Bacterial Infection-Associated Glomerulonephritis in Adults and Children

Bacterial Infection-Associated Glomerulonephritis in Adults and Children

Kikachukwu Otiono

Rahul Chanchlani


Infection-associated glomerulonephritis (IAGN) describes a spectrum of glomerular diseases associated with bacterial, viral, fungal, and protozoal infections. The most common bacteria responsible for IAGN are Streptococcus and Staphylococcus, but other bacteria can cause the disease as well, although rarely, such as Salmonella, Yersinia, Escherichia, and Pseudomonas.1,2,3 In the past, the typical clinical vignette for IAGN depicted a child with streptococcal impetigo or pharyngitis followed by acute nephritis—this is known as postinfectious or poststreptococcal glomerulonephritis (PSGN). However, there has been a shift in recent years in the epidemiology and clinical assessment of IAGN.4 Contemporary studies made it apparent that IAGN is increasingly prevalent in immunocompromised adults and in older adults. In these populations, various clinical entities are involved, such as gram-negative bacteria, infective endocarditis (IE), and cerebrospinal fluid shunt infections.5 As such, the traditional understanding of IAGN has evolved.

The underlying mechanism(s) behind glomerular diseases associated with infection are not fully understood, but existing studies have demonstrated that etiologic agents trigger an autoimmune response that causes glomerular inflammation and injury. As described in Couser and Johnson (2014), IAGN occurs when there is a “transition from an initial immune response to an exogenous agent into an autoimmune response.”5 In other words, the primary immune response to infection activates biologic processes such as complement activation, endothelial injury, and leukocyte infiltration—all of which result in acute glomerular inflammation.6

This chapter provides an overview of the spectrum of bacterial IAGN in both adults and children, including the morphologic features, clinical manifestations, treatment considerations, and differential diagnoses. Specifically, this chapter reviews the following infections: PSGN, Staphylococcus-associated glomerulonephritis (SAGN), infective endocarditis-associated glomerulonephritis (IE-associated GN), and shunt nephritis (Table 16.1).7


Pathogenesis and General Considerations

PSGN is caused by an immunologically mediated response to nephritogenic strains of Streptococcus pyogenes (also known as group A Streptococcus or GAS).

Immune complex formation and deposition, the proliferation of chemical mediators and cytokines, and local activation of the complement cascade all propel the inflammatory process that causes glomerular injury.8,9 It is important to note that the pathogenetic mechanisms that cause acute PSGN have not been fully elucidated, although there are multiple theories.

The enduring understanding of the disease points to Streptococcus pyogenes of M types 1, 2, 4, and 12 as the cause of glomerular injury from upper respiratory tract infections (ie, pharyngitis), whereas M types 47, 49, and 55 are associated with pyoderma-induced nephritis.9 In recent literature, the nephritogenic antigen nephritis-associated plasmin receptor (NAPlr) and streptococcal pyrogenic exotoxin B (SpeB) have been associated with PSGN.10,11 Typing of streptococcal strains is not performed in general clinical practice; thus, it is often unclear whether patients have been exposed to a nephritogenic strain.


Broadly speaking, IAGN reveals scattered large subepithelial electron-dense deposits on electron microscopy. These deposits are classically known as humps (Figure 16.1C), which are typically seen in acute injury, and then become scarce during chronic disease (Figure 16.1C).12,13,14 The humps correspond to deposits of immunoglobulin G (IgG) and C3 found on immunofluorescence.12

The histologic features of PSGN are illustrated in Figure 16.1. On light microscopy, PSGN is a diffuse proliferative and exudative GN (Figure 16.1A) with endocapillary hypercellularity and neutrophils.15 This pattern is often referred to as acute exudative glomerulonephritis (GN).6 In rare cases of PSGN, there may be crescent formation. Crescentic GN is an extracapillary proliferation of inflammatory cells, forming two or more layers in the Bowman space.16,17 The formation of crescents occurs in a variety of glomerulopathies and typically denotes severe glomerular injury. However, some studies have shown that there is no correlation between histology and clinical severity.18

Under direct immunofluorescence, PSGN generally reveals coarse, granular complement factor (C3) staining (Figure 16.1B).6,9 In addition, there are distinct staining patterns described in the literature, namely, the “garland,” “starry-sky,” and “mesangial” patterns. If the stain consists of large, confluent deposits in the glomerular capillary wall with coarse granular bumps, this is known as the garland pattern.19 Of note, the garland pattern is classically associated with a severe
clinical course and a worse prognosis.20 The starry sky pattern demonstrates scattered fine and coarse staining in the glomerular wall and mesangium with a few large deposits.19 Conversely, mesangial staining predominates in the mesangial pattern.21 Both the starry-sky and mesangial patterns are associated with less severe disease.6

Clinical Findings

PSGN typically affects children between ages 4 and 15, and it continues to be the most common cause of acute nephritis in children, especially in developing countries.22,23 PSGN is usually diagnosed based on evidence of recent GAS infection and clinical manifestations of acute nephritic syndrome.

Laboratory Findings

For diagnosis, a throat or skin culture may not prove useful because acute nephritis typically presents days to weeks after the associated streptococcal infection. More frequently, the antecedent streptococcal infection is established by elevated titers of antibodies to extracellular streptococcal antigens. These elevated titers are a serologic marker of recent GAS infection, measured by the streptozyme test. The streptozyme test measures five antibodies: antistreptolysin (ASO), antihyaluronidase (AHase), antistreptokinase, antinicotinamidase-adenine dinucleotide (anti-NAD), and anti-DNase B antibodies (Visual Abstract 16.1).28 ASO and anti-NAD tend to rise following pharyngitis infection, whereas anti-DNAase B and AHase may be elevated after pharyngitis or skin infections.29 It is important to note that recent literature on the streptozyme test is scarce. However, Blyth and Robertson (2006) established age-specific population normal values from over 2000 specimens and highlighted the variability in sensitivity and specificity of the titers. For example, the specificity of a single antibody titer in PSGN can range from 86.4% to 93.2%. They concluded that a combination of ASO and anti-DNase B is required to achieve maximum sensitivity and specificity.30 On the other hand, the C3 level is greatly decreased in the first few weeks of the disease for most patients, but does return to baseline in 6 to 8 weeks.28 Urinalysis may show hematuria (microscopic or gross, with or without red blood cell casts) and variable levels of proteinuria and pyuria. Nephrotic-range proteinuria is uncommon. Elevated serum creatinine may occur during the acute phase. Rarely, children present with rapidly progressive GN.31

Differential Diagnosis

The differential diagnosis of PSGN largely includes other causes of glomerular disease, and a kidney biopsy may be required for diagnostic clarity. For children
with a classic presentation of GN and typical laboratory findings of positive streptococcal antibodies with low C3 level, kidney biopsies are generally deferred.

Immunoglobulin A nephropathy (IgAN): Patients with IgAN typically have an antecedent infection (usually an upper respiratory tract infection), much as in PSGN.32 However, IgAN usually presents at an older age than does PSGN. The peak incidence of IgAN is adults in their 20s and 30s. Another distinguishing feature between IgAN and PSGN is that the hematuria in the setting of IgAN occurs during or shortly after the infection (referred to as synpharyngitic hematuria). Conversely, hematuria typically presents 1-2 weeks after infection in patients with PSGN.33 In addition, recurrent episodes of hematuria tend to occur more often with IgAN compared to PSGN. Complement levels are usually normal in IgAN.32

C3 glomerulopathy (C3G): Broadly speaking, activation of the complement system occurs via three pathways: the classic, the lectin, and the alternative pathways (see Chapter 1).34 The pathogenesis of C3G is linked to an unfettered activation of the alternative complement pathway35 due to autoantibodies and/or dysfunction in regulatory proteins.36 With regard to pathologic features, C3G is defined by the dominant glomerular deposition of C3 and the absence of Igs.37 The emergence of C3G complicates the clinical and pathologic algorithm for physicians because of its similarities to PSGN. For example, C3G has been known to occur in the setting of an infection and elevated ASO titers, and often presents with hematuria, proteinuria, and hypertension.38,39 In addition, biopsy findings in C3G include endocapillary proliferation and subepithelial humps—classic findings in PSGN.40 However, patients with C3G typically have a longer course of the disease, whereas PSGN tends to resolve within a few weeks. C3G should be suspected in patients with atypical PSGN symptoms, such as persistent proteinuria, low C3 (after 12 weeks), and a decline in kidney function.39 Genetic testing for complement abnormalities is required when C3G is suspected, which poses a challenge in low-resource settings.36,41 A recent study that examined the pathophysiology of PSGN in children noted that PSGN was associated with activation of the alternative complement pathway and the presence of transient anti-factor B autoantibodies. The full details of the pathogenesis of PSGN remain unclear; however, further research into the mechanisms of complement activation may assist in distinguishing PSGN from C3G.24 Of note, it has been proposed that PSGN and C3G may represent a disease spectrum rather than distinct clinical entities (Visual Abstract 16.2).42

Postinfectious GN due to other infectious agents: Acute GN may occur in the setting of viruses or other bacterial agents and presents very similarly to PSGN without the antecedent GAS infection. Some examples of these other microbial agents include Staphylococcus aureus, Escherichia coli, Pseudomonas, Epstein-Barr virus, and hepatitis B virus.43

Treatment Considerations

PSGN usually resolves without intervention; therefore, symptomatic treatment is the mainstay of treatment. By definition, the glomerular injury in question is postinfectious; antibiotics are generally not recommended. Research has suggested that treating at-risk populations or households with an index case with penicillin prophylaxis may prevent new cases of PSGN.28 There is no evidence that immunosuppression is useful in treating patients with PSGN.44

Symptomatic therapy consists of treating the clinical manifestations of volume overload (hypertension and edema) with sodium and water restriction and loop diuretics such as furosemide.45 If patients develop hypertensive encephalopathy, emergent treatment with oral or parenteral antihypertensives is indicated. In severe cases of anuria, azotemia, hypertension, or electrolyte abnormalities, dialysis therapy may be required as a life-saving intervention.45

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Apr 18, 2023 | Posted by in NEPHROLOGY | Comments Off on Bacterial Infection-Associated Glomerulonephritis in Adults and Children
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