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 beneficial 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 parallel-group 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 follow-up, 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 significant differences between groups. Urinary protein/creatinine ratio (percentage reduction 95% confidence intervals CI) decreased in patients treated with lisinopril alone to -33% (CI -12-56) to -31% (CI 0-68) and to -50% (CI -9-90), in patients treated with candesartan to -28% (CI -12-45), to -41% (CI -30-52) and to -48% (CI -32-63), in patients treated with the combination of both to -60% (CI -44-77) to -54% (CI -38-69) and to -70% (CI -57-83) at two, three, and six months, respectively. All comparisons with baseline achieved statistical significance 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).


CONCLUSIONS
Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated.
Luño
José
J
Department of Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. joseluno@terra.es
Barrio
Vicente
V
Goicoechea
Maria Angeles
MA
González
Cesar
C
de Vinuesa
Soledad García
SG
Gómez
Francisco
F
Bernis
Carmen
C
Espinosa
Mario
M
Ahijado
Francisco
F
Gómez
José
J
Escalada
Pedro
P
D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000652:urine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017706:Lisinopril / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013030:Spain; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D003404:Creatinine; D017706:Lisinopril; C081643:candesartan