Low-dose dual blockade of the renin-angiotensin system improves tubular status in non-diabetic proteinuric patients.
OBJECTIVE
Treatment with agents that inhibit the renin-angiotensin system is commonly regarded as a gold standard renoprotective strategy in patients with chronic kidney diseases. For maximum antiproteinuric effect, the dose titration of these agents is recommended. This therapeutic strategy is not used for proteinuric patients who are not able to receive high doses of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonists.


METHODS
In patients with primary glomerulonephritis (n=24), a randomized, triple-treatment, triple-period, cross-over study was performed to compare the effects of combined therapy with benazepril 5 mg and losartan 25 mg and monotherapy with either agent alone at a two-fold higher dose on the extent of tubular injury as assessed by alpha1-microglobulin (alpha1-m) excretion and the plasma level of transforming growth factor-beta1 (TGF-beta1).


RESULTS
Combination therapy significantly reduced alpha1-m excretion compared to either agent used alone: 178.29+/-27.36 to 99.63+/-13.03 mg/g creatinine for losartan + benazepril vs 178.29+/-27.36 to 161.59+/-23.22 mg/g creatinine for benazepril alone (p<0.05; ANOVA) and 178.29+/-27.36 to 99.63+/-13.03 mg/g creatinine for losartan + benazepril vs 178.29+/-27.36 to 173.45+/-27.69 mg/g creatinine for losartan alone (p<0.05; ANOVA). There was a significant correlation between change in alpha1-m excretion and reduction in proteinuria (r=0.704; p=0.023). There were no differences in TGF-beta1 level between the studied treatments. Systemic blood pressure reduction did not differ among the therapies.


CONCLUSIONS
Combination therapy with angiotensin-converting enzyme inhibitor and angiotensin II subtype 1 receptor antagonists at very small doses may be superior to monotherapy with these agents at higher doses as far as tubular injury is concerned. We speculate that such a therapeutic strategy may be a useful approach for patients who are known not to be capable of receiving optimal renoprotective doses of these regimens.
Renke
Marcin
M
Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Gdansk, Poland. mrenke@amg.gda.pl
Tylicki
Leszek
L
Rutkowski
Przemyslaw
P
Wojnarowski
Klaudiusz
K
Lysiak-Szydlowska
Wieslawa
W
Rutkowski
Boleslaw
B
D000293:Adolescent; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D001552:Benzazepines / Q000008:administration & dosage* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019808:Losartan / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000652:urine; D008875:Middle Aged; D009391:Nephelometry and Turbidimetry; D011507:Proteinuria / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D012084:Renin-Angiotensin System / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D016896:Treatment Outcome; D014360:Trypsin Inhibitor, Kunitz Soybean / Q000652:urine
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D015415:Biomarkers; D008562:Membrane Glycoproteins; C109148:SPINT2 protein, human; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014360:Trypsin Inhibitor, Kunitz Soybean; D003404:Creatinine; D019808:Losartan; C044946:benazepril