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Poststreptococcal glomerulonephritis (PSGN) results from nephrogenic streptococci, specific strains of group A beta-hemolytic streptococci.  It is a result of an inflammatory response (type III hypersensitivity reaction) characterized by rapid deterioration of kidney function, specifically affecting the glomeruli and the small blood vessels of the kidneys.  PSGN is often seen in children six weeks post skin infection (impetigo) or 1-2 weeks after a sore throat.
NBK538255

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Antigens from streptococcal A and antibodies from glomeruli form complexes and deposit into the glomerulus of kidneys. Type III hypersensitivity is not organ specific, but symptoms appear where the complexes are deposited. In the case of PSGN, kidney function will be impaired.

https://www.ncbi.nlm.nih.gov/books/NBK333429/

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Abstract

Acute glomerulonephritis that results from streptococcal infections is the best-studied immune complex-mediated glomerulonephritis. Initially described in the convalescence of scarlet fever, the incidence of acute post streptococcal glomerulonephritis (APSGN) has decreased worldwide, particularly in developed countries where it is now rare and is limited to adult patients who have debilitating conditions. In developing countries, the annual burden of APSGN remains at a level of least 9 cases per 100,000 inhabitants. Two antigenic fractions of the streptococcus (streptococcal GAPDH/nephritis-associated plasmin receptor, and streptococcal pyrogenic exotoxin B and its zymogen precursor) are currently under scrutiny as putative nephritogens. Glomerulonephritis results from the glomerular deposition of circulating immune complexes and by the in situ formation of immune complexes. In-situ formation of immune complexes is a characteristic associated with cationic antigens that have a charge-facilitated penetration through the polyanionic glomerular basement membrane. The plasmin-binding capacity of streptococcal antigens favors immune complex deposition and inflammation. The typical pathological changes are endocapillary proliferation with varying degrees of leukocyte infiltration, and C3, IgG, and IgM immune deposits. Electron microscopy shows the hallmark lesion of subepithelial electron dense deposits ("humps"). The immediate prognosis is excellent in children, but adults have a significant early mortality, which partially results from cardiovascular disease. The long-term development of end-stage renal disease is exceptional in children. However, studies in aboriginal communities indicate that patients with a history of APSGN have a higher incidence of albuminuria, and that APSGN represents a risk factor for the subsequent development of chronic renal failure, if associated with diabetes and obesity.

Introduction

Acute poststreptococcal glomerulonephritis (APSGN) is the prototype of post-infectious glomerulonephritis and is associated with a previous skin or throat infection by group A streptococcus ( Streptococcus pyogenes), or occasionally groups C or G streptococcus. According to Becker and Murphy ( Becker & Murphy, 1968), the development of dark and scanty urine was a feared complication of the epidemics of scarlet fever in the fourteenth century, and clinical descriptions of the "dropsy that follows scarlet fever" have appeared in medical literature since at least 1812 ( Wells, 1812). APSGN was probably the cause of death of Wolfgang Amadeus Mozart in 1791 ( Zegers, Weigl, & Steptoe, 2009).

The observation that the disease appeared in the convalescent period of scarlet fever led Clemens von Pirquet ( von Pirquet, 1911) to postulate that post-scarlatinal nephritis was caused by the development of harmful antibodies (as opposed to the beneficial antibodies in vaccination) and coined the term " allergy" (altered reactivity) to define this pathogenic modality. This landmark paper opened the field of immune complex-mediated diseases. The demonstration of the streptococcal etiology of scarlet fever ( Dochez & Sherman, 1924) and the recognition that acute rheumatic fever and glomerulonephritis, both complications of streptococcal infections, have epidemiological and biological differences and rarely, if ever, occur in the same patient; this suggested the existence of rheumatogenic and nephritogenic strains of the bacterium to Seegal and Earle ( Seegal & Earle, 1941), and prompted the search for nephritogenic antigens (reviewed in ( Rodríguez-Iturbe & Batsford, 2007)).

Epidemiology

APSGN may occur in epidemic outbreaks or in clusters of cases, and it may occur in isolated patients. Epidemic outbreaks reported in the past as a consequence of upper respiratory or skin streptococcal infections have periodically appeared in specific regions of the world, such as the Red Lake Indian Reservation in Minnesota ( Anthony, Kaplan, Wannamaker, Briese, & Chapman, 1969); in Port of Spain, Trinidad ( Poon-King, et al., 1967); in Maracaibo, Venezuela ( Rodríguez-Iturbe, 1984); and in the Northern Territory of Australia ( Marshall, et al., 2011). The most recent epidemics have occurred in the indigenous communities of the Northern Territory of Australia, resulting from pyoderma after infection with emm55 group A streptococcus ( Marshall, et al., 2011) and in the rural region of Nova Serrana, Brazil, caused by the ingestion of unpasteurized milk obtained from cows with mastitis caused by Streptococcus zooepidemicus ( Balter, et al., 2000). Streptococcus zooepidemicus has also caused clusters of cases (5-15 patients) reported in the last two decades in poor communities in industrialized countries ( Nicholson, et al., 2000).

In recent decades, the incidence of APSGN has declined significantly worldwide. The reduction of the incidence of APSGN is probably the result of easier and earlier access to appropriate medical care for streptococcal infections. Reports from France ( Simon, et al., 1994), Italy ( Coppo, Gianoglio, Porcellini, & Maringhini, 1998), China ( Zhang, Shen, Feld, & Stapleton, 1994), Chile ( Berríos, et al., 2004), Singapore ( Yap, et al., 1990), the United States ( Roy & Stapleton, 1990), and Venezuela ( Rodríguez-Iturbe & Musser, 2008) all indicate that APSGN is now an infrequent disease, and its rarity in affluent societies has been considered a factor for delayed diagnosis in patients who do not have gross hematuria ( Pais, Kump, & Greenbaum, 2008).

In industrialized countries, APSGN is now a disease of elderly patients that tend to have debilitating conditions, malignancy, alcoholism, or diabetes ( Montseny, Meyrier, Kleinknecht, & Callard, 1995). Nevertheless, APSGN remains a significant health problem in underdeveloped societies. Endocapillary glomerulonephritis, assumed to be of poststreptococcal etiology, is the most common glomerulonephritis found in children in developing countries ( Rodríguez-Iturbe & Mezzano, 2005) and in aboriginal populations ( Currie & Brewster, 2001). Two independent studies have estimated the incidence of APSGN in developing countries. Carapetis et al. ( Carapetis, Steer, Mulholland, & Weber, 2005) analyzed 11 population studies and found that the annual burden of APSGN in developing countries was 9.3 cases per 100,000 people. We evaluated the incidence of APSGN in developing countries, using the reports of pediatric acute renal failure due to glomerulonephritis ( Rodríguez-Iturbe & Musser, 2008). We assumed that the cases of acute glomerulonephritis were in fact APSGN, which was explicitly stated in most series, but not in all. These patients had severe renal failure because they were seen at a referral hospital and admitted to the intensive care unit, if one was available, and then dialyzed. The total number of cases in the general population was estimated, considering that uncomplicated cases of APSGN are 100 to 300 times more common than those of life-threatening disease. Using this approach, the annual incidence of APSGN in developing countries was estimated to be 9.5 (low estimate) to 28.5 (high estimate) cases per 100,000 people. This low value is remarkably close to the estimate of Carapetis et al. ( Carapetis, Steer, Mulholland, & Weber, 2005) and the higher value exceeds it by three-fold-yet, these authors acknowledged that theirs was likely an underestimation and that the actual incidence was probably a great deal higher.

Etiology and pathogenesis

APSGN is an immune complex-mediated disease. Several mechanisms may participate in the pathogenesis of renal damage ( Table 1). Nephritogenic immune complexes are formed in circulation and deposited in the glomeruli; alternately, the antigen and antibody arrive separately and meet in or outside the glomerular basement membrane, causing in situ immune complex disease. Immune cell recruitment, production of chemical mediators and cytokines, and local activation of the complement and coagulation cascades drive an inflammatory response that is localized in the glomeruli. Glomerular deposition of circulating immune complexes depends on the antigen load, the antigen:antibody ratio, and the size of the immune complexes ( Dixon, Feldman, & Vazquez, 1961; Germuth, Senterfit, & Dreesman, 1972). In situ formation of immune complexes is favored by cationic antigens that have a charge-dependent facilitated penetration into the polyanionic glomerular basement membrane, and tend to occur in conditions of antigen excess ( Vogt, et al., 1990).

Nephritogenic antigens

Traditionally, APSGN was considered to be caused by an antigen present in group A streptococci. Streptococcus pyogenes of M types 1, 2, 4, and 12 were associated with epidemic nephritis resulting from upper respiratory infections and M types 47, 49 and 55 were associated with epidemic nephritis following pyoderma. However, nephritis may also follow infections with group C streptococci since Str. zooepidemicus has been identified as the cause of an epidemic in Brazil ( Balter, et al., 2000) and several clusters of cases ( Nicholson, et al., 2000; Francis, Nimmo, Efstratiou, Galanis, & Nuttall, 1993); therefore nephritogenic antigen(s) are present in streptococci from several groups.

Throughout the years, many putative streptococcal nephritogenic antigens have been studied without definite confirmation of their causal relationship with glomerulonephritis ( Rodríguez-Iturbe & Batsford, 2007).

The nephritogenic potential of streptokinase was investigated by Nordstrand et al. ( Nordstrand, Norgren, Ferretti, & Holm, 1998) in mice with the experimental tissue cage model, and demonstrated glomerular streptokinase deposits in association with hypercellularity, complement deposition, and proteinuria. Subsequent studies by this group evaluated allelic variants of streptokinase using site-specific integration plasmids, and demonstrated the nephritogenic properties of the nephritis-associated streptokinase gene ska I( Nordstrand, McShan, Ferretti, Holm, & Norgren, 2000).

Presently, two streptococcal antigenic fractions with substantial claims to nephritogenicity are being actively investigated. These are the nephritis associated plasmin receptor (NAPlr), identified as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) ( Oda, et al., 2010; Yoshizawa, et al., 2004), and the streptococcal pyrogenic exotoxin (erythrotoxin) B (SPEB) and its zymogen precursor (zSPEB) ( Poon-King, Bannan, Viteri, Cu, & Zabriskie, 1993; Vogt, Batsford, Rodríguez-Iturbe, & García, 1983).

Work by Fujino et al. ( Fujino, et al., 2007) has shown that the expression and gene sequence of NAPlr is present in streptococci from several groups. Anti- NAPlr antibody levels are found in 92% of the sera from convalescent APSGN patients and in 60% of the uncomplicated streptococcal infections in Japan ( Yoshizawa, et al., 2004). NAPlr is present in early biopsies of APSGN and, since it is not co-localized with complement or IgG, its role as a nephritogen is thought to be related to its plasmin-binding capacity, which facilitates immune complex deposition and inflammation ( Oda, et al., 2010). The nephritogenic potential of plasmin-binding activity has been noted, not only in NALPr but also in SPEB, streptokinase, and enolase. Oda et al. (Personal communication, discussed in ( Rodríguez-Iturbe & Musser, 2008)) remarked that this property may represent a common nephritogenic property of both NALPr and SPEB, since both of these antigens were identified by their group in the mesangium of biopsies of APSGN. Along with this possibility, patients with APSGN exhibit an increase in urinary plasmin-like activity ( Oda, et al., 2010; Oda, et al., 2008).

SPEB, an extracellular cysteine proteinase, is a cationic (pK>8.0) antigen that is co-localized in the glomeruli with complement and Ig deposits, and is the only streptococcal antigen that has been demonstrated within the electron dense subepithelial deposits (humps) that are the hallmark of APSGN ( Batsford, Mezzano, Mihatsch, Schlitz, & Rodríguez-Iturbe, 2005). It is likely that this localization is facilitated by the cationic charge of this antigen, as earlier studies have postulated ( Vogt, et al., 1990; Vogt, Batsford, Rodríguez-Iturbe, & García, 1983). High anti-SPEB/zSPEB antibody titers have been found in the vast majority of convalescent sera sampled from patients in Latin America ( Parra, et al., 1998). SPEB/zSPEB induces chemotaxis and increases angiotensin II production by mesangial cells ( Romero, Mosquera, Novo, Fernandez, & Parra, 1999; Viera, Pedreanez, Rincon, & Mosquera, 2009). Recent studies have demonstrated that the Fc portion of antibodies directed to SPEB bind to the C-terminal domain (rSPEB 345-398), and that immunization with this domain prevents group A streptococcal infection in mice ( Tsao, et al., 2013). The attractiveness of a charge-related GBM penetration in the pathogenesis of APSGN ( Oite, Batsford, Mihatsch, Takamiya, & Vogt, 1982) has led Zhang et al. ( Zhang, Ignatowski, Spengler, Noble, & Stinson, 1999) to examine if histones that are cationic elements may be part of the pathogenesis of APSGN. Their studies showed that histones enter the circulation after streptococcal lysis and are capable of inducing in situ immune-complex formation.

Finally, recent evidence suggests that there is not a single nephritogenic antigen, since studies by Beres et al. ( Beres, et al., 2008) have shown that the gene that encodes for SPEB was absent in the Str. zooepidemicus isolated from patients in the Brazil epidemic, and therefore that this antigenic fraction was not involved in this epidemic. Notably, in studies of the Str. zooepidemicus of the Brazil epidemic, Nicholson et al. ( Nicholson, et al., 2000) found that 33 of 44 patients were seropositive for the Szp5058 fusion protein that was isolated from the causative streptococcal strain, and noted that the antiphagocytic properties of Szp proteins may play a role in the pathogenesis of glomerulonephritis.

Both NALPr and SPEB are capable of inducing monocyte chemoattractant protein 1 (MCP1) and IL-6 in mesangial cells ( Khan, et al., 2007; Pedreanez, Viera, Rincon, & Mosquera, 2006; Rincon, Viera, Romero, & Mosquera, 2003) and SPEB elicits the release of a variety of cytokines and interleukins from peripheral blood leucocytes ( Viera, Pedreanez, Rincon, & Mosquera, 2007).

Humoral and cellular immunity

Activation of the complement system is a consequence of the antigen/antibody reactivity found in glomeruli. The alternate pathway of complement activation is usually activated in APSGN and is manifested by a depression of C3 levels. However, some patients may also have a reduction in their levels of C1 and C4. In these patients, there may be a role for Protein H, a surface streptococcal protein that may activate the classic pathway of complement activation, in combination with IgG ( Berge, Kihlberg, Sjöholm, & Björck, 1997). In addition, in some patients, there may also be complement activation by the lectin pathway ( Ohsawa, et al., 1999); but APSGN may develop in individuals who are genetically unable to activate this pathway ( Skattum, Akesson, Truedsson, & Sjöholm, 2006).

In addition to humoral immunity, cellular immune mechanisms are also activated in APSGN. It has long been known that there is an overexpression of cellular adhesion molecules (ICAM-1, LFA-1) and infiltration of lymphocyte and macrophages in the glomeruli of these patients. ( Parra, Platt, Falk, Rodríguez-Iturbe, & Michael, 1984; Parra, Romero, Henriquez-La Roche, Pineda, & Rodríguez-Iturbe, 1994). Higher numbers of CD4-positive lymphocytes are present in renal biopsies obtained in the first 3-4 weeks of the disease and decrease afterwards ( Parra, Platt, Falk, Rodríguez-Iturbe, & Michael, 1984). Increased glomerular expression of IL-8 correlates with neutrophil infiltration and transforming growth factor-β with mesangial expansion ( Mezzano, Burgos, Olavarría, & Caorsi, 1997).

Autoimmune reactivity

High titers of anti-IgG rheumatoid factors have been reported in as many as two-thirds of the patients with APSGN in the first week of the disease ( Rodríguez-Iturbe, 1984), and anti-human IgG deposits within the glomeruli are present in 29% of the biopsies ( Rodríguez-Iturbe, 2008) and were eluted from the kidney of a fatal case of the disease ( Rodríguez-Iturbe, Rabideau, García, & McIntosh, 1980). This anti-IgG reactivity may be due to autoantigenic changes to IgG modified by neuraminidase (sialidase). Using methods that measure the release of acetyl neuraminic acid from substrates by a thiobarbituric acid assay, neuraminidase activity was found in group A and B streptococci and, more specifically, in streptococcal strains isolated from patients with nephritis ( Mosquera & Rodríguez-Iturbe, 1984). However, a more sensitive methylumbelliferyl acetyl neuraminidase fluorescence test failed to demonstrate neuraminidase activity in culture supernatants of a large number of Streptococcus pyogenes strains ( Savic & Ferretti, 1994). Neuraminidase activity and free sialic acid have been found in the plasma of patients with acute APSGN ( Asami, Tanaka, Gunji, & Sakai, 1985; Rodríguez-Iturbe, Katiyar, & Coello, 1981; Rodríguez-Iturbe, Rubio, & García, 1981). The existence of sialic acid depleted glomerular structures was investigated through the glomerular binding capacity of the lectin Arachis Hypogaea (peanut agglutinin), a lectin with a highly specific affinity for galactopyranosyl galactosamine radicals that are exposed after sialic acid removal. Positive intraglomerular staining with this FITC-lectin was detected in the majority of early APSGN biopsies. ( Mosquera & Rodríguez-Iturbe, 1986). Neuraminidase may have the additional effect of facilitating the infiltration of desialized leucocytes in the glomeruli ( Marín, Mosquera, & Rodríguez-Iturbe, 1995). The simultaneous presentation of APSGN and thrombotic microangiopathy was considered to be the result of streptococcal neuraminidase ( Duvic, Desramé, Hérody, & Nédélec, 2000).

Another possible mechanism for the production of anti-Ig is the binding of the Fc fragment of IgG to type II receptors on the surface of group A streptococcus. This binding induces intense anti-IgG reactivity and glomerulonephritis with anti-IgG deposits, which may have nephritogenic potential ( Burova, et al., 2012; Burova, et al., 1998).

Other autoimmune phenomena that have been reported in patients with APSGN include anti-DNA antibodies, anti-C1q antibodies ( Kozyro, et al., 2006), and antineutrophil-cytoplasmic autoantibodies (ANCAs). ANCAs have been found in two-thirds of the patients with azotemia, and in 70% of the patients with crescentic APSGN and a rapidly progressive course ( Ardiles, Valderrama, Moya, & Mezzano, 1997). Despite the variety of findings of autoimmune reactivity, the clinical relevance of these phenomena remains undefined in APSGN.

Genetic aspects

The familial incidence of APSGN was noted in one of the earliest descriptions of the disease. In 1812, Wells ( Wells, 1812) noted that "when one child of a family has been attacked with this disease, the other children of the same family who passed through scarlet fever are more liable to become dropsical, than the children of another family, who had also labored under that fever but among whom no instance of dropsy has occurred," and attributed this predisposition to "similarity of constitution derived from common parents." Subsequent studies have shown that the attack rate of APSGN in the general population in epidemic situations ranges between 5% and 28%, while the development of APSGN (clinical and subclinical) in siblings of index cases in non-epidemic conditions is 38% ( Rodríguez-Iturbe, Katiyar, & Coello, 1981). Studies by Layrisse et al. ( Layrisse, Rodríguez-Iturbe, García-Ramírez, Rodríguez, & Tiwari, 1983) suggested that DR4 HLA antigens were more common in unrelated patients with APSGN, and investigations in Japan ( Naito, Kohara, & Arakawa, 1987) reported association between DR1 antigens and APSGN. Nevertheless, the genetic characteristics that are responsible for predisposition (or resistance) to the disease have not been identified.

Clinical and serological characteristics

As previously indicated, APSGN in developed countries is now a disease of patients with chronic debilitating diseases. The clinical characteristics and the prognosis in these patients are different from the milder clinical course in children. In children with APSGN massive proteinuria and cardiovascular complications are rare and early mortality exceptional. In elderly individuals with APSGN, proteinuria in the nephrotic range occurs in 20% of the patients, congestive heart failure in 43%, and azotemia in 83% ( Melby, Musick, Luger, & Khanna, 1987).

The classic patient with APSGN is a child (the male:female ratio is 2:1) between the ages of 2 and 18. The latent period between upper respiratory infection and nephritis is 7-10 days and 2-4 weeks in cases that follow skin infection. The typical clinical presentation is of acute nephritic syndrome (hematuria, edema, hypertension, and oliguria); in a minority of cases, APSGN may be manifested by nephrotic syndrome; and in rare cases, by a rapidly progressive (crescentic glomerulonephritis) clinical course. In a typical case of post-streptococcal nephritis, improvement is observed after 2-7 days when the urine volume increases, followed rapidly by resolution of edema and return of the blood pressure to normal levels. Asymptomatic disease may be manifested by microscopic hematuria and a fall in serum complement levels, and is 4-5 times more common than clinical disease in non-epidemic conditions ( Rodríguez-Iturbe, Katiyar, & Coello, 1981; Dodge, Spargo, & Travis, 1967).

The most consistent serological finding in the acute period is a reduction in serum complement levels, which return to normal levels in less than a month. In the first week of the disease, high rheumatoid factor titers and cryoglobulins may be found in as many as two-thirds of the patients ( Rodríguez-Iturbe, 1984). The best markers for nephritogenic streptococcal infection are serum antibody levels to NALPr ( Yamakami, et al., 2000) or SPEB/zSPEB ( Parra, et al., 1998), but these determinations are not generally available. Since positive cultures are not always obtained, antistreptococcal antibody titers are usually used to demonstrate the existence of an antecedent streptococcal infection. Antistreptolysin O titers and anti-DNase B titers are the most frequently elevated in upper respiratory infections and pyodermitis, respectively. A streptozyme test that includes 4 major antigens (DNase B, Streptolysin O, hyaluronidase and streptokinase) is reported to be positive in more than 80% of the cases ( Rodríguez-Iturbe, 1984).

Renal biopsy is seldom performed in uncomplicated cases of APSGN in children with a typical clinical picture, particularly in epidemic situations. Biopsy is usually done in adult patients or when unusual features raise diagnostic doubts. These features generally include a normal serum complement early in the disease, or a persisting low complement more than one month after the onset of the acute nephritic syndrome. Clinical presentations with proteinuria in the nephrotic range or developing rapidly progressive renal failure are rare enough in APSGN that histopathological confirmation of the diagnosis is essential.

Pathology of Acute Post-Streptococcal Glomerulonephritis

Light microscopic findings

The majority of cases (including 72% in a recently published series of adult patients ( Nasr, et al., 2008)) show diffuse proliferative and exudative glomerulonephritis (GN). The glomeruli in these cases are often enlarged and show global endocapillary hypercellularity with variable and often large numbers of neutrophils, as shown in Figures 1 and 2. Most of the remaining cases show focal proliferative and exudative GN, or predominantly mesangial proliferative GN, while a membranoproliferative GN (MPGN) pattern is rarely seen ( Montseny, Meyrier, Kleinknecht, & Callard, 1995; Nasr, et al., 2008; Rosenberg, et al., 1985; Silva, 2005). When a Masson's trichrome stain is performed, fuschinophilic, red-orange subepithelial, and mesangial deposits may be evident. Crescents, primarily segmental cellular crescents, are present in up to half of cases, and may be accompanied by segmental fibrinoid necrosis with disruption of the glomerular basement membrane (GBM) that is evident on a silver methenamine stain ( Nasr, et al., 2008; Montseny, Meyrier, Kleinknecht, & Callard, 1995).

After the first 1-2 weeks of the disease, there is a progressive decline in cellularity, initially from the loss of the neutrophils, which results in a combined mesangial and endocapillary proliferative GN. At this stage, the histologic appearance of the glomeruli may resemble that of an early MPGN. Over the ensuing weeks, endocapillary hypercellularity is lost, resulting in a predominantly mesangial proliferative GN that is visible by light microscopy.

In the acute phase of the disease, interstitial inflammation, which is typically comprised of a mixture of lymphocytes, monocytes, plasma cells, and neutrophils, is present in most cases. Focal intratubular neutrophils are not infrequent, with these cells coming from the inflamed glomeruli. In the study by Nasr et al. ( Nasr, et al., 2008), histologic evidence of acute tubular injury, characterized by the flattening of proximal tubular epithelium with loss of brush borders and nuclear enlargement, was seen in 60% of cases. Mild to moderate arteriosclerosis was also seen in the majority of these adult cases; cases with underlying diabetic nephropathy tended to have more frequent and more severe arteriosclerosis, as well as arteriolar hyalinization and thickening ( Nasr, et al., 2008).

Immunofluorescence Microscopy

Immunofluorescence findings in evolving stages of post-streptococcal GN have been elegantly defined by Sorger et al. ( Sorger, et al., 1982). In the early phase of the disease (the initial 2-3 weeks), the glomeruli show finely granular deposits of C3 and usually IgG in the capillary walls and mesangial areas, in what has been termed a "starry sky" pattern (as shown in Figure 3. Later in the disease, with resorption of many of the capillary wall deposits, there is a predominantly mesangial pattern of staining with a predominance of C3. In reality, not all of the deposits that contribute to the mesangial pattern are actually within the mesangium; as discussed below, many are subepithelial deposits within the mesangial "waist" that are resorbed more slowly than deposits in peripheral portions of the glomerular capillaries. A third pattern of staining, characterized by coarse granular to confluent granular staining along the glomerular capillary walls and termed the "garland" pattern, is most often seen early in the disease, but may be seen later as well ( Sorger, et al., 1982). It is this pattern that best shows the individual subepithelial "humps" that are the characteristic ultrastructural feature of this disease.

In acute (and subacute) post-streptococcal GN, deposits of C3 are invariably present, accompanied by IgG in most cases, and by IgM in approximately 50%, although the latter staining tends to be of low intensity ( Nasr, et al., 2008; Silva, 2005). IgA staining is uncommon and of low intensity when present, although IgA is often the dominant immunoglobulin present in post-staphylococcal GN ( Nasr, et al., 2008; Haas, Racusen, & Bagnasco, 2008; Nasr, et al., 2003). Nasr et al. ( Nasr, et al., 2008) found C1q staining, typically of low intensity, in approximately one-third of their cases. Staining for kappa and lambda light chains mirrors that for IgG, with respect to patterns that have similar staining intensity for both light chains. Focal and segmental blotchy to amorphous staining for fibrinogen, most typically at the periphery of glomerular tufts, is frequently noted within cellular crescents when these are present.

Electron Microscopy

The characteristic ultrastructural finding of acute poststreptococcal GN is the presence of large subepithelial electron-dense deposits with a "hump-like" appearance, as shown in Figure 4. The number of these deposits varies considerably between different cases; they can be quite segmental or rather numerous, although not so much so as to suggest a membranous nephropathy. The size of the subepithelial "humps" may also vary considerably within any given glomerulus. In early post-infectious lesions, these deposits are distributed at various points along glomerular capillaries, although even at this stage, there is some tendency for the greatest number of deposits to be concentrated at or near the glomerular basement membrane reflection over mesangial areas (the mesangial "waist" or "notch," which can be seen in Figure 5), a finding first noted by Heptinstall ( Heptinstall, 1974). In subacute and resolving cases, the fraction of subepithelial deposits localized to mesangial "waist" areas increases as more peripheral deposits are resorbed ( Nasr, et al., 2008; Sorger, et al., 1982; Haas, 2003). Mesangial deposits are present in the great majority of cases of acute poststreptococcal GN and may be abundant, and show subendothelial deposits in most cases, although these tend to be small and segmental ( Nasr, et al., 2008; Silva, 2005). Extraglomerular deposits are not a feature of this disease.

Treatment

If infection is present at the time of diagnosis, it should be treated. In epidemic situations and in high-risk communities, the administration of preventive antibiotic treatment to household members of index cases has been shown to decrease the number of cases of APSGN ( Johnston, Carapetis, Patel, Wallace, & Spillane, 1999).

Patients with an acute nephritic syndrome require restriction of sodium and fluid intake. For more than three decades, loop diuretics have been known to accelerate the resolution of edema and improve hypertension ( Powell, McCredie, & Rotenberg, 1980). Thiazide diuretics are ineffective and aldosterone antagonists carry the risk of hyperkalemia. In cases with severe hypertension, nifedipine may be useful. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers carry the risk of hyperkalemia. Nitroprusside may be needed to treat hypertensive encephalopathy, but only in exceptional cases. Pulmonary edema may complicate the clinical course and should be treated with oxygen, loop diuretics, and rotating tourniquets. Digitalis is ineffective and carries an increased risk of intoxication. Rare complications in APSGN include posterior reversible leukoencephalopathy ( Ahn & Ingulli, 2008) and immune-mediated pneumonitis ( Wiles, et al., 2011). Hemodialysis and peritoneal dialysis may also be required to treat azotemia, hyperkalemia, or severe circulatory congestion.

Crescentic APSGN with a rapidly progressive clinical course has improved in isolated reports in association with the treatment with intravenous pulses of methylprednisolone; however, the real benefit of intravenous steroids, immunosuppression, or anticoagulation remains unproven ( Zaffanello, Cataldi, Franchini, & Fanos, 2010).

Prognosis

The short-term prognosis of APSGN in children is excellent; but in adults, and particularly in debilitated adults, the mortality rate can be as high as 30%, as a consequence of a cardiovascular complication ( Melby, Musick, Luger, & Khanna, 1987).

The long-term prognosis, as related to the development of chronic kidney disease, is also different in children and in adults. In a recent study of a specific outbreak of PSGN that resulted from the consumption of cheese contaminated with Streptococcus zooepidemicus and that affected mostly adults, there was an alarming incidence of chronic renal disease: impaired renal function was found in 30% of the patients after 2 years of follow-up (10% of them in chronic dialysis therapy) ( Pinto, Sesso, Vasconcelos, Watanabe, & Pansute, 2001). In a particular subgroup of adult patients with APSGN that had massive proteinuria as the initial manifestation of the disease, the long-term prognosis was especially severe, with an incidence of chronic renal failure as high as 77% ( Vogl, Renke, Mayer-Eichberger, Schmitt, & Bohle, 1986). The worse prognosis in adults has been attributed to age-related impairment of the Fc-receptor function of the mononuclear phagocyte system ( Mezzano, et al., 1991). Deficiency of the complement factor H-related protein 5 has also been proposed as a factor that may result in a predisposition to the development of chronic renal disease ( Vernon, et al., 2012).

Regarding the long-term prognosis of APSGN in children, initial reports in 1930 and 1940 indicated an excellent prognosis, but follow-up periods were relatively short. Subsequent studies have produced widely contrasting results, with the incidence of abnormal laboratory findings ranging from 3.5% ( Potter, Lipschultz, Abidh, Poon-King, & Earle, 1982) to 60% ( Baldwin, Gluck, Schacht, & Gallo, 1974). Discrepancies may partially result from the different prognosis of PSGN in adults and in children, which is not always taken into account in the reported series. Studies by Gallo et al. ( Gallo, et al., 1980) in the 1980s reported that the incidence of glomerular sclerosis and fibrosis is nearly 50%, but the clinical relevance of these histological characteristics is uncertain. A revision of the follow-up studies in children 10-20 years after the acute episodes found that while approximately 20% of the patients had an abnormal urinalysis or creatinine clearance, less than 1% had developed end-stage kidney disease. Our own data ( Rodríguez-Iturbe & Musser, 2008), which includes 110 children with epidemic and sporadic PSGN followed prospectively over 15-18 years after the acute episode, indicate an incidence of 7.2% of proteinuria, 5.4% of microhematuria, 3.0% of arterial hypertension, and 0.9% of azotemia. These values are essentially similar to those found in the general population. We have also followed 10 cases of subclinical PSGN for 10-11 years, and the prognosis is excellent. In specific communities, such as in Australian aboriginal groups, it has been found that patients who had APSGN have an increased risk for albuminuria (adjusted odds ratio (OR) of 6.1, 95% confidence interval (CI) of 2.2-16.9) and hematuria (OR of 3.7, 95% CI of 1.8-8.0) in relation to controls who did not have APSGN ( Hoy, et al., 1998). Finally, the long-term prognosis of APSGN may be influenced by the coexistence of other risk factors of chronic renal failure. In patients with a history of APSGN, the association (two-hit) with both diabetes and metabolic syndrome are likely responsible for the high incidence of endstage renal disease in aboriginal communities in Northern Australia ( White, Hoy, & McCredie, 2001; Hoy, et al., 2012). It has been reported that persisting arterial stiffness, as determined by brachial-ankle pulse wave velocity, is found in patients with APSGN who develop chronic renal disease ( Yu, Yu, Yu, Lee, & Huang, 2011).

References

Dochez A. R., Sherman L. The significance of Streptococcus hemolyticus in scarlet fever and the preparation of a specific antiscarlatinal serum by immunization of the horse to Streptococcus hemolyticus scarlatinae. JAMA: The Journal of the American Medical Association. 1924;82(7):524-544.

Heptinstall, R. H. (1974). Pathology of the Kidney, 2nd Edition. Boston: Little, Brown.

Nordstrand, A., McShan, W. M., Ferretti, J. J., Holm, S. E., & Norgren, M. (2000). Allele substitution of the streptokinase gene reduces the nephritogenic capacity of group A streptococcal strain NZ131. (V. A. Fischetti, Ed.) Infection and Immunity, 68(3), 1019-1025. [ PMC free article: PMC97243 ] [ PubMed: 10678902 ]

Rodríguez-Iturbe, B. (2008). Acute endocapillary glomerulonephritis. In A. Davison, J. S. Cameron, J. P. Grünfeld, C. Ponticelli, E. Ritz, C. G. Winearls, et al. (Eds.), Oxford Textbook of Clinical Nephrology (pp. 611-623). Oxford: Oxford University Press.

Rodríguez-Iturbe, B., & Mezzano, S. (2005). Infections and kidney diseases: a continuing global challenge. In M. El Nahas, R. Barsoum, J. H. Dirks, & G. Remuzzi (Eds.), Kidney Diseases in the Developing World and Ethnic Minorities (pp. 59-82). Boca Raton: CRC Press.

Savic D. J., Ferretti J. J. Group A streptococci do not produce neuraminidase (sialidase). Medical Microbiology Letters. 1994;3:358-362.

Seegal D., Earle D. P. A consideration of certain biological differences between glomerulonephritis and rheumatic fever. The American Journal of the Medical Sciences. 1941;201(4):528-539.

Silva, F. G. (2005). Non-Neoplastic Kidney Diseases. Annapolis Junction: American Registry of Pathology.

von Pirquet C. Allergy. Archives of Internal Medicine. 1911;7:259-288, 382-436.

Wells, C. (1812). Observations on the dropsy which succeeds scarlet fever. In Transactions Of A Society For The Improvement Of Medical And Chirurgical Knowledge, Volume 3 (pp. 167-186). Ghent: Ghent University.

# data[].attributes.attachment_link.description
Acute glomerulonephritis that results from streptococcal infections is the best-studied immune complex-mediated glomerulonephritis. Initially described in the convalescence of scarlet fever, the incidence of acute post streptococcal glomerulonephritis (APSGN) has decreased worldwide, particularly in developed countries where it is now rare and is limited to adult patients who have debilitating conditions.

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https://acrobat.adobe.com/id/urn:aaid:sc:VA6C2:bd74be42-34e4-460d-a089-516d7ba47f98

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Post-streptococcal glomerulonephritis treatment consists of Beta-lactams antimicrobials. Some of the most commonly used types of B-lactams used by providers is Penicillin G Benzathine. Another medication used for treatment is erythromycin if the patient were to have a penicillin allergy. Apart from eradicating the microbe from the body, treatment plans include lessening physical symptoms. For example, it is a priority to control edema and blood pressure. Edema is managed by a diet with minimal amounts of salt and water intake; Blood pressure is controlled by use of diuretics which will increase urinary output. For patients experiencing more severe symptoms they may need dialysis, to limit physical exertion, and other medications like steroids, immunosuppressive agents, and plasmapheresis (Geetha M.D., 2021).

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Risk factors for PSGN is similar to group A strep pharyngitis or skin infection. PSGN is commonly seen in children, although it can occur in adults as well. Pharyngitis-associated PSGN is more commonly seen among children of early school age. Pyoderma-associated PSGN is most commonly seen among children of pre-school age. There is no known risk factors specifically related to PSGN. Yet, the risk of PSGN is increased if a nephritogenic strain of group A strep is introduced into a household. Patients are at increased risk of PSGN after having a strep throat, scarlet fever, or impetigo.

Centers for Disease Control and Prevention. (2022, June 27). Post-streptococcal glomerulonephritis: https://www.cdc.gov/groupastrep/diseases-hcp/post-streptococcal.html#:~:text=There%20are%20no%20known%20risk,is%20introduced%20into%20a%20household.

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PSGN conforms to the type III hypersensitivity reactions based upon the activation of the complement system. This is caused by the antigen/antibody reactivity found in the glomeruli located within the kidneys. The inflammatory response is a result of this activation.

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Type III hypersensitivity (immune complex mediated) - causes, symptoms & pathology

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Hematuria

Edema, especially around the face and hands and feet

Decreased need to urinate

Oliguria (decreased urine output)

Fatigue

Anemia

Proteinuria

CV: dyspnea, tachypnea, enlarged tender liver, hypertension (which can lead to headaches, vomiting, somnolence, and other CNS manifestations)

https://www.cdc.gov/groupastrep/diseases-public/post-streptococcal.html

https://pageburstls.elsevier.com/reader/books/9780323789905/epubcfi/6/140%5B%3Bvnd.vst.idref%3DCh039_1271-1283_B9780323789875000422%5D!/4/2%5Bc0039%5D/18/8/8/4%5BTABC000422t0010%5D/6/6/4/4/2%5Bu0045%5D/3:7%5Besi%2Con%5D

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Doris Anton
Mary Affrunti
Ellen Scola
Amber Camp
Ayan Omar
Karina Fernandez

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PSGN affects the kidneys, but it is not a strep infection of the kidneys. The body’s natural immune system can cause it after fighting strep throat, scarlet fever, or impetigo. The accumulation of antibodies containing streptococcal antigen immune complexes occurs within the kidney glomeruli. This causes the kidneys to become inflamed and makes them less capable of filtering urine. This can cause urinary retention which can swell the kidneys and increases sodium retention. This can be treated through the use of a diuretic medication.
https://www.mayoclinic.org/diseases-conditions/glomerulonephritis/symptoms-causes/syc-20355705