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Original Paper
Accepted: January 28, 2002
Nephron 2002;92:297–303
Effective Antibiotic Treatment of
Methicillin-Resistant Staphylococcus
aureus-Associated Glomerulonephritis
Yasushi Nagaba a Yoshiyuki Hiki b Togo Aoyama a Takashi Sano a
Takatoshi Matsuo a Takeshi Shimizu a Sumio Tateno a Hisato Sakamoto a
Kouju Kamata a Hidekazu Shigematsu c Masaaki Higashihara a
Yutaka Kobayashi a
a Department
of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa,
of Internal Medicine, Nagoya University Daiko Medical Center, Nagoya, and c Department of
Pathology, Shinshu University School of Medicine, Matsumoto, Japan
b Department
Abstract
Background: A new type of glomerulonephritis following
a methicillin-resistant Staphylococcus aureus (MRSA) infection has been reported. The purpose of this study is to
elucidate the clinicopathological features and the responsiveness to treatment of the disease. Methods: We
studied the treatment of 8 patients with glomerulonephritis related to MRSA infection. We observed the eight
cases and analyzed clinical features, laboratory findings
and histopathological data. Results: On admission, all
patients had no renal abnormalities. One to four months
after suffering from MRSA infection, severe proteinuria
and hematuria developed. Renal biopsy specimens revealed moderate to severe mesangial proliferative glomerulonephritis with various degrees of crescent formation. Immunofluorescence studies showed IgA and C3.
Antibiotic therapy was performed in six cases, resulting
ABC
© 2002 S. Karger AG, Basel
0028–2766/02/0922–0297$18.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
Accessible online at:
www.karger.com/journals/nef
in successfully reducing the proteinuria in parallel with
the decreased activity of MRSA infection in five cases.
The other 2 cases received corticosteroid treatment after
complete cessation of MRSA infection, but they had a
relapse of MRSA infection and later died from sepsis.
Conclusions: These results suggested that MRSA-associated glomerulonephritis might respond to antibiotic
treatment in most cases. This also indicated that special
care must be taken in the application of steroid therapy
for the glomerulonephritis with crescents, even though
the MRSA infection has gone into an inactive state.
Copyright © 2002 S. Karger AG, Basel
Introduction
Glomerulonephritis occurring in the course of staphylococcal infection has been reported frequently since the
first paper in 1961 by Powell et al. [1]. Bacterial endocarditis [2, 3] and infected ventriculo-jugular shunt [4, 5] had
been two main causes of the disease. Recently, Koyama
and coworkers [6–8] found a new type of glomerulone-
Yasushi Nagaba, MD
Department of Internal Medicine
Kitasato University School of Medicine
1-15-1 Kitasato, Sagamihara City, Kanagawa 228-8555 (Japan)
Tel. +81 42 778 9981, Fax +81 42 778 9980, E-Mail yanagaba@med.kitasato-u.ac.jp
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Key Words
Methicillin-resistant Staphylococcus aureus W
Glomerulonephritis W Antibiotics
Table 1. Clinical features in 8 patients with glomerulonephritis related to MRSA infection
Case
No.
Age
Sex
Underlying condition
Focus of infection
Onset after Purpura
infection
weeks
1
2
3
4
5
6
7
8
73
56
75
35
51
67
54
23
M
M
M
F
M
M
M
M
submaxillary cancer
subarachnoid hemorrhage
diffuse panbronchiolitis
atopic dermatitis
deep burn
abdominal aortic aneurysm
hepatocellular carcinoma
psoriatic arthritis
pneumonia
pyelonephritis
pneumonia
skin abscess
skin graft infection
aortic graft infection
abscess of abdominal cavity
skin abscess
6
8
8
16
4
4
8
12
Patients and Methods
Patients
Eight patients (7 males, 1 female) aged 23–75 years were examined. All patients were admitted to Kitasato University Hospital for
treatment of various diseases other than renal disease between
November 1989 and October 2000. At the time of admission, they
had no proteinuria and serum creatinine levels were within normal
limits. They also had no history of renal disease. Glomerulonephritis
developed after MRSA infection in all cases.
298
Nephron 2002;92:297–303
Laboratory Examination
Laboratory data were obtained by standard methods during routine examinations at Kitasato University Hospital. Blood, sputum,
urine and pus from various foci were cultured, and sensitivity to antibiotics was tested to identify MRSA.
Histological Examination
Renal biopsy was performed in all patients. For light-microscopic
examination, renal biopsy specimens were fixed with 10% buffered
formalin solution, dehydrated in alcohol, embedded in paraffin, and
cut into sections. Sections were stained with hematoxylin and eosin
(HE), periodic acid Schiff (PAS), periodic acid silver methenamine
(PAM) and Masson-Trichrome. For immunofluorescence examination, specimens were embedded in OCT compound (Sakura Co.,
Tokyo) and immediately frozen in liquid nitrogen. Specimens were
cut into sections and fixed with acetone. All sections were stained
with fluorescein isothiocyanate (FITC)-conjugated sheep antihuman
IgG, IgA, IgM, C1q, C3, C4 and fibrinogen (Cappel, Durham, N.C.,
USA). For electron microscopy, all specimens were fixed with glutaraldehyde and osmium tetroxide, ultrathin sections were stained
with lead citrate and uranyl acetate, and they were examined with an
electron microscope (Hitachi, Tokyo).
Results
Clinical Features and Laboratory Findings
Clinical features of the 8 patients with MRSA-associated glomerulonephritis are listed in table 1. Clinical data of
glomerulonephritis for each case on admission, at the
onset and minimal level after treatment are shown in figure 1. Table 2 lists the immunological findings at the
onset of glomerulonephritis. All patients had normal renal
function and no urinary abnormalities on admission. Underlying conditions were skin diseases in three patients,
cancer in two patients, and lung, cerebral disease and aortic aneurysm in one patient each. MRSA was detected in
all patients. The foci of MRSA infection were visceral
Nagaba et al.
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phritis following methicillin-resistant Staphylococcus aureus (MRSA) infection. This type has a different character
from the classical type of glomerulonephritis that follows
staphylococcal infection, and a unique mechanism is
thought to be involved in the process of acquiring this glomerulonephritis. The clinical feature of this glomerulonephritis is rapidly progressive glomerulonephritis (RPGN)
with polyclonal Á-globulinemia (IgA and IgG), and proliferative glomerulonephritis with crescent lesions is often
observed histopathologically. Immunofluorescence study
reveals predominant mesangial IgA deposits as well as C3.
These findings suggest that the enterotoxins of MRSA
play a role as superantigens in the occurrence of this
unique glomerulonephritis.
We report here 8 patients with MRSA-associated glomerulonephritis. The patients showed similar clinical
courses and histopathological findings. The glomerulonephritis in these patients was speculated to occur due to the
same pathogenesis. The purpose of this study is to elucidate the clinicopathological features and the responsiveness to the treatment of this disease.
+
+
–
+
+
+
+
+
Fig. 1. Proteinuria, urinary occult blood and
level of serum creatinine on admission, at
the onset of glomerulonephritis and minimum levels after treatment in antibiotics
treatment patients and steroid treatment
patients. UP = Urinary protein; UB = urinary occult blood; Cr = serum creatinine;
MINO = minocycline; OFLX = ofloxacin;
VCM = vancomycin.
abscess in 5 patients and skin abscess in 3 patients. The
period from MRSA infection to the onset of glomerulonephritis ranged from 4 to 16 weeks. While they were suffering from MRSA infection, severe proteinuria and hematuria developed in addition to a polyclonal increase in Áglobulins (IgG and IgA) in all patients. Rapid increase of
serum creatinine levels was observed in 5 patients. Circu-
lating immune complex (CIC) was detected in all patients,
but the increases of the titers varied. Five patients had
slight increases of antinuclear antibody (ANA) titer. In 7
patients, purpura was noticed at the same time as the
onset of glomerulonephritis. Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was negative
in 2 cases and not measured in 6 cases.
Treatment of MRSA Glomerulonephritis
Nephron 2002;92:297–303
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299
Table 2. Hematological and immunological findings at onset
Case No. WBC
/mm3
Hb
g/dl
Plt
!104
ANA
!
IgG
mg/dl
1
2
3
4
5
6
7
8
13.2
11.6
11.8
12.1
8.6
10.4
16.5
11.9
38
38
48
22
31
32
23
31
160
40
–
40
–
40
–
40
2,440
1,910
2,460
1,900
1,550
2,270
2,150
2,220
12.5–
17.0
15.0–
35.0
Normal
range
11,100
10,200
5,500
5,300
12,100
10,000
10,200
8,700
4,000–
9,000
–
960–
1,960
IgA
mg/dl
521
1,040
697
529
553
572
419
285
IgM
mg/dl
C3
mg/dl
C4
mg/dl
CH50
U/ml
CIC
Ìg/dl
Á-gl
%
78
372
154
169
95
72
288
184
64
49
79
84
56
69
53
49
27
43
39
41
42
36
32
24
33
ND
60
46
39
18
53
38
13.4
2.6
5.1
2.7
2.9
1.5
1.1
3.9
33.2
26.6
34.9
22.1
23.1
25.7
25.3
34.4
120–450 70–360
50–105 14–44
25–45
0–3.0
10.5–
19.9
WBC = White blood cells; Hb = hemoglobin; Plt = platelets; ANA = antinuclear antibodies; CIC = circulating immune complex;
Á-gl = Á-globulin.
300
Nephron 2002;92:297–303
formed again; however, he died of sepsis. Bacterial endocarditis and subarachnoid hemorrhage with bacterial embolism were found at autopsy.
Case 8, a 24-year-old man, was admitted to our hospital for management of psoriatic arthritis with skin infection. MRSA was cultured from skin abscess and blood.
Minocycline was given intravenously, general condition
was soon improved, but MRSA cultured from a skin
lesion persisted. Three months after MRSA infection was
detected, proteinuria and hematuria were first pointed
out and proteinuria gradually increased to the nephrotic
range. Five months after MRSA infection, percutaneous
renal biopsy was performed. Light-microscopic examination revealed mesangial proliferative glomerulonephritis
with cellular crescents. Prednisolone was started for persistent massive proteinuria and impairment of renal function after C-reactive protein (CRP) was negative. The
dose was 500 mg intravenously for the first 3 days and
50 mg orally for a month, with gradual tapering. The level
of serum creatinine and proteinuria did not improve.
Three months after steroid treatment was started, sudden
consciousness disturbance developed. Computed tomography showed massive subcortical hemorrhage, and, finally, he died. Cerebral bacterial embolism was found at
autopsy.
Histopathological Examination
Light-microscopic findings revealed necrotizing crescentic glomerulonephritis (fig. 2A) in 4 patients and mildto-moderate mesangial proliferative glomerulonephritis
in 4 patients. Crescent formation of various degrees was
Nagaba et al.
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Treatment with antibiotics alone was performed in 6
patients. Four patients were treated with vancomycin
alone, case 3 with minocycline and ofloxacin, case 4 with
minocycline alone. All antibiotics were administered initially intravenously. Together with improvement of the
MRSA infection by antibiotic therapy, proteinuria decreased and serum creatinine levels normalized within
several weeks in 5 patients. Hemodialysis therapy was
required in 1 patient (case 5) with severe glomerular and
tubular damage. Recovery of renal function was not
achieved (fig. 1).
Another 2 patients (cases 7 and 8) received corticosteroid treatment. Case 7, a 55-year-old man, underwent a
partial resection of the liver for hepatocellular carcinoma.
He developed a liver abscess, treated initially by vancomycin, and subsequently by percutaneous drainage.
MRSA was detected in the culture of abscess material and
blood. A small cavity in the liver could be detected by
abdominal ultrasonography, after CRP and the culture of
the material from drain were negative. Four weeks after
onset of MRSA infection, proteinuria and hematuria were
detected for the first time. Five months after MRSA infection, renal biopsy was performed, and mesangial proliferative glomerulonephritis with cellular crescents was seen
on light-microscopic examination. Prednisolone was
started orally at a daily initial dose of 40 mg. Serum creatinine and proteinuria were improved by the treatment,
but relapse of MRSA infection occurred 4 months after
starting corticosteroid treatment. Recurrence of liver abscess was established by ultrasonography, and then vancomycin therapy and percutaneous drainage were per-
Fig. 2. A Light micrograph of a glomerulus showing tuft necrosis and cellular crescents. !270, PAM. B Immunofluorescence
micrograph of a glomerulus showing mesangial IgA deposits. !270. C Electron micrograph of a part of a glomerulus exhibiting
paramesangial dense deposits and infiltration of monocytes in the capillary lumen and mesangium. Mesangial cell proliferation and
endothelial swelling are prominent. !3,500. Mc = Mesangial cell; En = endothelial cell; Mo = monocyte; Dp = deposit.
Treatment of MRSA Glomerulonephritis
Discussion
In 1995, Koyama’s group [6–8] reported a new type of
glomerulonephritis occurring during the course of MRSA
infection. They proposed that this new type be called
superantigen-related glomerulonephritis (SARN), because the enterotoxin of MRSA was identified to act as a
superantigen in the pathogenesis of glomerulonephritis
following MRSA infection. Superantigens are potent immunostimulatory proteins of bacterial or viral origin that
activate a large population of T cells by binding to the V
beta domain of the T cell antigen receptor (TCR) at nanomolar concentrations when bound to major histocompati-
Nephron 2002;92:297–303
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detected in 7 patients. Tubulointerstitial nephritis was
observed in 6 patients (table 3). Immunofluorescence examination revealed IgA (fig. 2B) and C3 deposits in all the
patients with a mesangial pattern (table 4). On the other
hand, IgG deposits were found in only 1 patient. Electronmicroscopic findings revealed electron-dense deposits
(fig. 2C) in mesangial areas in all patients (table 4).
Table 3. Histological and immunofluorescence findings
IF
Case
No.
LM
glomerular lesions
crescents/ TIN
glomeruli
IgG
IgA
IgM
C3
C4
C1q
fib
1
2
3
4
5
6
7
8
necrotizing crescent GN
mesangial proliferative GN
mesangial proliferative GN
mesangial proliferative GN
necrotizing crescent GN
mecrotizing crescent GN
mesangial proliferative GN
necrotizing crescent GN
17/33
0/3
2/32
2/20
22/23
12/35
2/20
9/22
–
–
–
++
–
–
–
–
++
+
++
++
+
+
++
+++
++
–
+
+
++
–
–
–
+
+
++
+
+++
+
++
++
–
–
–
–
+
–
–
–
–
–
–
–
+
–
–
–
+
+
–
++
++
+
–
–
+
++
–
+/–
++
++
–
+/–
LM = Light microscopic; IF = immunofluoresce; TIN = tubulointestinal nephritis; fib = fibrinogen; M = mesangial
pattern; P = peripheral pattern.
Case
No.
Deposits
Mes
End
Epi
1
2
3
4
5
6
7
8
+
+
+
+
+
+
+
+
–
–
–
–
–
–
–
+
–
–
–
–
–
–
–
+
CMI
Mesan- Glomeruli
giolysis
monocytes PMN
–
–
+
+
+
+
–
+
+
–
–
–
+
–
+
+
+
–
+
+
+
+
–
+
+
–
–
+
+
+
–
+
Mes = Mesangial; End = endothelial; Epi = epithelial; CMI = circumferential mesangial interposition; PMN = polymorphonuclear
leukocyte.
bility complex (MHC) class II molecules, but they do not
require processing. Superantigens have been implicated
as a causative factor in a number of human diseases. A
typical example is toxic shock syndrome where enterotoxin as a superantigen releases massive cytokines, mainly
tumor necrosis factor-ß, interferon-Á, interleukin 1 and
interleukin 6. The clinical effects of superantigens can be
not only acute but also chronic. Recent evidence suggests
that superantigens may play a central role in the pathogenesis of several autoimmune disorders such as rheumatoid arthritis, Kawasaki disease [9] and multiple sclerosis
[10].
302
Nephron 2002;92:297–303
MRSA was first identified in the United Kingdom in
1961. The prevalence of MRSA infection has been reported by several dozen facilities worldwide. About 60%
of S. aureus isolates obtained from patients in Japan during 1992 and 1993 were MRSA [11]. Infection with
MRSA is a significant problem for hospitalized patients
in Japan. MRSA infection may occur in the compromised
host such as elderly patients, especially patients with
chronic disease or after surgery. Another important clinical feature is that MRSA infection often persists for longer
periods, since most antibiotics are ineffective. Prolonged
septicemia is an important precondition for the development of glomerulonephritis [6–8]. With increasing numbers of MRSA infection, MRSA-associated glomerulonephritis has been found in our hospital.
The 8 patients in this study were thought to be compatible with the type of glomerulonephritis reported by
Koyama’s group based on similarities of their clinical features and pathology. First, MRSA-associated glomerulonephritis was observed to follow a clinical course of rapidly progressive glomerulonephritis with nephrotic syndrome in most of the cases. This clinical feature may
reflect the fact that superantigens could activate a large
number of T cells in a short time. Second, laboratory findings showed a polyclonal increase of serum IgG and IgA,
together with an increase of immune complexes. Third,
histological findings revealed mesangial proliferative glomerulonephritis with crescent formation and the deposition of IgA and C3 in a mesangial pattern in glomeruli.
One of the marked characteristics in this type of glomerulonephritis is the predominant mesangial deposition of
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Table 4. Electron-microscopic findings
IgA. This is the apparent point of digression from the classical type of glomerulonephritis induced by ventriculojugular shunt and bacterial endocarditis, which generally
presents a predominant deposition of IgG [2–5]. Yoh et
al. [12] suggested that IgA was a key factor in the development of MRSA-associated glomerulonephritis.
The levels of serum creatinine and proteinuria changed
in parallel with the activity of MRSA infection. The glomerulonephritis associated with MRSA infection was
very responsive to antibiotics in most cases. Yoh et al.
[12], in their case report, also reported that the levels of
serum creatinine and proteinuria paralleled the course of
the MRSA infection. Thus, this type of glomerulonephritis could be expected to improve if the MRSA infection
improves. In reality, however, the problem remains that it
is sometimes difficult to clinically confirm the complete
clearance of the MRSA infection. CRP level and white
blood cell count are useful markers of MRSA infection.
But they do not always accurately reflect the activity of
MRSA infection such as the presence of capsulated abscess. In this study, steroid therapy was performed in 2
patients after CRP and white blood cell count had decreased to normal range, because renal biopsies revealed
mesangial proliferative glomerulonephritis with crescent
formation and clinical feature was RPGN syndrome.
Both cases eventually died of sepsis due to the adverse
effects of corticosteroid. Considering these results, the
first choice of treatment of MRSA-associated glomerulonephritis should be antibiotic therapy.
In conclusion, MRSA-associated glomerulonephritis
may show favorable responsiveness to antibiotic treatment in the majority of cases. This also indicated that special care must be taken in the application of steroid therapy for glomerulonephritis with crescents, even though the
MRSA infection has gone into an inactive state.
References
Treatment of MRSA Glomerulonephritis
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