Causes and pathogenesis of acute poststreptococcal glomerulonephritis

Acute poststreptococcal glomerulonephritis was first described by Shick in 1907. He noted a latent period between scarlet fever and the development of glomerulonephritis and suggested a common pathogenesis of nephritis after scarlet fever and experimental serum sickness. After the streptococcal cause of scarlet fever was identified, the subsequent nephritis was considered an "allergic" reaction to the introduction of bacteria. Although nephritogenic streptococci have been identified and characterized, the sequence of reactions leading to the formation of immune deposits and inflammation in the renal glomeruli has not yet been fully elucidated. The attention of many researchers has been focused on the characterization of these nephritogenic streptococci and their products, resulting in three main theories of the pathogenesis of acute poststreptococcal glomerulonephritis.

First, nephritogenic streptococci produce proteins, endostreptosins, with unique antigenic determinants that have a strong affinity for the structures of normal renal glomeruli. Once in circulation, they bind to these areas of the glomeruli and become “implanted” antigens that can directly activate complement and to which antistreptococcal antibodies bind, forming immune complexes.

The second hypothesis suggests that normal IgG molecules may be damaged by neuraminidase secreted by streptococci, causing them to become immunogenic and be deposited in intact glomeruli. These cationic IgGs, lacking sialic acids, become "implanted" antigens and, by binding to anti-IgG-AT (which is a rheumatoid factor), form immune complexes. Recently, the possibility of antigenic mimicry between nephritogenic streptococci and antigens of normal renal glomeruli has been discussed. This hypothesis suggests the production of antistreptococcal antibodies that cross-react with antigenic determinants normally located within the glomerular basement membranes. It is believed that these may be antibodies to M proteins, since these proteins distinguish nephritogenic forms of streptococci from non-nephritogenic ones.

In patients with acute poststreptococcal glomerulonephritis, antibodies reacting with membrane antigens of M-type 12 streptococcus were detected, and since these antibodies were absent in patients with streptococcal pharyngitis without nephritis, they were considered responsible for the development of glomerulonephritis. Nephritogenic properties are also assumed for the surface proteins of M-type 6 streptococcus, which selectively bind to proteoglycan-rich areas of the glomerular basement membrane. An antigen with MB 40-50 thousand Da and pi 4.7, called endostreptosin or water-soluble preabsorbing antigen (due to its ability to absorb antibodies from the serum of convalescents), was isolated from nephritogenic streptococci. Elevated titers of antibodies to this antigen were found in 70% of patients with acute poststreptococcal glomerulonephritis.

Finally, a cationic streptococcal protease was isolated that shared epitopes with the human glomerular basement membrane and was found to be streptococcal pyrogenic (erythrogenic) endotoxin D. Cationic antigens are most likely nephritogens, since they easily penetrate the negatively charged filtration barrier and are localized in the subepithelial space. An antibody response to cationic streptococcal protease (most often directed to its precursor, zymogen, with an MB of 44,000 Da and pi of 8.3) was detected in 83% of patients with acute poststreptococcal glomerulonephritis and is a much better marker of the disease than antibodies to DNAse B, hyaluronidase, or streptokinase.

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Morphological changes in acute poststreptococcal glomerulonephritis

In cases where the diagnosis remains unclear, a renal biopsy is performed to clarify the cause of acute poststreptococcal glomerulonephritis. In patients with nephrotic levels of proteinuria, mesangiocapillary glomerulonephritis is more often detected in a renal biopsy than acute poststreptococcal glomerulonephritis. Early differentiation between these two diseases is essential, since a completely different therapeutic approach is used for mesangiocapillary glomerulonephritis, especially in children - "aggressive" immunosuppressive therapy.

Morphological picture of acute diffuse proliferative poststreptococcal glomerulonephritis

Inflammation	Proliferation	Immune deposits
At the onset of the disease, the glomeruli are infiltrated by polymorphonuclear neutrophils, eosinophils, and macrophages (“exudation phase”). At the height of the disease, macrophages	Intraglomerular: common Half moons: more often focal, less often widespread	IgG, C3, properdin, diffuse granular deposition type (starry sky at early stages; garlands at later stages), subepithelial humps, subendothelial and mesangial deposits

The most typical changes are observed in the biopsy material performed at the very beginning of the disease: hypercellularity of the glomeruli with varying degrees of infiltration of the capillary loops and mesangial region by polynuclear leukocytes, monocytes and eosinophils. In cases of predominant proliferation of mesangial and endothelial cells, the term "proliferative nephritis" is used. In cases where infiltration by polynuclear leukocytes predominates, the term "exudative glomerulonephritis" is used. With pronounced proliferation of the parietal epithelium and accumulation of monocytes in the extracapillary space, extracapillary glomerulonephritis (glomerulonephritis with "crescents") is diagnosed. In this case, focal and segmental crescents are usually observed; Diffuse extracapillary glomerulonephritis with crescent formation in more than 50% of glomeruli is rare and portends a poor prognosis.