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Non-Steroidal Anti-Inflammatory Nephrotoxicity* RICHARD MANIGLIA, B.A.T ALLAN B

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Non-Steroidal Anti-Inflammatory Nephrotoxicity* RICHARD MANIGLIA, B.A.T ALLAN B ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 18, No. 3 Copyright © 1988, Institute for Clinical Science, Inc. Non-Steroidal Anti-Inflammatory Nephrotoxicity* RICHARD MANIGLIA, B.A.t ALLAN B. SCHWARTZ, M.D.,$ and SHEILA MORIBER-KATZ, M.D.f§ f Department of Pathology and Laboratory Medicine, tDepartment of Medicine, §Division of Renal Pathology and Electron Microscopy, Hahnemann University School of Medicine, Philadelphia, PA 19102 ABSTRACT Non-steroidal anti-inflammatory drugs have a wide range of use in clini­ cal practice because of their analgesic and anti-inflammatory properties. However, their potential nephrotoxicity has been noted. The case histo­ ries were studied, retrospectively, in 13 patients who were taking non-ste- roidal anti-inflammatory drugs as follows: four on fenoprofen (Nalfon®), three on naproxen (Naprosyn®), two on ibuprofen (Motrin®), two on sulin- dac (Clinoril®), one on tolmetin (Tolectin®), and one on indomethacin (Indocin®) and who exhibited abnormal urinalysis or a deterioration in renal function. Nine of the patients underwent renal biopsies, and eight of these biopsies were positive for interstitial nephritis. In addition to the presentation of additional cases of non-steroidal anti-inflammatory drug nephrotoxicity, a brief review of the current theories of the nephrotoxic mechanism is presented. Introduction this paper will be the non-aspirin, non­ steroidal anti-inflammatory drugs Numerous reports exist that document (NSAID). Since these drugs have a wide the nephrotoxicity of drugs such as the spectrum of use in clinical practice, their synthetic penicillin (methacillin, carben- deleterious actions are of more than just icillin, ampicillin), other antibiotics academic interest. It is hoped that by (aminoglycosides, amphotericin B), understanding the nephrotoxic patho­ thiazide and loop diuretics, and anti­ physiologic mechanisms of non-steroidal neoplastic agents. The major concern of anti-inflammatory drugs, clinicians will be better able to treat those patients who * Send reprint requests to: Sheila Moriber-Katz, may be adversely affected by the admin­ M.D., Professor of Pathology and Laboratory Medi­ istration of these drugs. cine, Director, Division of Renal Pathology and Electron Microscopy, Hahnemann University, The clinical and histopathologic mani­ School of Medicine, Mail Stop #435, Broad and Vine festations of NSAID toxicity are not uni­ Streets, Philadelphia, PA 19102. form. Clinically, “the presenting features 240 0091-7370/88/0500-0240 $02.00 © Institute for Clinical Science, Inc. NON-STEROIDAL ANTI-INFLAMMATORY NEPHROTOXICITY 241 of nephrotoxicity are variable and immunofluorescence, and electron encompass acute or chronic, oliguric or microscopy. The study group consisted non-oliguric renal failure with or without of patients from Hahnemann University associated nephrotic syndrome.”17 In Hospital and cases referred from sur­ addition, the pathologic findings of the rounding community hospitals. renal lesions may vary from interstitial nephritis to minimal change disease to acute tubular necrosis. Of particular Clinical Findings interest to our study was the existence of The ages of the subjects ranged from renal failure associated with nephrotic 28 to 74 years with a mean age of 60 syndrome following non-steroidal anti­ years. The study included eight females inflammatory drug administration. and five males. None of the subjects of Renal failure and nephrotic syndrome, our study had previous histories of renal first reported in three patients taking disease. Four patients took fenoprofen fenoprofen (Nalfon®)1 has also been (Nalfon®) for periods ranging from 10 noticed in patients ingesting other non­ months to one year. In addition, they steroidal anti-inflammatory drugs, such took the following drugs: prednisone (2 as indomethacin (Indocin®), tolmetin patients), Ascriptin® (1 patient), heparin (Tolectin®), and ibuprofen (1 patient), Phenaphen® (1 patient), (Motrin®).1’3’4’5’7,9’10’11'17>22-23’24 Theories aspirin (1 patient), Lasix® (1 patient). developed to explain this reaction sug­ Three patients took naproxen (Napro­ gest two mechanisms: (1) non-steroidal syn®) for periods ranging from four anti-inflammatory agents inhibit prosta­ weeks to one year. In addition, they took glandin synthesis, and this decrease in the following drugs: aspirin (one prostaglandin production subsequently patient), liquid antacid (one patient), leads to renal failure via altered renal Inderal® (one patient), nitroglycerin (one hemodynamics; and (2) the renal failure patient), and Serax® (one patient). Two is associated with a disordered cell- patients took ibuprofen (Motrin®), one mediated immunity that is again the taking it sporadically and the other for result of the alterations in prostaglandin up to one year. Neither took additional synthesis. This paper will document drugs. Of the two patients who took additional cases of this type of drug- sulindac (Clinoril®), one used the drug induced renal failure, detailing the spec­ for eight days, while the duration of use trum of illness and the drugs implicated. for the other patient was not available. Additionally, a review of these theories One patient also used Ascriptin®. The of non-steroidal anti-inflammatory drug one patient taking tolmetin (Tolectin®) nephrotoxicity will be presented. took it for three months with no addi­ tional drugs. Indomethacin (Indocin®) Methods was used by one patient sporadically Case histories of 13 patients who were along with aspirin. taking non-steroidal anti-inflammatory drugs and who exhibited abnormal uri­ Signs and Symptoms nalysis or a deterioration in renal func­ tion were studied introspectively. Clini­ The four patients who were receiving cal information was tabulated from the fenoprofen (Nalfon®) had the following available medical records. Renal biop­ symptoms: nausea (two patients), vomit­ sies, from nine of these patients, were ing (one patient), dizziness (one patient), studied by routine light microscopy, and swelling following the injection of 242 MANIGUA, SCHWARTZ, AND MORIBER-KATZ hydrocortisone and procaine (one only three of the patients. The values patient). The three naproxen (Napro­ were 7 ml per min, 42 ml per min, and syn®) recipients had a variety of symp­ 26.1 ml per min. toms. One only had swelling. The sec­ Two of the three naproxen (Napro­ ond reported nausea, vomiting, and syn®) users had 24 hour urinary proteins weakness. The third naproxen (Napro­ of 16.8 mg per dl and +1 protein. The syn®) user reported having a sore throat third naproxen (Naprosyn®) user did not for one week, nausea, anorexia, chills, have this test performed. Urinalysis chest pain, and a decrease in urine out­ showed urinary granular casts (3 put. Symptoms associated with ibupro- patients), tubular epithelial cells (2 fen (Motrin®) involved swelling in one patients), WBCs (2 patients), RBCs (2 patient. The other ibuprofen (Motrin®) patients), bacteria (1 patient), and oval user was reported to have gained 20 lbs fat bodies (1 patient). Initial BUNs were in four days, cough, and sore throat. One 120 mg per dl and 93 mg per dl (one of the two sulindac (Clinoril®) users unavailable); initial serum creatinine reported having nausea, anorexia, vomit­ levels were 6.1 mg per dl, 24 mg per dl, ing, and lethargy. The lone indometha- and 8.7 mg per dl; creatinine clearances cin (Indocin®) user developed swelling of were not available for these patients. the left knee while the tolmetin (Tolec- For the two ibuprofen (Motrin®) tin®) patient reported nausea, vomiting, users, laboratory studies showed 3.5 g and insomnia. None of our patients and 10.0 g of protein in the 24 hour urine reported the appearance of any type of studies. The urinary sediment of these skin rash. While edema was not uni­ patients contained granular casts (1 formly reported, when it did exist, it patient) and oval fat bodies (1 patient). ranged from +1 to +3. The tolmetin The BUNs were 19 mg per dl and 32 mg (Tolectin®) and indomethacin (Indocin®) per dl; serum creatinine levels were 1.0 cases had no edema. mg per dl and 1.4 mg per dl; creatinine clearance was 76 ml per min for one patient and 68 ml per min for the other. Laboratory Findings The two sulindac (Clinoril®) users had the following quantities of protein in Laboratory studies were as follows: for their 24 hour collections: 16.6 grams and the four patients taking fenoprofen (Nal- + 3. Reported urinary sediment for one fon®), initial urinary protein values were patient contained granular casts, WBCs, 5.6 g per 24 hours, 12.1 g per 24 hours, and renal tubular cells. On presentation, 14.8 g per 24 hours, and +4 protein by BUNs were 126 mg per dl and 72 mg per dipstick. Analysis of urinary sediment dl; serum creatinine was 10.1 mg per dl revealed the presence of granular casts (3 and 2.2 mg. Creatinine clearance infor­ patients), red blood cells (RBCs) (2 mation was not available. patients), white blood cells (WBCs) (1 In the single case of tolmetin (Tolec­ patient), glucose (1 patient), hyaline tin®) use, 24 hour urinary analysis casts (1 patient), multiple tubular and revealed +1 protein; urinary sediment epithelial cells (1 patient). Initial blood- contained RBCs and WBCs, hyaline urea nitrogens (BUNs) were 60 mg per casts, and eosinophils. The BUN was 120 dl, 89 mg per dl, 164 mg per dl, and 26 mg per dl; serum creatinine was 11 mg mg per dl. Initial serum creatinines were per dl; creatinine clearance was not recorded at 8.2 mg per dl, 4.5 mg per dl, available. 20 mg per dl, and 2.0 mg per dl. Creati­ In the single case of indomethacin nine clearance levels were available for (Indocin®) use, this patient’s urine was NON-STEROIDAL ANTI-INFLAMMATORY NEPHROTOXICITY 243 found to contain 4.32 g of protein after a nine, 1.4 mg per dl, 1.0 mg per dl; 24 24 hour collection. The BUN was 73 mg hour urinary protein, 87 mg, 28 mg. The per dl; serum creatinine was 8.6 mg per lone tolmetin (Tolectin®) user received dl; creatinine clearance was 13.2 ml per steroids and dialysis.
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