurred in 460 patients taking
conventional drugs and in 887 taking newer
drugs (CI 0.96 (0.86 to 1.08), P=0.49)
Study
Year
Primary outcome: Cardiovascular mortality, fatal
and nonfatal cardiovascular events and strokes.
In the placebo group diabetes raised the risk of
all end points 2-to 2-fold (P≤0.05). However,
SCr >2.0 active treatment reduced the excess risk
mg/dL associated with diabetes to a non significant
Patients 60+ years, sitting
SYST China[97] (SCr >2.0 level (P values ranging from .12 to 86) except for
SBP 160-219 mm Hg and ↓20/5
Wang 2000 3y Nitrendipine Placebo mg/dL) nd cardiovascular mortality (P=0.04). Active
DBP <95 mm Hg (↓11/2)
UI10647760 (based on treatment had reduced the incidence of total
N=1253
exclusion mortality (P<0.01), fatal and nonfatal stroke
criteria) (P<0.05), and all cardiovascular end points
(P<0.01). In single and multiple regression, all
end points with the exception of fatal and
nonfatal stroke were positively correlated with
SBP.
Primary outcome: Fatal and non fatal stroke.
Active treatment reduced the total rate of stroke
from 13.7 to 7.9 endpoints per 1000 patients-
years (42% reduction; P=0.003). Non-fatal
SCr >2.0
stroke decreased by 44% (P=0.007). In the
mg/dL
Patients 60+years old, active treatment group, all fatal and non-fatal
SYST Eur[91] (SCr >2.0
sitting SBP 160-219 mm 151/79 cardiac endpoints, including sudden death,
Staessen 1997 2y Nitrendipine Placebo mg/dL) nd
Hg and DBP <95 mm Hg (161/84) declined by 26% (P=0.03). Non fatal cardiac
UI9297994 (based on
N=4695 endpoints decreased by 33% (P=0.03) and all
exclusion
fatal and non fatal cardiovascular endpoints by
criteria)
31% (p<0.001). Cardiovascular mortality was
slightly lower on active treatment (-27%,
P=0.07), but all cause mortality was not
influenced (-14%; P=0.22).
Primary outcome: All CV events or death from
65-84 years old, SBP
any cause.
ANBP2[31] >160 mm Hg or an
141/79 The HR for all CV events or death from any
Doggrell 2003 average DBP of >90 mm 4y ACEI Diuretic nd nd
(142/79) cause among subjects in the ACEI group as
UI12740004 Hg
compared with that of the Diuretic group was
N=6083
0.89 (95% CI, 0.79 to 1.00; P=0.05).
References
1. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final
results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA
265:3255-3264, 1991
2. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of
terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi
Epidemiologici in Nefrologia). Lancet 349(9069):1857-63, 1997
3. Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. National
Intervention Cooperative Study in Elderly Hypertensives Study Group. Hypertension 34:1129-1133, 1999
4. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the
HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet
355(9200):253-9, 2000
5. Agardh CD, Garcia-Puig J, Charbonnel B et al.: Greater reduction of urinary albumin excretion in hypertensive
type II diabetic patients with incipient nephropathy by lisinopril than by nifedipine. Journal of Human
Hypertension 10(3):185-92, 1996
6. Agha A, Amer W, Anwar E, Bashir K: Reduction of microalbuminuria by using losartan in normotensive patients
with type 2 diabetes mellitus: A randomized controlled trial. Saudi Journal of Kidney Diseases &
Transplantation429-435, 1920
7. Agodoa LY, Appel L, Bakris GL et al.: Effect of ramipril vs amlodipine on renal outcomes in hypertensive
nephrosclerosis: a randomized controlled trial. JAMA 285(21):2719-28, 2001
8. Amery A, Birkenhager W, Brixko P et al.: Influence of hypotensive drug treatment in elderly hypertensives: study
terminating events in the trial of the European Working Party on High Blood Pressure in the Elderly. Journal of
Hypertension - Supplement 3(3):S501-11, 1985
9. Amery A, Birkenhager W, Brixko P et al.: Influence of antihypertensive drug treatment on morbidity and
mortality in patients over the age of 60 years. European Working Party on High blood pressure in the Elderly
(EWPHE) results: sub-group analysis on entry stratification. Journal of Hypertension - Supplement 4:S642-S647,
1986
10. Anand IS, Bishu K, Rector TS et al.: Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor
blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart
failure. Circulation 120(16):1577-84, 2009
11. Appel LJ, Wright JT, Jr., Greene T et al.: Intensive blood-pressure control in hypertensive chronic kidney disease.
New England Journal of Medicine 363(10):918-29, 2010
12. Asselbergs FW, Diercks GF, Hillege HL et al.: Effects of fosinopril and pravastatin on cardiovascular events in
subjects with microalbuminuria. Circulation 110(18):2809-16, 2004
13. Baba S, -MIND Study Group: Nifedipine and enalapril equally reduce the progression of nephropathy in
hypertensive type 2 diabetics. Diabetes Research & Clinical Practice 54(3):191-201, 2001
14. Bakris G, Burgess E, Weir M et al.: Telmisartan is more effective than losartan in reducing proteinuria in patients
with diabetic nephropathy. Kidney International 74(3):364-9, 2008
15. Bakris GL, Sarafidis PA, Weir MR et al.: Renal outcomes with different fixed-dose combination therapies in
patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary
analysis of a randomised controlled trial. Lancet 375(9721):1173-81, 2010
16. Barnett AH, Bain SC, Bouter P et al.: Angiotensin-receptor blockade versus converting-enzyme inhibition in type
2 diabetes and nephropathy. New England Journal of Medicine 351(19):1952-61, 2004
17. Beckett NS, Peters R, Fletcher AE et al.: Treatment of hypertension in patients 80 years of age or older. New
England Journal of Medicine 358:1887-1898, 2008
18. Berl T, Hunsicker LG, Lewis JB et al.: Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of
patients with type 2 diabetes and overt nephropathy. Annals of Internal Medicine 138(7):542-9, 2003
19. Bertrand ME, Fox KM, Remme WJ et al.: Angiotensin-converting enzyme inhibition with perindopril in patients
with prior myocardial infarction and/or revascularization: a subgroup analysis of the EUROPA trial. Archives of
cardiovascular diseases 102(2):89-96, 2009
20. Brenner BM, Cooper ME, de ZD et al.: Effects of losartan on renal and cardiovascular outcomes in patients with
type 2 diabetes and nephropathy. New England Journal of Medicine 345(12):861-9, 2001
21. Bulpitt CJ, Beckett NS, Cooke J et al.: Results of the pilot study for the Hypertension in the Very Elderly Trial.
Journal of Hypertension 21:2409-2417, 2003
22. Burgess E, Muirhead N, Rene de CP et al.: Supramaximal dose of candesartan in proteinuric renal disease.
Journal of the American Society of Nephrology893-900, 1920
23. Casiglia E, Spolaore P, Mazza A et al.: Effect of two different therapeutic approaches on total and cardiovascular
mortality in a Cardiovascular Study in the Elderly (CASTEL). Japanese Heart Journal 35:589-600, 1994
24. Chan JC, Cockram CS, Nicholls MG et al.: Comparison of enalapril and nifedipine in treating non-insulin
dependent diabetes associated with hypertension: one year analysis. BMJ 305(6860):981-5, 1992
25. Chan JC, Ko GT, Leung DH et al.: Long-term effects of angiotensin-converting enzyme inhibition and metabolic
control in hypertensive type 2 diabetic patients. Kidney International 57(2):590-600, 2000
26. Cinotti GA, Zucchelli PC, Collaborative Study Group: Effect of Lisinopril on the progression of renal
insufficiency in mild proteinuric non-diabetic nephropathies. Nephrology Dialysis Transplantation 16:961-966,
2001
27. Dahlof B, Lindholm LH, Hansson L et al.: Morbidity and mortality in the Swedish Trial in Old Patients with
Hypertension (STOP-Hypertension). Lancet 338:1281-1285, 1991
28. Dalla VM, Pozza G, Mosca A et al.: Effect of lercanidipine compared with ramipril on albumin excretion rate in
hypertensive Type 2 diabetic patients with microalbuminuria: DIAL study (diabete, ipertensione, albuminuria,
lercanidipina). Diabetes, Nutrition & Metabolism - Clinical & Experimental 17(5):259-66, 2004
29. de Galan BE, Perkovic V, Ninomiya T et al.: Lowering blood pressure reduces renal events in type 2 diabetes.
Journal of the American Society of Nephrology883-892, 2009
30. Del Vecchio L., Pozzi M, Salvetti A et al.: Efficacy and tolerability of manidipine in the treatment of
hypertension in patients with non-diabetic chronic kidney disease without glomerular disease. Prospective,
randomized, double-blind study of parallel groups in comparison with enalapril. Journal of Nephrology
17(2):261-9,-Apr, 2004
31. Doggrell SA: ACE inhibitors versus diuretics: ALLHAT versus ANBP2. Expert Opin Pharmacother 4:825-828,
2003
32. el-Agroudy AE, Hassan NA, Foda MA et al.: Effect of angiotensin II receptor blocker on plasma levels of TGF-
beta 1 and interstitial fibrosis in hypertensive kidney transplant patients. American Journal of Nephrology
23(5):300-6,-Oct, 2003
33. Epstein M, Williams GH, Weinberger M et al.: Selective aldosterone blockade with eplerenone reduces
albuminuria in patients with type 2 diabetes. Clinical Journal of The American Society of Nephrology: CJASN
1(5):940-51, 2006
34. ESCAPE Trial Group, Wuhl E, Trivelli A et al.: Strict blood-pressure control and progression of renal failure in
children. New England Journal of Medicine 361(17):1639-50, 2009
35. Esnault VL, Brown EA, Apetrei E et al.: The effects of amlodipine and enalapril on renal function in adults with
hypertension and nondiabetic nephropathies: a 3-year, randomized, multicenter, double-blind, placebo-controlled
study. Clinical Therapeutics 30(3):482-98, 2008
36. Fujita T, Ando K, Nishimura H et al.: Antiproteinuric effect of the calcium channel blocker cilnidipine added to
renin-angiotensin inhibition in hypertensive patients with chronic renal disease. Kidney International
72(12):1543-9, 2007
37. Galle J, Schwedhelm E, Pinnetti S et al.: Antiproteinuric effects of angiotensin receptor blockers: telmisartan
versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathy. Nephrology
Dialysis Transplantation 23(10):3174-83, 2008
38. Gong L, Zhang W, Zhu Y et al.: Shanghai trial of nifedipine in the elderly (STONE). Journal of Hypertension
14:1237-1245, 1996
39. Hansson L, Lindholm LH, Ekbom T et al.: Randomised trial of old and new antihypertensive drugs in elderly
patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study.
Lancet 354:1751-1756, 1999
40. Heerspink HJ, Ninomiya T, Perkovic V et al.: Effects of a fixed combination of perindopril and indapamide in
patients with type 2 diabetes and chronic kidney disease. European Heart Journal 31(23):2888-96, 2010
41. Herlitz H, Harris K, Risler T et al.: The effects of an ACE inhibitor and a calcium antagonist on the progression
of renal disease: the Nephros Study. Nephrology Dialysis Transplantation 16(11):2158-65, 2001
42. Hou FF, Xie D, Zhang X et al.: Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized
controlled study of benazepril and losartan in chronic renal insufficiency. Journal of the American Society of
Nephrology 18(6):1889-98, 2007
43. Hou FF, Zhang X, Zhang GH et al.: Efficacy and safety of benazepril for advanced chronic renal insufficiency.
44. Iino Y, Hayashi M, Kawamura T et al.: Renoprotective effect of losartan in comparison to amlodipine in patients
with chronic kidney disease and hypertension--a report of the Japanese Losartan Therapy Intended for the Global
Renal Protection in Hypertensive Patients (JLIGHT) study. Hypertension Research - Clinical & Experimental
27(1):21-30, 2004
45. JATOS Study Group: Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly
hypertensive patients (JATOS). Hypertension Research - Clinical & Experimental 31:2115-2127, 2008
46. Klahr S, Levey AS, Beck GJ et al.: The effects of dietary protein restriction and blood-pressure control on the
progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. New England Journal
of Medicine 330(13):877-84, 1994
47. Kuypers DR, Neumayer HH, Fritsche L et al.: Calcium channel blockade and preservation of renal graft function
in cyclosporine-treated recipients: a prospective randomized placebo-controlled 2-year study. Transplantation
78(8):1204-11, 2004
48. Lacourciere Y, Belanger A, Godin C et al.: Long-term comparison of losartan and enalapril on kidney function in
hypertensive type 2 diabetics with early nephropathy. Kidney International 58(2):762-9, 2000
49. Laffel LM, McGill JB, Gans DJ: The beneficial effect of angiotensin-converting enzyme inhibition with captopril
on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American
Microalbuminuria Study Group. American Journal of Medicine 99(5):497-504, 1995
50. Levey AS, Uhlig K: Which antihypertensive agents in chronic kidney disease? Annals of Internal Medicine
144(3):213-5, 2006
51. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on
diabetic nephropathy. The Collaborative Study Group. New England Journal of Medicine 329(20):1456-62, 1993
52. Lewis EJ, Hunsicker LG, Clarke WR et al.: Renoprotective effect of the angiotensin-receptor antagonist
irbesartan in patients with nephropathy due to type 2 diabetes. New England Journal of Medicine 345(12):851-60,
2001
53. Li PK, Leung CB, Chow KM et al.: Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-
blind, randomized, placebo-controlled study. American Journal of Kidney Diseases 47(5):751-60, 2006
54. Lithell H, Hansson L, Skoog I et al.: The Study on Cognition and Prognosis in the Elderly (SCOPE): principal
results of a randomized double-blind intervention trial. Journal of Hypertension 21:875-886, 2003
55. Makino H, Haneda M, Babazono T et al.: Prevention of transition from incipient to overt nephropathy with
telmisartan in patients with type 2 diabetes. Diabetes Care 30(6):1577-8, 2007
56. Malacco E, Mancia G, Rappelli A et al.: Treatment of isolated systolic hypertension: the SHELL study results.
Blood Pressure 12:160-167, 2003
57. Mann JF, Gerstein HC, Pogue J et al.: Renal insufficiency as a predictor of cardiovascular outcomes and the
impact of ramipril: the HOPE randomized trial. Annals of Internal Medicine 134(8):629-36, 2001
58. Mann JF, Gerstein HC, Pogue J et al.: Renal insufficiency as a predictor of cardiovascular outcomes and the
impact of ramipril: the HOPE randomized trial. Annals of Internal Medicine 134:629-636, 2001
59. Mann JF, Gerstein HC, Yi QL et al.: Progression of renal insufficiency in type 2 diabetes with and without
microalbuminuria: results of the Heart Outcomes and Prevention Evaluation (HOPE) randomized study. American
Journal of Kidney Diseases 42:936-942, 2003
60. Mann JF, Green D, Jamerson K et al.: Avosentan for overt diabetic nephropathy. Journal of the American Society
of Nephrology 21(3):527-35, 2010
61. Mann JF, Schmieder RE, Dyal L et al.: Effect of telmisartan on renal outcomes: a randomized trial. Annals of
Internal Medicine 151:1-10, 2009
62. Mann JF, Schmieder RE, Dyal L et al.: Effect of telmisartan on renal outcomes: a randomized trial. Annals of
Internal Medicine 151(1):1-10, W1-2, 2009
63. Mann JF, Schmieder RE, McQueen M et al.: Renal outcomes with telmisartan, ramipril, or both, in people at high
vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet
372(9638):547-53, 2008
64. Marin R, Ruilope LM, Aljama P et al.: A random comparison of fosinopril and nifedipine GITS in patients with
primary renal disease. Journal of Hypertension1871-1876, 2001
65. Marre M, Lievre M, Chatellier G et al.: Effects of low dose ramipril on cardiovascular and renal outcomes in
patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo
controlled trial (the DIABHYCAR study). BMJ 328(7438):495, 2004
66. Maschio G, Alberti D, Janin G et al.: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the
progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal
Insufficiency Study Group. New England Journal of Medicine 334(15):939-45, 1996
67. Menne J, Farsang C, Deak L et al.: Valsartan in combination with lisinopril versus the respective high dose
monotherapies in hypertensive patients with microalbuminuria: the VALERIA trial. Journal of Hypertension
26(9):1860-7, 2008
68. Midtvedt K, Hartmann A, Foss A et al.: Sustained improvement of renal graft function for two years in
hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril. Transplantation
72(11):1787-92, 2001
69. Ninomiya T, Perkovic V, Gallagher M et al.: Lower blood pressure and risk of recurrent stroke in patients with
chronic kidney disease: PROGRESS trial. Kidney International 73(8):963-70, 2008
70. Norris K, Bourgoigne J, Gassman J et al.: Cardiovascular outcomes in the African American Study of Kidney
Disease and Hypertension (AASK) Trial. American Journal of Kidney Diseases 48(5):739-51, 2006
71. Ogihara T, Saruta T, Rakugi H et al.: Target blood pressure for treatment of isolated systolic hypertension in the
elderly: valsartan in elderly isolated systolic hypertension study. Hypertension 56:196-202, 2010
72. Pahor M, Shorr RI, Somes GW et al.: Diuretic-based treatment and cardiovascular events in patients with mild
renal dysfunction enrolled in the systolic hypertension in the elderly program. Archives of Internal Medicine
158(12):1340-5, 1998
73. Papademetriou V, Piller LB, Ford CE et al.: Characteristics and lipid distribution of a large, high-risk,
hypertensive population: the lipid-lowering component of the Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT). Journal of Clinical Hypertension 5:377-384, 2003
74. Parving HH, Lehnert H, Brochner-Mortensen J et al.: The effect of irbesartan on the development of diabetic
nephropathy in patients with type 2 diabetes. New England Journal of Medicine 345(12):870-8, 2001
75. Parving HH, Persson F, Lewis JB et al.: Aliskiren combined with losartan in type 2 diabetes and nephropathy.
76. Peng T, Hu Z, Xia Q et al.: A comparative study of the renoprotective effects of benidipine and valsartan in
primary hypertensive patients with proteinuria. Arzneimittel-Forschung 59(12):647-50, 2009
77. Perkovic V, Ninomiya T, Arima H et al.: Chronic kidney disease, cardiovascular events, and the effects of
perindopril-based blood pressure lowering: data from the PROGRESS study. Journal of the American Society of
Nephrology 18(10):2766-72, 2007
78. Persson F, Lewis JB, Lewis EJ et al.: Impact of baseline renal function on the efficacy and safety of aliskiren
added to losartan in patients with type 2 diabetes and nephropathy. Diabetes Care 33(11):2304-9, 2010
79. Peterson JC, Adler S, Burkart JM et al.: Blood pressure control, proteinuria, and the progression of renal disease.
The Modification of Diet in Renal Disease Study. Annals of Internal Medicine 123(10):754-62, 1995
80. Philipp T, Martinez F, Geiger H et al.: Candesartan improves blood pressure control and reduces proteinuria in
renal transplant recipients: results from SECRET. Nephrology Dialysis Transplantation 25(3):967-76, 2010
81. Rahn KH, Barenbrock M, Fritschka E et al.: Effect of nitrendipine on renal function in renal-transplant patients
treated with cyclosporin: a randomised trial. Lancet 354(9188):1415-20, 1999
82. Ravid M, Lang R, Rachmani R, Lishner M: Long-term renoprotective effect of angiotensin-converting enzyme
inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Archives of Internal Medicine
156(3):286-9, 1996
83. Remuzzi G, Ruggenenti P, Perna A et al.: Continuum of renoprotection with losartan at all stages of type 2
diabetic nephropathy: a post hoc analysis of the RENAAL trial results. Journal of the American Society of
Nephrology 15(12):3117-25, 2004
84. Ruggenenti P, Perna A, Gherardi G et al.: Renoprotective properties of ACE-inhibition in non-diabetic

nephropathies with non-nephrotic proteinuria. Lancet 354(9176):359-64, 1999
85. Ruggenenti P, Perna A, Loriga G et al.: Blood-pressure control for renoprotection in patients with non-diabetic
chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 365(9463):939-46,-18, 2005
86. 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. Annals of Internal Medicine
142(5):342-51, 2005
87. Saruta T, Hayashi K, Ogihara T et al.: Effects of candesartan and amlodipine on cardiovascular events in
hypertensive patients with chronic kidney disease: subanalysis of the CASE-J Study. Hypertension Research -
Clinical & Experimental 32(6):505-12, 2009
88. Sengul AM, Altuntas Y, Kurklu A, Aydin L: Beneficial effect of lisinopril plus telmisartan in patients with type 2
diabetes, microalbuminuria and hypertension. Diabetes Research & Clinical Practice 71(2):210-9, 2006
89. Solomon SD, Lin J, Solomon CG et al.: Influence of albuminuria on cardiovascular risk in patients with stable
coronary artery disease. Circulation 116(23):2687-93, 2007
90. Solomon SD, Rice MM, Jablonski A et al.: Renal function and effectiveness of angiotensin-converting enzyme
inhibitor therapy in patients with chronic stable coronary disease in the Prevention of Events with ACE inhibition
(PEACE) trial. Circulation 114(1):26-31, 2006
91. Staessen JA, Fagard R, Thijs L et al.: Randomised double-blind comparison of placebo and active treatment for
older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial
Investigators. Lancet 350:757-764, 1997
92. Trevisan R, Tiengo A: Effect of low-dose ramipril on microalbuminuria in normotensive or mild hypertensive
non-insulin-dependent diabetic patients. North-East Italy Microalbuminuria Study Group. American Journal of
Hypertension 8(9):876-83, 1995
93. Tuomilehto J: MRC trial of treating hypertension in older adults. BMJ 304:1631-1632, 1992
94. van R, I, Mulder PG, de Fijter JW et al.: Addition of isradipine (Lomir) results in a better renal function after
kidney transplantation: a double-blind, randomized, placebo-controlled, multi-center study. Transplantation
70(1):122-6, 2000
95. Viberti G, Wheeldon NM, MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators:
Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent
effect. Circulation 106(6):672-8, 2002
96. Vonend O, Marsalek P, Russ H et al.: Moxonidine treatment of hypertensive patients with advanced renal failure.
Journal of Hypertension 21(9):1709-17, 2003
97. Wang JG, Staessen JA, Gong L, Liu L: Chinese trial on isolated systolic hypertension in the elderly. Systolic
Hypertension in China (Syst-China) Collaborative Group. Archives of Internal Medicine 160:211-220, 2000
98. Woo KT, Chan CM, Tan HK et al.: Beneficial effects of high-dose losartan in IgA nephritis. Clinical Nephrology
71(6):617-24, 2009
99. Wright JT, Jr., Bakris G, Greene T et al.: Effect of blood pressure lowering and antihypertensive drug class on
progression of hypertensive kidney disease: results from the AASK trial. JAMA 288(19):2421-31, 2002

Kdigo BP GL Suppl Table Dec 2012

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Kdigo BP GL Suppl Table Dec 2012

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KDIGO CLINICAL PRACTICE GUIDELINE

FOR THE MANAGEMENT OF BLOOD PRESSURE

Supplemental Table 1. General population RCTs comparing BP targets in CKD subgroups

∆ Change KDOQI Kidney Disease Outcomes Quality Initiative

Any coronary 16 (7%) HR 0.62

7 Shaded studies were included in previous KDOQI guideline

20 From post-trial follow up data

25 For patients ≥61 y, target was ≤98 mmHg

36 Noted as statistically significant in letter to Annals by Good, 2005

53 Shaded studies were included in previous KDOQI guideline

63 Study only included African American patients

Death in patients Val-HeFT Serum

97 Shaded studies were included in previous KDOQI guideline

112 All Chinese patients

122 All Chinese patients

131 Calculated by ERT

137 Shaded studies were included in previous KDOQI guideline

144 All Chinese patients

148 AASK study includes death in composite outcome.

150 Study only included African American patients

154 Primary outcome

160 Study only included African American patients

168 Study only included African American patients

172 Primary outcome

174 All Chinese patients

179 ERT estimated from graph

183 All Chinese patients

199 All Chinese patients

203 All Chinese patients

215 All Chinese patients

221 All Chinese patients

233 All Chinese patients

236 All Chinese patients

242 Study only included African American patients

249 Study only included African American patients

257 Study only included African American patients

259 Primary outcome

262 Primary outcome

263 Primary outcome

266 Primary outcome

267 Calculated by ERT

271 Primary outcome

272 Study only included African American patients

288 Study only included African American patients

291 Estimated from graph

292 UACR 30-300 μg/mg

Major vascular event

308 Estimated from figure

318 Shaded studies were included in previous KDOQI guideline

327 Primary outcome

333 No of events calculated by ERT

348 Calculated by ERT

∆Proteinuria, Trevisan 1995 6 mo 54 54 SCr 1.0 147/90 142/87 62 -9

353 Shaded studies were included in previous KDOQI guideline

361 Estimated from graph

366 Shaded studies were included in previous KDOQI guideline

373 The J-MIND contains both micro- and normo-albuminuric patients

379 The J-MIND contains both micro- and normo-albuminuric patients

384 Shaded studies were included in previous KDOQI guideline

390 Estimated from figure

396 Estimated from figure

407 Calculated by ERT

415 Calculated by ERT