Acute Poststreptococcal Glomerulonephritis

Fig. 1.1

An enlarged glomerulus shows diffuse endocapillary hypercellularity with numerous neutrophils and closure of all glomerular capillaries. The glomerulus is increased in size and cellularity, H&E, ×200

Fig. 1.2

Acute diffuse proliferative glomerulonephritis with considerable infiltration of the glomerulus not only by neutrophils but also by eosinophiles. H&E, ×400

Fig. 1.3

Segmental glomerular necrosis with fibrin exudation into the Bowman’s space. H&E, ×400

The glomerular capillary walls are generally not thickened, although there may sometimes be mild thickening visible on light microscopy. The combination of expansion of the lobules, hypercellularity of the tuft, and localized thickening of the glomerular capillary walls may produce a membranoproliferative pattern of glomerular injury (Fig. 1.4).

Fig. 1.4

A glomerulus with endocapillary hypercellularity. Because of the increased cellularity within each lobule, there is an accentuation of the lobularity. H&E, ×200

In some patients, at high magnification, particularly if using the oil-immersion lens, minuscule fuchsinophilic nodules on the epithelial side of the glomerular capillary wall can be detected. These minute structures correspond to the subepithelial deposits (humps) seen by electron microscopy (Fig. 1.5).

Fig. 1.5

The subepithelial humps may be seen as fuchsinophilic red dots (arrow) under high magnification, using Masson’s trichrome stain, (×1000)

Glomerular crescents or small adhesions (synechiae) are usually rare (Fig. 1.6a–c). However, sometimes crescent formation may be so prominent that the term crescentic glomerulonephritis may be used, but usually only a small percentage of glomeruli are involved by crescents.

Fig. 1.6

Crescent formation in APSGN. a This cellular crescent (arrow) was noted in the renal biopsy of a 7-year-old girl with APSGN associated with acute kidney injury. Note that the compressed glomerular capillaries appear hypercellular. H&E, ×400. b The same glomerulus stained with PAS, ×400. c A large crescent completely obliterating the underlying glomerular capillaries in the biopsy of the same patient. H&E, ×400

The diagnosis of APSGN superimposed on diabetic glomerulosclerosis may be difficult, because the underlying changes of diabetic glomerulosclerosis may alter the typical histologic manifestations. Some degree of mesangial hypercellularity may occur in diabetic nephropathy. One has to look carefully for intracapillary accumulation of inflammatory cells, which is frequently not diffuse in APSGN superimposed on diabetic glomerulosclerosis (Fig. 1.7). Immunofluorescence shows various staining patterns in diabetic nephropathy, including linear staining for albumin and IgG along the glomerular and tubular basement membranes and smudgy or coarsely granular, frequently somewhat segmental, fluorescence for C3. One has to review carefully the electron micrographs in search for subepithelial humps as well as mesangial, intramembranous, and subendothelial deposits. Unfortunately, in many biopsies with diabetic glomerulosclerosis, electron-dense deposits, representing hyalin change, are abundant and these can be difficult to differentiate from true immune complex deposits.

Fig. 1.7

APSGN in a patient with underlying diabetic glomerulosclerosis. The patient developed acute glomerulonephritis with very high ASO titers and low serum C3 levels after a “sore throat”. Note the endocapillary hypercellularity superimposed on the preexisting mesangial expansion. PAS, ×400

The tubular changes are not as prominent as those involving the glomeruli. When proteinuria is present, there may be hyalin droplets (protein reabsorption droplets) or vacuoles (dissolved lipid droplets) in the proximal tubular epithelial cells. RBC casts may be seen in the lumen of the tubules (Fig. 1.8). PMN also can be present in the lumens, especially in the proximal regions of the proximal tubules. This feature is most commonly seen in patients with severe infiltration of PMN in the glomeruli. In patients with severe renal insufficiency, classic changes of ATN are usually evident (Fig. 1.9). In the most florid cases of APSGN with extensive crescent formation, there may be tubulitis, which is characterized by inflammatory cells between the tubular basement membrane and the tubular epithelium or within the tubular epithelium. Progressive tubular injury with tubular atrophy and loss is rarely seen.

Fig. 1.8

Red blood cell casts persisting in a 45-year-old patient with resolving APSGN. The biopsy was done several weeks after the onset of proteinuria, hematuria and low serum C3 levels (the proteinuria improved from 3 to 0.5 g/24 h at the time of biopsy), H&E, ×100

Fig. 1.9

Acute tubular necrosis in a 68-year-old nondiabetic male with APSGN. Note the several apoptotic tubular epithelial cells in dilated tubules (arrows). Such apoptotic cells should not be misinterpreted as neutrophil granulocytes, H&E, ×100

The degree of interstitial involvement in APSGN is variable. The interstitium may show edema with separation of the tubules. Scattered foci of inflammatory cell infiltrates, composed of mixtures of PMN, monocytes, and lymphocytes, are sometimes present (Figs. 1.9 and 1.10). Occasionally, severe interstitial mononuclear cell infiltration and scattered regions of interstitial fibrosis may be seen. However, usually, the interstitial changes are not remarkable. As noted earlier, interstitial changes may be found in relation to tubular changes [58].

Fig. 1.10

Interstitial inflammation in APSGN. a ATN in a case of severe pediatric APSGN. Note the interstitial edema, inflammation and the tubular injury with epithelial irregularities, and vacuolization of the tubular epithelium. Few tubules contain red blood cells (arrows), H&E, ×400. b Mixed active interstitial inflammatory cell infiltrate with numerous polymorphonuclear leukocytes in an adult diabetic patients with APSGN and acute kidney injury, H&E, ×400

The arteries and arterioles generally do not show significant pathologic changes. In older patients, preexisting vascular abnormalities, such as arterial and arteriolar sclerosis, may be seen. Arteritis has been described in APSGN [59], but systemic necrotizing vasculitis must be excluded in those patients. There are other accounts of arteritis [60] as well, but they are rare. Fibrinoid necrosis of the arterioles may be associated with severe hypertension. In rare instances, morphologic changes of thrombotic microangiopathy may be seen [61, 62].

Subclinical and Resolving Glomerulonephritis. Renal biopsies in patients with minimal urinary changes have been performed (usually in prospective studies) and show variable morphology. Sometimes there are no substantial abnormalities (Fig. 1.11). Increased cellularity of the glomeruli also has been noted, as well as morphologic changes similar to those in acute diffuse proliferative APSGN [63] In renal biopsies that are taken several weeks after the clinical onset of disease, there is usually diffuse mesangial hypercellularity; but the glomerular capillaries are patent (Fig. 1.12) [64]. Mesangial hypercellularity appears to persist for several months in patients, who eventually experience complete resolution of the glomerular lesion [65]. In the past, this phenomenon was termed as chronic latent glomerulonephritis. However, these findings should be interpreted with a caution, because an unusually thick paraffin section may give a false appearance of diffuse mesangial hypercellularity, and many cases termed chronic latent glomerulonephritis may not be resolving/resolved APSGN, but rather represent a nonspecific histologic pattern associated with various renal injuries that are unrelated to previous infections [66]. Buzio et al. [67] in a long-term follow-up study (more than 5 years) of 26 patients with APSGN, found diffuse mesangial hypercellularity in patients with persisting proteinuria.

Fig. 1.11

a Normal appearing glomerulus in the biopsy of a hepatitis C virus positive patient who developed microscopic hematuria and mild proteinuria. Immunofluorescence and electron microscopy detected C3-positive subepithelial humps, PAS, ×200. b Granular C3 deposits. No immunoglobulins were detected, ×200. c Scattered subepithelial humps were evident by electron microscopy. Uranyl acetate–lead citrate, ×8000

Fig. 1.12

Mesangial hypercellularity in a patient with resolving APSGN (same biopsy as Fig. 1.8), H&E, ×400

Complete morphologic resolution occurs after APSGN, but follow-up biopsies in such patients usually are not performed. In fact, “incidental healed” postinfectious glomerulonephritis may be more common than anticipated. Haas [31] reviewed 1012 consecutive renal biopsy specimens and found 57 biopsies in which ultrastructural findings indicated resolving/healed APSGN. According to Haas, resolving or largely healed APSGN was present in 10.5% of renal biopsy specimens, excluding biopsies with a primary diagnosis of immune complex glomerulonephritis [31]. The conclusions were based on ultrastructural findings (subepithelial deposits in glomerular mesangial notch regions); therefore, this incidence may be somewhat overestimated because the specificity of subepithelial deposits in the mesangial notch region for resolving APSGN needs further confirmation. Interestingly, in Haas’ study, 50% of the biopsies with incidental healing APSGN had evidence of mesangial hypercellularity [31].

Immunofluorescence Findings

Classically, in biopsies taken early in the clinical course of the disease (first 2 or 3 weeks), granular staining is noted along the glomerular capillary loops and also in the mesangium by immunofluorescence studies with anti-IgG and anti-C3 antibodies (Figs. 1.13, 1.14 and 1.15) [20, 65, 68–74]. The pattern is granular (“lumpy-bumpy”) and usually more coarse than in patients with idiopathic membranous glomerulonephritis. This staining may assume a ribbon-like (garland) pattern in some capillaries, because of the confluence of subepithelial deposits. The granular deposits correspond to the glomerular subepithelial deposits (humps), evident on electron microscopy.

Fig. 1.13

Garland pattern of immunofluorescence staining. The coarsely granular staining along the glomerular capillary loops may be segmentally confluent. a IgG, b C3 staining from the same case, ×400

Fig. 1.14

The “starry sky pattern” of immunofluorescence. a The finely to coarsely granular deposits are randomly distributes across the glomerulus. Direct immunofluorescence with an antibody to C3, ×400. b More widespread mesangial and segmental C3 positive glomerular capillary deposits, ×400

Fig. 1.15

Mesangial pattern of immunofluorescence in APSGN with granular C3 staining in the mesangium, ×400

Sorger et al. [69–71] described different categories of immunofluorescence patterns. They noted three main arrangements, named the garland pattern (Fig. 1.13a, b), the starry sky pattern (Fig. 1.14), and the mesangial pattern (Fig. 1.15). The garland pattern is manifested by a discrete, more densely packed, and sometimes confluent heavy disposition of IgG and C3, corresponding to numerous humps noted on the subepithelial side of the glomerular capillary wall [64, 66]. This pattern resembles the immunofluorescence-staining pattern in membranous glomerulonephritis, and is most often seen in patients with acute glomerulonephritis who have severe proteinuria (often with the nephrotic syndrome) (Fig. 1.13a, b). The starry sky pattern has a more irregular granular pattern, with the deposits being smaller and often situated on the GBM overlying the mesangial regions. This arrangement was most commonly seen in early cases of APSGN (Fig. 1.14a, b). Only a few large, typical humps were noted in these cases. This picture may turn into the mesangial pattern, characterized by a granular deposition of IgG and C3 (usually with predominance of C3). It seems to be most closely related to a resolving pattern (Fig. 1.15). The deposits are generally noted in the mesangium and are accompanied by mesangial hypercellularity.

There is no evidence that different etiologic factors are responsible for these three subtypes [70]. The individual immune response of the host and the stage of the disease are likely to play a role in the development of these different patterns. A diffuse granular pattern for IgG and, usually, C3 is also found in patients with subclinical glomerulonephritis [72, 75].

There is usually more intense and more constant staining with anti-C3 than with anti-IgG antibodies [68, 72, 73, 75]. Indeed, it is common to see granular glomerular C3 staining without relevant IgG staining. Some authors have noted the combination of granular and patchy interrupted linear staining along the glomerular capillary loops and in the mesangial regions [12, 34]. Sometimes, there seems to be an exclusively patchy interrupted linear pattern for C3 along GBMs close to the mesangium as well as in the mesangium, with no staining for IgG [76]. This interrupted linear pattern has been found most commonly in renal biopsies from patients at a late stage of APSGN [77]. C3 staining with negative IgG staining has been reported in the mesangial areas with no capillary wall deposits [71]. This mesangial pattern also tends to be seen in patients who undergo kidney biopsy later than usual (i.e., several weeks after the clinical onset of disease).

IgM staining is frequently present and was recorded in more than 50% of cases in one study [65]. Other authors [57] have not found significant IgM staining in biopsies from patients with APSGN. IgA staining is usually absent [12, 68, 75], but it has been noted from time to time [65, 72, 73]. If IgA immunofluorescence is strong, the possibility of an underlying staphylococcus infection has to be considered, irrespective of the presence or absence of diabetes mellitus. Staining for fibrin/fibrinogen-related antigen also can be seen in the mesangium (as well as in the Bowman’s space in the crescentic form) [12, 65, 75].

Deposits of immunoglobulins and, especially, complement components may be detected in the glomeruli for months to years after apparent clinical resolution of APSGN [31]. The intensity of the immunofluorescence staining usually correlates with the severity of the glomerular lesion, although severe diffuse glomerulonephritis may be accompanied by unimpressive or negligible immunofluorescence.

Electron Microscopic Findings

The most consistent classic diagnostic feature is the presence of glomerular subepithelial electron-dense deposits, often referred to as “humps” (Fig. 1.16) [12, 31, 71, 78–80]. A “hump” is a non-scientific term used in renal pathology to describe dome-shaped subepithelial electron dense immune-type deposits that bulge outward toward the Bowman’s capsule beyond the boundary of the GBM (unlike the subepithelial deposits seen in membranous glomerulonephritis). They are usually large in size. They are especially abundant in the first few weeks of APSGN, and they decline in number afterward. They are usually less than 1 μm wide and long, but they sometimes are up to 3 μm wide and 6 μm long. The electron density of the deposits is variable [81]. Although there is no direct correlation between the fine ultrastructural appearance of the deposit and the clinical or non-ultrastructural morphologic findings, Tornroth [80] has suggested that electron-lucent areas in the deposit may represent regions of resolution (Fig. 1.17).

Fig. 1.16

Large dome-shaped subepithelial deposits (humps) are the hallmark ultrastructural finding in APSGN. Uranyl acetate–lead citrate, ×10,000

Fig. 1.17

A subepithelial hump with decreased and variegated electron density. This finding is thought to represent resolving immune complex deposits. Uranyl acetate–lead citrate, ×80,000

The deposits are usually abundant and discrete and are most commonly found on that part of the GBM that overlies the mesangial regions. West and McAdams [82] reported that there may be no or only very few subepithelial deposits along the GBM covering the mesangium in some pediatric patients with APSGN in spite of prominent hypoalbuminemia and edema. On occasion, the subepithelial deposits may be numerous and along stretches of the GBM, particularly in cases with the garland pattern of immunofluorescence (Fig. 1.18). Discrete electron-dense immune-type deposits may be seen in the lamina densa and the subendothelial regions [12, 71, 79, 80, 83] (Figs. 1.18 and 1.19). Various numbers of mesangial electron dense deposits are usually present (Fig. 1.20). Although the glomerular subepithelial hump is the most characteristic lesion by electron microscopy, similar subepithelial deposits may be seen in other disorders, such as staphylococcus-associated glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis C3 glomerulopathy, lupus nephritis, and Henoch–Schönlein purpura.

Fig. 1.18

Numerous subepithelial humps of various sizes along the GBM. This is frequently seen in biopsies with the garland pattern of immunofluorescence. Note that there are subendothelial deposits as well (arrow). Uranyl acetate–lead citrate, ×1100

Fig. 1.19

In addition to subepithelial deposits, intramembranous deposits (arrow) are also common. Uranyl acetate–lead citrate, ×15,000

Fig. 1.20

Mesangial electron dense deposit in a case of APSGN. Uranyl acetate–lead citrate, ×20,000

Data from patients undergoing serial biopsies indicated that during the recovery phase, the glomerular subepithelial humps tend to rapidly disappear (usually within 6 weeks of the clinical onset of disease) [78]. Sometimes, they may be present for a longer period of time [79], but the clinical course in such cases is unclear. The fate of the glomerular subepithelial deposits has been studied by Tornroth [80], who has demonstrated that the electron density (osmiophilia) of the deposits diminishes with time, so that translucent or electron-lucent regions are formed. Glomerular intramembranous electron-lucent regions have been seen in later biopsies (after 1 month), and, in some cases, these regions protruded toward the epithelium and were covered on that side by a thick layer of basement membrane-like material.

Sometimes electron dense deposits were found deeper in the lamina densa, giving it a somewhat mottled appearance [80]. Kobayashi et al. [79] showed that the deposits became buried in the GBM and also acquired a fine granularity with an electron density less than that of the original humps. Glomerular subendothelial deposits, that were present early, disappear with time [79, 80]. Increased cellularity may persist in the mesangial regions for several months, even in those patients in whom the clinical picture and urinary sediment have returned to normal. An increase in mesangial matrix is often found in patients who have chronic proteinuria. It appears that there are more subepithelial humps in those patients with a severe, protracted clinical picture than in those with rapid clinical recovery [79]. The size of the deposits does not seem to correlate with clinical course or outcome [84].

Haas [31] emphasized the significance of scattered intramembranous and subepithelial remnant deposits in a renal biopsy in patients with possible history of APSGN. Using careful ultrastructural studies, Haas identified 57 renal biopsies with such deposits out of 543 biopsies that did not have a primary diagnosis of immune complex glomerulonephritis. Haas emphasizes the diagnostic significance of subepithelial deposits in the mesangial notch (or mesangial groove) region. The mesangial notch region represents a fold of the GBM overlying the mesangium. In our experience, isolated subepithelial deposits in the mesangial notch region usually represent a nonspecific finding and should not be interpreted as a specific lesion for remote postinfectious glomerulonephritis (Fig. 1.21).

Fig. 1.21

A large subepithelial deposit in a mesangial groove (notch) region. In our experience, such deposits, particularly if they have microspheres and membrane-like inclusions in them, usually represent a nonspecific degenerative change. Uranyl acetate–lead citrate, ×25,000

Differential Diagnosis

Acute Postinfectious Glomerulonephritis of Nonstreptococcal Origin

The morphology of the various nonstreptococcal postinfectious or infection-related glomerular nephritides vary somewhat, according to the underlying pathogen. Thus, glomerular subepithelial humps are usually less prominent, and one can find more intramembranous or subendothelial and mesangial deposits in a postinfectious glomerulonephritis of nonstreptococcal origin, such as in staphylococcus infection-associated glomerulonephritis or secondary to other infections (Table 1.2) (see Chaps. 2 and 3).

It is important to note that many infection-associated glomerulonephritides are not truly postinfectious. In postinfectious glomerulonephritis, by the time the symptoms of glomerulonephritis manifest, the infection has resolved; therefore, steroid/immunosuppressive treatment will usually not be harmful. In contrast, in infection-associated glomerulonephritides, the glomerulonephritis develops while the infection is still active, ongoing. Therefore, in infection-associated glomerulonephritis steroids or other immunosuppressive medications should be avoided [85].

In staphylococcus infection-associated glomerulonephritis, the glomerular deposits frequently contain IgA in addition to C3. Glomerular IgA deposits usually do not occur in APSGN. Making the distinction between APSGN and infection-associated glomerulonephritis is important from the perspective of history, pathogenesis, and clinical management. Unfortunately, steroid therapy in staphylococcus infection-associated glomerulonephritis can precipitate severe staphylococcal sepsis and even death and provides no observable benefits [85]. However, in some biopsies, based on morphologic examination alone, it is impossible to determine whether the etiologic agent is GAS or a nonstreptococcal pathogen. Only detailed clinical history and identification of the exact pathogen enables the definitive diagnosis. Rarely, both GAS and staphylococcal infections may be present in the same patient. Recently, we encountered a kidney biopsy from a patient with wound infection that had multiple micro-organisms, including S. pyogenes and Methicillin-resistant Staphylococcus aureus (MRSA), in the exudate. Kidney biopsy showed immune complex-mediated proliferative glomerulonephritis with focal fibrocellular crescents. Immunofluorescence and electron microscopy indicated C3-, IgA, and IgG-containing immune complex deposits in the mesangium and along the glomerular capillary loops. The glomerular capillary loops deposits were subepithelial, intramembranous, and subendothelial. Although the morphology was not inconsistent with APSGN, because of the ongoing infection and the presence of IgA, we favored staphylococcus infection-associated glomerulonephritis.

C3 Glomerulopathy

The newly emerging entity of C3 glomerulopathy (particularly the hypercellular C3 glomerulonephritis) can be very difficult to differentiate from APSGN based on morphologic findings alone. C3 glomerulopathy is associated with congenital or acquired dysregulation of the alternate pathway complement activation with glomerular C3 deposits in the absence of immunoglobulin deposits [86]. It has been proposed that C3 glomerulopathy encompasses C3 glomerulonephritis (in which proliferative renal lesions are seen with C3 deposits but with no immunoglobulin deposits), dense deposit disease, familial membranoproliferative glomerulonephritis type III and familial complement factor H-related protein 5 abnormality nephropathy [86]. Differentiating APSGN from C3 glomerulonephritis can be a difficult task, because in both conditions glomerular endocapillary and mesangial hypercellularity and C3 containing mesangial and glomerular capillary deposits, including subepithelial humps, may be present [87]. If the biopsy in APSGN is performed in the resolving stage, the glomerular hypercellularity is mostly seen in the mesangium and the C3 deposits may also be mainly mesangial. Serum C3 levels are usually low both in APSGN and in C3 glomerulopathy/glomerulonephritis. However, there are two major differences between APSGN and C3 glomerulonephritis. APSGN is preceded by a streptococcal infection and is a self-limiting benign disease with recovery without intervention. In contrast, C3 glomerulopathy is usually not preceded by an infection and the disease is associated with persistent proteinuria/hematuria, persistently low serum C3 levels and usually slow disease progression. The differential diagnosis can be particularly complex if an infection (such as a streptococcal infection) evokes the alternate pathway complement regulatory abnormality, which can happen in patients who have otherwise subclinical mild form of dysregulation of the alternate complement pathway activation [87, 88]. Differentiating dense deposits disease from APSGN is easy, because of the characteristic intramembranous dense deposits seen by electron microscopy. The other familial forms of C3 glomerulopathy can potentially cause a differential diagnostic problem, but the family history of renal disease and the persistent clinical symptoms should provide a clue.

Membranoproliferative Glomerulonephritis (MPGN)

The differentiation of MPGN (MPGN type I with C3 and IgG deposits) from APSGN is not a challenge for an experienced renal pathologist, if the case is typical. Unfortunately, in our experience, “typical” cases are becoming more and more an atypical occurrence in the renal biopsy material. Therefore, this differential diagnosis may be a challenge. In early stages of active MPGN type I, the glomerular hypercellularity can be quite striking and intracapillary polymorphonuclear leukocytes may be prominent. Immunofluorescence shows granular glomerular C3 deposition with IgG, which can be seen in both MPGN and APSGN, and occasionally, it is difficult to decide whether the immunofluorescence findings represent a garland pattern in APSGN or subendothelial deposits in MPGN. Ultrastructurally, MPGN is characterized by abundant subendothelial deposits, but the presence of subepithelial humps in MPGN is not unusual, and occasionally, quite a few humps can be seen. In APSGN, usually subepithelial humps predominate, but in many cases, subendothelial deposits are also seen. Mesangial deposits are present in both MPGN and APSGN. Based on these findings, it is evident that there are morphologic overlaps between APSGN and MPGN type I. The clinical presentation can also be quite similar because both diseases frequently present with nephritic syndrome and variable degrees of proteinuria and hypocomplementemia. Proteinuria occasionally can be quite prominent in APSGN. Serum complement levels (in particular, C3 levels) are low in both diseases. C3 nephritic factor is not always present in MPGN, and may occasionally be seen in APSGN. We have encountered a few renal biopsies in which we were unable to decide whether the biopsy represented an early active stage of MPGN type I or APSGN. In such cases, only careful follow-up will establish the diagnosis because the waste majority of APSGN cases will gradually improve and resolve, whereas MPGN type I, if untreated, usually progresses.

Cryoglobulinemic Glomerulonephritis

In a typical case, the differential diagnosis is easy because of the intracapillary hyalin thrombi, which represent cryoglobulin precipitates in the glomerular capillaries. However, particularly in a small biopsy specimen or in atypical cases, these hyalin thrombi may not be present and cryoglobulinemic glomerulonephritis shows the pattern of endocapillary proliferative glomerulonephritis. The predominant endocapillary cell in cryoglobulinemic glomerulonephritis is the monocyte, but it is not unusual to see many neutrophil granulocytes. The immunofluorescence pattern in cryoglobulinemic glomerulonephritis is distinctive (particularly in type I and type II cryoglobulinemia) if the cryoglobulin deposits are present. Unfortunately, as any glomerular disease, cryoglobulinemic glomerulonephritis also represents a disease spectrum and cases with little or no intraluminal cryoglobulin deposits in the glomerular capillaries occur. The distinctive IgG and IgM positive globules of type II cryoglobulinemia, which usually also stain for complement, may not be evident in such cases. Electron microscopy usually reveals the characteristic organized microtubular substructure in the cryoglobulin deposits, but this could be easily missed, particularly if not enough glomeruli are examined under the electron microscope. One important differential diagnostic hint is that in cryoglobulinemic glomerulonephritis humps are usually absent. Cryoglobulinemic glomerulonephritis in the differential diagnosis should be considered if there is an endocapillary proliferative glomerulonephritis with no or only few immune complex deposits and no subepithelial humps. The clinical history may be quite helpful in differentiating APSGN from cryoglobulinemic glomerulonephritis. Similarly to APSGN, C3 levels may be low in cryoglobulinemic glomerulonephritis, but cryoglobulinemic glomerulonephritis is typically associated with normal or slightly low serum C3 levels and very low C4 levels. A positive cryoglobulin test may be helpful, but, unfortunately, this test is unreliable and cryoglobulins occur in some patients with APSGN. Another useful test in the differential diagnosis is rheumatoid factor, which is detectable in most patients with cryoglobulinemic glomerulonephritis. Rarely, even the clinical history may be misleading, because cryoglobulinemic glomerulonephritis may undergo spontaneous remission giving the impression of a resolving APSGN.

IgA Nephropathy

Exacerbation of IgA nephropathy is common after upper respiratory tract infection with the appearance of gross hematuria, or nephritic syndrome. However, this form of IgA nephropathy is a synpharyngitic glomerulonephritis, developing while the upper respiratory tract infection is still ongoing or is immediately following it. Unlike in APSGN, there is no latency between the infection and the glomerulonephritis. Renal biopsy findings are quite different in IgA nephropathy and APSGN, but if, in addition to glomerular IgA deposition there is also prominent C3 staining, acute kidney injury, heavy proteinuria and if the infection is other than a common upper respiratory tract infection, one should consider an underlying staphylococcus infection (see Chap. 2).

Membranous Glomerulonephritis

In our experience this is not a difficult differential diagnosis; however, Sotsiou et al. [89] described two patients with presumed postinfectious glomerulonephritis who had morphologic features of membranous glomerulonephritis, such as spike formation on methenamine silver stain, intracapillary hypercellularity with neutrophils, garland-type granular deposits of IgG and C3 along the glomerular capillaries, and elevated ASO titers. Unfortunately, no follow-up data are provided and it is difficult to exclude the possibility that these cases in fact represented atypical membranous glomerulonephritis rather than atypical postinfectious glomerulonephritis. A transformation of an acute proliferative and exudative glomerulonephritis into a membranous glomerulonephritis has been reported in 3 cases [90]. These cases are very unusual, and the pathogenesis is debatable. Wu et al. [91] described a patient who developed APSGN superimposed on membranous glomerulonephritis.

Recently, Larsen et al. [92] described an interesting form of glomerulonephritis in young adults: membranous-like glomerulopathy with masked IgG-kappa deposits. With routine immunofluorescence on frozen sections, the deposits stain predominantly for C3. Electron microscopy shows numerous subepithelial deposits, which are frequently large, hump-like. However, serum C3 is usually normal and the patients do not have evidence of prior or ongoing infection. Repeating immunofluorescence on paraffin sections after digesting them with pronase reveals that the subepithelial deposits contain IgG-kappa.

Diffuse Proliferative (Class IV) Lupus Nephritis

Diffuse proliferative lupus nephritis shows a diffuse endocapillary proliferative pattern, frequently with the presence of glomerular PMN. Therefore, if immunofluorescence and electron microscopy are not available, the differential diagnosis, based on light microscopy alone, may be difficult. One has to remember that in proliferative lupus nephritis large hump-like subepithelial deposits may be seen by electron microscopy. Still, because of the characteristic immunofluorescence and ultrastructural findings and the clinical history, the differential diagnosis is easy in most cases.

Etiology and Pathogenesis

The relationship between streptococcal infection and acute glomerulonephritis is well established, and a large amount of information is available about the mechanism of action by which the infection leads to the characteristic glomerular changes [93]. It has been known for a long time that the blood and urine are sterile in patients with APSGN [94], and the kidney parenchyma is also sterile. The renal changes in APSGN were noted to be different from those seen in patients with streptococcal septicemia, in which the major changes are interstitial nephritis and abscess formation. Although streptococcal toxins could play a role in APSGN, it is unlikely, because the renal injury would be expected to occur at the peak of the infection (whereas APSGN develops after the infection subsides). Moreover, acute proliferative glomerulonephritis is not the type of morphologic change usually noted in patients with various circulating toxins and it would be anticipated that the renal changes would be proportional to the severity of the infection, which is not the case.

It is now widely accepted that APSGN and other forms of postinfectious or infection-associated glomerulonephritis is an immunologic phenomenon. A long time ago, Schick [5] noted that there is the latent interval between clinical signs of infection and the onset of APSGN and likened it to the course of events in acute serum sickness and other allergic states. The latent interval after infection has been well documented and usually ranges between 7 and 21 days (in average, 10–11 days).

Unfortunately, there is no perfect animal model for APSGN. Many attempts have been made to create an animal model of APSGN by the injection of intact streptococci [95, 96], crude culture supernatants [38], or specific components of the streptococci [97, 98]. Although some of these experimental models produced histologic lesions somewhat similar to the disease pattern in humans, they do not precisely mimic the gradual release of streptococcal products that probably occurs at the site of infection in the clinical condition in humans [97]. Also, many of the experimental studies were performed at a time when electron and immunofluorescence microscopy and other biochemical determinations were not available, making it difficult to carry out an adequate comparison [97].

Several streptococcal fractions have been studied in search of the trigger for the glomerulonephritis (Table 1.1). One streptococcal fraction, endostreptosin, has been extensively studied [99–106]. This antigen is demonstrable in the glomerulus only during the initial phase of APSGN and reacts with antibodies present in the convalescent sera of patients with acute phase of APSGN. In the late phases of the disease, the antigen can no longer be detected, presumably because antigenic sites have been covered by the specific antibody. Seligson et al. [105] have suggested that acute elevations of endostreptosin titers are generally diagnostic of APSGN. Although low titers of antibody have been found in as many as 70% of normal individuals, significantly higher titers of antibodies are found in patients with APSGN [105]. Most patients with acute rheumatic fever do not have high levels of this antibody titer. Lange et al. [103] also believed that elevated levels of antibody to endostreptosin are diagnostic of APSGN and correlate well with the course of the disease process. Endostreptosin is similar to the preabsorbing antigen described by Yoshizawa et al. [106–108] and Holm et al. [109].

Table 1.1

Streptococcal antigens potentially involved in the pathogenesis of poststreptococcal acute glomerulonephritis

Streptococcal antigen	References
Endostreptosin or preabsorbing antigen	[99–109]
Nephritis strain–associated protein (NSAP) (or streptococcal cationic protease exotoxin B [SPEB], exotoxin B, or nephritis plasmin-binding protein [NPBP])	[97, 98, 118–127, 176]
Nephritis-associated plasmin receptor (NAPlr) (or streptococcal glyceraldehyde-3-phosphate dehydrogenase [GADPH])	[124, 125, 128–133]
Streptococcal M protein and its fractions	[110–114]
Streptokinase	[115–117]

Yoshizawa et al. [108] isolated a 43-kDa protein from nephritogenic streptococci (“preabsorbing antigen”) and noted identical precipitation lines by immunodiffusion between rabbit antisera against preabsorbing antigen and the sera of patients with APSGN. These authors developed a rabbit glomerulonephritis model by administering preabsorbing antigen for 8 days [107]. Histologically, kidneys obtained from these animals showed proliferative glomerulonephritis, immunofluorescence showed glomerular capillary and mesangial C3 deposits, and electron microscopy revealed occasional subepithelial “hump”-like deposits. Interestingly, IgG and preabsorbing antigen in the glomerular or deposits were not detected [107].

Streptococcal M protein is a strong candidate for the important antigenic bacterial fraction [110]. M-protein fractions can form complexes with fibrinogen and localize in glomeruli [111], and glomerulonephritis can be induced with injection of M-protein–M-protein/fibrinogen complexes. M-protein may be antigenically cross-reactive with the GBM [112]. However, Treser et al. [113] have proposed that the nephritogenic fraction is different from the M-protein. Immunoglobulins from patients that are recovering from APSGN, when labeled, could identify free antigenic sites in renal biopsy specimens showing APSGN; the fact that this serum had these antibodies independent of the M type of the original infection suggested that a non-M antigen was present in the glomerulus [113]. On the contrary, Mori et al. [114] found that IgG titers against the C region of the M-protein of group A streptococci are elevated in patients with APSGN, as compared to patients with other uncomplicated streptococcal infections, such as pharyngitis, chronic glomerulonephritis, as well as in and healthy controls. IgG titers against the A and B regions of streptococcal M-protein were not different between these groups.

Some researchers have suggested that streptokinase is the most important bacterial antigen leading to APSGN [115–117]. Holm et al. [115] showed loss of nephritogenic potential of a nephritogenic type 49 streptococcus strain by deletion of a streptokinase gene by using a molecular construct prepared by electrotransformation.

An extracellular protein unique to nephritogenic streptococcus strains from cultures of type 12 organisms was identified by Villarreal et al. [118]. This fraction (called nephritis strain–associated protein, NSAP) was noted in 56% of renal biopsies with morphologic features of APSGN; it was not found in biopsies from patients with other forms of nonstreptococcal glomerulonephritis or rheumatic fever. The vast majority of patients with glomerulonephritis had serum antibodies to NSAP [119]. NSAP (also called streptococcal cationic protease exotoxin B [SPEB] or nephritis plasmin-binding protein [NPBP]) can directly induce tissue destruction by cleaving extracellular matrix proteins (such as fibronectin and vitronectin), and might aggravate inflammation via superantigenic effects on the immune system, similar to staphylococcal enterotoxins A and C. SPEB can directly bind to Class II MHC molecules on antigen-presenting cells and specific Vβ chain of T cell receptors, inducing proliferation and massive activation of T cells. Antibodies to streptococcal glyceraldehyde-3-phosphate dehydrogenase (GADPH) and SPEB (NSAP) have been found in patients with APSGN [120]. More recent studies by using double immunofluorescence staining methods for NSAP and collagen type IV demonstrate that NSAP is localized to the inner side of the GBM [121, 122].

A 46 kDa subunit of NSAP has antigenic, biochemical, and structural similarities to streptokinase from group C streptococcal organisms, and it binds to plasmin and is a plasminogen activator that has been isolated and purified [98]. This protein is not related to group A streptokinase or to a recently described streptococcal dehydrogenase protein [123, 124]. Amino acid sequence analysis and immunologic reactivity studies indicate that this protein is the streptococcal pyrogenic exotoxin B (SPEB) precursor (previously termed zymogen–streptococcal proteinase precursor) [124].

Vogt et al. [125] isolated and identified a number of different cationic proteins from nephritogenic streptococci. Studies from the group at the Rockefeller University indicate that the cationic protein described by Vogt et al. is structurally identical to SPEB [126]. This group and other investigators suggest an important role of SPEB in APSGN [126, 127]. Cu et al. [126] found that SPEB antibodies were present in the sera of patients with APSGN in significantly higher titers than in patients with acute renal failure, scarlet fever, and normal sera.

Another potential candidate to play a role in the pathogenesis of APSGN is nephritis-associated plasmin receptor (NAPlr) [124, 125, 128]. NAPlr is proved to be homologous with streptococcal GAPDH. Yoshizawa et al. [129] demonstrated that 92% of patients with early APSGN had anti-NAPlr in their serum and up to 80% of the renal biopsies of early cases of APSGN showed deposition of NAPlr. In a subsequent study, the authors showed that the distribution of glomerular plasmin-like activity and glomerular NAPlr is identical and postulated that NAPlr traps and maintains plasmin in the active form in the glomeruli, which, in turn, induces glomerular damage [130]. The authors propose that NAPlr will be released into the circulation following an infection with a nephritogenic strain of group A streptococci, which can bind to the glomerular mesangium and the GBM. This bound NAPlr traps plasmin and maintains its activity. Activated plasmin may degrade the GBM by itself or through activation of matrix metalloproteinases [130]. Activated plasmin may also attract neutrophils and macrophages to the site of inflammation. The circulating immune complexes, therefore, can easily pass the damaged GBM and accumulate along the subepithelial surface as large subepithelial deposits [130]. Transient immunostaining for NAP1r antigen has been demonstrated in the glomeruli during the early stages of APSGN and the staining diminishes within several months. This antigen is reported to be localized in mesangial cells, endothelial cells, and neutrophils, similar to the localization of SpeB antigen [130, 131]. However, glomerular NAP1r deposition has also been found in other glomerular diseases, such as Henoch–Schönlein purpura, lupus nephritis, and dense deposit disease [132, 133]. Therefore, the specificity of this nephritogenic antigen for APSGN is somewhat questionable.

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