Acute Interstitial Nephritis Due to Methicillin
JEFFREY E. GALPIN, M.D. JAMES H. SHINABERGER, M.D. THOMAS
M. STANLEY, M.D.
MICHAEL J. BLUMENKRANTZ,
M.D.
ARNOLD S. BAYER, M.D. GERALD S. FRIEDMAN, M.D.* JOHN Z. MONTGOMERIE, M.D.7 LUCIEN 8. GUZE, M.D. JACK W. COBURN, M.D. Los Angeles, California RICHARD J. GLASSOCK,
M.D.
Torrance,California
Fromthe Depamnentsof Medicineand Pathology, VA WadsworthHospitalCenter, HarborGeneral Hospital,and UCLA Schoolof Medicine,Los Angeles and Torrance, California. This paper was presented at the Southeastern Dialysis and Transplantation Associition 12th AnnualMeeting, Miami, Florida, August 5-7, 1977, and at the American Society of Nephrology 10th Annual Meeting, Washington,D.C., November 20-22, 1977. Requestsfor reprintsshouldbe addressed to Dr. Jeffrey E. Galpin,VA WadsworthHospital Center, Wilshire and Sawtelle Boulevards,Los Angeles,California90073. Manuscriptaccepted May 9, 1978. Present address: 1228 LynhurstDrive, Riverside, California92507. t Presentaddress:LosAngeles CountyHealth Services.Ranch0Los AmigosHospital,Downey, California90242. l
756
November 1978
Fourteen patients are described with a syndrome of methicillininduced interstitial nephritis. In all patients severe renal dysfunction developed with an average peak serum creatinine of 8 mg/lOO ml. An increased total peripheral eosinophil count was found in all patients. All patients had sterile pyuria and each of nine patients studied by Wright’s stain of urine sediment had marked eosinophiluria. These findings are suggestive of methiciliin-induced interstitial nephritis, although proteinuria was a variable finding in our patients. Eight of 14 patients in our study received prednisone therapy for their interstitial nephritis, and the time lapse between maximal and final base line serum creatinine levels was statistically less in the prednisone-treated compared to the nontreated groups. Clinical manlfestations of this syndrome are discussed, and the light and electron microscopic and immunofluorescent findings on renal biopsy are described. Methicillin (dimethoxyphenylpenicillin) is an active penicillinase resistant semi-synthetic penicillin [ 11. Nephropathy associated with various degrees of renal impairment has been noted to be associated with methicillin-induced nephritis [2-g]. Consideration of the pathogenetic etiology of this syndrome includes a direct toxicity or an immune reaction directed by either a cellular or humoral process [4,8-131. In this report we describe 14 patients with a syndrome consistent with methicillin-induced interstitial nephritis. Their clinical course encompasses a broad spectrum of manifestations. Certain characteristic clinical and laboratory findings are described which may aid in the rapid diagnosis of this disease. Finally, a therapeutic approach to this form of interstitial nephritis is reported and discussed. PATIENTS AND METHODS Fourteen patients were studied. The diagnosis of methicillin interstitial nephritis was considered when a clinical picture of fever, renal failure and, occasionally, rash occurred in association with peripheral eosinophilia, an elevated serum creatinine level, pyuria and, frequently, hematuria in a patient treated with methicillin and having no other likely cause for such a reaction. The drug-induced interstitial nephritis was further confirmed by renal biopsy and by its response to the discontinuation of methicillin therapy. Four of the patients were studied at Harbor General Hospital and 10 by the Nephrology Section of the Veterans Administration Wadsworth Hospital Center. Prednisone therapy was not considered at Harbor General Hospital. Eight of 10 patients at Wadsworth Veterans Hospital, however, received prednisone treatment, whereas the remaining two received no therapy. The latter patients were studied prior to the use of prednisone.
The American Journal of Medicine
Volume 65
25,M
63.M
49.F 42,M
57.M 56.M
43,M 60.M
56,M
41.M
62.M
55,M
51,M
55,M
1
2
3 4
5 6
7 a
9
10
11
12
13
14
Mitral valve replacement
Osteomyelitis (Staph. aureus) Chronic renal disease, mitral valve replacement
Sepsis (Staph. aureus) Bacterial endocarditis (Staph. aureus) Femoral popliteal bypass Osteomyelitis (Staph. aureus) Aortic value replacement Gangrene of toe, diabetes mellitus Cellulitis Suppurative thrombophlebitis Pyogenic arthritis (Staph. aureus) Cellulitis diabetes (Staph. aureus) Coronary bypass
Dtsglmsis
5.5
103 103’ 104f 101f
101% 103
103
102.5
7 0 0 0 7 0 5 6 0 10 7
0.5
9 14 21 6 13 15 13 16 14 6 17
12
91 112 94 30
38
7
120
108
88
216
161 49
875
10
12
105 105
24
5
449.5
104’ $
103t
100%
104.6’F.
2
a
Peak Temperature With Reaction
108
(9)
Total Dosage
14
9
12
6
22
4
18
23 14
7 3.5 12
21 6
14 14
29
9
4 5
6.5 8
15.5
12
Treatment (days)
Of
Daysot Methicillin TherapyAfter Dnsstof Reaction
Tb-PY When Reaction Noted
Dayof
Interstitial Nephritis
* Patient had fever with underlying disease, became afebrile and then became febrile with suggested drug reaction. t Patient also had arthralgias. x Patient had a spike in temperature and reported chills with each intravenous dose of methicillin. 0 Received one additional dose of 3 g.
NO.
Age (Yr) and Sex
Average
Duration
Clinical Features in 14 Patients with Methicillin-Induced
Case
TABLE I
None
None
None
Maculopapular petechial None
None
Maculopapular None
Maculopapulart None
None None
Maculopapular
None
Rashand Quality
Gentamicin (serum creatinine level began to rise before addition of this drug Cefazolin (no drugs for 6 days)
Penicillin, dicloxacillin None
lsoniazid
None
Gentamicin Gentamicin
None None
Penicillin None
None
None
OtherAntibiotics Administeredat Time of Reaction
ACUTE INTERSTITIAL
TABLE II
Case NO.
NEPHRITIS DUE TO METHICILLIN-GALPIN
ET AL.
Pertinent Laboratory Data in 14 Patients with Methicillin-Induced Interstitial Nephritis Peak Total Peripheral Eosinophil Counl(mm3)
Urinalysis RBClhPf WBClhPl
1 2 3 4 5 6 7 8 9 10 11 12 13
1,573 1,312 3,400 2,763 1.500 3,000 2,275 900 2,000 1,500 1,750 600 Markedly elevated (no exact count
40-80 5-6 30-40 Many None Many 8-10
14
2,970
Eosinophils (% of WBC)
Many 4-6 None 10-15 Many 8-10
20-40 10-20 10-15 Many Many Many 50-75 Many Many Many 50-100 Many Many
60 ND ND ND 50 50 30 10 15 40 12-15 ND ND
3-6
20-40
30
Renal
>l
Protein
Bacteria
Neg Neg Neg
Neg
Biapsv
Neg Neg Neg
Neg Neg
No Yes No Yes No Yes Yes No Yes Yes Yes Yes No
Neg
Neg
No
g/24 hr
Neg 3.8 g/24 hr >500 mg124 hr 2.85 g/24 hr 500 mgl24 hr Neg
Neg Neg Neg Neg Neg
Neg Neg
Neg Nag Neg
NOTE: RBC = red blood cells; WBC = white blood cells; hpf = high power field; ND = not determined, Neg = negative.
as described. After postfixation in 1 per cent unbuffered osmium tetroxide, dehydration in graded ethanols and embedment in Epons 812, semithin (0.5 to 1.5 pm) sections were stained with 1 per cent toluidine blue in 1 per cent borax. Ultrathin sections were prepared on the SorvallIPorter-Mum MT-2 ultramicrotome and stained with uranyl acetate and lead citrate. Ultrastructural surveys were carried out in the RCAEMU 3H electron microscope. The specimens submitted for immunofluorescence were frozen in isopentane at -70°C, cut on a cryostat at -2OOC into sections 4 to 6 @and then stained with fluoroscein isothiocyanate conjugated specific antihuman immunoglobulins
Renal biopsies were performed in eight patients. Tissues for light microscopy were initially fixed in 4 per cent neutral phosphate-buffered formaldehyde or in 1.5 per cent glutaraldehyde buffered to pH 7.3 or 7.4 in 0.1 M sodium cacodylate [ 141. Paraffin sections were cut at either 6 or 4 pm and stained with hematoxylin and eosin and periodic acid-Schiff reagent in all cases. In some cases, stains for elastin (Verhoeff), collagen (Masson trichrome) and basement membrane (Jones’ periodic acid-methenamine-silver) were also made. In the cases originating at the Wadsworth Hospital Center (Cases 5 through 14) tissues for electron microscopy were initially fixed in either paraformaldehyde or glutaraldehyde TABLE III
Renal Function in 14 Patients with Methiclllln-Induced Interstitial Nephrltis
Case
No. 1 2
UrineOutput Good Good
Requiring Dialysis
SerumCreatinlne (ylldl) Premethiclllin Peak
No No
0.6 1.2
1.6 4.4
3
Oliguric (6.0 >20 13.0 >6.0 8.5 3.8 12.0 1.7 14.0 6.9
7
8 9 10 11 12 13 14
Patients who received prednisone therapy. + Patient received two courses of prednisone. * Prednisone therapy delayed 20 days after rise in creatinine level. l
758
November 1978
The American Journal of Medicine
Volume 85
Flnal
DayshornRisein SerumCreatinineLevel UntilStabilizedat FinalBaseLine
0.6
32
3.7 2.2
30 158
2.0 0.8 About 2.0 1.0 1.8 1.0 1.1 1.0 1.0 2.8 1.7
50 28’ 58 20’ 37+ 25’ 20’ 34t 180 58‘ 17’
-
ACUTE INTERSTITIAL
G (IgG), M(IgM), A(IgA), the third component of complement (C3), albumin and fibrin [ 151. Wright’s stain was performed on at least one freshly voided centrifuged urine sediment from nine of these patients and from 43 patients with acute renal failure of other etiology. The sediment was air dried on a slide, and Wright’s stain was applied for 1 minute, followed by Wright’s buffer for 2 minutes. The specimen was then examined. RESULTS
The clinical and laboratory features of these 14 patients are outlined in Tables I, II, and Ill and summarized in Table IV. The 14 patients included 13 men and one woman, whose age ranged from 25 to 63 years. Ten patients were treated with methicillin for an underlying infection, whereas four were treated as part of a prophylactic regimen prior to and after cardiovascular surgery. Patients received 4 to 15.5 g of methicillin a day with an average of 8.3 g/day; the total dose received ranged from 30 to about 450 g, with an average of 124 g. The duration of therapy ranged from six to 29 days. The manifestations of methicillin-induced nephritis began an average of 11 days after the initiation of antibiotic therapy. Seven patients received only methicillin at the time the drug-associated symptoms first appeared, whereas seven patients received other antibiotics prior to the onset of their nephritis. A rash developed in only 28 per cent of the patients. In one patient (Case 10) both maculopapular and petechial lesions developed; the latter were biopsied and diagnosed as a vasculitis. One patient (Case 5) reported severe arthralgias during the course of his nephritis. All 14 patients had an elevated serum creatinine level and increased peripheral eosinophil count (
JEFFREY E. GALPIN, M.D. JAMES H. SHINABERGER, M.D. THOMAS
M. STANLEY, M.D.
MICHAEL J. BLUMENKRANTZ,
M.D.
ARNOLD S. BAYER, M.D. GERALD S. FRIEDMAN, M.D.* JOHN Z. MONTGOMERIE, M.D.7 LUCIEN 8. GUZE, M.D. JACK W. COBURN, M.D. Los Angeles, California RICHARD J. GLASSOCK,
M.D.
Torrance,California
Fromthe Depamnentsof Medicineand Pathology, VA WadsworthHospitalCenter, HarborGeneral Hospital,and UCLA Schoolof Medicine,Los Angeles and Torrance, California. This paper was presented at the Southeastern Dialysis and Transplantation Associition 12th AnnualMeeting, Miami, Florida, August 5-7, 1977, and at the American Society of Nephrology 10th Annual Meeting, Washington,D.C., November 20-22, 1977. Requestsfor reprintsshouldbe addressed to Dr. Jeffrey E. Galpin,VA WadsworthHospital Center, Wilshire and Sawtelle Boulevards,Los Angeles,California90073. Manuscriptaccepted May 9, 1978. Present address: 1228 LynhurstDrive, Riverside, California92507. t Presentaddress:LosAngeles CountyHealth Services.Ranch0Los AmigosHospital,Downey, California90242. l
756
November 1978
Fourteen patients are described with a syndrome of methicillininduced interstitial nephritis. In all patients severe renal dysfunction developed with an average peak serum creatinine of 8 mg/lOO ml. An increased total peripheral eosinophil count was found in all patients. All patients had sterile pyuria and each of nine patients studied by Wright’s stain of urine sediment had marked eosinophiluria. These findings are suggestive of methiciliin-induced interstitial nephritis, although proteinuria was a variable finding in our patients. Eight of 14 patients in our study received prednisone therapy for their interstitial nephritis, and the time lapse between maximal and final base line serum creatinine levels was statistically less in the prednisone-treated compared to the nontreated groups. Clinical manlfestations of this syndrome are discussed, and the light and electron microscopic and immunofluorescent findings on renal biopsy are described. Methicillin (dimethoxyphenylpenicillin) is an active penicillinase resistant semi-synthetic penicillin [ 11. Nephropathy associated with various degrees of renal impairment has been noted to be associated with methicillin-induced nephritis [2-g]. Consideration of the pathogenetic etiology of this syndrome includes a direct toxicity or an immune reaction directed by either a cellular or humoral process [4,8-131. In this report we describe 14 patients with a syndrome consistent with methicillin-induced interstitial nephritis. Their clinical course encompasses a broad spectrum of manifestations. Certain characteristic clinical and laboratory findings are described which may aid in the rapid diagnosis of this disease. Finally, a therapeutic approach to this form of interstitial nephritis is reported and discussed. PATIENTS AND METHODS Fourteen patients were studied. The diagnosis of methicillin interstitial nephritis was considered when a clinical picture of fever, renal failure and, occasionally, rash occurred in association with peripheral eosinophilia, an elevated serum creatinine level, pyuria and, frequently, hematuria in a patient treated with methicillin and having no other likely cause for such a reaction. The drug-induced interstitial nephritis was further confirmed by renal biopsy and by its response to the discontinuation of methicillin therapy. Four of the patients were studied at Harbor General Hospital and 10 by the Nephrology Section of the Veterans Administration Wadsworth Hospital Center. Prednisone therapy was not considered at Harbor General Hospital. Eight of 10 patients at Wadsworth Veterans Hospital, however, received prednisone treatment, whereas the remaining two received no therapy. The latter patients were studied prior to the use of prednisone.
The American Journal of Medicine
Volume 65
25,M
63.M
49.F 42,M
57.M 56.M
43,M 60.M
56,M
41.M
62.M
55,M
51,M
55,M
1
2
3 4
5 6
7 a
9
10
11
12
13
14
Mitral valve replacement
Osteomyelitis (Staph. aureus) Chronic renal disease, mitral valve replacement
Sepsis (Staph. aureus) Bacterial endocarditis (Staph. aureus) Femoral popliteal bypass Osteomyelitis (Staph. aureus) Aortic value replacement Gangrene of toe, diabetes mellitus Cellulitis Suppurative thrombophlebitis Pyogenic arthritis (Staph. aureus) Cellulitis diabetes (Staph. aureus) Coronary bypass
Dtsglmsis
5.5
103 103’ 104f 101f
101% 103
103
102.5
7 0 0 0 7 0 5 6 0 10 7
0.5
9 14 21 6 13 15 13 16 14 6 17
12
91 112 94 30
38
7
120
108
88
216
161 49
875
10
12
105 105
24
5
449.5
104’ $
103t
100%
104.6’F.
2
a
Peak Temperature With Reaction
108
(9)
Total Dosage
14
9
12
6
22
4
18
23 14
7 3.5 12
21 6
14 14
29
9
4 5
6.5 8
15.5
12
Treatment (days)
Of
Daysot Methicillin TherapyAfter Dnsstof Reaction
Tb-PY When Reaction Noted
Dayof
Interstitial Nephritis
* Patient had fever with underlying disease, became afebrile and then became febrile with suggested drug reaction. t Patient also had arthralgias. x Patient had a spike in temperature and reported chills with each intravenous dose of methicillin. 0 Received one additional dose of 3 g.
NO.
Age (Yr) and Sex
Average
Duration
Clinical Features in 14 Patients with Methicillin-Induced
Case
TABLE I
None
None
None
Maculopapular petechial None
None
Maculopapular None
Maculopapulart None
None None
Maculopapular
None
Rashand Quality
Gentamicin (serum creatinine level began to rise before addition of this drug Cefazolin (no drugs for 6 days)
Penicillin, dicloxacillin None
lsoniazid
None
Gentamicin Gentamicin
None None
Penicillin None
None
None
OtherAntibiotics Administeredat Time of Reaction
ACUTE INTERSTITIAL
TABLE II
Case NO.
NEPHRITIS DUE TO METHICILLIN-GALPIN
ET AL.
Pertinent Laboratory Data in 14 Patients with Methicillin-Induced Interstitial Nephritis Peak Total Peripheral Eosinophil Counl(mm3)
Urinalysis RBClhPf WBClhPl
1 2 3 4 5 6 7 8 9 10 11 12 13
1,573 1,312 3,400 2,763 1.500 3,000 2,275 900 2,000 1,500 1,750 600 Markedly elevated (no exact count
40-80 5-6 30-40 Many None Many 8-10
14
2,970
Eosinophils (% of WBC)
Many 4-6 None 10-15 Many 8-10
20-40 10-20 10-15 Many Many Many 50-75 Many Many Many 50-100 Many Many
60 ND ND ND 50 50 30 10 15 40 12-15 ND ND
3-6
20-40
30
Renal
>l
Protein
Bacteria
Neg Neg Neg
Neg
Biapsv
Neg Neg Neg
Neg Neg
No Yes No Yes No Yes Yes No Yes Yes Yes Yes No
Neg
Neg
No
g/24 hr
Neg 3.8 g/24 hr >500 mg124 hr 2.85 g/24 hr 500 mgl24 hr Neg
Neg Neg Neg Neg Neg
Neg Neg
Neg Nag Neg
NOTE: RBC = red blood cells; WBC = white blood cells; hpf = high power field; ND = not determined, Neg = negative.
as described. After postfixation in 1 per cent unbuffered osmium tetroxide, dehydration in graded ethanols and embedment in Epons 812, semithin (0.5 to 1.5 pm) sections were stained with 1 per cent toluidine blue in 1 per cent borax. Ultrathin sections were prepared on the SorvallIPorter-Mum MT-2 ultramicrotome and stained with uranyl acetate and lead citrate. Ultrastructural surveys were carried out in the RCAEMU 3H electron microscope. The specimens submitted for immunofluorescence were frozen in isopentane at -70°C, cut on a cryostat at -2OOC into sections 4 to 6 @and then stained with fluoroscein isothiocyanate conjugated specific antihuman immunoglobulins
Renal biopsies were performed in eight patients. Tissues for light microscopy were initially fixed in 4 per cent neutral phosphate-buffered formaldehyde or in 1.5 per cent glutaraldehyde buffered to pH 7.3 or 7.4 in 0.1 M sodium cacodylate [ 141. Paraffin sections were cut at either 6 or 4 pm and stained with hematoxylin and eosin and periodic acid-Schiff reagent in all cases. In some cases, stains for elastin (Verhoeff), collagen (Masson trichrome) and basement membrane (Jones’ periodic acid-methenamine-silver) were also made. In the cases originating at the Wadsworth Hospital Center (Cases 5 through 14) tissues for electron microscopy were initially fixed in either paraformaldehyde or glutaraldehyde TABLE III
Renal Function in 14 Patients with Methiclllln-Induced Interstitial Nephrltis
Case
No. 1 2
UrineOutput Good Good
Requiring Dialysis
SerumCreatinlne (ylldl) Premethiclllin Peak
No No
0.6 1.2
1.6 4.4
3
Oliguric (6.0 >20 13.0 >6.0 8.5 3.8 12.0 1.7 14.0 6.9
7
8 9 10 11 12 13 14
Patients who received prednisone therapy. + Patient received two courses of prednisone. * Prednisone therapy delayed 20 days after rise in creatinine level. l
758
November 1978
The American Journal of Medicine
Volume 85
Flnal
DayshornRisein SerumCreatinineLevel UntilStabilizedat FinalBaseLine
0.6
32
3.7 2.2
30 158
2.0 0.8 About 2.0 1.0 1.8 1.0 1.1 1.0 1.0 2.8 1.7
50 28’ 58 20’ 37+ 25’ 20’ 34t 180 58‘ 17’
-
ACUTE INTERSTITIAL
G (IgG), M(IgM), A(IgA), the third component of complement (C3), albumin and fibrin [ 151. Wright’s stain was performed on at least one freshly voided centrifuged urine sediment from nine of these patients and from 43 patients with acute renal failure of other etiology. The sediment was air dried on a slide, and Wright’s stain was applied for 1 minute, followed by Wright’s buffer for 2 minutes. The specimen was then examined. RESULTS
The clinical and laboratory features of these 14 patients are outlined in Tables I, II, and Ill and summarized in Table IV. The 14 patients included 13 men and one woman, whose age ranged from 25 to 63 years. Ten patients were treated with methicillin for an underlying infection, whereas four were treated as part of a prophylactic regimen prior to and after cardiovascular surgery. Patients received 4 to 15.5 g of methicillin a day with an average of 8.3 g/day; the total dose received ranged from 30 to about 450 g, with an average of 124 g. The duration of therapy ranged from six to 29 days. The manifestations of methicillin-induced nephritis began an average of 11 days after the initiation of antibiotic therapy. Seven patients received only methicillin at the time the drug-associated symptoms first appeared, whereas seven patients received other antibiotics prior to the onset of their nephritis. A rash developed in only 28 per cent of the patients. In one patient (Case 10) both maculopapular and petechial lesions developed; the latter were biopsied and diagnosed as a vasculitis. One patient (Case 5) reported severe arthralgias during the course of his nephritis. All 14 patients had an elevated serum creatinine level and increased peripheral eosinophil count (
