Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency. Administration of nonsteroidal anti-inflammatory drugs (NSATDs) to patients with chronically impaired renal function has been reported to cause abrupt and sustained reductions in rcnal plasma flow (RPF), glomerular filtration rate (OFR), and solute and water excretion in association with decreased renal prostanoid production. However, the time course 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) aod chronic (five days) oral administration of two different NSAIDs on renal function in patients with stable, mild to moderate chronic renal insufficiency (CR1) and in normal subjects. In patients, acute oral administration of ketoprofen (K) and indomethaein (I) resulted in significant decreases in GFR (K: from 36 3 to 20 4 mI/mm, P 0.001; I: from 37 6 to 30 7 mI/mm, p 0.032; in RPF (K: from 194 21 to 146 21 mI/mm, P = 0.002; I: from 222 33 to 147 18 mI/mm, P = 0.016); and in urinary POE, excretion (K: from t).6tl 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/C1) also decreased significantly after both agents. In normal subjects, OFR and RPF were not significantly decreased after acute dosing, whereas urinary POE2 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 OFR was slightly decreased after K but not I administration. Acute superimposed on chronic NSAID administration resulted in mild but nonsignificant decreases in RPF, OFR, and CH2O/CIN, whereas fractional excretion of NaC1 and urinary POE2 excretion decreased significantly. Daily, 24 hour ereatinine 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 POE2 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, 1 from 0.37 ii 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 OFR 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.
arterial blood volume has been clearly demonstrated. In patients with cirrhosis, inhibition of renal cyclo-oxygenase activity by oral administration of various nonsteroidal anti-inflammatory drugs (NSAIDs) is accompanied by sharp decreases in renal blood flow, glomerular filtration rate, and solute and water excretion [1, 21. Under these circumstances, it has been suggested that renal prostanoids (particularly, prostacyclin) exert a tonic vasodilatory effect which is subsequently attenuated by cyelo-oxygenase inhibitors, leaving the renal circulation vulnerable to the effects of extant vasoconstrictors (such as, angiotensin II and eatecholamines). In addition, oral administration of renal eyclo-oxygenase inhibitors has decreased renal perfusion and solute and water excretion in patients with mild, chronic-intrinsic renal disease (in the absence of reduced effective arterial blood volume) [3][4][5][6]. Because of these observations, many consider a diagnosis of renal insufficiency of any degree to represent a contraindication to administration of NSAIDs. However, it is not clear whether the deleterious effects of NSAIDs on renal function are sustained during chronic, persistent inhibition of baseline renal prostaglandin production in all patients with mild-to-moderate chronic renal insufficiency. This possibility is an important clinical issue because of the widespread use and efficacy of this class of anti-inflammatory agenls.
The purpose of the present study was to examine the effects of acute and chronic inhibition of renal eyelo-oxygenase activity on renal function in patients with mild, chronic renal insufficiency of diverse pathophysiological origin. The results suggest that each administered dose of N SAID causes a transient, reversible decrease in renal hemodynamies and solute and water excretion that may dampen with time. Overall, in patients with mild intrinsic renal insufficiency, use of NSAIDs had negligible adverse effects.
Methods
The importance of renal prostanoids in maintaining renal hemodynamies in humans under conditions of reduced effective Subjects
We performed a total of 30 studies, Eight normal subjects