Administration of nonsteroidal anti-inflammatory drugs (NSAIDS) to patients with chronically impaired renal function has been reported to cause abrupt and sustained reductions in renal plasma flow (RPF), glomerular filtration rate (GFR), and solute and water excretion in association with decreased renal prostanoid production. However, the time course of of these acute effects and whether they are sustained during chronic exposure to the NSAIDs are unknown. Accordingly, using standard clearance and balance techniques, we investigated the effects of acute (zero to four hours) and chronic (five days) oral administration of two different NSAIDs on renal function in patients with stable, mild to moderate chronic renal insufficiency (CRI) and in normal subjects. In patients, acute oral administration of ketoprofen (K) and indomethacin (I) resulted in significant decrases in GFR (K: from 36 ± 3 to 20 ± 4 ml/min, P = 0.001; I: from 37 ± 6 to 30 ± 7 ml/min, P = 0.032; in RPF (K: from 194 ± 21 to 146 ± 21 ml/min, P = 0.002; I: from 222±33 to 147±18 ml/min, P=0.016); and in urinary PGE2 excretion (K: from 0.60±0.25 to 0.08±0.02 ng/min, P=0.05; I: from 0.34 ± 0.06 to 0.18 ml/min, P = 0.016); and in urinary PGE2 excretion (K: from 0.60 ± 0.25 to 0.08 ± 0.02 ng/min, P = 0.05; I: from 0.34 ± 0.06 to 0.18 ± 0.06 ng/min, P = 0.042). Fractional excretion of sodium chloride and fractional free water clearance (CH2O/C(In)) also decreased significantly after both agents. In normal subjects, GFR and RPF were not significantly decreased after acute dosing, whereas urinary PGE2 and fractional excretions of NaCl and free water decreased significantly. After chronic administration of both agents to patients, RPF had returned to control levels while GFR was slightly decreased after K but not I administration. Acute superimposed on chronic NSAID administration resulted in mild but nonsignificant decreases in RPF, GFR, and CH2O/C(IN), whereas fractional excretion of NaCl and urinary PGE2 excretion decreased significantly. Daily, 24 hour creatinine clearance measurements decreased slightly but returned toward control levels by day five (K: from 42 ± 4 to 36 ± 6, NS and I: from 56 ± 8 to 53 ± 9, NS) whereas daily urinary PGE2 excretion was still decreased from pre-drug control values at day five (K: from 0.48 ± 0.17 to 0.19 ± 0.05, P = 0.11, I from 0.37 ± 0.06 to 0.17 ± 0.04, P = 0.015). Body weight, sodium balance and blood pressure were not significantly altered. These data indicate that acute administration of NSAIDs to patients with chronic renal insufficiency results in decreases in RPF and GFR which are transient and reversible within the time frame of a standard dosing regimen. It appears that after chronic NSAID administration a superimposed single dose of NSAID causes a similar transient effect that may be less in magnitude.
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