Acute Interstitial Nephritis Due to Pantoprazole

4 downloads 0 Views 44KB Size Report
Pantoprazole belongs to the class of proton-pump in- hibitors, which covalently inhibit hydrogen–potassi- um–adenosine triphosphatase in gastric parietal cells.
CASE REPORTS

Acute Interstitial Nephritis Due to Pantoprazole Amy Ra and Sheldon W Tobe

OBJECTIVE: To describe what is believed, as of November 4, 2003, to be the first case published in the literature of acute interstitial nephritis (AIN) due to pantoprazole. CASE SUMMARY: A 77-year-old white woman presented to the hospital with elevated serum creatinine, oliguria for the past 24 hours,

arthralgia, fatigue, fever, and bilateral flank pain. The patient had initiated treatment with oral pantoprazole 40 mg/d for gastroesophageal reflux 2 months prior to admission. After 5 weeks of therapy, she stopped taking pantoprazole due to general malaise. Upon admission, all home medications, including pantoprazole, were reinitiated based on the patient’s medication list. Serum creatinine increased to 6.1 mg/dL on day 4 of admission from a baseline of 1.0 mg/dL. Pantoprazole therapy was promptly discontinued, and prednisone 40 mg/d was initiated. Urinalysis revealed eosinophils, and a subsequent renal biopsy confirmed a diagnosis of AIN. The serum creatinine level gradually declined over 2 weeks, and the patient was discharged home with a serum creatinine level of 1.6 mg/dL. The Naranjo probability scale suggests a highly probable relationship between AIN and pantoprazole therapy in this patient. DISCUSSION:

Drug hypersensitivity reactions are the most common cause of AIN. There have been several reported cases of omeprazole-induced AIN. Although there are very few prospective data on the efficacy of treatment of drug-induced AIN, corticosteroids may have a role in recovery of renal function. Prednisone doses of 1 mg/kg/d have been suggested.

CONCLUSIONS: Physicians should be aware that drug-induced AIN can be associated with proton-pump inhibitors. Early detection of

this rare adverse reaction may prevent acute renal insufficiency. KEY WORDS: acute interstitial nephritis, pantoprazole, renal failure.

Ann Pharmacother 2004;38:41-5. Published Online, 5 Dec 2003, www.theannals.com, DOI 10.1345/aph.1D085

antoprazole belongs to the class of proton-pump inP hibitors, which covalently inhibit hydrogen–potassium–adenosine triphosphatase in gastric parietal cells. This class of drugs is more effective than histamine H2-receptor antagonists in reducing gastric acid secretion and in the treatment of acid-related disorders.1,2 These agents have been found to be extremely safe. Interstitial nephritis is a rare adverse event that has been associated with omeprazole, which was marketed in the late 1980s. The first reported case of acute interstitial nephritis (AIN) due to omeprazole appeared in 1992, and subsequent cases have been reported.3-22 Pantoprazole has been widely prescribed since its introduction onto the Canadian market in 1997 Author information provided at the end of the text.

www.theannals.com

and the US market in 2000. Until now, no cases of AIN due to pantoprazole have been reported in the literature. This case report demonstrates what is believed to be the first case of AIN associated with pantoprazole. Case Report A 77-year-old white woman with chronic idiopathic thrombocytopenic purpura (ITP) and monoclonal gammopathy of undetermined significance (MGUS) was admitted to the hospital with an elevated serum creatinine level, oliguria for the past 24 hours, arthralgia, fatigue, fever, and bilateral flank pain. Her past medical history included a hysterectomy, appendectomy, and tonsillectomy. She had no previous history of renal disease and no known drug allergies. The patient was being treated for hypertension with bisoprolol 5 mg/d, amlodipine 5 mg/d, and fosinopril 10 mg/d, which she had been taking for the past 7 months. In addition, she was being treated for glaucoma with latanoprost 1 drop at bedtime and timolol 0.5% 1 drop daily, both to the right eye. She also

The Annals of Pharmacotherapy Downloaded from aop.sagepub.com by guest on October 11, 2013



2004 January, Volume 38



41

A Ra and SW Tobe

had been taking bromazepam 3 mg/d for the last year as needed for sleep, and denied use of nonsteroidal antiinflammatory drugs and herbal remedies. The patient had been diagnosed with ITP and MGUS 1 year prior to admission after suffering recurrent early-morning nose bleeds. Six months prior to admission, she had epistaxis associated with increased blood pressure and palpitations. Investigations for pheochromocytoma were negative. Three months prior to admission, she was found to have a hemoglobin of 10.3 g/dL. Vitamin B12, folate, and ferritin serum levels were normal, and a subsequent bone marrow biopsy showed no evidence of myeloma. Two months prior to admission, an upper gastrointestinal tract series demonstrated evidence of reflux, for which the woman was prescribed oral pantoprazole 40 mg/d. She stopped pantoprazole therapy on her own 3 weeks prior to admission, attributing general malaise to this medication but not informing her physician. The week prior to admission, her family physician assessed her for increasing fatigue. Laboratory results revealed a hemoglobin of 9.2 g/dL and a significantly elevated serum creatinine level of 3.0 mg/dL. Fosinopril was discontinued by the family physician when these results became available. Baseline serum creatinine 12 weeks before initiation of pantoprazole therapy was 1.0 mg/dL. The patient was seen urgently by the hematology clinic, and arrangements were made to admit her to the nephrology unit to investigate the rising serum creatinine level. On admission, the patient was afebrile (36 ˚C), with a respiratory rate of 18 breaths/min and a blood pressure of 150/90 mm Hg. Laboratory results revealed serum creatinine 2.8 mg/dL, urea 40.9 mg/dL, hemoglobin 9.5 g/dL, platelet count 121 × 109/L, and white blood cell count 20.6 × 103/mm3, with 65% neutrophils, 29% monocytes, 6% lymphocytes, and 0% eosinophils and basophils. Urinalysis revealed 1+ protein on dipstick and >10 white blood cells/hpf on microscopy. Pantoprazole, amlodipine, bisoprolol, and lorazepam were prescribed on admission based on the patient’s current medication list. On day 2, oral ciprofloxacin 750 mg/d was started for suspected urinary tract infection. Serum creatinine on days 2, 3, and 4 rose to 4.1, 5.2, and 6.1 mg/dL, respectively. On day 4, urine testing using Hansel’s stain was positive for eosinophils. Based on this finding, further detailed questioning about her medication intake prompted the patient to reveal that she had stopped pantoprazole therapy 3 weeks prior to admission. The pantoprazole ordered on admission was promptly discontinued. Prednisone 40 mg/d (0.6 mg/kg/d) was initiated because the presence of pyuria and eosinophiluria suggested a diagnosis of interstitial nephritis and renal function was deteriorating rapidly. On day 5, the creatinine level reached a high of 6.4 mg/dL. No abnormalities were found on renal ultrasound. A renal biopsy performed on day 6 confirmed a diagnosis of AIN. On light microscopy, the interstitium was expanded by heavy, diffuse mixed infiltrate composed of polymorphonuclear cells, lymphocytes, plasma cells, and histiocytes. Immunofluorescence was negative. Electron microscopy showed wrinkling of the glomerular capillary walls with focal collapse of the capillary loops. The serum creatinine and urea levels started to decline on day 6 and, by day 15, measured 1.3 and 39.8 mg/dL, respectively. Ciprofloxacin was discontinued on day 7 due to a negative urine culture and sensitivity, but was restarted 3 days later due to an onset of fever. An esophagogastroduodenoscopy was done to investigate the patient’s nausea and abdominal pain; generalized hemorrhagic gastritis was found. Intravenous ranitidine 50 mg every 8 hours was started on day 15 and, after 1 week, was changed to oral ranitidine 150 mg twice daily. Proton-pump inhibitors were avoided due to a concern of cross-reactivity. After a 3-week hospital stay, complicated by hematuria following the biopsy, the patient was discharged home with a final serum creatinine level of 1.6 mg/dL. She was advised to avoid all proton-pump inhibitors. A follow-up clinic visit 2 weeks after discharge revealed a serum creatinine level of 1.8 mg/dL. Prednisone was tapered and discontinued 3 months after initiation.

Discussion The clinical presentation of drug-induced AIN is variable, with eosinophilia in 80%, fever in approximately 75%, and skin rash present in 1 month prior to diagnosis was associated with permanent renal insufficiency in 88% of drug-induced cases. Another study showed that, among 18 reported cases of AIN secondary to omeprazole, patients received an average of 2.7 months of therapy (range 1 wk–7 mo) with omeprazole 20– 40 mg/d at the time of diagnosis.21 Only 1 of the 18 patients suffered permanent renal dysfunction.5 The pathophysiology of drug-induced AIN has largely been extrapolated from animal models of immune-mediated experimental AIN.26 These models suggest that the drug or one of its metabolites may either act as a hapten, mimic a renal antigen, act as a planted antigen, or deposit in the interstitium as a circulating immune complex. An in-depth discussion of the pathogenesis of drug-induced AIN has been examined.23,26,28 To our knowledge, the pathogenesis of omeprazole-induced AIN has not been elucidated. However, an interesting association between omeprazoleinduced AIN and patients with immunologic derangements has been described.18 The authors observed that omeprazole-induced AIN had occurred in several patients with underlying immunologic abnormalities (ocular myasthenia, sarcoidosis, Sjögrens syndrome, positive immunoglobulin G perinuclear antineutrophil cytoplasmic antibody titer).5,10,12,18 It is unclear why there have been a number of reported cases of omeprazole-induced AIN and no reported cases of pantoprazole-induced AIN until now.3-22 Both omeprazole and pantoprazole are metabolized extensively via the hepatic CYP2C19 isoenzyme and, to a lesser extent, CYP3A.30 These benzimidazole derivatives are chemically related and their major metabolites are structurally similar as well. Perhaps the different pharmacodynamic properties of these drugs might offer an explanation. Proton-pump inhibitors are prodrugs that are activated in an acid environment.

2004 January, Volume 38

www.theannals.com

Acute Interstitial Nephritis Due to Pantoprazole

Pantoprazole, however, has a greater pH selectivity than omeprazole and is more stable under neutral to moderately acidic conditions in vitro. Thus, it is less likely to become activated in such compartments of the body.31 In addition, pantoprazole binds specifically in vitro to the active region of the proton pump, whereas omeprazole has additional sites of binding. Another reason for the lesser number of reports with pantoprazole is that there may be fewer individuals exposed to pantoprazole due to its newer status on the market compared with omeprazole. Treatment involves supportive therapy and removal of the offending agent, if known.32 Although there are very few prospective data on the efficacy of treatment of druginduced AIN, corticosteroids are the most commonly used immunosuppressive therapy.28 The results of 2 small retrospective studies showed that patients with drug-induced AIN treated with oral prednisone had better recovery of renal function than untreated controls.33,34 In one study, 8 of 14 patients with methicillin-induced AIN received an average daily dose of prednisone 60 mg for a mean duration of 9.6 days.33 A greater proportion of patients in the treatment group returned to their previous normal serum creatinine level. The average time from peak creatinine to a new baseline level was 9.3 days in the prednisone group and 54 days in the untreated controls. More rigorous studies are needed to make stronger conclusions on steroid therapy in drug-induced AIN. Despite the absence of studies that establish the optimal dose and duration of therapy, prednisone dosages of 1 mg/kg/d have been suggested for treatment of drug-induced AIN.26,27 Patients will not likely benefit from steroid therapy if their kidney biopsy reveals a great degree of interstitial fibrosis.28 If steroids are to be used, they should be initiated as early as possible, since interstitial fibrosis can be detected 10 –14 days after the onset of interstitial inflammation.28 Steroids may be deemed necessary if renal function is declining rapidly, if oliguria persists for >1–2 days after removing the offending agent, if dialysis is likely to be initiated, or if recovery is slow.32 Ciprofloxacin has also been frequently reported to cause AIN; however, in our patient, we believe that it was not the cause of renal dysfunction.27-29 Serum creatinine continued to drop toward baseline despite the patient being rechallenged with ciprofloxacin. Her other medications: amlodipine, bisoprolol, and lorazepam, were unlikely to have been the cause of AIN. Table 1 outlines the trend of serum creatinine levels during the patient’s hospital stay and the day that each medication was initiated and discontinued. Although one case of amlodipine-induced AIN has been reported, it was not likely the cause of AIN in our patient.35 Serum creatinine was already decreasing while the patient was still receiving amlodipine. Bisoprolol and bromazepam were discontinued in the hospital to rule out the possibility that they were the offending agents. Metoprolol was initiated by the cardiology service after an episode of atrial fibrillation, and a formulary benzodiazepine was selected for bedtime sedation. The initiation of metoprolol and lowww.theannals.com

razepam was not associated with an increase in the serum creatinine level. Since drug-induced AIN is believed to be due to immune reactions, drugs with similar chemical structures would likely show cross-reactivity.26 Therefore, it was likely that bisoprolol and bromazepam were not the offending agents. Our patient did not present with the classic triad of eosinophilia, fever, and rash. The urinalysis was positive for eosinophils, but a renal biopsy was deemed necessary due to the complexity of the case. A diagnosis of AIN was discovered after 2 months of starting pantoprazole 40 mg/d. The patient had stopped the drug after 5 weeks, believing it to be the source of her malaise. Inadvertent rechallenge with pantoprazole on admission caused a rapid increase in the serum creatinine level. After discontinuation of the drug and initiation of prednisone therapy within 10 days, her creatinine returned to near baseline values. The patient had chronic ITP and MGUS, which may strengthen the hypothesis that patients with underlying immunologic abnormalities may be more susceptible to omeprazole-induced AIN.18 The adverse reaction with pantoprazole was deemed highly probable as determined by the Naranjo probability scale.36 Summary We believe that pantoprazole may have been responsible for this patient’s AIN. Other medications were ruled out as the cause of AIN. Physicians and other healthcare professionals should be aware that drug-induced AIN can be associated with proton-pump inhibitors other than omeprazole, such as pantoprazole. Early detection of this rare adverse reaction and prompt discontinuation of the offending agent may potentially prevent acute renal failure.

Table 1. Trend of Serum Creatinine Levels Versus Duration of Drug Therapya Day of Admission 1 2 3 4 5 6 7 8 9 10 11b 12 13 14

Serum Creatinine (mg/dL)

Drug Therapy A

B

C

D

E

F

2.9 4.2 5.2 6.2 6.5 6.3 5.9 5.0 3.2 2.1 1.9 1.6 1.4 1.4

A = pantoprazole; B = ciprofloxacin; C = amlodipine; D = bisoprolol; E = lorazepam; F = prednisone. a Shaded area indicates the duration of drug therapy. b Metoprolol started.

The Annals of Pharmacotherapy



2004 January, Volume 38



43

A Ra and SW Tobe

Amy Ra BScPhm, Staff Pharmacist, Sunnybrook & Women’s College Health Sciences Centre, Toronto, Ontario, Canada Sheldon W Tobe FRCP(C), Assistant Professor of Medicine, Nephrology, University of Toronto, Toronto; Division Director, Nephrology, Sunnybrook & Women’s College Health Sciences Centre Reprints: Sheldon W Tobe FRCP(C), Sunnybrook & Women’s College Health Sciences Centre, 2075 Bayview Ave., Suite A240, Toronto, Ontario M4N 3M5, Canada, fax 416/480-6940, [email protected]

References 1. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders. Drugs 1998;56: 307-35. 2. Fitton A, Wiseman L. Pantoprazole. A review of its pharmacological properties and therapeutic use in acid-related disorders. Drugs 1996;51: 460-82. 3. Ruffenach SJ, Siskind MS, Lien YH. Acute interstitial nephritis due to omeprazole. Am J Med 1992;93:472-3. 4. Kuiper JJ. Omeprazole-induced acute interstitial nephritis (letter). Am J Med 1993;95:248. 5. Christensen PB, Albersen KEP, Jensen P. Renal failure after omeprazole (letter). Lancet 1993;341:55. 6. Assouad M, Vicks SL, Pokroy MV, Willcourt RJ. Recurrent acute interstitial nephritis on rechallenge with omeprazole (letter). Lancet 1994; 344:549. 7. Gronich JH, Snipes ER, Stein HD. Omeprazole related acute interstitial nephritis (AIN) with renal failure (abstract). J Am Soc Nephrol 1994; 5:394. 8. Lewis CR, Somerville C, Agar JWM. Omeprazole induced acute interstitial nephritis (letter). Aust N Z J Med 1994;24:578. 9. Jones B, Hewson E, Price A. Acute interstitial nephritis due to omeprazole (letter). Lancet 1994;344:1017-8. 10. Singer S, Parry RG, Deodhar HA, Barnes JN. Acute interstitial nephritis, omeprazole and antineutrophil cytoplasmic antibodies (letter). Clin Nephrol 1994;42:280. 11. Omeprazole, musculoskeletal problems and interstitial nephritis. Aust Adverse Drug React Bull 1995;14:14-5. 12. Fleury D, Storkebaum H, Mougenot B, Bridoux F, Gobert P, Lemaitre V, et al. Acute interstitial nephritis due to omeprazole (letter). Clin Nephrol 1995;44:129. 13. O’Donnell D. Acute renal failure due to omeprazole (letter). Med J Aust 1996;165:234-5. 14. d’Adamo G, Spinelli C, Forte F, Gangeri F. Omeprazole-induced acute interstitial nephritis. Ren Fail 1997;19:171-5. 15. Badov D, Perry G, Lambert J, Dowling J. Acute interstitial nephritis secondary to omeprazole. Nephrol Dial Transplant 1997;12:2414-6. 16. Yip D, Kovac S, Jardine M, Horvath J, Findlay M. Omeprazole-induced interstitial nephritis. J Clin Gastroenterol 1997;25:450-2. 17. Landray MJ, Ringrose T, Ferner RE, Arnold IR. Pyrexia, anaemia and acute renal failure secondary to omeprazole. Postgrad Med J 1998;74: 416-22. 18. Montseny JJ, Meyrier A. Immunoallergic granulomatous interstitial nephritis following treatment with omeprazole. Am J Nephrol 1998;18: 243-6. 19. Geetha D. Omeprazole-induced acute interstitial nephritis. Am J Gastroenterol 1999;94:3375-6. 20. Post AT, Voorhorst G, Zanen AL. Reversible renal failure after treatment with omeprazole. Neth J Med 2000;57:58-61. 21. Myers RP, McLauglin K, Hollomby DF. Acute interstitial nephritis due to omeprazole. Am J Gastroenterol 2001;96:3428-31. 22. Delve P, Lau M, Yun K, Walker R. Omeprazole-induced acute interstitial nephritis. N Z Med J 2003;116:U332. 23. Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kid Int 1989;35:1257-70. 24. Eknoyan G. Tubulointerstitial diseases and toxic nephropathies. In: Goldman L, Bennett C, eds. Cecil’s textbook of medicine. 21st ed. Philadelphia: WB Saunders, 2000:594-600. 25. Ruffing KA, Hoppes P, Blend D, Cugino A, Jarjoura D, Whittier FC. Eosinophils in urine revisited. Clin Nephrol 1994;41:163-6.

44



The Annals of Pharmacotherapy



26. Rossert J. Drug-induced acute interstitial nephritis. Kid Int 2001;60:804-17. 27. Alexopoulos E. Drug-induced acute interstitial nephritis. Ren Fail 1998;20:809-19. 28. Michel DM, Kelly CJ. Acute interstitial nephritis. J Am Soc Nephrol 1998;9:506-15. 29. Schwarz A, Krause PH, Kunzendorf U, Keller F, Distler A. The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis. Clin Nephrol 2000;54:179-90. 30. Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 1996;31:9-25. 31. Cheer SM, Prakash A, Faulds D, Lamb HM. Pantoprazole. An update of its pharmacological properties and therapeutic use in the management of acid-related disorders. Drugs 2003;63:101-32. 32. Reddy S, Salant DJ. Treatment of acute interstitial nephritis. Ren Fail 1998;20:829-38. 33. Galpin JE, Shinaberger JH, Stanley TM, Blumenkrantz MJ, Bayer AS, Friedman GS, et al. Acute interstitial nephritis due to methicillin. Am J Med 1978;65:756-65. 34. Chazan JA, Garella S, Esparza A. Acute interstitial nephritis. A distinct clinico-pathological entity? Nephron 1972;9:10-26. 35. Ejasz AA, Fitzpatrick PM, Haley WE, Wasiluk A, Durkin AJ, Zachariah PK. Amlodipine besylate induced acute interstitial nephritis. Nephron 2000;85:354-6. 36. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.

EXTRACTO OBJETIVO: Describir lo que se cree que es el primer caso publicado en la literatura de una nefritis intersticial aguda causada por el pantoprazol. RESUMEN DEL CASO: Una mujer de 77 años, de la raza blanca, se presentó al hospital con la creatinina sérica elevada, oliguria durante las últimas 24 horas, artralgia, cansancio, fiebre, y dolor bilateral en los flancos. La paciente había comenzado un tratamiento con 40 mg/día de pantoprazol oral para el reflujo gastroesofágico, 2 meses previo a la admisión. Luego de 5 semanas de terapia, la paciente suspendió el pantoprazol, debido a un malestar general. Al momento de la admisión, se reiniciaron todos los medicamentos que tomaba en el hogar, incluido el pantoprazol, según la lista de medicamentos de la paciente. La creatinina sérica aumentó a 6.1 mg/dL al cuarto día de la admisión, de una línea de base de 1.0 mg/dL. La terapia con el pantoprazol se suspendió, rápidamente, y se inició con 40 mg/día de prednisona. El urinálisis reveló eosinofilia y una biopsia renal, subsiguiente, confirmó el diagnóstico de nefritis intersticial aguda. La creatinina sérica disminuyó, gradualmente, en 2 semanas y la paciente fue dada de alta al hogar con una creatinina sérica de 1.6 mg/dL. La escala de probabilidad de Naranjo sugiere una relación ‘altamente probable’ entre la nefritis intersticial aguda y la terapia del pantoprazol en este paciente. DISCUSIÓN: Las reacciones de hipersensibilidad a los medicamentos son la causa más común de nefritis intersticial aguda. A pesar de haber muy poca información prospectiva sobre la eficacia del tratamiento de nefritis intersticial aguda inducida por medicamentos, los corticosteroides pueden tener un rol en la recuperación de la función renal. Se ha sugerido una dosis de 1 mg/kg/día de prednisona. CONCLUSIONES: Los médicos deben conocer que los inhibidores de la bomba de protones pueden ser la causa de la nefritis intersticial aguda inducida por medicamentos. La detección temprana de esta reacción adversa rara podría prevenir una insuficiencia renal aguda.

Rafaela Mena RÉSUMÉ

Décrire ce qui semble être le premier cas de néphrite interstitielle aiguë (NIA) secondaire au pantoprazole. RÉSUMÉ DU CAS: Une dame de 77 ans se présente à l’hôpital oligurique depuis 24 heures, associé à une créatininémie élevée, arthralgie, fièvre, fatigue et douleur aux 2 flancs. La patiente avait débuté un traitement OBJECTIF:

2004 January, Volume 38

www.theannals.com

Acute Interstitial Nephritis Due to Pantoprazole

pour du reflux gastrique 2 mois plus tôt avec pantoprazole 40 mg par jour, qu’elle avait cessé après 5 semaines. A l’admission, la pantoprazole a été redébuté selon la liste personnelle de médicaments. La créatinine sérique a alors bondi de 1.0 à 6.1 mg/dL en 4 jours. Le pantoprazole est cessé et de la prednisone (40 mg par jour) est débuté. L’analyse urinaire révèle des éosinophiles et une biopsie rénale subséquente a confirmé le diagnostic de NIA. La créatininémie a progressivement diminué sur 2 semaine, jusqu’à 1.6 mg/dL le jour de son départ. L’échelle de probabilité de Naranjo suggère une relation hautement probable entre la NIA et le pantoprazole chez cette patiente.

www.theannals.com

Les réactions d’hypersensibilité aux médicaments sont les causes les plus courantes de NIA. De plus, il existe plusieurs rapports de NIA causé par l’oméprazole. Enfin, les corticostéroïdes n’ont pas de rôle démontré dans le traitement des NIA, mais des doses de 1 mg/kg ont été suggérées pour hâter la reprise de la fonction rénale. CONCLUSIONS: Les médecins doivent suspecter les inhibiteurs de pompe à proton lorsqu’un patient se présente en NIA. La détection rapide de cet effet rare peut prévenir une insuffisance rénale aiguë. DISCUSSION:

The Annals of Pharmacotherapy

Jean Longtin



2004 January, Volume 38



45