Renal/Urology · PANCE / PANRE

Nephritic Syndrome

Glomerular inflammation with hematuria, RBC casts, hypertension, and mild-to-moderate proteinuria.

Also known as: nephritic syndrome, glomerulonephritis, GN, RPGN

Overview

Clinical syndrome resulting from glomerular inflammation, characterized by hematuria (often with dysmorphic RBCs and RBC casts), variable proteinuria (typically <3.5 g/day), hypertension, edema, and azotemia. Spans a spectrum from indolent to rapidly progressive glomerulonephritis (RPGN).

Epidemiology

Incidence varies by etiology. Post-streptococcal GN is the most common cause worldwide in children. IgA nephropathy is the most common primary glomerulonephritis globally. ANCA-associated vasculitis and lupus nephritis dominate adult RPGN.

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Question 1RenalMedium
A 7-year-old boy is brought in for 2 days of tea-colored urine and puffy eyes. Three weeks ago he was treated for streptococcal pharyngitis. On exam his blood pressure is 138/90 mmHg and he has periorbital edema. Urinalysis shows 3+ blood with dysmorphic red cells and red cell casts, and 1+ protein. Serum creatinine is mildly elevated. Which of the following findings best supports the suspected diagnosis?
  • APositive anti-GBM antibody on serology
  • BPositive c-ANCA targeting proteinase 3
  • CLow serum C3 with a preserved C4 level
  • DElevated total serum IgA antibody level
Reveal answer & full explanation
Correct answer: C — Low serum C3 with a preserved C4 level
  • APositive anti-GBM antibody on serology
  • BPositive c-ANCA targeting proteinase 3
  • CLow serum C3 with a preserved C4 level
  • DElevated total serum IgA antibody level

Why Low serum C3 with a preserved C4 level is correct

  • The vignette (tea-colored urine, periorbital edema, hypertension, RBC casts 1-3 weeks after strep pharyngitis) is classic post-streptococcal glomerulonephritis.
  • Post-strep GN activates the alternative complement pathway, producing a depressed C3 with a preserved C4; positive ASO/anti-DNase B titers confirm recent streptococcal infection.
  • Complement classification of GN: LOW C3 = post-strep, MPGN, lupus, cryoglobulinemia; NORMAL C3 = IgA nephropathy, anti-GBM, ANCA-associated vasculitis.

Why the others are wrong

  • Positive anti-GBM antibody on serology — defines anti-GBM (Goodpasture) disease, a pulmonary-renal RPGN with linear IgG on biopsy and a normal C3; it does not follow strep pharyngitis.
  • Positive c-ANCA targeting proteinase 3 — points to granulomatosis with polyangiitis (pauci-immune crescentic GN with sinopulmonary disease and normal complement), not a post-infectious GN in a child.
  • Elevated total serum IgA antibody level — suggests IgA nephropathy, which causes synpharyngitic hematuria within days of a URI and has a normal C3, not the 1-3 week post-strep latent period seen here.
Question 2RenalMedium
A 7-year-old boy is brought in for 2 days of cola-colored urine and puffy eyes. Three weeks ago he was treated for a skin infection on his legs. On exam his blood pressure is 138/90 mm Hg and he has periorbital and pedal edema. Urinalysis shows 3+ blood with dysmorphic red cells and red cell casts; serum creatinine is mildly elevated. Serum C3 is low with a normal C4, and the anti-DNase B titer is elevated. Which of the following best explains the findings?
  • APauci-immune neutrophil-mediated glomerular necrosis
  • BLinear deposition of anti-basement-membrane antibody
  • CGlomerular deposition of circulating immune complexes
  • DMesangial deposition of IgA-containing immune complexes
Reveal answer & full explanation
Correct answer: C — Glomerular deposition of circulating immune complexes
  • APauci-immune neutrophil-mediated glomerular necrosis
  • BLinear deposition of anti-basement-membrane antibody
  • CGlomerular deposition of circulating immune complexes
  • DMesangial deposition of IgA-containing immune complexes

Why Glomerular deposition of circulating immune complexes is correct

  • Nephritic syndrome 1-3 weeks after a streptococcal skin infection, with low C3, a normal C4, and a positive anti-DNase B, is classic post-streptococcal glomerulonephritis.
  • Streptococcal antigens form immune complexes that deposit in the subepithelial glomerular space, activate complement (driving the low C3), and provoke proliferative, inflammatory injury.
  • The resulting endothelial and mesangial inflammation breaches the filtration barrier, letting RBCs into Bowman space and producing dysmorphic RBCs and RBC casts.

Why the others are wrong

  • Linear deposition of anti-basement-membrane antibody is the mechanism of anti-GBM (Goodpasture) disease, which causes a pulmonary-renal syndrome with a normal C3, not low C3 after strep.
  • Pauci-immune neutrophil-mediated glomerular necrosis describes ANCA-associated vasculitis, which is ANCA-positive with normal complement and few immune deposits.
  • Mesangial deposition of IgA-containing immune complexes is IgA nephropathy, in which hematuria is synpharyngitic (within days of a URI, not 1-3 weeks later) and C3 is normal.
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Risk factors

  • Recent infection: streptococcal (post-strep GN), staphylococcal, hepatitis B/C
  • Autoimmune disease: SLE, ANCA vasculitis, anti-GBM (Goodpasture)
  • Family history: Alport syndrome, IgA nephropathy
  • Cryoglobulinemia (often hep C-related)
  • Recent URI (synpharyngitic hematuria of IgA nephropathy)

Pathophysiology

Immune-mediated glomerular injury — immune complex deposition, in situ antibody formation, or pauci-immune inflammation — disrupts the filtration barrier and triggers proliferative changes. Endothelial and mesangial inflammation allow RBC passage into Bowman space, generating dysmorphic RBCs and RBC casts. Loss of nephron mass causes azotemia and sodium retention → hypertension and edema.

Clinical presentation

Symptoms

  • Cola-colored, tea-colored, or smoky urine (gross hematuria)
  • Periorbital and peripheral edema
  • Headache, malaise (from hypertension)
  • Oliguria in severe or rapidly progressive cases
  • Constitutional symptoms (fever, weight loss, arthralgia) in systemic vasculitis or SLE

Signs / physical exam

  • Hypertension (sometimes severe)
  • Periorbital edema, peripheral edema
  • Skin findings: palpable purpura (IgA vasculitis, cryoglobulinemia), malar rash (SLE)
  • Respiratory: hemoptysis suggests pulmonary-renal syndrome (anti-GBM, ANCA)
  • Sinusitis, saddle-nose deformity in GPA

Classic findings

Tea-colored urine plus periorbital edema and hypertension in a child 1-3 weeks after sore throat — classic for post-streptococcal GN.

Differential diagnosis

  • IgA nephropathy — Synpharyngitic hematuria (within days of URI), mesangial IgA deposits; common in young adults
  • Post-streptococcal GN — 1-3 weeks after group A strep pharyngitis or impetigo; low C3, normal C4; positive ASO/anti-DNase B
  • Anti-GBM disease (Goodpasture) — Pulmonary hemorrhage + RPGN; linear IgG on biopsy; anti-GBM antibody positive
  • ANCA-associated vasculitis (GPA, MPA, EGPA) — Pauci-immune crescentic GN; c-ANCA (PR3) in GPA; p-ANCA (MPO) in MPA/EGPA; sinopulmonary involvement
  • Lupus nephritis — SLE features; ANA, anti-dsDNA, low C3/C4; biopsy classes I-VI guide therapy
  • Membranoproliferative GN (MPGN) — Mixed nephritic/nephrotic; low C3; hepatitis C with cryoglobulinemia, monoclonal gammopathy
  • Alport syndrome — Hereditary X-linked; hematuria, sensorineural hearing loss, lenticonus; type IV collagen mutation
  • Thin basement membrane disease — Benign familial hematuria; isolated microhematuria; thin GBM on EM; preserved function

Diagnostic workup

Diagnostic criteria

Nephritic syndrome = hematuria (often gross) with RBC casts and dysmorphic RBCs + variable proteinuria + hypertension + azotemia. Kidney biopsy is the definitive test for adults and complicated pediatric cases to determine pattern and guide immunosuppression.

Labs

  • Urinalysis with microscopy — dysmorphic RBCs, RBC casts (diagnostic of glomerular bleed)
  • Spot UPCR or 24-h urine protein
  • BMP, CBC, creatinine trend
  • Complement: C3 and C4 (low in post-strep, lupus, MPGN, cryoglobulinemia; normal in IgA, anti-GBM, ANCA)
  • ANA, anti-dsDNA (lupus); ANCA with PR3/MPO; anti-GBM antibody
  • ASO, anti-DNase B (post-strep)
  • Hepatitis B/C serologies, HIV; cryoglobulins; SPEP/UPEP

Imaging

  • Renal ultrasound to assess size and exclude obstruction
  • Chest imaging if pulmonary symptoms or suspected pulmonary-renal syndrome

Diagnostic algorithm

DiseaseComplementKey SerologyBiopsy IF Pattern
Post-streptococcal GNLow C3, normal C4ASO, anti-DNase BGranular IgG/C3, 'humps'
IgA nephropathyNormal(galactose-deficient IgA1)Mesangial IgA
Lupus nephritisLow C3 and C4ANA, anti-dsDNA, anti-Sm'Full house' (IgG, IgA, IgM, C3, C1q)
Anti-GBM (Goodpasture)NormalAnti-GBM antibodyLinear IgG along GBM
ANCA (GPA/MPA)Normalc-ANCA/PR3 or p-ANCA/MPOPauci-immune crescentic
MPGNLow C3 ± low C4Cryoglobulins, hep CSubendothelial deposits, 'tram-tracking'
Differentiating glomerulonephritides by complement status, serology, and immunofluorescence pattern.

Treatment

First-line

  • Treat underlying etiology — antibiotics for active infection, immunosuppression for autoimmune cause
  • BP control: ACEi or ARB (lisinopril, losartan); avoid in acute AKI exacerbation
  • Loop diuretic — furosemide, torsemide — for volume overload
  • Sodium and fluid restriction
  • Empiric pulse methylprednisolone (1 g IV daily × 3) for biopsy-proven or strongly suspected RPGN while definitive workup pending

Second-line / adjunct

  • ANCA vasculitis: induction with rituximab or cyclophosphamide + glucocorticoids; plasma exchange for severe pulmonary hemorrhage or anti-GBM disease
  • Anti-GBM disease: plasma exchange + cyclophosphamide + steroids
  • Lupus nephritis: mycophenolate or cyclophosphamide + glucocorticoids; voclosporin or belimumab as add-on
  • Cryoglobulinemic GN: treat underlying hep C with direct-acting antivirals; rituximab for refractory
  • Hemodialysis if uremia, refractory hyperkalemia, or volume overload not responding to medical therapy

Complications

  • Rapidly progressive renal failure (RPGN)
  • Hypertensive emergency, posterior reversible encephalopathy syndrome (PRES)
  • Pulmonary hemorrhage (anti-GBM, ANCA, lupus)
  • Volume overload, heart failure
  • Progression to CKD/ESRD
  • Treatment-related: infection from immunosuppression, cyclophosphamide bladder toxicity, steroid morbidity

PANCE pearls

  • RBC casts = glomerular bleeding until proven otherwise. Dysmorphic RBCs (especially acanthocytes) also localize to the glomerulus.
  • Complement classification of GN: LOW C3 = post-strep, MPGN, lupus, cryoglobulinemia. NORMAL C3 = IgA, anti-GBM, ANCA, HSP/IgA vasculitis.
  • Pulmonary-renal syndrome (hemoptysis + AKI) = anti-GBM disease, GPA, MPA, or lupus. Send anti-GBM and ANCA urgently.
  • RPGN = loss of >50% kidney function in days to weeks; biopsy shows crescents in >50% of glomeruli. Treat empirically while awaiting biopsy.
  • Post-strep GN has excellent prognosis in children; adults more likely to develop CKD.

References

  • KDIGO 2021 — KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases
  • EULAR/ERA-EDTA 2024 — EULAR Recommendations for the Management of ANCA-Associated Vasculitis: 2022 Update (Hellmich et al., 2024)
  • ACR 2024 — ACR Guideline for the Treatment of Lupus Nephritis (Arthritis Rheumatol 2024)

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