Glomerulonephritis

Glomerulonephritis (GN) is a heterogeneous group of immune-mediated disorders characterized by glomerular inflammation, presenting with variable combinations of hematuria, proteinuria, hypertension, edema, and declining GFR. [1] It is broadly classified into five pathogenic categories: immune-complex GN, ANCA-associated (pauci-immune) GN, anti-GBM GN, C3 glomerulopathy, and monoclonal immunoglobulin-associated GN. [1-2]

The following figure illustrates the immunopathological mechanisms converging to produce the clinical syndromes of nephritis:

1. History

• Onset and timing: Abrupt vs. insidious onset of dark/cola-colored urine, decreased urine output, facial or peripheral edema, weight gain
• Preceding infection: Pharyngitis or skin infection 1–3 weeks prior (post-streptococcal); ongoing infection (endocarditis, abscess, shunt infection) [1][4]
• Systemic symptoms: Fever, malaise, arthralgias, rash, hemoptysis (pulmonary-renal syndrome), sinusitis, epistaxis (ANCA vasculitis)
• Symptom characterization: Hematuria (gross vs. microscopic, clot-free in GN), foamy urine (proteinuria), periorbital edema worse in the morning [4]
• Progression: Rapid decline in urine output over days to weeks suggests RPGN — a renal emergency [1]
• Important negatives: Absence of dysuria, flank pain radiating to groin, or clots (which suggest non-glomerular causes) [4]

2. Alarm Features

• Rapidly progressive GN (RPGN): Loss of kidney function over days to weeks — requires emergent workup and often empiric treatment before biopsy results [1]
• Pulmonary-renal syndrome: Hemoptysis + AKI → consider anti-GBM disease (Goodpasture) or ANCA vasculitis; requires urgent plasma exchange [4-5]
• Oliguria/anuria at presentation, especially with anti-GBM disease [1]
• Severe hypertension with encephalopathy, seizures, or flash pulmonary edema [6-7]
• Nephrotic-range proteinuria with active sediment (overlap syndrome)
• Systemic vasculitis signs: Palpable purpura, mononeuritis multiplex, nasal/sinus destruction

3. Medications

Drug-induced GN contributors

• Hydralazine: Most common drug-associated ANCA-GN (p-ANCA/MPO positive in 98%); risk increases with doses >200 mg/day and duration >1 year [8]
• Procainamide, minocycline, propylthiouracil, levamisole-adulterated cocaine: Drug-induced ANCA vasculitis [9]
• NSAIDs: Can cause minimal change disease, membranous nephropathy, or interstitial nephritis [10-11]
• Penicillamine, gold salts: Membranous nephropathy [12]
• Interferons, bisphosphonates (pamidronate): FSGS [13]
• Immune checkpoint inhibitors, anti-VEGF agents (bevacizumab, lenvatinib): Thrombotic microangiopathy and various glomerular lesions [10][14]

Common treatments

• Supportive: ACEi/ARB for BP and proteinuria control; loop diuretics for volume overload [1][15]
• Immunosuppressive (disease-specific): High-dose glucocorticoids, cyclophosphamide, rituximab, mycophenolate mofetil [1][4]
• Plasma exchange: Anti-GBM disease, severe ANCA-GN with pulmonary hemorrhage [1][4]

Contraindicated/caution

• Avoid immunosuppression in infection-related GN with active infection (may worsen outcomes) [1]
• NSAIDs should be avoided in the setting of AKI
• Potassium-sparing diuretics require caution with declining GFR

4. Diet

• Sodium restriction: <2 g/day (<90 mmol/day) — primary intervention for BP and edema control [1][4]
• Protein intake: 0.8–1.0 g/kg/day; avoid high-protein diets which can worsen proteinuria; replace nephrotic losses gram-for-gram up to 5 g/day [4]
• Fluid restriction: In oliguric patients or those with significant edema
• Plant-based protein sources preferred when possible [4]
• Long-term: Weight optimization, calorie restriction if BMI elevated (30–35 kcal/kg/day if GFR <60) [4][16]
• Fish oil supplementation has been studied in IgA nephropathy but evidence remains inconclusive [17]

5. Review of Systems

• HEENT: Sinusitis, epistaxis, nasal crusting (GPA/Wegener), oral ulcers (SLE), pharyngitis (post-streptococcal)
• Pulmonary: Hemoptysis, dyspnea, cough (pulmonary hemorrhage, fluid overload)
• Cardiovascular: Chest pain, orthopnea, PND (volume overload, pericarditis)
• Skin: Palpable purpura (IgA vasculitis, cryoglobulinemia), malar rash (SLE), livedo reticularis
• MSK: Arthralgias, arthritis (SLE, cryoglobulinemia, HSP)
• Neuro: Peripheral neuropathy (cryoglobulinemia, vasculitis), headache (hypertensive emergency)
• GI: Abdominal pain (HSP), nausea/vomiting (uremia)
• Constitutional: Fever, weight loss, night sweats (vasculitis, endocarditis, malignancy)

6. Collateral History and Family History

• Family history: Alport syndrome (X-linked, hearing loss + hematuria), thin basement membrane disease, polycystic kidney disease, familial IgA nephropathy [18]
• Consanguinity: Increases risk of genetic forms of GN and complement pathway disorders [19]
• Social history: IV drug use (endocarditis-associated GN, heroin nephropathy), cocaine use (levamisole-associated ANCA vasculitis), occupational exposures (hydrocarbons, silica — associated with ANCA vasculitis)
• Travel history: Endemic infections (hepatitis B/C, HIV, malaria, schistosomiasis) [20]
• Medication reconciliation: Thorough review including OTC supplements (lipoic acid), skin-lightening creams (mercury) [11]

7. Risk Factors

• Infections: Group A streptococcus (children), Staphylococcus aureus including MRSA (elderly/diabetics), hepatitis B/C, HIV, endocarditis [1][4][21]
• Autoimmune disease: SLE, rheumatoid arthritis, Sjögren syndrome [4]
• Age: Post-streptococcal GN peaks in children 2–10 years; in developed countries, infection-related GN increasingly affects elderly with comorbidities [21-22]
• Malignancy/monoclonal gammopathy: Especially in patients >50 years [1][4]
• Genetic: Complement pathway variants (C3 glomerulopathy), COL4A mutations (Alport)
• Lifestyle: Smoking (accelerates progression, associated with nodular glomerulosclerosis), obesity [1][23]
• Diabetes: Worsens prognosis of IgA-dominant infection-associated GN [1]

8. Differential Diagnosis

Cannot-miss diagnoses

• RPGN (anti-GBM, ANCA vasculitis, severe immune-complex GN) — renal emergency [24]
• Thrombotic microangiopathy (HUS/TTP) — schistocytes, thrombocytopenia, AKI
• Malignant hypertension with secondary renal injury

Most important alternative diagnoses

• IgA nephropathy — most common GN worldwide; synpharyngitic hematuria (within 1–2 days of URI, unlike 2-week latency of post-streptococcal GN) [15]
• Lupus nephritis — young women, multisystem disease, low C3/C4, positive ANA/anti-dsDNA [1]
• ANCA-associated vasculitis (GPA, MPA, EGPA) — pauci-immune on biopsy, systemic vasculitis features [5]
• Anti-GBM disease — linear IgG on IF, pulmonary hemorrhage in ~60% [1]
• Membranoproliferative GN / C3 glomerulopathy — persistent hypocomplementemia [1]

Mimics

• Interstitial nephritis (drug-induced) — eosinophiluria, WBC casts
• Urological hematuria (stones, malignancy) — isomorphic RBCs, clots present
• Rhabdomyolysis — positive dipstick for blood but no RBCs on microscopy

9. Past Medical History

• Prior episodes of gross hematuria (IgA nephropathy recurrences)
• History of autoimmune disease (SLE, RA, Sjögren)
• Chronic infections (hepatitis B/C, HIV, endocarditis)
• Diabetes (worsens prognosis of infection-related GN) [1]
• Prior kidney biopsy results
• History of kidney transplant (recurrent GN in allograft)
• Surgical history: ventriculoatrial shunts (shunt nephritis) [4]

10. Physical Exam

Vital signs

• Hypertension (often present; target SBP <120 mmHg for long-term management) [1][15]
• Tachycardia, tachypnea (volume overload)

Focused exam

• General: Periorbital and peripheral edema, anasarca, weight gain
• Cardiovascular: JVD, S3 gallop, pulmonary crackles (volume overload); new murmur (endocarditis)
• Lungs: Crackles (pulmonary edema), hemoptysis (pulmonary-renal syndrome)
• Skin: Palpable purpura (IgA vasculitis, cryoglobulinemia), malar rash (SLE), livedo reticularis, skin ulcers, nail-fold infarcts
• Abdomen: Flank tenderness (renal capsular distension), hepatosplenomegaly
• ENT: Saddle nose deformity, nasal septal perforation, serous otitis (GPA)
• Eyes: Scleritis, episcleritis (vasculitis)
• Neuro: Sensory neuropathy (cryoglobulinemia), mononeuritis multiplex
• MSK: Joint swelling/tenderness

11. Lab Studies

Initial workup (recommended to send full panel from the start): [1]

• Urinalysis with microscopy: Dysmorphic RBCs (>25% suggests glomerular origin), RBC casts (pathognomonic for GN), proteinuria [4][18]
• Proteinuria quantification: 24-hour urine collection preferred; spot urine protein-to-creatinine ratio acceptable [1]
• Complete metabolic panel: BUN, creatinine, eGFR (CKD-EPI formula), electrolytes [1]
• CBC: Anemia (chronic disease, microangiopathic), thrombocytopenia (TTP/HUS, SLE)
• Complement levels: C3 and C4 — low C3 alone (post-infectious GN, C3 glomerulopathy); low C3 and C4 (SLE, cryoglobulinemia) [1]
• Serologies:
  • ANCA (MPO and PR3) — vasculitis [5]
  • Anti-GBM antibodies — Goodpasture disease [1]
  • ANA, anti-dsDNA — SLE [1]
  • ASO titer, anti-DNase B — post-streptococcal GN [1]
  • Hepatitis B, C, HIV serologies [1]
  • Cryoglobulins and rheumatoid factor (if purpura, neuropathy, or low C4) [1]
• Serum protein electrophoresis, immunofixation, free light chains (patients >50 years) [1][4]
• CRP, ESR — inflammatory markers
• Blood cultures — if endocarditis suspected [1]

Expected abnormalities by subtype

12. Imaging

• Renal ultrasound: First-line imaging; assess kidney size (normal or enlarged in acute GN; small kidneys suggest chronicity), echogenicity, rule out obstruction, exclude solitary kidney before biopsy [19][27]
• Chest X-ray: Pulmonary edema (volume overload), pulmonary hemorrhage (diffuse alveolar infiltrates in anti-GBM/ANCA disease)
• CT chest (if hemoptysis): Evaluate for diffuse alveolar hemorrhage
• Echocardiography: If endocarditis suspected (vegetations), or to assess volume overload and cardiac function [28-29]
• Imaging is NOT required to diagnose GN — diagnosis is clinical + serologic + biopsy

13. Special Tests

• Kidney biopsy: The gold standard for diagnosis — light microscopy, immunofluorescence, and electron microscopy. Indications include: [1][30]
  • Unclear etiology after serologic workup
  • RPGN
  • Atypical features or atypical course
  • Nephrotic syndrome with active sediment
  • Persistently low C3 beyond 12 weeks (suggests C3 glomerulopathy rather than post-infectious GN) [27]
• Complement pathway evaluation: C3 nephritic factor, factor H, factor I, factor B levels, genetic testing for complement mutations (C3 glomerulopathy) [1]
• ANCA multiplex assay: Simultaneous MPO-ANCA, PR3-ANCA, anti-GBM, and anti-dsDNA testing available for rapid RPGN evaluation [31]
• Bone marrow biopsy: If monoclonal Ig-associated GN suspected [4]

14. ECG

• Not a primary diagnostic tool for GN, but indicated in the following settings:
  • Hyperkalemia (peaked T waves, widened QRS, sine wave pattern) — common in oliguric AKI [32]
  • Volume overload/hypertension: LVH pattern (increased voltage, strain pattern)
  • Pericarditis (uremic) — diffuse ST elevation, PR depression
  • Endocarditis evaluation — conduction abnormalities (PR prolongation suggests perivalvular abscess)
• Echocardiographic studies in acute post-streptococcal GN show LV diastolic dysfunction and left atrial enlargement from volume overload, generally reversible [28-29]

15. Assessment

Clinical summary: GN presents along a spectrum from asymptomatic urinary abnormalities to fulminant RPGN with renal failure. The most common presentation is asymptomatic hematuria and proteinuria with or without reduced kidney function; full-blown nephritic syndrome is uncommon. [1]

Severity stratification

• Mild: Isolated microscopic hematuria ± subnephrotic proteinuria, preserved GFR
• Moderate: Nephritic syndrome (hematuria, proteinuria, edema, hypertension, mild AKI)
• Severe/RPGN: Rapidly declining GFR over days to weeks, oliguria, crescentic GN on biopsy — renal emergency [1][24]

Complications

• Hypertensive emergency, flash pulmonary edema, seizures [6-7]
• Pulmonary hemorrhage (anti-GBM, ANCA vasculitis) [1]
• AKI requiring dialysis
• Progression to CKD/ESKD
• Cardiovascular disease risk ~2.5× general population [33]
• Thromboembolism (especially with nephrotic-range proteinuria)

16. Treatment Plan

Initial stabilization (ED/acute setting)

• ABCs; IV access; continuous monitoring if hemodynamically unstable
• Treat hypertensive emergency: IV nicardipine or labetalol; avoid nitroprusside in renal failure
• Volume overload: IV furosemide (start 40–80 mg IV; higher doses if CKD); fluid and salt restriction [27]
• Correct hyperkalemia emergently if present (calcium gluconate, insulin/dextrose, kayexalate, dialysis if refractory)
• Urgent dialysis if indicated (refractory hyperkalemia, severe acidosis, volume overload, uremic symptoms)

Disease-specific treatment

• Post-infectious GN: Supportive care; antibiotics if active streptococcal infection; prognosis excellent in children [1][7]
• ANCA vasculitis: Induction with glucocorticoids + rituximab (preferred) or cyclophosphamide; plasma exchange for severe AKI or pulmonary hemorrhage [5]
• Anti-GBM disease: Plasma exchange daily × 2–3 weeks + cyclophosphamide (2–3 mg/kg/day × 2–3 months) + prednisone (1 mg/kg/day, max 60 mg, tapered over 6–9 months); initiate treatment before biopsy if high clinical suspicion [1][4]
• Lupus nephritis: Per ISN/RPS class; Class III/IV: glucocorticoids + mycophenolate or cyclophosphamide
• IgA nephropathy: Optimized supportive care (RASi, sodium restriction, BP <120/70); consider SGLT2 inhibitors; corticosteroids if proteinuria >1 g/day despite 3 months of supportive care [4][26]
• C3 glomerulopathy: MMF + glucocorticoids for proteinuria >1.5 g/day; eculizumab for refractory cases [1]

General long-term management

• ACEi or ARB at maximally tolerated doses (target SBP <120 mmHg) [1][15]
• Sodium restriction <2 g/day [1][4]
• Smoking cessation, weight optimization, regular exercise [1][26]
• Statin therapy per CKD guidelines [26]

17. Disposition

Admission criteria

• RPGN or rapidly declining renal function
• Pulmonary hemorrhage / pulmonary-renal syndrome
• Severe hypertension or hypertensive emergency
• Significant volume overload requiring IV diuretics
• AKI requiring or potentially requiring dialysis
• Need for urgent plasma exchange (anti-GBM disease)
• Significant edema, severe hypertension, or AKI in children [27]

Observation

Discharge criteria

• Stable renal function, controlled BP, manageable edema
• Serologic workup sent, nephrology follow-up arranged
• Mild/asymptomatic hematuria and proteinuria with preserved GFR — outpatient nephrology referral

Specialist consultation triggers

• Nephrology: All suspected GN cases; urgent for RPGN, need for biopsy, or immunosuppression
• Rheumatology: If SLE or systemic vasculitis suspected
• Hematology: If monoclonal gammopathy-associated GN suspected [4]
• Pulmonology/Critical care: Pulmonary hemorrhage
• Infectious disease: Endocarditis-associated GN, shunt nephritis

18. Follow Up / Return Precautions

Follow-up timing

• RPGN/severe GN: Daily monitoring inpatient; outpatient within 1 week of discharge
• Moderate GN: Nephrology follow-up within 1–2 weeks
• Mild/asymptomatic: Nephrology referral within 2–4 weeks
• Post-streptococcal GN in children: Recheck creatinine, urinalysis, and BP at 4 weeks; confirm C3 normalization by 12 weeks [1][27]

Long-term monitoring (all GN patients)

• Serial serum creatinine, urinalysis, proteinuria quantification, and BP [1][27]
• Complement levels until normalization (persistently low C3 beyond 12 weeks warrants biopsy) [27]
• ANCA titers in vasculitis (rising titers may precede relapse)
• Cardiovascular risk assessment and management [33]

Return precautions — counsel patients to seek immediate care for:

• Decreased urine output or dark/bloody urine
• Rapid weight gain or worsening swelling
• Severe headache, vision changes, or confusion (hypertensive emergency)
• Coughing up blood (pulmonary hemorrhage)
• Shortness of breath at rest
• Fever or signs of infection (especially if on immunosuppression)

Expected recovery

• Post-streptococcal GN in children: Creatinine normalizes within ~4 weeks; hematuria resolves within 3–6 months; excellent prognosis [1]
• ANCA vasculitis and anti-GBM disease: Prognosis depends on creatinine at presentation; patients presenting with creatinine <5.7 mg/dL have 95% 1-year kidney survival [1]
• IgA nephropathy: Chronic course; ~20–40% progress to ESKD over 20 years without treatment
• All patients require indefinite monitoring for relapse and CKD progression

References

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