Effect of high dose ramipril with or without indomethacin on glomerular selectivity.
BACKGROUND
Despite the accumulating evidence of their efficacy, angiotensin-converting enzyme inhibitors (ACEi) still provide imperfect renoprotection. Up-titration above conventional doses and combined therapy with other antiproteinuric agents may serve to achieve renoprotection in patients at risk of rapid disease progression.


METHODS
The effect of maximum tolerated ACEi doses (ramipril 15 mg/day, range 5 to 20) alone or combined with indomethacin (75 mg x 2/day) on urinary protein excretion (UPE) and glomerular barrier size-selective function was evaluated in 19 patients with chronic non-diabetic nephropathies and persistent proteinuria.


RESULTS
Maximum ramipril doses decreased UPE more effectively than non-ACEi therapy. Proteinuria reduction was associated with significant reduction (>50%) of the non-selective glomerular membrane shunt, but did not correlate with concomitant changes in arterial pressure and renal hemodynamics, nor was it influenced by treatment duration. The reduction in UPE and sieving coefficient of the largest neutral dextrans exceeded by twofold the reduction achieved by conventional ACEi doses in historical controls with similar renal dysfunction and proteinuria, previously studied under identical experimental conditions. Indomethacin did not influence renal effects of maximum ramipril doses and was prematurely withdrawn in six patients because of reversible side effects. Serum potassium significantly increased only in combination with indomethacin and never required treatment withdrawal.


CONCLUSIONS
Up-titration to maximally tolerated doses safely increases ACEi antiproteinuric effect and may serve to achieve maximum renoprotection in the long-term. Combination with indomethacin is poorly tolerated and ineffective. Innovative approaches are needed to use ACEi more effectively.
Pisoni
Roberto
R
Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy.
Ruggenenti
Piero
P
Sangalli
Fabio
F
Lepre
Maria Serena
MS
Remuzzi
Andrea
A
Remuzzi
Giuseppe
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D003911:Dextrans / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage*; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000188:drug therapy / Q000503:physiopathology; D017257:Ramipril / Q000008:administration & dosage*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003911:Dextrans; D017257:Ramipril; D007213:Indomethacin