Staphylococcus-associated glomerulonephritis in adults

INTRODUCTION — The term postinfectious glomerulonephritis has primarily referred to poststreptococcal glomerulonephritis. This is still appropriate in children, but in adults, as described below, staphylococcus-associated glomerulonephritis (previously referred to as post-staphylococcal glomerulonephritis) may be as or more common.

This topic will review staphylococcus-associated glomerulonephritis in adults. Other causes of infection-related glomerulonephritis, including poststreptococcal glomerulonephritis and glomerulonephritis associated with endocarditis or with viral, fungal, protozoal, or parasitic infections, are discussed elsewhere:

●(See "Poststreptococcal glomerulonephritis".)

●(See "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt".)

●(See "Overview of kidney disease associated with hepatitis C virus infection".)

●(See "Kidney disease associated with hepatitis B virus infection".)

●(See "Overview of kidney disease in patients with HIV".)

●(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Infections'.)

●(See "Schistosomiasis and glomerular disease".)

●(See "Echinococcosis: Clinical manifestations and diagnosis", section on 'Other organs'.)

TERMINOLOGY — Proposed general terms for glomerulonephritis induced by infections are infection-associated or infection-related glomerulonephritis [1]. The most commonly used term for streptococcus-related disease is poststreptococcal glomerulonephritis because the kidney disease typically begins after the usually pharyngeal or skin infection has either resolved spontaneously or been effectively treated.

By contrast, most of the other causes of bacterial infection-associated glomerulonephritis, including that due to staphylococcal infection, occur when the patient is still infected. Thus, we prefer the term staphylococcus-associated glomerulonephritis to distinguish it from glomerulonephritis that can develop when the infection is no longer active (eg, poststreptococcal glomerulonephritis). (See "Poststreptococcal glomerulonephritis".)

Immunoglobulin A (IgA)-dominant infection-related glomerulonephritis, which can occur with staphylococcal infection, is a distinct morphologic variant of infection-related glomerulonephritis characterized by dominant or codominant glomerular deposits of IgA [2-4].

PATHOGENESIS — Staphylococcus-associated glomerulonephritis is an immune complex-mediated disease [5]. The antigen component of the immune complex is derived from the infective agent, similar to poststreptococcal glomerulonephritis. (See "Poststreptococcal glomerulonephritis", section on 'Pathogenesis'.)

The pathogenesis of staphylococcus-associated glomerulonephritis has not been adequately studied, and it remains largely unknown. It likely involves glomerular deposition of preformed circulating immune complexes. It is possible that in situ immune complex formation may occur (as it does in poststreptococcal glomerulonephritis) due to cationic staphylococcal antigens planted in the glomeruli [6-8]. However, glomerular deposition of preformed circulating immune complexes is likely to be a more important pathogenic mechanism in staphylococcus-associated glomerulonephritis, because in staphylococcus-associated glomerulonephritis, the circulating antigens and the antibodies directed against these antigens coexist in the circulation for prolonged periods of time [5]. With this prolonged antigenemia, there is a greater opportunity for immune complexes to form in the circulation, which then deposit causing glomerulonephritis and, in some cases, cutaneous vasculitis.

Staphylococcus-associated glomerulonephritis requires continued antigen production, and therefore continued active (and usually prolonged) infection, to perpetuate the kidney inflammation. If the infection is effectively treated, the activity of the glomerulonephritis should eventually abate. This same paradigm applies to glomerulonephritis due to other non-streptococcal bacteria, viral infections such as hepatitis B and C, and parasitic infections.

Staphylococcal antigens may act as super antigens, activating T cells, which results in polyclonal B cell activation and production of polyclonal IgA, immunoglobulin G (IgG), and immunoglobulin M (IgM) [9,10]. Some of these antibodies, often IgA, react with staphylococcal antigens [11,12]. This may explain, in part, why glomerular immune deposits in patients with staphylococcus-associated glomerulonephritis usually show heavy IgA deposits that are dominant or codominant with IgG. In this respect, staphylococcus-associated glomerulonephritis is distinct from poststreptococcal glomerulonephritis but can be misdiagnosed as primary IgA nephropathy. (See 'Differential diagnosis' below.)

EPIDEMIOLOGY — Staphylococcus-associated glomerulonephritis is uncommon (less than 1 percent of kidney biopsies) and primarily occurs in middle-aged or older adult patients [2,6,13-17]. In older adult patients in resource-abundant countries, glomerulonephritis due to bacterial infection may be more often due to Staphylococcus than group A beta-hemolytic Streptococcus. This may not be the case in resource-limited countries. As an example, in a series of 501 adult patients with bacterial infection-related glomerulonephritis from the Indian subcontinent (mean age 40 years), the organism was isolated in 226 of 353 (64 percent) patients with available data, and among them the responsible organism was streptococcus in 61 percent, Escherichia coli in 14 percent, and staphylococcus in 11 percent [18]. In addition, many affected adults have a predisposition to staphylococcal infection such as diabetes, alcoholism, cancer, or intravenous drug addiction.

CLINICAL MANIFESTATIONS — Adults with staphylococcus-associated glomerulonephritis usually present with a concurrent infection and frequently with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema. The most common manifestations are summarized below.

Findings at presentation — The clinical manifestations of staphylococcus-associated glomerulonephritis are similar to those in other causes of glomerulonephritis. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

In studies of patients with staphylococcus-associated glomerulonephritis (which also included patients with glomerulonephritis due to other bacteria), the following findings have been noted [13-15]:

●Peripheral edema was present in approximately 50 percent of patients, and new-onset hypertension was present in 12 to 29 percent, with other patients (31 percent in one of the studies) having a history of underlying hypertension [13].

●The urine sediment revealed hematuria in almost all patients with or without leukocyturia and red cell casts. The degree of proteinuria was variable, with 22 to 35 percent having overt nephrotic syndrome.

●New-onset or exacerbated heart failure is not uncommon in older adult patients due to the higher prevalence of underlying cardiovascular disease and the reduced ability to handle the salt and water retention associated with glomerulonephritis [15,19]. In the series of 109 older adult patients, new heart failure was noted in 26 percent of patients overall and in 30 percent of the subset of patients with staphylococcal infection [15].

Patients with staphylococcus-associated glomerulonephritis, particularly older adult patients, usually have a diagnosed concurrent staphylococcal infection, although the infection may be undiagnosed in some patients (cultures may be negative, at least initially). This contrasts with poststreptococcal glomerulonephritis, in which the infection is resolved by the time the glomerulonephritis is discovered. As an example, in the study of older adult patients cited above, the clinical diagnosis of staphylococcal infection coincided with the first clinical recognition of glomerulonephritis in 43 percent of patients [15]. The median time from clinical diagnosis of staphylococcal infection to diagnosis of kidney disease was one week (range 0 to 12 weeks), which varied with the site of infection: zero weeks for heart and bone infections and one week for skin and lung infections.

Cutaneous vasculitis can occur in patients with staphylococcus-associated glomerulonephritis, imitating IgA vasculitis (Henoch-Schönlein purpura) or antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis [2,20,21].

Most common sites of infection — The site of infection is varied in adults with staphylococcal infection [1]. In a study of 78 patients with staphylococcus-associated glomerulonephritis, the most common sites of infection were [2]:

●Heart/endocarditis – 18 patients (23 percent)

●Skin, including leg ulcers and cellulitis – 17 patients (22 percent)

●Bone/osteomyelitis – 17 patients (22 percent)

●Lung/pneumonia – 6 patients (8 percent)

●Visceral abscess – 6 patients (8 percent)

●Urinary tract infection – 2 patients (6 percent)

Laboratory findings — The laboratory findings at the time of presentation are similar to those in other forms of glomerulonephritis. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

In one study of older adult patients, the laboratory findings in 50 patients with staphylococcus-associated glomerulonephritis were as follows [15]:

●Hematuria – 98 percent (15 percent macroscopic)

●Leukocyturia – 65 percent

●Mean protein excretion – 3 g/day (21 percent had all features of the nephrotic syndrome)

●Mean serum creatinine at the time of biopsy – 5.1 mg/dL (451 micromol/L)

Patients with staphylococcus-associated glomerulonephritis commonly but not universally have hypocomplementemia. As an example, 39 of the 50 patients with staphylococcus-associated glomerulonephritis included in the study of older adult patients cited above had testing for serum complement [15]. Of these 39 patients, 82 percent had hypocomplementemia (low C3 with normal C4 in 56 percent, low C3 and C4 in 41 percent, and low C4 with normal C3 in 3 percent). In addition, positive serologic testing for ANCA can be observed in 25 to 30 percent of patients with staphylococcus-associated glomerulonephritis [2,22]. A peptide of plasmid-encoded 6-phosphogluconate dehydrogenase, present in some Staphylococcus aureus strains, induces anti-myeloperoxidase autoimmunity in mice, and this peptide is immunogenic in humans [23]. This could explain the development of ANCA autoimmunity in some patients with staphylococcus-associated glomerulonephritis.

Other causes of glomerulonephritis that are associated with hypocomplementemia are mentioned below. (See 'Serologic testing' below.)

Bacterial cultures — In contrast to poststreptococcal glomerulonephritis, there are no serologic tests to detect staphylococcal infection. Thus, an inciting staphylococcal infection can only be identified from a positive culture. Most cases of staphylococcus-associated glomerulonephritis are caused by S. aureus, with a higher incidence of methicillin-resistant S. aureus than methicillin-sensitive S. aureus, although coagulase-negative staphylococcus species including S. epidermidis and S. hemolyticus can rarely cause the disease [2,15]. S. epidermidis is the most commonly reported organism causing shunt nephritis [24]. (See "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt".)

In some patients, an infectious agent cannot be identified [1,6,13-15,25], and suspicion of staphylococcus-associated glomerulonephritis is based upon a probable infection. If there is no clear history of infection, then the main clinical clue other than kidney biopsy is hypocomplementemia, which is present in many but not all patients. However, hypocomplementemia also occurs in a number of other causes of glomerulonephritis. (See 'Serologic testing' below.)

EVALUATION AND DIAGNOSIS

When to suspect the diagnosis — The presence of staphylococcus-associated glomerulonephritis should be suspected in patients with clinical manifestations of active glomerulonephritis (eg, hematuria with or without red cell casts, often accompanied by proteinuria and an elevation in serum creatinine) in conjunction with a known or suspected recent or concurrent staphylococcal infection.

Diagnostic evaluation

Serologic testing — In patients with suspected staphylococcus-associated glomerulonephritis, we obtain the following serologic tests to evaluate for other potential causes of glomerulonephritis:

●Serum C3 and C4 complement levels

●Antinuclear antibody (ANA)

●Anti-double-stranded DNA (anti-dsDNA) antibody

●Antineutrophil cytoplasmic autoantibodies (ANCA)

●Anti-glomerular basement membrane (anti-GBM) antibodies

●Serology for hepatitis C virus, hepatitis B virus, and HIV

●Serum cryoglobulins

●Serum free light chains and serum protein electrophoresis with immunofixation

As noted above, patients with staphylococcus-associated glomerulonephritis often have hypocomplementemia. As examples, low C3 and C4 are not characteristic of IgA nephropathy, ANCA-associated vasculitis, or anti-GBM disease. However, hypocomplementemia is absent in some patients with staphylococcus-associated glomerulonephritis, and hypocomplementemia combined with an active urine sediment can be seen with other diseases, such as lupus nephritis, C3 glomerulonephritis, mixed cryoglobulinemia, and in infrequent patients with atheroembolic disease involving the kidney who have an active urine sediment. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

The pattern of hypocomplementemia may sometimes help distinguish staphylococcus-associated or other bacterial causes of glomerulonephritis, in which the typical pattern is low C3 and normal C4 levels, from these other disorders [6]. As examples, lupus nephritis is usually associated with reduced levels of both C3 and C4, and mixed cryoglobulinemia is frequently characterized by low C4 and normal C3. However, there is overlap, as approximately one-third of patients with bacterial infection-related glomerulonephritis have low C3 and C4; in addition, a positive ANA may be seen with shunt nephritis due to staphylococcal infection [6].

Up to 22 percent of patients with staphylococcus-associated glomerulonephritis, with or without crescents on biopsy, are positive for ANCA [2]. The majority of these patients have infectious endocarditis and antibodies against proteinase 3 (PR3) [2].

The general evaluation of glomerulonephritis is discussed elsewhere. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Evaluation of glomerulonephritis'.)

Kidney biopsy — We suggest that a kidney biopsy be performed in most adults suspected of having staphylococcus-associated glomerulonephritis after bacteremia has resolved. However, a kidney biopsy may not be required if all three of the following criteria are satisfied:

●There is clear evidence of overt glomerulonephritis, marked by glomerular hematuria, heavy proteinuria (greater than 1 g/day), and an abnormally elevated serum creatinine. (See "Etiology and evaluation of hematuria in adults", section on 'Glomerular versus nonglomerular bleeding'.)

●A serious infection is present, and Staphylococcus aureus is documented by a positive blood culture (ideally two positive blood cultures, each from a different site), wound culture, or tissue culture (eg, bone biopsy of suspected osteomyelitis). (See 'Most common sites of infection' above.)

●The staphylococcal infection is concurrent with the development of the glomerulonephritis.

Even if all three of the above criteria are met, we still suggest obtaining a kidney biopsy if there is laboratory evidence suggestive of an alternative diagnosis. (See 'Serologic testing' above.)

Histologic findings — The characteristic histologic findings in staphylococcus-associated glomerulonephritis include the following:

●Light microscopy – The most common histologic pattern of injury on light microscopy is diffuse endocapillary proliferative and exudative glomerulonephritis with more than 50 percent of glomeruli showing occlusion of the peripheral capillaries by endocapillary hypercellularity, including abundant intracapillary infiltrating neutrophils [13,15]. Less common histologic patterns include focal proliferative and mesangial proliferative glomerulonephritis, crescentic and/or necrotizing glomerulonephritis (defined by the presence of crescents and/or necrosis in at least 50 percent of glomeruli), and membranoproliferative glomerulonephritis (MPGN). Tubulointerstitial changes commonly accompany the glomerulonephritis and include red blood cell casts and varying degrees of acute tubular injury, interstitial inflammation, and interstitial edema.

The site of infection may impact on the glomerular findings. As an example, a crescentic and necrotizing pattern is the most common finding in patients with glomerulonephritis associated with infective endocarditis [22,26,27], and MPGN is the most common pattern in patients with glomerulonephritis associated with an infected ventriculoatrial shunt (also called shunt nephritis) [28,29]. (See "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt", section on 'Clinical features and kidney biopsy findings'.)

●Immunofluorescence microscopy – Immunofluorescence microscopy typically reveals C3 dominant or codominant (with IgA or IgG) glomerular staining (picture 1). In most cases, there is coarsely granular mesangial and glomerular wall staining, resembling the "starry sky pattern," while a minority exhibit predominantly glomerular capillary wall positivity ("garland pattern") or predominantly mesangial staining ("mesangial pattern") [13,15,30].

C3 can be the only immunoreactant detected by immunofluorescence (seen in 27 percent of patients with staphylococcus-associated glomerulonephritis in a study of older adult patients [15]), but more often there is co-deposition of one or more immunoglobulins and/or C1q. Patients with staphylococcus-associated glomerulonephritis often have IgA-dominant disease (picture 2) [3,6,15]. In one study, IgA staining was trace in 25 percent of biopsies, mild in 19 percent, moderate in 44 percent, and strong in 12 percent [2]. IgA dominance in patients with bacterial infection-related glomerulonephritis appears to occur mainly in association with staphylococcal infection, which is in contrast to the predominant IgG deposition in poststreptococcal glomerulonephritis [3,4,6,13,15,16,20,31,32].

In patients who have C3 deposition with no significant immunoglobulin deposition, staphylococcus-associated glomerulonephritis may be difficult to distinguish from C3 glomerulonephritis. Helpful distinguishing histologic and clinical features are discussed below. (See 'Distinction from C3 glomerulonephritis' below.)

●Electron microscopy – Electron microscopy typically shows large, hump-shaped subepithelial electron dense deposits (picture 3). In resolving disease, the humps are preferentially located overlying the glomerular basement membrane reflection over the mesangium.

Humps are not specific for staphylococcus-associated glomerulonephritis as they are also common in C3 glomerulonephritis and dense deposit disease. Small mesangial, subendothelial, and/or intramembranous deposits are not infrequent in adults with staphylococcus-associated glomerulonephritis.

Establishing the diagnosis — In most adults, a presumptive diagnosis can be made in patients with at least two of the following criteria:

●Hypocomplementemia (primarily low C3).

●Endocapillary proliferation and exudative glomerulonephritis on light microscopy (picture 4).

●C3 dominant or codominant glomerular staining on immunofluorescence microscopy (picture 1). However, many if not most patients with staphylococcus-associated glomerulonephritis have IgA-dominant or codominant disease (together with intense C3 staining).

●Hump-shaped subepithelial deposits on electron microscopy (picture 3).

However, hypocomplementemia and these pathologic findings are not completely specific for glomerulonephritis due to a bacterial infection. Thus, a confirmed diagnosis of staphylococcus-associated glomerulonephritis requires that the disease activity (eg, hematuria, hypocomplementemia if present) abate after successful eradication of the infection, although there may be persistent elevation of the serum creatinine and proteinuria reflecting irreversible kidney injury.

DIFFERENTIAL DIAGNOSIS — In adults who present with acute glomerulonephritis, the differential diagnosis is broad; however, components of the diagnostic evaluation can help to differentiate staphylococcus-associated glomerulonephritis from most other causes of glomerulonephritis. (See 'Diagnostic evaluation' above.)

Nevertheless, there are three other glomerulonephritides that are more challenging to distinguish from staphylococcus-associated glomerulonephritis. These are discussed below.

Distinction from C3 glomerulonephritis — In patients who have C3 deposition with no significant immunoglobulin deposition on immunofluorescence microscopy, staphylococcus-associated glomerulonephritis may be difficult to distinguish from C3 glomerulonephritis.

The following clinical features can help distinguish between these two disorders (see "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'C3 glomerulonephritis'):

●Hematuria can occur within a few days after an upper respiratory infection in patients with C3 glomerulonephritis [33], an association that has not been reported with staphylococcal infection.

●Persistent or recurrent active glomerulonephritis over a prolonged period is common in C3 glomerulonephritis. Furthermore, depression of C3 usually persists in C3 glomerulonephritis. This is in contrast to the typical resolution of active disease and normalization of complement levels in staphylococcus-associated glomerulonephritis, although signs of irreversible injury during the acute episode may persist, such as an elevated serum creatinine and/or proteinuria. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'C3 glomerulonephritis'.)

●The presence of membranoproliferative glomerulonephritis (MPGN) on kidney biopsy and prolonged hypocomplementemia, a pattern not typically seen with staphylococcus-associated glomerulonephritis.

Pathologic findings on immunofluorescence and electron microscopy may also be helpful:

•Immunofluorescence microscopy in C3 glomerulonephritis typically reveals intense C3 glomerular staining without IgG deposition and minimal or no staining for other immunoreactants. C3 deposition also occurs in staphylococcus-related glomerulonephritis (picture 1), but it is usually accompanied by immunoglobulin deposition which, as noted above, is in some cases IgA dominant (picture 2). (See 'Histologic findings' above.)

•Electron microscopy in C3 glomerulonephritis typically reveals both mesangial deposits and capillary wall deposits in subendothelial, intramembranous, and/or subepithelial locations (picture 5). The finding of large mesangial, subendothelial, and/or intramembranous deposits should favor C3 glomerulonephritis over staphylococcus-associated glomerulonephritis. By contrast, a preferential localization of subepithelial deposits on the glomerular basement membrane reflection over the mesangium and evidence of resorption within the deposits favor staphylococcus-associated glomerulonephritis [6]. (See 'Histologic findings' above.)

Distinction from IgA nephropathy — IgA-dominant staphylococcus-associated glomerulonephritis can be difficult to distinguish from primary IgA nephropathy that is triggered or reactivated by infection. (See "IgA nephropathy: Clinical features and diagnosis".)

The following clinical and pathologic features suggest a diagnosis of staphylococcus-associated glomerulonephritis rather than primary IgA nephropathy:

●Initial presentation at an older age or in a patient with diabetes.

●Acute kidney injury at the time of initial presentation, which can also occur in IgA nephropathy when there is gross hematuria. (See "IgA nephropathy: Treatment and prognosis" and "IgA nephropathy: Clinical features and diagnosis", section on 'Clinical features'.)

●Hypocomplementemia, which is not typically seen in IgA nephropathy.

●Diffuse exudative glomerulonephritis on light microscopy (picture 4) rather than the typical mesangial proliferative disease in IgA nephropathy (picture 6). By contrast, the presence of segmentally sclerosed (scarred) glomeruli favors IgA nephropathy [34].

●Stronger intensity of immunofluorescence staining for C3 than IgA in the glomerular deposits (picture 1) rather than the predominant global mesangial IgA staining in IgA nephropathy (picture 7). On the other hand, IgA staining of sclerosed glomeruli favors IgA nephropathy [34].

●Subepithelial humps on electron microscopy (picture 3) rather than mesangial deposits in IgA nephropathy (picture 8).

Rarely, patients with IgA-dominant staphylococcus-associated glomerulonephritis develop a vasculitic skin rash (with or without IgA deposition in the small vessels of skin), mimicking IgA vasculitis [21]. Conversely, there are anecdotal reports of IgA vasculitis in adults associated with staphylococcal infection [35,36]. A presentation with acute kidney injury, hypocomplementemia, a stronger intensity of immunofluorescence staining for C3 than IgA in the glomerular deposits, and the presence of numerous subepithelial humps on electron microscopy favor IgA-dominant staphylococcus-associated glomerulonephritis over IgA vasculitis. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

A mass spectrometry-based exploratory study comparing staphylococcus-associated glomerulonephritis with IgA nephropathy and normal controls found the glomerular proteomes of staphylococcus-associated glomerulonephritis and IgA nephropathy to be very similar, except for significantly higher levels of monocyte/macrophage proteins (mainly lysozymes and S100A9) in staphylococcus-associated glomerulonephritis (consistent with the higher frequency and severity of endocapillary hypercellularity in this disease compared with primary IgA nephropathy). However, this study did not identify disease-specific biomarkers [37].

Distinction from poststreptococcal glomerulonephritis — Staphylococcus-associated glomerulonephritis differs from poststreptococcal glomerulonephritis in several important ways:

●Poststreptococcal glomerulonephritis is predominantly a childhood disease, whereas staphylococcus-associated glomerulonephritis, with rare exceptions [25,38], is a disease of adults, particularly older adults.

●As previously stated, in contrast to poststreptococcal glomerulonephritis in which the kidney disease typically manifests a few weeks after resolution of infection, staphylococcus-associated glomerulonephritis usually occurs when the patient is still infected.

●The site of infection can be variable (eg, skin, soft tissue, heart, indwelling catheter, empyema, etc). Unlike poststreptococcal glomerulonephritis, upper respiratory tract infection is not usually a cause of staphylococcus-associated glomerulonephritis. (See 'Most common sites of infection' above.)

●The kidney prognosis is much worse than in poststreptococcal glomerulonephritis, particularly in patients with underlying diabetic nephropathy. (See 'Prognosis' below.)

●Cutaneous vasculitis can occur in patients with staphylococcus-associated glomerulonephritis [2,20,21]. By contrast, cutaneous vasculitis is not a manifestation of poststreptococcal glomerulonephritis.

TREATMENT — Treatment of staphylococcus-associated glomerulonephritis in adults should focus on eradicating the infection, relieving symptoms, and controlling hypertension and edema. We do not use immunosuppressive therapy in such patients.

Eradicate the infection — Active infection should be eradicated with appropriate antibiotics, and if needed, surgery should be performed [5,6,13-15]. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Management'.)

Control hypertension and edema — Antihypertensive drugs, diuretics, and dietary salt restriction are often necessary in the acute setting to control hypertension and edema. Hypertension in patients with staphylococcus-associated glomerulonephritis (and in most other causes of acute glomerulonephritis) is primarily due to fluid retention, which also is responsible for edema formation. As a result, dietary salt restriction and diuretics, often beginning with loop diuretics, are a reasonable first-line therapy. The goals of diuretic therapy are to control both the hypertension and, if present, edema. (See "Overview of hypertension in acute and chronic kidney disease", section on 'Acute glomerular disease' and "Overview of hypertension in acute and chronic kidney disease", section on 'Treatment of hypertension in acute glomerular or vascular disease' and "Overview of hypertension in acute and chronic kidney disease", section on 'Use of diuretics and goal of therapy'.)

If hypertension cannot be controlled in the acute setting with salt restriction and diuretics alone, adding an inhibitor of the renin-angiotensin system (eg, angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]) is a reasonable approach, since salt restriction and diuretics tend to increase the activity of the renin-angiotensin system, which will increase the antihypertensive response to angiotensin inhibition. In a series of 501 patients with adult bacterial infection-related glomerulonephritis from the Indian subcontinent (in which most cases were due to streptoccocal infection), the use of renin-angiotensin system blockade was associated with greater kidney survival [18]. (See "Overview of hypertension in acute and chronic kidney disease", section on 'Treatment of hypertension in acute glomerular or vascular disease'.)

If residual kidney disease persists after the acute glomerulonephritis has resolved (ie, chronic kidney disease), then inhibitors of the renin-angiotensin system are first-line antihypertensive drugs in such patients, particularly in patients with persistent proteinuria above 1000 mg/day. These issues are discussed separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD'.)

Do not use immunosuppressive therapy — We do not treat patients with staphylococcus-associated glomerulonephritis with immunosuppressive therapy. Immunosuppressive therapy in this setting is not well studied, and there is no clear evidence of benefit. In addition, in patients with active infection, as is often the case in patients with glomerulonephritis due to Staphylococcus, giving high-dose glucocorticoids may potentially lead to clinical worsening or even death [1,5,39-41]. Furthermore, glucocorticoids could lead to dysglycemia. In the above mentioned study from India, 12 percent of patients treated with glucocorticoids developed dysglycemia compared with none of the patients not receiving glucocorticoid therapy [18].

Data are limited on the efficacy of immunosuppressive therapy in adults with staphylococcus-associated glomerulonephritis. There are no randomized trials. In a retrospective study of 109 older adult patients with bacterial infection-associated glomerulonephritis, 46 percent of whom had staphylococcus-associated glomerulonephritis [15], 22 were treated with glucocorticoids for variable periods of time. The indication for glucocorticoid therapy was an elevated serum creatinine with or without crescents. Three patients had a complete remission, 12 had a persistent elevation in serum creatinine, seven progressed to end-stage kidney disease (ESKD), and four died. There was no correlation between glucocorticoid therapy and kidney outcomes. Lack of benefit has also been noted in other observational studies of patients with bacterial infection-related glomerulonephritis, including staphylococcus-associated glomerulonephritis [6,13,14,42].

MONITORING THE CLINICAL COURSE — Patients with presumptive staphylococcus-associated glomerulonephritis should be monitored for signs of resolution of active disease, including elimination of active infection, remission of hematuria, reduction in serum creatinine toward the previous baseline value, reduction in proteinuria, and if present, resolution of hypocomplementemia. There are no data on the optimal timing of monitoring these parameters. We suggest the following approach in patients without rapidly progressive crescentic glomerulonephritis (who require more intensive monitoring):

●Urine protein-to-creatinine ratio (UPCR) and measurement of serum creatinine weekly for at least four weeks until the serum creatinine returns to baseline (if known) or is stable.

●Microscopic hematuria may take months to completely resolve. Thus, if the serum creatinine returns to baseline or becomes stable, we repeat the urine dipstick analysis at one- to two-month intervals until hematuria has disappeared.

●Proteinuria typically resolves more slowly than hematuria, and proteinuria can persist for many months [6]. We follow the UPCR every one to three months for one year.

●If hypocomplementemia was present initially, we measure C3 levels at one-month intervals. If the glomerulonephritis is infection related, hypocomplementemia should resolve within two months of appropriate antibiotic therapy.

In adults with staphylococcus-associated glomerulonephritis, successful eradication of the infection should result in resolution of the glomerulonephritis. However, many patients do not have complete resolution of the serum creatinine to their prior baseline and will also have persistent proteinuria. The persistent proteinuria and/or an elevated serum creatinine concentration in such patients is thought to represent irreversible scarring with inactive and sclerosing glomerular lesions [14]. In this setting, monitoring of the serum creatinine and UPCR can be performed less frequently, and a repeat kidney biopsy is usually not warranted in the absence of an active urine sediment or persistent hypocomplementemia. A possible exception to this general recommendation may occur in patients in whom the initial kidney biopsy suggested that C3 glomerulonephritis might be present rather than staphylococcus-associated glomerulonephritis, although this is much more of an issue with streptococcal infection.

Persistent or recurrent staphylococcus-associated glomerulonephritis is uncommon and should suggest an alternate diagnosis such as C3 glomerulonephritis. Persistent disease can occur with persistent staphylococcal infections, as may be seen with an infected ventriculoatrial shunt, leading to what has been called shunt nephritis (see "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt", section on 'Clinical features and kidney biopsy findings'). Recurrent glomerulonephritis has been reported in patients with recurrent or new infection [14].

PROGNOSIS — The long-term kidney outcomes in patients with bacterial infection-associated glomerulonephritis (ie, not specifically staphylococcus-associated glomerulonephritis) were evaluated in a study of 86 adults in which 48 had at least three months of follow-up; four patients who had attained complete remission in less than three months were also included [13]. At a mean follow-up of 25 months, the following findings were noted:

●Among the 41 patients without underlying diabetic nephropathy, 23 (56 percent) attained complete remission, 11 (27 percent) had persistent kidney function impairment, and 7 (17 percent) progressed to end-stage kidney disease (ESKD) requiring kidney replacement therapy.

●Among the 11 patients with underlying diabetic nephropathy, most of whom had staphylococcus-associated glomerulonephritis, two (18 percent) had persistent kidney function impairment, and nine (82 percent) progressed to ESKD. Similarly poor kidney outcomes in patients with underlying diabetic nephropathy have been reported in other studies [42].

The kidney prognosis also appears to be worse in older patients [15,25,42]. In one series of 109 older adult patients (age 65 years or more), 34 patients with staphylococcus-associated glomerulonephritis had three months or more of follow-up [15]. Among these patients, eight (24 percent) had complete recovery of kidney function, 11 (32 percent) had persistent kidney function impairment, and 15 (44 percent) progressed to ESKD, 11 of whom required dialysis at the time of kidney biopsy. Other risk factors for the development of ESKD included the presence of diabetic nephropathy and a higher degree of tubular atrophy and interstitial fibrosis on kidney biopsy, which are markers of chronic disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Staphylococcus-associated glomerulonephritis is an immune complex-mediated kidney disease in which the antigen component of the immune complex is derived from the infective agent, similar to poststreptococcal glomerulonephritis. The details of the pathogenesis of staphylococcus-associated glomerulonephritis are not entirely clear. (See 'Pathogenesis' above.)

●Clinical manifestations – Adults with staphylococcus-associated glomerulonephritis usually present with a concurrent infection and frequently with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema. Cutaneous vasculitis can occur, imitating immunoglobulin A (IgA) vasculitis or antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. The majority of patients will have hypocomplementemia (usually with a low C3). An inciting staphylococcal infection can be identified from a positive culture. In some patients, an infectious agent cannot be identified, and suspicion of staphylococcus-associated glomerulonephritis is based upon a probable infection. (See 'Clinical manifestations' above.)

●Diagnosis – The presence of staphylococcus-associated glomerulonephritis should be suspected in patients with clinical manifestations of active glomerulonephritis (eg, hematuria with or without red cell casts, often accompanied by proteinuria and an elevation in serum creatinine) in conjunction with a known or suspected recent or concurrent staphylococcal infection. (See 'When to suspect the diagnosis' above.)

•In patients with suspected staphylococcus-associated glomerulonephritis, we perform serologic testing to evaluate for other potential causes of glomerulonephritis. A kidney biopsy may be required to make the diagnosis. (See 'Diagnostic evaluation' above.)

•A presumptive diagnosis of staphylococcus-associated glomerulonephritis can be made if at least two of the following criteria are satisfied in a patient with evidence of Staphylococcus infection concurrent with the onset of glomerulonephritis:

-Hypocomplementemia (primarily low C3)

-Endocapillary proliferation and exudative glomerulonephritis on light microscopy (picture 4)

-C3 dominant or codominant glomerular staining on immunofluorescence microscopy (picture 1)

-Hump-shaped subepithelial deposits on electron microscopy (picture 3)

However, hypocomplementemia and these pathologic findings are not completely specific for glomerulonephritis due to a bacterial infection. Thus, a confirmed diagnosis of staphylococcus-associated glomerulonephritis requires that the disease activity (eg, hematuria, hypocomplementemia if present) abate after successful eradication of the infection, although there may be persistent elevation of the serum creatinine and proteinuria reflecting irreversible kidney injury. (See 'Establishing the diagnosis' above.)

●Treatment – Treatment of staphylococcus-associated glomerulonephritis in adults should focus on eradicating the infection, relieving symptoms, and controlling hypertension and edema. We do not use immunosuppressive therapy in such patients. (See 'Treatment' above.)

●Clinical course – In adults with staphylococcus-associated glomerulonephritis, successful eradication of the infection should result in resolution of the glomerulonephritis. This resolution is usually manifest by stabilization of the serum creatinine, disappearance of hematuria, and normalization of complement levels, a process that may take months. However, many patients with staphylococcus-associated glomerulonephritis do not have complete resolution of the serum creatinine to their prior baseline and will also have persistent proteinuria. (See 'Monitoring the clinical course' above.)