The patient was an 80-year-old man who arrived at the emergency room with breathing problems. He presented a history of chronic obstructive pulmonary disease (COPD), hypertension, diabetes mellitus and early (stage 1) chronic renal failure with normal levels of creatinine and no sign and symptoms of renal disease. A chest X-ray showed pneumonia. Therefore, he was first treated with 1 g daily of ceftriaxone IV. We did not observe any clinical improvement, and for this reason, a sputum culture was performed to guide the right antibiotic treatment. Subsequently, we started a new antibiotic therapy with trimethoprim/sulfamethoxazole (TMP/SMX) adjusted to renal functioning. Appropriate medical treatment was administered, as well as urine alkalinisation. After the first day of treatment, the patient’s clinical and laboratory status worsened very quickly, with an increased level of serum creatinine from 1.5 to 3.5 mg/dL. We stopped administering the antibiotic therapy immediately. However, we observed acute renal failure with a serum creatinine level of 9.0 mg/dL and four days after his admission, the patient

died. Literature showed that patients can develop acute kidney injury (AKI) during or immediately following TMP/SMX therapy. Intrinsic renal impairment –rather, interstitial nephritis– appeared

responsible for the great majority of cases, and impairment was transient if therapy was discontinued.

In our study, despite the therapy with TMP/SMX was immediately discontinued, and our patient underwent appropriate medical treatment, urine alkalinisation and, then, haemodialysis, the AKI was rapidly fatal.

In conclusion, particular attention should be paid to prescribing TMP/SMX to patients affected by chronic renal failure

Gabriella Nucera

Giulia Cantoni

Lisa Caliari

Pietro Marino

Valentina Raffaelli

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Journal of Health and Social Sciences 2017; 2,2:215-220215Trimethoprim/sulfamethoxazole-induced acute renal failure: A case reportGabriella Nucera1, Valentina Raff aelli1, Lisa Caliari1, Giulia Cantoni1, Pietro Marino1CASE REPORT IN INTERNAL MEDICINEKEY WORDS: Acute kidney injury; anti-Bacterial agents; renal insuffi  ciency, acute; trimethoprim/sulfamethoxazole.AbstractTh e patient was an 80-year-old man who arrived at the emergency room with breathing problems. He presented a history of chronic obstructive pulmonary disease (COPD), hypertension, diabetes mellitus and early (stage 1) chronic renal failure with normal levels of creatinine and no sign and symptoms of renal disease. A chest X-ray showed pneumonia. Th erefore, he was fi rst treated with 1 g daily of ceftriaxone IV. We did not observe any clinical improvement, and for this reason, a sputum culture was performed to guide the right antibiotic treatment. Subsequently, we started a new antibiotic therapy with trimethoprim/sulfamethoxazole (TMP/SMX) adjusted to renal functioning. Appropriate medical treatment was administered, as well as urine alkalinisation. After the fi rst day of treatment, the patient’s clinical and laboratory status worsened very quickly, with an increased level of serum creatinine from 1.5 to 3.5 mg/dL. We stopped administering the antibiotic therapy immediately. However, we observed acute renal failure with a serum creatinine level of 9.0 mg/dL and four days after his admission, the patient died. Literature showed that patients can develop acute kidney injury (AKI) during or immediately following TMP/SMX therapy. Intrinsic renal impairment –rather, interstitial nephritis– appeared responsible for the great majority of cases, and impairment was transient if therapy was discontinued. In our study, despite the therapy with TMP/SMX was immediately discontinued, and our patient underwent appropriate medical treatment, urine alkalinisation and, then, haemodialysis, the AKI was rapidly fatal. In conclusion, particular attention should be paid to prescribing TMP/SMX to patients aff ected by chronic renal failure.Affi  liations: 1 M.D., Department of Emergency, ASST Fatebenefratelli Sacco, PO Fatebenefratelli, Milan, Italy. Corresponding author: Dr. Gabriella Nucera, M.D., Professor, Faculty of Nursing Science, University of Milan, Milan, Italy and ASST Fatebenefratelli Sacco, PO Fatenbenefratelli Hospital, Milan, Italy. Piazza Principessa Clotilde,3 Milan, Italy. E-mail: gabriella.nucera@asst-fbf-sacco.it Journal of Health and Social Sciences 2017; 2,2:215-220216RiassuntoIl nostro paziente era un uomo di 80 anni giunto in pronto soccorso per difficoltà respiratorie. Era affetto da malattia polmonare cronica ostruttiva (BPCO), ipertensione, diabete mellito e lieve in-sufficienza renale cronica (stadio 1) con normali livelli di creatinina ed assenza di segni e sintomi di malattia renale. Un esame radiografico del torace ha evidenziato una polmonite. Pertanto, egli ven-ne trattato inizialmente con 1 gr/die di ceftriaxone ev. Non avendo osservato alcun miglioramen-to clinico, abbiamo eseguito un esame colturale sull’escreato per scegliere l’antibiotico specifico. Pertanto, abbiamo iniziato un antibioticoterapia con trimetoprim/sulfametossazolo (TMP/SMX) con un dosaggio modificato per la funzionalità renale. Abbiamo somministrato appropriata terapia medica ed alcalinizzato le urine. Dopo il primo giorno di trattamento, le condizioni cliniche e di laboratorio del paziente peggiorarono molto rapidamente, con un aumento dei livelli di creatinine-mia da 1,5 a 3,5 mg/dL. Abbiamo sospeso immediatamente l’antibioticoterapia. Tuttavia, abbiamo osservato la comparsa di insufficienza renale acuta con un livello di creatininemia pari a 9 mg/dL e, dopo 4 giorni dal ricovero, il paziente è morto. La letteratura scientifica ha mostrato che i pazienti durante o immediatamente dopo il trattamento con TMP/SMX possono sviluppare insufficien-za renale acuta. Il danno renale idiopatico, piuttosto che la nefrite interstiziale sembrano essere i responsabili per la maggior parte dei casi evidenziati in letteratura ed il danno renale è transitorio se la terapia viene sospesa. Nel nostro caso, nonostante l’immediata sospensione della terapia con TMX/SMX, l’appropriato trattamento medico, l’alcalinizzazione delle urine e poi l’emodialisi, l’in-sufficienza renale acuta è stata rapidamente mortale. In conclusione, particolare attenzione dovreb-be essere prestata alla prescrizione di TMX/SMX in pazienti affetti da insufficienza renale cronica. Competing interests - none declared.Copyright © 2017 Gabriella Nucera et al. FS PublishersThis is an open access article distributed under the Creative Commons Attribution (CC BY 4.0) License, which per-mits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. See http:www.creativecommons.org/licenses/by/4.0/.Cite this article as: Nucera G, Raffaelli V, Caliari L, Cantoni G, Marino P. Trimethoprim/sulfamethoxazole-induced acute renal failure: A case report. J Health Soc Sci. 2017;2(2):215-220TAKE-HOME MESSAGEParticular attention should be paid when prescribing trimethoprim/sulfamethoxazole to patients affected by chronic renal failure.Received: 10/06/2017 Accepted: 10/07/2017 Published: 15/07/2017DOI 10.19204/2017/trmt8Journal of Health and Social Sciences 2017; 2,2:215-220217INTRODUCTION Over the past 40 years, scholars have identi-fied many adverse events associated with tri-methoprim/sulfamethoxazole (TMP/SMX) [1]. According to a recent review, patients with chronic renal insufficiency are at incre-ased risk of adverse effects associated with the use of TMP/SMX [2, 3]. Although un-common, this drug can also cause renal injury in otherwise healthy patients. This adverse effect generally manifests as a form of drug hypersensitivity syndrome, most commonly acute interstitial nephritis [4]. A much less common mechanism by which TMP/SMX may cause acute kidney injury is obstructive tubulopathy resulting from the intralumi-nal precipitation of sulfamethoxazole [5]. In this study, we show a case of probably TMP/SMX-induced acute renal failure in a patient with early chronic kidney disease (CKD). CASE REPORTThe patient was an 80-year-old man who ar-rived at the emergency room with breathing problems. He presented a history of chro-nic obstructive pulmonary disease (COPD), hypertension, diabetes mellitus and early (sta-ge 1) chronic renal failure with normal levels of creatinine and no sign and symptoms of re-nal disease. The physical examination showed dyspnoea (respiratory rate = 35) and regular heart sounds with a regular heart rate (HR = 77 bpm). Electrocardiographic (ECG) mo-nitoring was normal, and the blood pressure was 150/70 mm Hg. A thoracic auscultation showed basal crackles. The neurological and abdominal examination was negative. A chest X-ray showed pneumonia; the most common phlogosis indices were elevated (C- reactive protein = 99 mg/L, white cells = 11,800, se-rum creatinine = 11,500). Therefore, he was admitted to the Emergency Department and was first treated with 1 g daily of ceftriaxone IV. We did not observe any clinical improve-ment, and for this reason, a sputum culture was performed to guide the right antibiotic treatment. It was positive for Acinetobacter baumannii. Subsequently, we started a new antibiotic therapy with TMP/SMX adjusted to renal functioning, which was based on the judgment of a specialist in infectious disease and susceptibility testing. Our patient had no prescription for any nephrotoxic medicinal products, and appropriate medical treatment was administered, as well as urine alkalini-sation. After the first day of treatment, the patient’s clinical and laboratory status wor-sened very quickly, with an increased level of serum creatinine from 1.5 to 3.5 mg/dL. We stopped administering the antibiotic therapy immediately. Laboratory tests excluded acu-te liver disorders. We started haemodialysis according to the nephrologist’s prescription, but the patient’s status required intensive care support. We observed acute renal failure with a serum creatinine level of 9.0 mg/dL. Finally, four days after his admission, the patient died. DISCUSSION Sulfa-containing medications can cause cry-stal-induced acute renal failure from intra-tubular deposition or renal impairment from allergic interstitial nephritis [6–12]. Intra-tubular crystal deposition can also occur with sulfamethoxazole. Because it is a weak acid, it is relatively insoluble in acid urine and tends to precipitate in the tubular lumen when the urine pH decreases to ≤ 5.5 [11, 12]. Indeed, both sulfadiazine and, less commonly repor-ted, sulfamethoxazole can readily precipitate in the kidneys in certain clinical settings and cause an obstruction of the tubular lumen in the distal nephron from crystals admixed with cellular debris and proteinaceous material [6–12]. In the literature, the administration of sulfadiazine is associated with acute renal fai-lure when used in greater than usual doses to treat toxoplasmosis and Pneumocystis carinii infections in AIDS patients, especially in the case of associated hypoalbuminemia and the impairment of venous blood flow from inter-stitial congestion and haemorrhage [6–10]. Oliguric acute renal failure, which develops on average within 7 days of starting therapy, often showed the development of sulpha-cry-stal tubular or calyceal deposition [6–10]. An examination of the urine sediment revealed red blood cells mixed with sulphonamide Journal of Health and Social Sciences 2017; 2,2:215-220218crystals, which could resemble needle-shaped crystals, rosettes and ‘shocks of wheat’ [6–10]. Sulfamethoxazole is another drug from the sulphonamide class that, since the 1970s, has seldom been reported to cause pleomorphic crystalluria [13, 14]. Recently, two repor-ts showed yellow to brown fan-shaped cry-stals (2009) [15] and different size and sha-pe (2011) sulfamethoxazole-induced crystals [16]. However, sulfamethoxazole is widely used in clinical practice in association with trimethoprim; therefore, little is known about their role in causing acute renal failure. Ver-desca et al. discussed the case of two patients treated with sulfamethoxazole who develo-ped a crystalluria that was very similar to the sulfadiazine one [17]. Fraser et al. published the only systematic evaluation of alterations in renal function during therapy with TMP/SMX in largely middle-aged male hospitali-zed patients. It was discovered that 11.2% of patients developed acute kidney injury (AKI) during or immediately following TMP/SMX therapy [18]. In slightly more than half of the cases, no other factors contributing to AKI were identified, and the TMP/SMX was felt to be responsible. This study did not show a relationship between the dose of TMP/SMX and the likelihood of developing AKI. In-trinsic renal impairment –rather, interstitial nephritis or competition for creatinine cle-arance – appeared responsible for the great majority of cases, and impairment was tran-sient if therapy was discontinued. Indeed, in nearly all cases likely due to TMP/SMX, AKI was resolved promptly after the discontinua-tion of therapy, and only one patient required dialysis [18]. According to Perazella, TMP/SMX may also form crystals in the urine of volume-depleted patients, resulting in AKI, and crystalluria may be seen in 0.4%–49% of these patients [19]. However, such crystals were not detected in Fraser’s review [18]. In our study, despite the therapy with TMP/SMX was immediately discontinued, and our patient underwent appropriate medical tre-atment, urine alkalinisation and, then, hae-modialysis, the acute renal failure was rapidly fatal. According to Fraser’s review, a multiva-riate model showed that patients with hyper-tension and diabetes mellitus had an incre-ased risk for renal insufficiency, especially if these conditions were poorly controlled. Our patient was affected by COPD, hypertension, diabetes mellitus and early (stage 1) chronic renal failure. According to the literature, ne-phrotoxicity from sulphonamides is preven-table, because the correction of hypovolemia with isotonic intravenous solutions (NaCl, NaHCO3) can prevent crystal precipitation in tubules [6–12, 19]. The addition of a loop diuretic promotes high urine flow rates, and maintaining an alkaline urine pH increased sulphonamide solubility. Daily monitoring of the urine for crystalluria allows the prompt adjustment of sulphonamide dosing, and the discontinuation of sulphonamide therapy might be necessary. Dialysis and other sup-portive care measures can reduce associated morbidity. However, in our case, all these me-asures were ineffective. Therefore, particular attention should be paid to prescribing TMP/SMX to patients affected by chronic renal fai-lure.Journal of Health and Social Sciences 2017; 2,2:215-220219References1. Ho JM-W, Juurlink DN. Considerations when prescribing trimethoprim–sulfamethoxazole. CMAJ: Ca-nadian Medical Association Journal. 2011;183(16):1851–1858. doi:10.1503/cmaj.111152.2. Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimetho-prim-sulfamethoxazole. Ann Intern Med. 1996;124:316. 3. Mori H, Kuroda Y, Imamura S, Toyoda A, Yoshida I, Kawakami M, et al. Hyponatremia and/or hyper-kalemia in patients treated with the standard dose of trimethoprim-sulfamethoxazole. Intern Med. 2003;42:665–669.4. Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003;289:1652–1658.5. Schwarz A, Perez-Canto A. Nephrotoxicity of antiinfective drugs. Int J Clin Pharmacol Ther. 1998;36:164–167. 6. Simon DI, Brosius FC, Rothstein DM. Sulfadiazine-induced crystalluria revisted. The treatment of Toxoplasma encephalitis in patients with acquired immune deficiency syndrome. Arch Intern Med. 1990;150:2379–2384.7. Carbone LG, Bendixen B, Appel GB. Sulfadiazine-associated obstructive nephropathy occurring in a patient with acquired immune deficiency syndrome. Am J Kidney Dis. 1988;12:72–75. 8. Hein R, Brunkhorst R, Thon WF. Symptomatic sulfadiazine crystalluria in AIDS patients: a report of two cases. Clin Nephrol. 1993;39:254–256. 9. Sasson JP, Dratch PL, Shortsleeve MJ. Renal ultrasound findings in sulfadiazine-induced crystalluria. Radiology. 1992;185:739–740. 10. Molina JM, Belenfant X, Doco-Lecompte T. Sulfadiazine-induced crystalluria in AIDS patients with toxoplasma encephalitis. AIDS. 1991;5:587–589. 11. Buchanan N. Sulfamethoxazole, hypoalbuminemia, crystalluria, and renal failure. BMJ. 1978;2:172.12. Siegel WH. Unusual complications of therapy with sulfamethoxazole-trimethoprim. J Urol. 1977;117:397–399.13. Buchanan N. Sulphamethoxazole, hypoalbuminaemia, crystalluria, and renal failure. BMJ. 1978 Jul 15;2(6131):172.14. Siegel WH. Unusual complication of therapy with sulfamethoxazole-trimethoprim. J Urol. 1977;117(3):397.15. Shrishrimal K, Wesson J. Sulfamethoxazole crystalluria. Am J Kidney Dis. 2011;58(3):492–493.16. Dereball VK, McGregor JG, Colindres RE, Singh HK, Kshirsagar AV. The Case: Acute kidney injury in a patient with P. carinii pneumonia. Kidney Int. 2009;75(8):865–866.17. Verdasca S, Cucchiari D, Monari M, Podestà MA, Badalamenti S. Sulfamethoxazole crystalluria. G Ital Nefrol. 2015;32(3). pii: gin/32.3.5.18. Fraser TN, Avellaneda AA, Graviss EA, Musher DM. Acute kidney injury associated with trimethoprim/sulfamethoazole. J Antimicrob Chemother. 2012;67(5):1271–1277.19. 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Trimethoprim/sulfamethoxazole-induced acute renal failure: A case report

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