Antiproteinuric efficacy of losartan in comparison with amlodipine in non-diabetic proteinuric renal diseases: a double-blind, randomized clinical trial

Manuel Praga1, Carlos Fernández Andrade2, José Luño3, Manuel Arias4, Rafael Poveda5, Jose Mora6, Marti Valles Prat7, Francisco Rivera8, Jose María Galceran9, Jorge Martínez Ara10, Román Aguirre11, Carmen Bernis12, Rafael Marín13 and Jose María Campistol14

1 Hospital 12 de Octubre, Madrid, 2 Hospital Virgen del Rocio, Sevilla, 3 Hospital Gregorio Marañón, Madrid, 4 Hospital Marques de Valdecilla Santander, 5 Hospital de Bellvitge, Barcelona, 6 Fundación Puigvert, Barcelona, 7 Hospital Josep Trueta, Gerona, 8 Hospital General de Alicante, 9 Hospital de Palamos (Gerona), 10 Hospital La Paz, Madrid, 11 Hospital de Galdakano, Vizcaya, 12 Hospital de la Princesa, Madrid, 13 Hospital Central de Asturias and 14 Hospital Clínico y Provincial, Barcelona, Spain

Correspondence and offprint requests to: Dr Manuel Praga, Servicio de Nefrología, Hospital 12 de Octubre, Carretera de Andalucía, Km 5,400, 28041 Madrid, Spain. Email: mpragat{at}senefro.org



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Proteinuria is a significant independent determinant of the progression of chronic renal diseases. It induces an increased synthesis of angiotensin II, endothelin and profibrogenic growth factors, such as transforming growth factor-ß (TGF-ß), by mesangial and tubular cells. The antiproteinuric effect of angiotensin-converting enzyme inhibitors (ACEIs) in diabetic and non-diabetic nephropathies predicts long-term renoprotection afforded by these drugs. Angiotensin II receptor antagonists are renoprotective in patients with type 2 diabetes, but studies about their effect in non-diabetic proteinuric nephropathies are very scarce.

Methods. We randomly assigned 97 patients with non-diabetic nephropathies and proteinuria >1.5 g/24 h to treatment with losartan (50 mg daily) or amlodipine (5 mg daily) for 20 weeks. Doses of the study medications were titrated to achieve a target blood pressure <140/90 mmHg in both groups. Primary outcome was the decrease in the level of 24 h proteinuria. Secondary outcomes were changes in the plasma and urinary levels of TGF-ß.

Results. The baseline characteristics in both groups were similar. Proteinuria decreased by 32.4% (95% confidence interval -38.4 to -21.8%) after 4 weeks of treatment and by 50.4% (-58.9 to -40.2%) after 20 weeks in the losartan group, whereas no significant proteinuria changes were observed in the amlodipine group (P < 0.001). There was no significant correlation between the level of baseline proteinuria and the proteinuria decrease induced by losartan. Both losartan and amlodipine induced a similar and significant blood pressure reduction. Target blood pressure was achieved with the initial dose of study medication (50 mg daily) in 76% of losartan group patients and in 68% of the amlodipine group patients (5 mg daily). Urinary TGF-ß significantly decreased with losartan (-22.4% of the baseline values after 20 weeks of treatment), whereas it tended to increase with amlodipine (between-group difference P < 0.05). A significant correlation between proteinuria decrease and urinary TGF-ß reduction was found in the losartan group (r = 0.41, P < 0.005). Serum creatinine and serum potassium remained stable during the study in both groups.

Conclusions. Losartan induced a drastic decrease in proteinuria accompanied by a reduction in urinary excretion of TGF-ß in patients with non-diabetic proteinuric renal diseases.

Keywords: angiotensin II blockade; losartan; progression of renal disease; proteinuria; transforming-growth factor-ß (TGF-ß)



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The level of proteinuria has long been recognized as a prognostic marker of paramount importance in any chronic renal disease. Prospective studies have shown that proteinuria is a significant independent determinant of the progression of chronic renal diseases, demonstrating a strong association of greater proteinuria with more rapid decline in renal function [1–3]. In the last few years, a large number of experimental studies have provided compelling evidence of the harmful effects that proteins abnormally filtered by a diseased glomerulus induce on glomerular and tubulointerstitial structures [4–6]. Increased synthesis of angiotensin II and endothelin-1 by the kidney has been demonstrated in proteinuric renal diseases [4–6]. Angiotensin II stimulates the synthesis of transforming growth factor-ß (TGF-ß), and angiotensin II blockade by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) results in a decrease in TGF-ß expression and matrix accumulation [7]. Overproduction of TGF-ß, the most important fibrogenic cytokine identified so far, plays a key role in renal fibrosis, through an increased synthesis of matrix proteins such as collagen, fibronectin and proteoglycans, and increased production of protease inhibitors such as PAI-1 and TIMP [4,5,7].

In this scenario, any therapeutic intervention that reduces the level of proteinuria should have an important beneficial influence on the progression of proteinuric nephropathies. This assessment has been validated by the results of several therapeutic trials performed in the last decade. ACEIs, drugs whose antiproteinuric and renoprotective properties had been demonstrated repeatedly in experimental models of renal disease progression, showed a significant beneficial influence on the progression of both diabetic and non-diabetic nephropathies in prospective and multicentre studies [8,9]. The slowing in the progression of renal insufficiency was always strongly related to proteinuria decrease induced by ACEIs, whereas it appears to be largely independent of the blood pressure-lowering effects induced by these agents [8,9].

ARBs have reproduced the beneficial effects of ACEIs in experimental models of renal disease. Recent prospective, multicentre studies have shown that ARBs delay the progression of nephropathy in patients with type 2 diabetes [10,11]. As in the trials using ACEIs, the beneficial influence of ARBs was associated with a significant proteinuria decrease. In contrast, information about the renoprotective effects of ARBs in non-diabetic proteinuric nephropathies is scarce.

We undertook a prospective and multicentre study in patients with non-diabetic proteinuric renal diseases in order to compare the effect of an ARB (losartan) and a calcium channel blocker (amlodipine) on the levels of 24 h proteinuria. Secondary objectives of the study were to assess the effect of both treatments on the plasma and urinary levels of TGF-ß, as well as to evaluate the safety and tolerability of both treatments.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
We conducted an investigator-initiated, prospective, double-blind, randomized study of 20 weeks duration in 14 centres in Spain. The study protocol was reviewed and approved by each centre’s institutional review board, and signed consent was obtained from all patients prior to study entry.

Patients
The criteria for eligibility included age older than 18 years, a chronic proteinuric nephropathy (defined by a proteinuria >1.5 g/24 h) of non-diabetic cause, and hypertension (a systolic blood pressure of >140 mmHg while sitting and/or a diastolic blood pressure of >90 mmHg while sitting). Serum creatinine was required to be <=2.5 mg/dl. Patients were excluded if they had severe hypertension (systolic blood pressure >170 mmHg and/or diastolic blood pressure >105 mmHg despite treatment with antihypertensive agents, or patients requiring more than one antihypertensive drug), secondary types of hypertension (renal artery stenosis, primary aldosteronism, pheochromocytoma or other reversible forms of hypertension), rapidly deteriorating renal function (defined by an increase of >50% in the level of serum creatinine during the last 6 months) or severe obesity (body mass index >35 kg/m2). We also excluded patients who required diuretics because of oedema, who had received a diagnosis of type 1 or type 2 diabetes, who had had a myocardial infarction within the previous 6 months or who had any history of heart failure.

Sample size calculation
Assuming a standard deviation on proteinuria reduction of 1.50 g/24 h, in order to detect a difference of 1.00 g/24 h in mean reduction in proteinuria between both treatment arms with a power equal to 90% and a type I error of 0.05 (two-tailed), it was calculated that a sample size of 49 patients per group would be necessary.

Study design
All the patients that met the eligibility criteria followed a wash-out/placebo period during which all the antihypertensive drugs, including diuretics, were withdrawn and a placebo was administered. The duration of this wash-out/placebo period was 8 weeks for patients taking ACEIs or ARAs, 4 weeks for those receiving other classes of antihypertensive agents and 2 weeks for patients without antihypertensive treatment. During this wash-out/placebo period, an {alpha}-blocker (doxazosin) could be prescribed to patients with a systolic blood pressure >170 mmHg and/or diastolic blood pressure >105 mmHg.

After completing the wash-out/placebo period, patients who fulfilled the enrolment criteria were assigned randomly to receive either losartan 50 mg or amlodipine 5 mg once daily, in a double-blind design. After 4 weeks (week 4), hydrochlorothiazide (12.5 mg once daily) was added if the blood pressure was above the target level of a systolic blood pressure of <140 mmHg and a diastolic blood pressure of <90 mmHg. After an additional 4 weeks (week 8), the dose of losartan or amlodipine was increased to 100 mg and 10 mg once daily, respectively, if blood pressure was still above the target level. If after another 4 weeks (week 12) systolic blood pressure was still >140 mmHg or diastolic blood pressure was >90 mmHg, the dose of hydrochlorothiazide was increased to 25 mg once daily (see Figure 1, study design).



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Fig. 1. Study design.

 
Clinical and laboratory procedures
At study entry and completion, a complete physical examination and electrocardiogram (ECG) were obtained. After randomization (week 0 or baseline), included patients undertook visits after 2, 4, 8, 12, 16 and 20 weeks. Blood pressure was measured at every visit, using a standard mercury sphygmomanometer. It was measured in the sitting position after at least 5 min of rest. The proper cuff size was used on the same arm throughout the study. Korotkoff phase V was used as the criterion for diastolic blood pressure. Three consecutive measurements, at 1 min intervals, were performed, and the average of the three readings was calculated. Heart rate was also recorded at every visit. Patients were questioned at each visit about the occurrence of adverse symptoms.

All analyses were performed after an overnight fast. Blood was drawn for routine haematology and blood chemistry [including standard blood count, serum creatinine, urea, sodium, potassium, bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, glucose, uric acid, total and high-density lipoprotein (HDL) serum cholesterol and triglycerides] at baseline and at weeks 4 and 20. Serum creatinine and serum potassium were also measured at week 2. Twenty-four hour proteinuria was measured at baseline and at weeks 4, 8 and 20. In addition, urinary creatinine and sodium were measured in the urine collections at baseline, week 4 and week 20. Plasma levels of TGF-ß were determined at baseline and at weeks 4 and 20. The 24 h urine collections for measurement of urinary TGF-ß were obtained at baseline, week 4 and week 20.

Measurements of 24 h proteinuria and urinary creatinine, as well as the measurement of TGF-ß, were performed by a central laboratory. The remaining measurements were determined by local laboratories. Standard blood count, proteinuria and blood chemistry were measured by routine techniques. Plasma and urinary concentration of TGF-ß1 were measured by enzyme-linked immunosorbent assay (ELISA; Quantikine, R&D Systems Inc., Minneapolis, MN, USA) as described previously [12].

Outcome measures
The primary efficacy measure was the decrease in the level of 24 h proteinuria. The secondary end points were changes in the plasma and urinary levels of TGF-ß.

Statistical analysis
In order to normalize the data, right asymmetrical continuous variables (proteinuria and TGF-ß) were log-transformed, and therefore geometric means were calculated. For other continuous variables (BP and laboratory parameters), arithmetic means were calculated.

Baseline measurements were assessed with arithmetic and geometric means, and post-baseline measurements were assessed with LS-arithmetic means and LS-geometric means adjusted for baseline measurement.

For arithmetic means, the SD and 95% confidence interval (CI) are presented. For geometric means and LS-means, only the 95% CI is presented.

For continuous variables, between-group comparisons were performed with analysis of co-variance, with baseline measurement as a co-variate; least squared means were presented. For discrete variables, e.g. adverse events, differences between groups were assessed with the relative risk and {chi}2 test P-value, or Fisher’s exact test when the {chi}2 criteria were not met.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
A total of 112 eligible patients entered the wash-out/placebo period. Fifteen patients were excluded because of severe hypertension (eight patients), proteinuria <1.5 g/24 h (three patients), refusal to sign informed consent (three patients) and severe oedema (one patient). The remaining 97 patients were randomly assigned to receive losartan (50 patients) or amlodipine (47 patients). For the 97 included patients, there were no significant changes in serum creatinine during the wash-out/placebo period. Creatinine clearance showed a mild, non-significant decrease from 78 ± 40 (69–86)ml/min at the onset of the wash-out/placebo period to 77 ± 37 (70–85) ml/min at baseline. The baseline demographic, clinical and laboratory characteristics of the two groups were similar (Tables 1 and 2). Adverse clinical events resulted in discontinuation in three patients (6%) in the losartan group and in six patients (12%) in the amlodipine group. These patients were included in the intention-to-treat analyses.


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Table 1. Baseline characteristics

 

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Table 2. Renal disease diagnosis

 
Clinical management
The blood pressure measurements for the two groups are shown in Figure 2. Both treatments provided a significant reduction of both systolic and diastolic blood pressures. Blood pressure decreased from 149 (146–151)/93 (91–94) mmHg at baseline to 131 (128–135)/83 (81–85) mmHg at week 20 in the losartan group (P < 0.00001) and to 136 (133–141)/85 (84–88) mmHg at week 20 in the amlodipine group (P < 0.00001). There were no significant differences in the reduction of blood pressure between both groups (Figure 2). The proportion of patients in whom the target blood pressure was achieved was similar in both groups (62% in the losartan group and 53% in the amlodipine group, NS). Almost half of the patients in the losartan group (23 patients) achieved the target blood pressure (<140 mmHg for systolic and <90mmHg for diastolic blood pressure) with the initial dose of 50 mg daily without diuretics, whereas other 15 patients needed the addition of diuretics. Only 12 (24%) patients in this group needed to increase losartan doses to 100 mg daily. In the amlodipine group, 32 patients (68%) maintained the initial dose of 5 mg daily throughout the study, with or without diuretics, because of the achievement of target blood pressure.



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Fig. 2. Evolution of systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure during the study.

 
Primary outcome
Levels of 24 h proteinuria in both groups are shown in Figure 3. There were no significant changes in the amlodipine group throughout the study: 2.8 (2.4–3.3) g/24 h at baseline, 3.1 (2.5–3.6) g/24 h after 4 weeks, 2.7 (2.3–3.1) g/24 h at week 8 and 2.5 (2.1–3.1) g/24 h at week 20. In contrast, proteinuria showed a drastic decrease in the losartan group: it decreased from 2.8 (2.4–3.3) g/24 h at baseline to 1.9 (1.7–2.2) g/24 h (P < 0.0001) after 4 weeks [-32.4% (-38.4 to -21.8%)], 1.6 (1.4–1.9) g/24 h (P < 0.0001) at week 8 [-41.3% (-48.16 to -29.9%)] and 1.4 (1.1–1.7) g/24 h at week 20 (P < 0.0001) [-50.4% (-58.9 to 40.2%)] (P < 0.0001 with respect to the amlodipine group at every measurement).



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Fig. 3. Changes in proteinuria during the study (*P < 0.0001, reduction between groups).

 
No correlation was found between the level of proteinuria at baseline and the percentage proteinuria reduction at week 20 considering the whole group of 97 randomized patients and patients of the losartan and amlodipine groups separately.

There were no significant further reductions in the level of proteinuria in those patients (n = 11) in whom the dose of losartan was increased to 100 mg after week 8 because of blood pressure >140/90 mmHg: 4.3 (2.9–6.3) g/24 h at baseline, 2.1 (1.3–3.3) g/24 h at week 8 [-50.3% (-30 to -64.6%)] and 1.8 (1.1–3.1)g/24 h at week 20 [-12.4% (24.2 to -38.3%) with respect to values at week 8].

Secondary outcomes
In the losartan group, daily urinary excretion of TGF-ß decreased from 16.2 (14.0–19.0) ng/24 h at baseline to 13.5 (9–14.2) ng/24 h at week 4 [-16.3% (-33.2 to 5.0%)] and to 12.5 (10.1–15.6) ng/24 h at week 20 [-22.2% (-37.6 to 3.6%)] (P < 0.05 with respect to baseline values). In the amlodipine group, TGF-ß increased from the baseline levels to 17.1 (13.7–21.3)ng/24 h at week 4 and to 17.6 (14.1–22.2) ng/24 h at week 20. These differences between the losartan and amlodipine groups were significant (P < 0.05) (Figure 4). A significant correlation between the percentage proteinuria decrease and urinary TGF-ß changes was found in the losartan group (r = 0.41, P < 0.0034), whereas no correlation was found in the amlodipine group.



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Fig. 4. Changes in urinary TGF-ß at weeks 4 and 20.

 
There were no significant changes in plasma levels of TGF-ß either in the losartan group [6.9 (5.7–8) ng/ml at baseline, 8.1 (6.5–10.1) ng/ml at week 4 and 7 (5.6–8.7)ng/ml at week 20] or in the amlodipine group [6.9 (5.7–8) ng/ml, 8.2 ng/ml and 8 (6.4–10) ng/ml, respectively].

Effects on other laboratory parameters
As shown in Table 3, there were no significant changes in haematocrit, haemoglobin, leukocyte count or platelet count either in the losartan group or in the amlodipine group. Serum creatinine showed a non-significant increase from 1.4 ± 0.5 to 1.6 ± 0.7 mg/dl in the losartan group and from 1.3 ± 0.5 to 1.4 ± 0.6mg/dl in the amlodipine group, whereas creatinine clearance decreased from 74 ± 37 to 70 ± 37 ml/min in the losartan group and from 82 ± 38 to 81 ± 43 ml/min in the amlodipine group. There were also no significant changes in the levels of serum glucose, uric acid, total and HDL cholesterol and triglycerides (Table 3). Serum potassium showed a mild, non-significant, increase (from 4.3 ± 0.3 to 4.5 ± 0.5 mEq/l) in the losartan group. There were no significant changes in the levels of 24 h urinary sodium excretion.


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Table 3. Evolution of laboratory parameters during the study

 
Adverse experiences
Seven patients (14%) in the losartan group and 12 (25%) in the amlodipine group had minor adverse experiences related to study medications throughout the study (NS). Adverse clinical events resulted in discontinuation of three patients (6%) in the losartan group (anxiety, dizziness and serum creatinine increase) and of six patients (12%) in the amlodipine group (anaemia, angina pectoris, diarrhoea and oedema in three patients). There were three serious adverse events, not related to study treatments: two in two patients of the losartan group (fever and dysuria) and one in the amlodipine group (angina pectoris).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In our study, losartan induced a drastic decrease in proteinuria in patients with non-diabetic proteinuric renal disease, moderate hypertension and a serum creatinine <2.5 mg/dl. In contrast, patients treated with amlodipine did not show significant variations in the level of proteinuria throughout the study. Proteinuria decrease was also evident among our losartan group patients with lower levels of baseline proteinuria, and no correlation between baseline proteinuria and the degree of proteinuria reduction was observed.

Only a few studies, including a small number of patients, had previously investigated the effects of ARBs on the proteinuria levels of chronic non-diabetic renal diseases [1318]. Our study confirms and extends these preliminary data, demonstrating for the first time in a multicentre, randomized design including a large number of patients a significant reduction in proteinuria by losartan in patients with non-diabetic nephropathies.

In the last few years, several prospective clinical studies have shown that proteinuria is a significant independent determinant of the progression of chronic renal diseases, reporting a strong association of greater proteinuria with a more rapid decline in renal function [13,811]. Conversely, those therapeutic measures that decrease proteinuria are accompanied by a significant slowing in the rate of renal failure progression. Most of these data come from the prospective studies performed with ACEIs, that have demonstrated a beneficial influence of these drugs on the long-term evolution of both diabetic and non-diabetic proteinuric renal diseases [8,9]. Recent studies have demonstrated that ARBs are effective in delaying the progression of nephropathy in type 2 diabetes [10,11]. Our study, showing a drastic antiproteinuric effect of losartan in non-diabetic renal diseases, might predict a long-term renoprotection by ARBs in these diseases. However, the short duration of our study should be emphasized; further studies with longer follow-up are required in order to confirm these aspects.

Both losartan and amlodipine induced a significant and sustained blood pressure reduction (Figure 2). Lower values of both systolic and diastolic blood pressure in the losartan group were observed; however, analysis of co-variance did not find significant differences in blood pressure values between both groups throughout the study. As in previous studies with ACEIs, the reduction in proteinuria by losartan was already significant after 4 weeks of treatment. In spite of a similar reduction of blood pressure, patients treated with amlodipine did not show significant changes in the level of proteinuria. Dihydropyridine calcium channel blockers, including amlodipine, lack the antiproteinuric effect that non-dihydropiridine calcium channel blockers such as diltiazem and verapamil have shown in some studies. Sixty-two percent of patients in the losartan group and 53% in the amlodipine group reached the target blood pressure (<140/90 mmHg) during the study. Interestingly, almost half of the patients in both groups reached the target blood pressure with the initial dose of both losartan (50 mg daily) and amlodipine (5 mg daily), without the addition of diuretics or titration of doses. It should be considered, however, that patients with severe hypertension or those receiving more than one antihypertensive drug were excluded from the study, as stated in Methods. In addition, blood pressure was targeted to <140/90 mmHg, whereas, according to current guidelines, values <130/80 mmHg should be recommended for the long-term control of patients with proteinuria and renal insufficiency. Most patients in the losartan group showed a drastic decrease in proteinuria with the initial dose of 50 mg daily. In fact, those patients (n = 11) in whom losartan dose was titrated to 100 mg daily because of blood pressure >140/90 mmHg at week 8 did not show a greater decrease in proteinuria after losartan increase; all of them had shown a clear decrease in proteinuria with the initial dose of 50 mg daily. A recent study [18] has reported a greater antiproteinuric effect of 100 mg of losartan daily in comparison with 50 mg daily in 10 patients with proteinuric non-diabetic nephropathies. Although our study includes a larger number of patients, it should be emphasized that it was not designed specifically to analyse the optimal antiproteinuric dose of losartan.

In the last few years, pathogenic mechanisms through which proteinuria induces the appearance of interstitial infiltrates and progressive tubulointerstitial fibrosis have been partially clarified. Increased synthesis of angiotensin II by the kidney plays a central role in these events, activating the transcription factor NF-{kappa}B and increasing the expression of several cytokines, chemoattractants, cell adhesion molecules and growth factors [47]. Among them, TGF-ß has a pivotal role in renal scarring, stimulating the synthesis of matrix proteins and decreasing matrix degradation by increasing the activity of protease inhibitors [7]. In our study, we assessed the influence of losartan and amlodipine treatments on urinary and plasma levels of TGF-ß. We found a significant between-group difference, with a significant decrease of urinary TGF-ß after 20 weeks of losartan treatment, whereas it tended to increase with amlodipine. The reduction of urinary TGF-ß showed a significant correlation with the proteinuria decrease in the losartan group. These findings are relevant, because several experimental studies have provided compelling evidence of the important role of TGF-ß in the progression of both diabetic and non-diabetic chronic nephropathies, suggesting that TGF-ß should be a therapeutic target in these diseases [7]. In addition, several experimental and clinical studies strongly suggest that urinary TGF-ß represents a very sensitive marker of the activity of TGF-ß in the renal system [19,20]. In contrast to the significant decrease of urinary TGF-ß, we did not observe significant changes in the plasma levels of TGF-ß. It is possible that longer periods of observation (the duration of our study was 20 weeks) are needed in order to assess the real influences of ARBs or other treatments on the plasma levels of these factors.

Both losartan and amlodipine treatments were well tolerated throughout the study. Seven patients (14%) in the losartan group and 12 patients (25%) in the amlodipine group showed minor adverse events related to the study medications. Only one patient in the losartan group showed a significant increase in serum creatinine levels leading to study discontinuation, and hyperkalaemia was not recorded among losartan patients. No significant changes in laboratory parameters were observed (Table 2), including serum creatinine, creatinine clearance and serum potassium.

In summary, losartan induced a drastic proteinuria decrease and a significant decrease of urinary TGF-ß in patients with non-diabetic proteinuric nephropathies. Studies with a longer follow-up are required in order to evaluate whether or not these effects are accompanied by a long-term renoprotection of ARBs in non-diabetic renal diseases.



   Acknowledgments
 
The authors acknowledge the participation of the following: Clinical Investigators at the Hospital Virgen del Rocio, Sevilla, Coral Navarro and Rodrigo Zamora; Hospital 12 de Octubre, Madrid, Enrique Morales and Mari Cruz Casal; Hospital Marques de Valdecilla, Santander, Gema Fernandez Fresnedosos; Hospital de Bellvitge, Barcelona, Rosa Ramos; Hospital Dr Josep Trueta, Gerona, Josep Bronsoms; Hospital General de Alicante, Jesús Olivares; Hospital Gregorio Marañon, Madrid; Ma Angeles Goicoechea, Ma Soledad García de Vinuesa and Francisco Gómez; Hospital Clínico y Provincial, Barcelona, Aleix Cases. Central Laboratory: Wladimiro Jiménez and Pablo Iñigo, Hospital Clinico y Provincial, Barcelona. Statistician: Eduardo Sobreviela, Logitest, Madrid. Study Coordinator: Lourdes Lopez-Bravo, Merck Sharp & Dohme, Spain. This work was supported by a grant from Merck Sharp & Dohme, Spain.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 29.11.02
Accepted in revised form: 3. 4.03