Bayliff, Charles

MacAulay, Stacey

Mehta, Sanjay

The Canadian Journal of Hospital Pharmacy (CJHP) / Le Journal canadien de la pharmacie hospitalière (JCPH)

139C J H P – Vol. 55, No. 2 – April 2002 J C P H – Vol. 55, no 2 – avril 2002Acute interstitial nephritis is a disease affecting therenal tubules and interstitium.1 It is thought to occursecondary to an allergic hypersensitivity reaction.1 Theclinical presentation is variable and nonspecific, andmay include fever, maculopapular rash, arthralgia,edema, hypertension, eosinophilia, eosinophiluria,pyuria, hematuria, proteinuria, oliguria, leukocytosis,elevation of serum immunoglobulin E, hyperkalemia,and acidosis.1,2 Acute interstitial nephritis can have aninfectious, inflammatory, or drug-related cause.2Numerous drugs have been implicated in acuteinterstitial nephritis, some of which include nonsteroidalanti-inflammatory drugs, diuretics, anticonvulsants,allopurinol, and antibiotics.2-4 Fluoroquinolones arecommonly used antibiotics that are thought to be relatively nontoxic.5 However, the potential exists forthese agents to cause substantial morbidity, as illustrated by published reports of fluoroquinolone-induced acute interstitial nephritis.6-25 Ciprofloxacinaccounts for the majority of these cases,6-22 with just afew reports for norfloxacin.10,23,24 A MEDLINE search forJanuary 1966 to December 2001 yielded only one published report of acute interstitial nephritis secondaryto levofloxacin, a newer fluoroquinolone.25 Two cases of fluoroquinolone-induced acute interstitial nephritis are reported here, one due to norfloxacin and the other to levofloxacin. As the use ofthis class of anti-infectives increases and as new members of the class are introduced, it is important thatpharmacists be aware of the growing evidence of thisclinically important adverse effect. CASE REPORTSCase 1A 70-year-old woman with primary pulmonaryhypertension was admitted to the respirology service forpersistent and increasing nausea accompanied by occasional vomiting and anorexia over a 2-week period,which had resulted in a 4.5-kg weight loss. Headachesoccasionally accompanied the nausea.Her medical history included New York Heart Association class IV primary pulmonary hypertension,hypothyroidism, a 2-year history of intermittent nausea,and recurrent urinary tract infections, for which she hadpreviously received norfloxacin. She had a remote history of cholecystectomy and hysterectomy. The patient was reportedly allergic to sulfa drugs.The family and social histories were unremarkable.Her medications used at home includedepoprostenol (by infusion), diltiazem, amiloride,furosemide, warfarin, a potassium supplement, levothyroxine, omeprazole, tolterodine, dimenhydri-nate, acetaminophen with codeine, vitamin E, glucosamine, and oxygen. At the time of admission, shewas on day 9 of treatment with norfloxacin 400 mg PO bid.On physical examination, the patient’s heart ratewas 100 beats/min, blood pressure 106/52 mm Hg, respiratory rate 24 breaths/min, and temperature 36.2°C. Her face and upper torso appeared flushed, consistent with epoprostenol therapy. Jugular venouspressure was elevated, and mild pedal edema wasCASE REPORTFluoroquinolone-Induced Acute Interstitial Nephritis: Two Case ReportsStacey MacAulay, Charles Bayliff, and Sanjay MehtaC J H P – Vol. 55, No. 2 – April 2002 J C P H – Vol. 55, no 2 – avril 2002140noted. Cardiac examination revealed a right ventricularheave, hard pulmonic component of S2, and a gradeIII/VI diastolic murmur. Laboratory investigations revealed serum creatinine193 µmol/L (normal range 55 to 115 µmol/L) and bloodurea nitrogen 15.2 mmol/L (normal range 2.5 to 7.0 mmol/L). Two months earlier, serum creatinine andblood urea nitrogen had been 91 µmol/L and 7.8 mmol/L respectively. Other abnormalities includedsodium 132 mmol/L (normal range 135 to 145 mmol/L),potassium 5.4 mmol/L (normal range 3.5 to 5.0 mmol/L), bicarbonate 17 mmol/L (normal range 24 to 32 mmol/L), albumin 28 g/L (normal range 35 to50 g/L), total serum amylase 33 U/L (normal range 36 to128 U/L), international normalized ratio (INR) 4.0 (normal range 2.0 to 3.0), and partial thromboplastintime 66 s (normal range 28 to 38 s). The platelet countwas 81 x 109/L (normal range 150 to 400 x 109/L), which,although below normal, was consistent with previousrecords for this patient. Electrocardiography showed a right bundle branchblock and T-wave abnormalities.The substantially worsening and debilitating nauseathat had necessitated admission to hospital was thoughtto be due to the use, over the 9 days before admission,of unadjusted doses of norfloxacin in the setting of renalfailure. Hence, the norfloxacin was discontinued on day3 of the hospital stay (for a total duration of treatmentof 12 days); the nausea subsequently diminished.Several studies were undertaken to investigate theacute renal compromise. Urinalysis showed below-normal sodium and osmolality, minimal hematuria consistent with an INR of 4.0 or acute interstitialnephritis (or both), trace proteinuria, and eosinophils.Renal ultrasonography revealed no obstruction. Onday 10 of the hospital stay (7 days after discontinuationof norfloxacin), acute interstitial nephritis secondary tonorfloxacin was diagnosed, and prednisone 40 mg PO daily was initiated. The patient was discharged onday 14, at which time she was asymptomatic (serum creatinine 185 µmol/L and blood urea nitrogen 22 mmol/L). Upon follow-up 12 days after discharge,serum creatinine and blood urea nitrogen had decreased to 109 µmol/L and 11.5 mmol/L respectively. Case 2A 44-year-old woman was admitted to the authors’institution for assessment of severe pulmonary arterialhypertension and pericardial effusion in the setting ofmixed connective tissue disease. The patient had a 3-week history of shortness ofbreath and a continuous cough, accompanied by anincrease in the volume of her usual white sputum. Shereported sharp, burning retrosternal chest pain and hadhad several episodes of nausea and vomiting. Her family physician prescribed azithromycin, which hadprovided only minimal relief. Levofloxacin was thenprescribed and had been taken for 6 days before admission. She had become increasingly short of breath,and her cough and chest pain had worsened. She wasadmitted to another hospital in the region, where severepulmonary hypertension, possible pneumonia, andrenal failure were diagnosed. She was treated for 1 daywith methylprednisolone and levofloxacin before beingtransferred to the authors’ hospital.Her medical history was significant for an overlapconnective tissue disorder with features of CREST (calcinosis, Raynaud’s, esophagus, sclerodactyly, telangiectasia) syndrome and mixed connective tissuedisease, as well as for cardiomegaly and hypothyroidism. She had experienced an episode ofpneumonia approximately 6 months previously. She was allergic to IV pyelography dye; the allergymanifested as urticaria, pruritis, and fever.Upon admission to the authors’ facility, the patienthad been taking levofloxacin 500 mg PO daily for 7 days, as well as omeprazole, fluticasone, and salbutamol (the latter 2 drugs by inhaler). The patient reported dizziness associated with postural changes, headache, chest pain, nausea andvomiting, prior observation of blood in her stool, occasional “muddy-colour” urine, bloody urine a fewmonths before, severe flank pain occurring a fewmonths previously that had radiated over her back andunder her ribcage, and a recent weight gain of approximately 2 kg despite reduced dietary intake.On examination, her heart rate was 96 beats/min,blood pressure 120/84 mm Hg without postural change,and respiratory rate 18 breaths/minute; she was afebrile.Jugular venous pressure was elevated, and she hadbilateral increase in breath sounds, bilateral but equaldecrease in tendon reflexes, tibial edema, and telangiectasia of the hands and face. The results of the remainder of the physical examination were unremarkable.Abnormal laboratory findings included serum creatinine 195 µmol/L and blood urea nitrogen 17.2 mmol/L. Six months earlier, her serum creatininehad been 80 µmol/L. Other abnormalities included sodium 130 mmol/L, monocytes 1.0 x 109/L (normalrange 0.2 to 0.8 x 109/L), reticulocyte distribution width141C J H P – Vol. 55, No. 2 – April 2002 J C P H – Vol. 55, no 2 – avril 200215.5 (normal range 12.0 to 15.0), and albumin 28 g/L.Urinalysis revealed urinary eosinophils and urinary protein of at least 3 g/L.Chest radiography showed cardiomegaly andabsence of pleural effusion. Electrocardiographyshowed sinus tachycardia at 100 beats/min, incompleteright bundle branch block, and a nonspecific flatteningof T-waves at leads V1 to V3.The acute compromise in renal function was presumed to be secondary to levofloxacin-inducedacute interstitial nephritis, given the normal serum creatinine level 6 months earlier and the finding ofeosinophils in the urine. Levofloxacin was discontinuedon the third day of the hospital stay, for a total durationof therapy of 10 days. Prednisone 30 mg PO daily wasinitiated, and she was discharged on the 11th day of thehospital stay; at that time, serum creatinine was 165 µmol/L and blood urea nitrogen 10.2 mmol/L. Follow-up at 3 months revealed serum creatinine of 116 µmol/L and blood urea nitrogen of 7.6 mmol/L.DISCUSSIONSeveral features of these 2 case reports are consistent with fluoroquinolone-induced acute intersti-tial nephritis, as reported in the literature. In each ofthese patients, the serum creatinine and blood ureanitrogen levels rose within 10 days of initiation of theoffending agent. Most cases of drug-induced acute interstitial nephritis develop within 10 days, but the condition may develop within hours to weeks after initiation of therapy.2-4 As well, urinary eosinophils andproteinuria were present in both of these patients.2-4Edema was present in both cases and hematuria in oneof the cases1-3; however, it is unclear if other factors,specifically pulmonary hypertension and concomitantwarfarin therapy, played a role in these observed abnormalities. With discontinuation of the fluoroquinolones, renal status improved and wasapproaching normal at follow-up appointments (23 daysand approximately 3 months after discontinuation ofnorfloxacin and levofloxacin respectively). In mostreported cases of fluoroquinolone-induced acute interstitial nephritis, renal function returns to normal ornearly normal over a period of days to months.2,3,26 Incontrast to the patients described here, fever and rashwere noted in other published reports.2-4,26 Flushing secondary to epoprostenol infusion might have impeded the ability to detect a rash in patient 1. It isnoteworthy that both of these patients had pulmonaryhypertension, a rare disease characterized by substantialmorbidity and a high mortality rate.27 The association, ifany, between fluoroquinolone-induced acute interstitialnephritis and pulmonary hypertension is unknown. In summary, pharmacists should be aware that several fluoroquinolones have been associated withacute interstitial nephritis, including ciprofloxacin, norfloxacin, and levofloxacin. Although ciprofloxacin ismost often cited in connection with acute interstitialnephritis, this may simply represent prescribing patterns. Given that this adverse drug reaction occurswith several of the fluoroquinolones, it may be due to aclass effect. The possibility of a class effect makes itessential that pharmacists be vigilant in monitoring forthis adverse drug reaction with any dose of a fluoroquinolone.26 Patients who experience acute interstitial nephritis caused by one fluoroquinoloneshould be considered susceptible to the others, giventhe substantial morbidity of the reaction. If renal insufficiency with features of acute interstitial nephritisoccurs in the presence of a fluoroquinolone and othercauses of renal insufficiency have been excluded, thefluoroquinolone should be promptly discontinued. Further management may include corticosteroid therapy; however, this strategy remains controversial.2,4References1. Abraham PA, Matzke GR. Drug-induced renal disease. In:Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BJ, Posey LM,eds. Pharmacotherapy. A pathophysiologic approach. Stamford(CT): Appleton & Lange; 1999. p. 822-44.2. Davison AM, Jones CH. Acute interstitial nephritis in the elderly: a report from the UK MRC Glomerulonephritis Registerand a review of the literature. Nephrol Dial Transplant1998;13(Suppl 7):12-6.3. Alexopoulos E. Drug-induced acute interstitial nephritis. RenFail 1998;20:809-19.4. Murray KM, Keane WR. Review of drug-induced acute interstitial nephritis. Pharmacotherapy 1992;12:462-7.5. Walker RC. The fluoroquinolones. Mayo Clin Proc 1999;74:1030-7.6. Allon M, Lopez EJ, Min KW. Acute renal failure due tociprofloxacin. Arch Intern Med 1990;150:2187-9.7. Bailey JR, Trott SA, Philbrick JT. Ciprofloxacin-induced acuteinterstitial nephritis. Am J Nephrol 1992;12:271-3.8. George MJ, Dew RB 3rd, Daly JS. Acute renal failure after an overdose of ciprofloxacin [letter]. Arch Intern Med 1991;151:620. 9. Gerritsen WR, Peters A, Henny FC, Brouwers JR. Ciprofloxacin-induced nephrotoxicity [letter]. Nephrol Dial Transplant1987;2:382-3.10. Hadimeri H, Almroth G, Cederbrant K, Enestrom S, Hultman P,Lindell A. Allergic nephropathy associated with norfloxacin andciprofloxacin therapy. Report of two cases and review of the literature. Scand J Urol Nephrol 1997;31:481-5.11. Helmink R, Benediktsson H. Ciprofloxacin-induced allergicinterstitial nephritis. Nephron 1990;55:432-3.12. Hootkins R, Fenves AZ, Stephens MK. Acute renal failure secondary to oral ciprofloxacin therapy: a presentation of threecases and a review of the literature. Clin Nephrol 1989;32:75-8.C J H P – Vol. 55, No. 2 – April 2002 J C P H – Vol. 55, no 2 – avril 200214213. Lo WK, Rolston KV, Rubenstein EB, Bodey GP. Ciprofloxacin-induced nephrotoxicity in patients with cancer. Arch InternMed 1993;153:1258-62.14. Murray KM, Wilson MG. Suspected ciprofloxacin-induced interstitial nephritis. Drug Intell Clin Pharm 1990;24:379-80.15. Raja N, Miller WE, McMillan R, Mason JR. Ciprofloxacin-associatedacute renal failure in patients undergoing high-dose chemotherapy and autologous stem cell rescue. Bone MarrowTransplant 1998;21:1283-4.16. Rastogi S, Atkinson JL, McCarthy JT. Allergic nephropathy associated with ciprofloxacin. Mayo Clin Proc 1990;65:987-9.17. Reece RJ, Nicholls AJ. Ciprofloxacin-induced acute interstitialnephritis [letter]. Nephrol Dial Transplant 1996;11:393.18. Rippelmeyer DJ, Synhavsky A. Ciprofloxacin and allergic interstitial nephritis [letter]. Ann Intern Med 1988;109:170.19. Rolston KVJ, Rubenstein EB. Ciprofloxacin nephrotoxicity [letter]. Arch Intern Med 1993;153:2705-6. 20. Rosado LJ, Siskind MS, Copeland JG. Acute interstitial nephritisin a cardiac transplant recipient receiving ciprofloxacin [letter].J Thorac Cardiovasc Surg 1994;107:1364-79.21. Shih DJ, Korbet SM, Rydel JJ, Schwartz MM. Renal vasculitisassociated with ciprofloxacin. Am J Kidney Dis 1995;26:516-9.22. Ying LA, Johnson CA. Ciprofloxacin-induced interstitial nephritis.Clin Pharm 1989;8:518-21.23. Boelaert J, de Jaegere PP, Daneels R, Schurgers M, Gordts B,van Landuyt HW. Case report of renal failure during norfloxacintherapy [letter]. Clin Nephrol 1986;25:272.24. Nakamura M, Ohishi A, Aosaki N, Hamaguchi K. Norfloxacin-induced acute interstitial nephritis [letter]. Nephron 2000;86:204-5.25. Solomon NM, Mokrzycki MH. Levofloxacin-induced allergic interstitial nephritis [letter]. Clin Nephrol 2000;54:356.26. Lomaestro BM. Fluoroquinolone-induced renal failure. Drug Saf2000;22:470-85.27. D’Alonzo GE, Barst RJ, Ayres SM, Begofsky EH, Brundage BH,Detre KM, et al. Survival in patients with primary pulmonaryhypertension. Results from a national prospective registry. AnnIntern Med 1991;115:343-9.Stacey MacAulay, BScPharm, PharmD, is a Pharmacist with the Evi-dence-Based Prescribing Initiative at the London Health Sciences Cen-tre, London, Ontario. At the time of writing, she was enrolled in theDoctor of Pharmacy Program at the University of Toronto and wascompleting a clinical rotation with Charles Bayliff.Charles Bayliff, BScPhm, PharmD, is a Pharmaceutical Care Coordi-nator at the London Health Sciences Centre, London, Ontario.Sanjay Mehta, MD, FRCPC, is a Respirologist at the London HealthSciences Centre, London, Ontario.Address correspondence to:Dr Stacey MacAulayEvidence-Based Prescribing InitiativeRoom S-121London Health Sciences Centre375 South StreetLondon ONN6A 4G5e-mail: stacey.macaulay@lhsc.on.ca 

Fluoroquinolone-Induced Acute Interstitial Nephritis: Two Case Reports

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