Journal of the American Society of Nephrology
2007 JASN IMPACT FACTOR 7.111 HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP 
    advanced
CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION


Published ahead of print on May 9, 2007
J Am Soc Nephrol 18: 1889-1898, 2007
© 2007 American Society of Nephrology
doi: 10.1681/ASN.2006121372
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ASN.2006121372v1
18/6/1889    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hou, F. F.
Right arrow Articles by Jiang, J. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hou, F. F.
Right arrow Articles by Jiang, J. P.

Clinical Nephrology

Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: A Randomized Controlled Study of Benazepril and Losartan in Chronic Renal Insufficiency

Fan Fan Hou*, Di Xie*, Xun Zhang*, Ping Yan Chen{dagger}, Wei Ru Zhang*, Min Liang*, Zhi Jian Guo* and Jian Ping Jiang*

* Renal Division, Nanfang Hospital, and {dagger} Department of Biostatistics, Southern Medical University, Guangzhou, People’s Republic of China

Address correspondence to: Dr. Fan Fan Hou, Renal Division, Nanfang Hospital, 1838 North Guangzhou Avenue, Guangzhou 510515, People’s Republic of China. Phone: +86-20-61641591; Fax: +86-20-87281713; E-mail: ffhou{at}public.guangzhou.gd.cn

Received for publication December 19, 2006. Accepted for publication March 27, 2007.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 
The Renoprotection of Optimal Antiproteinuric Doses (ROAD) study was performed to determine whether titration of benazepril or losartan to optimal antiproteinuric doses would safely improve the renal outcome in chronic renal insufficiency. A total of 360 patients who did not have diabetes and had proteinuria and chronic renal insufficiency were randomly assigned to four groups. Patients received open-label treatment with a conventional dosage of benazepril (10 mg/d), individual uptitration of benazepril (median 20 mg/d; range 10 to 40), a conventional dosage of losartan (50 mg/d), or individual uptitration of losartan (median 100 mg/d; range 50 to 200). Uptitration was performed to optimal antiproteinuric and tolerated dosages, and then these dosages were maintained. Median follow-up was 3.7 yr. The primary end point was time to the composite of a doubling of the serum creatinine, ESRD, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease. Compared with the conventional dosages, optimal antiproteinuric dosages of benazepril and losartan that were achieved through uptitration were associated with a 51 and 53% reduction in the risk for the primary end point (P = 0.028 and 0.022, respectively). Optimal antiproteinuric dosages of benazepril and losartan, at comparable BP control, achieved a greater reduction in both proteinuria and the rate of decline in renal function compared with their conventional dosages. There was no significant difference for the overall incidence of major adverse events between groups that were given conventional and optimal dosages in both arms. It is concluded that uptitration of benazepril or losartan against proteinuria conferred further benefit on renal outcome in patients who did not have diabetes and had proteinuria and renal insufficiency.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 
Interruption of the renin-angiotensin axis with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) slows the progression of chronic renal insufficiency in the presence or absence of diabetes (1–5). However, many patients progress to ESRD despite using an ACEi or ARB (1–5). Optimizing renin-angiotensin system (RAS) blockade to provide more effective renal protection has received considerable attention. Increasing evidence suggests that, in addition to effective BP control, proteinuria should be considered as an independent risk factor and an essential treatment target for renal protection (2,6,7). Reduction of proteinuria with RAS blockade results in protection against protein-induced renal fibrosis, which should translate into preservation of renal function in the long term (8,9). Animal studies have demonstrated that maximal renal benefit from ACEi or ARB requires higher dosages than those needed to normalize BP (10,11). Small clinical studies have shown that titrating ACEi or ARB to higher dosages is effective at reducing proteinuria (12–15), although there have been conflicting reports (16,17). Taken together, these data suggest that the recommended dosages of ACEi or ARB in current practice, which are based on their BP-lowering effect, might be inadequate to halt satisfactorily renal progression. However, most of the dosage-response studies to date looked exclusively at reductions in proteinuria but failed to evaluate hard end points as the outcome parameter. This is partly explained by the short observation period (between 8 wk and 9 mo) in these studies. Optimal antiproteinuric dosages of ACEi or ARB have not been explored thoroughly with respect to long-term renal outcomes and, importantly, tolerability and safety in patients with renal insufficiency.

Several studies have provided evidence that ARB are renoprotective in patients with type 2 diabetes (3,4,18). It is to be confirmed whether an ARB is as effective as an ACEi in retarding progression in nondiabetic nephropathy, because data from a trial that was designed primarily to compare the effects of combined therapy with ACEi and ARB to each monotherapy suggest that there is no difference in renal protection between ACEi and ARB (19).

The primary aim of this study was to evaluate whether the optimal antiproteinuric dosages of benazepril (an ACEi) or losartan (an ARB), as compared with their conventional dosages, can safely improve the renal outcome in patients who do not have diabetes and have proteinuria and chronic renal insufficiency. The second aim was to compare the long-term renoprotection of benazepril and losartan at their optimal antiproteinuric dosages.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 Disclosures
 References
 
Design and Patients
Renoprotection of Optimal Antiproteinuric Doses (ROAD) was a prospective, randomized, open, blinded end point (PROBE) study that was conducted at Nanfang Hospital Renal Division. An adjudicating group, whose members were unaware of patients’ treatment assignments, reviewed the data to determine which patients had reached study end points and to evaluate safety. The study protocol was approved by the Nanfang Ethics Committee, and all patients provided written informed consent. A study period of 3 yr was chosen on the basis of the results of previous trials that involved patients with nondiabetic chronic nephropathy and that suggested that a 3-yr follow-up is adequate to assess efficacy (2,5).

Between January 2002 and May 2003, consecutive patients who were aged 18 to 70 yr and had chronic kidney disease (CKD) were screened for the study at the Nanfang Hospital Renal Division, which has a catchment that includes eight cities near Guangzhou with a total population in the year 2000 of 29.8 million. Eligible patients had not received ACEi or ARB for at least 6 wk before screening and met the following inclusion criteria: A serum creatinine level of 1.5 to 5.0 mg/dl (133 to 442 µmol/L) and a creatinine clearance (20) of 20 to 70 ml/min per 1.73 m2, with variations of <30% in the 3 mo before screening; diagnosis of nondiabetic renal disease (as established on the basis of patient history and as a result of serum biochemical tests and renal biopsy); and persistent overt proteinuria (defined as urinary protein excretion of >1.0 g/d for ≥3 mo without evidence of urinary tract infection or overt heart failure [a New York Heart Association class of III or IV]). Exclusion criteria were an immediate need for dialysis; current treatment with corticosteroids, nonsteroidal anti-inflammatory drugs, or immunosuppressive drugs; hyper- or hypokalemia (serum potassium concentration ≥5.6 or ≤3.5 mmol/L); renovascular disease; myocardial infarction or cerebrovascular accident in the year preceding the trial; connective-tissue disease; and obstructive uropathy.

Randomization and Interventions
Eligible patients got their sequence numbers from the coordinator and were randomly allocated into four groups according to a computer-generated randomization sequence list using a blocking size of 8. The list was prepared by the Department of Biostatistics, Southern Medical University. For safety’s sake, all patients entered an 8-wk pretitration phase in which patients in groups 1 and 2 received 10 mg of benazepril (1) and those in groups 3 and 4 received 50 mg of losartan daily (21). After 4 wk of therapy with the study drugs, patients who continued to show inadequate BP control (i.e., a systolic BP [SBP] of >130 mmHg and/or a diastolic BP of >80 mmHg) had an additional antihypertensive agent (diuretic, calcium channel blocker, beta blockers, centrally acting agent, or combination of these medications, excluding ACEi and ARB) added to their treatment regimen. All patients were under close observation, including weekly measurements of BP, serum creatinine, and serum potassium.

At completion of the pretitration phase, patients with stable renal function (<30% increase from inclusion baseline in serum creatinine, confirmed by at least three separate measurements) and serum potassium levels <5.6 mmol/L and without other adverse events then entered the titration period. Patients in groups 1 and 3 remained on fixed dosages of benazepril (10 mg/d) or losartan (50 mg/d), respectively. Patients in groups 2 and 4 had their dosages of benazepril or losartan uptitrated as follows: Patients in group 2 received monthly uptitration of benazepril from a starting dosage of 10 mg/d to 20, 30, and 40 mg/d. Patients in group 4 were treated with increasing dosages of losartan (from 50 to 100, 150, and 200 mg/d) with each titration period of 4 wk. BP (measured with a mercury-column sphygmomanometer in the sitting position 3 to 4 h after the administration of the study drug) was measured every week by staff who were blind to the study design and recorded as mean of three readings. Urinary protein excretion, serum creatinine, and potassium levels were measured every 2 wk during the titration period. The dosage of study drug was downtitrated to the previous level in the following circumstances: The antiproteinuric effect of the study drug had reached its plateau (i.e., urinary protein excretion did not fall by ≥10% [22] versus the previous titration period [determined by two values that were obtained 4 wk apart at same dosage; the accuracy of urine collection was confirmed by determination of specimen’s creatinine content]), or SBP decreased to <120 mmHg despite withdrawal of all additional antihypertensive medication. Patients who developed hyperkalemia (serum potassium ≥6.0 mmol/L) that was refractory to medical treatment or whose serum creatinine increased >30% versus previous values had the study drug dosage downtitrated to the previous step or withdrawn. In patients who were not responsive to uptitration (defined as <10% reduction in proteinuria from the levels at the start of titration), the study drug was uptitrated monthly to the maximum licensed dosage (benazepril 40 mg/d in group 2; losartan 200 mg/d in group 4). When still no response was observed, the dosage was decreased to the starting dosage; patients remained in the study and were included in the analyses. Patients in groups 2 and 4 were maintained on their study drug once their individual optimal antiproteinuric and tolerated dosage was achieved. Additional antihypertensive agents (as described previously) were administered or withdrawn, as required, to maintain BP control. The patients (including withdrawn cases) were followed up every month thereafter for data collection.

All patients were instructed to reduce their salt intake to approximately 5 to 7 g/d, to eat 0.5 to 0.7 protein/kg body wt per d, and to restrict their intake of foods that are rich in potassium. Dietary compliance was assessed by evaluation of 24-h urinary excretion of urea and chloride.

Outcome Variables
The primary efficacy variable was time to the first event for the composite end point: Doubling of the serum creatinine concentration, ESRD, or death. Doubling of serum creatinine concentration from the baseline value was confirmed by a second serum creatinine value that was obtained at least 4 wk after the initial doubling. ESRD was defined by the need for long-term dialysis or renal transplantation.

Secondary end points included changes in urinary protein excretion rate and the progression of renal disease as assessed by estimated GFR (eGFR) that was calculated by Modification of Diet in Renal Disease (MDRD) equation (23). To avoid the imprecision of the MDRD equation in Chinese, we also included evaluated creatinine clearance (24) to reflect the rate of decline in renal function.

Statistical Analyses
The sample size was estimated before the study with the nQuery Advisor software 5.0 (Statistical Solutions Ltd., Cork, Ireland). Our preliminary study in patients with renal insufficiency showed that the rate of the primary end point among patients who were treated with 10 mg of benazepril was approximately 33%, whereas in those who received 20 mg of benazepril, 23% reached the primary end point (25). Thus, we estimated that the optimal antiproteinuric dosage of benazepril would reduce this rate to 10%. The enrollment of 70 patients in each group of benazepril arm would provide the study with a statistical power of 80% at a two-sided significance level of 0.05.

Because no data on long-term renal effect of ARB in patients with nondiabetic nephropathy were available at the start of the study, we assumed that treatment with an optimal antiproteinuric dosage of losartan would also reduce the rate of the primary end point to 10% versus the conventional dosage. It was estimated that to give the study an 80% power to detect statistical significance, at least 70 patients in each group of the losartan arm had to complete the study.

The primary and secondary end points were analyzed according to the intention-to-treat (ITT) principle. We included data from all patients who entered active treatment. The missing data were treated using lost operation carry forward principle to satisfy ITT analysis. For further confirmation of the result, the primary end points were also analyzed by using the per-protocol principle. The Cox regression model based on the assessment of goodness-of-fit by –2 log likelihood ratio was used to determine the hazard ratio for the primary end point. The model was also adjusted by baseline variables as the covariables, which were proteinuria, eGFR, and SBP, at end point to detect their effect. The risk reduction was calculated as 100% x (1 – hazard ratio). Event curves were based on Kaplan-Meier analysis, and significance was assessed by log-rank test.

Changes in urinary protein excretion, creatinine clearance, and BP were analyzed by repeated-measures ANOVA. Multiple comparisons were conducted with LSD t test when ANOVA was significant. The relationship between proteinuria reduction and the rate of the decline of renal function was analyzed by Pearson correlation. Two-tailed P ≤ 0.05 were considered statistically significant. Analyses were performed with SPSS 13.0.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 Disclosures
 References
 
A total of 406 patients were screened during January 2002 to May 2003, and 360 were identified for study participation and randomly assigned to the four groups (Figure 1). The baseline characteristics of the patients were similar in the four groups (Table 1). The mean age and the distribution of the primary causes of renal dysfunction across the groups were similar to those reported in the registry of the Chinese Society of Nephrology (26). The median length of follow-up was 3.7 yr (min-max, approximately 2.0 to 4.5).


Figure 1
View larger version (39K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 1. Study flow diagram.

 

View this table:
[in this window]
[in a new window]

  		Table 1. Baseline characteristics of the patientsa

 
Fifty patients withdrew during the pretitration phase with main cause of dry cough (30 [60%] of 50). Seventeen of them were lost to follow-up: Eight because of poor adherence (one in group 1, two in group 2, two in group 3, and three in group 4), and nine because of refusal to continue the treatment (five in group 1 and four in group 2; Figure 1). Four patients were lost to follow-up after the pretitration phase because they moved away (one in group 1 and three in group 4; Figure 1).

Primary Outcomes
In the benazepril arm, 15 of 84 patients who were treated with optimal antiproteinuric dosages (group 2) reached the primary end point, compared with 26 of 83 patients who received the conventional dosage (group 1; 17.9 versus 31.3%; P = 0.025; Figure 2A). Likewise, in the losartan arm, 13 of 84 patients who received optimal antiproteinuric dosages (group 4) reached the primary end point, as compared with 26 of 88 patients who received the conventional dosage (group 3; 15.5 versus 29.5%; P = 0.022; Figure 2A). Treatment with optimal antiproteinuric dosages of benazepril or losartan, compared with their relevant conventional dosage, resulted in overall reduction in the risk for a primary end point by 51% (95% confidence interval [CI] 4.8 to 73.3) in the benazepril arm and 53% (95% CI 5.5 to 74.1) in the losartan arm (P = 0.028 and 0.022, respectively). The decrease in the risk remained significant after adjustment for the SBP at end point (hazard ratio 50.5% in benazepril and 47.6% in the losartan arm; P = 0.030 and 0.031, respectively), for baseline urinary protein excretion (P = 0.037 in the benazepril and 0.039 in the losartan arm), and for baseline eGFR (P = 0.039 in the benazepril and 0.035 in the losartan arm). The ITT analyses of the individual components of the primary end point indicated that the risk for doubling of serum creatinine level was 49% lower in the benazepril arm and 50% lower in the losartan arm among patients who received optimal antiproteinuric dosages than among those who were given the conventional dosage (P = 0.041 and P = 0.040, respectively). Use of the optimal antiproteinuric dosage of benazepril or losartan also reduced the risk for ESRD by 47% (95% CI 4.2 to 72.1) in the benazepril arm and 47% (95% CI 3.6 to 76.9) in the losartan arm (P = 0.042 and P = 0.046, respectively). The per-protocol analyses of the primary end points showed the similar results (Figure 2B). There was no statistically significant difference between benazepril and losartan in the overall relative risk reduction at their respective optimal antiproteinuric dosages or at conventional dosages.


Figure 2
View larger version (14K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 2. Kaplan-Meier estimates of the percentage of patients who reached the primary composite end point of a doubling of the serum creatinine level, ESRD, or death according to intention-to-treat (A) or per-protocol principal (B).

 
Secondary Outcomes
In both the benazepril and losartan arms, there was a significantly greater reduction in the level of proteinuria among patients who were given optimal antiproteinuric dosages than conventional dosages (Figure 3A). The median of final changes from baseline in benazepril arm at 4, 12, 24, and 36 mo was 51, 50, 53, and 50% in group 2 and 37, 35, 36, and 38% in group 1 (P < 0.05). Among the patients who received losartan, the changes of urinary protein excretion at 4, 12, 24, and 36 mo were 52, 51, 52, and 53% in group 4 and 36, 36, 39, and 41% in group 3 (P < 0.05). The proteinuria reduction remained significant after adjustment for differences in the SBP (P = 0.033 and 0.034 for benazepril and losartan, respectively). There was no significant difference in proteinuria reduction between benazepril and losartan at both conventional and optimal antiproteinuric dosages.


Figure 3
View larger version (29K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 3. Median of changes in urinary proteinuria excretion (A), median of creatinine clearance (B), estimated GFR (eGFR; C), BP in all patients (D), median of systolic BP in patients with decline of eGFR ({Delta}eGFR) >5 or ≤5 ml/min per 1.73 m2 (E), and median of urinary excretion of urea and chloride (F).

 
Use of optimal antiproteinuric dosages versus conventional dosages reduced the decline in renal function by 60% in the benazepril arm (P = 0.021) and 55% in the losartan arm (P = 0.037), as assessed by creatinine clearance (Figure 3B). In addition, the optimal antiproteinuric dosage was associated with slowing in the decline of eGFR in both benazepril (P = 0.02) and losartan arms (P = 0.03; Figure 3C). There was a close correlation between the extent of the reduction in proteinuria at 3 mo and the rate of decline in the eGFR (r = –0.554, P < 0.001) and creatinine clearance at the study end (r = –0.487, P < 0.001). Changes in renal function were similar between benazepril and losartan arms at both conventional and optimal antiproteinuric doses (P > 0.05).

Dosage-Response Relationship
Optimal antiproteinuric efficacy of benazepril was obtained with a 20-mg dosage in 43 (61%) patients, 30-mg dosage in 11 (16%) patients, 40-mg dosage in three (4%) patients, and >40-mg dosage (i.e., proteinuria reduction >10% of previous level at maximum dosage of 40 mg) in three (4%) patients. The mean dosage at the end of the uptitration phase was 20.8 mg (SD 7.4). Dosage titration with losartan revealed a similar pattern. Optimal antiproteinuric efficacy was obtained with a 100-mg dosage in 48 (57%) patients, 150-mg dosage in 12 (14%) patients, 200-mg dosage in nine (11%) patients, and >200-mg dosage (i.e., proteinuria reduction >10% of previous level at maximum dosage of 200 mg) in three (4%) patients. The mean dosage at the end of the uptitration phase was 117.7 mg (SD 42.6). Four (6%) patients in group 2 and six (7%) patients in group 4 were not responsive to uptitration and were maintained on the starting dosages of the study drugs.

Uptitration was stopped in five patients before the optimal antiproteinuric dosage had been reached because of SBP <120 mmHg (two in group 2 and three in group 4). Two patients titrated back because of reversible hyperkalemia (one in group 2 and one in group 4). Five patients (three in group 2 and two in group 4) withdrew during uptitration because of adverse events.

The antihypertensive efficacy was similar within arms and between arms during the study (P > 0.05; Figure 3D). There was no statistically significant difference in SBP between patients with decline of eGFR >5 or ≤5 ml/min per 1.73 m2 (Figure 3E). Urinary excretion of urea and chloride was comparable among groups during the study (Figure 3F). Classes of conventional antihypertensive drugs that were used before and during the study are listed in Table 2.


View this table:
[in this window]
[in a new window]

  		Table 2. Use of conventional antihypertensive medications

 
Safety
No patient died during the study period. The incidence of dry cough was significantly higher in the benazepril arm as compared with the losartan arm, but it did not seem to be dosage related (Table 3). There were no dosage-related differences between benazepril and losartan with respect to the incidence of nonfatal cardiovascular events or other adverse events. Hyperkalemia occurred in eight (4.4%) patients in the benazepril arm and eight (4.4%) patients in the losartan arm. Of these 16 patients, six were successfully treated with dietary modifications, concomitant diuretic therapy, and optimized acid-base balance. The remaining 10 patients withdrew from the study. The mean hemoglobin levels at baseline and during the study were comparable in groups. The proportion of patients who receiving recombinant human erythropoietin and the mean dosage of recombinant human erythropoietin were similar among the groups during the follow-up (data not shown).


View this table:
[in this window]
[in a new window]

  		Table 3. Adverse events after randomization

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 Disclosures
 References
 
The results of the ROAD study indicate that treatment with optimal antiproteinuric dosages of the ACEi benazepril or the ARB losartan, as compared with their conventional antihypertensive dosages, resulted in significant reduction in the risk for the primary end point (doubling of serum creatinine concentration, ESRD, or death) in patients who did not have diabetes and had overt proteinuria and chronic renal insufficiency. The greater reduction in proteinuria and the slower decline in creatinine clearance and eGFR that were seen in the titration groups provide further evidence of the long-term renal protection that is afforded by this strategy. Although previous clinical studies have shown that titrating an ACEi or an ARB to higher dosages reduces proteinuria more effectively (27–30), to our knowledge, this is the first study to demonstrate that titration of these therapies against urinary protein excretion provides further benefit not only on proteinuria but also on a renal hard end point.

BP is one of the most important predictors for renal outcome (1–7). In this study, SBP was rigorously controlled under a level of 130 mmHg but not 120 mmHg, because it has been evidenced that the risk for both renal and cardiovascular diseases starts to increase at a SBP as low as 127 mmHg (31,32). BP and the use of conventional antihypertensive drugs were comparable at baseline and during treatment in the four groups. RAS blockade reduced the risk for renal progression even when adjusted for BP. Benazepril and losartan both are long-acting RAS blockers. Although the study was not able to examine the 24-h BP, the previous studies that used the similar dosage of benazepril (20 mg/d) and losartan (approximately 50 to 100 mg/d) achieved stable control of 24-h BP (33,34). These data suggest that the additive renal protection that is conferred by uptitration of benazepril or losartan might not be completely dependent on BP. This rationale is further supported by the data from animal studies that indicated non–BP-dependent protective effects against renal fibrosis during high-dosage therapy with ACEi or ARB (10,35).

The extent of renal dysfunction at baseline may influence the outcome (1,2). However, the baseline renal function was comparable among the four groups, and renal function was stable as evidenced by the small variations of creatinine clearance before the study. Furthermore, the decrease in the risk for renal outcome remained significant after adjustment for baseline eGFR. Therefore, we may not attribute the observed renal benefit to the difference in baseline renal dysfunction.

The median of proteinuria reduction that was observed at 3 mo of titration treatment was approximately 1.0 g/d. The Ramipril Efficacy in Nephropathy (REIN) study showed that for each 1.0-g/d reduction in proteinuria seen at 3 mo of ACEi therapy, subsequent GFR decline was slowed by 2.0 ml/min per yr (36). Consistent with the other studies (22,37), proteinuria in this cohort was further reduced by approximately 12 to 17% by increase of benazepril or losartan from its conventional dosage to higher dosages. However, this less impressive difference was associated with significant benefit in renal outcome, suggesting that proteinuria is a strong time-dependent predictor for renal progression (2) and should be reduced as much as possible. Furthermore, RAS blockade has been shown to have benefit on renal progression, which is in addition to the antiproteinuric effect (10,38).

Our study was designed to establish the optimal strategy for reducing proteinuria with RAS blockers. Considering the increasing recognition of individual differences in responsiveness and tolerability to antiproteinuric interventions (39,40), we individually titrated benazepril or losartan to its optimal antiproteinuric dosage. We found that the optimal antiproteinuric efficacy was obtained at the 20-mg dosage of benazepril or 100-mg dosage of losartan in more than half of the patients who received titration. Approximately 25% of patients needed even higher dosages of benazepril or losartan for proteinuria control. It is important, however, to note that <8% of patients were refractory to the antiproteinuric effect of benazepril or losartan. Uptitration of these drugs to the maximum licensed dosages (benazepril 40 mg, losartan 200 mg) did not seem to overcome such therapy resistance. Although it is obviously important to determine the patient factors that may be related to the response variability, this study was not appropriate to analyze these factors, because only a few patients showed therapy resistance.

Uptitration of benazepril or losartan was generally well tolerated in this study. Only 4% of patients stopped titration because of intolerability before the optimal antiproteinuric dosages were achieved. Long-term use of the optimal antiproteinuric dosages of benazepril or losartan seemed to be well tolerated in patients with chronic renal insufficiency. Dry cough was the most common adverse event in the benazepril arm, but it did not seem to be dosage related. The overall incidence of other adverse events between groups that were given conventional and titrated dosages was similar in both the benazepril and losartan arms. Five percent of patients in the titration groups experienced an increase in serum potassium levels of >6.0 mmol/L, but only six patients withdrew from the study. However, we cannot exclude the possibility that the lower rate of serious hyperkalemia in patients with higher dosages of benazepril or losartan may be related to the lower potassium intake (suggested by the lower protein intake, approximately 0.5 g/kg per d) in this cohort and the wide use of diuretics (75%) during follow-up.

This study also provided direct evidence that the long-term renoprotective effects of benazepril and losartan were remarkably similar at the optimal antiproteinuric dosages. These two classes of drugs, at comparable BP control, achieved a similar reduction in both proteinuria and the risk for the primary end point in patients who did not have diabetes and had overt proteinuria and renal insufficiency. Data from a trial that was designed primarily to compare the effects of combined ACEi and ARB treatment with each monotherapy provided indirect evidence supporting this notion (19). Given the finding that both drugs have a dosage-response relationship for renal protection, it is fair to assume that, in clinical practice, full-dosage titration of a RAS blocker aimed at optimal reduction of proteinuria might be more important than the choice of the initial drug. Combination of ACEi and ARB have been shown to be superior to either agent alone (19). However, the safety of this approach remains to be further confirmed, especially in patients with advanced CKD.

Because this was an open-label study, there is a possibility of bias in the recording of the results. However, the Prospective Randomized Open Blinded End-Point (PROBE) design is a well-accepted approach that is as rigorous as the double-blind design, at least when, as in this case, hard end points are considered (41). Although the study was of single-center design, the clinical characteristics of our cohort were similar to those reported in the registry of China. Therefore, our cohort can reflect the general status of nondiabetic CKD, at least in Chinese.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
Disclosures
 References
 
In patients who did not have diabetes and had overt proteinuria and chronic renal insufficiency, use of optimal antiproteinuric dosages of benazepril and losartan was associated with a significant improvement in renal outcome as compared with their conventional dosages in current clinical practice. The renoprotective effects might be comparable between the ACEi benazepril and the ARB losartan in this population.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
References
 
None.


   Acknowledgments
 
This study was supported by a National Nature and Sciences Grant for Major Projects (30330300), a People's Liberation Army Grant for Major Clinical Research (2000), and National 11th Five-Years Plan Foundation (to F.F.H.).

The abstract was presented at the annual meeting of the American Society of Nephrology; November 14 through 19, 2006; San Diego CA.


   Footnotes
 
Published online ahead of print. Publication date available at www.jasn.org.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 

  1. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P; The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 334 : 939 –945, 1996[Abstract/Free Full Text]
  2. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia): Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349 : 1857 –1863, 1997[CrossRef][Medline]
  3. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345 : 861 –869, 2001[Abstract/Free Full Text]
  4. Mann JF, McClellan WM, Kunz R, Ritz E: Progression of renal disease: Can we forget about inhibition of the renin-angiotensin system? Nephrol Dial Transplant 21 : 2348 –2351, 2006[Free Full Text]
  5. Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, Jiang JP, Liang M, Wang GB, Liu ZR, Geng RW: Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 354 : 131 –140, 2006[Abstract/Free Full Text]
  6. Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, Maschio G, Brenner BM, Kamper A, Zucchelli P, Becker G, Himmelmann A, Bannister K, Landais P, Shahinfar S, de Jong PE, de Zeeuw D, Lau J, Levey AS: Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 135 : 73 –87, 2001 [published erratum appears in Ann Intern Med 137: 299, 2002][Abstract/Free Full Text]
  7. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, de Jong PE, de Zeeuw D, Shahinfar S, Toto R, Levey AS; AIPRD Study Group: Progression of chronic kidney disease: The role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition—A patient-level meta-analysis. Ann Intern Med 139 : 244 –252, 2003[Abstract/Free Full Text]
  8. Wolf G, Ritz E: Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications. Kidney Int 67 : 799 –812, 2005[CrossRef][Medline]
  9. Ruggenenti P: Angiotensin-converting enzyme inhibition and angiotensin II antagonism in nondiabetic chronic nephropathies. Semin Nephrol 24 : 158 –167, 2004[CrossRef][Medline]
  10. Peters H, Border WA, Noble NA: Targeting TGF-beta overexpression in renal disease: Maximizing the antifibrotic action of angiotensin II blockade. Kidney Int 54 : 1570 –1580, 1998[CrossRef][Medline]
  11. Fogo AB: Progression and potential regression of glomerulosclerosis. Kidney Int 59 : 804 –819, 2001[CrossRef][Medline]
  12. Laverman GD, Henning RH, de Jong PE, Navis G, de Zeeuw D: Optimal antiproteinuric dose of losartan in nondiabetic patients with nephrotic range proteinuria. Am J Kidney Dis 38 : 1381 –1384, 2001[Medline]
  13. Aranda P, Segura J, Ruilope LM, Aranda FJ, Frutos MA, Lopez V, Lopez de Novales E: Long-term renoprotective effects of standard versus high doses of telmisartan in hypertensive nondiabetic nephropathies. Am J Kidney Dis 46 : 1074 –1079, 2005[CrossRef][Medline]
  14. Weinberg MS, Weinberg AJ, Zappe DH: Effectively targetting the renin-angiotensin-aldosterone system in cardiovascular and renal disease: Rationale for using angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors. J Renin Angiotensin Aldosterone Syst 1 : 217 –233, 2000[Free Full Text]
  15. Andersen S, Rossing P, Juhl TR, Deinum J, Parving HH: Optimal dose of losartan for renoprotection in diabetic nephropathy. Nephrol Dial Transplant 17 : 1413 –1418, 2002[Abstract/Free Full Text]
  16. Haas M, Leko-Mohr Z, Erler C, Mayer G: Antiproteinuric versus antihypertensive effects of high-dose ACE inhibitor therapy. Am J Kidney Dis 40 : 458 –463, 2002[CrossRef][Medline]
  17. Ruggenenti P, Mise N, Pisoni R, Arnoldi F, Pezzotta A, Perna A, Cattaneo D, Remuzzi G: Diverse effects of increasing lisinopril doses on lipid abnormalities in chronic nephropathies. Circulation 107 : 586 –592, 2003[Abstract/Free Full Text]
  18. Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators: Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: A blood pressure-independent effect. Circulation 106 : 672 –678, 2002[Abstract/Free Full Text]
  19. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial. Lancet 361 : 117 –124, 2003 [published erratum appears in Lancet 361: 1230, 2003][CrossRef][Medline]
  20. Levey AS: Clinical evaluation of renal function. In: Primer on Kidney Diseases, 2nd Ed., edited by Greenberg A, San Diego, Academic Press, 1998 , pp 20 –26
  21. Gradman AH, Arcuri KE, Goldberg AI, Ikeda LS, Nelson EB, Snavely DB, Sweet CS: A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. Hypertension 25 : 1345 –1350, 1995[Abstract/Free Full Text]
  22. Bos H, Andersen S, Rossing P, De Zeeuw D, Parving HH, De Jong PE, Navis G: Role of patient factors in therapy resistance to antiproteinuric intervention in nondiabetic and diabetic nephropathy. Kidney Int 57[Suppl 75] : S32 –S37, 2000
  23. Levey AS, Greene T, Kusek JW, Beck GJ: A simplified equation to predict glomerular filtration rate from serum creatinine [Abstract]. J Am Soc Nephrol 11 : 155A , 2000
  24. Adler SG. Quantitative and qualitative measurement of urinary protein. In: Textbook of Nephrology, 4th Ed., edited by Massry SG, Glassock RJ, Philadelphia, Lippincott Williams & Wilkins, 2001 , pp 1784 –1786
  25. Zhang GH, Hou FF, Zhang X, Liu QF: Can angiotensin-converting enzyme inhibitor be used in chronic kidney disease patients with serum creatinine level greater than 266 micromol/L [in Chinese]? Zhonghua Nei Ke Za Zhi 44 : 592 –596, 2005[Medline]
  26. Dialysis and Transplantation Registration Group, Chinese Society of Nephrology: The report about the registration of dialysis and transplantation in China 1999. Chin J Nephrol 17 : 77 –78, 2001
  27. Pisoni R, Ruggenenti P, Sangalli F, Lepre MS, Remuzzi A, Remuzzi G: Effect of high dose ramipril with or without indomethacin on glomerular selectivity. Kidney Int 62 : 1010 –1019, 2002[CrossRef][Medline]
  28. Schmieder RE, Klingbeil AU, Fleischmann EH, Veelken R, Delles C: Additional antiproteinuric effect of ultrahigh dose candesartan: A double-blind, randomized, prospective study. J Am Soc Nephrol 16 : 3038 –3045, 2005[Abstract/Free Full Text]
  29. Palla R, Panichi V, Finato V, Parrini M, Andreini B, Bianchi AM, Giovannini L, Migliori M, Bertelli AA: Effect of increasing doses of lisinopril on proteinuria of normotensive patients with IgA nephropathy and normal renal function. Int J Clin Pharmacol Res 14 : 35 –43, 1994[Medline]
  30. Laverman GD, Navis G, Henning RH, de Jong PE, de Zeeuw D: Dual renin-angiotensin system blockade at optimal doses for proteinuria. Kidney Int 62 : 1020 –1025, 2002[CrossRef][Medline]
  31. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, Shulman NB, Stamler J: Blood pressure and end-stage renal disease in men. N Engl J Med 334 : 13 –18, 1996[Abstract/Free Full Text]
  32. Sheinfeld GR, Bakris GL: Benefits of combination angiotensin-converting enzyme inhibitor and calcium antagonist therapy for diabetic patients. Am J Hypertens 12 : 80S –85S, 1999[Medline]
  33. Andersen S, Tarnow L, Rossing P, Hansen BV, Parving HH: Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int 57 : 601 –606, 2000[Medline]
  34. Jacobsen P, Andersen S, Jensen BR, Parving HH: Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 14 : 992 –999, 2003[Abstract/Free Full Text]
  35. Navis G, Kramer AB, de Jong PE: High-dose ACE inhibition: Can it improve renoprotection? Am J Kidney Dis 40 : 664 –666, 2002[CrossRef][Medline]
  36. Ruggenenti P, Perna A, Remuzzi G; GISEN Group Investigators: Retarding progression of chronic renal disease: The neglected issue of residual proteinuria. Kidney Int 63 : 2254 –2261, 2003[CrossRef][Medline]
  37. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345 : 870 –878, 2001[Abstract/Free Full Text]
  38. Miyata T, van Ypersele de Strihou C: Renoprotection of angiotensin receptor blockers: Beyond blood pressure lowering. Nephrol Dial Transplant 21 : 846 –849, 2006[Free Full Text]
  39. Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ: Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet 353 : 2008 –2013, 1999[CrossRef][Medline]
  40. Lufft V, Kliem V, Hamkens A, Bleck JS, Eisenberger U, Petersen R, Ehlerding G, Maschek H, Pichlmayr R, Brunkhorst R: Antiproteinuric efficacy of fosinopril after renal transplantation is determined by the extent of vascular and tubulointerstitial damage. Clin Transplant 12 : 409 –415, 1998[Medline]
  41. Hansson L, Hedner T, Dahlof B: Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood Press 1 : 113 –119, 1992[Medline]



This article has been cited by other articles:


Home page
 Therapeutic Advances in Cardiovascular DiseaseHome page
A. M. Saran and T. D. DuBose Jr
Cardiovascular disease in chronic kidney disease
Therapeutic Advances in Cardiovascular Disease, December 1, 2008; 2(6): 425 - 434.
[Abstract] [PDF]

Home page
 Cleveland Clinic Journal of MedicineHome page
S. HIRSCH
An update on proteinuric chronic kidney disease: the dual-goal approach.
Cleveland Clinic Journal of Medicine, October 1, 2008; 75(10): 705 - 713.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
T. Berl
Maximizing inhibition of the renin-angiotensin system with high doses of converting enzyme inhibitors or angiotensin receptor blockers
Nephrol. Dial. Transplant., August 1, 2008; 23(8): 2443 - 2447.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ASN.2006121372v1
18/6/1889    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hou, F. F.
Right arrow Articles by Jiang, J. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hou, F. F.
Right arrow Articles by Jiang, J. P.

HOME CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP