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. Recovery labora­ min. tory values were BUN, 50 mg per dl; serum creatinine 2.1 mg per dl; creati­ Treatment and Follow-up nine clearance, 37 ml per min, and 52 mg of protein in the 24 hour urine col­ Three of the four fenoprofen (Nalfon®) lection. The single indomethacin (Indo- patients received steroid treatment for a cin®) user received steroid and dialysis duration of six to seven weeks. Two treatment. Recovery laboratory results received 60 mg per day while the third were found only for BUN (41 mg per dl) received 5 mg every other day. Two of and serum creatinine (6.2 mg per dl). the four fenoprofen (Nalfon®) users had dialysis treatments ranging from one to Renal Biopsy Information eight weeks. Recovery laboratory results, after the drugs were discontin­ Nine of our 13 non-steroidal, anti­ ued, were as follows (when available): inflammatory drug users had renal biop­ BUN, 13 mg per dl, 50 mg per dl, 40 to sies. The results (when obtainable) 44 mg per dl, and 71 mg per dl; serum showed that interstitial nephritis was creatinine, 0.8 mg per dl, 2.1 mg per dl, apparent in eight of the nine biopsy 1.6 mg per dl, and 2.5 mg per dl; creati­ cases. nine clearance, 64 mg per min, 37 ml per min; 69 ml per min; recovery 24 L ig h t M ic ro sco py hour urinary proteins, 72 mg, 52 mg, 22.8 mg, and trace protein. Three patients who had taken feno­ None of the three naproxen (Napro­ profen (Nalfon®) had biopsies which syn®) users received steroid treatment. exhibited a variety of patterns revealed Two of the patients received dialysis by light microscopy. The glomeruli of treatments for three and 10 days, respec­ one patient were reported to have focal tively. Recovery lab information was as periglomerular fibrosis plus occasional follows (when available): BUN, 35 mg contracted glomeruli; another patient per dl, 22 mg per dl; serum creatinine, exhibited unhyalinized glomeruli show­ 1.0 mg per dl, 2.6 mg per dl, 1.2 mg per ing fullness in the interstitial tissue. dl; protein in urine was negative for one Eosinophils, plasma cells, lymphocytes patient. and leukocytes were found (figure 1). One of the two ibuprofen (Motrin®) This area was edematous. users received steroid treatment (120 mg The two patients who received every other day), but neither had dialy­ naproxen (Naprosyn®) had biopsies sis. Recovery laboratory results were which exhibited focal glomerular fibrosis BUN, 22 mg per dl and 14 mg per dl; and glomerulosclerosis in about 30 to 50 serum creatinine 1.0 mg per dl and 1.8 percent of the glomeruli. Membranes mg per dl; creatinine clearance 80 ml per showed a slight thickening. In the inter­ min and 15 ml per min; 24 hour urinary stitial tissue, there was evidence of proteins, 1.9 g and 3.4 mg. chronic inflammation and edema (fig­ One of the two sulindac (Clinoril®) ure 2). users received dialysis treatment. Light microscopy of the one tolmetin Recovery laboratory results were: BUN, (Tolectin®) user’s biopsy showed a diffuse 26 mg per dl, 15 mg per dl; serum creati­ extensive inflammatory infiltrate consist­ MANIGLIA, SCHWARTZ, AND MORIBER-KATZ

F ig u r e 1. This case of fenoprofen induced acute renal failure shows an interstitial infiltrate of neutrophils, plasma cells, lymphocytes, and macro­ phages. Notice the focal tubular vacuolization. (Hematoxylin and eosin, x 200)

F ig u r e 2. A case of Naprosyn®-induced acute renal failure demonstrates marked interstitial edema and a cellular infiltrate of neutrophils, plasma cells, lymphocytes, macro­ phages, and eosinophils. (Hematoxylin and eosin, x 200)

ing of eosinophils, plasma cells, lympho­ chronic inflammation with fibrosis. cytes and macrophages. Edema was Plasma cells, lymphocytes, and eosino­ prominent (figure 3). phils were present. Hyaline material and The biopsy of the one patient who RBCs were present in the tubular areas received indomethacin (Indocin®) (figure 4). showed scarring of the glomeruli and The one patient who received sulindac thickening of the basement membrane. (Clinoril®) showed edema and inflamma­ The interstitial tissue had extensive tion in the interstitial tissues. Plasma NON-STEROIDAL ANTI-INFLAMMATORY NEPHROTOXICITY 245

F ig u r e 3. Tubular epithelial vacuolization and “cloudy swelling” are seen in this renal biopsy associated with tolmetin administration. Eosino­ phils are present in the interstitium. (Arrow) (Hematoxylin and eosin, x 450)

F ig u re 4. This renal biopsy demonstrates severe acute tubular necrosis. In most tubules, illustrated here, only tubular basement mem­ brane remains. Notice the interstitial nests of inflam­ matory cells. (Hematoxy­ lin and eosin, X 225) 246 MANIGLIA, SCHWARTZ, AND MORIBER-KATZ cells and eosinophils were present. The cent). The interstitial tissue had exten­ glomeruli were unhyalinized and the sive edema and inflammation, deposits tubules unremarkable. of plasma cells, leukocytes, eosinophils, fibrin, and macrophages. In one case, I mmunofluorescence M ic ro sc o py the tubules were unremarkable, but the other case exhibited nonspecific atrophic Immunofluorescence study of the changes. renal biopsies showed a wide variety of The single patient who received tol- results. The glomeruli were found to metin (Tolectin®) showed 10 percent contain IgG (five cases), IgA (two cases), effacement of the foot processes. The C-3 (two cases), albumin (one case), and interstitial region exhibited an extensive fibrinogen (one case). The patterns of the inflammatory infiltrate of plasma cells, deposits in the glomeruli were described histiocytes, lymphocytes, eosinophilia, as weak, sparse deposits or linear and and neutrophilia. granular deposits or diffuse and weakly The single patient who received indo- linear deposits. The tubules were found methacin (Indocin®) showed diffuse to contain IgA (one case), albumin (three fusion of foot processes and thickening of cases), C-3 (two cases) and fibrinogen the basement membranes of the glomer­ (one case). The patterns of these deposits uli. Eosinophils, fibroblasts, and colla­ were described as weak, sparse focal gen were seen in the interstitium. deposits or as focal linear deposits or as The one patient who received sulindac diffuse granular deposits. The interstitial (Clinoril®) showed diffuse widespread tissue was revealed to have fibrinogen effacement of foot processes. The inter­ (five cases), albumin (four cases), IgA stitial tissue showed focal edema. (two cases), IgG (four cases), IgE (four Biopsy results of the ibuprofen cases), C-3 (three cases), C-4 (one case), (Motrin®) user showed widespread and IgM (one case). Patterns in the effacement of the foot processes. Arteri­ interstitial tissue were described as oles were noted to show osmiophilic prominent, conspicuous, granular, and deposits beneath the endothelium. diffuse. Discussion E le c t r o n M icro sco py The major clinical benefits derived The patients who received fenoprofen from the use of non-steroidal anti­ (Nalfon®) had biopsies which showed inflammatory drugs revolve around their widespread effacement of foot processes. analgesic, anti-pyretic, and anti-inflam­ The glomerular basement membrane matory properties. Non-steroidal anti­ was thickened in two cases. In two cases, inflammatory drugs provide these bene­ the interstitial tissue and tubules were ficial results by inhibiting prostaglandin normal. In the other case, the interstitial synthesis, specifically by inhibiting the tissue had focal edema and inflammation enzyme cyclo-oxygenase. consisting of lymphocytes, macrophages, The central building block for prosta­ eosinophils, neutrophils, and plasma glandin synthesis is arachidonic acid, cells (figures 5 and 6). which is a fatty acid bound to phospholi­ The two patients who received pids in the cell membrane. Arachidonic naproxen (Naprosyn®) exhibited efface­ acid is released from the cell membrane ment of the foot processes (10 to 50 per­ via the action of an enzyme within the NON-STEROIDAL ANTI-INFLAMMATORY NEPHROTOXICITY 247

F ig u r e 5. An electron micrograph of a patient given fenoprofen shows effacement of foot processes (Arrows). No electron dense deposits are seen. This patient presented with acute renal failure and the nephrotic syndrome. (Lead citrate and uranyl acetate; x 7,500) 248 MANIGLIA, SCHWARTZ, AND MORIBER-KATZ

F igure 6. A high magnification electron micrograph of the patient illustrated in figure 5 clearly shows slender glomerular basement membranes and fused foot processes. (Lead citrate and uranyl acetate; X 23,000) NON-STEROIDAL ANTI-INFLAMMATORY NEPHROTOXICITY 249 phospholipase class. There is still debate lates the extent of vasoconstriction.5 Tan over whether phospholipase A2, phos­ et al20 reported the case of a patient who pholipase C, or diglyceride lipase is developed acute renal failure when tak­ responsible for this liberation.14 The ara- ing indomethacin (Indocin®). During chidonic acid can then enter one of two indomethacin (Indocin®) treatment, the pathways; it can become the substrate of patient’s BUN rose to 111 mg per dl and lipoxygenase which will result in the pro­ the serum creatinine level was recorded duction of leukotrienes or it can be oxy­ at 7.3 mg per dl. The patient’s urinary genated by cyclo-oxygenase which will output was less than 300 ml per a 24 eventually lead to the production of hour period. What the investigators of prostaglandins. The cyclo-oxygenase this case also discovered was that “after oxygenation step leads to the production three days of indomethacin (Indocin®) of cyclic endoperoxides (PGG2 and therapy, urinary PGE2 level was dimin­ PGH2). The pathway branches further at ished. ”20 When the patient was taken off this point to form the vast array of differ­ indomethacin (Indocin®), the PGE2 level ent prostaglandins. The non-steroidal was restored and renal function also anti-inflammatory drugs act by inhibit­ returned to normal. This took approxi­ ing cyclo-oxygenase. The decrease in mately 30 days and required hemodialy­ cyclo-oxygenase activity is not absolute sis treatment. The conclusion of this arti­ but is a decrease in activity of the cle was that “Prostaglandins may be criti­ enzyme relative to previous levels.14 The cal for the integrity of renal function, and inhibition is reversible and activity will the use of prostaglandin inhibitors such return to normal once the non-aspirin as indomethacin (Indocin) and other non-steroidal anti-inflammatory drug is non-steroidal anti-inflammatory drugs withheld.14 may be deleterious in patients with In the kidney, the most important underlying renal disease.”20 prostaglandins belong to the dienoic Walshe and Venuto23 presented the series and are PGI2, PGE2, and PGF2. case of another patient with an adverse These prostaglandins are produced in reaction to indomethacin (Indocin®). the kidney by medullary interstitial This patient had a history of cardiac trou­ cells. It is believed that this synthesis is ble and was given indomethacin (Indo­ prompted by ischemia and circulating cin®) as a treatment for an attack of gout. vasoconstrictors.8 The action of prosta­ The indomethacin (Indocin®) impaired glandins such as PGI2 results in the com­ renal function; however, when adminis­ pensatory vasodilation needed by the tration of this drug was stopped, renal kidney to maintain adequate renal func­ function returned to normal. Walshe and tion. Venuto proposed that “Indomethacin How prostaglandins control renal was causally related to the acute deterio­ blood flow is becoming clearer with each ration in renal function and worsening of passing year. It has been demonstrated her cardiac status.”23 They also noticed that when 50 mg of indomethacin (Indo- that the amount of prostaglandin E cin®) are given to a patient, renal vascu­ recovered in the urine decreased during lar resistance increases by 30 percent.1 the time that indomethacin was being When prostaglandin E2 is given in this taken. Walsh and Venuto further state same patient, renal vascular resistance that Prostaglandin E has an important and renal blood flow return to normal. role in the normal functioning of the kid­ In essence, this prostaglandin is com­ neys. In this case, the patient’s conges­ pensatory, and it homeostatically modu­ tive heart failure acted as a vasocon- 250 MANIGLIA, SCHWARTZ, AND MORIBER-KATZ stricting influence which made greater explain our findings of interstitial than normal amounts of PGE necessary nephritis in eight out of nine renal biop­ to insure normal renal function.23 sies. An explanation of our findings may The papers previously mentioned, best be found in the role played by pros­ which were published early in the inves­ taglandins in inflammation. tigation of the nephrotoxicity of non-ste- Finkelstein et al proposed in 1982 that roidal anti-inflammatory drugs, point to the nephropathy of fenoprofen (Nalfon®) the importance of hemodynamic factors was a “manifestation of disordered cell- in the evolution of non-steroidal, anti­ mediated immunity.”9 It has been noted inflammatory drug-induced renal fail­ that the inflammatory infiltrate in most ure. When the synthesis of endogenous cases of acute interstitial nephritis asso­ renal prostaglandin is inhibited by the ciated with non-steroidal anti-inflamma­ use of non-steroidal anti-inflammatory tory drug use has consisted mainly of drugs, the vasodilatory actions of these cytotoxic T cells.3,9 While B cells may agents are reduced, and there is a “pre­ also be present in the infiltrate, they are ponderance of vasoconstrictor mecha­ less prominent. It is known that prosta­ nisms mediated through the renin- glandin E2 and prostacyclin act as an angiotensin system and possibly also inhibitor on T-cell function,24 thereby through a relative increase in platelet preventing cell-mediated immune reac­ derived thromboxane activity.”17 It is tions. When non-steroidal anti-inflam- believed that these alterations in renal matory drugs are used by a patient, their blood flow may have more serious con­ suppression of PGE2 and prostacyclin sequences in patients with disease pro­ allows T-cell function to progress unin­ cesses involving the kidney, as in hyper­ hibited. As a result, lymphokine produc­ tensive patients with some degree of tion is promoted and a delayed hyper­ arterial and arteriolar nephrosclerosis,17 sensitivity reaction freely advances.24 and in congestive heart failure resulting Within this immunologic mechanism in hypo-perfusion of the kidneys.14 there may also be an explanation for the These conditions, which compromise development of proteinuria. It is renal function, require a greater reliance believed that when the lymphocytes are on the vasodilatory actions of the prosta­ no longer being inhibited by PGE2 and glandins to maintain normal renal func­ prostacyclin, they are free to produce a tion. If the availability of these critical vascular permeability factor that contrib­ prostaglandins is reduced, “vasocon- utes to protein loss. It has been sug­ stricting agents, being relatively unop­ gested that increased levels of lympho- posed, can lead to marked alterations in kines plus the vascular permeability the renal circulation and ultimately lead­ factor may result in the effacement of ing to a decrease in measured glomerular foot processes seen by electron micros­ filtration rate. ”14 If there is increased copy. 17 This would lead to proteinuria. synthesis of vasodilatory prostaglandins It appears that the hemodialysis and to compensate for an underlying disease immunologic theories of non-steroidal state in the kidney, interference with anti-inflammatory drug nephrotoxicity this compensatory mechanism could lead have validity. Perhaps this is not an to renal failure. either/or situation in which one theory While the hemodynamic conse­ must be chosen over the other. Rather, quences of prostaglandin inhibition the two pathophysiologic mechanisms explain the development of reversible may work in tandem. It may be that the renal failure after non-steroidal anti­ manifestations of either mechanism are inflammatory drug use, they do not more prominent in a certain subsection NON-STEROIDAL ANTI-INFLAMMATORY NEPHROTOXICITY 251 proteinuria and kidney function in the nephrotic of patients with a predisposition to the syndrome. Acta Med. Scand. 199:121-125, nephrotoxic actions of non-steroidal anti­ 1976. inflammatory drugs. It has been noted 2. B a b e r , N., H alliday, L., Littler, T., O r m e , M., Si b e o n , G., and CHAN, K.: The effect of that the alterations in hemodynamic fac­ indomethacin on renal function in man. Scand. tors may have more significance for J. Rheumatol. 9:52-54, 1980. patients with underlying disease status 3. B en d er , W., W h elto n , A., Beschorner, W., D arw ish, M., H all-C raggs, M., and So lez, that already involve the kidneys (like K.: Interstitial nephritis, proteinuria, and renal congestive heart failure, hypertensive failure caused by non-steroidal anti-inflamma- nephropathy, and perhaps even connec­ tory drugs. Am. J. Med. 76:1006-1012, 1984. 4. B randstitter, D. R., and M ar, D. D.: Revers­ tive tissue diseases). This subgroup of ible oliguric renal failure associated with ibupro- patients has developed a great reliance fen treatment. Brit. Med. J. 4:1194-1195, 1978. on the compensatory mechanism that 5. B rezin, J. H., Katz, S. M., Swartz, A. B., et al.: Reversible renal failure and nephrotic syn­ the renal prostaglandins provide via drome associated with non-steroidal anti-inflam­ vasodilation. It is easy to predict that this matory drugs. New Eng. J. Med. 301:1271— group of patients will have a higher like­ 1273, 1979. 6. C iabattoni, G., C inotti, G. A., P eiru cci, A., lihood of developing renal failure when et al.: Effects of sulindac and ibuprofen in using non-steroidal anti-inflammatory patients with chronic glomerular disease. drugs. Predicting when the immunologic 310:279-283, 1984. 7. C urt, A. G., Kaldany, A., W hitley, G. L., et mechanism, resulting in acute interstitial al.: Reversible rapid progressive renal failure nephritis, will play a role is less clear. In with nephrotic syndrome due to fenoprofen cal­ a patient without underlying renal dis­ cium. Ann. Int. Med. 92:72-73, 1980. ease, as was the case with the subjects of 8. C u t l e r , R. E., Fa r l a n d , S. C., andNoGUEiRA, M. J.: Drugs and the kidney. Current Therapy, our study, perhaps this is the major vol. 8, Gonick, H. C., ed. Chicago, Year Book mechanism contributing to the develop­ Medical Publishers, 1986, pp. 149-207. ment of renal failure. The renal biopsy 9. F in k elstein , A., F raley, D. S., Strachura, I., et al.: Fenoprofen nephropathy: Lipoid data clearly showed that there was an nephrosis and interstitial nephritis. Amer. J. inflammatory component to the devel­ Med. 72:81-87, 1982. opment of renal failure in our patients. 10. G reenstone, M., H artley, B., G abriel, R., et al.: Acute nephrotic syndrome with reversible This does not imply that the hemody­ renal failure after phenylbutazone. Brit. Med. J. namic factors of non-steroidal anti­ 252:950-951, 1981. inflammatory drug use are inconsequen­ 11. H anola, S. P.: Renal effects of fenoprofen (let­ tial in the patient population. Rather, ter) Ann. Int. Med. 93:508, 1980. 12. Katz, S. M., C apaldo, R., E verts, E. A., et perhaps, the immunologic consequences al.: Tolmetin: Association with reversible renal are more serious than the hemodynamic failure and acute interstitial nephritis. J. Am. Med. Assoc. 246:243-245, 1981. consequences when they occur in a kid­ 13. Kim berly, R. P., Bo w d e n , E. R., K er se r , ney without underlying disease. Conse­ R. H., et al.: Reduction of renal function by quently, the opposite may be true when newer non-steroidal anti-inflammatory drugs. Amer. J. Med. 64:804-807, 1978. an already diseased kidney is exposed to 14. Lifsch itz, M. D.: Renal effects of non-steroidal non-steroidal anti-inflammatory drugs. anti-inflammatory agents. J. Lab. Clin. Med. Hopefully, in the future, some marker 102:313-323, 1983. 15. Linton , A. L., C lark, W. E , D ried g er , A. A., will be recognized that will enable clini­ et al.: Acute interstitial nephritis due to drugs. cians to predict when patients will be Ann. Int. Med. 93:735- 741, 1980. susceptible to the immunologically 16. M c C arthy, J. T ., T o r r es, V. E ., R o m e r o , J. C., et al.: Acute intrinsic renal failure induced mediated nephrotoxicity of non-steroidal by indomethacin: Role of prostaglandin synthe­ anti-inflammatory drugs. tase inhibition. Mayo Clin. Proc. 57:289-296, 1986. 17. P irani, C. L., Valeri, A., D ’Agati, V., et al.: References Renal toxicity of non-steroidal anti-inflammatory 1. Arisz, L., D o h l e r , N. J. M ., B r e n t j e n s , drugs. Contrib. Nephrol. 55:159-175, 1987. J. R. M., et al.: The effect of indomethacin on 18. Stachura, I., Jayakumar, S., and Bourke, E.: 252 MANIGLIA, SCHWARTZ, AND MORIBER-KATZ

T and B lymphocyte subsets in fenoprofen Cartw right, D., et al.: Effects of acute and nephropathy. Amer. J. Med. 75:9—16, 1983. chronic dosing of NSAIDs in patients with renal 19. Sw ainson, C. P., G r iffith s, P., and Watson, insufficiency. Kidney Int. 30:760-768, 1986. M. L.: Chronic effects of oral sulindac on renal 22. U srerti, M ., M il et i, M ., D ’Auria, C. G., et haemodynamics and hormones in subjects with al.: Reversal of proximal tubular dysfunction by chronic renal disease. Clin. Sci. 70:243—247, indomethacin. Nephron 21:358-360, 1982. 1986. 23. Walsh e, J. J. and Ven u to , R. C.: Acute oliguric 20. Ta n , Y. S., Sh a pir o , R., and Kis h , M. A.: renal failure induced by indomethacin: Possible Reversible acute renal failure induced by indo- mechanism. Ann. Int. Med. 92:47-49, 1979. methacin. J. Amer. Med. Assoc. 241:2732- 2733, 24. W en d la n d , L. M., Wagone, R. D., and H ol­ 1979. ley, E. K.: Renal failure associated with feno­ 21. T o t o , R. D ., A n d e r s o n , S. A ., B r o w n - profen. Mayo Clin. Prog. 55:103-107, 1980.