British Journal of Rheumatology 1992 ;31:163-168
EFFECTS OF NAPROXEN ON RENAL FUNCTION IN OLDER PATIENTS WITH MILD TO MODERATE RENAL DYSFUNCTION BY L. S. SIMON*f, C. M. BASCHt, D. Y. YOUNG* AND D. R. ROBINSONt Department of Medicine, Harvard Medical School; *New England Deaconess Hospital Medical Service; and tthe Arthritis Unit, Massachusetts General Hospital, Boston, MA, USA; tSyntex Laboratories Inc, Palo Alto, CA, USA
KEY WORDS: Non-steroidal anti-inflammatory drugs (NSAID), The elderly, Renal dysfunction, Renal haemodynamics, Serum thromboxane B2 (TxB2), Urinary prostaglandins E2 (PGE2) and I2 (prostacyclin, 6-keto-PGFla).
THE non-steroidal anti-inflammatory drugs (NSAIDs) have been successfully administered to large numbers of patients in clinical trials and in daily practice. Although in general, the NSAIDs are well tolerated, there may be certain groups of patients who may be at greater risk from renal dysfunction [1,2]. Some of the patients reported to be at special risk include patients treated with diuretic therapy, patients with intrinsic renal disease such as nephrotic syndrome, or individuals with decreased effective renal blood flow. Over the years there have been demographic changes in the clinical use of the NSAIDs. It has been noted that these drugs are used more frequently in the elderly population [3-5]. These older patients are more likely to suffer from the above noted complicating diseases, to sustain a natural fall in glomerular filtration rate with increasing age [6], or to be prescribed other drugs that have the potential to interact poorly with the NSAIDs [2, 7]. Although NSAIDs have many different biological effects, the major mechanism of action as well as the major mechanism for most potential toxicities for these drugs is inhibition of the prostaglandin cascade [8—10]. In addition to promoting inflammation in most circumstances, the prostaglandins have been described to be important in maintaining adequate renal plasma flow during states of relative renal ischaemia [11-20]. These clinical conditions include severe congestive heart failure (CHF), hypovolaemia such as seen with enthusiastic over-diuresis, cirrhotic conditions, or those
diseases complicated by the presence of ascites. The prostaglandins, particularly E2 and I2 (prostacyclin) are important vasodilators in the kidney. Whereas PGE, appears to exert most of its effects in the renal medulla and is particularly important in inhibiting the tubular reabsorption of sodium and chloride, prostacyclin is the major renal cortical prostaglandin. It exerts an important effect on glomerular filtration rate and has been thought to be the important prostaglandin for maintenance of intrinsic renal blood flow during states of renal hypoperfusion due to ineffective intravascular volume [7,11,13,15]. In addition to altering the mechanisms whereby prostaglandins participate in the control of intrinsic renal arterial blood flow, certain NSAIDs have been associated with the development of interstitial nephritis or membranous glomerulonephritis [9, 21]. There are also reports that describe the interference by NSAIDs with the effects of both antihypertensive medications [22,23] and diuretics in some patients [23-26]. Many studies have attempted to demonstrate the safety or toxicity of the various NSAIDs [11,13-17]. Most of the studies were performed on a small group of patients for only a few days, measured serum creatinine or urinary creatinine clearance or more recently approximate glomerular filtration rate by the experimental infusion of "Tc-diethylenetriaminepentaacetic acid. A majority of these studies chose mostly women to evaluate. This is reportedly due to the difficulties in the measurement of the urinary prostaglandins, particularly PGE2, when the urinary collections are contaminated by seminal secretions [11,15,27]. Therefore, we have designed a study to determine
Submitted 24 October 1990; revised version accepted 28 March 1991. Correspondence to L. Simon, MD, New England Deaconess Hospital, 110 Francis Street, Suite 5A, Boston, MA 02215, USA. 163
Downloaded from http://rheumatology.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 27, 2015
SUMMARY We have evaluated 45 elderly patients with both musculoskeletal problems and mild to moderate renal dysfunction. We treated these patients with a non-steroidal anti-inflammatory drug (NSAID) for 2 weeks. The serum creatinine, urinary creatinine clearance and blood pressure were monitored before and after therapy. In some patients serum levels of thromboxane B2 (TxB2) and the urinary prostaglandins E2 (PGE2) and I2 (prostacyclin) measured as 6-keto-PGFla were also monitored before and after therapy and correlated with the clinical measurements. This study has demonstrated that in the entire patient group, the trial drug was tolerated extremely well. There were no changes in the serum creatinine or in the urinary creatinine clearance after 2 weeks of therapy. There was also no change in the early morning diastolic blood pressure. In the 11 patients in whom the serum and urinary prostaglandins were measured, the serum thromboxane levels fell with therapy to a level of 1.5% of the initial value. The urinary levels of PGEj also fell but not to the same degree. The urinary PGE2 levels fell to 28% of the baseline values. There was no significant change in the levels of urinary 6-keto-PGFlo (prostacyclin). These observations suggest that prostacyclin may be the important prostaglandin in maintaining normal renal haemodynamics when patients are treated with NSAIDs.
164
BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXXI NO. 3
METHODS The patients were recruited at two different medical centres. The Institutional Review Boards (IRB) at each institution reviewed and approved the protocols. Patients were recruited if they were above 55 years of age, required a NSAID for a musculoskeletal condition, and their CrCI was
EFFECTS OF NAPROXEN ON RENAL FUNCTION IN OLDER PATIENTS WITH MILD TO MODERATE RENAL DYSFUNCTION BY L. S. SIMON*f, C. M. BASCHt, D. Y. YOUNG* AND D. R. ROBINSONt Department of Medicine, Harvard Medical School; *New England Deaconess Hospital Medical Service; and tthe Arthritis Unit, Massachusetts General Hospital, Boston, MA, USA; tSyntex Laboratories Inc, Palo Alto, CA, USA
KEY WORDS: Non-steroidal anti-inflammatory drugs (NSAID), The elderly, Renal dysfunction, Renal haemodynamics, Serum thromboxane B2 (TxB2), Urinary prostaglandins E2 (PGE2) and I2 (prostacyclin, 6-keto-PGFla).
THE non-steroidal anti-inflammatory drugs (NSAIDs) have been successfully administered to large numbers of patients in clinical trials and in daily practice. Although in general, the NSAIDs are well tolerated, there may be certain groups of patients who may be at greater risk from renal dysfunction [1,2]. Some of the patients reported to be at special risk include patients treated with diuretic therapy, patients with intrinsic renal disease such as nephrotic syndrome, or individuals with decreased effective renal blood flow. Over the years there have been demographic changes in the clinical use of the NSAIDs. It has been noted that these drugs are used more frequently in the elderly population [3-5]. These older patients are more likely to suffer from the above noted complicating diseases, to sustain a natural fall in glomerular filtration rate with increasing age [6], or to be prescribed other drugs that have the potential to interact poorly with the NSAIDs [2, 7]. Although NSAIDs have many different biological effects, the major mechanism of action as well as the major mechanism for most potential toxicities for these drugs is inhibition of the prostaglandin cascade [8—10]. In addition to promoting inflammation in most circumstances, the prostaglandins have been described to be important in maintaining adequate renal plasma flow during states of relative renal ischaemia [11-20]. These clinical conditions include severe congestive heart failure (CHF), hypovolaemia such as seen with enthusiastic over-diuresis, cirrhotic conditions, or those
diseases complicated by the presence of ascites. The prostaglandins, particularly E2 and I2 (prostacyclin) are important vasodilators in the kidney. Whereas PGE, appears to exert most of its effects in the renal medulla and is particularly important in inhibiting the tubular reabsorption of sodium and chloride, prostacyclin is the major renal cortical prostaglandin. It exerts an important effect on glomerular filtration rate and has been thought to be the important prostaglandin for maintenance of intrinsic renal blood flow during states of renal hypoperfusion due to ineffective intravascular volume [7,11,13,15]. In addition to altering the mechanisms whereby prostaglandins participate in the control of intrinsic renal arterial blood flow, certain NSAIDs have been associated with the development of interstitial nephritis or membranous glomerulonephritis [9, 21]. There are also reports that describe the interference by NSAIDs with the effects of both antihypertensive medications [22,23] and diuretics in some patients [23-26]. Many studies have attempted to demonstrate the safety or toxicity of the various NSAIDs [11,13-17]. Most of the studies were performed on a small group of patients for only a few days, measured serum creatinine or urinary creatinine clearance or more recently approximate glomerular filtration rate by the experimental infusion of "Tc-diethylenetriaminepentaacetic acid. A majority of these studies chose mostly women to evaluate. This is reportedly due to the difficulties in the measurement of the urinary prostaglandins, particularly PGE2, when the urinary collections are contaminated by seminal secretions [11,15,27]. Therefore, we have designed a study to determine
Submitted 24 October 1990; revised version accepted 28 March 1991. Correspondence to L. Simon, MD, New England Deaconess Hospital, 110 Francis Street, Suite 5A, Boston, MA 02215, USA. 163
Downloaded from http://rheumatology.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 27, 2015
SUMMARY We have evaluated 45 elderly patients with both musculoskeletal problems and mild to moderate renal dysfunction. We treated these patients with a non-steroidal anti-inflammatory drug (NSAID) for 2 weeks. The serum creatinine, urinary creatinine clearance and blood pressure were monitored before and after therapy. In some patients serum levels of thromboxane B2 (TxB2) and the urinary prostaglandins E2 (PGE2) and I2 (prostacyclin) measured as 6-keto-PGFla were also monitored before and after therapy and correlated with the clinical measurements. This study has demonstrated that in the entire patient group, the trial drug was tolerated extremely well. There were no changes in the serum creatinine or in the urinary creatinine clearance after 2 weeks of therapy. There was also no change in the early morning diastolic blood pressure. In the 11 patients in whom the serum and urinary prostaglandins were measured, the serum thromboxane levels fell with therapy to a level of 1.5% of the initial value. The urinary levels of PGEj also fell but not to the same degree. The urinary PGE2 levels fell to 28% of the baseline values. There was no significant change in the levels of urinary 6-keto-PGFlo (prostacyclin). These observations suggest that prostacyclin may be the important prostaglandin in maintaining normal renal haemodynamics when patients are treated with NSAIDs.
164
BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXXI NO. 3
METHODS The patients were recruited at two different medical centres. The Institutional Review Boards (IRB) at each institution reviewed and approved the protocols. Patients were recruited if they were above 55 years of age, required a NSAID for a musculoskeletal condition, and their CrCI was
