Evidence Table 10Data abstraction of nondiabetic chronic kidney disease trials

ACE/ARB: Coronary heart disease (CHD)
SN abstractions
Author Year
Country
Trial Name
(Quality Score)
Study Design

Setting

Follow-up interval
Eligibility criteria

Inclusion criteria

Exclusion criteria
Proteinuric CKD
-Types
-Biopsy proven?
-Degree of proteinuria
Level of CKD
-Stages
-Method of defining CKD
InterventionsRun-in/Washout PeriodAllowed other medications/interventionsMethod of Outcome Assessment and Timing of AssessmentAge
Gender
Ethnicity
Other population characteristicsNumber screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedResultsResults: Quality of life; healthcare utilizationPopulation subgroup analysesMethod of adverse events assessmentAdverse Events ReportedTotal withdrawals; withdrawals due to adverse eventsCommentsComments, internal use
Agarwal 2001
US
no trial name
Fair
Study design: cross-over, randomized, controlled trial.

Setting: NR

Duration: not explicitly stated: 10 weeks based on treatment groups and wash-out period.
Inclusion criteria:
Age 18–80
Proteinuria ≥ 1 gm/day
Hypertension (mean arterial pressure >97 mmHg)
Serum potassium ≤ 5.5 mEq/L
Current use of Lisinopril 40 mg/day for > 3 mo

Exclusion criteria:
Previous use of ARB
Estimated creatinine clearance < 30 ml/min
Types of CKD:
4 glomerulonephritis
12 Diabetic nephropathy

Proteinuria ≥ 1 gm/day required.
Baseline proteinuria ranged from 3–4 gm/d
Stage of CKD not specifically addressed.

Estimated CrCl required to be >30 ml/min; baseline CrCl NR.

Baseline GFR ranged from 60–70 ml/min GFR obtained via iothalamate clearance
Participants randomized to two groups:
P: Placebo x4 weeks first then crossover to Losartan 50mg/d x4 weeks.
L: Losartan 50mg/d x4 weeks first then crossover to Placebo x4 weeks.
2 week wash-out between initial arm and cross-over armPatients were maintained on baseline dose of Lisinopril 40mg/d as well as other anti-hypertensive therapy.

Other anti-hypertensive’s used included:
calcium channel blockers β-blockers
α-blockers
Loop diuretics
Thiazide diuretics
Primary hypothesis stated to be that Losartan would decrease proteinuria by at least 25% when added to ACE-I compared to placebo added to ACE-I.

Assessment done 4 times (before and after each treatment period, and included:
GFR via iothalamate
24 hr urine collection of protein
Serum laboratory values
Mean age: 53 +/− 9

Gender (male/female): 14/16

Ethnicity:
6 white
10 black
Mean baseline creatinine overall: 2.0 +/− 0.8 mg/dL

Baseline proteinuria per group:
P: 3.6 +/− 0.71 gm/d
L: 3.56 +/− 0.75 gm/d
Baseline GFR per group:
P: 69 +/− 10 ml/min
L: 63 +/− 9 ml/min

Baseline seated blood pressure:
156 (SD 18,88) +/− 12 mmHg
Number screened: NR

Number eligible: NR

Number enrolled: 17
Number withdrawn: 1

Lost to follow up: not reported (one withdrawal was due to inability to keep scheduled appointments - unclear if “lost” to follow up).

Analyzed: 16
Change in proteinuria (baseline to post treatment):
P: 3.6 +/− 0.71 gm/d to 3.08 +/− 0.55 gm/d
L: 3.56 +/− 0.75 gm/d to 3.42 +/− 0.87 gm/d
Placebo corrected change: +1%
95% CI −20% to +28%
p = 0.82, no significant difference noted between groups.

Change in creatinine (baseline to post treatment):
P: 2 +/− 0.2 mg/dL to 2.1 +/− 0.21 mg/dL
L: 2.1 +/− 0.22 to 2.1 +/− 0.23 mg/dL
Placebo corrected change −0.11
95% CI −0.31 to +0.10
p = 0.30, no significant difference noted between groups.

Change in GFR (baseline to post treatment):
P: 69 +/− 10 ml/min to 64 +/− 9 ml/min
L: 63 +/− 9 ml/min to 68 +/− 11 ml/min
Placebo corrected change +14%
95% CI 3% to 26%
p = 0.017; GFR found to increase significantly in L vs. P

No statistically significant change in systolic or diastolic ambulatory blood pressures between groups.
NRNRNRNRWithdrawal: 1
*due to patients inability to keep scheduled appointments for assessment testing

Withdrawals due to adverse effects: none reported
Bakris
2000 US
VAL-K
Fair
Study design:
multicenter, randomized, double-crossover

Setting: NR

Duration: not explicitly stated; 12 weeks based on treatment groups and wash-out periods.
Inclusion criteria:
Age 18–75
Serum potassium between 4.3–5.5 mEq/L
History of Hypertension CrCl 30–80 ml/min

Exclusion criteria:
Unstable renal function/active renal disease
Use of diuretics for edema
Use of 3+ drugs for HYPERTENSION control
Recent drug or alcohol abuse
Allergy to ACE-I/ARB or allergy to iodine
History of HIV
Liver disease (AST or ALT >3 times upper limit of normal or total bilirubin or alkaline phosphatase >2.5 upper limit of normal)
Average BP >200/115 (sitting)
Unstable angina or acute MI treatment within 3 mo
History of stroke within 3 mo, transient ischemic attack within 6 mo
History of ventricular arrhythmia requiring therapy
HF (NYHA Class II, III, or IV)
Use of NSAIDS (>20 days per mo; ASA okay)
Pregnancy, lactation, or women of childbearing potential
History of GI malabsorption or GI surgery
Types of CKD: NR

Proteinuric: NR
Stage of CKD not specifically addressed.

Participants required to have calculated
CrCl between 30–80 ml/min, confirmed with 24 hr urine collection at time of enrollment.

GFR at baseline noted to be:
62 +/− 4 ml/min/1.73m2 pre-Lisinopril
66 +/− 5 ml/min/1.73m2 pre-Valsartan

GFR measured via iohexal clearance.
Crossover study with 4 phases. After initial run-in, participants were randomized (1:1 fashion) to either:
[L] Lisinopril 10mg/d
[V] Valsartan 80 mg/d

Each treatment period lasted 4 weeks, followed by washout and then cross-over for 4 weeks into the alternate group.
2 week run-in pre-randomization

2 week wash-out between cross- over arms

No anti-hypertensive therapy during run-in or wash-out
No additional meds noted

If diastolic blood pressure >115 mmHg during initial wash-out, participant was excluded

If blood pressure could not be reduced to <180 mmHg systolic or <100 mmHg diastolic while on randomized drug of interest, then that participant was excluded.
Primary analysis was to compare the average percentage change from baseline in serum potassium levels between ACE-I and ARB.

Secondary analysis was to compare the average differences from baseline in levels of plasma renin, angiotensin II, and urinary values of potassium, aldosterone, and sodium.

At the end of run-in and washout and at the end of each 4 week treatment period, the following were measured:
-GFR via iohexol clearance
-24 hr urine collection for sodium, potassium, and aldosterone
-serum labs including potassium and creatinine
Mean age: 56 +/− 2 years

Gender (male/female) 21/14

Ethnicity
19 of 35 African American
16 of 35 Caucasian
Baseline pre-treatment GFR:
L: 62 +/− 4 ml/min/1.73m2
V: 66 +/− 5 ml/min/1.73m2

Baseline pre-treatment systolic blood pressure:
L: 150 +/−4 mmHg
V: 149 +/− 3 mmHg
Number screened: 84

Number eligible: 37

Number enrolled: 37
Number withdrawn: 2

Lost to follow-up: NR (unclear if any of the withdrawals were due to loss of follow up).

Analyzed: 35
No significant change in GFR noted with therapy in either group
L: post GFR 65 +/− 5 (p = 0.37)
V: post GFR 64 +/− 5 (p = 0.53)
95% CI NR

Similar decline in blood pressure between groups. No information given on statistical differences in blood pressure control between groups.
N/AParticipants were sub-divided into groups based on eGFR > or < 60 ml/min/1.73m2, but no outcomes of interest were examined for these subgroups.NRNRWithdrawals: 2 (reason for withdrawal not stated)The primary purpose of this study was to examine changes in potassium, aldosterone, and angiotensin II levels in patients with CKD on ACE-I vs. ARB. No significant difference was found in potassium levels between those treated with ACE-I vs. ARB (p > 0.05).

Whether or not these patients had proteinuria was not stated.
Campbell 2003
Italy
no trial name
Fair
Study design:
prospective, randomized, cross-over study

Setting: outpatient nephrology clinic

Duration:32 weeks
Inclusion criteria:
Age 18 and older
CrCl between 20–70 ml/min
Proteinuria of > 1 gm/d
Hypertension (diastolic blood pressure 90–115 mmHg or less in patients on anti-hypertensive therapy)

Exclusion criteria:
Contraindication to withdrawal of chronic ACE-I or ARB therapy
Treatment with steroids, NSAIDS, immunosuppressive or cytotoxic agents in 6 mo prior.
History of renovascular disease
Obstructive uropathy
Unstable angina
Acute myocardial infarction or cerebral vascular accident in 6 mo prior
NYHA class III-IV
serum potassium >6
Clinically significant hepatic disease (AST or ALT >3 times normal, bilirubin >1.5 times normal)
White blood cell count <3000/mm3
Clinical suspicion of renal vein thrombosis Known hypersensitivity to ACE-I or ARB Cancer
Collagen vascular disease
Treatment with other investigational drugs
Pregnancy/lactation/ineffective contraception
Types of CKD:
IgA nephropathy
Chronic glomerulonephritis Other
Unknown (no biopsy)

Biopsy proven? Not required

Degree of proteinuria: >1 gm/d required. At baseline, mean proteinuria was 3.3 gm/d.

Baseline proteinuria determined by mean value of protein in two 24-hr urine collections 2 weeks apart.
Stage of CKD: not specifically addressed

CrCl 20–70 ml/min required.
CrCl average at baseline was 69 ml/min

CrCl measured on 24 hr urine as the mean of 3 urine collections.
GFR measured via inulin and para-aminohippuric acid.
After completing run-in, participants were randomized to one of six treatment sequences. These sequences allowed each participant to cross-over into each of the following treatment groups:
(V80) Valsartan 80mg/d
(B10) Benazepril 10mg/d
(V40+B5) Valsartan 40mg/d + Benazepril 5 mg/d

After 2 weeks doses were increased as follows:
(V160) Valsartan 160 mg/d
(B20) Benazepril
(V80+B10)
*If hyperkalemia or symptomatic hypotension resulted after dose increase, then doses were reduced to initial lower levels.*

Each treatment period lasted 8 weeks.

23 of 24 received higher (second) dose of each medication. 1 of 24 received only lower dose of each medication as that participant’s diastolic blood pressure was <90 mmHg on lower doses of medication.
8 week run-in prior to randomization. No ACE-I, ARB, or potassium sparing diuretics were allowed during that time.

No wash-out period described.
Diastolic blood pressure goal was <90. Additional medications were allowed during run-in and during treatment groups if needed to achieve that goal.

Additional meds included:
Clonidine
Loop diuretics
Thiazide diuretics
Primary end point not described.

Primary aim stated as: to test the hypothesis that, among proteinuric patients with chronic nephropathies, combined therapy with half doses of ACE-I and ARB may achieve greater reduction of proteinuria than treatment with full doses of each drug.

Second aim was noted to be to assess to which extent the antiproteinuric effect of each treatment was due to an effect on glomerular barrier size selectivity or on a specific intrarenal hemodynamic effect.

At the end of run-in and at the end of each treatment period, the following measurements were completed:
-blood pressure
-three 24 hr collections of urine for CrCl, protein, and urine sodium.
-blood chemistries
-GFR via inulin and para-aminohippuric acid clearance studies
Mean age: 48.9 +/− 13.2 years

Gender (male/female): 23/1

Ethnicity: NR
Urinary protein excretion at baseline:
3.28 +/− 2.6 gm/d

CrCl at baseline:
69.14 +/− 19.86 ml/min

Serum creatinine at baseline:
1.67 +/− 0.46 mg/dL

GFR at baseline:
46.5 +/− 12.8 ml/min/1.73m2
Number screened: NR

Number eligible:

NR Number enrolled: 24
Number withdrawn: zero

Lost to follow-up: zero

Analyzed: 24
Protein reduction from baseline to end of treatment (percent reduction):
V: 3.28 +/− 2.6 gm/d to 2.04 +/− 2.36 gm/d (−41.5%)
B: 3.28 +/− 2.6 gm/d to 1.76 +/− 1.88 gm/d (−45.9%)
V+B: 3.28 +/− 2.6 gm/d to 1.39 +/− 1.54 gm/d (−56%); greater reduction (compared to V, p<0.002 and compared to B, p = 0.02)
Reduction in proteinuria was numerically superior in B vs V, but that difference was not statistically significant

Maximal protein reduction was achieved in the following patterns (mean baseline proteinuria levels in parentheses)
V: in 4 participants (2 +/− 1.1 gm/d)
B: in 7 participants (2.4 +/− 2.4 gm/d)
V+B: in 13 participants (4.4 +/− 2.7 gm/d)
*Those who achieved greatest protein reduction in V+B also had significantly higher baseline proteinuria values, p<0.01 vs B and p < 0.05 vs V, 95% CI NR).

CrCl at baseline and after treatment:
V: 69.14 +/− 19.86 ml/min to 67.88 +/− 17.21 ml/min
B: 69.14 +/− 19.86 ml/min to 66.22 +/− 15.33 ml/min
V+B: 69.14 +/− 19.86 ml/min to 67.65 +/− 18.49 ml/min

GFR at baseline and after treatment:
V: 46.5 +/− 12.8 ml/min/1.73m2 to 47.9 +/− 14.6 ml/min/1.73m2
B: 46.5 +/− 12.8 ml/min/1.73m2 to 47.7 +/− 14.6 ml/min/1.73m2
V+B: 46.5 +/− 12.8 ml/min/1.73m2 to 48.1 +/− 17.1 ml/min/1.73m2
Change in GFR in V+B vs V showed p = 0.04, V+B vs B showed p = 0.048, 95% CI NR.

Systolic and Diastolic blood pressures at baseline (groups were not statistically different):
V: 129+/−12 and 79+/−8 mmHg
B: 126+/−9 and 80+/−8 mmHg
V+B: 124+/−12 and 78+/−9 mmHg
NRNRSerum and urine lab studies as noted.
Otherwise NR.
Hyperkalemia of >0.5 mEq/L above baseline (necessitating change in therapy): zero among all groups.Total withdrawals: zero

Total withdrawals due to adverse events: zero
Chrysostomou 2006
Australia
no trial name
Fair
Study design: randomized, double-blind, placebo-controlled study.

Setting: Participants recruited from nephrology dept of Royal Melbourne Hospital.

Duration: 3 months
Inclusion criteria:
Age 18–75
24-hr urine protein excretion >1.5 gm/d on 2 occasions 3 months apart
Creatinine <2.2 mg/dL with <20% variability n preceding 3 months
Treatment with ACE-I for at least 6 mo prior to enrollment.

Exclusion criteria:
Diastolic blood pressure >115 mmHg
Systolic blood pressure >220 mmHg
Serum potassium level >5 mmol/L
Serum bicarbonate = 20 mmol/L
Acute myocardial infarction or stroke in 6 mo prior
Treatment with steroids, NSAIDS, or immunosuppressant agents.
Evidence or suspicion of renovascular disease, obstructive uropathy, collagen disease, cancer, drug or alcohol abuse, pregnancy, breastfeeding, or ineffective contraception.
Types of CKD:
Diabetic nephropathy
Glomerulonephritis
Interstitial nephritis
Other

Biopsy proven: NR

Degree of proteinuria: >1.5 gm/d required.
Baseline characteristics indicate proteinuria ranged from 1.2–9.9 gm/d.
Level of CKD: not specifically addressed

Creatinine <2.2 mg/dL required.

CrCl at month zero ranged from 57–81 ml/min.

For purposes of inclusion, CKD was defined primarily by presence of proteinuria. CrCl was followed during the study, via 24-hr urine collections and Cockroft Gault calculations.
Simple randomization followed by 4–12 week run-in.

After run-in patients entered “compliance” phase during which they were on Ramipril 5mg/d in addition to losartan-placebo and spironolactone-placebo. Minimum time for compliance phase was 4 weeks.

After compliance, patients were randomized to blinded treatment phase:
(R) Ramipril 5 mg/d + Irbesartan placebo + Spironolactone placebo (n= 10)
(R + I) Ramipril 5mg/d + Irbesartan 150 mg/d + Spironolactone placebo (n= 10)
(R + S) Ramipril 5 mg/d + Irbesartan placebo + Spironolactone 25mg/d
(RIS): Ramipril 5 mg/d + Irbesartan 150 mg/d + Spironolactone 25mg/d

Patients remained randomized and double-blinded for 3 months on these regimens. Doses were changed only for hyperkalemia (potassium >6 mmol/L).

After 3 mo patient codes were opened, but patients remained on allocation until 6 mo and were given the option to begin spironolactone. Treatment was continued for 12 months.
4–12 week run-in after randomization.

Patients were treated with Ramipril alone 10mg/d during run-in.

Diastolic blood pressure goal was < 90 mmHg.
Target diastolic blood pressure was <90 mmHg. Additional non-ACE-I, non-ARB, and non-dihydropyridine CCBs could be utilized to achieve that goal.

Additional BP meds used included:
-diuretics
-central α agonists
-dihydropyridine calcium channel blockers
-β-blockers
-α-blockers
Primary end point: between group difference in percentage reduction in 24 hour urinary protein excretion after 3 months of therapy.

Secondary end points:
-between group difference in urinary protein excretion at 6 months
-percentage reduction of 24 hour urine protein excretion at 3 and 6 mo separately for each group
-changes in blood pressure and CrCl

Post hoc analysis:
-reduction in protein excretion at 6 and 12 months among those who received spironolactone.

Serum labs and vital signs were measured:
-at the beginning and end of compliance phase, and every 4 weeks during initial 12 weeks of week after treatment phase
-then every 3–6 months
*serum potassium was additionally measured one week after treatment phase was started.*

24-hr urine studies for protein and creatinine were measured:
-at the beginning of compliance phase
-at end of compliance phase
-at the end of 12-week treatment phase
-at 6 mo and at 12 mo
Mean age:
R: 59.2
R + I: 56.3

Gender (male/female):
R: 7/3
R + I: 8/2

Ethnicity: NR
Mean 24 hr urinary protein excretion:
R: 2.6 gm/d
R + I: 2.5 gm/d

Mean CrCl at month zero:
R: 81.6 ml/min (range 46.9–122)
R + I: 67.4 mil/min (range 41.7–94.3)

Mean Systolic blood pressure at month zero:
R: 133 +/− 19.5 (range 110–1160) mmHg
R+I: 132 +/− 11.4 (range 120–150) mmHg
Number screened: NR

Number eligible:NR

Number enrolled: 41
Withdrawn: 1

Lost to follow-up: NR

Analyzed: 41
Percent change in proteinuria at 3 mo:
R: −1.4, 95% CI −16.7, 13.9
R+I: −15.7, 95% CI −35.2, 3.8
Inter group comparison ANOVA p = 1

Percent change in proteinuria at 6 mo:
R: 0.8, 95% CI −38.5, 40.1
R+I: −11.1, 95% CI −35.9, 13.7
Inter group comparison ANOVA p = 1

Mean creatinine clearance at 3 mo:
R: 84.5 ml/min
R+I: 67.4 ml/min
p = 0.45

Mean creatinine clearance at 6 mo:
R: 82.4 ml/min
R+I: 65.2 ml/min
p = 0.26

No statistically significant differences in systolic blood pressures between groups at any time point. At 6 months there was a difference in that diastolic blood pressure was higher in R compared to other groups (p = 0.046).
NRAnalysis among diabetic nephropathy vs. non-diabetic nephropathy as CKD etiology; no evidence of interaction between treatment effects was found based on cause of nephropathy.

Diabetic vs. non-diabetic likelihood ratio test:
3 mo X2 (3) = 1.65, p = 0.649
6 mo X2 (3) = 4.50, p = .0213
NRFeeling unwell/light-headed:
R: 1
R+I: zero
R+S: zero
RIS: zero

Potassium >6 mmol/L:
R: zero
R+I: zero
R+S: 1 (at 2 mo)
RIS: 2 (one at 3 mo and one at 6 mo)
Total withdrawal: 1 (due to feeling unwell/light-headed); no hypotension documented

Withdrawals due to adverse events: 1 (as above)

Withdrawals due to reason other than adverse events: zero
This study also compared use of spironolactone in reduction in proteinuria. Those participants treated with ACE-I + spironolactone or ACE-I + ARB + spironolactone showed significant reduction in proteinuria compared to ACE-I alone. There was no difference in reduction of proteinuria between ACE-I + spironolactone or ACE-I + ARB + spironolactone.
Esnault
2005
France
no trial name
Fair
Study design: single-center, prospective, randomized, open label, crossover study.

Setting: outpatient clinic

Duration: 25 weeks
Inclusion criteria:
Age 18–80
Glomerulonephritis that has not required and is not resistant to immunosuppressive treatments
Proteinuria at >1 gm/d after 6 mo therapy with Ramipril and other anti-hypertensive’s*.
No changes in proteinuria by >50% for 2 mo prior to enrollment

Exclusion criteria:
Creatinine >2.8 mg/dL
Increase in serum creatinine by >20% after introduction of Ramipril
History of intolerance to or contraindication to ACE-I or ARB
Office systolic blood pressure of <110 mmHg

*Other antihypertenives included: calcium channel blockers, central acting drugs, diuretics, β-blockers, and α-blockers
Types of CKD:
Diabetic nephropathy
IgA nephropathy
Focal segmental glomerulosclerosis
Minimal change disease
Amyloidosis
Mesangioproliferative glomerulonephritis

Biopsy proven: NR

Degree of proteinuria: >1 gm/d required for enrollment. Mean baseline level of proteinuria was 3.7 gm/d.
Level of CKD: not specifically addressed.

Creatinine <2.8 required.

No GFR or CrCl measurements noted
After run-in, participants were randomized to:
(V) Valsartan 160 mg/d
(R) Ramipril 10 mg/d
(V+R) Valsartan 80mg/d and Ramipril 5 mg/d

3 treatment sequences were used to ensure every treatment was represented equally during each treatment period as part of the cross-over design.

Patients remained on each treatment for 4 weeks; between each cross-over arm there was a 4 week wash-out period. All participants were to receive each therapy option for 4 weeks as part of cross-over design.

Participants entered 4th treatment period for 4 weeks:
V+R + Furosemide (40mg/d if not on any previously, or 40mg/d additionally to previous furosemide dose)
Patients were required to have been on Ramipril 5mg/d for 6 mo prior to enrollment.

1 week run-in; medications during run-in NR

4 week washout between each treatment arm during which time patients were on Ramipril 5mg/d (with diuretic if needed)
Other anti-hypertensives were allowed, and included: calcium channel blockers, central acting drugs, diuretics, β-blockers, and α-blockersPrimary end point: mean urinary protein/creatinine ratio in two consecutive 24 hour collections of urine at the end of each treatment period.

Secondary end points:
-mean 24 hr proteinuria
-home systolic and diastolic blood pressure
-serum creatinine levels

The following measurements were made at the end of run-in, at the end of each 4 week treatment period, and at the end of each wash-out period:
-two 24-hr urine samples for protein, creatinine, electrolytes, and albumin
-serum lab tests (including creatinine) review of home vital signs

At the end of each active treatment period, participants underwent physical exam and vital sign measurements.
Mean age: 49.3 +/− 20.4 yrs

Gender (male/female): 12:6

Ethnicity: NR

Race: 100% Caucasian
Mean proteinuria: 3.71 +/− 2.1 gm/d

Mean creatinine: 1.7 +/− 0.7 mg/dL

Mean systolic blood pressure: 149.06 +/− 29.1 mmHg

Mean number of additional anti-hypertensive drugs: 2.6 (range 1–6)
Number screened: NR

Number eligible: NR

Number enrolled: 18
Number withdrawn: 2

Lost to follow-up: zero

Analyzed: 18 (intention to treat)
Mean urinary protein/creatinine ratio after treatment:
R: 2.98 +/− 2.02 gm/g
V: 3.2 +/− 2.32 gm/g
V+R: 3.01 +/− 2.68 gm/g
For inter-group comparison, no significant difference was found, p = 0.39 with serum creatinine and systolic blood pressure as fixed effects, and p = 0.48 without (95% CI NR).

Mean 24 hr urinary protein excretion after treatment:
R: 3.60 +/− 2.9 gm/d
V: 3.02 +/− 1.51 gm/d
V+R: 3.01 +/− 2.07 gm/d
For inter-group comparison, p = 0.63 with serum creatinine and systolic blood pressure as fixed effects, and p = 0.70 without (95% CI NR).

No significant difference noted between these treatment groups and the baseline ramipril dose of 5mg/d (p = 0.8 for baseline vs R, p = 0.47 for baseline vs V, and p = 0.78 for V+R). 95% CI NR.

Serum creatinine levels after treatment:
R: 1.9 mg/dL
V: 1.8 mg/dL
V+R: 1.8 mg/dL
Reported as no significant difference; p value and 95% CI NR

No significant difference between groups for systolic or diastolic blood pressure.
NRSubgroup analysis was done comparing individuals with and without diabetes.

Protein/creatinine ratio was higher at baseline in diabetics vs. non-diabetics (p = 0.033).

In both diabetic and non-diabetic, there was no significant difference in reduction in protein/creatinine ratio in any treatment groups vs. baseline (Ramipril 5mg/d).

There was a trend for V+R to lead to a greater reduction in proteinuria among diabetics vs. non-diabetics (p = 0.08, 95% CI NR).
At each physical exam (after each active treatment period), participants were asked questions regarding symptomatic hypotension and side effects.No significant difference in number of symptomatic hypotension events was observed between treatment groups.Total withdrawals: 2

Withdrawals due to adverse events: 1 (laryngeal edema; noted in the context of increased ACE dose - specific group during event not reported)

Withdrawals due to reason other than adverse events: 1 (pregnancy)
Ferrari 2002
Switzerland
no trial name
Fair
Study design:
prospective, randomized, open-blinded endpoint cross-over.

Setting: outpatient nephrology clinics

Duration: 32 weeks
Inclusion criteria:
Biopsy proven glomerulonephritis
Increased office blood pressure >140/90 mmHg, MAP >107 mmHg, or history of anti-hypertensive treatment.
Stable proteinuria of >1.5 gm/d
CrCl >30 ml/min

Exclusion criteria:
Pregnant/nursing women
Diabetes
Use of immunosuppressive therapy
Refractory edema
BP >200/110 when off anti-hypertensives for 2 weeks prior to initiation of study
Types of CKD:
Focal segmental glomerulosclerosis
Membranoproliferative glomerulonephritis
IgA nephropathy

Biopsy proven: yes

Degree of proteinuria: >1.5 gm/d required.
Baseline values NR.
Stage of CKD: not specifically addressed

CrCl >30 ml/min required.

CrCl measured via 24 hr urine assessment.

Baseline CrCl 77 +/− 27 ml/min.
After run-in, participants were randomized to one of three groups:
(F) Fosinopril 20mg/d
(I) Irbesartan 150 mg/d
(F+I) Fosinopril 20mg/d + Irbesartan 150mg/d

Each treatment period lasted 6 weeks.
6 week run-in (control) period.

4 week wash-out between each treatment arm.
Diuretics allowed if participants required diuretics at time of enrollment to control edema.

4 patients received diuretic therapy (3 furosemide, 1 metolazone).
Primary end points not specifically stated. Goal stated to be to test whether or the antiproteinuric effect of a combination of ACE-I and ARB is superior to monotherapy with either agent.

Reported outcomes included:
-blood pressure
-urinary protein excretion
-CrCl
-serum labs including electrolytes and creatinine

Blood pressure and 24 hr urine studies were completed:
-at baseline
-at week 3 and week 6 of each study period
-at the end of each wash-out period

Serum lab values (blood chemistry, complete blood count with reticulocyte count) and ambulatory blood pressures were additionally assessed:
-at the end of each treatment period.
Mean age:
48 +/− 4 years

Gender: 7 men, 4 women

Ethnicity: NR
Mean serum creatinine at baseline:
1.5 +/− 0.7 mg/dL

Mean CrCl at baseline: 77 +/− 27 ml/min

Mean systolic and diastolic blood pressures at baseline:
144+/−12 mmHg systolic
91+/−9 mmHg diastolic
Number screened: NR

Number eligible: NR

Number enrolled: 11
Withdrawn: 1

Lost to follow-up: NR

Analyzed: 10
Mean reduction in proteinuria baseline to endpoint:
F: 7.9 +/− 7.2 to 5.3 +/− 5.2 gm/d (−33%)
I: 7.9 +/− 7.2 to 5.0 +/− 4.9 gm/d (−37%)
F+I: 7.9 +/− 7.2 to 3.3 +/− 3.7 gm/d (−58%)
Combination therapy reduced proteinuria more than either drug alone (p = 0.039, 95% CI NR).

When values were corrected for concomitant changes in CrCl, the reduction in proteinuria in F+I remained significantly more than in F or I alone (p < 0.05, 95% CI NR).

Changes in blood pressure did not correlate significantly with changes in proteinuria. (Pearson correlation matrix 0.149, p = 0.43).
No statistically significant differences in blood pressure control between treatment periods.

Mean CrCl, creatinine, and potassium remained the same throughout the study.
NRNRNRTransient dizziness:
F: zero
I: zero
F+I: 2

Cough:
F: zero
I: zero
F+I: zero

Reversible increase in serum creatinine:
F: 2
I: zero
F+I: zero

Serum potassium >5 mmol/L:
F: 2
I: 1
F+I: 2
*none required changes in therapy, no potassium values of ≥5.5 mmol/L.*
Total withdrawals: 1

Withdrawals due to adverse events: zero

Withdrawals due to reasons other than adverse events: 1 *for development of nephrotic syndrome during baseline period.*
Hannedouche 2001
France
no trial name
Fair
Study design: multi-center, parallel group, double-dummy active- control trial

Setting: NR

Duration: 12 weeks
Inclusion criteria:
Age 18–70
Diastolic supine blood pressure 95–114 mmHg
Stable renal disease (meaning change in serum creatinine ≤ 20% in 3 mo prior)
CrCl 30–80 ml/min

Exclusion criteria:
History of renal transplantation
Renal artery stenosis (bilateral or unilateral if solitary kidney)
Secondary hypertension
Nephrotic syndrome
Recent history HF, myocardial infarction, cardiac surgery, or coronary angioplasty
Diabetes requiring insulin therapy
Types of CKD: NR

Biopsy proven: NR

Baseline proteinuria ranged from 1.6–1.8 +/−2.4 gm/d. (Some patients may not have been proteinuric per this data.)
Stage of CKD was not specifically addressed.

CrCl 30–80 ml/min required.

Baseline serum creatinine ranged from 1.8–1.9 +/−0.8 mg/dL.

Baseline CrCl ranged from 50–51 +/−15 ml/min.
Participants were initially randomized to:
Telmisartan 40mg/d (T40) (n = 45)
Enalapril 10mg/d (E10) (n = 26)
*randomization 2:1 in favor of Telmisartan.*

At 4 weeks:
T40 with supine trough diastolic blood pressure <90 mmHg = no change
T40 with supine trough diastolic blood pressure 90–114 mmHg changed to 80 mg/d (T80)
E10 with supine trough diastolic blood pressure <90 mmHg = no change
E10 with supine trough diastolic blood pressure 90–114 mmHg chnaged to 20 mg/d (E20)

At 8 weeks:
T40 with supine trough diastolic blood pressure <90 mmHg = no change
T40 with supine trough diastolic blood pressure 90–114 mmHg changed to 80 mg/d (T80)
E10 with supine trough diastolic blood pressure <90 mmHg = no change
E10 with supine trough diastolic blood pressure 90–114 mmHg chnaged to 20 mg/d (E20)
T80 with supine trough diastolic blood pressure 90–114 mmHg, once daily furosemide 40 mg/d started (T80+F)
E20 with supine trough diastolic blood pressure 90–114 mmHg, once daily furosemid 40 mg/d started (E20+F)
14 day single-blind placebo run-in; patients received double-dummy Telmisartan and Enalapril placebo.NR

29% of Telmisartan-treated patients and 43% of Enalapril treated patients met requirements for addition of furosemide.
Primary safety endpoint was percent change from baseline in CrCl (calculated); >20% change considered significant.

Primary efficacy endpoints were changes in mean diastolic and systolic blood pressures after treatment.

Secondary safety endpoints included changes in baseline EKG and orthostatic changes in vitals signs.

Secondary efficacy endpoints included change in systolic and diastolic blood pressure.

Evaluations at 2 weeks prior to randomization, and then as follows:
Week zero (time of initial randomization)
Week 2
Week 4
Week 8
Week 12
*Evaluations included serum laboratory values, 24-hour urine collection for protein and creatinine, and blood pressure measurements.*

Medication counts were done at each visit to evaluation compliance.
Mean age:
Telmisartan: 53.6 +/− 12.1
Enalapril: 53.1 +/− 11.0

Gender (% male/female):
Telmisartan: 69/31
Enalapril: 81/19

Ethnicity: NR
Mean creatinine:
Telmisartan (T): 1.9 +/− 0.8 mg/dL
Enalapril (E): 1.8 +/− 0.5 mg/dL

Mean proteinuria:
T: 1.6 +/− 2.4 gm/d
E: 1.8 +/− 2.4 gm/d

Mean CrCl:
T: 50.1 +/− 15.3 ml/min
E: 51 +/− 13 ml/min

Mean supine systolic blood pressure trough:
T: 164.2 +/− 15.5 mmHg
E: 166.8 +/− 22.8 mmHg

Mean supine diastolic blood pressure trough:
T: 102 +/− 5.6 mmHg
E: 102.3 +/− 6.4 mmHg
Screened: 95

Eligible: NR

Enrolled: 71
Withdrawn: 10

Lost to follow-up: 2 reported

Completed protocol: 57
**2 participants not accounted for in withdrawals; additional info NR.**

Analyzed:
for safety outcome: 66
for efficacy outcome: 68
Mean change in proteinuria:
T: −0.44 +/− 1.1 gm/d (decrease by 26.5%)
E: −1.0 +/− 1.6 mg/d (decrease by 57.2%)
Difference in decrease in proteinuria between groups was not statistically significant, p = 0.14).

Mean change in serum creatinine:
T: 0.2 +/− 0.3 mg/dL
E: 0.1 +/− 0.2 mg/dL

Median percent decrease in CrCl:
T: 4.6%
E: 2.8%
No participants reached primary safety endpoint (meaning no change in CrCL >20%). Change in CrCl between T and E reported as not significant.

There was no statistically significant change in blood pressure between groups.
NRNRAdverse events spontaneously reported by participant or observed by investigator were recorded at each visit.Hypotension (n; %):
T: 1; 2.2
E: 0; 0

Asthenia (n; %):
T: 0; 0
E: 1; 3.8

Pain: (n; %):
T: 1; 2.2
E: 0; 0

Dizziness (n; %):
T: 1; 2.2
E: 0; 0

Abdominal pain; diarrhea/nausea/anorexia:
T: 0; 0
E: 4; 15.2
Cough (n; %): :
T: 0; 0
E: 1; 3.8

Uremia (n; %):
T: 0; 0
E: 1; 3.8

Dysuria (n; %):
T: 1; 2.2
E: 0; 0
6 withdrawals due to adverse events:
-1 for UTI
-1 for acute renal failure in setting relapsed renal neoplasm
-1 for acute renal failure (did not improve after withdrawal)
-3 for GI disturbance/nausea/headache/hypotension/vertigo
There is a typo on page 250 in table 1; plasma creatinine for Telmisartan is listed as 1169.2 micromole/L; actually 169.2 micromole/L.
Hou 2007
China
ROAD (Reno protection of Optimal Antiproteinuric Doses)
Good
Study design:
prospective, randomized, open blinded end-point study

Setting: Nanfang Hospital renal division

Duration: 3 years
Inclusion criteria:
Age 18–70
No ACE-I or ARB for at least 6 weeks prior to screening
Serum creatinine 1.5–5 mg/dL
CrCl 20–70 ml/min
Less than 30% variation in CrCl in the 3 mo prior to screening
History of non-diabetic renal disease (based on history, blood tests, and biopsy)
Proteinuria > 1 gm/d for at least 3 mo prior to screening in the absence of urinary tract infection or overt HF (NYHA class III or IV).

Exclusion criteria:
immediate need for dialysis current treatment with corticosteroids, NSAIDS, or immunosuppressive drugs.
Hyper or Hypokalemia (serum potassium ≥ 5.6 mmol/L or ≤ 3.5 mmol/L
renovascular diseas
myocardial infarction or cerebrovascular accident in the year preceding screenin
connective tissue diseas
obstructive uropathy
Types of CKD:
Glomerular
Hypertension
Polycystic kidney disease
Interstitial
Unknown

Biopsy proven? Unclear

> 1 gm/d proteinuria required. Baseline proteinuria ranged from 1.4–2 gm/d

Proteinuria was measured via 24 hr urine collection.
Stage of CKD: not specifically addressed.

CrCl 20–70 ml/min required.

Baseline CrCl ranged from 33–35 ml/min
Baseline eGFR ranged from 30.38–33.6 ml/min/1.73m2
Participants were block randomized into 4 groups:
(B10) Benazepril 10mg/d (n = 90)
(Bmax) Benazepril started at 10mg/d, then up-titrated (n = 90)
(L50) Losartan 50mg/d (n = 90)
(Lmax) Losartan started at 50mg/d, then up-titrated (n = 90)

After the run-in, participants in Bmax and Lmax followed the following up-titration schedule (B10 and L50 remained on starting doses):
Bmax: monthly up-titration by 10mg to 20mg/d, 30mg/d, and then 40 mg/d.
Lmax: monthly up titration by 50 mg to 100 mg/d, 150 mg/d, and then 200 mg/d.

Urinary protein, serum creatinine, and serum potassium were measured every 2 weeks during up-tiration, and doses were reduced if:
-urinary protein excretion did not fall by ≥ 10% compared to previous titration period (confirmed by 2 values, 4 weeks apart on same dosage)
-systolic blood pressure <120 mmHg despite withdrawl of other anti-hypertensives
-Serum potassium ≥ 6 mmol/L, refractory to medical treatment
-creatinine >30% compared to previous value (reduced to previous dose or withdrawn)

If participants were un-responsive to up-titration (meaning <10% reduction in proteinuria), they were titrated up to maximum dose.
If still no response, dose was reduced to starting dose.
8 week run-in (referred to as “pre-titration phase” within the study) during which time:
B10 and Bmax received Benazepril 10mg/d
L50 and Lmax received Losartan 50mg/d

During run-in, participants had weekly measurements of BP, serum creatinine, and serum potassium.

Participants proceeded to titration phase if:
-stable creatinine (<30% creatinine increase from baseline value, confirmed by 3 measurements)
-Serum potassium levels <5.6 mmol/L
If blood pressure remained above 130 mmHg systolic or 80 mmHg diastolic, then additional anti-hypertensives could be added.

Additional meds included:
-diuretics
-central α agonists
-calcium channel
blockers
-β-blockers
-combination of above (no additional ACE-I or ARB)

The median number of anti-hypertensives in each group was 2.
Primary end point: time to first event for composite end point which included doubling of serum creatinine concentration, ESRD, or death. (doubling of serum creatinine was defined by a second creatinine 4 weeks later, ESRD was defined by need for long term dialysis or transplantation).

Secondary end points included:
Changes in urinary protein excretion rate
Progression of renal disease assessed by GFR and CrCl.

At baseline, after run-in, q2 q weeks in max dose groups, and q mo overall, the following tests were completed:
blood pressure
serum labs
24 hr urine collection for protein, CrCl, urea, chloride

During run-in serum labs were done weekly
Mean age:
B10: 51.9 +/− 12.6 years
Bmax: 49.1 +/− 14.3 years
L50: 51.5 +/− 13.3 years
Lmax: 51.0 +/− 13.5 years

Male gender (n; %):
B10: 59; 66%
Bmax: 56; 62%
L50: 56; 62%
Lmax: 55; 61%

Ethnicity: NR
Mean serum creatinine at baseline:
B10: 2.7 +/− 0.9 mg/dL
Bmax: 2.8 +/− 0.9 mg/dL
L50: 2.8 +/− 1.1 mg/dL
Lmax: 2.9 +/− 1.0 mg/dL

Mean eGFR at baseline:
B10: 30.6 +/− 11.3 ml/min/1.73m2
Bmax: 30.5 +/− 14 ml/min/1.73m2
L50: 31.4 +/− 14.1 ml/min/1.73m2
Lmax: 29.9 +/− 12.4 ml/min/1.73m2

Mean CrCl at baseline:
B10: 33.9 +/− 14.7 ml/min/1.73m2.
Bmax: 35.1 +/− 12.2 ml/min/1.73m2.
L50: 34.4 +/− 15.5 ml/min/1.73m2
Lmax: 33.8 +/−14.0 ml/min/1.73m2

Median proteinuria at baseline:
B10: 1.4 gm/d
Bmax: 2.1 gm/d
L50: 1.6 gm/d
Lmax: 2.0 gm/d
Number screened: 406

Number eligible: NR

Number enrolled: 360
Number withdrawn: 50 pre-titration phase and 18 more past-titration phase.

Lost to follow-up: 21

Analyzed: 360 (intention to treat)
Percent who reached primary end point:
B10: 31.3%; Bmax: 19.9%; Significantly fewer primary end points were noted for Bmax compared to references.r10, p = 0.025.
L50: 29.5%; Lmax: 15.5%; Significantly fewer primary end points were noted for Lmax compared to L50, p = 0.022.

Overall reduction in risk of primary end point:No difference between L and B at any dose.
51% reduction in Bmax comapred references.r10, 95% CI 4.8; 73.3, p = 0.028
53% reduction in Lmax compared to L50, 95% CI, 5.5; 74.1, p = 0.022

Reduction in risk of primary endpoint remained statistically significant after adjustment for:
-systolic blood pressure (B arm p = 0.03, L arm p = 0.031),
-proteinuria (B arm p = 0.0337, L arm p = 0.039)
-baseline eGFR (B arm p = 0.039, L arm p = 0.035)

Percent reduction in risk of ESRD:
47% in Bmax vs references.r10, 95% CI 4.2,;72.1, p = 0.042
47% in Lmax vs L50, 95% CI 3.6; 76.9, p = 0.046

Reduction in decline in renal function by CrCl (and by GFR) with optimal antiproteinuric dose vs lower dose:
Benazepril arm: 60%, p = 0.021 for CrCl (p = 0.02 for GFR)
Losartan arm: 55%, p = 0.037 for CrCl (p = 0.03 for GFR)

Optimal antiproteinuric efficacy:
B20mg (61%), references.r30mg (16%), references.r40mg (4%), B>40mg (4%)
L100mg (57%), L150mg (14%), L200 (11%), L>200mg (4%)
There was no difference in reduction in proteinuria for Losartan versus Benazapril at any dose.

Antihypertensive efficacy was similar in both arms (p > 0.05).
NRNRNRNon-fatal cardiovascular events/Myocardial infarction/HF/Stroke:
B10: 4/2/1/1
Bmax: 5/2/2/1
L50: 5/2/2/1
Lmax: 4/2/1/1

Hyperkalemia:
B10: 3
Bmax: 5
L50: 3
Lmax: 5

Acute decline in renal function:
B10: 2
Bmax: 3
L50: 3
Lmax: 3

Dry cough:
B10: 17
Bmax: 15
L50: zero
Lmax: zero

Hypotension:
B10: 1
Bmax: 2
L50: 1
Lmax: 1
Total withdrawals: 68

Withdrawals due to adverse events:
B10: 21 (17 cough, 1 elevated creatinine, 2 hyperkalemia, 1 hypotension)
Bmax: 23 (cough 15, elevated creatinine 3, hyperkalemia 3, hypotension 2)
L50: 6 (elevated creatinine 3, hyperkalemia 2, hypotension 1)
Lmax: 6 (elevated creatinine 2, hyperkalemia 3, hypotension 1)

Withdrawals for reason other than adverse events:
B10: 2 (lost to follow-up)
Bmax: 2 (lost to follow-up)
L50: 2 (lost to follow-up)
Lmax: 6 (lost to follow-up)
Kahvecioglu
2007
Turkey
no trial name
Poor
Study design: clinical head to head trial

Setting: outpatient clinic

Duration: 12 months
Inclusion criteria:
Biopsy-proven non-diabetic renal disease
Creatinine <2 mg/dL
Stable proteinuria of >0.5gm/d (no more than 20% change in 3 mo prior)
Medications only for primary renal disease (meaning steroids and/or immune suppression)

Exclusion criteria:
Systemic or urinary tract infections
Pregnancy
Hyperkalemia
History of hypersensitivity to study drugs
Active gastric ulcer
Stage 2 or secondary hypertension
Use of antihypertensive drugs
Recent myocardial infarction
Uncontrolled angina or serious arrhythmias
Serious peripheral vascular disease
Obstructive pulmonary disease
Serious liver disease
Diabetes
Heart rate <55 beats per minute
Types of CKD:
IgA nephropathy
Membranous nephropathy
Membranoproliferative glomerulonephritis
Focal segmental glomerulosclerosis

Biopsy proven: yes

Degree of proteinuria: >0.5 gm/d required.
Baseline characteristics indicate baseline proteinuria ranged from 1.5–2.2 gm/d

Proteinuria measured by 24 hr assessment
Level of CKD: not specifically addressed

Creatinine <2 mg/dL required

CrCl at baseline ranged from 94–114 ml/min via Cockcroft Gault.
Participants were separated into three groups (unclear if randomized):
Losartan 100mg/d (L) (n = 7)
Losartan 50mg/d + Ramipril 5mg/d (L=R) (n = 7)
Losartan 50mg/d + Carvedilol 25 mg/d (n = 7)

Patients remained in these treatment groups for 12 months
2 week run-in during which patients received Losartan 50 mg/d.

No wash-out period.
NREnd points note specifically addressed. Primary aim was stated as:
to compare the effects of carvedilol with Ramipril and Losartan in patients with proteinuric glomerulonephritis.

Reported outcomes included:
-proteinuria
-systolic and diastolic blood pressure
-serum albumin
-creatinine and CrCl
-Serum sodium and potassium

The following assessments were completed routinely:
CrCl calculation
Serum labs
24 hr proteinuria assessment

Assessments were done at:
-baseline (prior to run-in)
-at time of separation into treatment groups
-in follow up at 1 mo, 6mo, and 12 mo
Mean age:
L: 42 +/− 11
L+R: 43 +/− 15

Gender: (female/male)
L: 1/6
L+R: 1/6

Ethnicity: NR
Proteinuria before run-in:
L: 1.8 +/− 1.1 gm/d
L+R: 2.2 +/− 1.4 gm/d

Proteinuria after run-in:
L: 1.6 +/− 1.1 gm/d
L+R: 2.1 +/− 1.2 gm/d

Creatinine after run-in:
L: 1.1 +/− 0.2 mg/dL
L+R: 1.1 +/− 0.3 mg/dL

CrCL after run-in:
L: 96 +/− 27 ml/min
L+R: 101 +/− 25 ml/min

Potassium after run-in:
L: 4.4 +/− 0.3 mEq/L
L+R: 4.4 +/− 0.7 mEq/L

Baseline systolic blood pressure:
L: 137 +/− 7 mmHg
L+R: 137 +/− 5 mmHg
Number screened: NR

Number eligible: NR

Number enrolled: 31
Number withdrawn: 10

Lost to follow-up: 6 (not specified which treatment groups)

Analyzed: 21
Comparisons were made only between baseline, 1, 6, and 12 mo assessments from within each group; inter-group comparisons were not made.

Changes in proteinuria between 1st and 12th months:
L: −61%; p = 0.04
L+R: −62%, p = 0.06
95% CI NR

Creatinine clearance at 1st and 12th month:
L: 93 +/− 21 ml/min to 94 +/− 28 ml/min
L+R: 1015+/− 27 ml/min to 114 +/− 41 ml/min
P values NR, 95% CI NR; reported as no statistically significant difference.

No statistical comparisons for changes in blood pressure between groups were reported. They noted a statistically significant decline in systolic blood pressure for both L and L+R; they noted a statistically significant decline in diastolic blood pressure for L but not for L+R.
NRNRNR2 withdrawals were related to intolerance to anti-hypertensives (treatment groups not specified).Total withdrawals: 10

Withdrawals due to adverse events: 2

Withdrawals due to reason other than adverse events: 2
-both were withdrawn because they required changes in their immunosuppressive regimens (1 in Ramipril group, one in carvedilol group, zero in Losartan group).

Withdrawals due to incomplete follow-up: 6
Kim
2003
Korea
No trial name
Fair
Study design: randomized cross-over.

Setting: Inpatient vs. outpatient unclear.
Undertaken at “Inha University Hospital.”

Duration: 36 weeks
Inclusion criteria:
Biopsy proven IgA or Diabetic nephropathy
Blood pressure <130/80 on Ramipril ≥ 5 mg/d for 6 mo prior to enrollment.
CrCl 25–90 ml/min/1.73 m2
Urinary protein excretion >1 gm/d

Exclusion criteria:
Use of steroid or cytotoxic therapy in 6 mo prior to enrollment
Types of CKD:
IgA nephropathy
Diabetic nephropathy

Biopsy proven? Yes

Proteinuria >1 gm/d required.

Baseline proteinuria was 3.9 gm/d.
Proteinuria was measured via 24 hr urine collection.
Stage of CKD not specifically addressed.

CrCl 25–90 ml/min/1.73 m2 required.

Baseline CrCl was 30.1 ml/min/1.73 m2.
CrCl was established with 24 hr urine study.
After run-in, participants (all of whom were already on at least 5mg Ramipril) were randomized to one of the following groups:
(R+C) Ramipril at prior dose + candesartan 4mg
(R+P) Ramipril at prior dose + placebo

Each participant was then crossed-over into the opposite group.

Each study group lasted 12 weeks.

The run-in period with Ramipril without ARB or placebo was considered the control group (R).
Run-in: 12 week period during which baseline medications were not changed.

No washout period was reported.
No analysis to remove the need for a washout was reported.
Other medications were allowed if needed for blood pressure control.

Allowed medications included:
Diuretic (n = 10)
Diuretic + calcium channel blocker (n = 2)
Diuretic + calcium channel blocker + vasodilator (n = 2)

34% of participants required additional therapy with these agents.
Primary end point not specifically stated.

Main aim was reported to be to examine if the same regimen of combination therapy of ACE-I and ARB was equally effective in diabetic and non-diabetic nephropathy in the reduction of proteinuria.

The following assessments were completed at the end of the 12 week run-in and after each treatment group (weeks 12, 24, 36):
serum labs
blood pressure
24 hour urine collection for CrCl and proteinuria
Mean age: 34 +/− 5 (range 24–53)

Gender (female/male): 22/19

Ethnicity: NR
Mean CrCl: 60.1 +/− 4 ml/min/1.73 m2

Mean 24 hr proteinuria at baseline: 3.9 +/− 0.3 gm/d

Mean dose of Ramipril: 5.7 +/− 0.4 mg/d (range5–7.5 mg/d)
Number screened: NR

Eligible: NR

Enrolled: 43
Number withdrawn: 2

Lost to follow up: zero

Analyzed: 41
Mean decrease in proteinuria:
R alone (baseline): 4 +/− 0.2 gm/d
R+P: 4.1 +/− 0.3 gm/d
R+C: 3.5 +/− 0.2 gm/d
There was a statistically significant difference between R+C and both R+P and R (p < 0.05 for each, 95% CI NR)

Changes in creatinine clearance:
R alone: 61.2 +/− 3.7 ml/min/1.73 m2
R+P: 60.3 +/− 4.1 ml/min/1.73 m2
R+C: 59.3 +/− 4.6 ml/min/1.73 m2
Differences in CrCl between groups was reported as p value NS (discrete p values and 95% CI NR).

No significant change in blood pressure lowering effect between groups was noted (p was NS).
NRParticipants with IgA nephropathy were compared to those with diabetic nephropathy looking at reduction in proteinuria on these treatment regimens.

Reduction in proteinuria among IgA:
R: 4.2 +/− 0.3 gm/d
R+P: 4.3 +/− 0.2 gm/d
R+C: 3.1 +/− 0.3 gm/d
There was a significant difference found between R+C and both R and R+P (p< 0.05, 95% CI NR).
No change in blood pressure lowering effect was noted between groups.

Reduction in proteinuria among Diabetic nephropathy:
R: 4.1 +/− 0.3 gm/d
R+P: 3.9 +/− 0.3 gm/d
R+C: 3.8 +/− 0.2 gm/d
P values for inter-group comparisons reported as NS (95% CI NR).
No change in blood pressure lowering effect was noted between groups.
NRHyperkalemia: 1 (also had azotemia)

Hypotension: 1

**not specified by study group.**
Total withdrawals: 2

Withdrawals due to adverse events: 2
1 for hyperkalemia
1 for hypotension
Laverman
2002
The Netherlands
no trial name
Fair
Study design: prospective, open-label, cross-over.

Setting: outpatient renal clinics

Duration: 78 weeks
Inclusion criteria:
Age 18–70
CrCl ≥ 30 ml/min/1.73m2
Stable proteinuria at ≥ 2 gm/d
Diastolic blood pressure 80–110 mmHg after 6 weeks off all anti-hypertensive medications

Exclusion criteria:
History of cardiovascular disorders
History of diabetes
Frequent NSAID use (>2 doses per week)
Types of CKD:
focal segmental glomerulosclerosis membranous nephropathy
IgA nephropathy
Non-conclusive biopsy

Biopsy proven? Alluded to, but not specifically stated

Proteinuria ≥ 2 gm/d required. Baseline median proteinuria was 4.5 gm/d.
Stage of CKD not specifically addressed.

CrCl ≥ 30 ml/min/1.73m2 required

Baseline median CrCl was 80 ml/min/1.73m2

Method for CrCL measurement not specifically reported (via calculation vs. urine collection).
All participants underwent 6 week period off all anti- hypertensive medications. If diastolic blood pressure remained between 80–110 mmHg after that period, they were randomized to either:

(LIS) Lisinopril escalating doses 10mg/d, 20mg/d, 40mg/d, and10mg/d
(LOS) Losartan escalating doses 50mg/d, 100mg/d, 150mg/d, 50mg/d
*Each dose treatment period was 6 weeks.

After another 6 week period off medication, participants were switched to the alternate escalating dose method.

After completion of second escalating dose method, all participants were placed on combination therapy of LIS+LOS at doses that had been found to be each individuals maximal proteinuria reduction dose.
6 week run-in, during which time no anti-hypertensive medication was allowed.

6 week washout between escalating dose arms during which time no anti- hypertensive medication was allowed.
NonePrimary end point not specifically stated.

Primary aim described as to investigate the combination of the optimal dose of ACE-I and ARB for anti-proteinuric effect, and to test whethercombination of those doses results in more reduction in proteinuria than either alone.
At baseline, at the end of each dose treatment period, after washout, and after combination therapy, the following evaluations were made:
-two 24-hr urine collections for protein and creatinine
-blood pressure measurements
-calculation of day/night proteinuria ratios
-serum lab tests including creatinine and electrolytes
Median age: 51 (95% CI 44;55)

Ratio male/female: 6/3

Ethnicity: NR

Race: all Caucasian
Baseline median CrCl: 80 (95% CI 66;96)

Previous medication history:
6 on Enalapril
1 on Enalapril + hydrochlorothiazide
1 on Lisinopril + hydrochlorothiazide
1 on Losartan

Baseline median proteinuria: 4.5 gm/d (95% CI 3.6;6.4)

Median systolic blood pressure at baseline:
137 mmHg (95% CI 130;152)
Median diastolic blood pressure at baseline:
80 mmHg (95% CI 66;96)
Number screened: NR

Number eligible: NR

Number enrolled: 10
Number withdrawn: 1

Lost to follow-up: zero

Analyzed: 9
Dose of maximal antiproteinuric efficacy (proteinuria at that dose):
LOS: 100mg/d (2.8 gm/d, 95% CI 1.5;4.6)
LIS: 40mg/d (1.4 gm/d, 95% CI 0.5;3.2)

Combined therapy dosing was based on each individuals maximal anti-proteinuric doses; doses were as follows:
LOS 150 + LIS 40 in 3 participants
LOS 100 + LIS 40 in 2 participants
LOS 100 + LIS 20 in 2 participants
LOS 50 + LIS 40 in 2 participants

Reductions in proteinuria on monotherapy vs combination therapy (median; 95% CI, p vs baseline and inter-group comparisons):
LOS: 2.2 gm/d (1.2;4.8) p < 0.05 vs baseline
LIS: 1.4 gm/d (0.5;2.9) p < 0.05 vs baseline, p < 0.05 vs LOS
LOS+LIS: 1 gm/d (0;2.6) p < 0.05 vs baseline ; p < 0.05 vs LOS or LIS

Changes in CrCl (median, 95% CI, p value):
LOS: 73 ml/min/1.73m2, 95% CI 59;89, p value NS compared to baseline
LIS: 72 ml/min/1.73m2, 95% CI 52;92, p value NS compared to baseline
LOS+LIS: 66 ml/min/1.73m2, 95% CI 51;80, p < 0.05 compared to baseline
*where p values listed as NS, actual numbers NR*

LOS+LIS lowered mean arterial pressures lower than LOS (p < 0.05) but not lower than LIS.
NRNRNRSerum potassium >5.5 mmol/L:
LOS: 1
LIS: 2
LOS+LIS: 2

Dizziness:
LOS: 1
LIS: 1
LOS+LIS 2

Adverse events did not lead to any withdrawals.
Total withdrawals: 1

Withdrawals due to adverse events: zero

Withdrawals due to reasons other than adverse events: 1 (due to inability to maintain scheduled visits)
Luno
2002
Spain
Fair
Study design: multi-center, prospective, open, randomized, active controlled and parallel group

Setting: outpatient

Duration: 24 weeks
Inclusion criteria:
Age 18–80
Primary proteinuric nephropathy for >6 mo
Proteinuria > 2 gm/d (by two 24-hr urine collections) GFR >50 ml/min/1.73m2

Exclusion criteria:
Serum albumin <3 g/dL
Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg
Serum potassium > 5 mmol/L
Secondary glomerular disease
Diabetes, Amyloidosis, lupus
Severe cardiovascular even tin 3 mo prior to randomization
Severe cardiac, pulmonary, or hepatic disease
HIV
Neoplasia
Use of corticosteroids or immune suppression therapy in 6 mo prior to entry
Women who were of childbearing age but not using an effective method of birth control
Types of CKD: NR

Biopsy proven? Recommended but not required

Proteinuria >2 gm/d required. Baseline mean proteinuria ranged from 3.6–4 gm/d.
Stage of CKD: not specifically addressed

CrCl > 50 ml/min/1.73m2 required. Baseline CrCl ranged from 84–100 ml/min/1.73m2.

CrCl measured via 24 hr urine collection.
After 2 week run-in, participants were randomized to:
[L] Lisinopril 10mg/d (n = 14)
[C] Candesartan 8mg/d (n= 15)
[L+C] Lisinopril 5mg/d + Candesartan 4mg/d (n = 16)

If systolic blood pressure was higher than 125 mmHg or diastolic blood pressure was higher than 75 mmHg, then doses were doubled every 2 weeks to a maximum dose of:
[L] Lisinopril 40mg/d
[C] Candesartan 32 mg/d
[L+C] Lisinopril 20mg/d + Candesartan 16 mg/d
*Dose increased to achieve goal of blood pressure <125/75 mmHg.*
2 week run-in period was used.
During that time only metoprolol and hydrochlorothiazide were used for blood pressure management. All previous ACE-I and ARB were held.
Additional medication was allowed to achieve blood pressure goal of <125/75 mmHg. Additional medications included:
β-blockers calcium channel blockers Thiazide diuretics
Primary end point was not specifically stated.

Primary objective: a reduction in proteinuria excretion with Lisinopril, candesartan, or a combination of both therapies in primary proteinuric nephropathies.

Prior to run-in, at inclusion, at beginning of treatment, and at weeks 2, 4, 6, 8, 12, and 24, participants had office visits and blood pressure measurements.

At baseline and at weeks 6, 12, and 24, participants had the following assessments done:
-serum labs including creatinine and electrolytes
-24 hr urine for protein, sodium, potassium, and creatinine.
Age:
C: 45 +/− 18 years
L: 50 +/− 16 years
C+L: 42 +/− 13

Gender (men/women):
C: 10/5
L: 12/2
L+C: 9/7

Ethnicity: NR
Baseline CrCl:
C: 104 +/− 36 ml/min
L: 84 +/− 26 ml/min
C+L: 96 +/− 34 ml/min

Baseline protein/creatinine ratio:
C: 4 +/− 2.5
L: 3.6 +/− 2.9
C+L: 3.8 +/− 2.1

Baseline serum potassium level:
C: 4.3 +/− 0.3 mmol/L
L: 4.3 +/− 0.3 mmol/L
C+L: 3.8 +/− 2.1 mmol/L

Systolic blood pressure:
C: 133 +/− 14 mmHg
L: 135 +/− 20 mmHg
C+L: 135 +/− 20 mmHg
Number screened: NR

Eligible: NR

Enrolled: 46
Number withdrawn: 1

Lost to follow-up: zero

Analyzed 45 (intention to treat)
Urine protein/creatinine ratio (beginning to 2 mo and to 3 mo compared to baseline): (% change, 95% CI, p value)
C: 3.99 +/− 0.63 to 3.14 +/− 0.67 (−28%,12, −45, p = 0.019) and 2.34 +/− 0.42 (−41%; −30, −52, p < 0.001)
L: 3.6 +/− 0.7 to 3.6 +/− 0.77 (−33%; −12, −56, p = 0.008) and 2.44 +/− 0.97 (−31%; 0, −68, p = 0.019)
C+L: 3.8 +/− 0.53 to 1.55 +/− 0.41 (−60%; −44, −77, p = 0.004) and 1.89 +/− 0.51) −54%; −38, −69), p < 0.001)

Urine protein/creatinine ratio (beginning to after treatment at 6 mo):
C: 3.99 +/− 0.63 to 2.8 +/− 0.49 (−48%, 95% CI −32 −63, p < 0.001)
L: 3.6 +/− 0.7 to 1.83 +/− 0.68 (−50%, 95% CI −9; −90, p = 0.013)
C+L: 3.8 +/− 0.53 to 1 +/− 0.25 (−70%, 95% CI −57; −83, p < 0.001)
*p values intra-group protein reduction compared to baseline.

Reduction in urinary protein excretion, between group comparisons:
C+L vs C: C+L resulted in more proteinuria reduction at 2 and at 6 months (p = 0.004 at 2 months and p = 0.23 at 6 months)
C+L vs L: C+L resulted in more proteinuria reducation only at 2 months (p = 0.03 at 2 mo, p at 6 mo NR).

Blood pressure goal of <125/75 reportedly achieved by all groups by 4 weeks; no statistical significance of blood pressure control between groups.

Changes in creatinineclearance showed no signficant difference between treatment groups at any time point.
NRMaximum dose of Candesartan (32 mg/d) was tolerated by 56%.

Maximum dose of Lisinopril (40 mg/d) was tolerated in 31%.

Maximum dose of combination therapy (Lisinopril 20 mg/d + candesartan 16 mg/d) was tolerated in 35%.

Medium dose of Candesartan (16 mg/d) was achieved in 23%.

Medium dose of Lisinopril (20mg/d) was achieved in 35%.

Medium dose of combination therapy (Lisinopril 10 mg/d + candesartan Candesartan 8 mg/d) was achieved in 39%.
Lab tests done as reported. Otherwise NR.Serum potassium >5.5 mmol/L: 8 instances
Not specified by group.
2 instances > 6 mol/L.

Participants in L or C+L experienced K > 5.5 mmol/L more than those on C (p < 0.001).

No other adverse events reported.
Total withdrawals: 1

Withdrawals due to adverse events: zero

Withdrawals due to reason other than adverse events: 1 (never took study medication, so was excluded)
Matsuda
2003
[Differing Anti-proteinuric action of candesartan and Losartan in chronic renal disease]
Japan
Fair
Study design:
randomized controlled trial

Setting: NR

Duration: 96 weeks
Inclusion criteria:
Hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg)
Proteinuria of >0.5 gm/d
Serum creatinine < 3 mg/dL
CrCl >30 ml/min/1.73m2

Exclusion criteria:
Diabetic nephropathy
Polycystic kidney disease
Chronic Pyelonephritis
Types of renal disease:
proliferative glomerulonephritis (n = 58)
membranous nephropathy (n = 2)
focal segmental glomerulosclerosis (n = 2)

Biopsy proven? NR

>0.5 mg/d proteinuria required for inclusion.

Mean proteinuria at baseline ranged from 2.5–3 gm/d.

Proteinuria was measured via 24 hour urine collection. assessment.
Stage of CKD not specifically addressed.

CrCl >30 ml/min/1.73m@ required, Serum creatinine <3 mg/dL required.

Baseline CrCl ranged from 79–97 ml/min/1.73m2

CrCl was measured via 24 hour urine collection. assessment.
Participants were initially randomly assigned to ACE-I or ARB treatment groups. After 4 week observation period, participants divided into one of four groups:
[T] Trandolapril 0.5 mg/d (n = 15)
[P] Perindopril 2 mg/d (n = 15)
[L] Losartan 25 mg/d (n = 15)
[C] Candesartan 4 mg/d (n = 17)

Doses were titrated within each group to achieve blood pressure <135/85 mmHg
4 week observation period noted prior to group assignment. No additional information reported.14 of 62 participants were on antiplatelet therapy prior to enrollment (dipyridamole or dilazep dihydrochloride); these medications were continuedPrimary end point not specifically reported.

Stated aim was to evaluate the effect of candesartan and Losartan on the development of proteinuria over 96 weeks.

Blood pressure was measured at each visit.

24 hour urine for creatinine clearance and protein was completed during control period and at weeks 12, 24, 48, 72, and 96.
Age:
T:51 +/− 4 years
P: 50 +/− 5 years
L: 51 +/− 3
C: 58 +/−5

Gender (male/female):
T: 9/6
P: 8/7
L: 7/8
C: 9/8

Ethnicity: NR
Baseline serum creatinine:
T: 0.9 +/− 0.1 mg/dL
P: 0.9 +/− 0.1 mg/dL
C: 1 +/− 0.1 mg/dL
L: 1.1 +/− 0.2 mg/dL

Baseline CrCl:
T: 115 +/− 18 ml/min/1.73m2
P: 98 +/− 10 ml/min/1.73m2
C: 102 +/− 18 ml/min/1.73m2
L: 89 +/− 15 ml/min/1.73m2

Baseline urinary protein excretion:
T: 2.7 +/− 0.5 gm/d
P: 2.7 +/− 0.5 gm/d
C: 3 +/− 0.6 gm/d
L: 2.5 +/− 0.4 gm/c

Baseline serum potassium:
T: 4.3 +/− 0.1 mEq/L
P: 4.3 +/− 0.1 mEq/L
C: 4.3 +/− 0.1 L: 4 +/− 0.2 mEq/L

Baseline systolic blood pressure and diastolic blood pressure (mmHg):
T: 154+/−6 and 90+/−3
P: 155+/−3 and 91+/−4
C: 152+/−2 and 93+/−2
L: 150+/−4 and 93+/−3
Number screened: NR

Eligible: NR

Enrolled: 62
NRPercent reductions in proteinuria at 12 weeks and 96 weeks:
T: 37+/−6% (p < 0.05) at 12 weeks and 53+/− 7% (no p value given) at 96 weeks.
P: 42+/−6% (p<0.05) at 12 weeks and 60.7% at 96 weeks (no p value given).
C: 38+/−4% at 12 weeks (no p value given) and sustained anti-proteinuric effect throughout study ((no p value given).
L: 12 +/−3% (P< 0.05) at 12 weeks and 36+/−4% at 96 weeks.
*Significantly less reduction in proteinuria was noted in L compared to C (p<0.05) but no comparisons of ACE to ARB were made.

No significant effect on CrCl was seen throughout the study, numbers not reported.

No significant differences in blood pressure were noted between treatment groups at any period, no numbers given.
NRNRLab tests done as reported. Otherwise NR.NRNR
Mori-takeyama
2008
Japan
no trial name
Fair
Study design:
Prospective, parallel, open-label

Setting: NR

Follow-up: 36 months
Inclusion criteria:
Biopsy-proven glomerulonephritis
History of Candesartan dose of 4mg/d for 6 months prior to enrollment.

Exclusion criteria: history of diabetes, history of renal artery stenosis, steroids or immune suppression therapy within 6 months prior, history of malignant hypertension, history of stroke, TIA, unstable angina, arrhythmia, or heart failure.
Types of CKD:
Repeat biopsy was done on 52 of the 86 enrolled patients and Glomerulonephritis types were specified for those 52 as:
-membranoproliferative glomerulonephritis (n=39)
(mesangioproliferative Glomerulonephritis)
-Minor glomerular abnormality (n= 5)
-focal segmental glomerulosclerosis (n=2)
(focal segmental glomerulosclerosis)
-Membranous nephropathy (n=2)

History of biopsy proven Glomerulonephritis was required.

Proteinuria >0.3 gm/day required
Mean proteinuria at baseline 1.4 gm/d
CKD stages were not specifically defined or included as inclusion/exclusion.

GFR was reported in baseline characteristics and outcomes, and was measured via para-aminohippuric acid and thiosulfate clearance methods.

Per the baseline characteristics table, baseline creatinine 0.8–0.9.
Participants were randomly allocated to a treatment regimen based on the last digit of their ID number into group A or group B.

Group A (to be referred to as “C”): candesartan alone,; candesartan dose increased from 4 mg/d to 6mg/d at study initiation.

Group B (to be referred to as “C+B”): candesartan and Benazepril; dose of Benazepril of 2.5mg/d added to candesartan 4 mg/d at time of study initiation.

Target BP: 125/75
In C, candesartan was increased by 8 and 12 mg every 6 months to reach target BP.
In C + B, Benazepril was increased to 5 and 10 mg/d every 6 months to reach target BP.
Run in: All participants were on candesartan 4 mg/d for 6 months prior to enrollment.

No wash-out following run-in
If target BP not reached at 18 months, adjuvant hypertensives could be added. (additional drugs use were not specified)Primary endpoint not specifically stated.

Aim stated to be to evaluate the antiproteinuric and renal protective effect of candesartan alone and with Benazepril in patients with chronic glomerulonephritis.

The following measurements were completed every three months:
-blood pressure
-GFR and renal plasma flow (evaluated by para-aminohippuric acid and thiosulfate methods).
-Proteinuria was quantified by pyrogallol red- molybdate method.
-Complete blood count, serum electrolytes, and urea nitrogen were measured via automated analyzer.
-PRA, PAC, and atrial natriuretic peptide were determined by radioimmunoassay.
Mean age:
 C: 37.8 +/− 12
 C + B: 36.9 +/− 12%

%male:
 C: 63%
 C + B: 56%

Ethnicity: not explicitly stated
Mean potassium:
 C: 4.1 +/− 0.2
 C+B: 3.9 +/− 0.3

Mean serum creatinine:
 C: 0.8 +/− 0.3
 C+B: 0.9 +/− 0.3

Mean GFR:
 C: 94.3 +/− 12.8
 C+B: 95.6 +/− 28.6

Mean proteinuria:
 C: 1.4 +/− 0.6
 C+B: 1.3 +/− 0.5

Mean systolic blood pressure and diastolic blood pressure:
 C: 132 +/− 8.6 mmHg and 84 +/− 4.9 mmHg
 C+B: 135.8 +/− 6.8 mmHg and 81.2 +/− 5.2 mmHg
Number screened: NR

Eligible: NR

Enrolled: 86
Number withdrawn: 9

Lost to follow-up: NR

Analyzed: 77
Total reduction in proteinuria (baseline to post treatment):
C: 1.4 +/− 0.6 gm/d to 0.7 +/− 0.3 gm/d, p < 0.01 compared to baseline
C+B: 1.3 +/− 0.5 gm/d to 0.5 +/− 0.2 gm/d, p < 0.01 compared to baseline
Anti-proteinuric effect of C+B was statistically greater than that of C after 18 months (p < 0.01, 95% CI NR)

No significant change in GFR or renal plasma flow between groups was noted, p values and 95% CI NR.

Difference in BP reduction rate was not significant between the two groups.
NRn/aNROnly specific adverse event reported was cough, which was only reported regarding its incidence in group B (Candesartan+Benazepril, noted in 39.1%).Total withdrawals: 9

Withdrawals due to cough: 6 (all in C+B

Withdrawals classified by study group as “not due to side effects”: 3 (2 in C, 1 in C+B)
Nakao
2003
Japan
COOPERATE (Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease)
Poor
Study design: double-blind randomized trial

Setting: outpatient nephrology clinic

Duration: 3 years
Inclusion criteria:
Age 18–70
chronic nephropathy (serum creatinine 1.5–4.5 mg/dL or eGFR 20–70 ml/min/1.73m2)
Variation of creatinine or eGFR of lessl than 30% in 3 mo prior to enrollment
Non-diabetic renal disease (by history, exam, urinalysis, serum labs, and biopsy if available) Proteinuria > 0.3 gm/d for at least 3 mo prior to enrollment

Exclusion criteria:
Evidence of urinary tract infection or stage III-IV
NYHA heart failure
History of allergic reaction to drugs (especially ACE-I)
Immediate need for renal replacement therapy
Treatment-resisstant edema
Need for steroids, NSAIDS, or immunosuppressive drugs
Proteinuria >10 gmd/or serum albumin <2.8 g/dL
Renovascular or malignant hypertension
Myocardial infarction of cerebrovascular accident in the year prior to enrollment
Severe peripheral vascular disease, HF, chronic hepatic disease, connective tissue disease, obstructive uropathy, cancer, or COPD
Drug or alcohol misuse
Pregnancy or breastfeeding
Types of CKD:
Glomerular
Hypertension
Polycystic kidney interstitial
Unknown

Biopsy proven? Yes
*Biopsies were performed after enrollment to confirm type of kidney disease.*

Proteinuria >0.3 gm/d but <10gm/d required.
Baseline proteinuria ranged from 2.5–2.5 gm/d
Stage of CKD not specifically addressed.

eGFR of 20–70 ml/min/1.73m2 required

Baseline eGFR ranged from37.5–38.4 ml/min/1.73m2

eGFR was calculated.
After run-in, participants were randomized to:
[L] Losartan 25mg + placebo daily (n = 89)
[T] Trandolapril 1mg + placebo daily (n = 86)
[L+T] Losartan 12.5gm and Trandolapril 0.5 mg daily (n = 88)

Every 3–4 weeks the drug dose was increased to reach the fixed maximum dose:
[L] Losartan 100 mg/d (25mg am, 25 mg, noon, 50mg evening) with placebo
[T] Trandolapril 3mg/d (1.5mg bid) with placebo
[L+T] Losartan 100mg/d + Trandolapril 3mg/d
Run-in: 18 week period prior to randomization.

No antihypertensives were used for the first 3 weeks or last 3 weeks.

After initial 3 weeks, Trandolapril was started at 0.5mg/d and increased by 1mg every 3 weeks to maximum dose of 6 mg/d to determine optimal anti-proteinuric dose.

3 urine samples for urine protein were done at the end of each 3 week period.

Anti-proteinuric effect plateaud at 3mg/d; 3mg/d was then used asmaximum dose of Trandolapril after randomization.

Run-in identified a sub-section of participants with decreased response to ACE (change in proteinuria of −3 to −7% compared to a mean of −44% in most others. These participants were then-on referred to as “low responders.”
Goal blood pressure after randomization was <130/80 mmHg. Additional blood pressure medications could be used to achieve that goal.

Additional medication that was allowed included:
-long acting dihydropyridine calcium channel blockers
- α-blockers
-centrally acting drugs
Primary endpoint: “renal survival” – combined endpoint looking at time to doubling of serum creatinine or end-stage renal disease (eGFR <7 ml/min/1.73m2)

Secondary endpoint: to assess the effects of the three treatments on changes in blood pressure and daily urinary protein excretion, and to note any adverse reactions.

Patient appointments were completed with a nephrologist q1 month up through 6 months and then q3 months. Each visit included the following assessments:
-serum labs
-urine labs
-physical exam with blood pressure
-24 hr urine study (done to check adherence to dietary restrictions)
Mean age:
L: 44.8 +/− 4.8 years
T: 45.9 +/− 5.8 years
L+T: 45.2 +/−4.9 years

Gender (male/female):
L: 48/41
T: 46/40
L+T: 47/41

Ethnicity: NR
Baseline serum creatinine:
L: 3 +/− 0.1 mg/dL
T: 3 +/− 0.1 mg/dL
L+T: 3.1 +/− 0.1 mg/dL

eGFR (calculated, ml/min/1.73m2):
L: 38.4 +/− 4
T: 37.9 +/− 3.7
L+T: 37.5 +/− 3.9

Urinary protein excretion (gm/d):
L: 2.4 +/− 1.1
T: 2.5 +/− 1.2
L+T: 2.5 +/− 1.1

Systolic blood pressure (mmHg):
L: 130 +/− 9.3
T: 129.9 +/− 10.2
L+T: 130.3 +/−10.5

Number of “low responders” to Trandolapril:
L: 11 (13%)
T: 10 (12%)
L+T: 11 (13%)
Number screened: 336

Number eligible: 301

Number enrolled: 263
Number withdrawn:
After screening - 35
After eligible - 38
After enrolled - 7

Lost to follow-up: 7

Analyzed: 256

Stated as intention to treat; those lost to follow up could not be analyzed for primary end point.
Primary end point, renal survival:
L+T vs. T showed HR of 0.38 (95% CI 0.18–0.63, p = 0.11) for primary end point
L+T vs. L showed HR 0.4, 95% CI 0.17–0.69, p = .016) for primary end point

Percent in each group to reach primary end point:
L: 23% (n = 20)
T: 23% (n = 20)
L+T: 11% (n = 10)

Percent in each group to reach end stage renal disease:
L: 3% (n = 3)
T: 8% (n = 7)
L+T: 1% (n = 1)

Maximum median change in urinary protein excretion:
L: −42.1%
T: −44.3%
L+T: −75.6%

Fall in Systolic blood pressure:
L: 5.1 mmHg (SD 1,6)
T: 5.2 mmHg (SD 1,3)
L+T: 5.3 mmHg (SD 1,4)
Fall in Diastolic blood pressure:
L: 2.9 mmHg (SD 0,9)
T: 2.9 mmHg (SD 0,8)
L+T: 3.0 mmHg (SD 0,7)
NRParticipants were evaluated for primary end point via type of renal disease (glomerulonephritis vs hypertensive renal disease).
-among participants with GN:
L: 23% reached primary end point
T: 27% reached primary end point
L+T: 10% reached primary end point
-among participants with hypertensive renal disease:
L: 7%
T: 13%
L+T: 7%
*Authors suggest that this indicates lesser effect on primary endpoint in hypertensive renal disease vs GN, p values NR.*

Participants in L+T were analyzed by level of proteinuria for achieving primary endpoint:
<1 gm/d: HR 0.69, 95% CI 0.22–2.28, p = 0.49
1–3 gm/d: HR 0.33, 95% CI 0.19–2.74, p = 0.29
>3 gm/d: HR 0.4, 95% CI 0.21–1.84, p = 0.33
“Overall effect”: 0.34, 95% CI 0.19–2.68, p = 0.31 -- unclear what is compared for this overall effect statement
**These values were initially reported incorrectly (p = 0.049, p = 0.029, p = 0.033) and retraction was printed in original journal at later date.**
Comparison between treatment groups for antiproteinuria effect were made among participants broken down into level of baseline proteinuria. Results are reported as significantly better in L+T across all baseline protein categories. Numbers are reported for group <1 gm/d:
L: −1.2%
T: −1.4%
L+T: −2.5%
p = 0.032
Other than lab tested as noted, NRNon-fatal cardiovascular event (Stroke/angina/myocardial infarction/hypotension/sudden death):
L: 0/1/1/0/1
T: 1/1/0/1/0
L+T: 1/1/0/1/0

Hyperkalemia:
L: 4
T: 8
L+T: 7

Dry cough:
L: 1
T: 5
L+T: 5

Gastrointestinal symptoms/skin reaction:
L: 2/1
T: 2/1
L+T: 2/1

Total adverse reaction:
L: 11
T: 19
L+T: 18

Discontinuation/moved away/protocol invalidation:
L: 2/1/0
T: 1/0/0
L+T: 2/0/1
Total withdrawals: 7

Withdrawals due to adverse effects:
L: 2
T: 1
L+T: 2

Withdrawals due to reason other than adverse effect:
L: 1 (moved away)
T: 0
L+T: 1 (protocol invalidation)
This study (the COOPERATE trial) was officially retracted by the original publishing journal, The Lancet, in October 2009. Concerns over statistical analysis prompted a formal review by the original study University Hospital in Japan. Their investigation revealed that the study was not double-blind, and that only verbal consent was obtained from patients prior to study initiation. They were unable to verify the presence or role of a statistician in the study analysis. Additionally, sample chart reviews were unable to authenticate patient data.
Nakao
2004
Japan
COOPERATE sub-study (Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease)
Poor
Study design:
randomized, double-blinded

Setting: outpatient renal clinics

Duration: 3 years
Inclusion criteria:
Age 18–70
chronic nephropathy (serum creatinine 1.5–4.5 mg/dL or eGFR 20–70 ml/min/1.73m2)
Variation of creatinine or eGFR of lessl than 30% in 3 mo prior to enrollment
Non-diabetic renal disease (by history, exam, urinalysis, serum labs, and biopsy if available)
Proteinuria > 0.3 gm/d for at least 3 mo prior to enrollment

Exclusion criteria:
Evidence of urinary tract infection or stage III-IV NYHA heart failure
History of allergic reaction to drugs (especially ACE-I)
Immediate need for renal replacement therapy
Treatment-resisstant edema
Need for steroids, NSAIDS, or immunosuppressive drugs
Proteinuria >10 gmd/or serum albumin <2.8 g/dL
Renovascular or malignant hypertension
Myocardial infarction of cerebrovascular accident in the year prior to enrollment
Severe peripheral vascular disease, HF, chronic hepatic disease, connective tissue disease, obstructive uropathy, cancer, or COPD
Drug or alcohol misuse
Pregnancy or breastfeeding
Types of CKD:
Glomerular
Hypertension
Polycystic kidney interstitial
Unknown

Biopsy proven? Yes
*Biopsies were performed after enrollment to confirm type of kidney disease.*

Proteinuria >0.3 gm/d but <10gm/d required. Baseline proteinuria was approximately 2.5 gm/d
Stage of CKD not specifically addressed.

eGFR of 20–70 ml/min/1.73m2 required

Baseline eGFR ranged from 37.5–38.4 ml/min/1.73m2

eGFR was calculated
92 participants of the original 263 COOPERATE participants entered the ambulatory blood pressure (ABP) sub-study.

After run-in, participants were randomized to:
[L] Losartan 25mg + placebo daily (n = 30)
[T] Trandolapril 1mg + placebo daily (n = 31)
[L+T] Losartan 12.5gm and Trandolapril 0.5 mg daily (n = 31)

Every 3–4 weeks the drug dose was increased to reach the fixed maximum dose:
[L] Losartan 100 mg/d (25mg am, 25 mg, noon, 50mg evening) with placebo
[T] Trandolapril 3mg/d (1.5mg bid) with placebo
[L+T] Losartan 100mg/d + Trandolapril 3mg/d
Run-in: 18 week period prior to randomization.

No antihypertensives were used for the first 3 weeks or last 3 weeks.

After initial 3 weeks, Trandolapril was started at 0.5mg/d and increased by 1mg every 3 weeks to maximum dose of 6 mg/d to determine optimal anti-proteinuric dose.

3 urine samples for urine protein were done at the end of each 3 week period.

Anti-proteinuric effect plateaud at 3mg/d; 3mg/d was then used as maximum dose of Trandolapril after randomization.

Run-in identified a sub-section of participants with decreased response to ACE (change in proteinuria of −3 to −7% compared to a mean of −44% in most others. These participants were then-on referred to as “low responders.”
Goal blood pressure after randomization was <130/80 mmHg. Additional blood pressure medications could be used to achieve that goal.

Additional medication that was allowed included:
-long acting dihydropyridine calcium channel blockers
-α-blockers
-centrally acting drugs
Primary endpoint: “renal survival” - combined endpoint looking at time to doubling of serum creatinine or end-stage renal disease (eGFR <7 ml/min/1.73m2)

Secondary endpoint: to assess the effects of the three treatments on changes in blood pressure and daily urinary protein excretion, and to note any adverse reactions.

Patient appointments were completed with a nephrologist q1 month up through 6 months and then q3 months. Each visit included the following assessments:
-serum labs
-urine labs
-physical exam with blood pressure
-24 hr urine study (done to check adherence to dietary restrictions)

As part of sub-study, ambulatory blood pressure monitors were used for 24 hrs on the day prior to randomization, at 6mo, 1 year, 2 year’s and 3 years after enrollment.
Mean age among sub-study:
L: 43.4 +/− 3.5
T: 42.9 +/− 4.8
L+T: 43.2 +/− 4.4

Gender (%male):
L: 56.8%
T: 55.9%
L+T: 58.9%

Ethnicity: NR
Baseline calculated eGFR (ml/min/1.73m2):
L: 45.6 +/− 4.9
T: 46.8 +/− 4.1
L+T: 45.9 +/− 5.1

Median baseline urinary protein excretion (gm/d):
L: 1.9 +/− 1.1
T: 2.0 +/− 1.2
LT: 1.9 +/− 1.1
Number screened for sub study: NR

Number eligible for sub study: NR

Number enrolled in sub study: 92
Number withdrawn: 7

Lost to follow-up: NR

analyzed: 85
Percent reduction in daily urinary protein excretion:
L: −45% (95% CI −10.2 to −54.8%)
T: −44% (95% CI −11 to −50.3%)
L+T: −74% (95% CI −54 to −81%)

The improved anti-proteinuric effect of L+T was sustained throughout the trial (p = 0.013).

Number who reached primary end point:
L: 4
T: 5
L+T: 1

No difference in outpatient BP or ambulatory BP at baseline.
At 6 mo, comparing three groups, no significant differences were seen (p = 0.19 outpatient blood pressure and p = 0.21 ABP).
At one year, still no significant difference seen among outpatient blood pressure or ABP between groups.
NRNRNRNRTotal withdrawals: 7

Withdrawals due to adverse effects: NR

**Authors report that 3 in L, 2 in T, and 2 in L+T did not repeat ambulatory blood pressure measurements due to reasons “not related to this trial.”**
This study was a sub-study of the COOPERATE trial - see comments above.
Remuzzi
1999
Italy
no trial name
Poor
Study design: randomized, controlled trial.

Setting: outpatient nephrology clinic

Duration: 2 months
Inclusion criteria:
Age 20–65
Biopsy-proven IgA nephropathy
Proteinuria of 0.5 –4 mg/d
Creatinine 0.9–2.4 mg/dL

Exclusion criteria:
Immunosuppressive or NSAID therapy in the 3 mo prior to enrollment
Types of CKD:
IgA nephropathy

Biopsy proven: yes

Degree of proteinuria: goal range 0.5–4 gm/d.
Baseline mean proteinuria ranged from 1.4–2.4 gm/d.
Level of CKD: not specifically addressed

Creatinine 0.9–2.4 mg/dL required

Baseline GFR ranged from 54–66 ml/min/1.73m2; GFR was determined via inulin and para-aminohippuric acid methods.
At the end of run-in, patients were randomized to:
(E) Enalapril 20mg/d (n = 11)
(I) Irbesartan 100 mg/d (n = 9)

Participants were followed in these groups for 28 days.
4 week single-blind placebo wash-out prior to randomization.Use of anithypertensives were stopped prior to selection visit.
Any further use of anti-hypertensive throughout (other than study meds) was NR.
Primary endpoint not explicitly stated. Reported results included:
-CrCl
-theoretical analysis of glomerular membrane transport
-renal plasma flow
-filtration fraction, fractional excretion of neutral dextrans and albumin

The following assessments were completed at week 3 and week 8:
-24 hr urine protein assessment
-GFR measurement
Age: Only general range given (20–65)

Gender:
Female: 4
Male: 16

Ethnicity: NR
Baseline GFR:
E: 66 +/− 19 ml/min/1.73m2
I: 54 +/− 15 ml/min/1.73m2

Baseline 24 hr protein values:
E: 1.44 +/− 1.11 gm/d
I: 2.48 +/− 2.02 gm/d

Systolic blood pressure:
E: 133 +/− 9 mmHg
I: 147 +/− 13 mmHg
Number screened: NR

Number eligible: NR

Number enrolled: 20
Number withdrawn: NR

Lost to follow-up: NR

Analyzed: 20
After 28 days there was no significant decline in GFR in patients treated with either Enalapril or Irbesartan.

GFR baseline vs. end of treatment:
E: 66 +/− 19 to 65 +/− 25
I: 54 +/− 15 to 55 +/− 11
No inter-group comparison given, no p values or CI given.

24 hr urinary protein excretion baseline vs. end of treatment:
E: 1.44 +/− 1.11 gm/d to 2.48 +/− 2.02 gm/d, 38.6% change, p < 0.05 intra-group endpoint vs. baseline
I: 2.48 +/− 2.02 gm/d to 1.54 +/− 1.46 gm/d, 45.4% change, p < 0.01 intra-group endpoint vs. baseline

There was no inter-group comparison between Enalapril and Irbesartan for reduction in proteinuria.

Blood pressure reduction was not equal between groups.
Percent change in systolic blood pressure from baseline to end of treatment:
E: 6.4%
I: 3%
Percent change in diastolic blood pressure from baseline to end of treatment:
E: 12.4%
I: 9.1%
NRNRNRNRTotal withdrawals: NRThe Enalapril group and Irbesartan group were uneven at baseline in terms of level of proteinuria and degree of hypertension. Per the results, that is why authors described a percent change in proteinuria as opposed to an inter-group comparison.
Renke
2004
Poland
no trial name
Fair
Study design: prospective, randomized

Setting: NR

Duration: 9 months
Inclusion criteria:
Age 18–70
History of hypertension
History of biopsy-proven Glomerulonephritis (not including IgA nephropathy).
Daily proteinuria
Creatinine < 2 mg/dL

Exclusion criteria:
Immunosuppressive therapy received in 6 mo prior
Diagnosis of complete nephrotic syndrome
History of biopsy proven GLOMERULONEPHRITIS was required.

Types of GLOMERULONEPHRITIS included:
Mesangial GLOMERULONEPHRITIS
Mesangiocapillary GLOMERULONEPHRITIS
Membranous GLOMERULONEPHRITIS
Focal segmental glomerulosclerosis
Other

Proteinuria requirement was listed as “daily” but per baseline characteristics averaged between 2–3 gm/day in each group.
CKD stages not specifically stated, but creatinine of <2 mg/dL was required.

CrCl was noted in baseline characteristics for each group; >90 ml/min on average in each group.

CrCl was quantified by the mean of two 24-hr urine collections.
Participants were randomized to one of three groups:
L: 25mg Losartan daily (n=18)
E: 10mg Enalapril daily (n=18)
L+E: 25mg Losartan and 10mg Enalapril daily (n=16)
Run-in: 4 week period during which all ACE-I or ARB therapy was discontinued. Alternate antihypertensive therapy was used during that time to achieve BP <140/90.Additional antihypertensives used to achieve BP <140/90.

Additional meds used included β-blockers, calcium channel blockers, β-blockers with calcium channel blockers, and α-blockers.

L: 8 of 18 on additional meds
E: 5 of 18 on additional meds
L+E: 3 of 16 on additional meds
Primary endpoint not specifically stated.

Hypothesis: the combination of ACE-I and ARB will produce a more profound anti-proteinuric effect than either agent as monotherapy.

Evaluations at baseline and at 3 and 9 months, which included:
-two 24-hr urine studies to measure proteinuria and CrCl. Mean of two samples used to define urinary protein excretion and CrCl.
Mean Age:
L: 40.4 +/− 11.9
E: 43.4 +/− 10.1
L+E: 37.7 +/− 12.7

Gender: (males/females)
L: 7/11
E: 12/6
L+E: 11/5

Ethnicity: NR
CrCl:
L: 95.5 +/− 25.3 ml/min
E: 93.9 +/− 37.7 ml/min
L+E: 94.8 +/− 31.8 ml/min

Proteinuria:
L: 2.17 +/− 1.52 gm/d
E: 2.6 +/− 1.69
L+E: 3.25 +/− 1.82

Serum creatinine:
L: 1.04 +/− 0.2
E: 1.25 +/− 0.3
L+E: 1.2 +/− 0.3

Mean Systolic blood pressure and Diastolic blood pressure (mmHg) :
L: 137 +/− 11.6 and 88.2 +/− 7.5
E: 134 +/− 13.4 and 87.8 +/− 9.3
L+E: 140 +/− 17.2 and 90.8 +/− 11.4
Number screened: NR

Number eligible: NR

Number enrolled: 54
Withdrawn: 2

Lost to follow up: zero reported

Analyzed: 52
No significant change in CrCl in any group (p values, 95% CI NR).

Percent decrease in proteinuria after 3 and 9 months respectively:
L: 22.6% and 44.2%; p < 0.01 at 3 mo and at 9 mo from baseline
E: 43.07% and 49.6%; p < 0.01 at 3 mo and and at 9 mo from baseline
L+E: 63% and 51%; p < 0.001 at 3 mo and <0.01 at 9 mo from baseline

Change in proteinuria compared between groups:
Non-significant p values are NR
Only statistically significant change was greater reduction in proteinuria in L+E compared to L at 3 mo (p < 0.01).

No statistically significant changes in systolic blood pressure between groups.
Decrease in diastolic blood pressure was more significant in Losartan at 3 mo only (p = 0.04).
Decrease in diastolic blood pressure was more significant in subjects receiving combination therapy compared to Enalapril (p = 0.009)
N/ANRNRNot specifically reported other than with regards to withdrawals.Total withdrawals: 2

Withdrawals due to adverse events: 1
*allergic reaction to study medication - to which drug not
stated.*

Withdrawals due to reason other than adverse events:1
*withdrawal for development of nephrotic syndrome requiring steroid therapy*
The combination therapy group started with a significantly higher burden of proteinuria compared to the single therapy groups.

Mechanism for randomization was not specified.
Renke
2005
Poland
No trial name
Fair
Study design: randomized, open, cross-over

Setting: renal outpatient clinics

Duration: 20 weeks
Inclusion criteria:
Age 18–60
Biopsy proven glomerulonephritis
Stable proteinuria
Serum creatinine <2 mg/dL
History of being unable to receive maximum doses of ACE-I or ARB in the past (due to hypotension or hyperkalemia)

Exclusion criteria:
nephrotic syndrome
Diabetes
Renal artery stenosis
Use of steroids or immunosuppressive agents within 6 mo prior to enrollment
Pregnancy or breastfeeding
History of malignant hypertension, cerebrovascular accident, transient ischemic attacks, unstable angina, arrhythmias, or decompensated HF in 6 mo prior
History of hypersensitivity to ACE-I or ARB
Types of CKD:
Mesangial glomerulonephritis (14)
IgA nephritis (5)
Mesangiocapillary glomerulonephritis (4)
Membranous nephropathy (1)

Biopsy proven? Yes

Degree of proteinuria: only required to be stable. Baseline proteinuria mean noted to be 2.13 +/− 0.24 gm/d.

Urine protein excretion was measured as the mean of two 24-hr urine collection protein values.
Stage of CKD: not specifically addressed

Creatinine <2 mg/dL required.

Baseline mean CrCl 85.73 +/− 7.63 ml/min.
CrCl measured as mean of two 24 hour urine collections.
After run-in, participants were randomized to one of 6 sequences. Each sequence resulted in each participant crossing-over into each of the following groups:
[L] Losartan 50mg/d
[B] Benazepril 10 mg/d
[L+B] Losartan 25mg/d + Benazepril 5 mg/d

Each treatment period lasted 4 months.
8 week run-in: No ACE-I or ARB during run-in.

First 6 weeks of run-in, blood pressure could be controlled using Doxazosin. Last 2 weeks of run-in, no anti-hypertensive medication was utilized.

No washout periods. Authors explicitly planned 4 mo for each treatment group, citing evidence that treatment effect from ACE-I and ARB was known to dissipate after 2 months, so that by the end of each of their 4 mo treatment periods, no treatment effect should be present.
Doxazosin was utilized if needed to achieve BP ≤ 140/90.Primary end point: the urine alpha 1 m level as a marker of tubular injury (assessed at the end of each of the three treatment periods).

Secondary end point: plasma TGF-beta1 level and mean 24-hr blood pressure.

Additional reported outcomes included changes in proteinuria and CrCl.

At the end of the run-in and each treatment period, the following assessments were made:
blood pressure
serum labs including creatinine
two 24-hr urine collections (mean of protein and CrCl utilized).
Mean age: 35.46 +/− 2.36

Gender (male/female): 12/12

Ethnicity: NR
Mean creatinine: 1.18 +/− 0.08 mg/dL

Mean CrCl: 85.72 +/− 7.63 ml/min

Mean proteinuria: 2.13 +/− 0.24 gm/d
Number screened: NR

Eligible: NR

Enrolled: 30
Number withdrawn: 6

Lost to follow up: zero

Analyzed: 24
Changes in proteinuria:
L+B reduced proteinuria more than L alone (p <0.01)
L+B reduced proteinuria more than B alone (p <0.01)
Specific values NR, 95% CI NR

Changes in CrCl from baseline 89.69 (SEM 6.93) ml/min:
L: 85.18 (6.94) ml/min
B: 84.35 (6.63) ml/min
L+B: 82.33 (6.9) ml/min
No statistically significant differences noted from baseline or between groups.

No statistically significant changes in blood pressures between groups.
NRNRLab tests done as noted. Otherwise NR.*Results were not reported by treatment group*

Hypotension: 2
Allergic reaction to Losartan: 1
Cough: 1 (on Benazepril, but unknown if B or L+B)
Pregnancy: 1
Personal reasons: 1
Total withdrawals: 6

Withdrawals due to adverse events: 4

Withdrawals due to reasons other than adverse events: 2 (pregnancy and personal reasons)
Ruilope
2000
Spain
no trial name (from the European group for the Investigation of Valsartan in Chronic Renal Disease)
Fair
Study design: multinational (France, Germany, Italy, Spain), multi-center, randomized, active- controlled, parallel group, open label.

Setting: outpatient

Duration: 5 weeks
Inclusion criteria:
Age >18
Chronic renal disease
CrCl 20–45 ml/min
Mean diastolic blood pressure 80–110 mmHg

*irrespective of level of proteinuria*

Exclusion criteria:
Secondary hypertension
Malignant hypertension
Serious heart or liver disease
Immune disorders
Malignancy
Disease treated with steroids
Use of NSAIDS
Immune or cytotoxic therapy in prior 12 mo
Types of CKD:
IgA nephropathy (5%)
Other glomerulonephritis (23%)
Nephrosclerosis (27%)
Other (45%)

Baseline proteinuria not explicitly stated, but 45–63% reportedly had = 1 gm/d at baseline.
Stage of CKD was not specifically addressed.

CrCl 20–45 ml/min was required.

Baseline serum creatinine ranged from 2.6–2.9 mg/dL.
Participants were initially randomized to:
Valsartan 160 mg/d (V160) or Valsartan 80mg/d (V80)

After 1 week, further randomization to:
V160 (n = 22)
V160 + Benazepril 5mg/or 10 mg/d (B5/10) (n = 44)
V80 + references.r5/10 (n = 42)
*participants with CrCl 30–45 received 10mg/d and CrCl 20–30 received 5mg/d*

1 week later, if no change in serum creatinine by >30%, participants remained in these groups for 5 weeks.
NRAdditional non-ACE-I antihypertensives were allowed for hypertension management.
Additional medications used included:
furosemide
nifedipine
amlodipine
clonidine
nitrendipine
atenolol
Primary end point was the number of renal events. “Renal events” was defined as acute renal failure, rapidly progressing renal failure, hospitalization due to any clinical event related to renal failure, or hospitalization due to any severe electrolyte abnormality (including hyperkalemia).

Secondary end points: serum potassium and creatinine.

Visit 1 was conducted upon enrollment (week 1), at time of initial randomization to V160 or V80),

Visit 2 was conducted one week later (week 2), at time of additional randomization.

Visit 3 was conducted 1 week later (week 3).

Visit 4 was conducted in week 5.

At each visit, blood and an overnight urine sample were obtained. These provided serum creatinine measurements as well as protein/creatinine ratio.
Mean age:
V160: 57.3 +/− 14.8 years
V160 + references.r5/10: 56.9 +/− 11.7 years
V80 + references.r5/10: 57.6 +/− 12.2 years

Gender (% female/male):
V160: 27/73
V160 + references.r5/10: 34/66
V80 + references.r5/10: 30/70

Race: (% Caucasian/Black)
V160: 96/4
V160 + references.r5/10: 98/2
V80 + references.r5/10: 100/0
Percent ≥ age 65:
V160: 50
V160 + references.r5/10: 41
V80 + references.r5/10: 30

Percent with proteinuria = 1 gm/d:
V160: 45
V160 + references.r5/10: 59
V80 + references.r5/10: 63
Number screened: NR

Number eligible: NR

Number enrolled: 109
Withdrawals: 6

Lost to follow-up: NR

Analyzed: 108
*1 participant not analyzed - no information reported on that participant.*
Change in serum creatinine by group:
V160: 0.12 mg/dL (p = 0.045)
V160+ references.r5/10: 0.10 (p = 0.03)
V80 + references.r5/10: 0.17 (p = 0.0006)

Change in proteinuria by group (p values compared to baseline within that group):
V160: −0.09 +/− 1.76 gm/d (p = 0.811); 95% CI: −0.87,0.69
V160+ references.r5/10: −0.82 +/− 1.63 gm/d (p = 0.002); 95% CI: −1.33,0.32
V80 + references.r5/10: −0.36 +/− 1.26 gm/d (p = 0.071); 95% CI: −0.76,0.03

Inter-group reduction in proteinuria comparisons:
V80+B5/10 vs. V160 + references.r5/10: p = 0.109 (95% CI −0.11 to 1.07)
V80+B5/10 vs. V160: p = 0.501 (95% CI −0.95 to 0.47)
V160+B5/10 vs. V160: p = 0.047 (95% CI −1.044 to −0.01)

Change in systolic blood pressure was not statistically significant between groups.
Change in diastolic blood pressure was statistically significantly only in V160 + references.r5/10 vs. V160 (p = 0.00009).
NRNRSymptoms or signs either observed by investigator and/or reported by the patient were recorded as adverse events.Total percent adverse events within each group:
V160: 45.5%
V160+ references.r5/10: 25%
V80 + references.r5/10: 33.3%

Event rate hyperkalemia (potassium ≥ 6 mmol/L) within each group (n; %):
V160: 1; 4.5%
V160+ references.r5/10: 5; 11.9%
V80 + references.r5/10: 2; 4.5%

Event rate dizziness within each group (n; %):
V160: 1; 4.5%
V160+ references.r5/10: 2; 4.8%
V80 + references.r5/10: 3; 6.8%

Event rate headache within each group (n; %):
V160: 0; 0%
V160+ references.r5/10: 3; 7.1%
V80 + references.r5/10: 0; 0%

Cough was reported in 2 individuals (1 in V160 and 1 in V160+B5/10)
Withdrawals: 6
-2 for hyperkalemia (potassium = 6 mmol/L)
-1 for dizziness/vision changes
-1 for GI symptoms
-1 for malaise/headache
-1 for hypotension
Primary outcome of interest in this study was number of renal events, defined as acute renal failure, rapidly progressing renal failure, hospitalization due to any clinical event related to renal failure, or hospitalization due to any severe electrolyte abnormality (including hyperkalemia).

No events consistent with this primary outcome were observed.
Russo
2001
Italy
no trial name
Poor
Study design: randomized cross-over

Setting: NR

Duration: 32 weeks
Inclusion criteria:
Biopsy proven IgA Nephropathy
Blood pressure < 140–90 mmHg
Stable proteinuria between 1–3 gm/d (non-nephrotic range)
CrCl >90 ml/min/1.73 m2
No drug therapy in 12 weeks prior to enrollment

Exclusion criteria: not specifically stated
Types of CKD: IgA nephropathy

Biopsy proven: yes

Degree of proteinuria: required 1–3 gm/d.
Mean of 1.52 gm/d per baseline characteristics.
Stage of CKD; not explicitly stated

Method of defining CKD: CrCl is specified, but method of obtaining that measurement NR.
Participants were randomized to:
(E10) Enalapril 10mg/d
(L50) Losartan 50mg/d
Continued for 4 weeks, then dose was increased in each group:
(E20) Enalapril 20mg/d
(L100) Losartan 100mg/d
Continued for 4 weeks (8 weeks total in these treatment groups.

Then washout followed by crossover to alternate arm, again with dose increase after 4 weeks. (8 weeks total)

All participants then underwent combination therapy:
E+L at 10 and 50 mg/d respectively for 4 weeks, then
E+L at 20 and 100 mg/d respectively fro 4 weeks (8 weeks total).
Run-in: NR

Washout: 4 weeks between each 8-week treatment arm
NonePrimary endpoint not specifically stated. Goal of study stated to be to evaluate whether the antiproteinuric effect of Enalapril and Losartan may be dependent on the dose of co administered drugs and influenced by the reduction in systolic blood pressure.

Baseline measurements were done prior to therapy, including:
serum labs
office blood pressure and ambulatory blood pressure
peripheral plasma renin activity
measurement of urinary protein excretion (the mean of two consecutive 24 hr urine collections)

These measurements were repeated at the end of each study period.
Mean age: 25 =/− 18

Gender (female/male): 6/4

Ethnicity: NR
Mean CrCl at baseline: 109.6 +/− 8.4 ml/min/173m2

Mean proteinuria at baseline: 1.52 +/− 0.37 gm/d

Mean systolic blood pressure at baseline:
118.5+/−3.4 mmHg
Mean diastolic blood pressure at baseline:
75.9+/−1.8 mmHg
Number screened: NR

Number eligible: NR

Number enrolled: 19
Withdrawn: 9

Lost to follow-up: 1

Analyzed: 10
Reduction in proteinuria by each agent:
E: reduced proteinuria from 1.56 +/− 0.3 gm/d to 0.98 +/− 0.14 gm/d (p<0.05)
L: reduced proteinuria from 1.56 +/− 0.3 gm/d to 1.01 +/− 0.14 gm/d (p<0.05)
E+L: reduced proteinuria from 1.56 +/− 0.3 gm/d to 0.72 +/− 0.14 gm/d (p< 0.05), with additional reduction to 0.57
+/− 0.12 gm/d (p< 0.05) when dose was doubled.

No change in proteinuria reduction for E or L single drug therapy when dose was doubled.

CrCl in each treatment group at low and high dose respectively:
E: 108 +/− 11 ml/min/1.73m2, 108 +/− 9 ml/min/1.73m2
L: 106 +/− 8 ml/min/1.73m2, 111 +/− 9 ml/min/1.73m2
E+L: 110 +/− 9 ml/min/1.73m2, 110 +/− 12 ml/min/1.73m2
CrCl did not change significantly throughout the study. P-values and 95% CI NR.

Blood pressure was statistically lower in the double dose combination group (E+L), p < 0.05.
NRNRNR2 withdrawals were related to cough on ACE-I (specific treatment groups not specified)Total withdrawals:

Total withdrawals due to adverse events: 2 (cough)

Additional withdrawals not due to adverse events:
-2 withdrawals for non-compliance with therapy
-4 withdrew consent for reasons not related to side effects
-1 moved to a different city
Rutkowski
2004
Poland
no trial name
Fair
Study design:
Prospective, open-label, crossover

Setting: NR

Follow-up: Not explicitly stated; 14 mo (based on time frame of run-in and treatment groups)
Inclusion criteria:
Age 18–60
Proteinuria ≤ 3.5 gm/day
Creatinine < 2 mg/dL

Exclusion criteria:
history of diabetes, history of renal artery stenosis, steroids or immune suppression therapy within 6 months prior, history of hypersensitivity to ACE-I/ARB, or history of any of the following within 6 months: malignant hypertension, cerebrovascular accident, transient ischemic attack, arrhythmia, decompensated HF.
History of biopsy proven GLOMERULONEPHRITIS was required.

Types of GLOMERULONEPHRITIS included:
Mesangial GLOMERULONEPHRITIS
IgA nephropathy
Mesangiocapillary GLOMERULONEPHRITIS
Membranous GLOMERULONEPHRITIS

Proteinuria of ≤ 3.5 gm/day was required. Per their table on baseline characteristics of participants, average proteinuria was 2.13 +/− 0.24 gm/day.
CKD stages not specifically stated.

Creatinine of <2 mg/dL was required.

Mean CrCl per baseline characteristics:
85.72 +/− 7.63 ml/min.

CrCl obtained via 24 hr urine collections.
Participants were randomized to therapy to one of the following groups:
[L] Losartan 50mg/day
[B] Benazepril 10mg/day alone
[L+B] Losartan 25mg/day + Benazepril 5 mg/d

Randomization allocated participants to one of 6 treatment sequences during which each participant was crossed over into each treatment group.

Each treatment group lasted for 4 months.
Run-in: 8 week period during which participants were not given any ACE I or ARB therapy.

First 6 weeks of run-in patients were on Doxazosin; last 2 weeks patients were on no antihypertensive therapy.

Prior to data analysis the period effect and carryover effect were tested and found to be not significant.
Addition of Doxazosin was allowed to achieve BP goal <140/90.

Addition of Doxazosin was required in one subject during all treatment arms.
Primary end point: a difference in 24 hour protein measurement.

Subgroup analysis was performed in participants stratified by level of baseline proteinuria (<2gm/d vs. >2gm/d).

Secondary endpoints included office and ambulatory BP, serum creatinine level, K level, hemoglobin level, CrCl, and urine sodium excretion.

Follow up at the end of the run-in and at the end of each treatment period included 24 hr urine collections (for both proteinuria and CrCl).

Serum labs including creatinine were measured at least every 2 months.
Mean age: 35.7 +/− 2.7

Gender: 12men, 12 women

Ethnicity: NR
Mean baseline creatinine: 1.18 +/− 0.08

Number of participants treated with ACE-I/ARB prior to inclusion: 24 of 24 (19 with ACE-I and 5 with ARB).

Mean CrCl: 85.72 +/− 7.63 ml/min

Mean Proteinuria: 2.13 +/− 0.24 gm/d

Mean SYSTOLIC BLOOD PRESSURE: 139.52 +/− 3.62 mmHg
Mean DIASTOLIC BLOOD PRESSURE: 90.73 (range 86.88–95.5) mmHg
Number screened: NR

Number enrolled: 30
Withdrawn: 6

Lost to follow up: zero reported

Analyzed: 24
Percent decrease in proteinuria from baseline:
L: −28.17%
B: −20.19%
L+B: −45.54%
Significantly greater reduction in proteinuria was seen in L+B vs. L (p = 0.009)
Significantly greater reduction in proteinuria was seen in L+B vs. B (p < 0.001)

 16 patients showed maximal reduction in proteinuria in L+B
 4 patients showed maximal reduction in proteinuria in B
 4 patients showed maximal reduction in proteinuria in L

Antiproteinuric effect of L was greater than that of B numerically, but that difference was not statistically significant (p = 0.093).

There were no statistically significant differences in blood pressures achieved between different treatment arms.

No significant changes in serum creatinine or 24 hr creatinine clearance values were noted during the study. P values and 95% CI NR.
N/ASubgroup analysis for participants delineated by amount of baseline proteinuria:
>2 gm/d: 3.06 +/− 0.23 gm/d to 1.41 +/− 0.23 gm/d
<2 gm/d: 1.2 +/− 0.17 gm/d to 0.9 +/− 0.16 gm/d
Those with proteinuria >2gm/d showed significantly greater reduction in proteinuria compared to those with <2gm/d for all therapies (p < 0.001 for combination therapy, p = 0.026 for Losartan, and p = 0.019 for Benazparil).
Method to assess NR

Pre-specified that patients could be withdrawn for any of the following reasons:
withdrawal of consent, noncompliance with therapy, hyperkalemia (potassium > 6 mEq/L), worsening renal function (defined as serum creatinine level increase by greater than 50% confirmed on 2 occasions), cough on ACE-I therapy, and “any other severe adverse event.”
3 patients noted symptoms consistent with hypotension (SYSTOLIC BLOOD PRESSURE recorded at <100 in two of these three); of these two, one was on Losartan and one was on combination therapy.

Serum potassium values were reportedly no greater than 6 mEq/L for any treatment arm.

2 patients noted dry cough on ACE-I.
Total withdrawals: 6

Withdrawals due to adverse events: 5 (most not specified by treatment group)
 -2 for hypotension (one in L and one in L+B)
 -1 for allergic reaction to Losartan
 -1 for cough on ACE-I
 -1 for pregnancy

One participant chose to withdrawn for personal reasons.
Segura
2003
Spain
No trial name
Fair
Study design: randomized, parallel group open-label

Setting: NR

Duration: 6 months
Inclusion criteria:
Diagnosis of primary renal disease
Presenting BP >140/90 mmHg
Proteinuria >1.5 gm/d
On therapy with ACE-I alone or with other anti-hypertensive drugs for at least 3 mo prior to enrollment
CrCL >30 ml/min

Exclusion criteria: NR
Types of CKD: NR

Biopsy proven? NR

Degree of proteinuria: >1.5 gm/d required.

Baseline proteinuria ranged from 3.8–4.6 gm/d.

Proteinuria was measured via 24 hour urine collection.
Stage of CKD: not explicitly addressed.

CrCl >30 ml/min required Mean CrCL at baseline ∼75 ml/min

CrCl measured via 24 hr urine collection
After discontinuation of prior ACE-I therapy, participants were randomly assigned to one of the following:
[B] Benazepril 10–20 mg/d **
[V] Valsartan 80mg/d; increased to 160mg/d after 2 weeks
[B+V] Benazepril 10–20 mg/d** for 4 weeks, after which Valsartan 80mg/d was added. #
**Benazepril dose was dependent on CrCl; CrCl <50 ml/min received only 10mg/d.
# In B+V, Valsartan was increased from 80 mg/d to 160mg/d if needed. Presumably, authors are referring to “if needed” for blood pressure control.
Run in: NR

Washout: NR
Blood pressure goal was <140/90 mmHg. If BP was not achieved with study medication alone, then additional medications could be added.

Additional medications could include:
loop diuretics
Doxazosin
β-blockers
Primary end point: not explicitly stated.

Primary aim: to investigate in daily clinical practice the effects of monotherapy with an ACE-I or ARB up-titrated to maximal recommended doses, and to compare the effect of maximum monotherapy vs. combination therapy on proteinuria.

Visits were completed at baseline and at 7 days, 1 month, 3 months, and 6 months.
Measurements done at each visit included:
blood pressure
serum labs
24 hour urine for CrCl and proteinuria
Mean age:
B: 49.8 +/− 16.5 years
V: 49.7 +/− 12.4 years
B+V: 47.9 +/− 15.2 years

Gender (male/female):
B: 8/4
V: 8/4
B+V: 10/2

Ethnicity: NR
Mean SYSTOLIC BLOOD PRESSURE:
B: 154 +/− 16 mmHg
V: 152 +/−21 mmHg
B+V: 149 +/− 15 mmHg

Mean CrCl:
B: 72 +/− 25 ml/min
V: 74 +/− 23 ml/min
B+V: 68 +/− 29 ml/min

Proteinuria:
B: 3.8 +/− 2.4 gm/d
V: 4.6 +/− 3.4 gm/d
B+V: 4.1 +/− 2.4 gm/d
Number screened: NR

Eligible: NR

Enrolled: 36
Number withdrawn: NR

Lost to follow up: NR

Analyzed: 36
Mean change in proteinuria (and mean calculated percent decline):
B: 0.5 +/− 1.7 gm/d (−13%)
V: 1.2 +/− 2 gm/d (−26%)
B+V: 2.5 +/− 1.8 gm/d (−61%)
p < 0.05 comparing B to B+V per Figure 2 in this report; p value V vs. B and V vs. B+V NR but presumably not significant as not reported as significant in Figure 2. 95% CI NR.

Change in CrCl: NR

BP reduction was noted to be similar between the three groups, but SYSTOLIC BLOOD PRESSURE was significantly lower in V compared to B at 3 and 6 months.
NRNRNRNRNR
Song
2003
Korea
no trial name
Fair
Study design: double-blind, randomized, crossover

Setting: outpatient clinics

Duration: not specifically stated; 41 weeks based on treatment groups, run-in, and wash-out.
Inclusion criteria:
Ramipril therapy of >5mg/d for at least 6 mo
Blood pressure <130/80
CrCl 25–90 ml/min/1.73m2
24 hr urine for proteinuria with >1 gm/d

Exclusion criteria:
IgA nephropathy patients who had required steroids or cytotoxic therapy in 6 mo prior
History of proven cardiac or vascular disease
Uncontrolled diabetes
Malignancies
Types:
IgA nephropathy (IgA)
Diabetic nephropathy (DM) (Biopsy proven)

Proteinuria ? 1 gm/d required Baseline proteinuria ~4 gm/d
Stage of CKD not specifically addressed.

CrCl required to be between 25–90 ml/min

Baseline CrCl was 59–60 ml/min/1.73m2 for IgA and Diabetic nephropathy.

CrCl calculated as mean of CrCl from 2 24-hr urine collections.
R = Ramipril (dose ranged 5–7.5 mg/d) - taken at baseline by participants
C = Candesartan (4mg/d; if tolerated, increased to 8 mg/d at 12 weeks)
P = placebo

Participants were randomized to:
R+C for 16 weeks, 1 week washout, then R+P for 16 weeks
or
R+P for 16 weeks, 1 week washout, then R+C for 16 weeks
8 week run-in with Ramipril alone

1 week wash-out between cross-over arms
Not clearly reported.

15 of 34 patients were on additional BP meds when on Ramipril alone (prior to randomization).

2 patients are mentioned who required “additional diuretic.”
Primary endpoint not specifically stated.

Aim stated to be to examine therapeutic effect of dual blockade of RAS in participants with diabetic nephropathy and IgA nephropathy. 24 hour urine protein excretion and total urine Tumor growth factor (TGF)-beta were measured as surrogate markers of renal injury.

Two 24-hr urine collections and serum lab collections were done during 16th week of each cross-over arm.

Mean of lab values used to define:
CrCl
Creatinine
Proteinuria
Mean age: 34 +/− 5 years

Female: Male ratio: 19:13

Ethnicity: NR
Duration of Ramipril treatment prior to randomization:
10 +/− 3 months among IgA
13 +/− 4 months among DM

Serum creatinine during Ramipril run-in:
IgA: 1.4 +/− 0.1 mg/dL
DM: 1.4 +/− 0.1

CrCl during Ramipril run-in:
IgA: 60.3 +/− 4.6 ml/min/1.73 m2
DM: 59.4 +/− 2.7 ml/min/1.73 m2

24 hr urine protein during Ramipril run-in:
IgA: 4 +/− 0.2 gm/d
DM: 4.1 +/− 0.3 gm/d
108 screened (41 IgA, 67 DM)

34 eligible/enrolled (14 IgA, 20 DM)
Withdrawals: 2

Lost to follow-up: none reported

Analyzed: 32
Changes in proteinuria between groups by treatment and type of renal disease:
R: (baseline)
 IgA: 4 +/− 0.2 gm/d; DN: 4.1 +/− 0.3 gm/
R+C:
 IgA: 3.5 +/− 0.3 gm/d (p < 0.05 compared to R and R+P among IgA);
 DN: 4 +/− 0.2 gm/d (p not significant compared to R and R+P among DN)
R+P:
 IgA: 3.9 +/− 0.2 gm/d; DN: 4.2 +/− 0.3 gm/d

Mean % change in 24 hr urine protein excretion:
IgA: 95% CI 1.2 to 23.5, p < 0.05; showed a significant reduction in proteinuria for R+C vs R+P among IgA
 R+C: −12.3 +/− 4.5%; R+P: 0.1 +/− 3%
DN: 95% CI −6.8 to 13.5, p reported as not significant; no significant difference in proteinuria for R+C vs R+P among DN
 R+C: −0.8 +/− 4.7%; R+P: 1.3 +/− 4.7%

Greater reduction in proteinuria in R+C among IgA patients compared to DM patients (p < 0.05).

Changes in CrCl between groups by treatment and type of renal disease (ml/min/1.73m2):
R: (baseline)
 IgA: 60.3 +/− 4.6; DN: 59.4 +/− 2.7
R+C:
 IgA: 62.4 +/− 5.2; DN: 56.9 +/− 3.9
R+P:
 IgA: 63.8 +/− 5.3; DN: 60.2 +/− 4.3
No significant differences reported between groups, p values and 95% CI NR.

No statistically significant difference in mean arterial blood pressure between groups.
NRNRNRAt candesartan dose of 4mg, no adverse effects were reported.

At candesartan dose of 8 mg, patients reported the following:
5 patients; dizziness
3 patients; increase in serum potassium
1 patient; increase in serum creatinine
1 patient; increase in serum potassium and creatinine
1 patient; “refusal”

Among those with side effects:
2 received increased diuretic dose (presumably for high potassium)
1 received potassium-binding resin
Remaining adverse effects resolved with lowering candesartan dose.
Total withdrawals: 2

Withdrawals due to adverse effects: 2
Both among Diabetic nephropathy participants.
-1 withdrawal for azotemia/hyperkalemia
-1 withdrawal for hypotension
*Treatment group not specified*

Withdrawals due to reason other than adverse effects: none reported
All outcomes in this paper were shown by type of renal disease (IgA or DM); no combined outcomes for all patients together were reported.
Tylicki
2002
Poland
no trial name
Fair
Study design: prospective, randomized trial

Setting: NR

Duration: 3 months
Inclusion criteria:
Age 18–70
Biopsy proven primary glomerulonephritis
Systolic blood pressure 120–160 mmHg
Diastolic blood pressure 80–100 mmHg
Daily proteinuria
No ACE-I or ARB for 4 weeks prior to enrollment
Creatinine <2 mg/dL

Exclusion criteria:
Use of steroids or immune suppression within 6 mo prior to enrollment
IgA nephropathy
Nephrotic syndrome
Types of CKD:
Mesangial glomerulonephritis
Mesangiocapillary glomerulonephritis
Membranous nephropathy
Focal segmental glomerulonephritis

Biopsy proven: yes

Degree of proteinuria: specified only as daily
Per baseline characteristics, mean proteinuria ranged from 2.2–3.3 mg/d between groups.
Stage of CKD: not specifically stated

Creatinine <2 required.

Creatinine clearance ranged from 90–96 ml/min between groups at baseline.

Creatinine clearance was measured via mean of two 24-hr collections
Participants were randomized to:
(L) Losartan 25mg/d (n = 17)
(E) Enalapril 10 mg/d (n = 17)
(L+E): Losartan 25mg/d and Enalapril 10mg/d (n = 15)

Participants were followed in these groups for 3 months.
NRNRPrimary end point not specifically stated. Stated goal was to compare Losartan, Enalapril, and the combination of the two in a low doses known to equivalently lower blood pressure to examine the effects of these medications on proteinuria, renal function, and metabolic profile.

Reported outcomes included:
-systolic and diastolic blood pressure
-CrCl
-Urinary protein excretion
-lipid profile

Evaluations were completed at:
-baseline
-1 week after initiation of treatment
-3 months

Evaluations consisted of:
-blood pressure measurements
-serum laboratory measurements
-two 24 hr urine collections (the results of which were averaged to obtain CrCl and proteinuria values)
Mean age:
L: 41.2 +/− 11.8 years
E: 44.1 +/− 10.1 years
L+E: 36.6 +/− 13.1 years

Gender (male/female):
L: 7/10
E: 12/5
L+E: 11/4

Ethnicity: NR

Race: all Caucasian
24 hr urine protein excretion at baseline:
L: 2.13 gm/d
E: 2.64 gm/d
L=E: 3.29 gm/d

Serum creatinine at baseline:
L: 1.05 mg/dL/dL
E: 1.27 mg/dL
L+E: 1.2 mg/dL

CrCl at baseline:
L: 90.8 ml/min
E: 94.2 ml/min
L+E: 95.9 ml/min

Systolic blood pressure at baseline:
L: 138.09 mmHg
E: 134.02 mmHg
L+E: 139.33 mmHg

Diastolic blood pressure at baseline:
L: 88.7 mmHg
E: 87.4 mmHg
L+E: 89.3 mmHg
Number screened: NR

Number eligible: NR

Number enrolled: 51
Number withdrawn: 2

Number lost to follow-up: zero

Number analyzed: 49
Change in CrCl:
-greater decline in E (−15.2%) vs. L (percent decline NR), but not significant (p = 0.09, 95% CI NR)
-greater decline in L+E (−14.3%) vs. L (percent decline NR), but not significant (p = 0.08, 95% CI NR)

Urine protein excretion declined significantly in all groups. Reduction in proteinuria was as follows:
L: 25.35%
E: 45.1%
L+E: 65.96%
Reduction in proteinuria for L vs. E did not show a statistically significant difference. p-value, 95% CI NR.
Reduction in proteinuria for L+E vs. either as mono-therapy showed a significant difference (p = 0.009), 95% CI NR.

Diastolic blood pressure was lowered statistically more in those on combination therapy.
NRNRNR1 allergic reaction to study medication was reported (treatment group not specified).Total withdrawals: 2

Withdrawals due to adverse events: 1 (allergic reaction to study medication)

Withdrawals due to reasons other than adverse events: 1 (development of nephrotic syndrome requiring steroids)
Tylicki
2005
Poland
no trial name
Fair
Study design: single-center, prospective, open, randomized trial

Setting: outpatient nephrology clinic

Duration: 12 months for initial study; additional 3 months for those who completed 12-month protocol.
Inclusion criteria:
Age 18–65
Biopsy-proven primary glomerulonephritis (non-IgA only)
Serum creatinine < 2 mg/dL
Stable proteinuria
BP ≤ 150–95
No ACE-I or ARB for minimum of 4 weeks prior to enrollment

Exclusion criteria:
Steroid or immune suppression within6 months of enrollment.
IgA nephropathy
Nephrotic syndrome
Types of CKD:
Mesangial glomerulonephritis
Mesangiocapillary glomerulonephritis
Membranous nephropathy
(Biopsy proven disease)

Proteinuria at baseline ranged from 1.89–2.25 gm/d
Stage of CKD was not specifically addressed.

Serum creatinine ranged from 1.04–1.27 mg/dL

CrCl per baseline table ranged from 90.48–100.17 ml/min

CrCl and proteinuria were determined from the mean values from two 24-hr urine collections.
Participants were randomized to one of the following:
L = Losartan 25mg/d (n = 19)
E = Enalapril 10 mg/d (n = 14)

Each treatment group lasted 12 months.

Those in L who completed the 12 mo protocol then had
Losartan dose increased to 50mg/d for an additional 3 months.
NRNRPrimary end point: urine protein excretion evaluated as a marker of glomerular damage.

Secondary end points included urinary N-acetyl-beta-D-glucoasminidase excretion and blood pressure.

Assessment of creatinine, CrCl, and proteinuria was done upon entry, at 12 mo.

Creatinine, CrCl, and proteinuria assessment was repeated at 15 mo if patients in L completed additional 3 mo of therapy with higher dose Losartan.

CrCl and proteinuria were measured as means of two values obtained from two 24-hr urine collections. Serum creatinine measured via standard techniques.
Mean age:
L: 41.2
E: 43.7

Gender (male/female):
L: 8/11
E: 11/3

Ethnicity: NR
Serum creatinine at baseline:
L: 1.04 mg/dL
E: 1.27 mg/dL

CrCl at baseline:
L: 90.48 ml/min
E: 100.17 ml/min

24 hr protein excretion:
L: 1.89 gm/d
E: 2.25 gm/d

Hypertension (BP 140–150/90–95 mmHg):
L: 9
E: 4
Number screened: NR

Number enrolled: 40
Withdrawals: 7

Lost to follow-up: zero reported (4 patients “resigned” from study -unclear if they were followed).

Analyzed: 33
Urinary protein excretion (baseline to post treatment):
L: 1.89 +/− 0.27 to 1.27 +/− 0.22 (p < 0.05 change in urine protein compared to baseline)
E: 2.25 +/− 0.3 to 1.33 +/− 0.27 (p < 0.05 change in urine protein compared to baseline)
No significant difference between groups was noted, p values NR.

Percent decrease in proteinuria:
L: 32.8% (p < 0.029 post-treatment compared to baseline)
E: 40.9% (p < 0.041 post-treatment compared to baseline)

CrCl (baseline to post treatment):
L: 90.48 +/− 5.86 to 94.4 +/− 6.53 ml/min (no significant change from baseline)
E: 100.17 +/− 10.46 to 99.9 +/− 14.25 ml/min (no significant change from baseline)

No significant changes in systolic blood pressure or diastolic blood pressure were noted among L or E groups.
NRPercent decrease in urine protein excretion based on lower or higher Losartan doses:
L 25mg/d: 32.8%
L 50 mg/d: 40.7%
p comparing groups reported as not significant

Change in urine protein excretion with Losartan in participants delineated by baseline proteinuria (baseline to post treatment):
<1.5 gm/d: 0.81 gm/d to 0.95 gm/d (no significant difference from baseline, p value NR).
>1.5 gm/d: 2.86 gm/d to 1.57 gm/d (p < 0.002 post treatment vs. baseline)

Antiproteinuric effect of Losartan was more evident in participants who were normotensive (p < 0.041).
NRNRTotal withdrawals: 7

Withdrawals due to adverse events: 1
*one withdrawal for allergic reaction to Losartan*

Withdrawals due to reasons other than adverse effects: 6
-4 patients resigned from the study
-1 female patient was withdrawn for pregnancy
-1 patient in E was withdrawn for development of nephrotic syndrome
Yilmaz
2007
Sweden
no trial name
Fair
Study design: controlled, head to head

Setting: outpatient nephrology clinic

Duration: 3 months
Inclusion criteria:
GFR 30–59 ml/min/1.73m2
Proteinuria 1–2 gm/d
Hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg)
First-referral to nephrology clinic
No current treatment

Exclusion criteria:
Diabetes
BMI >30
Cholesterol >200mg/DL or triglycerides >150 mg/dL
Abnormal EKG (ischemic ST-T alterations or voltage criteria for Left ventricular hypertrophy (LVH))
History of myocardial infarction or coronary revascularization
Nephrotic syndrome
Elevated liver enzymes (AST or ALT ?40 U/L)
Types of CKD:
Focal segmental glomerulosclerosis (primary or secondary)
IgA nephropathy
Membranous nephropathy
Membranoproliferative glomerulonephritis
Hypertensive Nephrosclerosis
Minimal Mesangial proliferation

Biopsy proven: yes

Degree of proteinuria: 1–2 gm/d required. Per baseline characteristics, mean was 1.5 gm/d.
Stage of CKD: not specifically stated

Method of defining CKD: GFR via modified diet in renal disease (MDRD) equation

GFR 30–59 ml/min/1.73m2 required
Mean GFR at baseline ranged from 39–44 ml/min/1.73m2.
Patients were stratified into 2 groups by age, gender, and BMI:
[R] Ramipril 5mg/d (n = 32)
[V] Valsartan 160mg/d (n = 34)
Patients remained in these treatment groups for 3 months

A control group of 36 healthy participants was also defined for purposes of biochemical assessments done as part of this study.
Run-in: NR

Washout: NR
NRPrimary end point not specifically stated.

Main aim stated to be to investigate whether the beneficial effects of the renin-angiotensin-aldosterone system blockade in CKD has any relation to the alternation of asymmetric dimethylarginine levels.

Reported results included:
GFR
Proteinuria
Blood pressure (systolic and diastolic)
Lipid profiles
dimethylarginine (symmetric and asymmetric), Larginine, c reactive protein
Fasting serum glucose
Homeostasis model assessment

The above serum and urine assessments were completed at baseline and after the study intervention.
Mean age: 47.1 +/− 6.2 years

Gender:
34 men, 32 women

Race: Caucasian

**these variables reported only for group as a whole, not for treatment groups.**
Estimated GFR at baseline:
R: 44 +/− 11.8 ml/min/1.73 m2
V: 39.8 +/− 11.5 ml/min/1.73 m2

Proteinuria at baseline:
R: 1.49 +/− .29 gm/d
V: 1.49 +/− 0.41 gm/d

Systolic blood pressure at baseline:
R: 154.8 +/− 7.8 mmHg
V: 151.6 +/− 7.0 mmHg

Diastolic blood pressure at baseline:
R: 94.6 +/− 2.9 mmHg
V: 91.4 +/− 2.7 mmHg
Number screened: 318

Number eligible: NR

Number enrolled: 80
Number withdrawn: 14

Number lost to follow-up: NR

Number analyzed: 66
Pre and post GFR by group:
R: baseline 44 +/− 11.8; 3 mo 41.9 +/− 11.67 ml/min/1.73 m2
V: baseline 39.8 +/− 11.5; 3 mo 38.5 +/− 11.5 ml/min/1.73 m2
Not noted to be a statistically significant difference between groups, p-value and 95% CI NR

Pre and post proteinuria levels by group: (calculation of mean percent change)
R: baseline 1.49 +/− 0.29 gm/d; 3 mo 0.70 +/− 0.22 gm/d (−53%)
V: baseline 1.48 +/− 0.41 gm/d; 3 mo 0.96 +/− 0.36 gm/d (−38%)
Reduction in proteinuria was more significant in R than V, p = 0.002, 95% CI NR.

Reduction in systolic blood pressure was significantly more in R vs. V (p = 0.007)
Reduction in diastolic blood pressure was significantly more in R vs. V (p < 0.001)
NRNRNRAdverse effects occurred as follows:
8 in group R
6 in group V
*Specific effects experienced were not delineated by treatment group.

Cough: 5

Hyperkalemia; value not specified: 7

Non-compliance (listed by authors as adverse event): 2
Total withdrawals: 14

Withdrawals due to adverse effects: 14

Withdrawals due to reason other than adverse effects: zero
The control group in this study played a role in comparing levels of asymmetric dimethylarginine.
Zanabli
2004
US
no trial name
Poor
Study design: Open-label crossover

Setting: outpatient clinics

Duration: not explicitly stated; 12 weeks based on treatment groups and wash-out periods
Inclusion criteria:
History of treatment with ACE-I or ARB
Serum creatinine 1.2–4 mg/dL
Serum potassium >4.4 in of two most recent lab checks
Age 18–70

Exclusion criteria:
Uncontrolled Hypertension or HF
Dialysis
History of ACE-I/ARB allergy
On changing dose of β-blockers, NSAIDS, or diuretics
On potassium sparing diuretics
On potassium supplements
History of ventricular arrhythmia
Serum potassium >6
Current hospitalization
Women of childbearing age who are pregnant, breast-feeding, or not on contraceptives.
Types of CKD: NR

Proteinuria: NR
Baseline renal function: NR

Post treatment CrCl ranged from 31.9–33.5 ml/min

CrCl assessed with 24 hr urine collection
Participants were not randomized; therapy was given as follows:
[Lis] Lisinopril: 5mg/d for 2 weeks, then 10 mg/d for 2 weeks
THEN
[Los] Losartan: 50 mg/d for 2 weeks then 100 mg/d for 2 weeks
Run-in: 2 week period prior to starting Lisinopril treatment group

Washout: 2 week period between treatment with Lisinopril and Losartan

-no ACE-I/ARB during run-in or washout
Amlodipine allowed for elevated blood pressure

Not stated if other non-ACE-I/ARB antihypertensives were stopped as part of the study.
Primary endpoint not specifically stated.

Aim reported to be to investigate side effect of hyperkalemia in ACE-I vs. ARB.

24 hr urine collections were completed after each study phase (weeks 2, 6, 8, and 12).
Age: 39–68

Gender: 3 men, 4 women

Ethnicity: NR
Baseline characteristics NR, but initial “wash- out” showed lab values pre-therapy as:
Mean creatinine: 2.3 mg/dL
Mean CrCl: 32.3 ml/min
Number screened: NR

Number eligible: 30

Number enrolled: 9
Withdrawn: 2

Lost to follow-up: zero reported

Analyzed: 7
CrCl:
During Lisinopril therapy: 32.5 ml/min
During Losartan therapy: 33.5 ml/min

Creatinine:
During Lisinopril therapy: 2.4 mg/dL
During Losartan therapy: 2.4 mg/dL

No blood pressure data reported.
N/ANRInformation reportedly collected on medication side effects at each subsequent visit. Timeline of follow-up visits not explicitly stated.NRTotal withdrawals: 2
*both withdrawn for inability to comply with scheduled phlebotomy appointments.

Withdrawals due to adverse events: zero reported
Primary goal of study was to investigate changes in potassium among patients with CKD on ACE-I/ARB.

Types of CKD, level of CKD, and whether or not proteinuric at baseline was not specifically stated.

From: Evidence Tables

Cover of Drug Class Review: Direct Renin Inhibitors, Angiotensin Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers
Drug Class Review: Direct Renin Inhibitors, Angiotensin Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers: Final Report [Internet].
Norris S, Weinstein J, Peterson K, et al.
Portland (OR): Oregon Health & Science University; 2010 Jan.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.