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 peated surgical debridement. Spontaneous recovery of renal coronary bypass surgery that had been complicated by sternal function occurred after eradication of infection and final sur- osteomyelitis caused by the Staphylococcus aureus bacterium. gical wound repair. The relationship between acute bacterial Bacteremia and sepsis were not present. Renal biopsy demon- infections and glomerulonephritis and, in particular, the causal strated a florid, diffuse, proliferative glomerulonephritis with role of staphylococcal antigens in the pathogenesis of such glomerular immune complex deposition. Management in- lesions is discussed. (J Am Soc Nephrol 8: 1633-1639, 1997) cluded hemodialysis, prolonged antibiotic therapy, and re-

Coagulase-positive staphylococcus (Staphylococcus aureus) is mg/dl]) and in the immediate postoperative period. Over the the most common causative organism in acute osteomyelitis following days, the patient’s serum creatinine concentration (1). Along with coagulase-negative staphylococcal species, it increased progressively, and hemodialysis was instituted on has also been implicated in the pathogenesis of immune com- day 23 after CABG. There was no past or family history of plex (IC)-mediated diffuse proliferative glomerulonephritis renal disease and no known drug allergies. Prior medical (DPGN) in a variety of infections. These include bacterial history had included degenerative disc disease, stable abdom- endocarditis, ventriculoatrial shunt infections, pneumonia, and inal aortic aneurysm, stable benign prostatic hyperplasia, and visceral abscesses with or without septicemia (2-6). No clearly depression. documented cases of glomerulonephritis with acute renal fail- The patient had been readmitted to his home hospital with ure (ARF) in association with staphylococcal osteomyelitis fever and purulent discharge from his wound 8 days after have previously been reported. We describe an episode of surgery. Blood cultures were negative at this time and on three biopsy-proven DPGN with rapidly progressive ARF occurring other occasions during the illness. Wound packing and empiric after postoperative wound infection and sternal osteomyelitis antibiotic therapy with intravenous vancomycin had failed to caused by S. aureus. Spontaneous recovery occurred after improve his wound infection, and surgical debridement with eradication of the infection through prolonged antibiotic ther- rewiring of the sternum was first carried out 10 ten days after apy and multiple surgical debridements. CABG. Staphylococcus aureus had been cultured from wound tissue and sternal bone marrow at this time, and therapy with Case Report intravenous anti-staphylococcal antibiotic therapy had been Presentation and Management continued. The patient, a 72-year-old white man, was transferred to our At the onset of ARF, urinalysis was reported as showing institution from another medical facility for further manage- microhematuria (5 to 9 cells per high-power field) with gran- ment of postsurgical sternal wound infection and ARF. Thirty- ular casts. Additional pertinent studies during this period in- four days before transfer, he had undergone coronary artery cluded persistently normal platelet count and negative serolo- bypass graft surgery (CABG) for treatment of severe three- gies for hepatitis A, B, and C; antinuclear antibody, anti- vessel disease. Figure 1 summarizes the course of his ARF double-stranded DNA antibody, and perinuclear and both before and after transfer and highlights important thera- cytoplasmic antineutrophil cytoplasmic antibodies. Serum C3 peutic interventions. An increased serum creatinine concentra- and C4 complement levels were documented on day 22 after tion ( 133 pmolIL [1 .5 mg/dl]) had first been noted 18 days CABG at 91 mg/dl (normal range, 86 to 184 mg/dl) and 23 after CABG, having been normal on day 15 (80 jtmolIL [0.9 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 Received July 31, 1996. Accepted January 17, 1997. Correspondence to Dr. Stephen B. Erickson, Division of Nephrology, Mayo begun on day 28. Building, W l2B, Mayo Clinic and Foundation, 200 First St. SW, Rochester. MN 55905. Renal Biopsy Results 1046-6673/08010- l633$03.00/0 Journal of the American Society of Nephrology Eleven glomeruli, all viable, were available for light micros- Copyright © 1997 by the American Society of Nephrology copy. Endocapillary cellular proliferation was diffuse and gen- 1634 Journal of the American Society of Nephrology

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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- home with a serum creatinine concentration of 141 .tmolIL angial cells and polymorphonuclear leukocytes. A few ( I .6 mg/dl) and satisfactory wound healing. capillary loops displayed peripheral extension of mesangial cell cytoplasm and nuclei. Six glorneruli were examined on irnrnunofluorescent microscopy, revealing strong granular re- Th4i1!!! activity to inimunoglobulin G (IgG), both within glomerular This case clearly documents an IC-mediated, diffuse proliferative gbomerubonephritis occurring as a result of acute osteo- mesangiuni and along capillary walls. C3 complement had a myelitis. The temporal relationship between the staphybococcal similar but somewhat less intense distribution. IgA. 1gM, and infection and ARF in both onset and eventual resolution, along kappa and lambda light chains of identical texture were like- with the unequivocal histopathobogical findings, leave no wise identified in a similar but significantly less intense pat- doubt as to this association. As such it joins only a handful of tern. cases in which acute bone or joint infection has been clearly Electron microscopy (Figure 2B confirmed the presence of linked to a gbonierulonephritis (7-9). More broadly, however, immune deposits along the internal aspect of peripheral gb- it conforms to the well-recognized occurrence of jC-mediated merular basement membranes and in gbomerular mesangium, glomerulonephritis with certain infections in which the patho- associated with cellular proliferation and focal peripheral ex- genie organism is, to some degree, sequestered from rapid teflsion of mesangial cells. clearance by the immune system and in which progression to chronicity may result. These include ventricuboatrial shunt infections (3), bacterial endocarditis (2), visceral abscesses, Outconze empyema, and others (4,6,10). Such infections may be as As shown in Figure 1 , corticosteroid therapy was tapered clinically obvious as a septicenlia or may represent occult and discontinued shortly after transfer, and vancomycin was infection presenting with ARF of unclear cause. They can also continued until close to discharge. Multiple surgical debride- be regarded as distinct from classical postinfectious gbomeru- inents were carried out with definitive surgical wound closure bonephritis in which the onset of renal disease generally fol- with muscle-flap transposition on day 52 after CABG. Sternal lows the resolution of a self-limiting streptococcal infection. tissue culture was negative by day 42. Urine output began to The clear clinical and histological documentation in this case, increase shortly afterwards and hemodialysis was discontin- as well as the lack of confounding coexisting or preexisting ned. The patient was eventually discharged from hospital to 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 membranoproliferative features. Extracapillary proliferation and interstitial 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 prolonged active infection. One series, which also included cases of typical poststreptococcal glomerulonephritis, found that older age, higher serum creatinine concentration, and crescentic features on biopsy were predictive of poorer overall and renal survival (5).

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 nonsepticemic infections and both coagulase-positive and coagulase-negative staphybococcal species. Septicemic cases most commonly represent acute bacterial endocarditis due to S. aureus, although well-documented cases of DPGN with septicemic S. aureus pneumonia, empyema, and arthritis exist Figure 2. (A) Diffuse proliferative glomerulonephritis. Glomerular lobularity is enhanced because of endocapillary cellular proliferation (2,4,6,9, 1 1). Nonsepticemic cases predominantly represent in- and inflammatory infiltrates (examples indicated by arrowheads). fection of ventriculoatrial shunts by coagulase-negative staph- (Periodic acid-Schiff stain, X400). (B) Endocapillary cellular prolif- ylococcus (3). In addition, however, DPGN has been described eration with extension of mesangial and inflammatory cells into with impetigo and abscesses of lung and skin due to S. aureus peripheral capillary loops (closed arrowhead). Subendothelial im- in the absence of bacteremia (12,14,15). Our case best repre- mune-complex deposition (open arrowheads). (Electron micrograph, sents an example of the latter, uncommon group. Only one X1200). report of an association between gbomerulonephritis and staphybococcal osteomyelitis exists and, in fact, this describes ne- phrosis rather than ARF in three patients with chronic osteo- might best be classified as “infective glomerulonephritis.” It myelitis without evidence of amyloidosis (7). An additional also serves to highlight the potentially important role of staph- case of osteomyelitis with DPGN is included among a series ylococcal antigens in the pathogenesis of IC-mediated glomer- reported by Beaufils and colleagues, but the causative organ- ular disease. ism and the degree of renal impairment are not specified (10).

Infective Glomerulonephritis Pathogenesis Table 1 lists sites of bacterial infection that have been Although conventional histology and immunofluorescence reported to be associated with DPGN, excluding the better- microscopy allow classification of the renal lesion, in this case recognized associations with bacterial endocarditis and yen- they provide little useful information regarding pathogenesis. triculoatrial shunt infections. It is clear that a variety of Gram- The previously reported demonstration of staphylococcal pro- positive and Gram-negative organisms have been isolated teins within gbomerular immune deposits in similar cases of under these circumstances. Table 2 summarizes the accompa- DPGN supports a direct role for bacterial antigens in the flying clinical, laboratory, and histopathological features that disease process ( 16, 17). To formulate a hypothesis on how have been described. The reduction in serum levels of com- foreign antigens might generate such a process, however, it is plement components, which may be a valuable clue in classical necessary to look to data from in vivo models of IC-mediated postinfectious GN, “shunt nephritis,” and the GN of endocar- glomerulonephritis (1 8). Table 3 categorizes the important ditis, is often not present (4,6,10). An accompanying purpuric major steps in the pathogenic process in experimental models rash may be noted in up to 20% of cases (5, 10). The most 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, S. aureus, Klebsiella pneumonia, 4, 5, 6, 10, 14, 26, 27 empyema Pseudomonas aeruginosa, Proteus mirabilis, Pneumococcus, Moraxella alcaligenes Skin Wound infection, impetigo, skin S. Aureus 5, 6, 10, 12, 15 abscesses Abdomen Appendiceal abscess, subphrenic Escherichia coli, P. mirabilis, 2, 4, 5, 10 abscess, septic abortion, Clostridium petfringens, infected ascites S. aureus Spine/CSF Meningitis, vertebral abscess, S. aureus S postsurgical infection Bone and joint Septic arthritis, infected hip S. aureus 5, 8, 9, 10 prosthesis, osteomyelitis Paranasal sinuses/teeth Sinus abscess, dental abscess S. aureus 4, 5 Unidentified 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%) Infrequent (<50%) Oliguria Anuria Hypertension Purpuric skin rash Documented bacterial infection within days to weeks Arthralgias Raised serum creatinine Nephrotic syndrome Microhematuria/red cell casts Gross hematuria Moderate proteinuria (0.5 to 3.0 g/d) Circulating immune complexes Normal serum complement components Reduced serum complement components Cryogbobulinemia Histological Features Frequent Infrequent Diffuse glomerular proliferation and exudation Crescent formation Mesangial proliferation Membranoproliferative features Mild to moderate interstitial cellular infiltrate Severe interstitial cellular infiltrate Immunoglobulin chain and complement component deposition

potential importance in initiating or maintaining gbomerular then be viewed as a dynamic structure composed of self and injury under these circumstances. foreign material, which may be processed uneventfully or may Although it remains possible that the some deposits ob- set in motion an array of pathways capable of causing tissue served within the gbomerular wall represent circulating IC that injury. The factors that determine which course will ensue are have been “trapped” during filtration, it has been well-estab- likely to include the type, dose, route of presentation, and lished that ionic charge, as well as specific binding properties, persistence of foreign antigen, as well as individual, genetically may mediate the direct adhesion of foreign antigens to com- based variations in primary and secondary inflammatory re- ponents of the glomerular basement membrane (1 8, 19). Sub- sponses (18,20,21). The role of the complement system in sequent events include binding of specific antibodies to the these early events merits particular comment. It has been foreign antigen, as well as secondary humoral and cellular shown that the normal processing of circulating IC is depen- responses to this primary complex. The resulting lesion can dent on an interaction between complement components con- Glomerulonephritis in Acute Osteomyelitis 1637

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’

Major Pathogenic Event Disease-Modifying Variables

Exposure to bacterial antigen (±binding to Charge and binding properties of antigen, individual GBM components) variation in GBM components. Production of primary antibody to circulating or Route of exposure, dose of antigen, persistence of infection. bound antigen In-situ formation or trapping of IC in GBM and Site of antigen binding, secondary humoral and/or cellular secondary modifications to IC immune responses Early injury to glomerular structures Complement activation, complement receptor expression, local production of ROMs, cytokines and other inflammatory mediators; structural alterations to GBM Infiltration of glomerulus by inflammatory cells Glomerular expression of chemoattractants, adhesion molecules, activating factors; GBM exposure with platelet adhesion and activation Clinical expression of glomerulonephritis Pattern of release of inflammatory mediators and cytokines from neutrophils, monocytes, and platelets; variations in activity of protective pathways and feedback mechanisms Disease progression or resolution Duration of bacterial infection

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

tamed within these complexes and a group of receptors ex- tion factors may be induced during the early events of a disease pressed primarily by erythrocytes. These complement process and may represent important targets for the treatment receptors (E-CR) may also play a role in preventing the gen- of many immune-mediated diseases in the future. eration by tissue-bound IC of the complement products C3b In the case of infective glomerulonephritis, it is clear that and C5b-9, which directly injure gbomerular cells and lead to persistence of bacterial antigen is the primary determinant of the local production of a variety of cytokines. Individual dif- ongoing disease activity and only rarely have cases of active ferences in the level of E-CR or depletion by prolonged IC nephritis been reported after eradication of the causative infec- formation may be an important factor in disease pathogenesis tion. This emphasizes the role of the many inhibitors and (18,20,22). Administration of a soluble form of CR-i has been feedback mechanisms involved in modulating the inflamma- shown to reduce the severity of certain animal models of tory response to antigen-antibody complexes. Depletion or IC-mediated glomerulonephritis (22). genetically based variation in protective pathways, such as The type and severity of initial cellular damage within the free-radical scavenging, may also represent a central issue in glomerulus may dictate subsequent patterns of recruitment and the correlation between the underlying pathogenesis and the activation of neutrophils, platelets, and monocytes. Many sub- clinical course of individual cases (24). stances, produced both by native and infiltrating cells, may then contribute to progressive injury. Although the list of such Treatment mediators continues to grow and includes reactive oxygen The primary consideration in the management of ARF in the metabolites (ROM), proteases, eicosanoids, kinins, coagulation setting of active bacterial infection is the close prognostic components, chemoattractants, adhesion molecules, cytokines, relationship between renal recovery and successful eradication and growth factors, the precise role of each in various glomer- of the causative infection. This point is highlighted by our ular diseases remains to be defined. The value of in vivo patient’s clinical course, with resolution of his ARF commenc- models lies in the opportunity they present for the selective ing only after complete clearance of the infection. In many alteration of single elements of this network and observation of settings, this necessitates a multidisciplinary approach to rapid the effects on a defined disease process. In animal models of and accurate diagnostic and therapeutic planning. Of particular IC-mediated glomeruionephritis, central pathogenic roles have value is a clear microbiological diagnosis from the outset, with been predicted for neutrophil and platelet-derived products, frequent surveillance cultures when possible. Renal biopsy, in platelet-activating factor, ROM, and specific cytokines such as addition to demonstrating the severity of the glomerular lesion, interleukin 1 and transforming growth factor /3 (18,23,24). A may be most important as a means of eliminating other diag- more recent development has been the recognition that the noses that might impact strongly on management decisions. expression of certain groups of cytokines and other inflamma- The possibility of drug-related interstitial nephritis is a com- tory mediators may share a dependence on single gene tran- mon consideration in the context of active infection and may scription factors (for example, NF-KB) (25). These transcrip- 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 and Staphvlococcal aureus infections. C/in Nephrol 14: 256- cavitating lung lesions, it is important to distinguish between 261, 1980 infection-related glomerulonephritis and Wegener’ s granulo- 7. Boonshaft B, Maher iF, Schreiner GE: Nephrotic syndrome associated with osteomyelitis without secondary amyloidosis. matosis. In this setting, renal biopsy may be the most definitive Arc/i Intern Med 125: 322-327, 1970 test. In a variety of situations (e.g. , “shunt nephritis,” empy- 8. Maher ER, Thiru 5, Hamilton DV, Wheatly T: Acute renal ema, intraabdominal abscess, infected prosthetic material, and failure due to glomerulonephritis associated with Staphylococcal bone orjoint infections), the need for early or repeated surgical infection. Postgrad Med 60: 433-434, 1984 intervention will be heightened by the additional goal of pro- 9. Connolly CE, Gallagher B: Acute crescentic glomerulonephritis moting renal recovery. The failure of ARF to respond to as a complication of a Stapkv!ococcus aureus abscess of hip joint corticosteroid therapy in our patient argues against the use of prosthesis [Letter]. J C/in Pathol 40: 1486, 1987 immunosuppressive therapy for acute glomerulonephritis that 10. Beaufils M, Gibert C, Morel-Maroger L, Sraer JD, Kanfer A, occurs in the face of active bacterial infection, even with rapid Meyrier A, Kounlsky 0, Vachon F, Richet G: Glomerulonephri- progression of ARF. Occasional reports suggest that the un- tis in severe bacterial infections with and without endocarditis. common situation of persistent active renal disease despite Adt’ Nephrol 7: 217-234, 1978 clearly successful treatment of infection may merit a trial of 1 1 . McKinsey DS, McMurray TI, Flynn IM: Immune complex gb- corticosteroid therapy if no other contraindication exists merulonephritis associated with Staphylococcus aureus bacteremia: Response to corticosteroid therapy. Rev Infect Dis 12: (11,13). 125-127, 1990 12. Takaue Y, Tokumaru M: Staphybococcal skin lesions and acute Conclusions glomerubonephritis [Letterl. N Engl J Med 307: 1 2 1 3-12 14, 1982 This case documents an unusual association between staph- 13. Keller CK, Andrassy K, Waldherr R, Ritz E: Postinfectious ylococcal osteomyelitis and ARF secondary to immune corn- glomerubonephritis-Is there a link to alcoholism? Q J Med 87: plex-mediated DPGN. It serves to illustrate the range of bac- 97-102, 1994 terial infections that have been reported to cause 14. Danovitch GM, Nord EP, Barki Y, Krugliak L: Staphylococcal gbomerulonephritis in the presence or absence of bacteremia, as lung abscess and acute gbomerubonephritis. Isr J Med Sci 15: 840-843, 1979 well as the frequent implication of staphylococcal antigens in 15. Rosenberg HG, Donoso PL, Vial SU, Carranza C, Romero P: the pathogenesis of such lesions. The importance of early Clinical and morphological recovery between two episodes of microbiological and histological diagnosis and a multidisci- acute gbomerulonephritis: A light and electron microscopic study plinary approach to eradication of infection for both patient and with immunofluorescence. C/in Nephro/ 21: 350-354, 1984 renal survival are stressed. The role of corticosteroids or other 16. Pertschuk LP, Woda BA, Vuletin JC, Brigti Di, Soriano CB, immunosuppressives should be confined to the rare circurn- Nicastri AD: Glomerubonephritis due to Staphylococcus aureus stance in which renal disease remains active despite complete antigen. Am J C/in Patho! 65: 301-307, 1976 elimination of the underlying infection. Although infrequently 17. Yum MN, Wheat Li, Maxwell D, Edwards JL: Immunofluores- reported, it is possible that milder forms of infective gbomer- cent localization of Staphylococcus aureus antigen in acute bac- ulonephritis or episodes occurring in the setting of sepsis often terial endocarditis nephritis. Am J C/in Patho! 70: 832- 835, 1978 go unrecognized. With the continuing emergence of antibiotic- 18. Eddy AA, Michael AF: Immunopathogenic mechanisms of gb- resistant staphybococcal species, the association of immune merular injury. In: Rena! Pathology, 4th Ed., edited by Brenner BM, Tisher CC, Philadelphia, JP Lippincott Co., 1994, pp 162- complex-mediated glomerulonephritis with infections by this 221 organism is likely to remain an important consideration for the 19. Cosi FG, Mahan JD, Sedmak DD: Experimental glomerulone- clinical nephrologist. phritis induced by antigen that binds to gbomerular fibronectin. Am J Kidney Dis 15: 160-168, 1990 References 20. Hebert LA, Cosio FG, Birmingham Di, Mahan JD, Sharma HM,

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