Nephritic Syndrome

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1. Overview

Nephritic Syndrome is a clinical presentation of acute glomerulonephritis (GN), characterized by inflammatory proliferation of cells within the glomeruli causing inflammation and disruption of the glomerular basement membrane. [1,11,37]

It represents a distinct pathophysiological entity from nephrotic syndrome, where the primary defect is in the glomerular podocyte barrier rather than inflammatory damage. Understanding this distinction is critical for appropriate diagnosis and management. [1,42]

The syndrome is defined by the classic pentad:

1. Haematuria (Macroscopic or Microscopic with dysmorphic RBCs and red cell casts)
2. Hypertension (due to sodium and water retention)
3. Oliguria (Reduced urine output)
4. Mild to Moderate Oedema (Periorbital/Lower limbs)
5. Sub-nephrotic Proteinuria (Usually less than 3.5g/day)

The hallmark pathological feature is glomerular inflammation with cellular proliferation, which may be endocapillary (within the capillary loops), extracapillary (crescentic), or mesangial. This contrasts with the podocyte injury and non-inflammatory protein leak seen in nephrotic syndrome. [11,39]

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2. Epidemiology

Global Burden

The epidemiology of nephritic syndrome varies significantly by geographic region and the underlying cause. [65,67]

IgA Nephropathy (Berger's Disease):

• Most common primary glomerulonephritis worldwide (25-50% of all biopsied GN cases). [21,39,67]
• Highest prevalence in Asia (especially Japan, China, Korea). [21,67]
• Peak incidence in 2nd-3rd decades. [39]
• Male:Female ratio approximately 2-3:1. [39,67]
• Accounts for 30-40% of all glomerulonephritis in Asian populations vs 10-20% in Western populations. [67]

Post-Streptococcal Glomerulonephritis (PSGN):

• Predominantly affects children aged 2-14 years, but adult cases occur. [29,31,35]
• Incidence has declined dramatically in developed countries but remains prevalent in developing nations. [29,35]
• Follows Group A beta-haemolytic Streptococcal pharyngitis (1-3 weeks latency) or skin infection (3-6 weeks). [29,31]
• Male predominance (2:1). [29]
• Estimated global incidence: 470,000 cases annually with 5,000 deaths. [35]

Infection-Associated Glomerulonephritis (IAGN):

• Increasing recognition in adults with concurrent infections (Staphylococcus, Streptococcus). [11,18]
• Risk factors: diabetes, IV drug use, indwelling catheters, immunosuppression. [11]
• Mortality in adults can reach 10-20%. [11]

ANCA-Associated Glomerulonephritis:

• Incidence: 10-20 per million per year. [43,45]
• Bimodal age distribution: peaks at 50-60 years and >70 years. [43,45]
• No clear gender predominance. [45]
• PR3-ANCA (GPA) more common in northern Europe; MPO-ANCA more common in southern Europe and Asia. [43]

Anti-GBM Disease (Goodpasture's Disease):

• Rare: incidence 0.5-1.0 per million per year. [53,56]
• Bimodal age distribution: young men (20-30 years with pulmonary-renal syndrome) and elderly (60-70 years, predominantly renal). [53,56]
• Male:Female ratio 2:1 in younger patients, 1:1 in elderly. [53]

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3. Aetiology & Pathophysiology

Classification of Causes

Nephritic syndrome can result from a wide range of glomerular diseases. The KDIGO 2021 guidelines classify these by immunological mechanism and clinical presentation. [61]

Primary Glomerulonephritis (Renal-Limited Disease)

1. IgA Nephropathy (Most Common Worldwide) [21,39]

   • Deposition of polymeric IgA1 with abnormal O-glycosylation (galactose-deficient IgA1) in glomerular mesangium
   • Multi-hit hypothesis: genetic predisposition + mucosal antigen exposure + immune complex formation
   • Associated with upper respiratory infections ("synpharyngitic haematuria")

2. Post-Infectious Glomerulonephritis [29,31,35]

   • Post-Streptococcal GN: Classic nephritogenic strains (Type 12, 4, 1, 49)
   • Staphylococcus-related: Increasingly recognized in adults with bacteraemia, endocarditis [11,18]
   • Mechanism: Immune complex deposition (in situ or circulating) with complement activation

3. Membranoproliferative GN (MPGN) [3]

   • Type I (immune complex-mediated): Hepatitis C, cryoglobulinaemia, SLE
   • Type II (dense deposit disease): C3 nephritic factor causing alternative pathway dysregulation
   • Type III: Features of both

Secondary Glomerulonephritis (Systemic Disease)

1. ANCA-Associated Vasculitis [43,45]

   • Granulomatosis with Polyangiitis (GPA): c-ANCA (PR3 antibodies)
   • Microscopic Polyangiitis (MPA): p-ANCA (MPO antibodies)
   • Eosinophilic Granulomatosis with Polyangiitis (EGPA): MPO-ANCA in 40%
   • Mechanism: ANCA-mediated neutrophil activation causing necrotizing glomerulonephritis

2. Anti-GBM Disease (Goodpasture's Disease) [53,56,57]

   • Autoantibodies against alpha-3 chain of type IV collagen in GBM
   • Pulmonary-renal syndrome in 60-80% (alveolar haemorrhage + GN)
   • Renal-limited disease in 20-40%
   • Novel autoantigen: Peroxidasin also implicated [54]

3. Lupus Nephritis [59]

   • Class III (focal proliferative) and Class IV (diffuse proliferative) present with nephritic features
   • Immune complex deposition with complement consumption (low C3, C4)

4. IgA Vasculitis (Henoch-Schönlein Purpura) [22,23]

   • Small vessel vasculitis with IgA deposition
   • Classic tetrad: Palpable purpura, arthralgia, abdominal pain, nephritis
   • Renal involvement in 40-50% (similar histology to IgA nephropathy)

5. Cryoglobulinaemia [16]

   • Type II (mixed): Associated with Hepatitis C virus (HCV)
   • Mechanism: Cryoglobulin deposition causing MPGN pattern

Rapidly Progressive Glomerulonephritis (RPGN)

A clinical syndrome defined by rapid loss of renal function (doubling of creatinine within 3 months or less than 50% reduction in GFR). [37,41,44]

Pathologically characterized by crescentic GN (crescents in >50% of glomeruli). [37,44]

Three immunological categories:

1. Type I (Anti-GBM): 10-20% of cases [37,44]
2. Type II (Immune Complex): 40-50% - includes lupus, IgA nephropathy, post-infectious GN [37,44]
3. Type III (Pauci-Immune/ANCA): 50-60% - ANCA-associated vasculitis [37,44]

Pathophysiological Mechanisms

Exam Detail: #### Glomerular Injury Cascade

Step 1: Immune Complex Deposition or In-Situ Formation [11,39,45]

• Circulating immune complexes: Post-streptococcal GN, SLE
• In-situ immune complex formation: IgA nephropathy, membranous nephropathy
• ANCA-mediated injury: Direct neutrophil/monocyte activation without immune complex
• Anti-GBM antibodies: Direct antibody binding to GBM alpha-3(IV) collagen

Step 2: Complement Activation [51]

• Classical pathway (C1q → C4 → C2 → C3): Immune complex diseases (low C4, C3)
• Alternative pathway (C3 → C5 → MAC): ANCA-GN, MPGN Type II (low C3, normal C4)
• Membrane attack complex (C5b-9) formation causes direct endothelial injury
• Complement fragments (C3a, C5a) are potent chemoattractants

Step 3: Inflammatory Cell Infiltration [11,45]

• Neutrophils: Early dominant cell type; release proteases, reactive oxygen species
• Monocytes/Macrophages: Phagocytosis, cytokine production (IL-1, TNF-alpha)
• T-cells: CD4+ helper cells, CD8+ cytotoxic cells in crescentic GN

Step 4: Glomerular Proliferation [11,39]

• Endocapillary proliferation: Proliferation of endothelial and mesangial cells within capillary loops
• Mesangial proliferation: IgA nephropathy, MPGN
• Extracapillary proliferation (Crescents): Parietal epithelial cell proliferation in Bowman's space
  • "Cellular crescents: Acute, potentially reversible"
  • "Fibrocellular crescents: Subacute"
  • "Fibrous crescents: Chronic, irreversible scarring"

Step 5: Glomerular Basement Membrane Disruption [71]

• Inflammatory damage causes GBM gaps and ruptures
• Red blood cells extravasate through damaged GBM → Haematuria
• RBCs become dysmorphic (acanthocytes) as they pass through GBM
• RBCs mix with Tamm-Horsfall protein in tubules → Red Cell Casts (pathognomonic)

Step 6: Reduced GFR and Sodium Retention [8]

• Capillary loop obstruction by proliferating cells and inflammatory debris
• Reduced effective glomerular filtration surface area
• Decreased GFR → Activation of renin-angiotensin-aldosterone system (RAAS)
• Sodium and water retention → Oliguria, Hypertension, Oedema

Step 7: Proteinuria [11,42]

• Inflammatory damage to GBM allows protein leak
• Usually sub-nephrotic (less than 3.5g/day) but can overlap in severe cases
• Predominantly albuminuria with some tubular proteins (β2-microglobulin)

Key Pathophysiological Differences: Nephritic vs Nephrotic

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4. Clinical Presentation

Cardinal Features

The presentation can vary from asymptomatic microscopic haematuria detected incidentally to fulminant RPGN requiring urgent dialysis. [1,37]

1. Haematuria [71,72]

Macroscopic (Visible) Haematuria:

• Colour: Tea-coloured, cola-coloured, smoky, or rusty (NOT bright red like lower urinary tract bleeding)
• Acidic urine converts haemoglobin to methaemoglobin (brown pigment)
• Occurs in 30-50% of nephritic syndrome presentations [71]

Microscopic Haematuria:

• May be only finding in mild cases
• Dysmorphic RBCs (acanthocytes): Irregular membrane contour due to passage through damaged GBM [71]
  • >40% dysmorphic RBCs suggests glomerular origin (sensitivity 52%, specificity 98%) [71]
• Red Cell Casts: Pathognomonic for glomerulonephritis [71,72,73]
  • RBCs embedded in Tamm-Horsfall protein matrix
  • Indicate active glomerular bleeding
  • Sensitivity 10-40% (low), specificity >99% (high) [71]
  • More common in IgA nephropathy and infection-associated GN [72]

Timing Patterns:

• Synpharyngitic: Haematuria concurrent with URTI (IgA nephropathy) [21,39]
• Latent Period: 1-3 weeks post-infection (post-streptococcal GN) [29,31]

2. Oedema [8]

• Mechanism: Sodium and water retention due to reduced GFR, not hypoalbuminaemia [8]
• Distribution:
  • Periorbital puffiness (especially morning, gravity-dependent)
  • Lower limb oedema (bilateral, pitting)
  • Milder than nephrotic syndrome (rarely anasarca) [8]
• Clinical Sign: Oedema in nephritic syndrome typically with normal/near-normal serum albumin

3. Hypertension [1,8]

• Present in 50-80% of nephritic syndrome cases [1]
• Mechanism: Volume overload from sodium retention + RAAS activation [8]
• Can be severe (hypertensive urgency/emergency)
• Complications:
  • Posterior reversible encephalopathy syndrome (PRES)
  • Hypertensive heart failure
  • Cerebrovascular events

4. Oliguria [1,8]

• Urine output less than 400mL/24 hours
• Reflects acute reduction in GFR
• May progress to anuria in severe RPGN [37]

5. Proteinuria [1,42]

• Sub-nephrotic range: Typically less than 3.5g/day [1]
• Mechanism: Inflammatory GBM damage (not pure charge/size barrier loss) [42]
• Urine dipstick: Usually 1-2+ (can be 3+ in severe cases)
• Can overlap with nephrotic range in severe proliferative GN or crescentic GN

6. Acute Kidney Injury [1,37]

• Elevated serum creatinine
• Reduced eGFR
• In RPGN: Doubling of creatinine in less than 3 months [37,44]

Systemic and Specific Features by Aetiology

IgA Nephropathy [21,39]

• Classic Presentation: Young adult male with recurrent macroscopic haematuria during URTI
• Synpharyngitic Pattern: Haematuria within 1-2 days of infection onset (vs 1-3 weeks in post-strep GN)
• Usually no systemic features (unlike IgA vasculitis)
• May have loin pain during haematuria episodes
• 30-40% present with persistent asymptomatic microscopic haematuria [39]

Post-Streptococcal GN [29,31,35]

• History: Pharyngitis (1-3 weeks prior) or impetigo (3-6 weeks prior)
• Classic Age: Children 2-14 years (but adults can be affected)
• Presentation: Abrupt onset of visible haematuria, oedema, hypertension
• Systemic: Often feels unwell, low-grade fever
• Prognosis Difference: Children >95% complete recovery; adults 50% progress to CKD [29,35]

ANCA-Associated Vasculitis [43,45]

• Constitutional: Fever, weight loss, fatigue, arthralgia, myalgia
• GPA (Granulomatosis with Polyangiitis):
  • "Upper respiratory tract: Chronic sinusitis, nasal crusting/bleeding, saddle nose deformity"
  • "Lower respiratory tract: Pulmonary nodules/cavitation, haemoptysis"
  • "Renal: Rapidly progressive GN (50-80%) [43]"
• MPA (Microscopic Polyangiitis):
  • Pulmonary-renal syndrome (alveolar haemorrhage + GN)
  • Palpable purpura, peripheral neuropathy
• EGPA:
  • Asthma, eosinophilia, peripheral neuropathy
  • Renal involvement less common (20-30%)

Anti-GBM Disease [53,56,57]

• Pulmonary-Renal Syndrome (60-80%):
  • Haemoptysis (may precede renal involvement by weeks)
  • Dyspnoea, cough
  • Diffuse alveolar haemorrhage on imaging
• Renal-Limited Disease (20-40%):
  • RPGN without pulmonary involvement
  • More common in elderly [53]
• Risk Factors: Smoking, hydrocarbon exposure, infections [53,56]

Lupus Nephritis [59]

• Known SLE diagnosis in most (but can be presenting feature)
• Class III (focal proliferative) or Class IV (diffuse proliferative)
• Systemic SLE features: Malar rash, photosensitivity, oral ulcers, serositis, arthritis, cytopenias
• Complement: Low C3 AND C4 (distinguishes from post-strep GN where only C3 low)

IgA Vasculitis (Henoch-Schönlein Purpura) [22,23]

• Classic Tetrad:
  1. Palpable Purpura: Lower limbs and buttocks (100%)
  2. Arthralgia/Arthritis: Knees, ankles (75%)
  3. Abdominal Pain: Colicky, may have GI bleeding (50-75%)
  4. Nephritis: Haematuria ± proteinuria (40-50%)
• Predominantly children (peak 4-6 years) but adults affected
• Adult presentation often more severe renal disease [22]

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5. Differential Diagnosis

The key differential is Nephrotic Syndrome, but other renal and systemic conditions must be considered. [42]

Primary Differential: Nephritic vs Nephrotic

Note: Some conditions can present with mixed nephritic-nephrotic features, including:

• Severe IgA nephropathy (Oxford classification M1E1S1T1-2) [39]
• Lupus nephritis Class IV [59]
• MPGN [3]
• Crescentic GN with severe podocyte injury [37]

Other Renal Differentials

1. Acute Tubular Necrosis (ATN)

   • Cause: Ischaemia, nephrotoxins, sepsis
   • Distinguishing Features: No haematuria, no RBC casts, muddy brown granular casts, normal C3/C4

2. Acute Interstitial Nephritis (AIN)

   • Cause: Drugs (NSAIDs, PPIs, antibiotics), autoimmune
   • Distinguishing Features: White cell casts, eosinophiluria, rash, fever, normal complement

3. Urinary Tract Infection/Pyelonephritis

   • Distinguishing Features: Dysuria, fever, rigors, white cells >> red cells, positive culture, no RBC casts

4. Renal Infarction

   • Cause: Embolic (AF, endocarditis), thrombotic
   • Distinguishing Features: Abrupt flank pain, elevated LDH, normal urinalysis or minimal haematuria

Systemic Differentials (When Systemic Features Present)

1. Thrombotic Microangiopathy (TTP/HUS)

   • Features: Microangiopathic haemolytic anaemia (MAHA), thrombocytopaenia, AKI, schistocytes
   • Distinguishing: Normal complement, ADAMTS13 deficiency (TTP), Shiga toxin (HUS)

2. Atypical HUS (aHUS)

   • Features: MAHA, AKI, thrombocytopaenia WITHOUT diarrhoea prodrome
   • Distinguishing: Complement dysregulation (low C3, genetic mutations in complement regulators)

3. Cryoglobulinaemia (with HCV)

   • Features: Purpura, arthralgia, peripheral neuropathy, low C4 (very low)
   • Distinguishing: Positive HCV serology, cryoglobulins in blood

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6. Clinical Examination

A systematic approach is essential to identify severity, complications, and systemic features. [1]

General Inspection

• Appearance: Unwell, pale (anaemia), uraemic fetor (severe AKI)
• Skin:
  • "Purpura: Palpable (IgA vasculitis, ANCA vasculitis, cryoglobulinaemia)"
  • "Malar Rash: Lupus"
  • Periorbital Oedema: "Puffy eyes" (nephritic oedema)

Vital Signs

• Blood Pressure: MANDATORY
  • Hypertension in 50-80% [1]
  • Assess for hypertensive emergency (BP >180/120 with symptoms)
• Heart Rate: Tachycardia (fluid overload, uraemia)
• Respiratory Rate: Tachypnoea (pulmonary oedema, alveolar haemorrhage)
• Temperature: Fever (infection-associated GN, vasculitis)
• Oxygen Saturation: Hypoxia (pulmonary involvement)

Cardiovascular Examination

• JVP: Elevated (fluid overload)
• Heart Sounds:
  • S3 gallop (fluid overload)
  • Murmurs (endocarditis in infection-associated GN)
• Peripheral Pulses: Reduced (vasculitis)

Respiratory Examination

• Inspection: Tachypnoea, use of accessory muscles
• Auscultation:
  • Bibasal crackles (pulmonary oedema)
  • Diffuse crackles (alveolar haemorrhage in Goodpasture's/GPA)

Abdominal Examination

• Palpation:
  • Loin tenderness (may occur in IgA nephropathy)
  • Hepatosplenomegaly (SLE, endocarditis)
  • Ascites (rare in nephritic; suggests mixed picture or severe AKI)

Fluid Status Assessment

• Oedema:
  • Periorbital (grade severity)
  • Sacral (if bed-bound)
  • Lower limbs (bilateral pitting, measure to quantify)
• Overall Assessment:
  • Euvolaemic → Mild disease
  • Hypervolaemic → Moderate-severe disease
  • Anuric with severe overload → RPGN, requires urgent dialysis

ENT/Upper Respiratory (If Vasculitis Suspected)

• Nose: Crusting, bleeding, septal perforation (GPA)
• Ears: Hearing loss, otitis media (GPA)
• Sinuses: Tenderness (GPA)

Neurological Examination (If Vasculitis/SLE Suspected)

• Peripheral Neuropathy: Mononeuritis multiplex (ANCA vasculitis, cryoglobulinaemia)
• CNS: Confusion, seizures (uraemic encephalopathy, PRES, lupus cerebritis)

Skin Examination

• Purpura:
  • Distribution (legs/buttocks in IgA vasculitis)
  • Palpable vs non-palpable
• Rash: Malar, discoid (SLE)
• Splinter Haemorrhages/Osler Nodes: Endocarditis

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7. Investigations

A systematic approach progresses from bedside tests through first-line investigations to definitive renal biopsy. [61,71]

Bedside Tests

Urine Dipstick

• Blood: ++ to +++ (highly sensitive)
• Protein: + to ++ (sub-nephrotic)
• Leucocytes: May be positive (inflammation, not infection)
• Nitrites: Negative (excludes UTI)

Interpretation Pearl: Blood 3+ with Protein 1-2+ suggests nephritic > nephrotic

Urine Microscopy (CRUCIAL) [71,72,73]

Gold Standard for Diagnosis of Glomerular Haematuria

• Red Blood Cells:

  • "Dysmorphic RBCs: >40% dysmorphic suggests glomerular origin (specificity 98%) [71]"
  • "Acanthocytes: Ring forms with vesicle-shaped protrusions (most specific for GN) [71]"

• Red Cell Casts: Pathognomonic for glomerulonephritis [71,72,73]

  • Formed when RBCs become embedded in Tamm-Horsfall protein matrix in tubules
  • Sensitivity 10-40% (not always present), specificity >99% [71]
  • Presence indicates active glomerular inflammation and bleeding [72]

• Other Casts:

  • Granular casts (non-specific, seen in AKI)
  • White cell casts (suggests tubulointerstitial nephritis)
  • Hyaline casts (normal, non-specific)

Technique: Fresh urine (less than 1 hour), centrifuge 2000rpm for 5 minutes, examine sediment under microscopy. Phase contrast microscopy improves detection of dysmorphic RBCs. [71]

First-Line Blood Tests

Renal Function

• Serum Creatinine: Elevated in AKI
• eGFR: Reduced (may be severely reduced in RPGN)
• Urea: Elevated (often disproportionately high in GI bleeding or catabolic state)
• Electrolytes:
  • "Hyperkalaemia: Risk in AKI (RED FLAG - requires urgent treatment)"
  • "Hyponatraemia: Dilutional (volume overload)"
  • "Metabolic Acidosis: AKI"

Urine Protein Quantification

• Protein:Creatinine Ratio (PCR):
  • less than 350mg/mmol (sub-nephrotic)
  • Can be >350mg/mmol in severe proliferative GN [42]
• 24-hour Urine Collection:
  • less than 3.5g/24h (nephritic range)
  • Less commonly used (compliance issues)

Haematology

• FBC:
  • "Haemoglobin: Anaemia (chronic disease, uraemia, or alveolar haemorrhage)"
  • "Platelets: Normal (if low, consider TTP/HUS)"
  • "Eosinophilia: EGPA, AIN"
• Blood Film: Exclude schistocytes (TMA)

Inflammation Markers

• CRP/ESR: Elevated in vasculitis, infection-associated GN

Immunological Screen

Critical for determining underlying aetiology and guiding biopsy decision. [61]

Complement Levels [51]

Complement Normalisation:

• Post-strep GN: C3 normalises in 6-8 weeks (if persists >8 weeks, consider MPGN) [29,31]

ANCA (Antineutrophil Cytoplasmic Antibodies) [43,45]

• c-ANCA (PR3-ANCA): Granulomatosis with Polyangiitis (GPA)
  • Sensitivity 65-90%, Specificity >95% [43]
• p-ANCA (MPO-ANCA): Microscopic Polyangiitis (MPA), EGPA
  • Sensitivity 50-75%, Specificity >95% [43]

Interpretation: ANCA positivity + GN = ANCA-associated glomerulonephritis (biopsy shows pauci-immune crescentic GN) [45]

False Positives: Drugs (hydralazine, levamisole-contaminated cocaine), infections

Anti-GBM Antibodies [53,56]

• ELISA: Detects antibodies to alpha-3 chain of type IV collagen
• Sensitivity >95%, Specificity >95% [53]
• Interpretation: Positive = Anti-GBM disease (Goodpasture's) → Urgent plasma exchange [56,57]
• May co-exist with ANCA in 10-40% (dual-positive disease) [53]

Autoantibodies (If Lupus Suspected)

• ANA (Antinuclear Antibody): Screening test (sensitivity >95%, low specificity)
• Anti-dsDNA: Specific for SLE, correlates with disease activity (especially renal)
• Anti-Sm: Highly specific for SLE (low sensitivity 30%)
• Anti-Ro, Anti-La: Sjögren's syndrome overlap

Immunoglobulins

• Serum IgA:
  • Elevated in 50% of IgA nephropathy [39]
  • Low specificity (not diagnostic)

Infection Serology

• Anti-Streptolysin O (ASOT):
  • Elevated in 80-90% of post-streptococcal GN (pharyngitis) [29,31]
  • Titre >200 IU/mL significant
  • Peaks at 3-5 weeks post-infection, may be normal if presenting late
• Anti-DNase B:
  • More sensitive for skin infections (impetigo) [31]
• Throat/Skin Swab:
  • Culture Group A Streptococcus (often negative by time of presentation) [29]
• Hepatitis B/C Serology:
  • "HBV: Membranous nephropathy, MPGN"
  • "HCV: Cryoglobulinaemia, MPGN [16]"
• HIV Serology:
  • HIV-associated nephropathy (collapsing FSGS), immune complex GN

Cryoglobulins

• If suspected (HCV, purpura, low C4, arthralgia)
• Collect in warm tube, transport at 37°C

Imaging

Renal Ultrasound

• Indications: All patients with AKI/nephritic syndrome [61]
• Findings:
  • Normal or slightly enlarged kidneys (acute GN)
  • Increased echogenicity (oedema, inflammation)
  • Rule out obstruction
  • Assess for chronic changes (small kidneys suggest CKD)

Chest X-Ray

• Indications:
  • Suspected pulmonary oedema (dyspnoea, hypertension)
  • Suspected alveolar haemorrhage (Goodpasture's, GPA, MPA)
• Findings:
  • "Pulmonary oedema: Bilateral interstitial/alveolar infiltrates, Kerley B lines, cardiomegaly"
  • "Alveolar haemorrhage: Bilateral patchy/diffuse airspace opacification (may be difficult to distinguish from oedema)"

CT Chest (High Resolution)

• If pulmonary-renal syndrome: Assess for cavitation (GPA), ground-glass opacities (alveolar haemorrhage)

CT Sinuses

• If GPA suspected: Assess for chronic sinusitis, bony erosion, septal perforation

Gold Standard: Renal Biopsy [61]

Indications: [61]

1. Diagnostic Uncertainty: When clinical/serological picture does not clearly identify cause
2. Guide Treatment: Especially for immunosuppression decisions
3. Assess Prognosis: Degree of chronicity (scarring) vs acute inflammation (potentially reversible)
4. Persistent GN: AKI lasting >3 weeks or declining renal function despite conservative management
5. RPGN: Urgent biopsy if creatinine doubling less than 3 months

Contraindications:

• Uncontrolled hypertension (BP >160/100)
• Bleeding diathesis (correct first)
• Single kidney (relative)
• Small kidneys (less than 9cm suggests CKD, low yield)

Timing:

• Non-urgent GN: Within 1-4 weeks
• RPGN: Within 24-48 hours (if safe) [44]

Biopsy Techniques:

• Light Microscopy: Assess cellularity, crescents, sclerosis, interstitial fibrosis
• Immunofluorescence: Detect Ig and complement deposition patterns
• Electron Microscopy: Assess GBM, podocyte foot processes, deposits location

Pathological Patterns [11,39,45,53]

Oxford Classification of IgA Nephropathy (MEST-C Score): [28,39]

• M (Mesangial hypercellularity): M0 vs M1
• E (Endocapillary hypercellularity): E0 vs E1
• S (Segmental sclerosis): S0 vs S1
• T (Tubular atrophy/interstitial fibrosis): T0, T1, T2
• C (Crescents): C0, C1, C2
• Higher score → Worse prognosis

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8. Classification & Staging

Rapidly Progressive Glomerulonephritis (RPGN) Classification [37,44]

Clinical Definition:

• Rapid loss of renal function: Doubling of creatinine within 3 months OR >50% decline in eGFR
• Pathological: Crescents in >50% of glomeruli on biopsy

Immunological Classification:

Prognostic Factors (Poor Outcome): [37,44]

• Creatinine >500-600 μmol/L at presentation
• Oliguria/anuria
• >50% crescents on biopsy
• >50% global glomerulosclerosis (chronicity)
• Severe tubulointerstitial fibrosis
• Dialysis requirement at presentation (especially if >2 weeks)

IgA Nephropathy Prognostic Risk Stratification [39]

Oxford Classification (MEST-C): [28,39]

Clinical Risk Stratification:

Low Risk (Excellent prognosis):

• Normal BP, eGFR >60, PCR less than 50mg/mmol
• M0E0S0T0 on biopsy
• Estimated 10-year kidney survival >90%

Moderate Risk:

• eGFR 30-60, PCR 50-100mg/mmol, controlled BP
• MEST-C score 2-3
• 10-year progression to ESRD: 10-30%

High Risk:

• eGFR less than 30, PCR >100mg/mmol, hypertension
• MEST-C score ≥4, crescents >25%
• 10-year progression to ESRD: 30-50%

"Rule of Thirds" (historical observation): [39]

• 1/3 spontaneous remission
• 1/3 stable disease
• 1/3 progress to ESRD over 20-25 years

Post-Streptococcal GN Staging [29,31,35]

Paediatric vs Adult Prognosis:

Prognostic Factors for Poor Outcome:

• Age >60 years [11,35]
• Diabetes, pre-existing CKD [11]
• Severe AKI requiring dialysis [35]
• Crescents on biopsy [35]

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9. Management

Management depends on the underlying cause, severity of presentation, and presence of RPGN. [61]

A. General/Supportive Management

Applicable to ALL nephritic syndrome regardless of aetiology. [1,8,61]

1. Fluid and Sodium Management [8,61]

Goal: Achieve euvolaemia, control blood pressure

• Fluid Restriction:
  • 500-1000mL/day plus previous day's urine output
  • More restrictive if anuric or pulmonary oedema
• Sodium Restriction:
  • less than 2-3g/day (less than 100mmol/day)
  • No added salt diet
  • Reduces oedema and hypertension burden [8]

2. Diuretics [61]

• Furosemide (Loop Diuretic):

  • First-line for volume overload and hypertension
  • "Dose: 40-80mg OD/BD (may need higher doses in AKI)"
  • Monitor electrolytes (risk of hypokalaemia, BUT may have hyperkalaemia from AKI)
  • Increase dose if inadequate response (target urine output 1-2L/day)

• Metolazone (Thiazide-like):

  • Add if resistant to furosemide alone
  • Synergistic effect with loop diuretics

Monitoring: Daily weights, fluid input/output charts, clinical oedema assessment

3. Blood Pressure Control [61]

Target: less than 130/80 mmHg (KDIGO 2021) [61]

First-Line Agents:

1. ACE Inhibitors (e.g., Ramipril 2.5-10mg OD):

   • Dual benefit: BP control + proteinuria reduction
   • Caution: Monitor creatinine (acceptable rise less than 30% in first 2 months) and potassium (risk hyperkalaemia in AKI)
   • Contraindications: Pregnancy, bilateral RAS, hyperkalaemia >5.5mmol/L

2. Angiotensin Receptor Blockers (ARBs) (e.g., Losartan 50-100mg OD):

   • Alternative to ACE inhibitors (if cough intolerance)
   • Same cautions as ACE inhibitors

3. Calcium Channel Blockers (e.g., Amlodipine 5-10mg OD):

   • Effective antihypertensive
   • Useful in combination with ACE-I/ARB
   • Non-dihydropyridines (diltiazem) may have antiproteinuric effect

4. Beta-Blockers (e.g., Bisoprolol 2.5-10mg OD):

   • If tachycardia, ischaemic heart disease
   • Use cautiously in fluid overload (may worsen heart failure if severe)

5. Alpha-Blockers (e.g., Doxazosin 2-8mg OD):

   • Fourth-line agent for resistant hypertension

Hypertensive Emergency (BP >180/120 with symptoms):

• IV Labetalol, IV Hydralazine, or IV GTN
• Aim to reduce BP by 20-25% in first hour (avoid precipitous drop)

4. Dietary Modifications [61]

• Protein Restriction:
  • 0.8g/kg/day (if eGFR less than 30) to reduce uraemic symptoms and proteinuria
  • Avoid excessive restriction (malnutrition risk)
• Potassium Restriction:
  • If hyperkalaemia (avoid bananas, oranges, tomatoes, chocolate, nuts)
• Phosphate Restriction:
  • If hyperphosphataemia in severe AKI/CKD

5. Management of Hyperkalaemia [RED FLAG]

Mild (5.5-5.9 mmol/L):

• Dietary restriction, stop ACE-I/ARB/spironolactone
• Calcium resonium (oral K+ binder) 15g TDS

Moderate (6.0-6.4 mmol/L):

• As above + consider haemodialysis if AKI severe

Severe (≥6.5 mmol/L or ECG changes): URGENT TREATMENT

1. IV Calcium Gluconate 10%: 10mL over 2-5 minutes (cardiac membrane stabilisation)
2. Insulin-Dextrose: 10 units Actrapid in 50mL 50% Dextrose IV (shift K+ intracellularly)
3. Salbutamol Nebuliser: 10-20mg (shift K+ intracellularly)
4. Sodium Bicarbonate: 50mmol IV if acidotic (shift K+ intracellularly)
5. Haemodialysis: If refractory or anuric (definitive K+ removal)

6. Renal Replacement Therapy (Dialysis) [61]

Indications: AEIOU

• Acidosis: Severe metabolic acidosis (pH less than 7.1) refractory to bicarbonate
• Electrolytes: Hyperkalaemia refractory to medical management
• Intoxication: Not relevant to GN
• Overload: Pulmonary oedema refractory to diuretics
• Uraemia: Uraemic pericarditis, encephalopathy, bleeding (uraemic platelet dysfunction)

Additional Indication in GN:

• RPGN with severe AKI (may need temporary dialysis until immunosuppression takes effect)
• Goodpasture's disease (plasma exchange often combined with haemodialysis)

Modality: Haemodialysis preferred in acute setting (intermittent or continuous RRT if haemodynamically unstable)

---

B. Specific Disease-Directed Treatment

Guided by serology, clinical features, and renal biopsy. [61]

1. IgA Nephropathy [39,61]

Conservative Management (Low Risk):

• ACE-I/ARB to target BP less than 130/80, maximise antiproteinuric effect (target PCR less than 100mg/mmol)
• Supportive care as above
• No immunosuppression

KDIGO 2021 Guideline Recommendations: [61]

Emerging Therapies:

• Targeted-release budesonide (TARPEYO): Enteric-coated formulation targeting ileal Peyer's patches (mucosal immune modulation) [39]
• SGLT2 inhibitors: May reduce proteinuria and CKD progression (DAPA-CKD trial showed benefit in CKD including IgA nephropathy)

2. Post-Streptococcal Glomerulonephritis [29,31,35]

Predominantly Supportive (Self-Limiting in Most Cases)

• Antibiotics:

  • Penicillin V 500mg QDS for 10 days (or Azithromycin if penicillin-allergic)
  • Eradicate residual streptococcal infection
  • Does NOT alter course of GN (already immune-mediated) but prevents transmission [29,31]

• Supportive Care:

  • Fluid/sodium restriction, diuretics, antihypertensives (as above)
  • Spontaneous resolution expected in 1-2 weeks in children [29,35]

• Immunosuppression:

  • NOT routinely indicated (self-limiting) [29,31]
  • "Consider corticosteroids ONLY if:"
    • Severe crescentic GN with RPGN
    • Prolonged AKI (>4 weeks)
    • Adults with poor prognostic features [35]

Prognosis Monitoring:

• Complement (C3) should normalise in 6-8 weeks [29,31]
• If C3 persistently low >8-12 weeks → Consider alternative diagnosis (MPGN, C3 glomerulopathy) → Biopsy

3. ANCA-Associated Glomerulonephritis [43,45,61,63]

Urgent Immunosuppression Required

Goals:

1. Remission Induction: Stop active inflammation, preserve renal function
2. Remission Maintenance: Prevent relapse

KDIGO 2021 / EULAR 2022 Recommendations: [61,63]

Induction Therapy (3-6 months)

First-Line Regimens:

Option 1: Rituximab-based (Preferred)

• Rituximab: 375mg/m² IV weekly x 4 doses OR 1000mg IV day 1 and 15
• Plus Glucocorticoids:
  • Methylprednisolone 500mg-1g IV daily x 3 days (pulse therapy)
  • Followed by Prednisolone 1mg/kg/day (max 60mg) PO, taper over 3-6 months
• Evidence: RAVE trial showed Rituximab non-inferior to Cyclophosphamide, superior in relapsing disease [43,45]

Option 2: Cyclophosphamide-based

• Cyclophosphamide:
  • "IV: 15mg/kg (max 1.2g) every 2 weeks x 3, then every 3 weeks (total 6 months)"
  • "OR Oral: 2mg/kg/day (reduce dose if age >60, CKD)"
• Plus Glucocorticoids (as above)
• Evidence: CYCLOPS trial showed pulsed IV non-inferior to daily oral with fewer side effects [43]

Adjunctive:

• Plasma Exchange:
  • "Indications: Serum creatinine >500 μmol/L OR pulmonary haemorrhage (PEXIVAS trial showed NO benefit in mortality/ESRD, but still used in severe cases) [63]"
  • "Regimen: 7 exchanges of 60mL/kg over 14 days"

Maintenance Therapy (18-24 months minimum)

First-Line:

• Rituximab: 500mg IV every 6 months (preferred based on MAINRITSAN trial) [63]
• OR Azathioprine: 2mg/kg/day PO
• OR Mycophenolate Mofetil: 2g/day PO

Plus Low-Dose Prednisolone: 5-7.5mg/day (continue for 12-24 months then consider withdrawal)

Relapse Risk: 30-50% at 5 years (higher with PR3-ANCA vs MPO-ANCA) [43,63]

Refractory Disease

• Consider alternative agents: Avacopan (C5a receptor antagonist, allows steroid sparing)
• Plasma exchange (if not already used)
• IVIG: 2g/kg monthly

Monitoring:

• ANCA titre (rising titre may precede relapse)
• Urine microscopy (RBCs, casts)
• Creatinine, eGFR
• Adverse effects: Infection (PCP prophylaxis with co-trimoxazole), cytopenias, malignancy

4. Anti-GBM Disease (Goodpasture's Disease) [53,56,57,61]

Medical Emergency - Urgent Treatment Required

Triple Therapy:

1. Plasma Exchange (Plasmapheresis): [56,57]

   • Goal: Remove circulating anti-GBM antibodies
   • Regimen: Daily or alternate-day for 14 days (total 10-14 exchanges)
   • Volume: 60mL/kg (replace with 4-5% albumin ± FFP)
   • Continue until anti-GBM antibody titre undetectable
   • Evidence: Observational data shows improved renal survival (no RCTs) [56,57]

2. Cyclophosphamide: [56,57]

   • Oral 2-3mg/kg/day OR IV 0.75-1g/m² monthly
   • Duration: 3-6 months (until antibody negative)

3. High-Dose Corticosteroids: [56,57]

   • Methylprednisolone 500mg-1g IV daily x 3 days
   • Then Prednisolone 1mg/kg/day PO (taper over 6-12 months)

Pulmonary Haemorrhage:

• Requires urgent plasma exchange (even more critical than renal involvement)
• Mechanical ventilation if severe
• Transfuse if Hb less than 70-80g/L (haemoptysis can be life-threatening)

Prognostic Factors: [53,56]

• Creatinine less than 500-600 μmol/L at presentation: 80-90% renal recovery [56]
• Dialysis-dependent at presentation: less than 10% renal recovery if on dialysis >2-3 weeks [56]
• 100% crescents on biopsy: Very poor prognosis for renal recovery [53]

Relapse: Rare (less than 5%) once antibody negative [53]

Transplantation:

• Defer until anti-GBM antibody negative for ≥6 months (risk of recurrence in allograft if antibody positive) [56]

5. Lupus Nephritis [59,61]

Class III (Focal Proliferative) and Class IV (Diffuse Proliferative) require immunosuppression

KDIGO 2024 Lupus Nephritis Guideline: [59]

Induction Therapy (6 months)

First-Line Regimens:

Option 1: Mycophenolate Mofetil (MMF) + Corticosteroids

• MMF: 2-3g/day PO in divided doses
• Glucocorticoids: Methylprednisolone 250-500mg IV x 3 days, then Prednisolone 0.5-1mg/kg/day (taper to less than 7.5mg by 6 months)
• Evidence: ALMS trial showed MMF non-inferior to Cyclophosphamide with better tolerability [59]

Option 2: Cyclophosphamide (Euro-Lupus Regimen) + Corticosteroids

• Cyclophosphamide: 500mg IV every 2 weeks x 6 doses (low-dose Euro-Lupus protocol)
• Glucocorticoids (as above)
• Preferred if concern for fertility preservation (lower cumulative dose than NIH regimen) [59]

Adjunctive:

• Hydroxychloroquine: 200-400mg/day (all SLE patients, improves long-term outcomes)
• Calcineurin Inhibitors (Tacrolimus): Alternative if MMF/Cyclophosphamide contraindicated

Maintenance Therapy (≥3 years)

• MMF: 1-2g/day OR Azathioprine: 2mg/kg/day
• Prednisolone: ≤7.5mg/day
• Hydroxychloroquine: Continue indefinitely

Monitoring:

• Complement (C3, C4), anti-dsDNA (markers of disease activity)
• Urine PCR (target less than 50mg/mmol)
• Renal function

6. IgA Vasculitis (Henoch-Schönlein Purpura) [22,23,61]

Mild Nephritis (Haematuria, proteinuria less than 1g/day, normal renal function):

• Supportive care only (self-limiting in most children)
• ACE-I/ARB if proteinuria persists

Moderate-Severe Nephritis (Proteinuria >1g/day, AKI, crescents on biopsy):

• Corticosteroids: Prednisolone 1mg/kg/day x 4-8 weeks, taper
• Consider Cyclophosphamide or MMF if crescentic GN

Adult vs Paediatric:

• Children: Usually self-limiting
• Adults: Higher risk of chronic kidney disease (30-40%) [22,23]

7. Infection-Associated Glomerulonephritis (Non-Streptococcal) [11,18]

Primarily Supportive:

• Treat Underlying Infection:
  • "Staphylococcal bacteraemia/endocarditis: Prolonged IV antibiotics (flucloxacillin, vancomycin)"
  • Remove infected foci (catheters, pacemakers, abscesses)
• Supportive Renal Care (as per general management)

Immunosuppression:

• Generally AVOIDED (risk of worsening infection) [11]
• Consider ONLY if severe crescentic GN AND infection adequately treated

Prognosis: Worse than post-strep GN (mortality 10-20%, CKD in 30-50%) [11]

---

C. Monitoring During Treatment

Acute Phase (First 1-2 weeks):

• Daily: Weight, BP, fluid balance, clinical assessment
• 2-3 times/week: U&E, creatinine, urine output
• Weekly: Urinalysis, urine microscopy

Induction Phase (Immunosuppression):

• Weekly: FBC (cytopenias), U&E, LFTs
• Fortnightly: Urine PCR, creatinine
• Monthly: Immunology (ANCA, anti-GBM, complement, anti-dsDNA)

Maintenance Phase:

• Monthly: FBC, U&E, creatinine, urine PCR
• 3-monthly: Immunology (disease-specific markers)

Infection Prophylaxis During Immunosuppression:

• PCP Prophylaxis: Co-trimoxazole 480mg OD (if Cyclophosphamide, Rituximab, or high-dose steroids)
• Gastric Protection: PPI (if on corticosteroids)
• Bone Protection: Calcium + Vitamin D, consider bisphosphonate (if prolonged steroids)
• Vaccinations: Pneumococcal, influenza (avoid live vaccines if on immunosuppression)

---

10. Complications

Complications arise from the acute disease process, chronic kidney damage, or immunosuppressive treatment. [37,43,61]

Acute Complications

1. Rapidly Progressive Glomerulonephritis (RPGN) [37,44]

• Definition: Doubling of creatinine in less than 3 months, crescentic GN on biopsy
• Frequency: 10-20% of nephritic syndrome
• Mechanism: Extensive crescent formation → fibrous scarring → irreversible nephron loss
• Management: Urgent immunosuppression (as per aetiology), may need temporary dialysis
• Prognosis:
  • "If creatinine less than 500 μmol/L and treated early: 60-80% renal recovery [37,44]"
  • "If dialysis-dependent >2 weeks: less than 30% renal recovery [37]"

2. Pulmonary Oedema [8]

• Mechanism: Volume overload + hypertension → left ventricular failure
• Presentation: Dyspnoea, orthopnoea, pink frothy sputum, bibasal crackles
• Management:
  • IV Furosemide 40-80mg bolus (repeat or infusion if needed)
  • Oxygen therapy
  • IV GTN if hypertensive
  • Urgent dialysis if refractory (ultrafiltration)

3. Hypertensive Emergency [1]

• Definition: BP >180/120 with end-organ damage (encephalopathy, heart failure, AKI worsening)
• Complications:
  • "Posterior Reversible Encephalopathy Syndrome (PRES): Headache, confusion, seizures, visual disturbance"
  • Hypertensive heart failure
  • Intracerebral haemorrhage
• Management: IV antihypertensives (labetalol, hydralazine, GTN), aim 20-25% BP reduction in first hour

4. Hyperkalaemia [RED FLAG]

• Frequency: Common in AKI with oliguria
• ECG Changes:
  • "Mild: Tall tented T-waves"
  • "Moderate: Prolonged PR interval, flattened P-waves"
  • "Severe: Wide QRS, sine wave pattern → VF/Asystole"
• Management: See General Management section (urgent treatment protocol)

5. Pulmonary Haemorrhage (Pulmonary-Renal Syndrome) [43,53,56]

• Causes: Anti-GBM disease, ANCA vasculitis (GPA, MPA)
• Presentation: Haemoptysis, dyspnoea, hypoxia, diffuse alveolar infiltrates on CXR
• Investigation: Falling haemoglobin, high DLCO (uptake of CO by intra-alveolar blood)
• Management:
  • Urgent plasma exchange (especially anti-GBM) [56]
  • High-dose corticosteroids + Cyclophosphamide/Rituximab
  • Mechanical ventilation if severe
• Prognosis: Life-threatening, mortality 20-50% if severe [43,53]

6. Infection (During Immunosuppression) [43,61]

• Risk: Cyclophosphamide, Rituximab, high-dose steroids
• Common Infections:
  • "Bacterial: UTI, pneumonia, line-related sepsis"
  • "Opportunistic: "
    • Pneumocystis jirovecii pneumonia (PCP): Dry cough, dyspnoea, hypoxia (requires co-trimoxazole prophylaxis)
    • CMV reactivation: Fever, cytopenias, colitis
    • Fungal: Aspergillus, Candida (if neutropaenic)
• Prevention: PCP prophylaxis, vaccination (pre-immunosuppression), avoid live vaccines

Chronic Complications

7. Chronic Kidney Disease (CKD) / End-Stage Renal Disease (ESRD) [39,61]

• Frequency:

  • "Post-strep GN: less than 1% in children, 30-50% in adults [29,35]"
  • "IgA nephropathy: 30-40% progress to ESRD at 20 years [39]"
  • "ANCA-GN: 20-30% ESRD at 5 years despite treatment [43]"
  • "Anti-GBM: 60-80% ESRD if dialysis-dependent at presentation [53,56]"

• Risk Factors:

  • Severe AKI at presentation
  • Crescents >50%, global sclerosis >50% on biopsy
  • Persistent proteinuria despite treatment
  • Hypertension

• Management:

  • "CKD care: BP control, manage anaemia, bone-mineral disease, acidosis"
  • Prepare for RRT (dialysis, transplant) if eGFR approaching less than 15

8. Relapse of Glomerulonephritis [39,43]

• IgA Nephropathy: Recurrent macroscopic haematuria episodes (benign vs progressive variants) [39]
• ANCA Vasculitis: 30-50% relapse at 5 years (higher in PR3-ANCA, ENT/lung involvement) [43]
  • "Monitor: Rising ANCA titre, returning haematuria/proteinuria"
  • "Management: Re-induction therapy (Rituximab preferred for relapsing disease)"

9. Cardiovascular Disease [61]

• Increased risk due to:
  • Hypertension
  • CKD (uraemia, vascular calcification)
  • Proteinuria (inflammatory state)
  • Immunosuppression (corticosteroids → dyslipidaemia, diabetes)
• Prevention: Statin therapy, BP control, aspirin (if cardiovascular risk), smoking cessation

10. Immunosuppression-Related Complications [43,61]

• Cyclophosphamide:

  • "Haemorrhagic cystitis: Mesna prophylaxis, hydration"
  • "Infertility: Dose-dependent (consider fertility preservation, lower Euro-Lupus regimen)"
  • "Malignancy: Bladder cancer (long-term risk), lymphoma, leukaemia"
  • "Cytopenias: Monitor FBC weekly"

• Rituximab:

  • "Hypogammaglobulinaemia: Monitor Ig levels, IVIG if recurrent infections"
  • "Progressive Multifocal Leukoencephalopathy (PML): Rare but fatal (JC virus reactivation)"

• Corticosteroids:

  • Diabetes, weight gain, osteoporosis, cataracts, skin fragility, mood disturbance
  • "Prevention: Bone protection (calcium, vitamin D, bisphosphonate), PPI, ophthalmology screening"

---

11. Prognosis & Outcomes

Prognosis varies dramatically by underlying aetiology, severity at presentation, and response to treatment. [29,35,39,43,53,61]

Overall Prognosis by Aetiology

Prognostic Factors

Good Prognosis

• Clinical:

  • "Young age (less than 40 years, exception: post-strep GN worse in adults)"
  • Isolated microscopic haematuria (no proteinuria, normal renal function)
  • Creatinine less than 150 μmol/L at presentation
  • No oliguria
  • Prompt treatment (especially RPGN, anti-GBM)

• Pathological:

  • less than 50% crescents
  • less than 30% global glomerulosclerosis
  • Minimal tubulointerstitial fibrosis (T0)
  • No vascular sclerosis

Poor Prognosis

• Clinical:

  • Elderly (>60 years, especially infection-associated GN) [11]
  • Creatinine >500 μmol/L at presentation [37,44,53]
  • Oliguria/anuria
  • Dialysis-dependent at presentation (especially if >2-3 weeks) [37,53,56]
  • Severe hypertension
  • Persistent heavy proteinuria (>1g/day) despite treatment

• Pathological:

  • >50% crescents [37,44]
  • >50% global glomerulosclerosis [37]
  • Severe tubulointerstitial fibrosis (T2) [39]
  • Fibrous crescents (irreversible) vs cellular crescents (potentially reversible)

• Serological:

  • Persistently positive/rising ANCA (relapse risk) [43]
  • Failure of anti-GBM antibody to become undetectable [53]
  • Persistently low complement (>8-12 weeks in post-strep GN suggests alternative diagnosis) [29,31]

Long-Term Outcomes

Post-Streptococcal GN [29,31,35]

• Children:

  • >95% complete recovery with no long-term sequelae [29,35]
  • Haematuria resolves in 1-2 weeks, proteinuria in 3-6 months [29]
  • C3 normalises in 6-8 weeks [29,31]

• Adults:

  • Only 50-60% complete recovery [35]
  • 20-30% develop persistent proteinuria/hypertension [35]
  • 30-50% progress to CKD/ESRD over years [35]
  • "Key Message: Post-strep GN is NOT benign in adults [11,35]"

IgA Nephropathy [39]

"Rule of Thirds" (historical):

• 1/3 spontaneous remission (especially if isolated haematuria)
• 1/3 stable disease (persistent haematuria/proteinuria but preserved renal function)
• 1/3 progress to ESRD over 20-25 years

Modern Risk Stratification (Oxford MEST-C + Clinical):

• Low Risk (M0E0S0T0, eGFR >60, PCR less than 50, normal BP): 10-year kidney survival >90%
• Moderate Risk: 10-year progression to ESRD 10-30%
• High Risk (M1E1S1T2C2, eGFR less than 30, PCR >100): 10-year progression to ESRD 30-50%

Recurrence Post-Transplant: 30-50% histological recurrence, 10-20% graft loss [39]

ANCA-Associated Glomerulonephritis [43,45]

With Modern Immunosuppression (Rituximab/Cyclophosphamide + Steroids):

• 80-90% achieve remission (complete or partial) [43]
• 60-70% dialysis-free survival at 5 years [43]
• 20-30% progress to ESRD at 5 years [43]

Relapse:

• 30-50% relapse at 5 years [43]
• Higher relapse risk: PR3-ANCA > MPO-ANCA, upper respiratory/lung involvement, younger age [43]
• Maintenance therapy reduces relapse (Rituximab > Azathioprine/MMF in trials) [63]

Mortality:

• 5-year survival: 70-80% [43]
• Main causes of death: Infection (during immunosuppression), cardiovascular disease, malignancy [43]

Anti-GBM Disease [53,56,57]

Renal Prognosis:

• If Creatinine less than 500 μmol/L at presentation + early plasma exchange: 80-90% avoid dialysis [56]
• If Dialysis-dependent at presentation: less than 10% renal recovery (especially if >2-3 weeks on dialysis) [56]
• Overall: 60-80% progress to ESRD requiring long-term dialysis [53]

Patient Survival:

• 5-year survival: 70-80% [53]
• Pulmonary haemorrhage significantly increases mortality (20-50% if severe) [53]

Recurrence:

• less than 5% relapse once anti-GBM antibody undetectable [53]
• Recurrence in transplant: less than 5% (defer transplant until antibody negative ≥6 months) [56]

Lupus Nephritis [59]

With Modern Therapy (MMF/Cyclophosphamide + Corticosteroids):

• 80-90% achieve complete or partial remission (Class III/IV) [59]
• 10-20% ESRD at 10 years [59]
• Renal survival improved dramatically since introduction of MMF and low-dose corticosteroid protocols

Relapse: 30-40% (monitor complement, anti-dsDNA, urine PCR) [59]

Pregnancy: High-risk (flare risk, pre-eclampsia, fetal loss) - requires specialist MDT care

---

12. Prevention & Screening

Primary Prevention

Post-Streptococcal GN [29,31,35]

• Public Health Measures:

  • Improved sanitation, reduced overcrowding (reduces streptococcal transmission)
  • Access to clean water
  • Prompt treatment of pharyngitis/impetigo in endemic areas

• Antibiotic Treatment of Strep Infection:

  • Treating active streptococcal pharyngitis/impetigo does NOT prevent GN in that individual (immune process already triggered) [29,31]
  • BUT prevents transmission to others (reduces community incidence)

IgA Nephropathy [39]

• No established primary prevention
• Genetic counselling if family history (familial clustering in 10-15%)

ANCA Vasculitis [43]

• Avoid triggers where possible (silica exposure, hydrocarbon solvents)
• Smoking cessation (associated with PR3-ANCA and pulmonary involvement)

Anti-GBM Disease [53,56]

• Smoking cessation (strongest risk factor for pulmonary involvement)
• Avoid hydrocarbon exposure (paint solvents, petrol)
• Prompt treatment of respiratory infections (may trigger disease in predisposed individuals)

Secondary Prevention (Early Detection)

Screening High-Risk Populations

Urine Dipstick Screening:

• Asian populations: Consider screening for IgA nephropathy (high prevalence) [39]
• Post-Streptococcal Infection: Urine dipstick 1-3 weeks after pharyngitis/impetigo in children (developing countries)
• SLE Patients: Regular urinalysis (3-6 monthly) to detect lupus nephritis early [59]
• Patients on Nephrotoxic Drugs: Regular monitoring

Annual Health Checks:

• Many Asian countries (Japan, Korea, Taiwan) have annual health check programs including urinalysis
• Detects asymptomatic microscopic haematuria/proteinuria → early IgA nephropathy diagnosis [39]

Surveillance After Nephritic Syndrome

Post-Streptococcal GN:

• Children: Urinalysis at 6 weeks, 6 months, 12 months (should normalise) [29]
• Adults: Long-term follow-up (annual urinalysis, BP, creatinine) - high risk of CKD [35]

IgA Nephropathy:

• Lifelong follow-up (annual minimum): BP, urinalysis, urine PCR, creatinine [39]
• Frequency increased if high-risk features (proteinuria >1g, hypertension, declining eGFR)

ANCA Vasculitis:

• Remission Monitoring: 3-monthly ANCA titre, urinalysis, creatinine (relapse detection) [43,63]
• Rising ANCA titre may precede clinical relapse (allows pre-emptive treatment)

Anti-GBM Disease:

• Monitor anti-GBM antibody titre until undetectable (relapse if re-emerges) [53]
• After antibody negative: 6-monthly urinalysis/creatinine for 2 years, then annual

Tertiary Prevention (Prevent Progression)

Optimise Modifiable Risk Factors [61]

• Blood Pressure Control: Target less than 130/80 mmHg (KDIGO 2021) [61]
• Proteinuria Reduction: ACE-I/ARB (even if normotensive if proteinuria >0.5g/day) [61]
• Smoking Cessation: Independent risk factor for CKD progression [61]
• Glycaemic Control: If diabetic (comorbid)
• Weight Loss: If obese (reduces proteinuria and cardiovascular risk)
• Dietary: Sodium restriction (less than 2-3g/day), protein restriction if eGFR less than 30 (0.8g/kg/day) [61]

CKD Progression Prevention [61]

• SGLT2 Inhibitors: (e.g., Dapagliflozin 10mg OD)

  • "Evidence from DAPA-CKD trial: Reduces CKD progression and cardiovascular events in CKD patients (including glomerulonephritis) [61]"
  • "Indication: eGFR >25, proteinuria"

• Finerenone (Non-steroidal Mineralocorticoid Receptor Antagonist):

  • Emerging evidence in CKD with proteinuria
  • Lower hyperkalaemia risk than spironolactone

---

13. Key Guidelines & Evidence

Major International Guidelines

1. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases [61]

   • Comprehensive guideline covering all glomerulonephritides
   • Evidence-based recommendations with GRADE methodology
   • Key Update: Supportive care (ACE-I, BP control) prioritised over immunosuppression in many conditions
   • Available: https://kdigo.org/guidelines/gn/

2. KDIGO 2024 Clinical Practice Guideline for the Management of Lupus Nephritis [59]

   • Updated 2024 (replaces 2012 guideline)
   • Key Changes: MMF preferred over Cyclophosphamide, lower steroid doses, hydroxychloroquine for all
   • Target: Urine PCR less than 50mg/mmol (complete remission)

3. EULAR/ERA-EDTA 2022 Recommendations for the Management of ANCA-Associated Vasculitis [63]

   • Key Update: Rituximab preferred over Cyclophosphamide for induction and maintenance
   • Avacopan (C5a receptor antagonist) as steroid-sparing agent
   • Plasma exchange role re-evaluated (PEXIVAS trial: no mortality/ESRD benefit but still used in severe cases)

4. British Society for Rheumatology (BSR) Guidelines on ANCA-Associated Vasculitis (2014, under revision)

   • UK-specific guidance on diagnosis and management

5. Kidney Health Australia - CARI Guidelines (2025 Commentary on KDIGO) [64]

   • Australian adaptation of KDIGO guidelines
   • Local context and resource considerations

Landmark Trials & Evidence

IgA Nephropathy

1. Oxford Classification (MEST-C Score) [28]

   • Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, 2009
   • Validated prognostic histological classification
   • PMID: 19571791

2. Supportive Care vs Steroids in IgA Nephropathy [39]

   • Meta-analyses show modest benefit of steroids in selected patients (persistent proteinuria >1g despite maximal supportive care)
   • Risk-benefit consideration (infection, diabetes, osteoporosis vs eGFR preservation)

ANCA Vasculitis

1. RAVE Trial (Rituximab vs Cyclophosphamide for ANCA Vasculitis) [43]

   • Stone et al., NEJM 2010
   • Rituximab non-inferior to Cyclophosphamide for induction
   • Superior in relapsing disease
   • PMID: 20647199

2. MAINRITSAN Trial (Rituximab vs Azathioprine for Maintenance) [63]

   • Guillevin et al., NEJM 2014
   • Rituximab superior to Azathioprine for preventing relapse (5% vs 29% at 28 months)
   • PMID: 25372085

3. PEXIVAS Trial (Plasma Exchange in ANCA Vasculitis) [63]

   • Walsh et al., NEJM 2020
   • NO benefit in death or ESRD from plasma exchange in ANCA-GN
   • Challenged routine use, but still used in severe cases (clinical judgment)
   • PMID: 32053298

4. ADVOCATE Trial (Avacopan in ANCA Vasculitis) [63]

   • Jayne et al., NEJM 2021
   • Avacopan (C5a receptor antagonist) non-inferior to prednisolone for remission, allowed steroid sparing
   • PMID: 33596356

Anti-GBM Disease

1. Plasma Exchange in Anti-GBM Disease [56,57]
   • No RCTs (ethical concerns - disease too rare and severe)
   • Observational data: Dramatic improvement in renal outcomes with plasma exchange vs historical controls
   • Levy et al., Ann Intern Med 2001 (PMID: 11567730) - Salama & Pusey review

Lupus Nephritis

1. ALMS Trial (MMF vs Cyclophosphamide in Lupus Nephritis) [59]

   • Appel et al., JASN 2009
   • MMF non-inferior to Cyclophosphamide for induction, better tolerability
   • PMID: 19661464

2. Euro-Lupus Nephritis Trial (Low-dose vs High-dose Cyclophosphamide) [59]

   • Houssiau et al., Arthritis Rheum 2002
   • Low-dose Euro-Lupus regimen (500mg IV x 6) non-inferior to high-dose NIH regimen (monthly for 6 months)
   • Lower toxicity, better fertility preservation
   • PMID: 11920403

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14. Common Exam Questions & Viva Points

High-Yield MRCP/FRACP Questions

1. "A 25-year-old man presents with cola-coloured urine and a concurrent sore throat. What is the most likely diagnosis and how would you confirm it?"

   Model Answer:

   • Diagnosis: IgA Nephropathy (Berger's Disease)
   • Key Feature: Synpharyngitic haematuria (concurrent with URTI, not delayed like post-strep GN)
   • Confirmation:
     • Urine microscopy: Dysmorphic RBCs, red cell casts (glomerular origin)
     • Complement: C3/C4 normal (excludes post-strep GN where C3 low)
     • Renal biopsy (gold standard): Mesangial IgA deposition on immunofluorescence
   • Differentiation from Post-Strep GN: Post-strep has 1-3 week latency period and low C3

2. "What are the causes of low serum complement (C3) in glomerulonephritis?"

   Model Answer:

   • Low C3, Normal C4 (Alternative Pathway):
     • Post-streptococcal GN
     • MPGN Type II (Dense Deposit Disease)
     • C3 glomerulopathy
   • Low C3 AND C4 (Classical Pathway):
     • Lupus nephritis
     • Cryoglobulinaemia (very low C4 is characteristic)
     • Bacterial endocarditis with immune complex GN
   • Normal C3 and C4:
     • IgA nephropathy
     • ANCA vasculitis (pauci-immune)
     • Anti-GBM disease

3. "Describe the pathological differences between nephritic and nephrotic syndrome."

   Model Answer: See table in Pathophysiology section

   • Nephritic: Inflammatory, proliferative, GBM rupture, cellular infiltration
   • Nephrotic: Non-inflammatory, podocyte injury, GBM intact but permeable

4. "A 70-year-old man presents with rapidly progressive renal failure over 2 weeks, haemoptysis, and dyspnoea. ANCA is positive (MPO). Describe your immediate management."

   Model Answer:

   • Diagnosis: Pulmonary-renal syndrome - Microscopic Polyangiitis (MPO-ANCA vasculitis)
   • Immediate:
     • Stabilise: ABC, oxygen, IV access
     • Bloods: FBC, U&E, ANCA, anti-GBM (dual-positive disease), blood cultures
     • Imaging: CXR (alveolar haemorrhage), CT chest
     • Urine: Microscopy (RBC casts), PCR
   • Urgent Treatment:
     • Immunosuppression:
       • Pulse methylprednisolone 500mg-1g IV daily x 3 days
       • Rituximab 375mg/m² IV weekly x 4 OR Cyclophosphamide IV
     • Plasma Exchange: Consider (severe disease with Cr >500 or pulmonary haemorrhage) - though PEXIVAS showed no benefit, still used in life-threatening disease
     • Supportive: Dialysis if AKI severe, transfuse if Hb low
   • Prophylaxis: Co-trimoxazole (PCP), PPI

5. "When would you perform urgent renal biopsy in suspected glomerulonephritis?"

   Model Answer:

   • RPGN: Creatinine doubling in less than 3 months (biopsy within 24-48 hours if safe)
   • Diagnostic Uncertainty: Serology negative but clinical picture suggestive
   • Severe Disease: Requiring immunosuppression decisions (confirm diagnosis and assess reversibility)
   • Absolute Contraindications: Uncontrolled hypertension (>160/100), bleeding diathesis, anticoagulation (reverse first)

Viva Opening Statements

Viva Point: IgA Nephropathy: "IgA Nephropathy, also known as Berger's Disease, is the most common primary glomerulonephritis worldwide, accounting for 30-40% of all glomerulonephritis in Asia and 10-20% in Western populations. It is characterised by mesangial deposition of polymeric IgA1 with abnormal O-glycosylation. Clinically, it typically presents in young adults with synpharyngitic haematuria - macroscopic haematuria occurring concurrently with upper respiratory tract infections. The Oxford MEST-C classification provides prognostic information based on histological features. Management involves blood pressure control with ACE inhibitors, and corticosteroids are reserved for patients with persistent proteinuria >1g/day despite maximal supportive care, according to KDIGO 2021 guidelines."

Post-Streptococcal GN: "Post-streptococcal glomerulonephritis is an immune complex-mediated glomerulonephritis occurring 1-3 weeks after Group A beta-haemolytic Streptococcal pharyngitis or 3-6 weeks after skin infection. It predominantly affects children aged 2-14 years in developing countries, though adult cases occur. Clinically, it presents with the classic nephritic pentad: haematuria, hypertension, oliguria, oedema, and sub-nephrotic proteinuria. Diagnosis is supported by low C3 complement (normalises in 6-8 weeks), positive ASOT, and renal biopsy showing diffuse proliferative glomerulonephritis with subepithelial 'humps' on electron microscopy. Management is predominantly supportive, with >95% complete recovery in children but only 50-60% in adults. Immunosuppression is not routinely indicated."

ANCA Vasculitis: "ANCA-associated vasculitis is a group of necrotizing small vessel vasculitides including Granulomatosis with Polyangiitis (c-ANCA/PR3), Microscopic Polyangiitis (p-ANCA/MPO), and Eosinophilic Granulomatosis with Polyangiitis. Renal involvement presents as pauci-immune crescentic glomerulonephritis and may progress rapidly without treatment. The RAVE trial demonstrated Rituximab is non-inferior to Cyclophosphamide for remission induction and superior in relapsing disease. Current EULAR 2022 guidelines recommend Rituximab plus glucocorticoids as first-line therapy. Maintenance therapy with Rituximab 500mg every 6 months reduces relapse risk from 29% to 5% compared to Azathioprine, as shown in the MAINRITSAN trial. Despite treatment, 20-30% progress to ESRD at 5 years, and relapse occurs in 30-50%."

Anti-GBM Disease: "Anti-GBM disease, also known as Goodpasture's disease, is a rare autoimmune condition (incidence 0.5-1 per million per year) caused by autoantibodies against the alpha-3 chain of type IV collagen in the glomerular basement membrane. It presents with rapidly progressive glomerulonephritis, and in 60-80% of cases, pulmonary-renal syndrome with alveolar haemorrhage. It is a medical emergency requiring urgent triple therapy: plasma exchange to remove circulating antibodies, Cyclophosphamide, and high-dose corticosteroids. Prognosis is highly dependent on renal function at presentation - if creatinine less than 500 μmol/L and treated early, 80-90% avoid dialysis, but if dialysis-dependent at presentation, less than 10% recover renal function. Relapse is rare (less than 5%) once antibodies become undetectable."

Common Mistakes (Exam Failures)

❌ Missing Red Flags:

• Failing to recognise RPGN (doubling creatinine less than 3 months) → delays urgent immunosuppression
• Not checking for pulmonary haemorrhage in ANCA/anti-GBM (can be life-threatening)
• Missing hyperkalaemia risk in oliguria/AKI (can cause sudden cardiac death)

❌ Wrong Investigations:

• Not performing urine microscopy (dipstick alone misses RBC casts, dysmorphic RBCs)
• Not checking complement levels (key to differentiating causes)
• Ordering ANCA/anti-GBM without clinical indication (false positives)

❌ Outdated Treatment:

• Using high-dose prolonged steroids in lupus nephritis (modern: lower dose, shorter duration with MMF/Cyclophosphamide)
• Not considering Rituximab as first-line in ANCA vasculitis (RAVE trial 2010 changed practice)
• Routine use of plasma exchange in ANCA-GN (PEXIVAS 2020 showed no benefit in mortality/ESRD)

❌ Diagnostic Errors:

• Confusing synpharyngitic haematuria (IgA nephropathy) with latent period (post-strep GN)
• Assuming all haematuria is glomerular (must confirm with microscopy - dysmorphic RBCs, casts)
• Diagnosing nephrotic syndrome when features are nephritic (check albumin, quantify proteinuria)

❌ Prognosis Misconceptions:

• Assuming post-strep GN is benign in adults (30-50% progress to CKD, unlike children)
• Thinking anti-GBM disease is treatable if already on dialysis (very poor renal recovery if dialysis >2-3 weeks)
• Underestimating relapse risk in ANCA vasculitis (30-50% at 5 years, requires long-term maintenance)

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15. Patient & Layperson Explanation

What is Nephritic Syndrome?

Nephritic syndrome is a group of symptoms caused by inflammation of the tiny filters in your kidneys called glomeruli.

Think of your kidneys as having millions of tiny sieves (glomeruli). Normally, these sieves:

• Let water and waste through (to make urine)
• Keep important things like blood cells and proteins in your body

In nephritic syndrome, these sieves become inflamed and damaged:

• They get blocked (so you make less urine and fluid builds up)
• They get holes (so blood cells leak through into your urine)

This is different from nephrotic syndrome, where the filters are leaky but not inflamed.

Why is My Urine Dark/Brown?

Your urine contains blood, but not like a cut that bleeds bright red.

Because urine is acidic, the blood turns brown or tea-coloured (like cola, rust, or smoky tea). This is called "haematuria."

This colour actually tells us it's from your kidneys, not from your bladder or prostate (which would be bright red).

What Caused It?

There are many possible causes, but the common ones are:

1. After an Infection (Post-Streptococcal GN):

   • Sometimes 1-3 weeks after a throat infection (Strep throat) or skin infection
   • Your immune system attacked the infection but accidentally damaged your kidneys too
   • More common in children, usually gets better on its own

2. IgA Nephropathy (Berger's Disease):

   • Your immune system makes too much of a protein called IgA, which gets stuck in your kidney filters
   • Often happens at the same time as a cold or sore throat
   • More common in young men, especially in Asia

3. Autoimmune Diseases:

   • Conditions like Lupus, Vasculitis, or Goodpasture's disease where your immune system attacks your own body
   • These need urgent specialist treatment

4. Other Infections:

   • Bacteria in your blood, heart valve infections, or other serious infections

What Symptoms Might I Have?

• Dark/brown urine ("cola-coloured")
• Puffy eyes (especially in the morning) or swollen ankles
• High blood pressure (you might have headaches or feel unwell)
• Less urine than normal (you might not need to pee as often)
• Feeling tired or unwell
• Sometimes: blood in spit (if lungs involved), rash, joint pain

How Do We Diagnose It?

1. Urine Test:

   • Dipstick: Checks for blood and protein
   • Microscopy: Looking at your urine under a microscope to see damaged blood cells and "casts" (clumps of cells that are a hallmark of kidney inflammation)

2. Blood Tests:

   • Kidney function (creatinine): Checks how well your kidneys are working
   • Immunology: Special tests to find out the cause (e.g., antibodies, complement levels)

3. Kidney Biopsy (Sometimes):

   • A tiny sample of kidney tissue is taken with a needle (under local anaesthetic)
   • This is the "gold standard" to confirm the diagnosis and guide treatment
   • Only done if we need to know the exact cause or if treatment decisions are difficult

How Do We Treat It?

Treatment depends on the cause and how severe it is.

General Treatment (For Everyone):

1. Less Salt and Fluid:

   • Reduces swelling and blood pressure
   • You might need to avoid adding salt to food and limit how much you drink

2. Water Tablets (Diuretics):

   • Help you pee more to get rid of extra fluid
   • Common one: Furosemide (Lasix)

3. Blood Pressure Tablets:

   • Very important to protect your kidneys
   • Common ones: ACE inhibitors (e.g., Ramipril) or ARBs (e.g., Losartan)
   • These also reduce protein leaking into your urine

Specific Treatment (Depends on the Cause):

1. If It's After a Strep Infection (Post-Strep GN):

   • Usually gets better on its own with just the general treatment above
   • Antibiotics to clear any remaining infection
   • Children usually make a full recovery (>95%)
   • Adults have a higher chance of long-term kidney problems (30-50%)

2. If It's IgA Nephropathy:

   • Most cases: Blood pressure tablets and monitoring
   • Severe cases: Steroid tablets to calm the immune system

3. If It's Autoimmune (Vasculitis, Lupus, Goodpasture's):

   • Urgent treatment with strong medicines to suppress your immune system:
     • Steroids (e.g., Prednisolone)
     • Chemotherapy drugs (e.g., Cyclophosphamide, Rituximab) - in lower doses than for cancer
   • Sometimes plasma exchange (like dialysis but removes antibodies from your blood)
   • These conditions can be serious and need specialist kidney doctors (nephrologists)

4. Dialysis:

   • Only needed if your kidneys are severely damaged and can't do their job
   • May be temporary (while treatment works) or long-term

Will I Get Better?

It depends on the cause:

• Post-Strep GN (Children): >95% make a full recovery with no lasting damage
• Post-Strep GN (Adults): 50-60% make a full recovery, but some develop long-term kidney problems
• IgA Nephropathy: Very variable - some people have one episode and it goes away, others have ongoing kidney problems
• Autoimmune Causes: With treatment, many people go into remission (disease controlled), but relapses can happen

Warning Signs to Watch For:

• If your urine gets darker again
• If swelling gets worse
• If you stop peeing or pee much less than normal (call doctor immediately)
• If you cough up blood (call ambulance - medical emergency)

Long-Term Follow-Up

Even if you feel better, you'll need regular check-ups:

• Urine tests: To check for blood and protein
• Blood pressure checks: High blood pressure damages kidneys over time
• Blood tests: To check kidney function

Some people need lifelong monitoring, especially if they have IgA nephropathy or autoimmune causes.

What Can I Do to Help My Kidneys?

1. Take your medicines (especially blood pressure tablets) even if you feel well
2. Reduce salt in your diet
3. Don't smoke (smoking damages kidneys and blood vessels)
4. Maintain a healthy weight
5. Control blood sugar if you have diabetes
6. Attend follow-up appointments (even if you feel fine)

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Document Status: Gold Standard (52/56) Last Updated: 2026-01-05 Author: MedVellum Content Generator (PubMed Evidence-Based) Target Examination: MRCP, FRACP, MRCPCH, Postgraduate Nephrology Review Cycle: Annual (or when major guideline updates published)

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