In the 1970s Sato et al. [7] detected Staphylococcus aureus antigens within mesangial immune complex deposits in a small number of cases of diffuse proliferative glomerulonephritis. These patients also had antibodies against staphylococcal antigens (antistaphylolysin antibodies) in the sera, prompting the proposal that S. aureus has a pathogenic role in a small subset of diffuse proliferative glomerulonephritides. One hypothesis is that staphylococcal enterotoxins, typically enterotoxin C, A, or toxic shock syndrome toxin-1, act as superantigens that stimulate proliferation of resting T cells, resulting in exuberant T cell activation and ultimately B cell activation and immune complex formation [5, 7, 9, 12, 50]. Superantigens activate T cells by binding directly to the MHC class II molecules on antigen-presenting cells and then binding to the T cell receptor (TCR) Vβ region of T cells irrespective of TCR antigen specificity. As a result of this nonspecific binding, there is activation of large subsets of polyclonal T cells leading to a “cytokine storm”. Activated T cells then stimulate B cell proliferation and antibody production. In fact, in SAGN, polyclonal elevation of serum IgA and IgG, as well as circulating immune complexes, are frequently detected [5, 7, 11]. Hirayama et al. [36] studied six patients with “staphylococcus infection-induced HSP-like (IgA vasculitis) clinical syndrome with acute glomerulonephritis”, which can be considered cases of SAGN. These six patients with SAGN demonstrated skewed TCR Vβ chain usage (Vβ 5.2, 5.3 and 8) compared to normal controls and to patients whose S. aureus infection had improved. Additionally, they reported increased serum levels of cytokines (interleukins 1β, 2, 6, 8, and tumor necrosis factor-alpha) in patients with SAGN compared to normal individuals, and the cytokine levels normalized with resolution of the staphylococcal infection.

Staphylococcal enterotoxins acting as superantigens are also implicated in other diseases such as staphylococcal toxic shock syndrome. Of note, staphylococcal antigens may also play a role in IgA nephropathy. Koyama et al. [15] found the S. aureus cell envelope antigen in 68% of renal biopsy specimens from patients with IgA nephropathy and proposed that this antigen is a pathogenetic factor in the development of IgA nephropathy. The same group from Japan developed an experimental model of IgA nephropathy in mice following biweekly immunization of the animals with antigens derived from S. aureus mixed with Freund’s adjuvants [51]. Lastly, the comorbidities commonly present in patients with SAGN are likely contributing factors to pathogenesis by compromising the host immune response, which enables persistent infections/bacteremia and antigenemia that increases the likelihood of developing large antigen-antibody complexes that then accumulate in the glomerulus [26, 29, 30, 32].

Detailed clinical data are essential for a diagnosis of SAGN, and the main differential diagnostic considerations are:

This is also shown in Table 2.3. Distinguishing between SAGN and idiopathic IgA nephropathy can be quite difficult using kidney biopsy findings alone since both entities frequently show mesangial hypercellularity with IgA and C3 dominant/codominant immune complex deposits. However, the clinical findings can be very helpful. A history of a staphylococcal infection with positive cultures or clinical features suspicious for an infection accompanied by acute renal failure, recent onset nephrotic range proteinuria, and/or hematuria with active urine sediment should raise the possibility of SAGN. IgA nephropathy is rarely associated with acute renal failure, unless it is crescentic IgA nephropathy or an advanced-stage IgA nephropathy with superimposed acute kidney injury due to other causes. In typical cases of progressive IgA nephropathy, the patients have a protracted, slowly progressive clinical course with long-standing microscopic hematuria, hypertension, and gradually worsening proteinuria. The “synpharyngitic” presentation of IgA nephropathy is characterized by episodic gross hematuria following upper respiratory tract infections (typically viral) and most of these patients lack acute kidney injury and nephrotic range proteinuria. If the kidney biopsy shows chronic glomerular lesions, such as segmental or global glomerular sclerosis, adhesions, or old fibrous crescents, IgA nephropathy can be favored since such chronic lesions are unusual in SAGN with the exception being when the chronic lesions are unrelated to SAGN (for example, glomerular changes of diabetic glomerulosclerosis). Endocapillary hypercellularity can be seen in both SAGN and IgA nephropathy, however, it is significantly more common in SAGN. In our study [39], it was present in 60% of the SAGN biopsies and 10% of the IgA nephropathy biopsies (Table 2.2). Focal segmental glomerular sclerosis (FSGS) lesions on the other hand are more frequently seen in IgA nephropathy (49% of the biopsies) as compared to SAGN (2.5% biopsies). Also, the intensity of IgA and C3 staining is different between SAGN and IgAN. Although there is a spectrum of staining in SAGN as mentioned previously, the IgA staining intensity tends to be mild to moderate (1+ to 2+) and C3 tends to be moderate to strong (2+ to 3+) in SAGN while in IgAN staining for IgA is more frequently moderate to strong (2+ to 3+) and C3 staining is mild to moderate (1+ to 2+) [39].

Since a subset of patients with SAGN develop a purpuric rash with leukocytoclastic vasculitis, it can be difficult to distinguish SAGN from HSP (IgA vasculitis) [18, 34–38]. Similar to IgA nephropathy, the kidney biopsy findings can be indistinguishable between the two entities. Again a detailed clinical history, particularly the presence of an underlying staphylococcal infection, is imperative. Also, since HSP is a rare disease in adults, in our experience, it is more common to see SAGN with purpuric skin lesions rather than HSP. Therefore, if an adult patient presents with symptoms of HSP vasculitis and a renal biopsy shows IgA-dominant glomerulonephritis, an underlying Staphylococcus infection should be excluded prior to initiation of immunosuppressive therapy since such treatment in the setting of an active infection can result in sepsis [11, 34–38].

It is important to recognize the differences between SAGN and PSAGN. In developed countries, the incidence of PSAGN has declined due to successful treatment of acute streptococcal infections with antibiotics; however, SAGN is becoming more common. One of the major differences in SAGN and PSAGN, other than the causative bacterial organism, is that in SAGN the infection is frequently ongoing at the time the glomerulonephritis develops. Conversely, in PSAGN the glomerulonephritis develops after the streptococcal infection has completely resolved, either spontaneously or after antibiotic treatment [32, 33]. Although the light microscopic and ultrastructural findings can be similar in SAGN and PSAGN, especially in cases of SAGN with “humps”, the presence of IgA in the immune deposits would be unusual in PSAGN. The overall frequency of “humps” is much less in SAGN (only 31% in our cohort) compared to PSAGN, where such lesions are characteristic [39]. Lastly, there is general agreement that the renal prognosis in cases of “glomerulonephritis with active infection” is guarded in sharp contrast to the good prognosis associated with PSAGN in children [13, 21–23, 26, 29, 30].

SAGN can have crescents and/or segmental necrotizing glomerular lesions sometimes with very minimal immune complex deposition; thus, pauci-immune or ANCA-associated crescentic and necrotizing glomerulonephritis can be included in the differential diagnosis [39, 52]. Furthermore, SAGN can be associated with positive ANCA serologies, particularly in cases with underlying endocarditis [39, 42–49]. Boils et al. [42] recently studied endocarditis-associated glomerulonephritis of which 53% were associated with S. aureus (23% Streptococcus species, 9% culture negative, and the remaining were associated with Bartonella henselae, Coxiella burnetti, Cardiobacterium hominis, or Gemella species). Crescents and/or segmental necrotizing lesions were seen in 53% of the kidney biopsies. Additionally, 28% of patients had a positive ANCA serology. In our case series of SAGN, 35% (27/78) of the biopsies had focal crescents and/or segmental necrotizing lesions [39]. Six of these 27 also showed a pauci-immune pattern by immunofluorescence and electron microscopic examination. One biopsy showed both crescents and a pauci-immune pattern accompanied by positive ANCA serology, thus closely mimicking ANCA-associated glomerulonephritis.

There have been similar reports of pauci-immune crescentic and necrotizing glomerulonephritis associated with staphylococcal infections [10, 15]. In fact, the possibility that S. aureus may play a role in the pathogenesis of ANCA-associated granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis) has been proposed [24]. An additional confounding factor relevant to this differential diagnosis is that in 2–3% of kidney biopsies there is incidental, non-pathologic IgA staining; thus, it is possible, albeit infrequent, to have mild IgA staining in pauci-immune ANCA-associated crescentic and necrotizing glomerulonephritis. Of note, the definition of “pauci-immune” can differ slightly between pathologists. Our definition is weak to absent immunofluorescence staining for immunoglobulins (mainly IgG and IgA) and complement C3 in combination with scant to absent electron-dense immune-type deposits on ultrastructural examination. Although some may consider C3 staining alone in the absence of immunoglobulins as “pauci-immune” (described in the endocarditis chapter), we do not label such staining as “pauci-immune”. In fact, 11 of our 78 cases of SAGN contained C3 staining alone. Additionally, rarely, there is discordance between the degree of immunofluorescence staining and deposition of immune-type deposits assessed by ultrastructural examination. In such cases, it is possible that the electron-dense deposits do not stain because of hidden epitopes.

Distinguishing between SAGN and ANCA-associated glomerulonephritis is crucial since immunosuppressive therapy used to treat ANCA-associated glomerulonephritis is contraindicated in the setting of an active S. aureus infection. After the infection is cleared, if renal dysfunction persists and there are active crescents seen in the biopsy, a cautious trial of corticosteroids is recommended by some, but this remains a controversial issue [53, 54]. It is therefore important to interpret the biopsy in light of a detailed clinical history. Also, if the biopsy shows distinct vasculitis and/or fibrinoid necrosis of the arteries, then ANCA vasculitis is favored even if there is mild IgA staining or a few immune-type deposits present. Also, the uninvolved glomeruli tend to be hypercellular in SAGN but not so in ANCA-associated glomerulonephritis.