Diffuse Proliferative Glomerulonephritis and Acute Renal

Failure Associated with Acute Staphylococcal Osteomyelitis

MATTHEW D. GRIFFIN,* JOHANNES BJORNSSON,t and STEPHEN B. ERICKSON*

*Department of Internal Medicine, Division of Nephrology, and tDepartment of Pathology, Mayo Clinic and

Mayo Foundation, Rochester, Minnesota.

Abstract. A 72-year-old man developed acute renal failure after

coronary bypass surgery that had been complicated by sternal

osteomyelitis caused by the Staphylococcus aureus bacterium.

Bacteremia and sepsis were not present. Renal biopsy demon-

strated a florid, diffuse, proliferative glomerulonephritis with

glomerular immune complex deposition. Management in-

cluded hemodialysis, prolonged antibiotic therapy, and re-

peated surgical debridement. Spontaneous recovery of renal

function occurred after eradication of infection and final sur-

gical wound repair. The relationship between acute bacterial

infections and glomerulonephritis and, in particular, the causal

role of staphylococcal antigens in the pathogenesis of such

lesions is discussed. (J Am Soc Nephrol 8: 1633-1639, 1997)

Coagulase-positive staphylococcus (Staphylococcus aureus) is

the most common causative organism in acute osteomyelitis

(1). Along with coagulase-negative staphylococcal species, it

has also been implicated in the pathogenesis of immune com-

plex (IC)-mediated diffuse proliferative glomerulonephritis

(DPGN) in a variety of infections. These include bacterial

endocarditis, ventriculoatrial shunt infections, pneumonia, and

visceral abscesses with or without septicemia (2-6). No clearly

documented cases of glomerulonephritis with acute renal fail-

ure (ARF) in association with staphylococcal osteomyelitis

have previously been reported. We describe an episode of

biopsy-proven DPGN with rapidly progressive ARF occurring

after postoperative wound infection and sternal osteomyelitis

caused by S. aureus. Spontaneous recovery occurred after

eradication of the infection through prolonged antibiotic ther-

apy and multiple surgical debridements.

Case ReportPresentation and Management

The patient, a 72-year-old white man, was transferred to our

institution from another medical facility for further manage-

ment of postsurgical sternal wound infection and ARF. Thirty-

four days before transfer, he had undergone coronary artery

bypass graft surgery (CABG) for treatment of severe three-

vessel disease. Figure 1 summarizes the course of his ARF

both before and after transfer and highlights important thera-

peutic interventions. An increased serum creatinine concentra-

tion ( 133 p�molIL [ 1 .5 mg/dl]) had first been noted 1 8 days

after CABG, having been normal on day 15 (80 jtmolIL [0.9

Received July 31, 1996. Accepted January 17, 1997.

Correspondence to Dr. Stephen B. Erickson, Division of Nephrology, Mayo

Building, W l2B, Mayo Clinic and Foundation, 200 First St. SW, Rochester.

MN 55905.

1046-6673/08010- l633$03.00/0

Journal of the American Society of Nephrology

Copyright © 1997 by the American Society of Nephrology

mg/dl]) and in the immediate postoperative period. Over the

following days, the patient’s serum creatinine concentration

increased progressively, and hemodialysis was instituted on

day 23 after CABG. There was no past or family history of

renal disease and no known drug allergies. Prior medical

history had included degenerative disc disease, stable abdom-

inal aortic aneurysm, stable benign prostatic hyperplasia, and

depression.

The patient had been readmitted to his home hospital with

fever and purulent discharge from his wound 8 days after

surgery. Blood cultures were negative at this time and on three

other occasions during the illness. Wound packing and empiric

antibiotic therapy with intravenous vancomycin had failed to

improve his wound infection, and surgical debridement with

rewiring of the sternum was first carried out 10 ten days after

CABG. Staphylococcus aureus had been cultured from wound

tissue and sternal bone marrow at this time, and therapy with

intravenous anti-staphylococcal antibiotic therapy had been

continued.

At the onset of ARF, urinalysis was reported as showing

microhematuria (5 to 9 cells per high-power field) with gran-

ular casts. Additional pertinent studies during this period in-

cluded persistently normal platelet count and negative serolo-

gies for hepatitis A, B, and C; antinuclear antibody, anti-

double-stranded DNA antibody, and perinuclear and

cytoplasmic antineutrophil cytoplasmic antibodies. Serum C3

and C4 complement levels were documented on day 22 after

CABG at 91 mg/dl (normal range, 86 to 184 mg/dl) and 23

mg/dl (normal range, 20 to 59 mg/dl), respectively. Renal

ultrasound showed both kidneys to be of normal size and

appearance without evidence of obstruction. Renal biopsy was

carried out on day 26 and high-dose corticosteroid therapy was

begun on day 28.

Renal Biopsy Results

Eleven glomeruli, all viable, were available for light micros-

copy. Endocapillary cellular proliferation was diffuse and gen-

Renal Biopsy

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Figure 1. Graph of serum creatinine values after coronary bypass surgery. demonstrating the course of acute renal failure episode and showing

the timing and duration of treatment modalities as well as the definitive surgical procedure.

eralized (Figure 2A). Proliferation was accounted for by rues-

angial cells and polymorphonuclear leukocytes. A few

capillary loops displayed peripheral extension of mesangial

cell cytoplasm and nuclei. Six glorneruli were examined on

irnrnunofluorescent microscopy, revealing strong granular re-

activity to inimunoglobulin G (IgG), both within glomerular

mesangiuni and along capillary walls. C3 complement had a

similar but somewhat less intense distribution. IgA. 1gM, and

kappa and lambda light chains of identical texture were like-

wise identified in a similar but significantly less intense pat-

tern.

Electron microscopy (Figure 2B confirmed the presence of

immune deposits along the internal aspect of peripheral gb-

merular basement membranes and in gbomerular mesangium,

associated with cellular proliferation and focal peripheral ex-

teflsion of mesangial cells.

Outconze

As shown in Figure 1 , corticosteroid therapy was tapered

and discontinued shortly after transfer, and vancomycin was

continued until close to discharge. Multiple surgical debride-

inents were carried out with definitive surgical wound closure

with muscle-flap transposition on day 52 after CABG. Sternal

tissue culture was negative by day 42. Urine output began to

increase shortly afterwards and hemodialysis was discontin-

ned. The patient was eventually discharged from hospital to

home with a serum creatinine concentration of 141 �.tmolIL

( I .6 mg/dl) and satisfactory wound healing.

Th4�i�1!!!This case clearly documents an IC-mediated, diffuse prolif-

erative gbomerubonephritis occurring as a result of acute osteo-

myelitis. The temporal relationship between the staphybococcal

infection and ARF in both onset and eventual resolution, along

with the unequivocal histopathobogical findings, leave no

doubt as to this association. As such it joins only a handful of

cases in which acute bone or joint infection has been clearly

linked to a gbonierulonephritis (7-9). More broadly, however,

it conforms to the well-recognized occurrence of jC-mediated

glomerulonephritis with certain infections in which the patho-

genie organism is, to some degree, sequestered from rapid

clearance by the immune system and in which progression to

chronicity may result. These include ventricuboatrial shunt

infections (3), bacterial endocarditis (2), visceral abscesses,

empyema, and others (4,6,10). Such infections may be as

clinically obvious as a septicenlia or may represent occult

infection presenting with ARF of unclear cause. They can also

be regarded as distinct from classical postinfectious gbomeru-

bonephritis in which the onset of renal disease generally fol-

lows the resolution of a self-limiting streptococcal infection.

The clear clinical and histological documentation in this case,as well as the lack of confounding coexisting or preexisting

disease, make it an ideal platform for the discussion of what

Glomerulonephntis in Acute Osteomyelitis 1635

common histological lesion described in all of the above cases

is diffuse endocapillary proliferation, sometimes with mem-

branoproliferative features. Extracapillary proliferation and in-

terstitial infiltrates may occur. Immune-type deposits have

been demonstrated in subendothelial, intramembranous, and

subepithelial locations (the latter often as typical “humps”)

(3,5,7-10,1 1-13). As regards clinical course and prognosis, in

general these cases have in common a lag time of 5 days to 4

weeks between onset of infection and renal disease, as well as

a strong dependence of renal recovery on successful treatment

of the underlying infection. Chronic renal impairment, varying

from mild to severe, usually occurs in the setting of a pro-

longed active infection. One series, which also included cases

of typical poststreptococcal glomerulonephritis, found that

older age, higher serum creatinine concentration, and crescen-

tic features on biopsy were predictive of poorer overall and

renal survival (5).

Figure 2. (A) Diffuse proliferative glomerulonephritis. Glomerularlobularity is enhanced because of endocapillary cellular proliferation

and inflammatory infiltrates (examples indicated by arrowheads).(Periodic acid-Schiff stain, X400). (B) Endocapillary cellular prolif-

eration with extension of mesangial and inflammatory cells into

peripheral capillary loops (closed arrowhead). Subendothelial im-

mune-complex deposition (open arrowheads). (Electron micrograph,X1200).

might best be classified as “infective glomerulonephritis.” It

also serves to highlight the potentially important role of staph-

ylococcal antigens in the pathogenesis of IC-mediated glomer-

ular disease.

Infective Glomerulonephritis

Table 1 lists sites of bacterial infection that have been

reported to be associated with DPGN, excluding the better-

recognized associations with bacterial endocarditis and yen-

triculoatrial shunt infections. It is clear that a variety of Gram-

positive and Gram-negative organisms have been isolated

under these circumstances. Table 2 summarizes the accompa-

flying clinical, laboratory, and histopathological features that

have been described. The reduction in serum levels of com-

plement components, which may be a valuable clue in classical

postinfectious GN, “shunt nephritis,” and the GN of endocar-

ditis, is often not present (4,6,10). An accompanying purpuric

rash may be noted in up to 20% of cases (5, 10). The most

Glomerulonephritis and Staphylococcal Infections

The predominance of staphylococcal infections, regardless

of the site of infection, is clear from Table 1 . A recent review

of infection-related glomerulonephritis at one institution found

that of 3 1 cases in which a causative organism had been

identified, 13 were associated with staphylococcal species (5).

Well-documented cases exist involving septicemic and non-

septicemic infections and both coagulase-positive and coagu-

lase-negative staphybococcal species. Septicemic cases most

commonly represent acute bacterial endocarditis due to S.

aureus, although well-documented cases of DPGN with septi-

cemic S. aureus pneumonia, empyema, and arthritis exist

(2,4,6,9, 1 1). Nonsepticemic cases predominantly represent in-

fection of ventriculoatrial shunts by coagulase-negative staph-

ylococcus (3). In addition, however, DPGN has been described

with impetigo and abscesses of lung and skin due to S. aureus

in the absence of bacteremia (12,14,15). Our case best repre-

sents an example of the latter, uncommon group. Only one

report of an association between gbomerulonephritis and staph-

ybococcal osteomyelitis exists and, in fact, this describes ne-

phrosis rather than ARF in three patients with chronic osteo-

myelitis without evidence of amyloidosis (7). An additional

case of osteomyelitis with DPGN is included among a series

reported by Beaufils and colleagues, but the causative organ-

ism and the degree of renal impairment are not specified (10).

Pathogenesis

Although conventional histology and immunofluorescence

microscopy allow classification of the renal lesion, in this case

they provide little useful information regarding pathogenesis.

The previously reported demonstration of staphylococcal pro-

teins within gbomerular immune deposits in similar cases of

DPGN supports a direct role for bacterial antigens in the

disease process ( 16, 17). To formulate a hypothesis on how

foreign antigens might generate such a process, however, it is

necessary to look to data from in vivo models of IC-mediated

glomerulonephritis (1 8). Table 3 categorizes the important

major steps in the pathogenic process in experimental models

and lists some of the variables that have been shown to be of

1636 Journal of the American Society of Nephrology

Table 1. Bacterial infections that have been reported to be associated with immune complex-mediated glomerulonephritis

(excluding bacterial endocarditis and ventriculoatrial shunt infections)

Site of Infection Type of Infection Organisms Reference

Lung Pneumonia, lung abscess,

empyema

S. aureus, Klebsiella pneumonia,

Pseudomonas aeruginosa,

Proteus mirabilis,

Pneumococcus, Moraxella

alcaligenes

4, 5, 6, 10, 14, 26, 27

Skin Wound infection, impetigo, skin

abscesses

S. Aureus 5, 6, 10, 12, 15

Abdomen Appendiceal abscess, subphrenic

abscess, septic abortion,

infected ascites

Escherichia coli, P. mirabilis,

Clostridium petfringens,

S. aureus

2, 4, 5, 10

Spine/CSF Meningitis, vertebral abscess,

postsurgical infection

S. aureus S

Bone and joint Septic arthritis, infected hip

prosthesis, osteomyelitis

S. aureus 5, 8, 9, 10

Paranasal sinuses/teeth Sinus abscess, dental abscess S. aureus 4, 5Unidentified sepsis N/A E. coli, S. aureus 5, 11, 28

Vascular Infected vascular graft Not reported 4, 10

Table 2. Reported clinical and histopathological features of immune-complex-mediated glomerulonephritis associated with

bacterial infections (excluding bacterial endocarditis and ventriculoatnal shunt infections)

Clinical Features

Frequent (>50%)

Oliguria

Hypertension

Documented bacterial infection within days to weeks

Raised serum creatinine

Microhematuria/red cell casts

Moderate proteinuria (0.5 to 3.0 g/d)

Normal serum complement components

Cryogbobulinemia

Frequent

Histological Features

Diffuse glomerular proliferation and exudation

Mesangial proliferation

Mild to moderate interstitial cellular infiltrate

Immunoglobulin chain and complement component deposition

Infrequent (<50%)

Anuria

Purpuric skin rash

Arthralgias

Nephrotic syndrome

Gross hematuria

Circulating immune complexes

Reduced serum complement components

Infrequent

Crescent formation

Membranoproliferative features

Severe interstitial cellular infiltrate

potential importance in initiating or maintaining gbomerular

injury under these circumstances.

Although it remains possible that the some deposits ob-

served within the gbomerular wall represent circulating IC that

have been “trapped” during filtration, it has been well-estab-

lished that ionic charge, as well as specific binding properties,

may mediate the direct adhesion of foreign antigens to com-

ponents of the glomerular basement membrane (1 8, 19). Sub-

sequent events include binding of specific antibodies to the

foreign antigen, as well as secondary humoral and cellular

responses to this primary complex. The resulting lesion can

then be viewed as a dynamic structure composed of self and

foreign material, which may be processed uneventfully or may

set in motion an array of pathways capable of causing tissue

injury. The factors that determine which course will ensue are

likely to include the type, dose, route of presentation, and

persistence of foreign antigen, as well as individual, genetically

based variations in primary and secondary inflammatory re-

sponses (18,20,21). The role of the complement system in

these early events merits particular comment. It has been

shown that the normal processing of circulating IC is depen-

dent on an interaction between complement components con-

Table 3. Likely sequence of pathogenic events in immune complex-mediated glomerulonephritis secondary to bacterial

antigens; variables that may play an important role in disease onset and severity based on data from experimental

models, are included�’

Infiltration of glomerulus by inflammatory cells

Clinical expression of glomerulonephritis

Disease progression or resolution

a GBM, glomerular basement membrane; IC, immune complex.

Glomerulonephritis in Acute Osteomyelitis 1637

Major Pathogenic Event

Exposure to bacterial antigen (±binding to

GBM components)Production of primary antibody to circulating or

bound antigen

In-situ formation or trapping of IC in GBM and

secondary modifications to IC

Early injury to glomerular structures

Disease-Modifying Variables

Charge and binding properties of antigen, individual

variation in GBM components.

Route of exposure, dose of antigen, persistence of infection.

Site of antigen binding, secondary humoral and/or cellular

immune responses

Complement activation, complement receptor expression,

local production of ROMs, cytokines and other

inflammatory mediators; structural alterations to GBM

Glomerular expression of chemoattractants, adhesion

molecules, activating factors; GBM exposure with

platelet adhesion and activation

Pattern of release of inflammatory mediators and cytokines

from neutrophils, monocytes, and platelets; variations in

activity of protective pathways and feedback mechanisms

Duration of bacterial infection

tamed within these complexes and a group of receptors ex-

pressed primarily by erythrocytes. These complement

receptors (E-CR) may also play a role in preventing the gen-

eration by tissue-bound IC of the complement products C3b

and C5b-9, which directly injure gbomerular cells and lead to

the local production of a variety of cytokines. Individual dif-

ferences in the level of E-CR or depletion by prolonged IC

formation may be an important factor in disease pathogenesis

(18,20,22). Administration of a soluble form of CR-i has been

shown to reduce the severity of certain animal models of

IC-mediated glomerulonephritis (22).

The type and severity of initial cellular damage within the

glomerulus may dictate subsequent patterns of recruitment and

activation of neutrophils, platelets, and monocytes. Many sub-

stances, produced both by native and infiltrating cells, may

then contribute to progressive injury. Although the list of such

mediators continues to grow and includes reactive oxygen

metabolites (ROM), proteases, eicosanoids, kinins, coagulation

components, chemoattractants, adhesion molecules, cytokines,

and growth factors, the precise role of each in various glomer-

ular diseases remains to be defined. The value of in vivo

models lies in the opportunity they present for the selective

alteration of single elements of this network and observation of

the effects on a defined disease process. In animal models of

IC-mediated glomeruionephritis, central pathogenic roles have

been predicted for neutrophil and platelet-derived products,

platelet-activating factor, ROM, and specific cytokines such as

interleukin 1 and transforming growth factor /3 (18,23,24). A

more recent development has been the recognition that the

expression of certain groups of cytokines and other inflamma-

tory mediators may share a dependence on single gene tran-

scription factors (for example, NF-KB) (25). These transcrip-

tion factors may be induced during the early events of a disease

process and may represent important targets for the treatment

of many immune-mediated diseases in the future.

In the case of infective glomerulonephritis, it is clear that

persistence of bacterial antigen is the primary determinant of

ongoing disease activity and only rarely have cases of active

nephritis been reported after eradication of the causative infec-

tion. This emphasizes the role of the many inhibitors and

feedback mechanisms involved in modulating the inflamma-

tory response to antigen-antibody complexes. Depletion or

genetically based variation in protective pathways, such as

free-radical scavenging, may also represent a central issue in

the correlation between the underlying pathogenesis and the

clinical course of individual cases (24).

Treatment

The primary consideration in the management of ARF in the

setting of active bacterial infection is the close prognostic

relationship between renal recovery and successful eradication

of the causative infection. This point is highlighted by our

patient’s clinical course, with resolution of his ARF commenc-

ing only after complete clearance of the infection. In many

settings, this necessitates a multidisciplinary approach to rapid

and accurate diagnostic and therapeutic planning. Of particular

value is a clear microbiological diagnosis from the outset, with

frequent surveillance cultures when possible. Renal biopsy, in

addition to demonstrating the severity of the glomerular lesion,

may be most important as a means of eliminating other diag-

noses that might impact strongly on management decisions.

The possibility of drug-related interstitial nephritis is a com-

mon consideration in the context of active infection and may

restrict the use of optimal antibiotic regimens if not ruled out

I 638 Journal of the American Society of Nephrology

histologically. When clinical evidence of nephritis occurs with

cavitating lung lesions, it is important to distinguish between

infection-related glomerulonephritis and Wegener’ s granulo-

matosis. In this setting, renal biopsy may be the most definitive

test. In a variety of situations (e.g. , “shunt nephritis,” empy-

ema, intraabdominal abscess, infected prosthetic material, and

bone orjoint infections), the need for early or repeated surgical

intervention will be heightened by the additional goal of pro-

moting renal recovery. The failure of ARF to respond to

corticosteroid therapy in our patient argues against the use of

immunosuppressive therapy for acute glomerulonephritis that

occurs in the face of active bacterial infection, even with rapid

progression of ARF. Occasional reports suggest that the un-

common situation of persistent active renal disease despite

clearly successful treatment of infection may merit a trial of

corticosteroid therapy if no other contraindication exists

(11,13).

ConclusionsThis case documents an unusual association between staph-

ylococcal osteomyelitis and ARF secondary to immune corn-

plex-mediated DPGN. It serves to illustrate the range of bac-

terial infections that have been reported to cause

gbomerulonephritis in the presence or absence of bacteremia, as

well as the frequent implication of staphylococcal antigens in

the pathogenesis of such lesions. The importance of early

microbiological and histological diagnosis and a multidisci-

plinary approach to eradication of infection for both patient and

renal survival are stressed. The role of corticosteroids or other

immunosuppressives should be confined to the rare circurn-

stance in which renal disease remains active despite complete

elimination of the underlying infection. Although infrequently

reported, it is possible that milder forms of infective gbomer-

ulonephritis or episodes occurring in the setting of sepsis often

go unrecognized. With the continuing emergence of antibiotic-

resistant staphybococcal species, the association of immune

complex-mediated glomerulonephritis with infections by this

organism is likely to remain an important consideration for the

clinical nephrologist.

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