Cyclooxygenase inhibition causes marked impairment of renal function in elderly subjects treated with diuretics and ACE-inhibitors.
BACKGROUND
Treatment with angiotensin-converting enzyme (ACE)-inhibitors is known to cause an initial reduction in glomerular filtration rate (GFR) in patients with congestive heart failure. The long-term beneficial effects of ACE-inhibitors in these patients can be counteracted by cyclooxygenase-inhibitors.


OBJECTIVE
To quantify the negative renal effects of the cyclooxygenase-inhibitor diclofenac in elderly healthy subjects and to assess how treatment with an ACE-inhibitor, after activation of the renin-angiotensin system, influences these renal effects.


METHODS
Fourteen elderly, healthy subjects received oral diclofenac and placebo in a double-blind cross-over fashion. The study was divided in two parts; in part one, subjects received no pre-treatment and in part two, the subjects were given pre-treatment with bendroflumethiazide and enalapril in order to activate the renin-angiotensin system.


RESULTS
Diclofenac induced significant (p<0.05) decreases in GFR, urine flow, excretion rates of sodium and potassium, electrolyte clearance, osmolality clearance and free water clearance both with and without renin-angiotensin system activation. Least square means (95% CI) of all observations during the first 6 h after dosing showed that diclofenac caused a reduction in GFR from 71 (64-78) to 59 (52-66) ml/min. After pre-treatment, diclofenac further reduced GFR from 60 (52-67) to 48 (40-55) ml/min. After diclofenac administration, urine flow fell from 7.4 (6.4-8.3) to 5.1 (4.2-6.1) ml/min, after pre-treatment, diclofenac gave a further reduction from 4.1 (3.1-5.1) to 2.2 (1.3-3.2) ml/min. More than half of the reductions were caused by the pre-treatment.


CONCLUSIONS
Renal function in elderly, healthy subjects is impaired after acute intake of diclofenac. This impairment is observed both with and without activation of the renin-angiotensin system and ACE-inhibitor treatment but is more pronounced after pre-treatment.
Juhlin
Tord
T
Department of Cardiology, Malmö University Hospital, Malmö, Sweden.
Björkman
Sven
S
Höglund
Peter
P
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D001539:Bendroflumethiazide / Q000008:administration & dosage / Q000009:adverse effects*; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects*; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D015577:Geriatric Assessment; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D011336:Probability; D012016:Reference Values; D018570:Risk Assessment
D000806:Angiotensin-Converting Enzyme Inhibitors; D016861:Cyclooxygenase Inhibitors; D004232:Diuretics; D004008:Diclofenac; D001539:Bendroflumethiazide; D004656:Enalapril