Kidney International, Vol. 62, Supplement 82 (2002), pp.

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Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies

NGELES GOICOECHEA, CESAR GONZA LEZ, LUN O, VICENTE BARRIO, MARIA A JOSE MEZ, CARMEN BERNIS, MARIO ESPINOSA, A DE VINUESA, FRANCISCO GO SOLEDAD GARCI MEZ, and PEDRO ESCALADA GO FRANCISCO AHIJADO, JOSE
n, and Unit of Nephrology, Fundacio n Hospital de Department of Nephrology, Hospital General Universitario Gregorio Maran o n, Madrid; Service of Nephrology, Hospital General de Elche, Alicante; Department of Nephrology, Hospital de La Alcorco rdoba, Co rdoba; Service of Nephrology, Princesa, Madrid; Department of Nephrology, Hospital Reina Soa de Co Hospital Virgen de la Salud, Toledo; and Hospital Narcea Carmen y Severo Ochoa, Asturias, Spain

Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies. Background. Blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or with angiotensin II type 1 (AT1) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies. Additionally, this benecial effect is not dependent on blood pressure control. Methods. To assess and compare the effects of lisinopril (up to 40 mg/day), candesartan (up to 32 mg/day) and combination therapy (lisinopril up to 20 mg/day plus candesartan up to 16 mg/day) on urinary protein excretion, 45 patients with primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8 2.4 g/g) and normal or slightly reduced renal function (CCr 95 33 mL/min) were enrolled in a six month multicenter, prospective, open, randomized, active-controlled and parallelgroup trial with 1:1:1 allocation. Blood pressure goal was set at or below 125/75 mm Hg for all patients, with additional antihypertensive medication prescribed if required. Results. Renal function, estimated by creatinine clearance, remained stable throughout the study. Hyperkalemia (K 5.5 mmol/L) was detected in 3.1% of all measurements in followup, and was more frequent in patients treated with lisinopril alone or lisinopril plus candesartan (P 0.001) than in those on candesartan alone. No other relevant adverse event was recorded. The blood pressure goal (125/75 mm Hg) was achieved by week 4 in all treatment groups (P 0.005 when compared to baseline), and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically signicant differences between groups. Urinary protein/creatinine ratio (percentage reduction 95% condence intervals CI) decreased in patients treated with lisinopril alone to 33% (CI 1256) to 31% (CI 068) and to 50% (CI 990), in patients treated with candesartan to 28% (CI 1245), to 41% (CI 3052) and to 48% (CI 3263), in patients treated with the combination of both to 60% (CI 4477) to 54% (CI 3869) and to

70% (CI 5783) at two, three, and six months, respectively. All comparisons with baseline achieved statistical signicance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with candesartan alone at two and six months (P 0.004 and P 0.023, respectively) and than treatment with lisinopril only at two months (P 0.03). Conclusion. Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a benecial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated.

Key words: ACE inhibitors, angiotensin receptor blockers, proteinuria, non-diabetic nephropathies, progressive renal disease.

2002 by the International Society of Nephrology

There is clear evidence that pharmacological blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors slows the progression of renal disease in diabetic [14] and non-diabetic nephropathies [5, 6], a benecial effect not only related to blood pressure control [7]. More recently, three studies have shown the nephroprotective properties of angiotensin II type 1 (AT1) receptor blockers (ARB) in patients with type 2 diabetic nephropathies [810]. Both classes of drugs have demonstrated a relevant antiproteinuric effect and the reduction of proteinuria appears to be a surrogate marker of the nephroprotective effect obtained with RAS inhibition [11, 12]. However, not all patients respond similarly to these treatments. Some patients exhibit a signicant benecial response with reduction of proteinuria and preservation of renal function while others do not. An insufcient response to ACE inhibition might be explained by the incomplete blockade of the RAS obtained with ACE inhibitors, which are unable to block completely the formation of angiotensin II (Ang II), because some generation of Ang II is produced via other non-ACE pathways [13]. Furthermore, Ang II levels return to normal values

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after chronic therapy with ACE inhibition, the so-called ACE escape phenomenon [14]. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, we believe that the association of ACE inhibitors and ARB might prove useful. ARB produces a complete blockade of the RAS and stimulates the vasodilating and non-proliferative actions of Ang II via the AT2 receptor [15]. Furthermore, ACE inhibitors, but not ARB, inhibit the metabolism of kinins, which increases the levels of bradykinin, also a potent vasodilator [16]. Recently, some authors have reported a superior effect of the combination of ACE inhibition and ARB on microalbuminuria and on clinical proteinuria in patients with primary nephropathies [1719], and in type 1 and type 2 diabetic patients [20, 21]. In order to evaluate the effects of dual blockade of the RAS system in primary proteinuric nephropathies, we designed a multicenter, prospective, open, randomized, active controlled and parallel group trial to compare the effects of three different drug regimenswith the ACE inhibitor lisinopril, combined with an ARB, candesartan, versus lisinopril or candesartan alone at equivalent dosesin a setting of strict blood pressure control. METHODS Eligibility criteria Male and female outpatients between 18 and 80 years old with primary proteinuric nephropathies for more than six months (renal biopsy was recommended although not required) were eligible for inclusion into the trial. Patients were included irrespective of their blood pressure if proteinuria measured by the sulfosalicylic acid method was greater than 2 g in a least two 24hour urine collections, and the glomerular ltration rate (GFR), estimated by creatinine clearance was greater than 50 mL/min/1.73 m2. Exclusion criteria Nephrotic patients with serum albumin 3.0 g/dL as well as those with hypertension stage 3 (SBP 180 mm Hg and/or DBP 110 mm Hg), hyperkalemia (5.0 mmol/L), secondary glomerular diseases, systemic diseases [diabetes mellitus, amyloidosis, systemic lupus erythematosus (SLE)], or those with any severe cardiovascular event in the last three months before randomization were excluded from the study. Patients with severe cardiac, pulmonary or hepatic disease, HIV infection, and neoplasia also were excluded from the trial, as were those who received corticosteroids and/or immunosuppressive therapy in the last six months before entry into the study. Women of childbearing age were included only after a negative gestation test and if they were using an effective method of birth control.

Study design This multicenter, prospective, open, randomized, active controlled and parallel group trial was conducted in seven centers in Spain. The study was approved by the appropriate institutional review boards and was conducted according to good clinical practice. All patients provided informed written consent before entry into the study. After a 14-day washout period with metoprolol up to 200 mg/day and/or hydrochlorothiazide up to 50 mg/day as antihypertensive drugs if needed for patients receiving ACE inhibitors or AT1 antagonists prior to inclusion, patients were randomly allocated to one of the three treatment groups in a 1:1:1 ratio. Treatment lasted 24 weeks for all groups. Randomization was centralized with blocks of six and codes were kept in sealed envelopes in each center. Primary objective The primary objective was a reduction in proteinuria excretion with lisinopril, candesartan or a combination of both therapies in primary proteinuric nephropathies. Interventions After a two-week wash-out period, patients were randomized to three treatment groups and received once daily either lisinopril 10 mg, candesartan 8 mg, or lisinopril 5 mg plus candesartan 4 mg for two weeks. Dosage of medication was doubled every two weeks up to lisinopril 40 mg, candesartan 32 mg, or lisinopril 20 mg plus candesartan 16 mg once daily, if either systolic blood pressure was higher than 125 mm Hg or diastolic greater than 75 mm Hg. Additional antihypertensive medication, such as beta-blockers, calcium channel blockers and/or thiazide diuretics alone or in combination were subsequently introduced from weeks 6 to 12 in order to achieve blood pressure goal, that is, BP 125/75 mm Hg in all groups. All concomitant therapy was recorded, specially those drugs known to inuence glomerular ltration rate (GFR) and proteinuria such as non-steroidal antiinammatory drugs (NSAIDs). Adverse events were recorded at each visit in response to open questions or as observed by investigators. Drop-outs Patients discontinued the trial in case of withdrawal of consent, hyperkalemia (6.5 mmol/L) despite treatment with cation exchange resins, worsening of renal function dened by an increase from baseline serum creatinine greater than 50% and conrmed in two occasions ten days apart, any severe adverse event or intercurrent medical problem requiring hospitalization, and cough in patients on ACE inhibitor therapy. Outcomes Follow-up was performed at the out-patient clinic for a total of eight study visits, two weeks before randomiza-

Lun o et al: Dual blockade of RAS in proteinuria Table 1. Summary of baseline characteristics of patients with proteinuric nephropathies Candesartan (N 15) Men/women N Age years BMI kg/m2 Blood pressure mm Hg Systolic Diastolic Serum/plasma SCr mg/dL K mmol/L Albumin g/dL Urine CCr mL/min Protein/creatinine 10/5 45 18 26.7 2.6 133 14 80 11 1.08 0.5 4.3 0.3 3.6 0.4 104 36 4.0 2.5 Lisinopril (N 14) 12/2 50 16 26.4 3.9 135 20 80 14 1.26 0.5 4.3 0.3 3.6 0.5 84 26 3.6 2.9 Candesartan lisinopril (N 16) 9/7 42 13 27.1 5.6 135 20 84 10 1.15 0.3 4.5 0.3 3.5 0.5 96 34 3.8 2.1

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Fig. 1. Percentage of patients who achieved the maximum, medium and minimum dose of medication in each study group. Symbols are: () maximum; ( ) medium; () minimum.

Data are means SD. P 0.05 for all comparisons by chi-square, ANOVA or Kruskal-Wallis tests, as appropriate.

tion (visit 2), at inclusion and beginning of treatment (visit 0), and at 2, 4, 6, 8, 12 and 24 weeks after randomization for blood pressure measurements and titration of medication if needed, as stated above. At each visit, the sitting blood pressure was measured thrice in the morning after ve minutes of rest, with an interval of two minutes, about 24 hours after the previous drug administration with an automatic device (Omron-705, CP), and the mean of the last two measurements was recorded. Complete blood cell count, blood biochemistry (Na, K, Cl, HCO3, glucose, urea, creatinine, uric acid, Ca, P, albumin, protein, ASAT, ALAT, alkaline phosphatase, lipid prole) and 24-hour urine collection (for protein, creatinine, Na and K excretion) were performed at baseline and at weeks 6, 12 and 24 by standard methods. Statistical methods Values are expressed as mean SD unless stated otherwise. The values of urinary protein/creatinine are expressed as mean SE with 95% condence intervals. Differences between means were assessed by repeated measures analysis of variance (ANOVA) for continuous variables if appropriate or by non-parametric analysis for variables that did not adjust to normal distribution. Comparison of changes in proteinuria corrected by urinary creatinine excretion from baseline over time was performed with non-parametric analysis (Wilcoxon, KruskalWallis and Mann-Whitney) since the variable did not follow a normal distribution even after logarithmic transformation. All analyses were based on intention to treat, dened by inclusion into the trial and least one efcacy data available after randomization, with the last value carried forward for missing values. All statistical analyses were performed with the SPSS 9.0 (SPSS Inc., Chicago, IL, USA) statistical software package.

RESULTS Between October 2000 and June 2001, 46 patients with primary proteinuric nephropathies were included into the trial, although one patient never took the study medication and was excluded from the study. There were 14 women and 31 men evenly distributed among groups with a mean age of 45 16 years, a mean systolic blood pressure of 134 18 mm Hg, diastolic blood pressure of 81 12 mm Hg, normal or slightly reduced renal function (CCr 95 33 mL/min) and urinary protein/creatinine ratio of 3.8 2.4 g/g of creatininte. There were no statistically signicant differences in the baseline characteristics of patients by treatment group (Table 1). The maximum dose of candesartan (that is, 32 mg/day) was tolerated by 56% of patients, whereas only 31% of patients achieved the maximum dose for lisinopril (40 mg/day), and 35% of patients achieved maximum dose in the combination therapy group (lisinopril 20 mg/day plus candesartan 16 mg/day). Medium doses (that is, lisinopril 20 mg/day, candesartan 16 mg/day, and lisinopril 10 mg/ day plus candesartan 8 mg/day) were achieved in 35%, 23% and 39%, respectively (Fig. 1). Renal function, estimated by creatinine clearance, remained stable throughout the study period, (Fig. 2) and there were no other changes in blood chemistries from baseline and between treatment groups at any point in the study (data not shown except for potassium). No patient discontinued the study because of hyperkalemia, however, serum potassium was greater than 5.5 mmol/L in eight instances (3.1% of all measurements) during the study period, but greater than 6.0 mmol/L in only two cases (Fig. 3). Patients treated with lisinopril alone or lisinopril plus candesartan had hyperkalemia greater than 5.5 mmol/L (P 0.001) more frequently than those on candesartan alone and mean potassium levels were also signicantly higher at three months in comparison with baseline in those patients treated with lisinopril or lisinopril plus candesartan (Fig. 3). No other relevant adverse event was observed.

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Fig. 2. Changes in creatinine clearance (CCr) by treatment groups throughout the study period. Symbols are: (solid line) candesartan; (dashed line) lisinopril; (dotted line) combination of candesartan and lisinopril therapy. There were not signicant changes between groups at any time.

Fig. 4. Blood pressure changes (mm Hg) by treatment groups throughout the study period. P 0.005 from rst month until end of follow-up for both systolic and diastolic compared to baseline, P was non-signicant between groups at any time point. Symbols are: (solid line) candesartan; (dashed line) lisinopril; (dotted line) combination of candesartan and lisinopril therapy.

Fig. 3. Mean SD serum potassium (mmol/L) by treatment groups during the study period. *P 0.036 comparing mean serum potassium in the lisinopril group at 3 months with baseline data. **P 0.042 comparing mean serum potassium in the combination therapy group at 3 months with baseline data. Symbols are: () baseline data; ( ) two months; ( ) 3 months; () 6 months.

Although baseline systolic blood pressure was higher in the groups of patients on ACE inhibitors and combination therapy, and diastolic blood pressure in the group on combined therapy (Table 1), the differences did not reach statistical signicance. The blood pressure goal, that is, 125/75 mm Hg, was achieved by week 4 in all treatment groups (P 0.005 when compared to baseline), and afterwards the mean systolic and diastolic blood pressure remained below that value until the end of the trial, with no statistical signicant differences between groups (Fig. 4). The urinary protein/creatinine ratio (mean SE) (percentage reduction 95% condence intervals CI) decreased in patients treated with lisinopril alone from 3.6 0.77 at baseline to 2.44 0.97 at two months (33%, CI 1256, P 0.008) to 2.54 0.70 at three months (31%, CI 068, P 0.019) and to 1.83 0.68 at six months (50%, CI 990, P 0.013), in patients treated with candesartan alone from 3.99 0.63 at baseline to 3.14 0.67 at two months (28%, CI 1245, P 0.019) to 2.34 0.42 (41%, CI 3052, P 0.001) at three months and to 2.18 0.49 at six months (48%,

Fig. 5. Mean SE of urinary protein/creatinine ratio (g/g) by treament groups during study period two, three and six months comparing with baseline. Symbols are: () baseline data; ( ) two months; ( ) three months; () six months.

CI 3263, P 0.001), and in patients treated with combination therapy (that is, lisinopril plus candesartan) from 3.8 0.53 at baseline to 1.55 0.41 at two months (60%, CI 4477, P 0.004) to 1.89 0.51 (54%, CI 3869, P 0.001) at three months and to 1.00 0.25 at six months (70%, CI 5783, P 0.001). Treatment with combination therapy was statistically more effective in proteinuria reduction than candesartan alone at two and six months (P 0.004 and P 0.023, respectively) and than lisinopril alone only at two months (P 0.03). The reduction in proteinuria was not signicantly different between groups at three months (Fig. 5). DISCUSSION The results of this clinical trial show a clear tendency toward a more marked antiproteineuric effect of the combination of ACE inhibitors and ARB than either drug alone in non-diabetic renal patients with proteinuria.

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Treatment with combined therapy reduces proteinuria by 70% at 6 months, which is 30% superior to proteinuria reduction obtained with either candesartan or lisinopril alone. Although this reduction was not signicantly different comparing lisinopril with the combination at the end of the study. It is important to note that this antiproteinuric effect is obtained in situation of strict blood pressure control (BP 125/75 mm of Hg) in all groups, which is the target BP goal recommended by the Modication of Diet in Renal Disease (MDRD) Study [2224] in renal patients with proteinuria greater than 1 g/day to slow the progressive decline in glomerular ltration rate observed in these patients. This BP goal was achieved by week 4 in all treatment groups, and then remained controlled until the end of the trial with no statistically signicant differences between groups. This nding discounts that the differences observed upon the reduction in proteinuria were explained only by the systemic BP effect. The antiproteinuric effect achieved in this study was evident with all three therapeutic regimens, but it appears to be more pronounced with the combination of both drugs despite that the maximal dose assigned in each group was equivalent, and it was in the combined therapy for each drug, half of the maximal dose achieved with either drug alone. These data indicate that blocking the RAS with either ACE inhibitors or ARB produces a signicant antiproteinuric effect; however, the combined therapy of both offers an additional renal protection. The rationale for combined therapy with ACE inhibitors and ARB is based on the different mechanism of these two drugs in the RAS blockade. Both drugs inhibit the action of Ang II. It is known that Ang II plays a pivotal role in the pathophysiological course of renal disease progression. Ang II has a direct effect on vascular tone and increases blood pressure, which plays a major role in sustaining renal disease progression [25], but also has a signicant effect on intrarenal hemodynamics [26] since it increases the ltration of protein across the glomerular capillary bed [27] and stimulates cell growth [28]. Ang II increases proteinuria throughout all these mechanisms. However, ACE inhibition could not completely inhibit the generation of Ang II, which may be produced via other non-ACE pathways [13]. In contrast, ARB completely abolishes the action of Ang II through blockading the AT1 receptor, producing an accumulation of Ang II that stimulates the vasodilatory and antiproliferative actions of Ang II mediated through the AT2 receptor [15]. On the other hand, ACE inhibitors but not ARB, decreases degradation of bradykinin, which is a potent vasodilator [16]. The additive antiproteinuric effects of the combination of ACE inhibitors and ARB have been previously observed in diabetic and non-diabetic kidney diseases, although in some of these observations the more marked antiproteinuric effect was associated with a greater de-

crease in blood pressure [20, 21]. Our data clearly show that this reduction in proteinuria induced by the combined therapy is not only related to BP changes. No change was observed in the creatinine clearance in any of the three groups during the entire study period, indicating that this more marked antiproteinuric effect during the combined therapy also was not related to changes in renal function. The reduction on proteinuria achieved by pharmacological blockade of the RAS with either ACE inhibition [1, 7, 11] or ARB [810] did not parallel the blood pressure response. Some authors have found an additional antiproteinuric effect when patients were given greater doses of ACE inhibitors or ARB [29, 30] and because urinary protein excretion provides a very strong clue in relation to renal disease progression [12], it has been suggested that the dosage of ACE inhibition or ARB selected for treatment in those patients with severe proteinuria should be titrated up to the higher tolerated dose to obtain a maximal antiproteinuric effect [31]. The key question is whether the observed additive benecial effect of combined therapy could be achieved with a further increase in ACE inhibition or ARB dosage. Trying to obviate this question, in our study the dosages of lisinopril and candesartan that were given to our patients, most of whom were normotensive, were in the high range and double of the dosage recommended in studies that achieved clear antiproteinuric and nephroprotective effects with both drugs. The dosage of medication was doubled every two weeks up to lisinopril 40 mg, candesartan 32 mg or lisinopril 20 mg plus candesartan 16 mg once daily. The dose of each drug was unchanged, unless intolerance appeared. To maintain the equivalence, the dosage used in patients on the combined therapy was half of the dose received by patients on each drug alone. The percentage of patients who reached the maximal indicated dose was not different in patients treated with combination therapy, 35% compared to those on lisinopril, since 31% of them tolerated the maximal dose. Nonetheless, ARB candesartan was better tolerated because 56% of the patients tolerated the maximal dose. Both drugs alone and in combination were well tolerated. Not one patient discontinued the study because of adverse effects. Although in most other studies comparing ACE inhibitor and ARB no differences were found with regard to serum potassium [1721], in our current study, patients treated with lisinopril alone or lisinopril plus candesartan more frequently had hyperkalemia than those on candesartan alone. These results agree with the data shown in other previous reports using valsartan versus lisinopril in which valsartan induces less frequently hyperkalemia than lisinopril in patients with reduced renal function [32]. Hyperkalemia, that is, serum potassium greater than 5.5 mmol/L, was detected on

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Lun o et al: Dual blockade of RAS in proteinuria with nephropathy due to type 2 diabetes. N Engl J Med 345:851 860, 2001 Gruppo Italiano Studi Epidemiologici in Nefrologia (GISEN): Randomized placebo-controlled trial of effect of ramipril on decline in glomerular ltration rate and risk to terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349:18571863, 1997 Remuzzi A, Bertani T: Pathophysiology of progressive nephropathies. N Engl J Med 339:14481456, 1998 Hollenberg NK, Fisher NDL, Price DA: Pathways for angiotensin II generation in intact human tissue-evidence from comparative pharmacological interruption of the renin system. Hypertension 32:387392, 1998 Nussberger J, Brunner DB, Waeber B, Brunner HR: Plasma angiotensins under sustained converting enzyme inhibition with enalapril in normal humans. J Hypertens 3(Suppl 3):S269S270, 1985 Siragy HM: The role of the AT2 receptor in hypertension. Am J Hypertens 3 Suppl(5 Pt 2):62S67S, 2000 Allen TJ, Cao Z, Youssef S, et al: The role of angiotensin II and bradykinin in experimental diabetic nephropathy: Functional and structural studies. Diabetes 46:16121618, 1997 Russo D, Pisano A, Balletta MM, et al: Additive antiproteinuric effects of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 33:851856, 1999 Ruilope LM, Aldigier JC, Ponticelli C, et al: Safety of the combination of valsartan and benazepril in patients with chronic renal disease. European Group for the Investigation of Valsartan in Chronic Renal Disease. J Hypertens 18:8995, 2000 Ferrari P, Marti HP, Pster M, Frey JF: Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade. J Hypertens 20:125130, 2002 Mogensen CE, Neldam S, Tikkanen I, et al: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: The candesartan and lisinopril microalbuminuria (CALM) study. BMJ 321:14401444, 2000 Jacobsen P, Andersen S, Rossing K, et al: Dual blockade of the renin angiotensin system in type 1 patients with diabetic nephropathy. Nephrol Dial Transplant 17:10191024, 2002 Klahr S, Levey AS, Beck GJ, et al: The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 330:877884, 1994 The Sixth Report of the Joint National Committee on Prevention: Detection, evaluation, and treatment of high blood pressure. Arch Intern Med 157:24132446, 1997 Guidelines Subcommittee: World Health Organization-International Society of Hypertension. Guidelines for the management of hypertension. J Hypertens 17:151183, 1999 Mogensen CE: The reno-protective role of AT(1)-receptor blockers. J Hum Hypertens 16(Suppl 3):S52S58, 2002 Hollenberg NK: Angiotensin converting enzyme inhibition and the kidney. Curr Opin Cardiol 3(Suppl 1):S19S29, 1988 Remuzzi A, Mohamed EI: Impact of renin-angiotensin system blockade on structure and function of glomerular membrane components in animal models of kidney disease. Exp Nephrol 4(Suppl 1):2733, 1996 Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal brosis. Hypertension 38(3 Pt 2):635638, 2001 Komers R, Cooper ME: Acute renal hemodynamic effects of angiotensin converting enzyme inhibition in diabetic hyperltration: The role of kinins. Am J Physiol 268:F588F594, 1995 Maillard MP, Wurzner G, Nussberger J, et al: Comparative angiotensin II receptor blockade in healthy volunteers: The importance of dosing. Clin Pharmacol Ther 71:6876, 2002 Weinberg MS, Weimberg AJ, Cord R, Zappe DH: The effect of high dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein excretion. JRAAS 2(Suppl 1):S196S198, 2001 Bakris GL, Siomos M, Richardson D, et al: ACE inhibition or angiotensin receptor blockade: Impact on potassium in renal failure. VAL-K Study Group. Kidney Int 58:20842092, 2000

eight instances throughout the study period and was greater than 6.0 mmol/L in only two cases. All of these eight cases had impaired renal function. Because of clinical relevance of high serum potassium levels, our data conrm that close monitoring of serum potassium is mandatory in patients with an impaired renal function treated with RAS blockade, with a high dose of ACE inhibitor either combined or not with ARB. No other relevant adverse event was recorded. In conclusion, the present data show that combined therapy with an ACE inhibitor and ARB produces a benecial antiproteinuric effect in patients with primary proteinuric nephropathies. This antiproteinuric effect of the dual blockade is not only dependent on blood pressure reduction or changes in renal function. Whether this antiproteinuric effect represents a surrogate marker of long-term preservation of renal function needs to be demonstrated and further prospective, long-term controlled trials are required in order to address this question. ACKNOWLEDGMENT
uThis study was supported by a grant from Astra Zeneca Farmace tica Espan a SA. Lun Reprint requests to Jose o, M.D., Department of Nephrology, n, c/Dr. Esquerdo, 46, Hospital General Universitario Gregorio Maran o 28007 Madrid, Spain. E-mail: joseluno@terra.es

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