Saudi Journal of Kidney Diseases and Transplantation

: 1994  |  Volume : 5  |  Issue : 3  |  Page : 365--370

Etiopathogenesis of acute poststreptococcal glomerulonephritis

Maha A Azzam, Tej K Mattoo 
 Department of Pediatrics, King Fahad National Guard Hospital, Riyadh, Saudi Arabia

Correspondence Address:
Maha A Azzam
Department of Pediatrics, King Fahad National Guard Hospital, P.O. Box 22490, Riyadh 11426
Saudi Arabia


The relationship between nephritogenic strains of group A beta-hemolytic streptococci (GABS) and acute poststreptococcal glomerulonephritis (APSGN) is well established. Recent studies have cast some doubts on the importance of the M-antigen which is widely used in classifying the nephritogenic strains of GABS. The renal injury occurs as a result of an immune-mediated process which involves the complement system. This leads to deposition of circulating immune complexes and/or their in-situ formation in the kidney resulting in renal damage. Newer antigenic fractions have been identified in GABS, which include; endostreptocin (ESS), nephritis strain associated protein (NSAP), and pre-absorbing antigen (Pa-Ag). These developments have allowed a better insight into the pathogenesis of APSGN.

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Azzam MA, Mattoo TK. Etiopathogenesis of acute poststreptococcal glomerulonephritis.Saudi J Kidney Dis Transpl 1994;5:365-370

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In 1836, Richard Bright [1] observed that scarlet fever was sometimes followed by kidney disease and in 1907, Schick [2] noted the existence of an interval between infection and the onset of the renal disease. It was not until 1929 that the relationship between group A streptococcal infection and acute glomerulonephritis was reported by Longcope [3] . In 1953, Rammelkamp et al. [4] demonstrated a correlation between certain types of group A streptococci and glomerulonephritis. Many years on, the role of this organism in causing acute poststreptococcal glomerulonephritis (APSGN) is undisputed, but the exact pathogenic mechanism of the renal disease remains elusive.


Streptococci are gram positive bacteria which are serologically divided into groups A to H and K to V. Group A streptococci, also called Streptococcus pyogenes, like other streptococci are subdivided on the basis of the type of hemolysis produced on the agar plate. The ones that produce a clear zone of hemolysis around the colony are called beta hemolytic streptococci. Acute glomerulonephritis follows infection with certain strains of group A beta-hemolytic streptococci (GABS) though group C and G have also been implicated [5],[6],[7] .

Relevant protein fractions of the bacteria which determine the typing and infectivity of GABS are labeled as M, T and R proteins . Of these, the M protein fraction has long been considered as the nephritogenic antigen. It is located in the external aspect of the bacterial cell wall [8] and the M types commonly identified in patients with APSGN include 1, 2, 4, 12,18, 25, 49, 55, 57 and 60. Acute poststreptococcal glomerulonephritis follows throat infection with types 12, 4, 1, 3, 25, 49 and skin infection with types 49, 55, 2, 57, 60 [9],[10],[11] . Recent studies however, have cast some doubts on the nephritogenic importance of the M antigen. These include an ever-increasing number of nephritogenic M-types and yet a relative resistance to the recurrence of APSGN as well as the attachment of IgG from convalescent patients to free antigenic sites in early renal biopsies from patients with APSGN irrespective of the M-type of the original infection [12] .


The precise mechanism by which nephritogenic streptococci induce renal injury is not fully understood. An immunemediated humoral mechanism is strongly indicated by the renal deposition of immunoglobulins and complement, presence of discrete electron-dense deposits in the sub-epithelial space, low serum complement levels in the acute phase, and high serum levels of antibodies to streptococcal antigens [11],[13] . Other possibilities which may have a role in the pathogenesis of APSGN include a direct toxic effect of streptococcal antigens on the glomerulus [10] and an abnormal cellular reactivity to altered glomerular basement membrane [14] .

Activation of complement system is at the core of immune-mediated renal damage in APSGN. This is reflected by a decrease in the serum complement levels in about 90% of these patients [11] . Complement is synthesized mostly by macrophages and hepatocytes and of all the complement components the most biologically active ones are C3 and the terminal complements (C5-C9). In order to function they must first be activated by either the classical or the alternate pathways. In the classical pathway an antigen-antibody complex is required to activate the first component (Cl) and this starts the cascade of complement activation through C2 and C4. The alternate pathway is not antibody dependent and by-passes the need for Cl, C4 and C2. It may be activated by lipid A component of bacterial endotoxins, C3 nephritic factor, cryoglobulins and cobra venom. C3 nephritic factor is an auto-antibody which stabilizes C3b Bb by binding to a determinant involving both parts of the complex. Both the activated pathways lead to cleavage of C3 which is a trigger for the amplification and activation of terminal complement components which mediate a number of inflammatory reactions resulting in target organ damage [15],[16] .

The reduction of early complement components such as Clq, C2, and C4 indicates a classic pathway activation. In APSGN the decrease in serum levels of Clq, C2 and C4 is much less than C3 as against a more frequent decrease in properd in Which favors the alternate pathway as the more commonly used channel [17],[18],[19] However, it has recently been shown that the classical pathway may also be involved in some patients [20] . The complement levels decrease early in the disease and return to normal levels in about eight weeks time. Serial measurements of serum C3 concentration therefore, provide a very useful monitor for the follow-up of APSGN [11] .

Though the role of complement in the pathogenesis of APSGN is established, it is not clear whether immune-mediated renal injury is a result of renal deposition of circulating immune complexes or due to their in-situ formation or both. The following are some arguments put forward in favor of and against these two possibilities.

(a) Deposition of circulating immune Complexes

It is widely believed that APSGN occurs as a result of production of soluble immune complexes which are deposited in the Kidney.

This is supported by;

(i) The appearance and disappearance of immune complexes with the onset and resolution of the disease

(ii) Indirect evidence derived from splenic deposition of IgG and C3 in some patients

(iii) The presence of cryoglobulins and increased levels of neuraminidase in the serum of some patients with APSGN [20] .

Cryoglobulins contain antibodies to the altered forms of autologous IgG [21], [22] . Neuraminidase reacts with sialic acid-rich Sites on the autologous immunoglobulins, glomerular capillary epithelium and endothelial cells. Depletion of sialic acid alters the immune response which results in the formation of anti-immunoglobulin "rheumatoid factor" and probably, antibodies against glomerular antigens [23],[24] . Group a streptococcal M-types associated with nephritis are usually neuraminidase producers [25] . Anti-globulin activity is also supported by the demonstration of anti-globulins in the sera of patients with APSGN [26] , glomerular fixation of anti-globulins in renal biopsies - [22] , and anti-IgG reactivity in a patient who died of acute APSGN [27] . Neuraminidase producing streptococci, however, are not unique to patients with APSGN and rheumatoid factor activity has been noted in patients with streptococcal infection without glomerulonephritis as well [28] .

Certain observations raise doubts about the deposition of circulating immune complexes as being the sole mechanism for renal injury in APSGN [29],[30],[31] . These include;

(i) Inconsistent presence of immune complexes in patients

(ii) Absence of renal involvement in some patients who have streptococcal infection and high levels of circulating immune Complexes

(iii) The finding that early components of the classical pathway Clq and C4 that are involved in immune complex formation are rarely seen in glomerular deposits

(iv) The occurrence of complement activation in the initial phase of APSGN through the alternate pathway and not via the classical pathway as expected in immune complex disease.

(b) In-situ formation of immune complexes

Studies on complement metabolism in APSGN suggest that the deposition of streptococcal antigen in the kidney precedes the fixation of antibody and complement [31],[32] . Similarly, sera from patients with APSGN contain antibodies which are directed against heparan sulfate proteoglycans of the glomerular basement membrane (GBM). These antibodies are probably formed as a result of the release of glomerular antigens following tissue injury [33],[34] . These observations favor the hypothesis that the immune complexes are formed in-situ.

 Streptococcal antigenic fractions

Three antigenic fractions produced by the majority of nephritogenic streptococci associated with APSGN are currently under considerable scrutiny as possible etiological factors in the pathogenesis of APSGN. These include endostreptocin (ESS), nephritis strain associated protein (NSAP), and preabsorbing antigen (Pa-Ag). The antibodies produced against these antigens bind to the renal biopsy material [35] . The three antigens though not identical, are very similar to each other.

Endostreptocin (ESS)

First described by Lange et al [36],[37],[38] , ESS is a cytoplasmic protein antigen from group A streptococci and has a molecular weight of 40,000 to 50,000 daltons. It appears in the glomerular basement membrane within days of onset of APSGN and disappears soon after, possibly coinciding with the appearance of ESS antibody. This antibody is known to appear in all patients with APSGN, but is seen in 10-74% of normal individuals as well [21] , though the titers are higher in patients with APSGN [36] . It has an anionic charge and deposits sub-endothelially where it acts as a planted antigen resulting in an in-situ immune complex formation. These immune complexes later migrate into the subepithelial space [36],[37] . The inability to identify ESS in the sub-epithelial humps, however, undermines this hypothesis [39] . Nephritisstrain associated protein (NSAP)

This extracellular protein was first identified by Villareal et al [35] in type 12 group A nephritogenic streptococci. Subsequently, Johnston and Zabriskie [40] identified its first 21 amino acids. It has a molecular weight of 46,000 daltons and its chemical structure and biochemical properties are believed to be similar to streptokinase from group A, C and G streptococci [40] .

Nephritis-strain associated protein, like streptokinase, activates plasminogen and the plasmin thus formed, splits the C3 molecule via the alternate pathway. C3b is deposited in the glomeruli and an in-situ formation of immune complexes results in the release of lysozymes and glomerular injury. Furthermore, glomerular antigens released in the circulation produce autoantibodies resulting in more renal damage [13] . Recently it has been shown that a major variable region VI exists in the middle of the streptokinase molecule. It is hypothesized that they are the domains with which streptokinases from nephritogenic strains bind to glomerular structures and activate plasminogen in-situ, thus triggering the proteolytic process leading to APSGN [41] .

Deposition of fibrin breakdown products and cellular proliferation as seen in APSGN could be attributed to NSAP and plasminogen interaction. Studies on fresh human kidneys, unsuitable for transplantation have revealed NSAP binding to normal human glomeruli without prior interaction with the specific antibody [32] . The role of NSAP as a nephritogenic antigen is also supported by the following;

(i) Evidence of plasma fibrinolytic hyperactivity with a simultaneous decrease in serum plasminogen level in the early stages of APSGN [42]

(ii) Prevention of NSAP release with early administration of penicillin in experimental animals [43]

(iii) Experimental induction of lesions similar to APSGN with the administration of purified NSAP in rabbits or mice [32],[44] (iv) presence of NSAP antibodies in 95% of the patients with APSGN and its infrequent presence in those with streptococcal infection without renal involvement [10],[21],[45],[46] .

Holm et al [10] have reported that NSAP introduced into rabbit results in renal lesions similar to those with nephritogenic streptococci whereas no such changes occur following streptokinase C administration. The authors conclude that despite chemical and immunological similarities the NSAP molecule is distinct from streptokinase C.

Preabsorbing antigen (PA-Ag)

First described by Yoshizawa et al [47],[48] , PA-Ag is a purified antigen derived from the endostreptocin complex [47],[48],[49] .

Evidence for its renal involvement comes from the following;

(i) detection of antibodies to PA-Ag in patients with APSGN, lasting up to 100 weeks after initial presentation and their absence in individuals with streptococcal infection without renal injury

(ii) immunoelectrophoresis and serum C5b-9 assay indicate that PA-Ag activates the alternate pathway of the complement.

(iii) PA-Ag has been demonstrated in the glomeruli in the early phase of APSGN [50] .

Examination of the extracellular products of nephritogenic streptococci has revealed the presence of a 46-KD protein that binds to human plasmin. This protein, called nephritis plasma binding protein (NPBP) reacts preferentially with APSGN sera. Analysis of this protein suggests that NPBP is the streptococcal pyrogenic exotoxin B precursor and might have a role in the pathogenesis of APSGN [51] .

Lastly, antigen charge is believed to be another factor involved in the pathogenesis of immune complex lomerulonephritis. Fixed anionic sites in the basement membrane confer an overall negative charge to this structure which repulses anionic moieties and attracts cationized macromolecules [52] . Studies on animals have revealed that certain cationized antigens accumulate in the glomerular basement membrane, bind circulating antibodies resulting in an in-situ formation of immune complexes [53] . Demonstration of antibodies to cationic antigens in patients with APSGN and staining of glomerular deposits by antisera to cationic extracellular streptococcal antigens support this possibility [54] .

In conclusion, the exact etiopathogenesis of APSGN is still unclear. The role of complement in the causation of renal injury seems to be vital. The exact nature of the antigenic fractions in GABS is not known though the identification of some newer antigens has thrown better insight into more clear understanding of this subject.


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