Effect of Dual Blockade of Renin-Angiotensin System on Proteinuria

Abstract Aim: Aim of the study was the evaluation of the effect of dual blockade of the renin-angiotensin system (RAS) on proteinuria. Material and Methods: Sixty patients, included in the study, were treated with angiotensinconverting enzyme inhibitor and angiotensin receptor blocker for a period of 3 months. Results: The dual blockade of RAS resulted with decrease of proteinuria, a slight increase of serum creatinine and was not associated with a lowering of blood pressure. C onclusion: Combined therapy with ACE-I and ARB results in a more complete blockade of the RAS than monotherapy. In proteinuric nephropathies it reduces significantly baseline proteinuria.


Introduction
The renin-angiotensin system plays a fundamental role in the maintenance and regulation of the extracellular fluid volume and blood pressure [1]. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) are widely used in the treatment of hypertension, chronic kidney disease, and heart failure [2,3]. Despite its potential advantages, combination therapy with an ACE inhibitor and an ARB is not without risks. Significant decline in renal function is a rare but possible adverse effect of this drug combination. A more frequent adverse effect is a slight reduction in glomerular filtration rate (GFR), also hyperkalemia. Acute compromise of renal function was observed in a child after coadministration of lisinopril and losartan [4].
Both ACE-I and ARB impede the progressive deterioration in renal function, which underscores renal injury, particularly in patients with diabetic nephropathy [5][6][7]. The renoprotective effects of these drugs, in part, relates to their ability to reduce proteinuria [8,9]. It was just a matter of time before ACE-I and ARB were given together as combination therapy, due to evidence suggesting that these agents are complementary in their actions. The studies of combination therapy in proteinuric chronic kidney disease (CKD) have proven interesting data for their antiproteinuric and renoprotective efficassity [10][11][12][13][14].
The aim of the present study was the evaluation of the effect of dual blockade of reninangiotensin system on proteinuria in non-diabetic patients.

Materials and Methods
Sixty non-diabetic patients with glomerular and intersticial disease were included in a prospective controlled study, with primary outcome the measure of proteinuria. The study had been approved by the Ethic Committee. At baseline 24 hour proteinuria was measured, as well as serum creatinine (SCr) and GFR, measured by Cockcroft-Gault formula, seric sodium, potassium and blood pressure (BP); at baseline clinic blood pressure was 168 ± 25.8 / 81 ± 1.1 mmHg, SCr was 1.39 ± 0.4 mg/dl, seric sodium 141 ± 3.5 mmol/l, seric potassium 4.2 ± 0.5 mmol/l, and urinary proteinuria was 3.1 ± 1.5 g/day. After the completion of the baseline exams, an ACE-I (enalapril 20 mg/day) or an ARB (valsartan 80 mg/day) was given for a period of 3 months; at the end of this period a repeat of all exams was done, and the combined treatment with ACE-I+ARB was started and continued for a further 3 months period, and at the end all the exams were repeated. All variables are presented as mean ± standard deviation. Differences were considered significant at the p<0.05 levels. We used paired t tests (which account for the same patients providing data for both treatment groups) to determine the effects of treatment.

Results
From 60 patients, 25 were females and 35 were males, with mean age 35.3 ± 4.7 (range: 35-70 years-old) ( Table 1). Monotherapy with ACE-I or ARB resulted in a non significant change of blood pressure, while seric level of potassium and sodium, Scr and GFR were not changed significantly. The 24 hour proteinuria decreased in both groups, but this was not significant. The combined treatment with ACE-I+ARB resulted in a significant reduction of proteinuria (2.1 ± 0.5 g/day vs. 3.1 ± 1.5 g/day at baseline, P<0.01). The renal function was not significantly altered (SCr increased not significantly to 1.5 ± 0.16 mg/dl (P=0.06), while seric level of potassium remained unchanged. The values of systolic and diastolic blood pressure were reduced but not significantly ( Table 2).

Discussion
This study shows that ACE-I and ARB are effective and well-tolerated antihypertensive agents. Although not all patients who are treated with ACEI or ARB show a clear antiproteinuric response [15], our data show efficacy of enalapril and valsartan as regard the decrease of proteinuria from the baseline values. The results of a limited number of studies support the notion that additive antihypertensive, cardioprotective, and antiproteinuric effects may be obtained when ACE-I and ARB are combined [16]. In chronic proteinuric non-diabetic nephropathies, most studies have shown a superior effect of the combination of ACE-I and ARB on proteinuria reduction in comparison with single therapy with ACE-I or ARB [8]. In our study, the dual blockade of renin-angiotensin system resulted in a decrease of proteinuria, although with a slight increase of serum creatinine due to hemodynamic effects of both these drugs, but without hyperkalemia. In our study the values of systolic and diastolic blood pressure were reduced but not significantly, this probably for the reason of a regular sodium diet. Recently, Slagman et al. reported that dietary sodium restriction to a level recommended in guidelines was more effective than dual blockade for reduction of proteinuria and blood pressure in non-diabetic nephropathy [17]. However, the results of recently published ONTARGET study has shown that combination of the two drugs (ACE-I and ARB) has not shown benefits in renal outcomes. The decision whether to initiate dual RAS blockade for an individual patient, therefore requires careful assessment of their risk of renal progression [18].
Our findings support the effects on protenuria of combined therapy with ACE-I and ARB. Further works would need to determine more accurate information of the changes in the GFR, BP under the influence of this applied therapy.
Conclusion: Combined therapy with ACE-I and ARB results in a more complete blockade of the RAS than monotherapy. In proteinuric nephropathies it reduces significantly baseline proteinuria.