APSGN is characterized by an abrupt onset of hematuria. In severe cases, oliguria and renal failure with associated edema and hypertension rapidly follow. APSGN usually occurs 1–2 weeks after a pharyngeal infection and 2–4 weeks after a skin infection. APSGN typically lasts for 2–4 weeks with clinical improvement starting 1 week after presentation [9]. Subclinical disease can occur and is manifested by microscopic hematuria, low serum C3 levels, and hypertension. In children with APSGN, nephrotic range proteinuria and severe azotemia are uncommon [8]. In adults with APSGN, up to 20% may present with nephrotic range proteinuria and over 60% present with severe azotemia [8]. The hematuria associated with APSGN is characterized by gross hematuria or “tea-colored” urine (30–50%). Generalized edema (60–70%) is common, as is new onset hypertension (50–90%), and renal dysfunction (REF). Severe, rapidly progressive, necrotizing and crescentic GN is rare and may predict a poor long-term prognosis [15–17].

Laboratory findings show “nephritic” urine sediment consisting of dysmorphic red blood cells (especially acanthocytes), red blood cell casts, and mixed red and white blood cell casts. Pyuria (neutrophils) can be extensive. Still, red cells typically outnumber neutrophils. The serologic hallmark of APSGN is activation of the alternative complement pathway (low serum C3, normal serum C4). In approximately 90% of cases, serum C3 and CH50 levels are suppressed early in the disease course, and then return to normal levels at remission [18]. Serum C4 levels are usually normal or only slightly low consistent with alternative, but not classical complement pathway activation.

There are several serologic studies available to assess for recent GAS infection. The streptozyme test measures five different antibodies that target various extracellular streptococcal products and is positive in 95% of patients with a pharyngeal infection and in 80% of patients with skin infection [9, 19]. Generally, the anti-streptolysin antibody (ASO) titer is increased after a pharyngeal infection with peak titer occurring about 3 weeks after presentation [20]. However, the ASO titer is not a good indicator if pyoderma is the inciting infection [19]. Instead, anti-DNAse B antibody titers are more likely to be elevated after streptococcal skin infections [20]. These studies are particularly helpful in cases where the infection history is unclear and can help distinguish APSGN from other forms of acute nephritis, especially in adults.

The features that differentiate APSGN from other forms of acute nephritis are shown in Table 5.2. The differential diagnosis for APSGN includes autoimmune diseases that cause acute nephritis. Lupus nephritis, Henoch–Schönlein purpura (HSP), IgA nephropathy, and membranoproliferative GN (MPGN) may all present similarly to APSGN. C3 nephritis or dense deposit disease may be indistinguishable from APSGN clinically as both present with evidence of nephritis and signs of alternative complement pathway activation. In patients with MPGN, however, the clinical abnormalities persist and do not remit spontaneously. Both IgA nephropathy and HSP may present after an upper respiratory tract infection but the infection is typically synpharyngitic and occurs 1–2 days after a mucosal infection. Additionally, serum complement levels are usually normal. Lupus nephritis is an immune complex mediated GN and can present with acute nephritis similar to APSGN, however, gross hematuria is not usually seen in LN. In contrast to APSGN, the classical complement pathway is activated during lupus nephritis flare and there is no apparent relationship to a preceding infection. Finally, GN related to chronic, ongoing infections, such as staphylococcus-associated GN (discussed below) may also present with clinical features similar to APSGN, including acute nephritis with activation of the alternative complement pathway.

Differentiating APSGN from other forms of acute nephritis may be challenging, particularly in adults. Only 10–20% of pharyngitic infections are caused by GAS [21] so APSGN may be diagnosed mistakenly in patients with other forms of acute nephritis if the pharyngitis is presumed to be secondary to GAS. Also staphylococcus does not cause a pharyngitis in immunocompetent patients. An alternative diagnosis should be sought in cases where the GN does not resolve after 4–8 weeks of supportive care. However, if an alternative diagnosis is present, such as a C3 nephritis or lupus nephritis, waiting for several weeks to confirm the diagnosis will delay therapy and expose the patient to chronic kidney damage. The kidney biopsy is invaluable in such cases and maybe necessary to definitively diagnose the cause of the acute nephritis.

The kidney biopsy, while the gold standard for diagnosis of most glomerular diseases, is not routinely done in patients suspected to have APSGN. The rationale is that the processes of APSGN can usually be deduced from its characteristic presentation and laboratory findings (see Table 5.2). Kidney biopsy is considered when atypical clinical features are present. For example, if the ASO or streptokinase titers are not elevated and the renal failure is severe (GFR < 30 ml/min/1.73 m²), or the nephritis is a recurrent problem then a kidney biopsy should be considered [22, 23]. The classic histologic features of APSGN include light microscopy findings of diffuse mesangial and endocapillary hypercellularity with neutrophil infiltration of the glomerular tuft, by immunofluorescence granular deposition of IgG and C3 in the capillary loops, and by electron microscopy showing the hallmark subepithelial humps. The presence of cellular crescents is uncommon but may be seen in severe cases. Since disease remission is based on resolution of clinical manifestations of nephritis, histologic remission is not typically considered but to have implications for long-term prognosis. For details on renal biopsy findings, see Chap. 1.

At present, there is no specific treatment for APSGN. The current approach is supportive and focuses on treating hypertension and volume overload. Acute infection has usually subsided by the time nephritis develops, thus antibiotic therapy is not usually helpful. Antibiotic therapy is, of course, recommended during the acute infection to reduce the triggers of APSGN and to prevent outbreaks. In the setting of epidemics or in high risk locations, prophylactic antibiotics should be provided to family members and other close contacts of APSGN patients [8]. This has been shown to decrease the incidence of disease in those settings [24]. As mentioned above, renal biopsy is not typically recommended since the disease is typically transient and usually goes into remission spontaneously. Clinical manifestations commonly begin to resolve 1 week after disease onset and renal function returns to baseline levels 3–4 weeks after disease onset. This is true even in cases of acute renal failure and in cases where kidney biopsy was performed and showed crescentic GN [25]. Microscopic hematuria may persist for up to 1–2 years and proteinuria may be slow to resolve [8]. Approximately 20% of patients will continue to have abnormal urine findings (hematuria or proteinuria) during long-term follow-up [26]. Overall most patients have an excellent outcome with supportive therapy alone, and disease recurrence is rare.

Supportive therapy includes symptomatic management of the acute nephritis. Sodium and fluid restriction along with diuretic therapy is considered as first line therapy to treat hypertension and volume overload. Angiotensin converting enzyme inhibitors may be used to manage hypertension, however, these agents are commonly avoided due to the potential for worsening renal function acutely and causing hyperkalemia. Additionally, APSGN usually remits within several weeks so the long-term benefit of renin-angiotensin-system blockade may be negligible. Vasodilators are commonly used if additional anti-hypertensive therapy is required. Hypertensive encephalopathy may also occur and requires parenteral therapy such as intravenous nicardipine. If volume overload persists, or metabolic derangements including hyperkalemia develop, dialysis should be considered until the APSGN remits and renal function improves.

Steroid/Immunosuppressive Therapy in APSGN. In patients with rapidly progressive crescentic GN, intravenous pulses of methylprednisolone are commonly recommended to treat the acute inflammation. However, whether immunosuppression is beneficial in crescentic GN due to APSGN is unclear. The available evidence is shown in Table 5.3. As shown, most of the evidence is from small retrospective studies [27–29]. In the only available prospective study, 10 children with crescentic GN due to APSGN were stratified to receiving either immunosuppression plus anticoagulation or supportive care alone [25]. For immunosuppression, five patients were selected to receive quintuple therapy with cyclophosphamide, azathioprine, prednisone, dipyridamole, and systemic anticoagulation. The other five patients were selected to receive supportive care only. All patients had greater than 50% crescents on the initial biopsy and repeat biopsy was performed in 8 of the 10 patients. After 3 months of treatment, the clinical and histologic outcomes were similar in both groups. However, at each interval up until 3 months of follow-up, the treatment group had a more rapid improvement in creatinine clearance [25]. After 60 months of follow-up, the serum creatinine and proteinuria levels were similar between the groups. There was no correlation between severity of crescent involvement and outcome. Also, most patients in both groups attained a complete remission after 6 months of follow-up. Additionally, the level of parenchymal scarring at repeat biopsy was similar between the groups.

In a more recent study, the outcomes of 27 children from New Zealand with severe APSGN were studied retrospectively. At baseline, 11 of the 27 patients had a crescentic GN. These patients were more likely to require acute dialysis at presentation [28]. Each of the patients with crescentic GN was treated with immunosuppression, either pulse methylprednisolone followed by oral prednisone alone, or in combination of cyclophosphamide. Renal outcomes were similar between the immunosuppressed group and the supportive care group. However, none of the patients who received supportive care only manifested crescentic GN at baseline [28]. This suggests that immunosuppression may have been beneficial because the group treated with immunosuppression started with worse APSGN but achieved the same outcome as those with less severe disease.

Clear conclusions cannot be made from the available evidence. Nevertheless, we suggest that immunosuppression, particularly with corticosteroids, may be helpful in severe cases of APSGN to suppress acute inflammation, limit chronic renal damage, and help facilitate a more rapid renal recovery. Figure 5.1 provides an algorithmic approach to the management of APSGN.

The prognosis for patients with APSGN is generally excellent especially in children [30–32]. This is true even for a patient who presents with acute renal failure and the renal biopsy shows crescentic GN [25]. Determining the long-term prognosis for children with APSGN has been an area of extensive study. Earlier studies suggested that the long-term prognosis was excellent but this was based on short follow-up. Studies with longer follow-up (5–18 years) showed that approximately 20% of APSGN patients have a persistently abnormal urinalysis (hematuria, proteinuria or both) but elevated serum creatinine is rare [26]. For example, in one study, after 18 years of follow-up, 7% of children with APSGN had persistent subnephrotic range proteinuria and 5% had microscopic hematuria [26]. However, less than 1% developed end-stage renal disease. However, in another study of 200 well-characterized Australian Aboriginal children, the risk of developing persistent albuminuria after 5 years of follow-up was 3–4 times greater in those with a history of APSGN [33].

Adults with APSGN have a worse renal and overall prognosis than children [26, 34]. APSGN in adults commonly occurs in elderly patients with significant comorbidities such as alcoholism or malignancy. In these patients, azotemia, congestive heart failure, and nephrotic range proteinuria were common during the acute illness. During follow-up, 30–50% of these patients will have residual hypertension, persistently abnormal urinalysis, or chronic kidney damage [26, 35, 36]. These abnormalities are likely related to the development of glomerulosclerosis from the APSGN [26]. This was initially suggested by Baldwin and colleagues in the 1970s, after they conducted a landmark study of 118 well-characterized patients with APSGN who underwent repeat renal biopsy and were followed for at least 2 years [26]. They found that glomerulosclerosis increased from 18% at diagnosis to 56% after 5–18 years of follow-up. Proliferative lesions decreased from 93% to 11% during this same time period. Overall, 60% of patients developed at least one histologic or clinical marker of chronic damage (proteinuria, hypertension, or decreased GFR). The outcomes in children were better with only 40% having at least one manifestation of chronic damage. However, the extent to which APSGN results in end-stage renal disease is still unclear. The general experience is that APSGN rarely results in end-stage renal disease and long-term prognosis is excellent.