Add-on angiotensin receptor blockade with maximized ACE inhibition

Kidney International, Vol. 59 (2001), pp. 2282–2289

Add-on angiotensin receptor blockade with maximized ACE inhibition RAJIV AGARWAL Division of Nephrology, Department of Medicine, Indiana University and RLR VA Medical Center, Indianapolis, Indiana, USA

Add-on angiotensin receptor blockade with maximized ACE inhibition. Background. Prolonged angiotensin-converting enzyme (ACE) inhibitor therapy leads to angiotensin I (Ang I) accumulation, which may “escape” ACE inhibition, generate Ang II, stimulate the Ang II subtype 1 (AT1) receptor, and exert deleterious renal effects in patients with chronic renal diseases. We tested the hypothesis that losartan therapy added to a background of chronic (⬎3 months) maximal ACE inhibitor therapy (lisinopril 40 mg q.d.) will result in additional Ang II antagonism in patients with proteinuric chronic renal failure with hypertension. Methods. Sixteen patients with proteinuric moderately advanced chronic renal failure completed a two-period, crossover, randomized controlled trial. Each period was one month with a two-week washout between periods. In one period, patients received lisinopril 40 mg q.d. along with other antihypertensive therapy, and in the other, losartan 50 mg q.d. was added to the previously mentioned regimen. Hemodynamic measurements included ambulatory blood pressure monitoring (ABP; Spacelabs 90207), glomerular filtration rate (GFR) with iothalamate clearances and cardiac outputs by acetylene helium rebreathing technique. Supine plasma renin activity and plasma aldosterone and 24-hour urine protein were measured in all patients. Results. Twelve patients had diabetic nephropathy, and four had chronic glomerulonephritis. The mean age (⫾ SD) was 53 ⫾ 9 years. The body mass index was 38 ⫾ 5.7 kg/m2, and all except two patients were males. Seated cuff blood pressure was 156 ⫾ 18/88 ⫾ 12 mm Hg. The pulse rate was 77 ⫾ 11 per min, and the cardiac index was 2.9 ⫾ 0.5 L/min/m2. Mean log 24-hour protein excretion/g creatinine or overall ABPs did not change. Mean placebo subtracted, losartan-attributable change in protein excretion was ⫹1% (95% CI, –20% to 28%, P ⫽ 0.89). Similarly, the change in systolic ambulatory blood pressure (ABP) was 4.6 mm Hg (–5.7 to 14.9, P ⫽ 0.95), and diastolic ABP was 1.5 mm Hg (–4.5 to 7.6, P ⫽ 0.59). No change was seen in cardiac output. However, there was a mean 14% increase (95% CI, 3 to 26%, P ⫽ 0.017) in GFR attributable to losartan therapy. A concomitant fall in plasma renin activity by 32% was seen (95% CI, –15%, – 45%, P ⫽ 0.002). No hyperkalemia, Key words: losartan, ambulatory blood pressure, renal hemodynamics, glomerular filtration rate, AT1 receptor. Received for publication October 18, 2000 and in revised form January 5, 2001 Accepted for publication January 11, 2001

 2001 by the International Society of Nephrology

hypotension, or acute renal failure occurred in the trial. These results were not attributable to sequence or carryover effects. Conclusions. Add-on losartan therapy did not improve proteinuria or ABP over one month of add on therapy. Improvement of GFR and fall in plasma renin activity suggest that renal hemodynamic and endocrine changes are more sensitive measures of AT1 receptor blockade. Whether add-on AT1 receptor blockade causes antiproteinuric effects or long-term renal protection requires larger and longer prospective, randomized controlled trials.

Patients with uncontrolled hypertension and proteinuria have an accelerated decline in renal function [1, 2]. In particular, when proteinuria is uncontrolled with angiotensin-converting enzyme (ACE) inhibition, patients have a more rapid decline in glomerular filtration rate (GFR) over the long term [3]. Chronic ACE inhibitor therapy may lead to accumulation of angiotensin I (Ang I) and stimulation of Ang II subtype 1 (AT1) receptor despite ACE inhibition. This accumulation of Ang II by stimulating the AT1 receptor can cause deleterious effects such as vasoconstriction, salt retention, inflammation, and fibrosis [4], and enhance the activity of the sympathetic nervous system by direct effects on the central and peripheral adrenergic transmission [5]. Half of the variance in ACE activity is dictated by ACE insertion-deletion polymorphism [6], such that it dictates the conversion of infused Ang I to Ang II [7], the systemic [8] and renal hemodynamic response to ACE inhibitors [9], as well as the progression of renal disease [10, 11]. Furthermore, pathways other than the ACE may be responsible for Ang II generation, particularly in tissues and blood vessels. Angiotensin receptor blockers (ARBs) could overcome these shortcomings of ACE inhibitors by directly antagonizing the AT1 receptor. In addition, because AT2 receptors mediate the beneficial effects of Ang II, by blocking the AT1 receptors with ARBs, Ang II would be available to stimulate the AT2 receptors. It is not known whether the addition of ARB in patients with chronic renal failure who have persistent proteinuria despite ACE inhibitor therapy has beneficial

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Fig. 1. Trial design.

effects on the kidney. Accordingly, we tested the hypotheses that AT1 receptor is stimulated even in patients with a maximally recommended dose of ACE inhibitor and that this stimulation can be abrogated by the addition of ARBs. Ambulatory blood pressures, proteinuria, GFR, cardiac output, renin, and aldosterone were measured to determine whether losartan can offer additional protection in patients treated with a maximal dose of ACE inhibitors. METHODS Subjects Patients between the ages of 18 to 80 years who had proteinuria of ⱖ1 g/day, hypertension defined as mean arterial pressure ⱖ97 mm Hg, and serum potassium of ⱕ5.5 mEq/L and who were on lisinopril therapy of 40 mg/day for more than three months were eligible for the study. Patients who had previously received ARBs or with estimated creatinine clearance of ⬍30 mL/min were excluded. Protocol The study was a two period, cross-over, randomized controlled trial (Fig. 1). Patients received either a sequence of losartan 50 mg/day ⫻ weeks, a two-week washout, placebo ⫻ 4 weeks or placebo ⫻ 4 weeks, two-week washout, and losartan 50 mg/day ⫻ 4 weeks. Lisinopril 40 mg/day along with other antihypertensive therapy was continued throughout the trial. Before and after each period GFR, plasma renin activity (PRA), plasma aldosterone (PA), 24-hour urine collection for protein, creatinine, Na, K, and urea, cardiac output (Qc), weight, and ambulatory blood pressures were measured. One week after starting, therapy patients were called for evaluation of blood pressure (BP) and serum chemistries. The study

was approved by the Institutional Review Board, and all patients gave written informed consent. Measurements Ambulatory blood pressure monitoring. Ambulatory blood pressures (ABPs) were recorded every 20 minutes during the day (6 a.m. to 10 p.m.) and every 30 minutes during the night (10 p.m. to 6 a.m.) using a Spacelab 90207 ABP monitor (SpaceLabs Medical Inc., Redmond, WA, USA). The accuracy of ABP was determined by an auscultatory method using a T piece connected to a mercury sphygmomanometer. Data were analyzed using ABP Report Management System software, version 1.03.05 (SpaceLabs Medical Inc.). ABP and heart rates were averaged over the entire course of recording. Glomerular filtration rate. Glomerular filtration rates were measured by iothalamate clearance. A continuous subcutaneous infusion at a rate of 125 ␮L/hour was started after a bolus intravenous injection 24 hours prior to the actual measurements. The following day, six samples of plasma were collected at times 0.0, 1.0, 1.5, 2.0, 2.5, and 3.0 hours while the subjects were water loaded. Plasma iothalamate concentrations were analyzed using a previously reported high-performance liquid chromatography technique [12]. The ratio of infusion rate to steady-state plasma concentration yielded the iothalamate clearance. The average of these six collections was expressed as the GFR. Plasma renin activity and plasma aldosterone. Plasma renin activity was measured with a Clinical Assays GammaCoat radioimmunoassay kit (Baxter Healthcare, McGaw Park, IL, USA). The PA concentration was measured by radioimmunoassay with antiserum from Diagnostic Products Corp. (Los Angeles, CA, USA). Cardiac output The cardiac output (Qc) was measured by the solublegas (acetylene) rebreathing technique, in triplicate at rest

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Agarwal: Add-on Ang I receptor blockade with maximized ACE inhibition

in a sitting position [13]. This method for measurement of Qc estimates pulmonary blood flow and pulmonary tissue volume by the Fick principle. The basis for these methods is that the soluble gas is taken up by lung tissue and by blood flowing through the lungs. Because the blood entering the lungs is assumed to contain no foreign gas and the blood leaving the lungs is assumed to contain the gas in direct proportion to its solubility and the measured partial pressure, it is possible to calculate the arterial-venous difference. In combination with the measurement of the rate of disappearance of the gas from the lung-rebreathing bag system, the blood flow can be calculated. Thus, two distinct steps in analysis are required: determination of the total lung-bag system volume and the calculation of the rate of uptake of acetylene. A known volume (1500 mL) of gas mixture containing 30% oxygen, 9% helium, 0.5% acetylene, and balance nitrogen is drawn into a calibrated volume syringe, and a bag is filled with this gas. The subjects rebreathe this mixture for 20 to 25 seconds till helium concentration reaches a plateau. The gas concentrations of helium and acetylene are measured in real time using a gas massspectrophotometer (Marquette Electronics, Inc., Milwaukee, WI, USA) connected to a computer with an analog to digital conversion board. Data are sampled at 20 Hz and stored to a memory file. Using computing software (First Breath Software, version 2; First Breath Inc.), the data are analyzed to calculate the Qc. Laboratory analysis. Serum chemistries, complete blood counts, urine protein, electrolytes, urea, and creatinine were measured by our hospital laboratory using routine methods. Data for proteinuria and other electrolyte excretions were normalized to grams of creatinine in urine to account for the variability in urine collections. Statistical analysis Analysis of variance model was used to test the significance of changes with losartan therapy. Carryover effects were tested and found to be nonsignificant. The normality and homogeneity of variance assumptions of the analysis of variance models were tested by the Shapiro-Wilk statistic and the Levene test, respectively. All tests were two sided at an ␣ level of 0.05. Data on proteinuria, GFR, PRA, and PA were log transformed prior to analysis to satisfy the assumption of normality. All analyses were adjusted for the placebo control, and 95% confidence intervals were constructed [14]. All statistical analysis were carried out using standard procedures on Statistica for Windows, release 4.5 (StatSoft, Inc., Tulsa, OK, USA) [15]. A paradigm of titration of ACE inhibitors to antiproteinuric rather than antihypertensive effect is emerging [16], and studies in patients with proteinuria show a 54% fall in proteinuria within one month of starting enalapril [17]. Therefore, the primary hypothesis of this study was

Table 1. Baseline Characteristics Parameter Age years Males/females Ethnicity BMI kg/m2 Etiology of CRF Antihypertensive medications all on Lisinopril 40 mg/day Number of antihypertensives Seated BP mm Hg Seated pulse rate beats/min Standing BP mm Hg Standing pulse rate beats/min Baseline serum creatinine mg/dL Resting cardiac output L/min Resting cardiac index L/min/m2

Mean ⫾ SD or (N) 53 ⫾ 9 14/16 6 white, 10 black 38 ⫾ 5.7 Diabetes (12), glomerulonephritides (4) Calcium channel blockers (12), ␤ blockers (6), ␣ blockers (5), loop diuretics (10), thiazide diuretics (3) 3.13 ⫾ 1.2 156 ⫾ 18/88 ⫾ 12 77 ⫾ 11 153 ⫾ 22/90 ⫾ 15 83 ⫾ 13 2.0 ⫾ 0.8 6.6 ⫾ 1.6 2.9 ⫾ 0.5

Abbreviations are: BMI, body mass index; CRF, chronic renal failure; BP, blood pressure.

that losartan will decrease proteinuria by at least 25% compared with placebo treatment. Our study had 87% power to detect such a change with a sample size of 16 and a 0.050 two-sided significance level [18]. Validation studies have shown coefficient of variation between days of iothalamate clearance by our method to be 7.7% (abstract; Agarwal et al, J Am Soc Nephrol 11:55A, 2000). This gave us a power of 78% to detect a 6% change in placebo-adjusted GFR using a sample size of 16 and a 0.05 two-sided significance level [18]. RESULTS Seventeen patients were enrolled, of whom 16 completed the study (Table 1). One patient could not keep scheduled appointments after the first GFR and ABP measurements and was dropped from the study. The average duration of lisinopril exposure prior to enrollment into the study was 18 ⫾ 6 months (range 3.5 to 26.6 months). Effects on laboratory and 24-hour urine parameters Body weight, hemoglobin, or serum chemistries did not change with add-on losartan therapy (Table 2). Of note, potassium levels did not increase with losartan. Baseline Na excretion was high, reflecting the usual diet of these patients. Urine urea nitrogen excretion rates also reflected the high protein intake in these patients. Urine protein excretion rate did not change over one month of losartan therapy (Fig. 2). Effects on systemic and renal hemodynamics There was no overall improvement in systolic or diastolic ABP compared with placebo. Resting seated cardiac output remained unchanged (Table 3). Average

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Agarwal: Add-on Ang I receptor blockade with maximized ACE inhibition Table 2. Changes in laboratory parameters and weight Placebo

Body weight kg Blood parameters Na mEq/L K mEq/L HCO3 mEq/L Creatinine mg/dL Glucose mg/dL Uric acid mg/dL Hb g/dL Urinary parameters (expressed as /g creatinine) Na mEq/24 h K mEq/24 h Urea g/24 h Protein g/24 h

Losartan Baseline

Postlosartan

Placebo corrected change

119 ⫾ 6.2

118 ⫾ 6.1

118 ⫾ 6.2

⫹0.1

141 ⫾ 0.6 4.1 ⫾ 0.13 24.3 ⫾ 0.72 2.0 ⫾ 0.2 173 ⫾ 21 7.7 ⫾ 0.48 12.6 ⫾ 0.49

141 ⫾ 0.6 4.1 ⫾ 0.10 25.4 ⫾ 0.94 2.1 ⫾ 0.21 132 ⫾ 15 7.8 ⫾ 0.57 12.6 ⫾ 0.54

140 ⫾ 0.7 4.3 ⫾ 0.10 25.1 ⫾ 1 2.1 ⫾ 0.22 159 ⫾ 17 8.1 ⫾ 0.46 12.9 ⫾ 0.52

141 ⫾ 0.7 4.3 ⫾ 0.15 24.6 ⫾ 0.87 2.1 ⫾ 0.23 161 ⫾ 26 8.7 ⫾ 0.99 12.6 ⫾ 0.53

⫹0.29 ⫹.06 ⫺1.6 ⫺0.11 ⫹42 ⫹0.37 ⫺0.36

⫺1.6, ⫺0.34, ⫺3.8, ⫺.31, ⫺26, ⫺1.05, ⫺1.15,

2.2 0.46 0.72 ⫹0.10 ⫹109 ⫹1.80 ⫹0.43

0.76 0.75 0.18 0.30 0.22 0.59 0.36

224 ⫾ 29 66 ⫾ 8 11.2 ⫾ 1.7 3.6 ⫾ 0.71

201 ⫾ 24 63 ⫾ 6 10.4 ⫾ 1.2 3.08 ⫾ 0.55

187 ⫾ 17 55 ⫾ 7 9.4 ⫾ 1.0 3.56 ⫾ 0.75

213 ⫾ 22 61 ⫾ 6 12.0 ⫾ 1.3 3.42 ⫾ 0.87

⫹10 0.74 ⫹0.74 ⫹1%

⫺20, ⫺5.5, ⫺0.91, ⫺20%,

⫹40 7.0 2.4 ⫹28%

0.485 0.803 0.353 0.89

Baseline

Postplacebo

119 ⫾ 6.1

95% CI

P

⫺2.4, 2.6

0.92

Data are mean ⫾ SEM.

Fig. 2. Twenty-four-hour urine protein excretion rate normalized before and after placebo, and before and after losartan administration. No overall drug effect was seen (P ⫽ 0.89).

Table 3. Systemic and renal hemodynamic parameters Placebo

Systolic ABP mm Hg Diastolic ABP mm Hg GFR lothalamate clearance mL/min Resting seated cardiac output L/min Data are mean ⫾ SEM.

Losartan

Baseline

Postplacebo

151 ⫾ 5 83 ⫾ 2 69 ⫾ 10 6.9 ⫾ 0.39

149 ⫾ 3 82 ⫾ 2 64 ⫾ 9 6.7 ⫾ 0.29

Baseline

Postlosartan

Placebo corrected change

148 ⫾ 4.25 82 ⫾ 3 63 ⫾ 9 6.8 ⫾ 0.42

151 ⫾ 6 83 ⫾ 3 68 ⫾ 11 6.6 ⫾ 0.38

⫹4.6 ⫹1.5 ⫹14% ⫹0

95% CI ⫺5.7, ⫺4.5, 3%, ⫺0.9,

14.9 7.6 26% ⫹0.9

P 0.95 0.59 0.017 0.99

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Agarwal: Add-on Ang I receptor blockade with maximized ACE inhibition

Fig. 3. Systolic 24-hour ambulatory blood pressures before (䊉) or after the one month (䊊) placebo (A) or losartan therapy (B) period. No change can be seen.

Fig. 4. Diastolic 24-hour ambulatory blood pressures before (䊉) or after the one month (䊊) placebo (A) or losartan therapy (B) period. No change can be seen.

Table 4. Supine plasma renin activity and plasma aldosterone Placebo

Plasma renin activity ng/mL/h Plasma aldosterone ng/mL PA/PRA ratio

Losartan

Baseline

Postplacebo

0.75 ⫾ 1.51 5.70 ⫾ 1.22 7.82 ⫾ 1.64

1.14 ⫾ 1.63 6.15 ⫾ 1.22 5.42 ⫾ 1.68

Baseline

Postlosartan

Placebo corrected change

95% CI

P

1.53 ⫾ 1.61 5.02 ⫾ 1.30 3.29 ⫾ 1.69

0.94 ⫾ 1.79 5.65 ⫾ 1.22 5.98 ⫾ 1.92

⫺58.8% ⫹7.6% ⫹175%

⫺31.5%, ⫺75.3% ⫺10.5%, 29.2% ⫹56%, ⫹386%

0.003 0.423 0.003

Data are geometric mean ⫾ SEM. PRA denotes plasma renin activity and PA denotes plasma aldosterone.

ABPs for the 16 patients are shown in Figures 3 and 4, demonstrating little change in blood pressure trends. In contrast, the placebo-corrected GFR improved by 14%. GFR tended to fall during placebo and rise with add-on losartan therapy. Effects on the renin-aldosterone system The renin-aldosterone system had remarkable effects (Table 4). Renin fell by 32%, despite that there was no

change in aldosterone. However, because of a fall in renin, the PA/PRA ratio increased by 175%. DISCUSSION There is uncertainty regarding the usefulness of combination ACE inhibition and ARB therapy in patients with chronic renal failure [19]. Therefore, we designed the study to examine the benefit of add-on therapy in

Agarwal: Add-on Ang I receptor blockade with maximized ACE inhibition

those patients who had persistent proteinuria despite maximal ACE inhibition. Because proteinuria by itself is damaging to the kidney [20] and is also a marker of progressive renal disease [2], it was reasonable to assume that add-on losartan therapy is likely to benefit this subgroup of patients particularly. Because this was an experimental study and not an outcomes study, these patients were studied intensively with measurements of GFR and the renin-angiotensin-aldosterone system (RAAS) and systemic hemodynamic monitoring. We reasoned that if losartan would have an effect, it would perturb the RAAS first and then the renal circulation; systemic hemodynamics and proteinuria would be less sensitive measures of RAAS perturbations because of the relatively low dose of losartan used. However, the primary objective of the study was to detect a change in proteinuria with add-on losartan therapy. The most important finding of our study was a lack of response to the add-on losartan therapy on 24-hour protein excretion over the short term. Unlike several other studies reported in the literature, only those patients who were taking the maximal dose of the ACE inhibitor lisinopril were studied. For example, combination therapy in normotensive volunteers demonstrates an additional increase in PRA when losartan was added to submaximal captopril therapy [21]. Also, normotensive volunteers do not have sympathetic activation, inflamed kidneys, or endothelial dysfunction, unlike what may be present in hypertensive, obese, chronic renal failure patients, which likely accounts for the differences. This current study is also at variance with what is seen in patients with IgA nephropathy with proteinuria [22]. In the latter study, eight patients were treated with small doses of four different ACE inhibitors and had an additional antiproteinuric effect when losartan was added. In both of these studies, a combination therapy of ACE inhibitor and ARB was more effective that either alone in reducing proteinuria. However, neither study maximized the dose of ACE inhibitor prior to adding losartan. Thus, two drugs working on the same (RAAS) hormonal system can only be called additive when one of them is at the top of the dose response. On the other hand, other studies that have compared ACE inhibitors with losartan in patients with type II diabetes mellitus, hypertension, and early nephropathy have shown similar magnitude of blood pressure reduction and urine albumin excretion, but less cough and hyperuricemia in patients randomized to losartan [23]. The current study had adequate power to detect a 25% fall in proteinuria, and it is unlikely that this effect was missed. Nevertheless, in these patients with severe proteinuria, it is possible that the duration of exposure to losartan over the course of the study was too short to show substantial changes in proteinuria. Indeed, over the longer term, proteinuria appeared to fall in those

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patients who were followed in the clinic for a longer duration. Data were obtained on 13 patients who had a follow-up from 4 to 12 months. Of the eight patients who continued on losartan, proteinuria declined to less than 50% of baseline in four patients, declined ⬍50% in two, and increased in the other two. None of these patients progressed to end-stage renal disease or doubled their creatinine. Of the five patients who discontinued losartan, one reached end-stage renal disease, one doubled his creatinine, one had an increase in proteinuria, and two had ⬍50% reduction in proteinuria. Obviously, these observational data need to be interpreted with caution; nevertheless, there appears to be a trend towards improvement in proteinuria over the longer term. Blood pressure was poorly controlled at baseline despite an average of 3.1 medications and did not improve with the addition of losartan. This is not surprising given that these patients had severe hypertension and were administered a relatively low dose of ARB. Our study was not designed to address the question of lowering blood pressure to improve proteinuria, rather than to assess the effect of additional Ang II antagonism in patients with persistent proteinuria despite a maximum dose ACE inhibition. Most important, our patients had substantially more severe disease, worse hypertension, and lower GFRs than the previously mentioned studies and that likely accounts for the different response to proteinuria. Furthermore, our study included only those patients in whom the dose of lisinopril was maximized for at least three months. An interesting finding of the study was a fall in PRA and a concomitant rise in GFR, although this was not the prime target question. These results were unexpected but may be explained by at least three factors. First, this combination of a fall in PRA and improvement in GFR may occur due to reduction in the renal sympathetic nerve activity in these patients [5], that is, elevated in patients with chronic renal failure [24] and reduced by the use of ACE inhibitors [5]. Furthermore, obesity itself can increase sympathetic nerve activity in the human kidneys [25]. Mechanisms of improvement in sympathetic activation may be due to either improved renal perfusion, reduced ischemia, and reduced adenosine generation [26] that may be mediated by stimulation of the AT2 receptors [27]. Alternatively, this reduction may be due to reduced AT1 receptor activation in the brain directly either by Ang II or through Ang III [28]. Because amlodipine, which also improves renal perfusion, does not reduce sympathetic nerve activity, it is thought that the central effects of ARBs are more important [26]. Furthermore, losartan can block peripheral neuroadrenergic transmission [29]. Lisinopril, which is water soluble and predominantly renally excreted [30], may not cross the blood–brain barrier, unlike losartan, which is more

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Agarwal: Add-on Ang I receptor blockade with maximized ACE inhibition

lipophilic and may penetrate the locus ceruleus and paraventricular nuclei more completely to cause a fall in sympathetic nerve activity [31]. Second, it is recognized that Ang II promotes inflammatory activity, including the expression of vascular adhesion molecules, chemokine generation, and provoking pro-oxidant activity [32, 33]. It follows that blockade of these effects via the AT1 receptor reduces inflammation, ischemia, GFR, and PRA. Third, AT1 receptor stimulation causes endothelial dysfunction that may be corrected by blockade of the receptor [34]. This improvement in endothelial dysfunction may restore nitric oxide-mediated vasodilation, improve renal perfusion, and cause a fall in PRA and improvement in GFR. Within the construct of the experimental design, it is difficult to explore the causative mechanisms responsible for our findings. It should also be noted that there are substantial species differences in the renin-angiotensin system [35, 36], and animal data pertaining to the renin-angiotensin system may not directly apply to humans. There is always a possibility that the concomitant antihypertensive therapy or other unknown factors could explain these findings. There was no change in aldosterone despite a fall in PRA. This suggests that other factors such as potassium may have overcome the renin-mediated effects on aldosterone synthesis and release [37]. In summary, these results show no improvement in blood pressure or proteinuria in over a one-month period in patients with add-on losartan therapy. An improvement in GFR with a reduction in renin activity was seen with this therapy in patients with hypertension, obesity, proteinuria, and chronic renal failure. This improvement in GFR and fall in PRA suggests improved sympathetic nerve activity, improved endothelial function, reduced inflammation, or a combination of these factors. Whether the latter will translate into long-term renal protection requires larger randomized controlled trials. ACKNOWLEDGMENTS This work was supported by Losartan Medical School Grants Program, Merck and Co. The study was performed with the technical assistance of J.G. Sikora. The author thanks J. Howard Pratt, M.D., and Mary Ann Wagner, B.S., for renin and aldosterone analysis. Reprint requests to Rajiv Agarwal, M.D., Division of Nephrology, Department of Medicine, Indiana University and RLR VA Medical Center, 1481 West 10th Street, 111N, Indianapolis, Indiana 46202, USA. E-mail: [email protected]

APPENDIX Abbreviations used in this article are: ACE, angiotensin-converting enzyme; AMB, ambulatory blood pressure; Ang, angiotensin; ARB, angiotensin receptor blocker; AT1, angiotensin II subtype 1 (receptor); BP, blood pressure; CCr, creatinine clearance; CI, confidence interval; ESRD, end-stage renal disease; GFR, glomerular filtration rate; PA, plasma aldosterone; PRA, plasma renin activity; Qc, cardiac output; RAAS, renin-angiotensin-aldosterone system;

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