Albuminuria Is a Target for Renoprotective Therapy Independent from Blood Pressure in Patients with Type 2 Diabetic Nephropathy: Post Hoc Analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Trial
Wouter B.A. Eijkelkamp*,
Zhongxin Zhang,
Giuseppe Remuzzi,
Hans-Henrik Parving,
Mark E. Cooper||,
William F. Keane,
Shahnaz Shahinfar,
Gilbert W. Gleim,
Matthew R. Weir¶,
Barry M. Brenner** and
Dick de Zeeuw*
* Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; Merck Research Laboratories, Merck & Co., Whitehouse Station, New Jersey; Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Steno Diabetes Center, Gentofte, and Faculty of Health Science, Aarhus University, Aarhus, Denmark; || Diabetes & Metabolism Division, Baker Medical Research Institute, Melbourne, Australia; ¶ Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; and ** Department of Medicine, Renal Division, Brigham and Women's Hospital, and Harvard School of Medicine, Boston, Massachusetts
Address correspondence to: Dr. Dick de Zeeuw, Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Ant Deusinglaan 1, 9713 AV Groningen, Netherlands. Phone: +31-50-3632810; Fax: +31-50-3632812; E-mail: d.de.zeeuw{at}med.umcg.nl
Received for publication May 9, 2006.
Accepted for publication February 26, 2007.
Albuminuria reduction could be renoprotective in hypertensivepatients with diabetic nephropathy. However, the current useof renin-angiotensin-system intervention is targeted to BP only.Therefore, this study investigated the adequacy of this approachin 1428 patients with hypertension and diabetic nephropathyfrom the placebo-controlled Reduction of Endpoints in NIDDMwith the Angiotensin II Antagonist Losartan (RENAAL) study.Investigated were the extent of discordance in treatment effectson systolic BP (SBP) and albuminuria and its association withrenal outcome in a multivariate Cox model. Among patients witha reduced SBP during treatment, a lack of albuminuria reductionwas observed in 37, 26, and 51% (total, losartan, and placebo,respectively) at month 6. SBP or albuminuria reduction was associatedwith a lower risk for ESRD, whereas combined SBP and albuminuriareduction was associated with the lowest risk for events. Acrossall categories of SBP change, a progressively lower ESRD hazardratio was observed with a larger albuminuria reduction. A lowerresidual level of albuminuria was also associated with lowerESRD risk. In conclusion, changes in albuminuria are not concordantin a substantial proportion of patients when titrated for BP.Meanwhile, the ESRD risk showed a clear dependence on albuminuriareduction. The ESRD risk also showed dependence on the residuallevel of albuminuria, even in patients who reached the currentSBP target. Antihypertensive treatment that is aimed at improvingrenal outcomes in patients with diabetic nephropathy may thereforerequire a dual strategy, targeting both SBP and albuminuriareduction.
Blocking the renin-angiotensin system (RAS) would be expectedto lower not only BP but also the leakage of proteins into theurinary space. Previous analyses of the Ramipril Efficacy inNephropathy (REIN) study, Reduction of Endpoints in NIDDM withthe Angiotensin II Antagonist Losartan (RENAAL) study, and IrbesartanDiabetic Nephropathy Trial (IDNT) indicated that albuminuriais a major renal risk factor in patients with nephropathy andthat the degree of short-term albuminuria reduction under treatmentis important in terms of long-term clinical outcome (1–6).However, these publications neither elaborated on the potentialdisparity between the BP and anti-albuminuric responses in individualpatients nor reported on the effect that such a differentialintraindividual response would have on renal outcome. It couldbe argued that an exclusively BP-driven titration may not bethe most efficacious treatment strategy because the level ofalbuminuria, as an independent risk factor for renal disease,is not always concordant with the change in BP (7). It is possiblethat pharmacologic intervention that is concurrently aimed atreducing BP as well as albuminuria could result in additionalclinical benefit beyond that achieved with BP lowering alone.The association between the albuminuric response and clinicaloutcome across various levels of BP response has not been investigated,although a clinically relevant issue would relate to whetherhypertensive patients with diabetic nephropathy would benefitfrom albuminuria reduction even when the currently recommendedsystolic BP (SBP) target is achieved (SBP <130 mmHg). Inan attempt to explore further the relationship between changesin BP and albuminuria on the one hand and renal morbidity onthe other hand, we performed a detailed post hoc analysis inhypertensive patients with diabetic nephropathy from the RENAALstudy. First, we investigated the extent of discordance in treatmenteffects on SBP and albuminuria to describe the potential clinicalimportance of this issue. Second, we examined the associationbetween differential BP and anti-albuminuric responses and renaloutcome. Ultimately, this should lead to answering the questionas to whether albuminuria reduction should be a treatment targetin addition to the commonly pursued target of BP reduction inhypertensive patients with diabetic nephropathy.
RENAAL Study Design
The RENAAL study was a double-blind, randomized, placebo-controlledstudy that was designed to evaluate the renoprotective effectsof a losartan-based antihypertensive regimen compared with atraditional BP-lowering regimen in patients with hypertension,type 2 diabetes, and nephropathy (8). During the 6-wk screeningphase, patients with hypertension continued to receive theirstandard antihypertensive therapy. If they had been taking angiotensinI–converting enzyme (ACE) inhibitors or angiotensin IIreceptor blockers (ARB), however, then these medications werediscontinued and replaced by alternative open-label medications,such as diuretics, calcium channel antagonists, or blockers.Patients were stratified according to their baseline level ofalbuminuria (a urinary albumin-to-creatinine ratio <2000or 2000) and randomly assigned to receive either losartan 50mg or placebo once daily, along with conventional antihypertensivetherapy. After 4 wk, the dosage of losartan or placebo was increasedto 100 mg once daily or placebo-equivalent dosage if the troughBP was above the target of 140/90 mmHg. After an additional8 wk, antihypertensive agents of the types described (but notACE inhibitors or ARB) were added or the dosage of these agentsincreased to achieve the target BP. On average, patients usedfour antihypertensive medications during the study. Fewer than10% of patients discontinued the study drug during the first6 mo. ESRD was a prespecified end point in the RENAAL study,which was defined as the need for long-term dialysis or renaltransplantation. Information on the clinical end points wascollected during a mean follow-up duration of 3.4 yr with therange of 2.3 to 4.6 yr. More detailed information on the studyprotocol and the main study outcome has been described elsewhere(8,9). This study was conducted with adherence to the Declarationof Helsinki. All patients provided signed informed consent.The protocol was approved by all relevant ethics committees.
Measures
This analysis focuses on SBP and albuminuria. Measurements ofBP were obtained at baseline and after 1 wk, 1 mo, and every3 mo after randomization for the duration of the study. Albuminuriawas assessed using the ratio of albumin (g/L) to creatinine(g/L) concentrations from a first-morning-void urine sample.Urine samples for the determination of albuminuria were collectedat baseline and every 3 mo after randomization for the durationof the study. Postrandomization BP and albuminuria were determinedby a prespecified time window around each scheduled visit. Boththe measurement of BP and the collection of the urine samplefor albuminuria were required to be performed within 1 d toobtain matched values for BP and albuminuria. In line with previouswork, the 6-mo time window for treatment-induced changes inthe specified variables was chosen for several reasons (1).First, this was the earliest time point at which most variablesof interest were available. Second, the treatment effect wasconsidered already present at this time. Third, few events occurredbefore month 6. The reduction in SBP was calculated as the valueobtained at baseline minus month 6, and the proportional albuminuriareduction was calculated as 100% x (1 – ratio of albuminuriaat month 6/baseline). The residual levels of SBP or albuminuriawere the corresponding values at month 6. All eligible patientsas originally randomly assigned to treatments with SBP and albuminuriadata at both baseline and month 6 were included in the analysis.For patients who had a missing value of either SBP or albuminuriaat month 6, the last observed postrandomization value was used.
Statistical Analyses
We explored the association of the reductions in SBP and albuminuriafrom baseline to month 6 with the risk for ESRD. The reductionin SBP was stratified by four categories: <–15, –15to 0, 0 to 15, and 15 mmHg. The albuminuria reduction was stratifiedby four categories: <–30, –30 to 0, 0 to 30,and 30%. In an additional analysis, the association of the residuallevel of SBP and albuminuria at month 6 with the risk for ESRDwas explored. The residual in SBP was stratified by four categories:<130, 130 to 140, 140 to 160, and 160 mmHg. The residualin albuminuria was stratified by four categories: <1, 1 to2, 2 to 3.5, and 3.5 g/g. The categories were chosen post hoc,with the aim of providing easily understandable thresholds andapproximately equal sample sizes and number of events for eachsubgroup. Similar stratification for proportional albuminuriareduction was used in previous publications (1,2). For explorationof the hazard risk profile, category factors for SBP and/oralbuminuria (either for reduction or residual) were used ina multivariate Cox model with the last category of the correspondingfactor as a common reference to compute the hazard ratio and95% confidence interval for the remainder of the categories.For testing of combined effects of reductions in SBP and albuminuria,interaction terms were added to the model. Treatment groupswere treated as strata in the model to remove potential confoundingas a result of study treatment allocation. The analysis wasalso adjusted for baseline covariates, including age, gender,race, body mass index, smoking, previous antihypertensive therapies(including blocker, blocker, dihydropyridine calcium channelblocker, nondihydropyridine calcium channel blocker, ACE inhibitor,or ARB), duration of hypertension (< or 10 yr), cardiovasculardisease history, serum creatinine, serum albumin, hemoglobin,total cholesterol, triglycerides on the natural scale, glucose,SBP, diastolic BP, and urine albumin/creatinine ratio on thenatural scale. The backward selection method was used for selectionof covariates for the final adjusted analyses ( = 0.01). Onthe basis of results of univariate analysis and previous work(9,10), the baseline covariates serum creatinine, serum albumin,hemoglobin, and urine albumin/creatinine ratio on the naturalscale were forced into the multivariate model. The number ofpatients, number of events, and number of events per 1000 patient-yearsof follow-up were provided by category. Patient counts and percentageswere also given by combined SBP and albuminuria reduction categoriesfor each treatment group (losartan or placebo). Patient characteristics,BP, and laboratory parameters at baseline were summarized forcombinations of SBP and albuminuria reduction categories. Meansand SD were provided for continuous variables, whereas numbersof patients and percentages were provided for class variables.The statistical package SAS version 8 was used for this analysis(SAS Institute, Cary, NC).
SBP and Anti-Albuminuric Response
A total of 1428 of the 1513 patients in the RENAAL study hadbaseline and up to month 6 SBP and albuminuria data availablefor this analysis, a substantial number of whom reached thepredefined BP target within these 6 mo (414 [29%] of 1428).A total of 452 patients showed a reduction in SBP in the losartangroup, 117 (26%) of whom had no reduction in albuminuria (Table 1).Similarly, a total of 386 patients showed a reduction in SBPin the placebo group, 195 (51%) of whom had no reduction inalbuminuria. Altogether, 335 (47%) of 715 losartan-treated patientsexperienced a reduction in both SBP and albuminuria, whereas105 (15%) of 715 losartan-treated patients did not exhibit areduction of either parameter. Thus, 275 (38%) of 715 losartan-treatedpatients had a response to one parameter but not the other.Scatter plots of SBP and albuminuria response in individualpatients are presented in Figure 1, showing a substantial proportionof patients with discordant effects in either treatment group.Baseline characteristics according to albuminuria and SBP responseare presented in Table 2. The mean baseline level of SBP and/oralbuminuria was higher in those who experienced a reductionin SBP and/or albuminuria, respectively. Other parameters werecomparable across the four categories.
Figure 1. (A) Scatter plot of systolic BP (SBP) versus albuminuria response in individual losartan-treated patients. (B) Scatter plot of SBP versus albuminuria response in individual placebo-treated patients.
Table 2. Baseline characteristics by albuminuria and SBP reduction at month 6a
Renal Outcome
The relationship of ESRD and SBP reduction at month 6 is presentedin Table 3. Patients with a lesser reduction in SBP comparedwith the reference group with a reduction in SBP 15 mmHg showedan increased risk for ESRD as reflected in progressively higherhazard ratios. A similar pattern was observed for the reductionin albuminuria, with a lesser reduction in albuminuria associatedwith a higher risk for ESRD (Table 3). The reduction in albuminuriawas an independent predictor for ESRD, regardless of eitherbaseline or change values in SBP (Table 4). There was no interactionof the reduction in albuminuria over reduction in SBP, whichwas not even significant after adjustment for other risk factors.The risk for ESRD according to combined SBP and anti-albuminuricresponses after adjustment for baseline risk factors is presentedin Figure 2A. The combination of a robust reduction in albuminuriaand SBP resulted in the most favorable clinical outcome. TheESRD risk showed dependence on albuminuria reduction acrossall categories of SBP reduction, whereas the ESRD hazard ratiowas comparable across SBP reduction categories within each stratumof albuminuria reduction. The presence of an SBP reduction inthose who had a good anti-albuminuric response did not havemuch additional effect on renoprotection. An additional analysisthat focused on the residual level of SBP and albuminuria afteradjustment for baseline risk factors yielded results in linewith the main analysis, showing a progressively lower risk forESRD with a lower level of residual albuminuria across all categoriesof SBP achieved (Figure 2B). Results were consistent when separatelyanalyzed in strata according to baseline albuminuria, baselineSBP, or treatment administered (data not shown). The baselinecovariates serum albumin, albuminuria, serum creatinine, hemoglobin,total cholesterol, age, gender, race, SBP, previous dihydropyridinecalcium channel blockers use, and duration of hypertension weresignificantly associated with the ESRD end point in the univariateanalysis.
Our analysis indicates that a reduction in either albuminuriaor SBP is of importance in terms of renal outcome and that thecombination of a reduction in both albuminuria and SBP resultsin the most favorable clinical outcome in hypertensive patientswith diabetic nephropathy. However, a substantial number ofpatients had no reduction in albuminuria in conjunction withreduced SBP or vice versa. This dissociation of antihypertensiveand anti-albuminuric responses was apparent regardless of whetherlosartan or placebo was administered in addition to conventionalantihypertensive medication. Importantly, even with albuminuria-loweringmedication such as losartan, nearly 40% of the patients hada dissociation of antihypertensive and anti-albuminuric responses.These findings raise the issue as to whether physicians shouldroutinely monitor not only the BP response but also the anti-albuminuricresponse in hypertensive patients with diabetic nephropathyand adjust the medications accordingly to provide both SBP andalbuminuria reduction.
This analysis demonstrates that the risk for ESRD has a cleardependence on the anti-albuminuric response. A larger albuminuriareduction was associated with a more favorable renal outcome,regardless of the SBP change during treatment (Figure 2A). Itis intriguing that one offers improved renal protection to patientswith diabetic nephropathy when one lowers albuminuria, evenwhen the BP of the individual remains unchanged or rises. Infact, the hazard ratio for ESRD seemed to be largely independentof treatment-induced SBP changes within the various strata ofalbuminuria reduction. An additional analysis regarding theresidual level of SBP and albuminuria yielded results in agreementwith these findings, showing a progressively lower ESRD riskwith a lower level of residual albuminuria independent fromthe level of SBP achieved (Figure 2B). Importantly, this wasalso observed in patients who reached the current SBP targetfor patients with diabetes (SBP <130 mmHg). These data indicatethat an exclusively BP-driven titration of treatment to improverenal outcomes may not be the most efficacious strategy in hypertensivepatients with diabetic nephropathy. The data challenge the conclusionsfrom a recently published meta-analysis by Casas et al. (11)stating that the improved renal outcomes with ACE inhibitorsor ARB in placebo-controlled trials probably result from a BP-loweringeffect only. Thus, the anti-albuminuric response could be animportant driver of therapeutic success within a given antihypertensiveregimen and achievement of a certain SBP goal, whereas a reducedlevel of albuminuria should not be assessed to occur universallyin hypertensive patients who respond with a lowered BP to RAS-inhibitingtreatment.
This relatively new concept obviously needs further confirmationin a prospective trial with an albuminuria-based titration ofpharmacologic treatment, aimed at establishing a causal relationshipbetween albuminuria reduction and improved renal outcome. Thepossibility exists that a good anti-albuminuric response mayrepresent an improved 24-h BP control. Our post hoc analysisrelates to a study that was not primarily aimed to investigatethe dependence of renal outcome on various levels of BP-loweringand anti-albuminuric responses. Nevertheless, there is accumulatingevidence to support the view that albuminuria reduction is animportant therapeutic goal. Previously, relevant findings werederived from a pooled analysis of the second Ramipril Efficacyin Nephropathy (REIN-2) study, the African American Study ofKidney Disease and Hypertension (AASK), the Modification ofDiet in Renal Disease (MDRD) study, and a study by Lewis etal. (12–15) in patients with diabetic and nondiabeticalbuminuric nephropathies. These trials of intensified BP controlshowed that more effective RAS inhibition, rather than moreeffective BP reduction, was the key component of the intensifiedtreatment strategies that was responsible for conferring maximalrenoprotection. Our data support these previous findings becausealbuminuria reduction generally requires interruption of theRAS coupled to BP reduction, as opposed to BP reduction alonethat can also be achieved via non-RAS pharmacologic approaches,including calcium antagonists and diuretics. When treatmentwith RAS-inhibiting therapy is initiated in a clinical setting,measurements of BP and albuminuria are easily available to thephysician to titrate the pharmacologic intervention. It wouldbe reasonable to assume that reduction of BP as well as albuminuriato the "normotensive" and "normo-albuminuric" range would suggestan effective inhibition of the RAS system in the vast majorityof patients who receive ACE inhibitor and/or ARB treatment.The findings of this analysis further suggest that a RAS inhibition–basedanti-albuminuric response could be considered as a therapeuticgoal besides the commonly pursued strategy of BP reduction.Apparently, it does not suffice to initiate RAS interventionwith titration solely directed to reducing BP, because manypatients have an insufficient concomitant anti-albuminuric response,even at the highest recommended dosage of losartan that leadsto a good BP response. Alternative approaches to reduce albuminuriamay therefore be considered, for example, by combining differentRAS-inhibiting treatments through co-administration of an ACEinhibitor and an ARB (16,17).
Our data show that treatment-induced changes in SBP and albuminuriado not run in parallel in a substantial proportion of patients.The risk for ESRD showed a clear dependence on albuminuria reduction,regardless of change in SBP. In agreement with this, the riskfor ESRD also showed dependence on the residual level of albuminuria,even in patients who reached the current SBP target for patientswith diabetes. An exclusively BP-driven titration of treatmentto improve clinical outcomes may therefore not be the most efficaciousstrategy in hypertensive patients with diabetic nephropathy.These data support the concept that antihypertensive treatmentaimed at improving renal outcomes in these patients may requirea dual treatment strategy, routinely targeting a reduction inalbuminuria in addition to reducing BP.
The RENAAL study was funded by Merck & Co. B.M.B, M.E.C.,D.d.Z., W.F.K., H.-H.P., G.R., and M.R.W. have received grantsupport from Merck. G.W.G., W.F.K., S.S., and Z.Z. are or havebeen employees of Merck and may own stock and/or hold stockoptions in the company.
Acknowledgments
We acknowledge Paulette A. Lyle for contributions to revisingthe manuscript and the tremendous supportive role of all RENAALinvestigators, support staff, and participating patients.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL.
Kidney Int 65
: 2309
–2320, 2004[CrossRef][Medline]
de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy.
Circulation 110
: 921
–927, 2004[Abstract/Free Full Text]
Atkins RC, Briganti EM, Lewis JB, Hunsicker LG, Braden G, Champion de Crespigny PJ, DeFerrari G, Drury P, Locatelli F, Wiegmann TB, Lewis EJ: Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy.
Am J Kidney Dis 45
: 281
–287, 2005[CrossRef][Medline]
Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia).
Lancet 349
: 1857
–1863, 1997[CrossRef][Medline]
Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G: Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy.
Lancet 352
: 1252
–1256, 1998[CrossRef][Medline]
Ruggenenti P, Perna A, Remuzzi G: Retarding progression of chronic renal disease: The neglected issue of residual proteinuria.
Kidney Int 63
: 2254
–2261, 2003[CrossRef][Medline]
Laverman GD, Andersen S, Rossing P, Navis G, de Zeeuw D, Parving HH: Renoprotection with and without blood pressure reduction.
Kidney IntSuppl 94
: S54
–S59, 2005
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S: 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]
Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, Ribeiro AB, Shahinfar S, Simpson RL, Snapinn SM, Toto R: The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: The RENAAL study.
Kidney Int 63
: 1499
–1507, 2003[CrossRef][Medline]
Keane WF, Zhang Z, Lyle PA, Cooper ME, de Zeeuw D, Grunfeld JP, Lash JP, McGill JB, Mitch WE, Remuzzi G, Shahinfar S, Snapinn SM, Toto R, Brenner BM: Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: The RENAAL study.
Clin J Am Soc Nephrol 1
: 761
–767, 2006[CrossRef][Medline]
Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, MacAllister RJ: Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: Systematic review and meta-analysis.
Lancet 366
: 2026
–2033, 2005[CrossRef][Medline]
Ruggenenti P, Perna A, Loriga G, Ganeva M, Ene-Iordache B, Turturro M, Lesti M, Perticucci E, Chakarski IN, Leonardis D, Garini G, Sessa A, Basile C, Alpa M, Scanziani R, Sorba G, Zoccali C, Remuzzi G: Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): Multicentre, randomised controlled trial.
Lancet 365
: 939
–946, 2005[CrossRef][Medline]
Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG: Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial.
JAMA 288
: 2421
–2431, 2002[Abstract/Free Full Text]
Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL: Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.
Ann Intern Med 123
: 754
–762, 1995[Abstract/Free Full Text]
Lewis JB, Berl T, Bain RP, Rohde RD, Lewis EJ: Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Collaborative Study Group.
Am J Kidney Dis 34
: 809
–817, 1999[Medline]
Doulton TW, He FJ, MacGregor GA: Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension.
Hypertension 45
: 880
–886, 2005[Abstract/Free Full Text]
Jacobsen P, Andersen S, Jensen BR, Parving HH: Additive effect of ACE inhibition and angiotensin II receptor blockage in type I diabetic patients with diabetic nephropathy.
J Am Soc Nephrol 14
: 992
–999, 2003[Abstract/Free Full Text]
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Abstract
Introduction
blockers. Patients were stratified according to their baseline level of albuminuria (a urinary albumin-to-creatinine ratio <2000 or 
2000) and randomly assigned to receive either losartan 50 mg or placebo once daily, along with conventional antihypertensive therapy. After 4 wk, the dosage of losartan or placebo was increased to 100 mg once daily or placebo-equivalent dosage if the trough BP was above the target of 140/90 mmHg. After an additional 8 wk, antihypertensive agents of the types described (but not ACE inhibitors or ARB) were added or the dosage of these agents increased to achieve the target BP. On average, patients used four antihypertensive medications during the study. Fewer than 10% of patients discontinued the study drug during the first 6 mo. ESRD was a prespecified end point in the RENAAL study, which was defined as the need for long-term dialysis or renal transplantation. Information on the clinical end points was collected during a mean follow-up duration of 3.4 yr with the range of 2.3 to 4.6 yr. More detailed information on the study protocol and the main study outcome has been described elsewhere (8,9). This study was conducted with adherence to the Declaration of Helsinki. All patients provided signed informed consent. The protocol was approved by all relevant ethics committees. 
blocker, 
