CLOXACILLIN-INDUCED ACUTE TUBULO INTERSTITIAL NEPHRITIS Roberto Garcfa-Ortiz, Roberto S. Espinoza, Gonzalo R. Silva, Rodrigo K. Alonso, Hector S. Opazo, and Donald C. Houghton
To report a case of possible cloxacillin-induced acute tubulo interstitial nephritis (AIN).
OBJECTIVE:
A 15-year-old male patient presented with hypertension, edema, lumbar pain, sterile pyuria, eosinophiluria (ten percent), and severe renal dysfunction three months after the ingestion of cloxacillin. A renal biopsy revealed diffuse edema and inflammatory infiltrate of the interstitium (five percent eosinophils). He received four sessions of peritoneal dialysis with dramatic improvement in urinary output and renal function. His biochemical parameters returned to nonnal values 21 days after admission, without the use of glucocorticosteroids.
CASE SUMMARY:
Published case reports on AIN induced by penicillin and related drugs are reviewed and compared. The role of interstitial edema in acute renal failure associated with drug-induced AIN is mentioned. DISCUSSION:
AIN is a rare but significant complication of therapy with penicillin and related drugs. The clinical picture is similar for all of these drugs, but skin rash and fever are absent in AIN induced by cloxacillin and cloxacillin-related drugs. Dialysis improved the patient's urinary output and renal function. Beta-Iactarn antibiotics should be avoided in patients with cloxacillin-induced AIN.
CONCLUSIONS:
Ann Pharmacother 1992;26:1241-2. ACUTE TUBULO INTERSTITIAL NEPHRITIS (AIN) is a rare cause of acute renal failure. AIN has been associated with infections and drug reactions.!" Bruckheimer and Abrahamov reported on a patient (the second case published) with probable AIN induced by cloxacillin," We report the third such case, the first with AIN-compatible renal biopsy. CASE REPORT A 15-year-old white male patient was examined at Hospital A. Nef in October 1988 because of a skin infection caused by Staphylococcus aureus. He was treated with cloxacillin 3 g/d for ten days. The patient denied taking any other medications. Ninety-two days following his initial examination, he returned with diarrhea, vomiting, and malaise. Within 72 hours, he was admitROBERTO GARCiA.ORTlZ, M.D., FACP, is the Head. Department of Nephrology; ROBERTO S. ESPINOZA, M.D., is the Head. Department of Pathology; GON. ZALO R. SILVA, M.D.. is a Member, Department of Nephrology; RODRIGO K. ALONSO, M.D., is a Resident, Department of Nephrology; HECTOR S. OPAZO, M.D.• is a Member. Department of Pathology, Hospital A. Nef, Faculty of Medicine. Universidad de Valparaiso. Chile; and DONALD C. HOUGHTON, M.D.• is a Member, Department of Pathology. Oregon Health Sciences University, Portland. OR. Reprints: Roberto Garcia-Ortiz, M.D., FACP. Nephrology Department. A. NefHospital, Faculty of Medicine, Universidad de Valparaiso. P.O. Box 9013-3. Viiia del Mar,Chile.
ted to the hospital with dyspnea, edema, hypertension, and uremic breath. No fever or skin rash was observed. The patient's medical history was unremarkable. His chest was clear to auscultation. His abdomen was soft, with lumbar pain to palpation. Neurologic examination revealed signs of cerebral organic damage (intelligence quotient 63). The chest X-ray film showed hilar congestion. Urine output was maintained. Urinalysis revealed protein 0.20 g/d, and 50-80 red and 10-15 white blood cells (WBCs) per high-power field. A urine stain revealed ten percent eosinophils in 120 WBC/mL. Urine culture was negative. Upon admission, penicillin G benzathine I 200 000 IU was administered because it was thought that the patient had acute poststreptococcalglomerulonephritis. Blood studies revealed hematocrit 0.31, and a WBC count of 8.6 x IO"/L (0.13 eosinophils). Plasma sodium concentration was 133 mmol/L, potassium 6.4 mmol/L, bicarbonate 18.2 mmol/L, blood urea nitrogen 56.7 mmol/L of urea, and creatinine 1.19 umol/L, Blood concentrations of antistreptolysin 0, C3 and C4 complements, and immunoglobulins were normal. A renal sonogram demonstrated normal kidneys. An ophthalmologic examination was normal. A renal biopsy revealed 30 glomeruli, all appearing normal, except for a minimal increasein mesangialcells. The glomeruliwere surrounded by edema and inflammatory infiltrate in the interstitium.The infiltrate was patchy and composed predominantly of lymphocytes, but includedhistiocytes, Iymphoblasts, and eosinophils(five percent).Tubular damage was found in areas with marked interstitial infiltrates.Immunofluorescence assay was negative and the electron microscopy was normal (Figure I). These histopathologic features are consistent with drug-inducedinterstitial nephritis." The patient underwent four peritoneal dialysis sessions. No steroids were administered. The patient was discharged asymptomatic 21 days after admission. After three years, his renal parametersremain normal. During his hospitalcourse it was noted that the creatinekinase plasma concentrations were elevated (600-1200 units/L). Additional laboratory studies performed led to the conclusion that the patient also has an asymptomatichereditarymusculardystrophy.
Although our patient's case does not demonstrate a direct cause-and-effect relationship between cloxacillin and AIN, it seems to be highly likely because other possible etiologies, such as viral or idiopathic AIN, are absent. These etiologies were discarded because eosinophiluri a, which was categorically present in our case, is most unusual in viral and idiopathic AIN. Moreover, hypergammaglobulinemia and tubular dysfunction are common in idiopathic AIN.4 Thus, we believe that this case illustrates drug-induced AIN.
The Annals ofPharmacotherapy •
1992 October, Volume 26 •
1241
AIN is a rare but significant complication of therapy with penicillin and related drugs.' Its true incidence is unknown, as its clinical presentation is nonspecific and diagnosis requires a renal biopsy. Our subject was a young man, with a medication history including only cloxacillin, who presented with severe acute renal failure, eosinophilia, eosinophiluria, leukocyturia, proteinuria, hematuria, and normal urinary output; all of these features have been reported previously in penicillin-induced AIN.s Our patient's renal histopathologic evidence was also typical of AIN. He did not, however, manifest fever or skin rash, both of which have been described in methicillin-induced AIN.3 Fever and skin rash were also absent in a reported case of oxacillin-induced AIN,7 a drug structurally related to cloxacillin. It is, therefore, possible that these reactions do not occur in all penicillin-induced AIN. Another feature not previously described is the delayed onset of acute renal failure after cloxacillin ingestion. The time intervals reported for penicillin-induced AIN range from 0.5 to 60 days,3,8,9 variability that may be explained by patients' individual degrees of immune responsiveness. If a patient has been previously exposed to a drug, one may expect a quick (three to five days) anamnestic secondary immune response. But if a drug is new to a patient, a slower interstitial immune response may emerge as a primary response." AIN treatment consists of eliminating the antigen when it can be identified. Our patient received penicillin before an etiologic diagnosis was made. If this additional penicillin worsened our patient's condition, it could not be established. The most striking feature in this case was the dramatic improvement of renal function with dialysis. This lends support to theories that account for AIN-associated acute renal failure with the presence of interstitial edema and secondary alterations in interstitial architecture rather than with changes in the glomerular filtration barrier," The questionable relationship between AIN and mild hereditary muscular dystrophy in this patient remains to be explained. As all beta-lactam antibiotics, including penicillins and cephalosporins, seem capable of producing AIN, and because cross-reactivity also has been described," the use of other penicillins or cephalosporins should be avoided in patients with cloxacillin-induced AIN. ~
1242
•
Figure I. Kidney biopsy showingedema and diffuse infiltrationof the interstitium (lymphocytes, histiocytes, lymphoblast), whichis mostdenseat the bottomleft. Detachment of thetubular epithelium andpresence of vacuoles in thecellsalsocan be observed(hematoxylin-eosin. originalmagnification x 720).
References 1. Toto RD. Acute tubulointerstitial nephritis. Am] Med Sci 1990;299: 392-410. 2. Linton AL, Clark WF, Driedger AA, Turnbull 01, Lindsay RM. Acute interstitial nephritis due to drugs. Ann InternMed 1980;93:735-41. 3. Galpin JE, Shinaberger JH, Stanley TM, Blumenkrantz MJ, Bayer AS, Friedman GS, et aI. Acute interstitial nephritis due to methicillin.
Am] Med 1978;65:756-65. 4. Cotran RS, Rubin RH, Tofkhoff-Rubin NE. Tubulointerstitial diseases. In: Brenner BM, Rector PC, eds. The kidney. Vol 2. 3rd ed. Philadelphia: WB Saunders, 1986:1143-73. 5. Baldwin OS, Levine BB, McCluskey RT, Gallo GR. Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl J Med 1968;279:1245-52. 6. Bruckheimer E, Abrahamov A. Cloxacillin-induced interstitial nephrius.Isr J Med Sci 1991;27:159-60. 7. Burton J, Lichtenstein N, Colvin R, Hyslop N Jr. Acute interstitial nephritis from oxacillin. Hopkins Med J 1974;134:58-61. 8. Colvin R, Burton J, Hyslop N Jr, Spitz L, Lichtenstein N. Penicillin associated interstitial nephritis (lener). Ann Intern Med 1974;81:404-5. 9. Appel GB, Kunis CL. Acute tubulo-interstitial nephritis. In: Cotran RS, Brenner BM, and Stein JH, eds. Tubulo-interstitial nephropathies. New York: Churchill Livingstone, 1983:151-85. 10. Neilson E. Pathogenesis and therapy of interstitial nephritis. Kidney Int 1989;35:1257-70. 11. Bohle A, Mackensen-Haen S, Gise HV. Significance of tubulointerstitial changes in the renal cortex for the excretory function and concentration ability of the kidney: a morphometric contribution. Am J
NephroI1987;7:421-33.
The AnnalsofPharmacotherapy • 1992 October, Volume 26
To report a case of possible cloxacillin-induced acute tubulo interstitial nephritis (AIN).
OBJECTIVE:
A 15-year-old male patient presented with hypertension, edema, lumbar pain, sterile pyuria, eosinophiluria (ten percent), and severe renal dysfunction three months after the ingestion of cloxacillin. A renal biopsy revealed diffuse edema and inflammatory infiltrate of the interstitium (five percent eosinophils). He received four sessions of peritoneal dialysis with dramatic improvement in urinary output and renal function. His biochemical parameters returned to nonnal values 21 days after admission, without the use of glucocorticosteroids.
CASE SUMMARY:
Published case reports on AIN induced by penicillin and related drugs are reviewed and compared. The role of interstitial edema in acute renal failure associated with drug-induced AIN is mentioned. DISCUSSION:
AIN is a rare but significant complication of therapy with penicillin and related drugs. The clinical picture is similar for all of these drugs, but skin rash and fever are absent in AIN induced by cloxacillin and cloxacillin-related drugs. Dialysis improved the patient's urinary output and renal function. Beta-Iactarn antibiotics should be avoided in patients with cloxacillin-induced AIN.
CONCLUSIONS:
Ann Pharmacother 1992;26:1241-2. ACUTE TUBULO INTERSTITIAL NEPHRITIS (AIN) is a rare cause of acute renal failure. AIN has been associated with infections and drug reactions.!" Bruckheimer and Abrahamov reported on a patient (the second case published) with probable AIN induced by cloxacillin," We report the third such case, the first with AIN-compatible renal biopsy. CASE REPORT A 15-year-old white male patient was examined at Hospital A. Nef in October 1988 because of a skin infection caused by Staphylococcus aureus. He was treated with cloxacillin 3 g/d for ten days. The patient denied taking any other medications. Ninety-two days following his initial examination, he returned with diarrhea, vomiting, and malaise. Within 72 hours, he was admitROBERTO GARCiA.ORTlZ, M.D., FACP, is the Head. Department of Nephrology; ROBERTO S. ESPINOZA, M.D., is the Head. Department of Pathology; GON. ZALO R. SILVA, M.D.. is a Member, Department of Nephrology; RODRIGO K. ALONSO, M.D., is a Resident, Department of Nephrology; HECTOR S. OPAZO, M.D.• is a Member. Department of Pathology, Hospital A. Nef, Faculty of Medicine. Universidad de Valparaiso. Chile; and DONALD C. HOUGHTON, M.D.• is a Member, Department of Pathology. Oregon Health Sciences University, Portland. OR. Reprints: Roberto Garcia-Ortiz, M.D., FACP. Nephrology Department. A. NefHospital, Faculty of Medicine, Universidad de Valparaiso. P.O. Box 9013-3. Viiia del Mar,Chile.
ted to the hospital with dyspnea, edema, hypertension, and uremic breath. No fever or skin rash was observed. The patient's medical history was unremarkable. His chest was clear to auscultation. His abdomen was soft, with lumbar pain to palpation. Neurologic examination revealed signs of cerebral organic damage (intelligence quotient 63). The chest X-ray film showed hilar congestion. Urine output was maintained. Urinalysis revealed protein 0.20 g/d, and 50-80 red and 10-15 white blood cells (WBCs) per high-power field. A urine stain revealed ten percent eosinophils in 120 WBC/mL. Urine culture was negative. Upon admission, penicillin G benzathine I 200 000 IU was administered because it was thought that the patient had acute poststreptococcalglomerulonephritis. Blood studies revealed hematocrit 0.31, and a WBC count of 8.6 x IO"/L (0.13 eosinophils). Plasma sodium concentration was 133 mmol/L, potassium 6.4 mmol/L, bicarbonate 18.2 mmol/L, blood urea nitrogen 56.7 mmol/L of urea, and creatinine 1.19 umol/L, Blood concentrations of antistreptolysin 0, C3 and C4 complements, and immunoglobulins were normal. A renal sonogram demonstrated normal kidneys. An ophthalmologic examination was normal. A renal biopsy revealed 30 glomeruli, all appearing normal, except for a minimal increasein mesangialcells. The glomeruliwere surrounded by edema and inflammatory infiltrate in the interstitium.The infiltrate was patchy and composed predominantly of lymphocytes, but includedhistiocytes, Iymphoblasts, and eosinophils(five percent).Tubular damage was found in areas with marked interstitial infiltrates.Immunofluorescence assay was negative and the electron microscopy was normal (Figure I). These histopathologic features are consistent with drug-inducedinterstitial nephritis." The patient underwent four peritoneal dialysis sessions. No steroids were administered. The patient was discharged asymptomatic 21 days after admission. After three years, his renal parametersremain normal. During his hospitalcourse it was noted that the creatinekinase plasma concentrations were elevated (600-1200 units/L). Additional laboratory studies performed led to the conclusion that the patient also has an asymptomatichereditarymusculardystrophy.
Although our patient's case does not demonstrate a direct cause-and-effect relationship between cloxacillin and AIN, it seems to be highly likely because other possible etiologies, such as viral or idiopathic AIN, are absent. These etiologies were discarded because eosinophiluri a, which was categorically present in our case, is most unusual in viral and idiopathic AIN. Moreover, hypergammaglobulinemia and tubular dysfunction are common in idiopathic AIN.4 Thus, we believe that this case illustrates drug-induced AIN.
The Annals ofPharmacotherapy •
1992 October, Volume 26 •
1241
AIN is a rare but significant complication of therapy with penicillin and related drugs.' Its true incidence is unknown, as its clinical presentation is nonspecific and diagnosis requires a renal biopsy. Our subject was a young man, with a medication history including only cloxacillin, who presented with severe acute renal failure, eosinophilia, eosinophiluria, leukocyturia, proteinuria, hematuria, and normal urinary output; all of these features have been reported previously in penicillin-induced AIN.s Our patient's renal histopathologic evidence was also typical of AIN. He did not, however, manifest fever or skin rash, both of which have been described in methicillin-induced AIN.3 Fever and skin rash were also absent in a reported case of oxacillin-induced AIN,7 a drug structurally related to cloxacillin. It is, therefore, possible that these reactions do not occur in all penicillin-induced AIN. Another feature not previously described is the delayed onset of acute renal failure after cloxacillin ingestion. The time intervals reported for penicillin-induced AIN range from 0.5 to 60 days,3,8,9 variability that may be explained by patients' individual degrees of immune responsiveness. If a patient has been previously exposed to a drug, one may expect a quick (three to five days) anamnestic secondary immune response. But if a drug is new to a patient, a slower interstitial immune response may emerge as a primary response." AIN treatment consists of eliminating the antigen when it can be identified. Our patient received penicillin before an etiologic diagnosis was made. If this additional penicillin worsened our patient's condition, it could not be established. The most striking feature in this case was the dramatic improvement of renal function with dialysis. This lends support to theories that account for AIN-associated acute renal failure with the presence of interstitial edema and secondary alterations in interstitial architecture rather than with changes in the glomerular filtration barrier," The questionable relationship between AIN and mild hereditary muscular dystrophy in this patient remains to be explained. As all beta-lactam antibiotics, including penicillins and cephalosporins, seem capable of producing AIN, and because cross-reactivity also has been described," the use of other penicillins or cephalosporins should be avoided in patients with cloxacillin-induced AIN. ~
1242
•
Figure I. Kidney biopsy showingedema and diffuse infiltrationof the interstitium (lymphocytes, histiocytes, lymphoblast), whichis mostdenseat the bottomleft. Detachment of thetubular epithelium andpresence of vacuoles in thecellsalsocan be observed(hematoxylin-eosin. originalmagnification x 720).
References 1. Toto RD. Acute tubulointerstitial nephritis. Am] Med Sci 1990;299: 392-410. 2. Linton AL, Clark WF, Driedger AA, Turnbull 01, Lindsay RM. Acute interstitial nephritis due to drugs. Ann InternMed 1980;93:735-41. 3. Galpin JE, Shinaberger JH, Stanley TM, Blumenkrantz MJ, Bayer AS, Friedman GS, et aI. Acute interstitial nephritis due to methicillin.
Am] Med 1978;65:756-65. 4. Cotran RS, Rubin RH, Tofkhoff-Rubin NE. Tubulointerstitial diseases. In: Brenner BM, Rector PC, eds. The kidney. Vol 2. 3rd ed. Philadelphia: WB Saunders, 1986:1143-73. 5. Baldwin OS, Levine BB, McCluskey RT, Gallo GR. Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl J Med 1968;279:1245-52. 6. Bruckheimer E, Abrahamov A. Cloxacillin-induced interstitial nephrius.Isr J Med Sci 1991;27:159-60. 7. Burton J, Lichtenstein N, Colvin R, Hyslop N Jr. Acute interstitial nephritis from oxacillin. Hopkins Med J 1974;134:58-61. 8. Colvin R, Burton J, Hyslop N Jr, Spitz L, Lichtenstein N. Penicillin associated interstitial nephritis (lener). Ann Intern Med 1974;81:404-5. 9. Appel GB, Kunis CL. Acute tubulo-interstitial nephritis. In: Cotran RS, Brenner BM, and Stein JH, eds. Tubulo-interstitial nephropathies. New York: Churchill Livingstone, 1983:151-85. 10. Neilson E. Pathogenesis and therapy of interstitial nephritis. Kidney Int 1989;35:1257-70. 11. Bohle A, Mackensen-Haen S, Gise HV. Significance of tubulointerstitial changes in the renal cortex for the excretory function and concentration ability of the kidney: a morphometric contribution. Am J
NephroI1987;7:421-33.
The AnnalsofPharmacotherapy • 1992 October, Volume 26
