In acute post-streptococcal glomerulonephritis the glomerular inflammation results from

Post-Streptococcal Glomerulonephritis

PSGN is an inflammatory disease of the kidneys that is usually associated with childhood pyoderma and is characterized by localized oedema and haematuria [304]. GAS may stimulate glomerular inflammation by several pathways which are likely to act in concert to initiate and perpetuate PSGN (for an excellent review see [305]). Complement activation is central to the pathogenesis of PSGN and the resolution of renal lesions has been shown to coincide with the transient reduction of serum complement levels. The deposition of circulating immune complexes within the small blood vessels of the kidneys has been shown to result in local activation of the complement system [305]. However, such immune complexes are present at similar levels within the serum of PSGN patients and those with uncomplicated GAS infections, suggesting that this alone is insufficient to induce nephritis [305,306].

Direct deposition of cationic GAS antigens within the glomerular tissues is also thought to play an essential role in the pathogenesis of PSGN. Patients with severe PSGN often present with prominent, electron-dense deposits within the subepithelial tissues of the glomerular basement membrane which are highly immunostimulatory [305]. Despite many years of research the identity of these nephrotogenic GAS antigens is yet to be elucidated [113].

Post-streptococcal glomerulonephritis (PSGN)

PSGN, the most common cause of childhood nephritis worldwide, occurs approximately 2 weeks after a group A streptococcus (GAS) skin or throat infection (Savige et al., 2019). Compared to the developed countries, where PSGN is more prevalent among elderly patients with debilitating conditions, in the developing countries, pediatric PSGN, with an annual incidence of about 9/100000, is more common (Rodriguez-Iturbe and Haas, 2016). Pathophysiology of PSGN is mediated by immune complexes. Antigens of GAS entering the circulation following the infection reside in glomeruli. Meanwhile, antibodies directed at these antigens are produced and form ICs with them either in the glomeruli or in the circulation, some of which aggregate in the glomeruli as well. Notably, before the activation of the adaptive immune response, streptococcal cell wall antigens activate innate immunity via the lectin pathway of the complement system. To date, two nephrogenic antigens; namely, nephritis-associated plasmin receptor (NAPlr) and streptococcal pyrogenic exotoxin B (SPE-B) have been found in GAS, which activate the alternative complement pathway, increase the production of circulatory ICs, and have high affinity to glomerular proteins (Eison et al., 2011; Rodriguez-Iturbe and Haas, 2016). Autoantibodies can also play a role in the PSGN pathophysiology (Balasubramanian and Marks, 2017). While PSGN is usually asymptomatic, some cases present with nephritic syndrome, exhibiting as hematuria, elevated creatinine levels, hypertension, and oliguria (Walker et al., 2014). The prognosis of PSGN is generally favorable. However, it can rarely lead to acute renal failure (VanDeVoorde, 2015). Detection of antistreptolysin O (in pharyngitis) and anti–DNase B (in impetigo) antibodies, together with low C3 levels, can help in the PSGN diagnosis (Maness et al., 2018). PSGN management is supportive treatment, unless an active infection is present, in which case antibiotics are used (Hunt and Somers, 2019).

Epidemiology

Poststreptococcal glomerulonephritis (PSGN) is more common in males (2:1) and usually affects children 2 to 14 years old. Traditionally, only certain nephritogenic strains of group A Streptococcus pyogenes result in GN. In the tropics and southern United States, PSGN usually follows streptococcal impetigo of M types 47, 49, 55, and 57. Throat infections with streptococcus types 1, 2, 4, and 12 are also nephritogenic.3,4 More recently, ingestion of unpasteurized milk contaminated with group C streptococcus (Streptococcus zooepidemicus) has caused clusters of cases and at least one large epidemic.5 The risk of nephritis in epidemics may range from 5% in throat infections to as high as 25% in M type 49 pyoderma. A genetic predisposition is suggested as there is an association of PSGN with HLA-DR4 and DR1 and higher attack rates in siblings than expected for the general population. The risk of PSGN is reduced by early antibiotic treatment.

PSGN is becoming less common in industrialized countries and is changing its epidemiologic pattern from one that primarily affects children to one that now occurs more commonly in debilitated elderly individuals, particularly alcoholics, diabetics, and intravenous drug users.2 Nevertheless, PSGN remains common in developing countries, where it may affect 9.3 to 9.8 cases per 100,000 population,4 especially in communities with poor socioeconomic conditions. The reduction in incidence of PSGN likely relates to more rapid and frequent use of antibiotics. The common practice of fluorination of water may also be protective as fluoride reduces the expression of virulence factors in cultures of S. pyogenes.

Post-Infectious Glomerulonephritis

Post-streptococcal glomerulonephritis (PSGN) was previously felt to be a relatively benign disease, especially in children, with resolution of clinical findings and minimal clinical sequelae once treated with appropriate antimicrobial therapy.53,54 However, a recent study in 1519 Australian Aboriginal residents living in a rural community found significantly higher levels of albuminuria and reduced eGFR<60 mL/min/1.73 m2 in the 200 individuals who had at least one episode of PSGN.55 This study highlights the importance of regular follow-up of patients once an episode of post-infectious GN resolves, in order to assess the clinical consequences of CKD. CKD in this patient population likely results from residual glomerular scarring leading to secondary FSGS, with subsequent glomerular hyperfiltration and glomerulomegaly in the remaining functioning nephrons. This subset of patients should receive treatment strategies focused on slowing the progression of CKD and reducing rates of albuminuria, including treatment of hypertension with RAAS inhibitors where clinically appropriate.

Staphylococcus aureus-associated GN with or without endocarditis is surpassing PSGN as the most common cause of post-infectious glomerulonephritis in the United States and other developed countries.56 This is largely the result of widespread effective anti-streptococcal antimicrobial therapy. There are few data on the risk of progressive CKD in the post-infectious staphylococcal population. Renal outcomes largely depend on the early eradication of infection which will help to ameliorate any ongoing immune complex-mediated glomerular injury. A particular subset of IgA-dominant post-infectious glomerulonephritis, more common in patients with diabetes, may have a more treatment-resistant course, with higher rates of progressive renal impairment.57

POST-STREPTOCOCCAL GLOMERULONEPHRITIS

Post-streptococcal glomerulonephritis is the result of skin or throat infection with nephritogenic strains of group A streptococci. Nephritic syndrome characteristically appears around 2 weeks after the infection. Whereas the role of streptococcal infection in causing the disease is widely accepted, the demonstration of streptococcal antigens and antibodies in glomeruli has been controversial.

Post-streptococcal glomerulonephritis is characterized by a nephritic syndrome consisting of smoky or rust-colored urine, generalized edema, hypertension, and nephritic urine sediment. Proteinuria is typically mild. Patients have rising titers of anti-streptolysin and depressed C3 levels early in nephritis but normal or minimally depressed C4 levels, indicating activation of the alternative complement pathway.

Complete clinical resolution of nephritis is the rule, and therefore renal biopsy is not usually indicated in children. In adults, biopsy is often necessary for diagnosis. Proliferative glomerulonephritis with polymorphonuclear leukocyte and monocyte infiltration, granular immune deposits of IgG and C3, and dome-shaped electron-dense subepithelial deposits (humps) are characteristic. The prognosis is excellent: almost all children will recover with supportive care. Progressive renal failure accompanied by severe hypertension appears to be more common in adults.

Incidence

APSGN occurs sporadically or in epidemic forms. Children are affected more than adults (peak age, 2–6 years) and males more commonly have overt nephritis, although there is a higher incidence of subclinical disease in females (588, 670). Only a fraction of infected individuals develop disease. The source of the infection is variable, but follows geographic distribution of nephritogenic strains (25). Group A streptococci accounts for most cases and specific subtypes predominate (672). Less commonly non-group A streptococci and other infectious organisms have been associated with a similar syndrome.

Poststreptococcal Glomerulonephritis

Poststreptococcal glomerulonephritis is common in children73 in developing countries 1 to 3 weeks after pharyngitis or impetigo. Most cases are asymptomatic, but in 20% of affected patients, the nephritic syndrome develops, manifesting as hematuria, hypertension, oliguria, and an elevated serum creatinine. Antistreptolysin O and anti–DNase B antibodies are detectable after throat and skin infections, respectively, and C3 levels are low. The prognosis usually is excellent, and no specific treatment is needed. In up to 1% of patients, however, acute renal failure with a crescentic glomerulonephritis develops, sometimes associated with ANCA.74 The role of corticosteroids and immunosuppressants in these patients is controversial.

Poststreptococcal Glomerulonephritis

The term glomerulonephritis refers to kidney inflammation accompanied by inflammation of the capillary loops in the renal glomeruli.7 Given this definition, renal biopsy is required to definitively identify glomerulonephritis. Thus this diagnosis is not formally made in the emergency department. Instead, a constellation of clinical and laboratory findings is used to support a presumptive diagnosis. Of the myriad causes of the acute forms of disease, the most common is poststreptococcal glomerulonephritis. Since the exact cause of acute glomerulonephritis is not identified in the emergency department, understanding the paradigm of poststreptococcal glomerulonephritis offers insight into this and other causes of acute glomerulonephritis.

Immune Complex Crescentic GN

These patients form a heterogeneous group in which multiple stimuli lead to proliferative GN with crescents. Immunohistology shows granular deposits of immunoglobulin and complement along capillary walls and in the mesangium. The causes include infections, systemic diseases, and pre-existing primary GN.

Renal lesions with other rheumatic diseases

Poststreptococcal GN rarely develops in individuals who contract acute rheumatic fever because the nephritogenic and rheumatogenic strains of β-hemolytic streptococci are different. However, cases of mesangial proliferative GN have been described.38

Persistent mesangial proliferative GN, manifested clinically as non–nephrotic-range proteinuria associated with microscopic hematuria, sometimes develops in patients with polymyositis and dermatomyositis.

A variety of renal abnormalities have been described in patients with psoriatic arthritis, including secondary amyloid and membranous GN.39

Common renal manifestations of sarcoidosis include hypercalcemia-associated nephrolithiasis and interstitial nephritis with granuloma formation.40 Infrequently, sarcoidosis may be manifested as obstructive uropathy secondary to retroperitoneal lymph node involvement. TINU syndrome is relatively uncommon and is characterized by eye pain associated with renal failure in young women.41 The differential diagnosis for interstitial nephritis associated with ocular findings should also include a number of rheumatologic disorders: sarcoidosis, ANCA-associated granulomatous vasculitis, SLE, Sjögren syndrome, and Behçet disease.