BASICS
DESCRIPTION
Postinfectious glomerulonephritis (PIGN) is an immune complex disease preceded by nonrenal infection with certain strains of bacteria, most commonly Streptococcus and Staphylococcus. The most common form of PIGN, poststreptococcal glomerulonephritis (PSGN), predominantly affects children. The clinical presentation varies from asymptomatic to the acute nephritic syndrome, characterized by gross hematuria, proteinuria, edema, hypertension (HTN), and acute kidney injury.
EPIDEMIOLOGY
A global decline in incidence, especially in developed countries is attributed to better hygiene and a decreased incidence of streptococcal skin infections. Of cases, 97% occur in developing countries. PSGN is primarily a pediatric disease, but a recent increase has been seen in nonstreptococcal GN in adults.
Incidence
- Pediatrics: 24.3 cases/100,000 persons per year in developing countries; 6 cases/100,000 persons per year in developed countries
- Adults: 2 cases/100,000 persons per year in developing countries; 0.3 cases/100,000 persons per year in developed countries
- Worldwide, 34% of cases are now seen in adults with a global burden of 68,000 cases per year.
- Male > female (2:1) (1)
ETIOLOGY AND PATHOPHYSIOLOGY
- Glomerular immune complex disease induced by specific nephritogenic strains of bacteria:
- Group A β-hemolytic Streptococcus (GAS)
- Staphylococcus (predominantly Staphylococcus aureus; more commonly methicillin-resistant S. aureus [MRSA], occasionally coagulase-negative Staphylococcus)
- Gram-negative bacteria including Escherichia coli, Yersinia, Pseudomonas, and Haemophilus (1)
- Proposed mechanisms for the glomerular injury (2):
- Deposition of circulating immune complexes with streptococcal or staphylococcal antigens-these complexes can be detected in patients with streptococcal- or staphylococcal-related GN but do not correlate to disease activity (3).
- In situ immune complex formation from deposition of antigens within the glomerular basement membrane (GBM) and subsequent antibody binding
- In situ glomerular immune complex formation promoted by antibodies to streptococcal or staphylococcal antigens
- Alteration of normal renal antigen leading to molecular mimicry that elicits an autoimmune response
- Glomerular immune complex causing complement activation and inflammation:
- Nephritis-associated plasmin receptor (NAPlr): activates plasmin, contributes to activation of the alternative complement pathway
- Streptococcal pyrogenic exotoxin B (SPE B): binds plasmin and acts as a protease; promotes the release of inflammatory mediators
- Activation of the alternative complement pathway causes initial glomerular injury as evidenced by C3 deposition and decreased levels of serum C3. The lectin pathway of complement activation has also been recently implicated in glomerular injury (4).
RISK FACTORS
- Children 5 to 12 years of age
- Older patients (>65 years of age) (1):
- Patients with immunocompromising comorbid conditions
- Diabetes
- Alcohol abuse
GENERAL PREVENTION
- Early antibiotic treatment for streptococcal and staphylococcal infections, when indicated, although efficacy in preventing GN is uncertain
- Improved hygiene
- Prophylactic penicillin treatment to be used in closed communities and household contacts of index cases in areas where PIGN is prevalent
COMMONLY ASSOCIATED CONDITIONS
Streptococcal infection, staphylococcal infection
DIAGNOSIS
HISTORY
- Patients present with acute nephritic syndrome, characterized by sudden onset of hematuria associated with edema and HTN 1 to 2 weeks after an infection
- A triad of edema, hematuria, and HTN is classic.
- Urine described as "tea-colored" or "cola-colored."
- PIGN in children usually follows GAS skin/throat infection.
- The latent period between GAS infection and PIGN depends on the site of infection: 1 to 3 weeks following GAS pharyngitis and 3 to 6 weeks following GAS skin infection.
- Adult PIGN most commonly follows staphylococcal infections (3 times more common than streptococcal infections) of the upper respiratory tract, skin, heart, lung, bone, or urinary tract. Studies show 7-16% of cases of adult PIGN have no preceding evidence of infection and, in 24-59% the offending microorganism cannot be identified (5)[A].
PHYSICAL EXAM
- Edema: present in ~2 of 3 adult patients due to sodium and water retention; less common in pediatric patients
- Gross hematuria: present in 25-60% of patients
- HTN: present in 80-90% of patients and varies from mild to severe; secondary to fluid retention Hypertensive encephalopathy is an uncommon but serious complication
- Microscopic hematuria: subclinical cases of PIGN
- Respiratory distress: due to pulmonary edema (rare)
DIFFERENTIAL DIAGNOSIS
The diagnosis of PIGN is generally by history once the diagnosis of acute nephritis is made, with documentation of a recent infection and nephritis beginning to resolve 1 to 2 weeks after presentation. However, with progressive disease >2 weeks, persistent hematuria/HTN >4 to 6 weeks, or no adequate documentation of a GAS or other infection, the differential diagnosis of GN needs to be considered and renal biopsy ordered:
- Membranoproliferative glomerulonephritis (MPGN): The presentation of MPGN may be indistinguishable initially with hematuria, HTN, proteinuria, and hypocomplementemia after an upper respiratory infection. However, patients with MPGN continue to have persistent nephritis and hypocomplementemia beyond 4 to 6 weeks and possibly also have a further elevation in serum creatinine. Patients with PIGN tend to have resolution of their disease and a return of normal C3 and CH50 levels within 2 to 4 weeks.
- Secondary causes of GN: Lupus nephritis and Henoch-Sch ¶nlein purpura nephritis have features similar to PIGN. Extrarenal manifestations and laboratory tests for these underlying systemic diseases help differentiate them from PIGN. Hypocomplementemia is not characteristic of Henoch-Sch ¶nlein purpura and the hypocomplementemia that occurs in lupus nephritis is with reductions in both C3 and C4, whereas C4 levels are normal in PIGN.
- IgA nephropathy often presents after an upper respiratory infection. It can be distinguished from PIGN based on a shorter time frame between the upper respiratory illness and hematuria, as well as history of gross hematuria, as PIGN recurrence is rare. IgA nephropathy is a chronic illness and will recur. Patients with IgA nephropathy have normal C3/C4 levels.
- Note: IgA-dominant PIGN is a newly recognized form of PIGN occurring in poststaphylococcal GN. This differs from primary IgA nephropathy in that these patients do not have a history of renal disease (1)[A].
- Pauci-immune crescentic GN: In elderly patients with severe renal failure and active urine sediment, this is much more common, so antineutrophil cytoplasmic antibody (ANCA) testing should be done (1)[A].
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (labs, imaging)
Urinalysis shows hematuria; can be with/without RBC casts and pyuria. Proteinuria is present, but nephrotic range proteinuria is uncommon in children (more likely in adults).
Follow-Up Tests & Special Considerations
- Culture: PSGN usually presents weeks after a GAS infection; only ~25% of patients will have either a positive throat or skin culture.
- Complement: 90% of pediatric patients (slightly fewer adult patients) will have depressed C3 and CH50 levels in the first 2 weeks of the disease, whereas C2 and C4 levels remain normal. C3 and CH50 levels return to normal within 4 to 8 weeks after presentation.
- Creatinine: Elevated to the point of renal insufficiency in 25-83% of cases, more commonly in adults (83%) (4)[A].
- Serology: Elevated titers of antibodies support evidence of a recent GAS infection. Streptozyme test measuring antistreptolysin O (ASO), antihyaluronidase (AHase), antistreptokinase (ASKase), anti-nicotinamide-adenine dinucleotidase (anti-NAD), and anti-DNAse B antibodies: positive in >95% of patients with PSGN due to pharyngitis and 80% with skin infections. In pharyngeal infection, ASO, anti-DNAse B, anti-NAD, and AHase titers are elevated. In skin infections, only the anti-DNAse and AHase titers are typically elevated.
Diagnostic Procedures/Other
Renal biopsy is rarely done in children; recommended in most adults to confirm the diagnosis and rule out other glomerulopathies with similar clinical presentations that require immunosuppressive treatment.
Test Interpretation
- Light microscopy: diffuse proliferative glomerulonephritis with prominent endocapillary proliferation and numerous neutrophils within the capillary lumen. Deposits may also be found in the mesangium ("starry sky"). Severity of involvement varies and correlates with clinical findings. Crescent formation is uncommon and is associated with a poor prognosis.
- Immunofluorescence microscopy: Deposits of C3 and IgG distributed in a diffuse granular pattern.
- Electron microscopy: dome-shaped subepithelial electron-dense deposits that are referred to as "humps." These deposits are immune complexes, and they correspond to the deposits of IgG and C3 found on immunofluorescence. Rate of clearance of these deposits affects recovery time.
- Renal biopsy: usually not performed in most patients to confirm the diagnosis of PIGN as clinical history is highly suggestive and resolution of PIGN typically begins within 1 week of presentation. A biopsy is done when other glomerular disorders are being considered, such as in the case of persistently low C3 levels beyond 6 weeks for possible diagnosis of MPGN, recurrent episodes of hematuria suggestive of IgA nephropathy, or a progressive increase in serum creatinine not characteristic of PIGN.
TREATMENT
MEDICATION
- No specific therapy exists for PIGN, and no randomized controlled trials indicate that aggressive immunosuppressive therapy has a beneficial effect in patients with rapidly progressive crescentic disease. Despite this, patients with >30% crescents on renal biopsy are often treated with steroids (4)[A].
- Older patients often require hospitalization to prevent and treat complications of heart failure (HF) from volume overload (1).
- Management is supportive, with focus on treating the clinical manifestations of PIGN. These include HTN and pulmonary edema:
- General measures include salt and water restriction and loop diuretics.
- Calcium channel blockers/angiotensin-converting enzyme (ACE) inhibitors may be used in cases of severe HTN (4)[A].
- Patients with evidence of persistent bacterial infection should be given a course of antibiotic therapy.
SURGERY/OTHER PROCEDURES
Acute dialysis is required in approximately 50% of elderly patients (1).
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Repeat urinalysis to check for clearance of hematuria and/or proteinuria.
- Consider other diagnosis if no improvement within 2 weeks.
- Recurrence is rare.
DIET
Renal diet if requiring instances of dialysis
PROGNOSIS
- Most children with PIGN have an excellent outcome, with >90% of cases achieving full recovery of renal function.
- Elderly patients, especially adults, develop HTN, recurrent proteinuria, and renal insufficiency long after the initial illness. Adults with multiple comorbid factors have the worst prognosis and highest incidence of chronic renal injury following PIGN (1).
- Complete remission in adult PIGN is only 26-56%. This has declined since the 1990s, suggesting prognosis is worsening (5).
- The presence of diabetes, higher creatinine levels, and more severe glomerular disease (e.g., crescents) on biopsy are all risk factors for developing end-stage renal disease (1).
REFERENCES
11 Nasr SH, Radhakrishnan J, D'Agati VD. Bacterial infection-related glomerulonephritis in adults. Kidney Int. 2013;83(5):792-803.22 Nadasdy T, Hebert LA. Infection-related glomerulonephritis: understanding mechanisms. Semin Nephrol. 2011;31(4):369-375.33 Uchida T, Oda T, Watanabe A, et al. Clinical and histologic resolution of poststreptococcal glomerulonephritis with large subendothelial deposits and kidney failure. Am J Kidney Dis. 2011;58(1):113-117.44 Ramdani B, Zamd M, Hachim K, et al. Acute postinfectious glomerulonephritis. Nephrol Ther. 2012;8(4):247-258.55 Wen YK. Clinicopathological study of infection-associated glomerulonephritis in adults. Int Urol Nephrol. 2010;42(2):477-485.
ADDITIONAL READING
- Eison TM, Ault BH, Jones DP, et al. Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis. Pediatr Nephrol. 2011;26(2):165-180.
- Nasr SH, Fidler ME, Valeri AM, et al. Postinfectious glomerulonephritis in the elderly. J Am Soc Nephrol. 2011;22(1):187-195.
- Nast CC. Infection-related glomerulonephritis: changing demographics and outcomes. Adv Chronic Kidney Dis. 2012;19(2):68-75.
- Rodriguez-Iturbe B, Musser JM. The current state of poststreptococcal glomerulonephritis. J Am Soc Nephrol. 2008;19(10):1855-1864.
- Singh GR. Glomerulonephritis and managing the risks of chronic renal disease. Pediatr Clin North Am. 2009;56(6):1363-1382.
CODES
ICD10
- N05.9 Unsp nephritic syndrome with unspecified morphologic changes
- N00.9 Acute nephritic syndrome with unsp morphologic changes
ICD9
580.0 Acute glomerulonephritis with lesion of proliferative glomerulonephritis
SNOMED
- 236395002 Post-infectious glomerulonephritis (disorder)
- 68544003 Acute post-streptococcal glomerulonephritis (disorder)
CLINICAL PEARLS
- PIGN is an immune complex disease occurring after infection with certain strains of bacteria, most commonly group A Streptococcus pyogenes.
- The clinical presentation varies from asymptomatic to the acute nephritic syndrome, characterized by gross hematuria, proteinuria, edema, HTN, and acute kidney injury.
- Treatment is primarily supportive and includes treating HTN and edema, along with antibiotics for any ongoing bacterial infection.
- Persistent nephritis and low C3 levels for >2 weeks should prompt evaluation for other causes of GN, such as MPGN or systemic lupus erythematosus nephritis.