- Email: [email protected]
Are selective COX-2 inhibitors nephrotoxic?
CASE REPORTS
Are Selective COX-2 Inhibitors Nephrotoxic? Mark A. Perazella, MD, and Jennifer Eras, MD ● Nonsteroidal anti-inflammatory drugs are well-known culprits in the development of acute renal insufficiency in high-risk patients. The recent release of the selective cyclooxygenase-2 enzyme inhibitors for the treatment of inflammatory diseases and pain syndromes has been associated with a clear-cut decrease in adverse gastrointestinal effects. However, the nephrotoxic potential of these agents in patients with prostaglandin-dependent states and chronic renal impairment is unknown. Many clinicians commonly wonder if these agents can be safely prescribed to such high-risk patients. We present two cases of acute renal failure complicating the course of therapy with celecoxib in patients with chronic renal insufficiency. r 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Celecoxib; renal failure; cyclooxygenase-2 (COX-2); nonsteroidal anti-inflammatory drugs (NSAIDs).
Editorial, p. 976
N
ONSTEROIDAL anti-inflammatory drugs (NSAIDs) with nonselective cyclooxygenase (COX) enzyme inhibition are commonly prescribed to patients for a variety of inflammatory diseases and pain syndromes. As a result, adverse gastrointestinal (GI) and renal effects are relatively common problems.1-4 The recent introduction of selective COX-2 enzyme inhibitors has reduced the GI toxicity that occurs with these drugs.4 However, the nephrotoxic potential of these new agents is currently unknown. This report describes two cases of reversible acute renal failure associated with the selective COX-2 enzyme inhibitor, celecoxib, in patients with chronic renal insufficiency. CASE REPORTS
Case 1 A 63-year-old man with a history of hypertension, coronary artery disease, left ventricular hypertrophy with preserved ventricular function, osteoarthritis, and chronic renal insufficiency (baseline serum creatinine level, 2.8 mg/dL) was prescribed celecoxib, 200 mg, orally twice daily to relieve arthritic pain in his back and knees that was poorly responsive to current therapy. Other chronically prescribed medications included amlodipine, 10 mg/d; atenolol, 25 mg twice daily; atorvastatin, 10 mg/d; isosorbide mononitrate, 30 mg/d; enteric-coated aspirin, 325 mg/d; and acetaminophen plus codeine three times daily as needed for pain. Physical examination showed a blood pressure of 145/86 mm Hg; pulse, 68 beats/min; and temperature, 98°F. Head and neck examination was unremarkable, whereas the heart had an S4 gallop. The lungs were clear, abdomen was benign, and extremities had no edema. The knees had small effusions and mild tenderness to palpation. Palpation of the lumbar spine elicited pain.
Sixteen days after the initiation of celecoxib therapy, the patient presented to the clinic with symptoms of dyspnea, fatigue, and pedal edema that had progressively worsened over the past 5 days. He denied chest pain, dizziness, nausea or vomiting, diarrhea, or fever. The patient did not ingest other NSAIDs. Physical examination was remarkable for a blood pressure of 190/95 mm Hg and a pulse of 75 beats/ min. Jugular venous distension was present at 45°. Lung examination showed bibasilar crackles, and the heart had an S4 gallop. The abdomen was unremarkable, and there was 2⫹ pitting edema of the ankles. Skin examination was within normal limits. Laboratory data showed the following values: sodium, 134 mEq/L; potassium, 5.1 mEq/L; chloride, 96 mEq/L; total CO2, 20 mEq/L; blood urea nitrogen, 73 mg/dL; and serum creatinine, 4.9 mg/dL. Complete blood count was normal except for a hemoglobin level of 9.2 g/dL and hematocrit of 28.5%. Liver function test results and creatinine phosphokinase levels were normal. Urinalysis showed a specific gravity of 1.018, trace protein, and negative blood, glucose, and leukocyte esterase. Examination of the urine sediment was unremarkable for cells but showed a few hyaline casts. Urine electrolyte levels were not obtained. Acute renal failure and volume overload caused by celecoxib therapy were diagnosed. Celecoxib was discontinued, and intravenous furosemide was administered. Over the next 5 days, renal function returned to near baseline (serum creatinine level, 2.9 mg/dL), and the state of volume overload resolved.
From the Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT. Received November 30, 1999; accepted in revised form January 28, 2000. Address reprint requests to Mark A. Perazella, MD, Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, LMP 2073, 333 Cedar St, New Haven, CT 06520. E-mail: [email protected]
r 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3505-0021$3.00/0 doi:10.1053/kd.2000.6404
American Journal of Kidney Diseases, Vol 35, No 5 (May), 2000: pp 937-940
937
938
PERAZELLA AND ERAS
Case 2 A 68-year-old man with a history of coronary artery disease, cardiomyopathy with a left ventricular ejection fraction of 45%, anemia (hemoglobin, 9.7 g/dL; hematocrit, 29%), type 2 diabetes mellitus, hypertension, gout, hyperlipidemia, and diabetic nephropathy (serum creatinine level, 3.5 mg/dL) was administered celecoxib, 200 mg, orally twice daily for treatment of gout of the right foot unresponsive to colchicine and narcotic analgesics. Chronically prescribed medications included lisinopril, 10 mg/d; torsemide, 20 mg/d; amlodipine, 5 mg/d; enteric-coated aspirin, 325 mg/d; atorvastatin, 20 mg/d; glyburide, 5 mg twice daily; digoxin, 0.125 mg every other day; colchicine, 0.6 mg/d; subcutaneous erythropoietin, 2,000 U/wk; and codeine, 30 mg every 4 to 6 hours for gouty pain. Physical examination showed blood pressure of 135/78 mm Hg; pulse, 88 beats/min; and temperature, 97.6°F. Head and neck examination was within normal limits except for changes indicative of proliferative diabetic retinopathy. The lungs were clear, and the heart had a 2/6 holosystolic murmur over the apex that radiated to the left axilla. Abdominal examination was normal; however, the lower extremities had 1⫹ pitting edema of the feet and ankles. Thirteen days after the start of celecoxib therapy, the patient presented to his physician reporting dyspnea with exertion, orthopnea, reduced urine output, fatigue, and increased lower-extremity edema. The patient denied other NSAID ingestion. Physical examination showed prominent jugular venous distension at 90°, bibasilar crackles on auscultation of the lungs, an S3 gallop and 2/6 holosystolic heart murmur, and bilateral 3⫹ pitting edema to midcalf. There was no asterixis, petechiae, or skin rash. Laboratory data showed the following abnormal serum values: sodium, 132 mEq/L; potassium, 5.4 mEq/L; chloride, 98 mEq/L; total CO2, 18 mEq/L; glucose, 225 mg/dL; blood urea nitrogen, 95 mg/dL; and serum creatinine, 5.6 mg/dL. Hemoglobin was 8.5 g/dL, and hematocrit was 26%. Liver function test results and muscle enzyme levels were normal. Urine sediment showed a few renal tubular epithelial cells and epithelial cell casts, but no red blood cells, white blood cells, or red blood cell casts. Urinalysis was pertinent for 2⫹ protein (consistent with baseline) and positive glucose, but no blood or leukocyte esterase. Urine electrolyte levels were not measured. Acute renal insufficiency complicated by congestive heart failure and mild hyperkalemia was ascribed to therapy with celecoxib. Discontinuation of celecoxib and treatment with intravenous furosemide resulted in the resolution of acute renal failure (serum creatinine level returned to baseline of 3.3 mg/dL) and volume overload over the next 7 days. No other medications were discontinued at this time.
DISCUSSION
NSAID therapy is complicated by a variety of renal complications, which include electrolyte disturbances (hyponatremia, hyperkalemia), disorders of salt balance (edema, hypertension), acute and chronic tubulointerstitial nephritis, papillary necrosis, glomerular lesions, and acute hemodynamic renal failure.1-3 Impaired synthe-
sis of renal prostaglandins produced locally in the kidney by NSAIDs underlies this pathological process in most cases.1-3,5 Acute renal insufficiency often develops when patients with prostaglandin-dependent disease states (volume depletion, cirrhosis, congestive heart failure, nephrosis, chronic renal failure) are administered NSAIDs, which inhibit COX enzyme activity and blunt the production of these compensatory (vasodilatory) prostaglandins.1-3,6 In the past, the COX-1 enzyme isoform was believed to be the important enzyme involved in renal prostaglandin synthesis. However, the COX-2 enzyme was recently noted to have an important role in prostaglandin production during inflammatory processes.7 As a result, this isoform was considered to be inducible, whereas the COX-1 isoform was believed to be constitutive and integral to the maintenance of organ (such as kidney, GI tract) integrity.7,8 The recent development of COX-2 selective inhibitors has been a major advancement in the treatment of inflammatory diseases and pain syndromes without the associated gastrotoxicity.4 However, the effect of selective COX-2 inhibition on renal function, especially in states of prostaglandin dependency, is essentially unknown.9 Animal (rat) models, using in situ hybridization and immunohistochemistry, show the constitutive expression of COX-2 enzyme in macula densa and ascending thick limb cells.10,11 Chronic salt depletion further increases COX-2 immunoreactivity in the macula densa and epithelial ascending thick limb cells, suggesting a role for this enzyme in the regulation of renin release.10,11 A study of seven adult human kidneys (nephrectomy specimens from patients with cancer) showed constitutive expression of COX-2 in locations different from those described in animal studies.12 COX-2 immunoreactive protein was localized to endothelial and smooth muscle cells of arteries, arterioles, and veins.12 In addition, COX-2 protein was also shown in vasa recta of the medulla and visceral epithelial cells (podocytes) of cortical glomeruli, but not in macula densa cells.12 Recently published abstracts provide some insight into the effect of COX-2 selective inhibitors on renal function in two groups of patients.13-15 In 29 healthy elderly subjects without renal insufficiency, treatment with celecoxib for 10 days was compared with the nonselective
COX-2 INHIBITORS AND ACUTE RENAL FAILURE
COX inhibitor, naproxen, in a prospective crossover trial.13 Glomerular filtration rate (GFR) declined significantly on day 6 of therapy (–7.53 versus –1.11 mL/min/1.73 m2) in naproxentreated patients compared with celecoxib-treated subjects.13 Urinary excretion of prostaglandins (PGE2, 6-keto-PGF1) was significantly reduced with both drugs, but no significant difference in urinary levels was noted between the two medications.13 In a multicenter, double-blind trial, 60 healthy elderly patients with a wide variation in creatinine clearance (30 to 80 mL/min) were randomized to treatment with the COX-2 selective inhibitor (rofecoxib) at two different doses (12.5 and 25 mg/d), indomethacin (50 mg three times daily), or placebo.14 A similar decline in GFR at day 6 of the study compared with baseline was noted for rofecoxib, 12.5 mg (mean change, –11.5%); rofecoxib, 25 mg (mean change, –12.7%); and indomethacin (mean change, –10.4%), but not for placebo.14 Finally, a multicenter study compared the effects of celecoxib, naproxen, and placebo in 75 patients with stable chronic renal insufficiency, defined by GFR in the 31.8- to 36.9-mL/min/ 1.73 m2 range.15 No significant difference in GFR was noted among the three groups at 6 days of study, despite a significant reduction in urinary prostaglandin levels in both treatment groups.15 In addition, neither drug had an effect on urinary sodium excretion or plasma renin activity.15 The two cases presented in this report clearly suggest that COX-2–selective NSAIDs may cause reversible acute renal failure and volume overload when administered to patients with stable chronic renal insufficiency. One of the patients (case 2) also had a compensated congestive cardiomyopathy that may have further increased the risk for the development of renal failure and volume overload. The patients described in this report were administered celecoxib for 13 and 16 days longer than the 6- and 10-day periods of study in the abstracts cited, respectively.13-15 It is possible that the longer duration of therapy in these two cases may have increased the risk for the development of acute renal failure. Another potential explanation in these patients is primary congestive heart failure–related acute prerenal insufficiency independent of celecoxib therapy. This cause is unlikely because both patients were stable with well-compensated heart disease at the time of initiation of celecoxib
939
therapy. Volume overload developed subsequent to therapy with this medication, further increasing prostaglandin dependency and the risk for NSAID-associated renal failure. However, it is reasonable to conclude at this point in time that COX-2–selective NSAIDs can cause acute renal failure and should be avoided or at least used cautiously for short periods of time (with close monitoring) in patients with chronic renal insufficiency. In addition, randomized, prospective studies should be undertaken to evaluate the renal safety of COX-2 selective agents compared with nonselective COX inhibitors in a large number of high-risk patients. NOTE ADDED IN PROOF
A 73-year-old woman with chronic renal failure (serum creatinine, 1.7 to 2.2 mg/dL); type 2 diabetes mellitus; type 4 renal tubular acidosis; peripheral vascular disease complicated by left, below-knee amputation; peripheral neuropathy; and Crohn’s disease was sent to the emergency department from her nursing facility after she was noted to develop loss of consciousness secondary to hypoglycemia (glucometer read ‘‘low’’). The patient awoke following 3 ampules of 50% dextrose. She reported 5 days of anorexia and decreased urine output of 2 days in duration. Her chronically prescribed medications included glyburide at 5 mg per day, ranitidine at 150 mg at bedtime, multivitamin at 1 tablet per day, oxybutynin at 5 mg twice per day, and sodium bicarbonate at 325 mg twice per day. Rofecoxib at 25 mg per day was added 14 days before presentation to treat chronic pain. Physical examination revealed a blood pressure of 108/65, a pulse of 104/minute, and a temperature of 97°F. Head and neck, lungs, heart, and abdominal examinations were unremarkable. No lower extremity edema was present and the left leg amputation site was unremarkable. Electrocardiogram results showed peaked T waves in the precordial leads and a widened QRS complex. Laboratory data showed the following serum abnormalities: sodium, 134 mEq/L; potassium, 8.5 mEq/L; chloride, 96 mEq/L; total CO2, 15 mEq/L; glucose, 73 mg/ dL; blood urea nitrogen, 169 mg/dL; and serum creatinine, 9.0 mg/dL. The calcium level was 9.4 mg/dL and the phosphate level was 8.0 mg/dL. The hemoglobin level was 10.9 g/dL and the hematocrit level was 33.1%. The patient was aggressively treated for hyperkalemia with
940
PERAZELLA AND ERAS
10 mL of intravenous calcium gluconate (10% solution), 50 mL of intravenous 50% dextrose, and intravenous insulin (10 U). Hemodialysis was initiated within the next few hours. After dialysis, pertinent labs included serum potassium at 4.4 mEq/L and phosphate at 3.1 mg/dL. A total of approximately 2 L of intravenous normal saline was administered during the first day of admission for presumed volume contraction, and no further rofecoxib was prescribed. The patient required no further dialysis, urine output increased to 750 mL/d by day 3, and her serum creatinine decreased to baseline (2.0 mg/dL) by day 8 of hospital admission. Reversible acute renal failure and hyperkalemia were attributed to rofecoxib therapy in a high-risk patient with chronic renal deficiency and intravascular volume depletion. ACKNOWLEDGMENT The authors thank Dr Jim Wood for his contribution of the last case.
REFERENCES 1. Schlondorff D: Renal complications of nonsteroidal anti-inflammatory drugs. Kidney Int 44:643-653, 1993 2. Perazella MA, Buller GK: Can ibuprofen cause acute renal failure in a normal individual? A case of acute overdose. Am J Kidney Dis 18:600-602, 1991 3. Perazella MA, Buller GK: NSAID nephrotoxicity revisited: Acute renal failure due to parenteral ketorolac. South Med J 86:1421-1424, 1993 4. Laine L: Nonsteroidal anti-inflammatory drug gastropathy. Gastrointest Endosc Clin North Am 6:489-504, 1996
5. Smith WL: Prostanoid biosynthesis and mechanisms of action. Am J Physiol 263:F181-F187, 1992 6. Clive DM, Stoff JS: Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 310:563572, 1984 7. Smith WL, DeWitt DL: Biochemistry of prostaglandin endoperoxide synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal antiinflammatory agents. Semin Nephrol 15:179-186, 1995 8. Crofford LJ: COX-1 and COX-2 tissue expression: Implications and predictions. J Rheumatol 24:15-19, 1997 9. Schneider A, Stahl RA: Cyclooxygenase-2 (COX-2) and the kidney: Current status and potential perspectives. Nephrol Dial Transplant 13:10-12, 1998 10. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD: Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94:2504-2510, 1994 11. Yang T, Singh I, Pham H, Sun D, Smart A, Schnermann JB, Briggs JP: Regulation of cyclooxygenase expression in the kidney by dietary salt intake. Am J Physiol 264:F481-F489, 1998 12. Komhoff M, Grone HJ, Klein T, Seyberth HW, Nusing RM: Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: Implication for renal function. Am J Physiol 272:F460-F468, 1997 13. Whelton A, Schulman G, Verburg KM, Drower EJ, Geis GS: Effects of celecoxib and naproxen on renal function in the elderly. J Am Soc Nephrol 10:471A, 1999 (abstr) 14. Swan SK, Lasseter KC, Ryan CF, Buechel KL, Lambrecht LJ, Pinto MB, Dilzer SC, Obrda O, Sundblad KJ, Larson PJ, Gertz BJ, Brater DC, Yao SL: Renal effects of multiple-dose rofecoxib, a COX-2 inhibitor, in elderly subjects. J Am Soc Nephrol 10:641A, 1999 (abstr) 15. Whelton A, Brater DC, Sica DA, Verburg KM, Drower EJ, Geis GS: Effects of celecoxib and naproxen on renal function in chronic renal insufficiency patients. J Am Soc Nephrol 10:92A, 1999 (abstr)
Are Selective COX-2 Inhibitors Nephrotoxic? Mark A. Perazella, MD, and Jennifer Eras, MD ● Nonsteroidal anti-inflammatory drugs are well-known culprits in the development of acute renal insufficiency in high-risk patients. The recent release of the selective cyclooxygenase-2 enzyme inhibitors for the treatment of inflammatory diseases and pain syndromes has been associated with a clear-cut decrease in adverse gastrointestinal effects. However, the nephrotoxic potential of these agents in patients with prostaglandin-dependent states and chronic renal impairment is unknown. Many clinicians commonly wonder if these agents can be safely prescribed to such high-risk patients. We present two cases of acute renal failure complicating the course of therapy with celecoxib in patients with chronic renal insufficiency. r 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Celecoxib; renal failure; cyclooxygenase-2 (COX-2); nonsteroidal anti-inflammatory drugs (NSAIDs).
Editorial, p. 976
N
ONSTEROIDAL anti-inflammatory drugs (NSAIDs) with nonselective cyclooxygenase (COX) enzyme inhibition are commonly prescribed to patients for a variety of inflammatory diseases and pain syndromes. As a result, adverse gastrointestinal (GI) and renal effects are relatively common problems.1-4 The recent introduction of selective COX-2 enzyme inhibitors has reduced the GI toxicity that occurs with these drugs.4 However, the nephrotoxic potential of these new agents is currently unknown. This report describes two cases of reversible acute renal failure associated with the selective COX-2 enzyme inhibitor, celecoxib, in patients with chronic renal insufficiency. CASE REPORTS
Case 1 A 63-year-old man with a history of hypertension, coronary artery disease, left ventricular hypertrophy with preserved ventricular function, osteoarthritis, and chronic renal insufficiency (baseline serum creatinine level, 2.8 mg/dL) was prescribed celecoxib, 200 mg, orally twice daily to relieve arthritic pain in his back and knees that was poorly responsive to current therapy. Other chronically prescribed medications included amlodipine, 10 mg/d; atenolol, 25 mg twice daily; atorvastatin, 10 mg/d; isosorbide mononitrate, 30 mg/d; enteric-coated aspirin, 325 mg/d; and acetaminophen plus codeine three times daily as needed for pain. Physical examination showed a blood pressure of 145/86 mm Hg; pulse, 68 beats/min; and temperature, 98°F. Head and neck examination was unremarkable, whereas the heart had an S4 gallop. The lungs were clear, abdomen was benign, and extremities had no edema. The knees had small effusions and mild tenderness to palpation. Palpation of the lumbar spine elicited pain.
Sixteen days after the initiation of celecoxib therapy, the patient presented to the clinic with symptoms of dyspnea, fatigue, and pedal edema that had progressively worsened over the past 5 days. He denied chest pain, dizziness, nausea or vomiting, diarrhea, or fever. The patient did not ingest other NSAIDs. Physical examination was remarkable for a blood pressure of 190/95 mm Hg and a pulse of 75 beats/ min. Jugular venous distension was present at 45°. Lung examination showed bibasilar crackles, and the heart had an S4 gallop. The abdomen was unremarkable, and there was 2⫹ pitting edema of the ankles. Skin examination was within normal limits. Laboratory data showed the following values: sodium, 134 mEq/L; potassium, 5.1 mEq/L; chloride, 96 mEq/L; total CO2, 20 mEq/L; blood urea nitrogen, 73 mg/dL; and serum creatinine, 4.9 mg/dL. Complete blood count was normal except for a hemoglobin level of 9.2 g/dL and hematocrit of 28.5%. Liver function test results and creatinine phosphokinase levels were normal. Urinalysis showed a specific gravity of 1.018, trace protein, and negative blood, glucose, and leukocyte esterase. Examination of the urine sediment was unremarkable for cells but showed a few hyaline casts. Urine electrolyte levels were not obtained. Acute renal failure and volume overload caused by celecoxib therapy were diagnosed. Celecoxib was discontinued, and intravenous furosemide was administered. Over the next 5 days, renal function returned to near baseline (serum creatinine level, 2.9 mg/dL), and the state of volume overload resolved.
From the Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT. Received November 30, 1999; accepted in revised form January 28, 2000. Address reprint requests to Mark A. Perazella, MD, Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, LMP 2073, 333 Cedar St, New Haven, CT 06520. E-mail: [email protected]
r 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3505-0021$3.00/0 doi:10.1053/kd.2000.6404
American Journal of Kidney Diseases, Vol 35, No 5 (May), 2000: pp 937-940
937
938
PERAZELLA AND ERAS
Case 2 A 68-year-old man with a history of coronary artery disease, cardiomyopathy with a left ventricular ejection fraction of 45%, anemia (hemoglobin, 9.7 g/dL; hematocrit, 29%), type 2 diabetes mellitus, hypertension, gout, hyperlipidemia, and diabetic nephropathy (serum creatinine level, 3.5 mg/dL) was administered celecoxib, 200 mg, orally twice daily for treatment of gout of the right foot unresponsive to colchicine and narcotic analgesics. Chronically prescribed medications included lisinopril, 10 mg/d; torsemide, 20 mg/d; amlodipine, 5 mg/d; enteric-coated aspirin, 325 mg/d; atorvastatin, 20 mg/d; glyburide, 5 mg twice daily; digoxin, 0.125 mg every other day; colchicine, 0.6 mg/d; subcutaneous erythropoietin, 2,000 U/wk; and codeine, 30 mg every 4 to 6 hours for gouty pain. Physical examination showed blood pressure of 135/78 mm Hg; pulse, 88 beats/min; and temperature, 97.6°F. Head and neck examination was within normal limits except for changes indicative of proliferative diabetic retinopathy. The lungs were clear, and the heart had a 2/6 holosystolic murmur over the apex that radiated to the left axilla. Abdominal examination was normal; however, the lower extremities had 1⫹ pitting edema of the feet and ankles. Thirteen days after the start of celecoxib therapy, the patient presented to his physician reporting dyspnea with exertion, orthopnea, reduced urine output, fatigue, and increased lower-extremity edema. The patient denied other NSAID ingestion. Physical examination showed prominent jugular venous distension at 90°, bibasilar crackles on auscultation of the lungs, an S3 gallop and 2/6 holosystolic heart murmur, and bilateral 3⫹ pitting edema to midcalf. There was no asterixis, petechiae, or skin rash. Laboratory data showed the following abnormal serum values: sodium, 132 mEq/L; potassium, 5.4 mEq/L; chloride, 98 mEq/L; total CO2, 18 mEq/L; glucose, 225 mg/dL; blood urea nitrogen, 95 mg/dL; and serum creatinine, 5.6 mg/dL. Hemoglobin was 8.5 g/dL, and hematocrit was 26%. Liver function test results and muscle enzyme levels were normal. Urine sediment showed a few renal tubular epithelial cells and epithelial cell casts, but no red blood cells, white blood cells, or red blood cell casts. Urinalysis was pertinent for 2⫹ protein (consistent with baseline) and positive glucose, but no blood or leukocyte esterase. Urine electrolyte levels were not measured. Acute renal insufficiency complicated by congestive heart failure and mild hyperkalemia was ascribed to therapy with celecoxib. Discontinuation of celecoxib and treatment with intravenous furosemide resulted in the resolution of acute renal failure (serum creatinine level returned to baseline of 3.3 mg/dL) and volume overload over the next 7 days. No other medications were discontinued at this time.
DISCUSSION
NSAID therapy is complicated by a variety of renal complications, which include electrolyte disturbances (hyponatremia, hyperkalemia), disorders of salt balance (edema, hypertension), acute and chronic tubulointerstitial nephritis, papillary necrosis, glomerular lesions, and acute hemodynamic renal failure.1-3 Impaired synthe-
sis of renal prostaglandins produced locally in the kidney by NSAIDs underlies this pathological process in most cases.1-3,5 Acute renal insufficiency often develops when patients with prostaglandin-dependent disease states (volume depletion, cirrhosis, congestive heart failure, nephrosis, chronic renal failure) are administered NSAIDs, which inhibit COX enzyme activity and blunt the production of these compensatory (vasodilatory) prostaglandins.1-3,6 In the past, the COX-1 enzyme isoform was believed to be the important enzyme involved in renal prostaglandin synthesis. However, the COX-2 enzyme was recently noted to have an important role in prostaglandin production during inflammatory processes.7 As a result, this isoform was considered to be inducible, whereas the COX-1 isoform was believed to be constitutive and integral to the maintenance of organ (such as kidney, GI tract) integrity.7,8 The recent development of COX-2 selective inhibitors has been a major advancement in the treatment of inflammatory diseases and pain syndromes without the associated gastrotoxicity.4 However, the effect of selective COX-2 inhibition on renal function, especially in states of prostaglandin dependency, is essentially unknown.9 Animal (rat) models, using in situ hybridization and immunohistochemistry, show the constitutive expression of COX-2 enzyme in macula densa and ascending thick limb cells.10,11 Chronic salt depletion further increases COX-2 immunoreactivity in the macula densa and epithelial ascending thick limb cells, suggesting a role for this enzyme in the regulation of renin release.10,11 A study of seven adult human kidneys (nephrectomy specimens from patients with cancer) showed constitutive expression of COX-2 in locations different from those described in animal studies.12 COX-2 immunoreactive protein was localized to endothelial and smooth muscle cells of arteries, arterioles, and veins.12 In addition, COX-2 protein was also shown in vasa recta of the medulla and visceral epithelial cells (podocytes) of cortical glomeruli, but not in macula densa cells.12 Recently published abstracts provide some insight into the effect of COX-2 selective inhibitors on renal function in two groups of patients.13-15 In 29 healthy elderly subjects without renal insufficiency, treatment with celecoxib for 10 days was compared with the nonselective
COX-2 INHIBITORS AND ACUTE RENAL FAILURE
COX inhibitor, naproxen, in a prospective crossover trial.13 Glomerular filtration rate (GFR) declined significantly on day 6 of therapy (–7.53 versus –1.11 mL/min/1.73 m2) in naproxentreated patients compared with celecoxib-treated subjects.13 Urinary excretion of prostaglandins (PGE2, 6-keto-PGF1) was significantly reduced with both drugs, but no significant difference in urinary levels was noted between the two medications.13 In a multicenter, double-blind trial, 60 healthy elderly patients with a wide variation in creatinine clearance (30 to 80 mL/min) were randomized to treatment with the COX-2 selective inhibitor (rofecoxib) at two different doses (12.5 and 25 mg/d), indomethacin (50 mg three times daily), or placebo.14 A similar decline in GFR at day 6 of the study compared with baseline was noted for rofecoxib, 12.5 mg (mean change, –11.5%); rofecoxib, 25 mg (mean change, –12.7%); and indomethacin (mean change, –10.4%), but not for placebo.14 Finally, a multicenter study compared the effects of celecoxib, naproxen, and placebo in 75 patients with stable chronic renal insufficiency, defined by GFR in the 31.8- to 36.9-mL/min/ 1.73 m2 range.15 No significant difference in GFR was noted among the three groups at 6 days of study, despite a significant reduction in urinary prostaglandin levels in both treatment groups.15 In addition, neither drug had an effect on urinary sodium excretion or plasma renin activity.15 The two cases presented in this report clearly suggest that COX-2–selective NSAIDs may cause reversible acute renal failure and volume overload when administered to patients with stable chronic renal insufficiency. One of the patients (case 2) also had a compensated congestive cardiomyopathy that may have further increased the risk for the development of renal failure and volume overload. The patients described in this report were administered celecoxib for 13 and 16 days longer than the 6- and 10-day periods of study in the abstracts cited, respectively.13-15 It is possible that the longer duration of therapy in these two cases may have increased the risk for the development of acute renal failure. Another potential explanation in these patients is primary congestive heart failure–related acute prerenal insufficiency independent of celecoxib therapy. This cause is unlikely because both patients were stable with well-compensated heart disease at the time of initiation of celecoxib
939
therapy. Volume overload developed subsequent to therapy with this medication, further increasing prostaglandin dependency and the risk for NSAID-associated renal failure. However, it is reasonable to conclude at this point in time that COX-2–selective NSAIDs can cause acute renal failure and should be avoided or at least used cautiously for short periods of time (with close monitoring) in patients with chronic renal insufficiency. In addition, randomized, prospective studies should be undertaken to evaluate the renal safety of COX-2 selective agents compared with nonselective COX inhibitors in a large number of high-risk patients. NOTE ADDED IN PROOF
A 73-year-old woman with chronic renal failure (serum creatinine, 1.7 to 2.2 mg/dL); type 2 diabetes mellitus; type 4 renal tubular acidosis; peripheral vascular disease complicated by left, below-knee amputation; peripheral neuropathy; and Crohn’s disease was sent to the emergency department from her nursing facility after she was noted to develop loss of consciousness secondary to hypoglycemia (glucometer read ‘‘low’’). The patient awoke following 3 ampules of 50% dextrose. She reported 5 days of anorexia and decreased urine output of 2 days in duration. Her chronically prescribed medications included glyburide at 5 mg per day, ranitidine at 150 mg at bedtime, multivitamin at 1 tablet per day, oxybutynin at 5 mg twice per day, and sodium bicarbonate at 325 mg twice per day. Rofecoxib at 25 mg per day was added 14 days before presentation to treat chronic pain. Physical examination revealed a blood pressure of 108/65, a pulse of 104/minute, and a temperature of 97°F. Head and neck, lungs, heart, and abdominal examinations were unremarkable. No lower extremity edema was present and the left leg amputation site was unremarkable. Electrocardiogram results showed peaked T waves in the precordial leads and a widened QRS complex. Laboratory data showed the following serum abnormalities: sodium, 134 mEq/L; potassium, 8.5 mEq/L; chloride, 96 mEq/L; total CO2, 15 mEq/L; glucose, 73 mg/ dL; blood urea nitrogen, 169 mg/dL; and serum creatinine, 9.0 mg/dL. The calcium level was 9.4 mg/dL and the phosphate level was 8.0 mg/dL. The hemoglobin level was 10.9 g/dL and the hematocrit level was 33.1%. The patient was aggressively treated for hyperkalemia with
940
PERAZELLA AND ERAS
10 mL of intravenous calcium gluconate (10% solution), 50 mL of intravenous 50% dextrose, and intravenous insulin (10 U). Hemodialysis was initiated within the next few hours. After dialysis, pertinent labs included serum potassium at 4.4 mEq/L and phosphate at 3.1 mg/dL. A total of approximately 2 L of intravenous normal saline was administered during the first day of admission for presumed volume contraction, and no further rofecoxib was prescribed. The patient required no further dialysis, urine output increased to 750 mL/d by day 3, and her serum creatinine decreased to baseline (2.0 mg/dL) by day 8 of hospital admission. Reversible acute renal failure and hyperkalemia were attributed to rofecoxib therapy in a high-risk patient with chronic renal deficiency and intravascular volume depletion. ACKNOWLEDGMENT The authors thank Dr Jim Wood for his contribution of the last case.
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