Noramidopyrine (Metamizol) and acute interstitial nephritis.

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Nephrite interstitielle aigue immuno-allergique a` la noramidopyrine. Presse Med 1984; enes [4,8]. Although signs of a systemic allergic reac-. 133: 1377–1380.
Nephrol Dial Transplant (1998) 13: 2110–2112

Nephrology Dialysis Transplantation

Case Report

Noramidopyrine (Metamizol ) and acute interstitial nephritis Valeria Berruti, Gennaro Salvidio, Stefano Saffioti, Roberto Pontremoli, Olga Arnone, Massimo Giannoni and Giacomo Garibotto Department of Internal Medicine, Division of Nephrology, University of Genoa, Italy

Introduction Noramidopyrine (Metamizol ) is a non-narcotic, analgesic and antipiretic pyrazolone derivative which belongs to the non-steroidal anti-inflammatory class of drugs (NSAID) [1]. This drug is used, even if subject to limitations, in Germany, Spain and Italy, and in many South American Countries. It is prohibited in other countries because of its capacity to induce agranulocytosis and aplastic anaemia. In addition to its effects on bone marrow, noramidopyrine may also cause cutaneous reactions, allergic idiosyncratic reactions such as bronchospasm, anaphylactic shock, toxic epidermal necrolysis [2], and severe hypotension [3]. In addition to acute renal failure (ARF ) secondary to loss of counterregulatory prostaglandins during plasma volume contraction, acute interstitial nephritis is a well-recognized side-effect of NSAIDs [4]. However, while both the clinical and pathological changes occurring in acute interstitial nephritis induced by NSAIDs are well recognized, reports on the renal toxicity of noramidopyrine are scant and the renal effects of this drug have not been thoroughly evaluated. We report on a case of acute renal failure due to acute interstitial nephritis (AIN ) following the ingestion of a self-prescribed mega-dose of noramidopyrine in an otherwise healthy man.

Case An otherwise healthy 45-year-old man was admitted to another hospital with complaints of lumbar pain and oliguria. The man was an entrepreneur in good physical fitness and had routinely received yearly physical examinations. About 1 year before, his serum creatinine was 1.1 mg/dl with a normal urinalysis. Five days before his admission he had developed malaise, fever (39°C ) and headache. To relieve his symptoms he had taken noramidopyrine (three 20 ml bottles, 0.5 g/ml ) over two consecutive days (total Correspondence and offprint requests to: Giacomo Garibotto MD, Dipartimento di Medicina Interna, Divisione di Nefrologia, Viale Benedetto XV, 6, I-16132 Genova, Italy.

amount ingested: 30 g). On admission his serum creatinine and blood urea nitrogen (BUN ) were 4.5 mg/dl and 39 mg/dl respectively. Urinalysis revealed 30 mg/dl protein, 3+ positive for blood (dipstick), and 5–10 red blood cells and 3–5 white blood cells per highpower field in the sediment. During the second hospital day he developed oliguria (200 ml/day); his serum creatinine and BUN were 9.2 mg/dl and 52 mg/dl respectively. On the third day after admission the patient was referred to our unit. Blood pressure and pulse were 130/80 mmHg and 68 beats/min respectively; temperature was 36.5°C. There were no skin eruptions or lymphadenopathy. Auscultation and percussion of the chest were within normal limits. Serum creatinine and BUN were increased to 12.7 mg/dl and 70 mg/dl respectively. Serum Na was 138 mEq/l, K 4.4 mEq/l, Ca 7.9 mg/dl and P 5 mg/dl. Arterial pH was 7.348, pCO 37.2 mmHg and [ HCO ] 20.1 mmo/l. Haem2 3 atological evaluation revealed an haematocrit of 32%; haemoglobin at 11.3 g/dl and a leukocyte count of 7800/mm3 with a small increase in the eosinophil count (580 cells/mm3). Blood cultures and a urine culture revealed no growth. Serological studies were unrevealing. C3, C4, IgG, IgA, IgM, ANCA, ANA tests, and cryoglobulins were within normal limits or undetectable. Total IgE was 397 mg/dl (normal 12–240). Bence Jones proteinuria was absent. Urinalysis revealed proteinuria (1 g/l ) and a moderate number of white blood cells, with no eosinophiluria and occasional red blood cells, hyaline-granular casts and no glucosuria. A further renal sonogram showed an increase in kidney size (approximately 13 cm in length each). A percutaneous renal biopsy was performed 2 days after hospitalization (Figures 1 and 2). The specimen revealed 15 glomeruli, all appearing normal. There was severe diffuse mononuclear and moderate eosinophil interstitial infiltration, with focal invasion and disruption of the epithelium of proximal and distal tubules. The vessels were normal. Immunofluorescence examination showed no glomerular or tubular immunoglobulin or complement deposits. A diagnosis of acute interstitial nephritis was made. The patient was treated with pulse methylprednisolone (500 mg daily for 3 days) followed by oral

© 1998 European Renal Association–European Dialysis and Transplant Association

Noramidopyrine (Metamizol ) and acute interstitial nephritis

Fig. 1. Diffuse interstitial infiltrate mainly consisting of lymphocytes and monocytes. The infiltrate is focally dense with substitution of tubular structures ( left). The glomerulus is normal (HH×250).

Fig. 2. Area of interstitial infiltration with massive mononuclear cell invasion of the tubules (PASM×250).

prednisone therapy (1 mg/kg/daily) for 1 week. This therapy was tapered and withdrawn within a month. He required four haemodialysis sessions 1, 2, 4 and 7 days after admission. His renal function progressively improved. Serum creatinine decreased from 12 mg/dl to 2.6 mg/dl after 6 days of steroid treatment. Sixteen days after hospitalization he was discharged; at this time his serum creatinine was 1.3 mg/dl.

Discussion Noramidopyrine was used more than 100 years ago for its antipyretic properties and subsequently has been widely used for its analgesic and anti-inflammatory actions. However, its use has been discouraged or has been prohibited due to the associated risk of severe agranulocytosis. Nevertheless, it is still currently used in some European countries. The drug is sold in preparations containing noramidopyrine alone, or in conjunction with multiple drugs. While the adverse effects of noramidopyrine on bone marrow are well

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known, its effects on the kidney are less explored. Noramidopyrine is listed among NSAID drugs causing acute interstitial nephritis [5]. Acute interstitial nephritis due to NSAIDs presents peculiar histological and clinical characteristics, which differ considerably from those of most drug-induced acute interstitial nephritides, such as those exemplified by the b-lactam antibiotics [6 ]. The patient presented here underwent acute interstitial nephritis after surreptitious ingestion of noramidopyrine. The amount of this drug consumed per day was about threefold the average normal daily dose (up to 3–4 g/day) [1]. The diagnosis of AIN was made on the basis of a rapid decrease of renal function after drug exposure, eosinophilia, proteinuria, and microhaematuria, and enlarged kidneys shown by ultrasound examination. The diagnosis was confirmed by renal biopsy revealing normal glomeruli with interstitial infiltration of mononucleates observed using lightmicroscopy. While other types of drug-induced interstitial nephritides are usually associated with an allergic syndrome, those due to NSAID are not [4,7]. Histological findings include interstitial oedema and an inflammatory infiltrate composed mostly of lymphocytes. The interstitial changes are focal in their distribution and are rarely associated with diffuse interstitial lesions. On electron microscopy, blunting and effacement of epithelial cell foot processes in the glomeruli may be found [7]. Moreover, NSAID-induced acute interstitial nephritis is characterized by less frequent tubulitis and eosinophilic infiltration than b-lactam-induced interstitial nephritis [6,8]. Spontaneous remission following withdrawal is common, but renal insufficiency may be severe and lead to persistent renal impairment [4,7,8]. The role of steroid therapy has been questioned. In 1964, Eknoyan and Matson [10] described a case of a woman with Hodgkin’s disease who developed acute renal failure and cylindruria during treatment with noramidopyrine, with partial recovery of renal function after discontinuation of the drug. Acute renal failure recurred after noramidopyrine reassumption, suggesting a toxic or an immune-mediated reaction. However, because no histology was available, it is difficult to attribute the clinical picture to an acute interstitial nephritis. Riou et al. [11] reported on a 46-year-old patient who developed a biopsy-proven acute interstitial nephritis after a 10-day treatment with noramidopyrine. Kleinknecht et al. [12] described a 56-year-old patient who developed acute renal failure due to acute interstitial nephritis after 6 days of treatment with a noramidopyrine-containing compound. Renal histology showed diffuse infiltrates made up of eosinophils and epithelioid cells with a nodular appearance. Acute tubular necrosis was also present. After withdrawal of the drug renal failure progressively improved, but at 2 months a decrease in GFR was already evident. Ban˜os Gallardo [13] described two cases of biopsy-proven acute interstitial nephritis due to this drug. In the first case, a 19-year-old man with hepatitis B developed haematuria, lumbar pain and

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acute renal failure 24 hours after consumption of noramidopyrine; pulse steroid therapy was associated with a complete recovery of renal function. The second case was a 31-year-old man who developed haematuria, fever and ARF shortly after treatment with noramidopyrine. In a few days there was complete, spontaneous recovery of renal function. Examination of the cases reported in the literature of noramidopyrine-associated acute interstitial nephritis indicate a general picture closer to other druginduced interstitial nephritis than to NSAIDs. The time-course between noramidopyrine administration and clinical presentation is quite short, from 24 h to a few days after the beginning of therapy. This is in contrast to the late clinical onset of nephrotoxicity in NSAID-induce AIN, where the interstitial lesion commonly appears after several months or up to 1 year of treatment. In a review of the clinical spectrum of NSAID-induced AIN, Porile et al. [7] indicate a median period of 3 months before presentation. Another distinctive sign of noramidopyrine-induced AIN is the lack of significant proteinuria. With NSAIDs, daily proteinuria has been reported to range between 1.5 and 17 g/day, often with nephrotic syndrome, while other drug type-induced acute interstitial nephritides result in daily protein excretion ranging between 75 and 750 mg/day [9]. Specific tubular abnormalities or electrolyte and acid–base disturbances have not been described. The effects of noramidopyrine on renal function range from moderate to advanced impairment, with most patients having oliguria. It has been shown that many cases of AIN resolve when the initiating factor has been removed. Probability of reversal and recovery of renal function seems to depend on duration of renal failure prior to diagnosis and the severity of infiltration of renal parenchyma. In the cases described here, ARF was completely reversible in four of six cases. It has been suggested that nephrotoxicity due to blactam antibiotics is probably mediated through hypersensitivity phenomena [8,9]. Whereas NSAID-induced renal toxicity seems to derive from inhibition of prostaglandin synthesis with associated haemodynamic effects and/or alteration in the production of leukotrienes [4,8]. Although signs of a systemic allergic reaction were absent in all cases of AIN due to noramidopyrine reported, and a mild eosinophilia was observed only in one case, eosinophilic infiltrates were present in three of five renal biopsies. This suggests that hypersensitivity plays a role in the AIN due to noramidopyrine. With the exception of the case presented here, acute interstitial nephritis has been observed at the usual pharmacological dose of drug

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[5,6 ]. However, the renal effects may be dosedependent; large doses of this drug have been associated with acute renal failure in animals [14]. Renal failure may occur because the elimination of this drug is mainly via the kidney [1] or because of acute haemodynamic effects due to inhibition of prostaglandin synthesis. Even though noramidopyrine is still widely used in a few European countries, the occurrence of acute interstitial nephritis seems to be rare. In conclusion, acute interstitial nephritis is a rare complication of treatment with noramidopyrine. While there is no known predisposing factor, this event may occur very early during treatment with this drug. The clinical setting is similar to acute interstitial nephritis due to antibiotics, but full-blown hypersensitivity syndrome is usually absent. Reversibility of renal failure has been documented. The occurrence of acute interstitial nephritis after a mega-dose of this drug suggests that it has toxic renal effects per se.

References 1. Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics. 5th edn. McMillan Publishing, New York, 1975; 325–328 2. Moffat J. Dipyrone-containing analgesics. S Afr Med J 1986; 70: 311–333 3. IGICE Epidemiology of adverse drug reactions in intensive care units. J Clin Pharmacol 1987; 31: 507–512 4. Schlondorff D. Renal complications of non steroidal antiinflammatory drugs. Kidney Int 1993; 44: 643–653 5. Schrier RW, Gottschalk CW. Diseases of the Kidney 5th edn. Little Brown, Boston, 1995 6. Agati VD. Interstitial nephritis related to nonsteroidal antiinflammatory agents and beta-lactam antibiotics: a comparative study of the interstitial infiltrates using monoclonal antibodies. Modern Pathol 1989; 2: 390 7. Porile JL. Acute interstitial nephritis with glomerulopathy due to non steroidal anti-inflammatory agents: a review of its clinical spectrum and effects of steroid therapy. J Clin Pharmacol 1990; 30: 468–475 8. Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int 1989; 35: 1257–1270 9. Appel GB, Kunis CL. Acute tubulo-interstitial nephritis. In: Cotran R, ed. Tubulo-interstitial Nephropathies. Churchill Livingstone, New York, 1983; 151–177 10. Eknoyan G, Matson JL. Acute renal failure caused by aminopyrine. JAMA 1964; 10: 156–157 11. Riou B, Richard Ch, Rimahilo A et al. Nephrite interstitielle aigue immuno-allergique a` la noramidopyrine. Presse Med 1984; 133: 1377–1380 12. Kleinknecht D, Vanhille Ph, Morel-Marogel L et al. Les nephrites interstitielles aigu¨es immuno-allergiques d’origine medicamenteuse. Aspects actuels. Actualite´s Nephrol Hoˆp Necker 1982; 111–145 13. Ban˜os Gallardo NI. Nephritis interstitial aguda con fracaso renal secundario a drogas. Rev Clin Esp 1987; 118: 3372–3374 14. Fazekas IG, Fazekas AG, Bertok EF. Experimental examination of mechanisms of pyramidon effect: effects of high pyramidon doses on renal function. Arch Int Pharmacol 1960; 129: 35–61 Received for publication: 5.9.97 Accepted in revised form: 8.4.98