Acute Post-Streptococcal Glomerulonephritis

Pathogenesis of Acute Post-Streptococcal Glomerulonephritis

Nephritogenic Strains and Latency

• Acute post-streptococcal glomerulonephritis (APSGN) is the prototypical postinfectious, immune complex-mediated glomerulonephritis.
• The disease is triggered by antecedent infection with specific nephritogenic strains of Group A $\beta$-hemolytic streptococci (Streptococcus pyogenes), and occasionally by group C or G streptococci.
• Different serotypes of the M virulence protein are associated with specific infection sites: M types 1, 2, 4, and 12 typically cause streptococcal pharyngitis, whereas M types 47, 49, and 55 are associated with pyoderma (impetiginous skin infections).
• The latency period between the onset of infection and the development of nephritis varies according to the site of infection: it is generally 1 to 2 weeks following a respiratory or throat infection, and 3 to 6 weeks following a skin infection.

Mechanisms of Glomerular Injury

• The pathogenesis involves multiple simultaneous mechanisms resulting from both streptococcal and host factors, ultimately leading to immune complex formation and severe complement activation.

Clinical Features

Typical Presentation

• APSGN predominantly affects children between 4 and 14 years of age (mean age ~7 years) and is twice as common in boys as in girls.
• Subclinical episodes (presenting only as microscopic hematuria and hypocomplementemia) are more common than overt disease, especially during epidemics.
• The classic presentation is an acute nephritic syndrome characterized by the sudden, abrupt onset of gross hematuria, edema, hypertension, and oliguria.
• Gross hematuria is reported in approximately 30% to 33% of patients and is typically described as smoky, brown, tea-colored, or cola-colored.
• Edema is present in up to 90% of symptomatic children; it usually begins as facial or periorbital puffiness that does not pit readily on pressure, and can progress to pedal edema.
• Hypertension occurs in 60% to 80% of children, is primarily volume-dependent, and can be severe enough to require immediate pharmacological intervention in about half of cases.

Atypical Presentation and Complications

• Atypical or severe presentations occur due to profound fluid retention, malignant hypertension, or severe glomerular injury.
• Hypertensive encephalopathy may manifest as severe headaches, blurred vision, altered mental status, visual hallucinations, or new-onset generalized convulsions (posterior reversible encephalopathy syndrome or PRES).
• Volume overload can rapidly progress to severe pulmonary edema, respiratory distress, orthopnea, and congestive heart failure.
• Acute Kidney Injury (AKI) with severe oliguria or anuria can occur, accompanied by hyperkalemia, hyponatremia, and severe metabolic acidosis.
• Nephrotic-range proteinuria or frank nephrotic syndrome is an uncommon presentation, occurring in less than 5% of cases.

Diagnosis and Pathology

Laboratory Evaluation

• Urinalysis reveals dysmorphic red blood cells, RBC casts, granular casts, leukocytes, and mild to moderate proteinuria (usually 1-2+ on dipstick).
• Blood tests indicate reduced renal function with elevated blood urea nitrogen (BUN) and serum creatinine, hemodilution resulting in normocytic anemia, and reactive thrombocytosis or hyponatremia/hyperkalemia associated with oliguria.
• Serologic evidence of a recent streptococcal infection is mandatory; the Antistreptolysin O (ASO) titer is elevated in over 80% of patients following pharyngitis, whereas the anti-DNAse B titer is more reliably elevated following streptococcal skin infections.
• Serum complement C3 and CH50 levels are significantly reduced in >90% of patients during the acute phase; importantly, these levels typically return to normal within 8 to 12 weeks.
• Complement C4 levels are typically normal or only mildly depressed.

Renal Pathology

• Renal biopsy is rarely indicated but may be performed if there is delayed resolution (e.g., oliguria/azotemia beyond 1-2 weeks, gross hematuria beyond 3-4 weeks), nephrotic-range proteinuria, normal C3 at onset, or persistently low C3 beyond 12 weeks.
• Light Microscopy: Glomeruli are enlarged, bloodless, and exhibit diffuse endocapillary and mesangial cell proliferation with prominent neutrophilic and monocytic infiltration (exudative changes).
• Immunofluorescence: Demonstrates "lumpy-bumpy" or granular deposits of IgG and C3 scattered along the glomerular capillary walls and mesangium, often described as a "starry sky" or "garland" pattern.
• Electron Microscopy: The pathognomonic feature is the presence of large, electron-dense, subepithelial deposits, commonly referred to as "humps".

Differential Diagnosis

Management

Supportive Care and Pharmacotherapy

• There is no specific therapy to reverse the immune complex-mediated glomerular inflammation; management is entirely supportive and directed at mitigating the acute consequences of volume overload and hypertension.
• Diet and Fluid Restriction: Strict restriction of sodium, potassium, and fluid intake is required until spontaneous diuresis occurs and serum creatinine levels begin to fall; daily fluid intake should be limited to insensible losses (400 mL/m²/day) plus measured urine output.
• Diuretics: Oral furosemide (1-3 mg/kg) is highly effective for managing mild to moderate volume-dependent hypertension and edema; intravenous furosemide (2-4 mg/kg) is utilized for impending or active pulmonary edema and severe heart failure.
• Antihypertensives: If diuretics are insufficient, calcium channel blockers (e.g., amlodipine, nifedipine) or vasodilators are used; ACE inhibitors and angiotensin receptor blockers (ARBs) should be avoided during the acute oliguric phase due to the high risk of exacerbating hyperkalemia.
• Antibiotic Therapy: A 10-day course of systemic antibiotics (e.g., penicillin) is administered if active streptococcal infection (pharyngitis or pyoderma) is present to limit the spread of nephritogenic strains to close contacts, although it does not alter the natural history or progression of the glomerulonephritis itself.

Management of Complications