Patterns of Tubulo-Interstitial Damage Associated With Nonsteroidal Antiinflammatory Drugs By Murray L. Levin HE NONSTEROIDAL antiinflammatory drugs (NSAIDs) have become some of the most commonly prescribed drugs in the physi cian’s armamentarium. It has been estimated that as many a§ 20 to 40 million Americans" have the Potential for use ofthese agents on a chronte basis Further evidence oftheir popularity is given by the fact that six of these agents ranked in the top 200 prescription drugs in 1981. Parallel with this sig- nificant popularity, the claim has been made that the NSAID agents rank only behind aminoglyco- sides as a cause of nephrotoxic acute renal failure caused by drugs.*4 Many different types of altered renal physiology and function have been described following the use of NSAIDs."*"" Table | summarizes the vari- ous clinical syndromes associated with the use of nonsteroidal agents RENAL FUNCTIONAL DISTURBANCES ASSOCIATED WITH NONSTEROIDAL, ANTIINFLAMMATORY AGENTS Renal function in certain groups of patients is particularly susceptible to the inhibition of the ef- fects of prostaglandins. These patients suffer from diseases or pathophysiologic states that are charac- terized by cither renal underperfusion or by the intense secretion of renin, They require vasodila tory prostaglandins to counterbalance the vasocon- strictor effects of renal nerve activity or circulat- ing vasoconstrictors such as angiotensin II and norepinephrine. If prostaglandin synthesis is in- hibited, constriction of renal afferent arterioles is ‘unopposed, and both renal plasma flow and glo- merular filtration rate fall. The syndrome is seen ‘most frequently in patients taking diuretics (perhaps more frequently with triamterene)'?* and those with congestive heart failure, cirrhosis, nephrotic syndrome, advanced age, systemic lupus cerythematosus,"* and preexisting renal disease. ‘This functional renal insufficiency is usually re versible within a few days of withdrawal of the offending nonsteroidal age. However, many pa- tients who continue to take the nonsteroidal agent while in an underperfused state may go on to have the full-blown picture of acute renal failure and ‘Seminars in Nephrology, Vol 8, No (March), 1988: pp 55:61 ‘may even require dialysis. Presently, since most of these patients do not undergo renal biopsy, itis impossible to state that all patients who experience acute renal failure do so as a pathophysiologic ex- tension of renal underperfusion caused by onop- posed high renin-angiotensin Il secretion states Several ofthese patients may actually have devel: ‘oped their acute renal failure secondary to acute tial nephritis of an allergic type.? Since prostaglandins, especially those of the E type, are frequently required for renin secretion, i comes as no great surprise that many patients have been described with acute hyperkalemia due to the secondary hypoaldasteronism caused by exposure to NSAIDs." In addition to renal underperfu sion, increased ascending limb sodium chloride reabsorption following the inhibition of prosta- slandin synthesis ean lead to salt retention."®* is also well known that prostaglandins, even stim- ulated by antidiueetic hormone (ADH), oppose the path of water flow induced by ADH-increased CAMP levels in the kidneys. Thus, inhibition of prostaglandin synthesis can lead to further water retention. Therefore, the common water and elec- trolyte abnormalities seen following exposure to NSAIDs are edema and hyperkalemia. Hyponatre- mia is a relatively rare complication.> Recently, a new syndrome associated with the use of suprofen was deseribed by Hart et al." ‘These authors described one case and gave data on 15 additional cases in which exposure to suproten, anew nonsteroidal inflammatory drug, was asso ciated with a syndrome of flank pain and mild, re versible acute renal failure. Theit index patient ex- perienced flank pain, nausea, vomiting, and abdominal pain within five hours after taking su- profen, Serum creatinine concentration on admi sion was 3.0 mg/dL. After peaking at 4.4 mg/dl, ‘rom the Seciion of Nephrology/Mypertension, Deparment Of Medicine. Northwestern University Metical School und Norwesers Memorial Hospital, Chicago, Adires reprint requests 10 Murray Lain, MD. Chief Section of Nephrology/Hyperiension. Norhwester University Medical School, 303 E. Chicago Ave, Chicago,IL 60611 © 1988 by Grune & Siration, Ine. 1927%.9295/88/0801-0002805.00/0,se Table 1. Renal Dysfunction Associated With Nonsteroidal Antinflammatory Orugs Functional renal insutfcioncy occurring in states of ‘enal underpertusion 0 high renin-angiotensin statas ‘Congestive heart failure ‘Concomitant use of diuretics Giernosis Nophrotc syndrome Preexisting renal disease ‘Advanced age ‘Acute renal tare 7 Extension of above with flank pain (suprofen) Hyperkalemia : Sosium and water retention Acute allergic intorstital nephsitis Interstitial noptiis with nephrotic range proteinuria Interstitial nephits without proteinuria, Nephrotc proteinuria without interstitial nepheis Papillary necrosis the patients serum creatinine returned to a level of 1.2 mg/dL 2 weeks after discharge. ‘The patient remained hypertensive despite the fact that he had been normotensive 2 years earlier. Of interest with regard to this syndrome were the Fats that almost all ofthe patients were young and in theit 305 and that only two women experienced it, ater having taken the drug for dysmenorrhea. In contrast, pa tients who develop interstitial nepheitis following the long-term use of NSAIDs are usually well into their 60s, perhaps because patients in this age g70up are those most likely to take NSAIDs on a chronic basis. In addition, the symptom of flank pain that was so prominent with the new syndrome Aescribed with the suprofen usage does occur in patients with interstitial nephritis and proteinuria as described below, but it occurs quite rarely. Ia fact, Kleinknecht et al! report that a maximum of four patients (and probably fewer) out of 62 with acute renal failure in association with other NSAIDs had symptoms of flank pain. Since no biopsy information was reported inthe description of the syndrome related to suprofen usage. the pathologic correlates of this syndrome ate un- known Nephrotic Syndrome Secondary to Nonsteroidal Aniinflammatory Drug Therapy, but Without Other Renal Pathologic Changes ‘AL least five patients have been reported with nephrotic syndrome with NSAID exposure, three showing only epithelial cell foot process fusion and two showing membranous changes. The fiest MURRAY L. LEVIN, patient, reported by Lorch et al, developed mile renal insufficiency (serum creatinine 2.5 mg/dL.) and nephrotic syndrome. She was also oliguric. The renal biopsy showed some tubulo-interstital fibrosis but no cellular infiltrate. Electron mieros- copy revealed fusion of foot processes. The patient was treated with prednisone and removal of all therapy including the fenoprofen, which she had been receiving for osteoanritis. Her renal func: tion improved and her proteinuria disappeared ‘There was no relapse. The patient had been receiv. ing her fenoprofen for an undetermined period of time, The second patient, reported by Lomvardias et al2} had been taking sulindac. Her serum creatinine was normal, but she was excreting 8.7 g of protein in 24 hours. Duration of sulindac therapy was approximately 3 months. Renal patho- logic changes were confined to foot process fusion ‘of the glomerular epithelial cells. No mention of interstitial nephritis was made in this report. Sulin- dac was withdrawn, and the patient had a. remis- sion of her nephrotic syndrome. third patient experienced a similar syndrome after exposure to salsalate and had a second episode following reex- posure.” ‘The other two cases were reported in the French literature and are quoted by Pirson and van Yper sele de Strihou."* Both of these patients received diclofenac and developed membranous lesions. Nephrotic syndrome remitted after withdrawal of the NSAID. ‘The pathophysiologic events leading to the de- velopment of nephrotic syndrome without other renal changes may be similar to that to be dis- cussed below for the nephrotic syndrome seen in conjunction with interstitial nephritis. Nonsteroidal Antiinflammatory Drug-Induced Interstitial Nephritis With and Without Nephrotic Syndrome During the last 7 t0 8 years, a syndrome asso- ciated with exposure to NSAIDs has excited much interest in nephrology. Forty-five cases are re- ported or reviewed in the reference articles.2° ‘This syndrome consists of the concomitant find: ings of renal insufficiency in conjunction with nephrotic syndrome and characterized by the path- logic demonstration of interstitial nephritis with lipoid nephrosis. Although most authors have described this syndrome as an acute interstitialNONSTEROIDALS AND RENAL INTERSTITIAL DISEASE Table 2. Clinical Characteristics of Nonsteroidal ‘Aatiinflammatory Orug-Associated Interstitial, Nephritis With Nephratic Syndrome and ‘Acute Allergic Interstitial Nepheits, IWS? AINE Duration of drug exposure «Satyr 588d Systemic symptoms (lover, rash) (6) 78 20 Eosinophila (4) a8 75-80 Eosinophituria (%) os: 20.85 Proteinuria >3 g/24 h(%) 100 <10 Peak serum ereatinine (mgldl) 1.5->10 3.7->10 ‘Abbreviations: ININS, Interstitial nephritis with nephrotic syndrome; AIN, allergic interstitial nephritis. "Review of 45 documented cases, nephritis, the average duration of therapy with NSAID has been several months, with a minimum exposure of a few days and maximum exposure of 2 years before the syndrome became clinically evi dent. Therefore, although the renal insufficiency and nephrotic syndrome appear 10 have a rela tively acute onset, they do not necessarily occur acutely following exposure to NSAIDs. The clini- cal characteristics of this syndrome are summa- rized in Table 2. For comparison, the clinical characteristics of allergic interstitial nephritis as. summarized by Linton et al*! are also outlined in ‘Table 2. The differences are striking In the first place, acute allergic interstitial nephritis is rarely if ever characterized by nephrotic syndrome. In addition, <25% of the cases of NSAID-induced interstitial nephritis and nephrotic syndrome have systemic signs and symptoms of fever, joint pains, rash, or peripheral eosinophilia. In fact, systemic symptomotology is a relative rarity in the syndrome associated with NSAIDs. In addition, the time of onset of allergic interstitial nephritis following exposure to the in citing agent (classically a B-lactam antibiotic) is ‘much shorter than the average onset of interstitial nephritis associated with NSAID therapy. ‘The clinical presentation of these patients typi cally is that ofthe rather acute onset of edema. The patients also have a loss of vigor, and many note oliguria. Gross hematuria is rare. They frequently note foamy urine, typical for nephrotic syndrome. Urinalysis reveals proteinuria, microscopic hema: turia, and microscopic pyuria. Protein excretion is usually far greater than 3 g/24 h, Serum creatinine concentration varies from only minimum elevation to > 10 mg/dL on first measurement 7 ‘The clinical course of these patients is quite var- iable, After withdrawal of the offending NSAID, some patients will enter spontancous remission of this syndrome within a few days. However, many patients will have such significant renal insuffi ciency that they will require support with either hemodialysis or peritoneal dialysis. Many patients have been dialyzed on several occasions. Some pa tients do not appear to experience spontaneous re. mission, and some have gone several months ‘without great improvement in renal function until steroid therapy has been instituted.% However, in ‘most instances in which steroid therapy has been used, such therapy has been instituted before a sig nificant time has elapsed to evaluate the clinical course of the patient. The true efficacy and neces: sity Of steroid therapy is therefore unknown. Pres- ently, a reasonable recommendation would be that such therapy should be instituted only if renal function does not return after 2 to 3 weeks of sup- portive therapy following withdrawal of the of. fending NSAID. Of significant interest is the fact that many pa- tients have undergone recurrence of this syndrome after inadvertent reexposure to the same NSAID, or after exposure to another NSAID of the same or 4 different chemical class.*% Once again, re moval of the offending agent usually results in re versal of the syndrome and return of renal function to preexisting levels. Recently, a patient was described to have had a spontaneous relapse of a nephrotic syndrome without drug reexposure in association with na proxen therapy.*? Renal biopsy performed after the relapse could not rule out 2 preexisting intersti- tial nephritis, although there was no evidence of an active interstitial process at the time. The biopsy revealed only fusion of foot processes in associa tion with interstitial fibrosis and arteriolosclerosis. ‘The patient had a remission with steroid therapy. ‘Thus far, this is the only patient to be reported with a relapse without reexposure to either the same or another NSAID. Immunofluorescemt analysis of biopsy speci ‘mens has usually been unrewarding. However, at Teast in some cases,2$ complement has been found to be deposited in a peritubular and interstitial fashion. Usually this has been the third component of complement. The importance of such comple- ment deposition in the pathogenesis of this syn drome is unknown, but speculation regarding it will be given below8 Pirani ot al have summarized the pathologic findings in this syndrome. Interstitial inflamma- tion is not so severe as that seen in the acute al tergic interstitial nephritis following 6-latam ant biotic therapy. Although Pirani et al found very few eosinophils in the interstitial infilerate,-this finding is quite variable, with some authors report ing many eosinophils in the interstitium. Cell re generation was scen quite commonly. Glomerulo- sclerosis was seen rather commonly in the NSAID ‘ype of interstitial nephritis. However, it must be stressed that the patients with this syndrome are usually elderly. Thus, the sclerotic glomeruli found could be more representative of the aging process than of the drug toxicity. The infiltrate in the interstitium in general con- sists more of small lymphocytes in this. group. Originally Finkelstein et aP® had characterized the lymphocytes as being 100% t cells. with eytoioxic- suppressor T cells being predominant. However, Stachura et aP® and Bender etal? have dernon- strated the presence of B cells in the interstitium of these patients. In fact, Bender et al® have pro- vided evidence that the T cells in the interstitial infiltrate of these patients do not differ in nature from those found in chronic interstitial nephritis tunassociated with NSAID exposure. Thus, the lat- ter authors have stated that che type of interstitial infiltrate is totaly nonspecific. [At this point, i€ should be mentioned that there have been several patients reported with acute i terstitial nephritis without nephrotic syadrome. Some of these patients. such as those reported by ‘Chan et al* and by Fellner et al,*# appear to be similar to previous patients summarized by Linton et al¥! with acute allergic interstitial nephritis. The patient described by Fawaz-Estrup and Ho** appeared to have allergic phenomena with eosino philia and rapid rising of BUN and creatinine fo lowing indomethacin therapy. A patient reported by Wendland et al?” also had signs and symptoms consistent with acute allergic interstitial nephits She had petechiae but no eosinophilia. However, she had grade 4 proteinuria and may have repre- sented an acue allergic interstitial nephritis as well as nephrotic syndrome. Green et al” reported a Patient who had no proteinuria and no eosino- Philia. Significant proteinuria was absent. This pa tient may not have represented a true acute allergic interstitial nephritis because of the absence of eo- sinophilia in either the blood or biopsy specimen MURRAY L. LEVIN A similar patient was reported by McCarthy et al following zomepirac exposure.** PATHOGENESIS OF NONSTEROIDAL ANTIINFLAMMATORY DRUG INDUCED RENAL DAMAGE ‘The pathogenesis of this syndrome remains speculative. Since the total number of cases in the world’s literature is probably less than 100, 45 of which are summarized in the present report (several more having been reported in the non English literature), these patients represent a very small minority of the total number who have re ceived NSAIDs.** Additionally, well over 50% of the patients reported have received fenoprofen. Nonetheless, almost all other NSAIDs have been implicated in at least one ease report. In addition, several patients have been reported to have had re- currences afier having received drugs of different chemical classes. Thus. there must be some com- ‘mon linkage between inhibition of prostaglandin synthesis and the pathogenesis of the interstitial nephritis and nephrotic syndcome seen in these pa- tients. Tthas been hypothesized that certain patients are susceptible to abnormal lymphocyte function after exposure (0 nonsteroidal inflammatory agents, ppethaps on a genetic basis.*? Ordinarily, once an antigen is processed by macrophages, these acti- vated macrophages synthesize prostaglandins that inhibit production of lymphokines by lympho cytes, resulting in a reduction or self-limitation of 2 chronic inflammatory response to antigen expo: sure.*®47 Macrophage prostaglandin synthesis can be inhibited by NSAIDs. Thus, lymphocyte proliferation and production of lymphokines will remain unchecked. Several of these lymphokines have been found to increase the permeability of capillaries to proteins. Therefore, unlimited pro- liferation of lymphocytes and lymphokine produe- tion may result in proteinuria. In addition, inhibi tion of the cyclo-oxygenase pathway for prostaglandin production can result in shunting of arachidonic acid (0 leukotriene and lipoxin pro- duction, Several of the leukotrienes and lipoxins can increase vascular permeability and can act as “chemotactins” for lymphocytes, eosinophils, and polymorphonuclear leukocytes. ? Therefore, the unchecked proliferation of lymphocytes with Iym- phokine, leukotriene, and lipoxin production as a consequence of cyclo-oxygenase inhibition byNONSTEROIDALS AND RENAL INTERSTITIAL DISEASE NSAIDs could account for both the interstitial in- filtrate and the nephrotic syndrome seen following NSAID therapy. It may very well be that this syn- drome is seen only in those patients whose macro- phages or lymphocytes are particularly sensitive to such inhibition, Recently, Nath et al? and Tolins et al demon: strated the importance of ammonia production leading to activation of the alternate complement pathway in the production of interstitial nephropa- thy. This has been demonstrated both in the chronic tubulo-interstitial nephropathy seen in rem- nant kidneys and in hypokalemic. nephropathy. ‘Ammonia amidates C3, leading to activation of the. pathway. Both models were produced in rats. Of interest is the finding of Jones etal. 55% that inhibi- tion of prostaglandin synthesis increases renal am- moniagenesis. Thus, an additional pathway by which complement activation could result in che moattraction of lymphocytes into the interstitium foliowing prostaglandin inhibition can be hypothe- sized. Even though biopsy material from most pa tients has not demonstrated complement deposi- tion in renal interstitium in the presence of interstitial nephritis, several patients have had such demonstration made. It is of interest that complement was deposited in both of the patients ‘who were biopsied in the original report of this. syndrome by Brezin etal. A synthesis of the possible pathophysiologic acophanes oral a nfo Cte Protalanion mL (crate Patsy) Fig 1 {or interstitial neph ‘meabiity in NSAID toxiclly. Narrow arrows indicate Proposed pathophysiologic mechanism is and increased glomerular p timulation. Broad arrows (dark and stippled) indicate inibition, See text for explanation. 58 events responsible for the pathogenesis of both the interstitial nephritis and the nephrotic syndrome seen with NSAID exposure is offered in Fig 1 Inhibition of prostaglandin production results in unchecked proliferation of lymphocytes and the production of lymphokines. Thus, both interstitial infiltration and increased glomerular permeability could occur. Additionally, shifting of arachidonic acid metabolism to leukotriene and lipoxin produc tion as a consequence of cyclo-oxygenase inhibi: tion could also result in increased interstitial i filteation and glomerular permeability. Finally, increased ammoniagenesis with accumulation in the interstitium of ammonia could lead to the ami- dation of the third component of complement with, activation of the alternate pathway and further at- traction of interstitial cells. By necessity, all of these speculative pathways would occur to a greater extent in susceptible individuals. These individuals might be those who have decreased cyclo-oxygenase activity on a genetic bass, RENAL PAPILLARY NECROSIS The final type of toxicity associated with NSAID therapy is that of renal papillary necrosis. Several patients with papillary necrosis have been reported." It has been hinted by at least some authors that this occurs with chronic therapy for diseases such as juvenile rheumatoid arthrtis.58 Whether this is indeed the case remains problem: atic. The author has seen one patient with apparent calcified papillae after long-term chronic therapy with several nonsteroidal agents for juvenile rheumatoid arthritis. ‘The mechanism by which papillary necrosis oc: curs in these patients is probably similar to that which occurs with other analgesic agents, is known that vasodilatory prostaglandins increase ‘and maintain blood flow at the juxtamedullary area of the kidney.* If prostaglandin synthesis is inhib: ited during episodes of decreased renal blood flow. flow to the juxtamedullary ares and into the renal medulla is inhibited to a great extemt, leaving the renal papillae ischemic. Thrombosis and ne- crosis of the papillae is the natural consequence of such reduction in flow. From the foregoing discussion. the following Fecommendations can be offered. A patient who is -receiving a NSAID: who presents with nephrotic syndrome and advancing renal failure should be presumed to have the syndrome of interstitial60 nephritis with nephrotic syndrome secondary to the NSAID. NSAID should be withdrawn and sup: portive measures, including dialysis when neces- Sary, should be given. If renal function does not return within two to three weeks, a trial of cortico: steroids should be atiempted. ‘A patient who presents with renal failure ‘without nephrotic syndrome while taking a nonste- roidal agent presents some diagnostic difticulties. If the patient is elderly, has a decreased cardiac ‘output or poor renal perfusion. the drug should be withdrawn and the patient should be observed for return of renal function. However, if peripheral eosinophilia or prolonged renal failure (of more MURAAY L. LEVIN than a few days duration) are encountered, renal biopsy should be considered to determine whether there is significant interstitial nephritis, If renal failure continues unabated despite measures taken 10 reestablish an appropriate circulating volume ‘and renal perfusion, either papillary necrosis should be. sought or the diagnosis of interstitial nephritis should be entertained strongly. If the lat ter is proved, a trial of steroids is indicated if renal failure does not improve after 2 to 3 weeks. ‘ACKNOWLEDGMENT “The author schnowledges the exper: secretarial assistance of rma Thoms REFERENCES |. Clive DM, Stoff JS: Renal syndromes associated with nonsteroidal antinflammacory drugs. N Engl J Med 310:363- 372, 1984, 2! Henrich WL: Nephrotoxicty of nonsteroidal an-iafam- matory agents. Am J Kidney Dis 2478-484, 1983 3. Garela §, Matarese RA: Renal effects of prostaglandins and cliial adverse effects of nonsteroidal at-nflamnaory agents. 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