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NCBI Bookshelf. 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 , inhabitants.

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. 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. 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.

This landmark paper opened the field of immune complex-mediated diseases. APSGN may occur in epidemic outbreaks or in clusters of cases, and it may occur in isolated patients. 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.

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.

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. Carapetis et al. 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 to times more common than those of life-threatening disease.

This low value is remarkably close to the estimate of Carapetis et al. 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.

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.

Pathogenetic mechanisms participating in acute poststreptococcal glomerulonephritis. 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. The nephritogenic potential of streptokinase was investigated by Nordstrand et al. Presently, two streptococcal antigenic fractions with substantial claims to nephritogenicity are being actively investigated.

Work by Fujino et al. Fujino, et al. 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.

Oda et al. It is likely that this localization is facilitated by the cationic charge of this antigen, as earlier studies have postulated Vogt, et al.

Recent studies have demonstrated that the Fc portion of antibodies directed to SPEB bind to the C-terminal domain rSPEB , and that immunization with this domain prevents group A streptococcal infection in mice Tsao, et al. 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. Notably, in studies of the Str. Nicholson, et al. 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 addition, in some patients, there may also be complement activation by the lectin pathway Ohsawa, et al. 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.

This anti-IgG reactivity may be due to autoantigenic changes to IgG modified by neuraminidase sialidase. 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.

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. Despite the variety of findings of autoimmune reactivity, the clinical relevance of these phenomena remains undefined in APSGN. Studies by Layrisse et al. Nevertheless, the genetic characteristics that are responsible for predisposition or resistance to the disease have not been identified. 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. 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. 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.

The best markers for nephritogenic streptococcal infection are serum antibody levels to NALPr Yamakami, et al. 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. 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. 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. 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.

Acute post-streptococcal glomerulonephritis GN with severe proliferative and exudative GN. The glomerulus is enlarged and markedly hypercellular with a large number of neutrophils. Note the red blood cells in some tubular lumens.

Hematoxylin and eosin more Acute post-streptococcal GN with proliferative and exudative GN. The glomerulus shows endocapillary hypercellularity with multiple neutrophils, although far fewer than the glomerulus in Figure 1. Periodic acid-Schiff PAS stain, original magnification more After the first 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. 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.

Immunofluorescence findings in evolving stages of post-streptococcal GN have been elegantly defined by Sorger et al. Sorger, et al. 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.

Immunofluorescence staining for C3 in acute post-streptococcal GN. 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. Nasr et al. 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.

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. 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.

Extraglomerular deposits are not a feature of this disease. Electron-microscopy in acute post-streptococcal GN. The periphery of this deposit is slightly less electron-dense than its center, indicating very early resorption.


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