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Glomerulonephritis (GN)

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Glomerular Anatomy - The Target of Disease

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Pathogenesis

1. In Situ Immune Complex Formation

2. Circulating Immune Complex Deposition

3. Pauci-Immune / ANCA-Mediated

4. Cell-Mediated Immunity

5. Alternative Complement Pathway Activation

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Clinical Presentation: The Nephritic Syndrome

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Classification: Major Types of GN

Nephritic Pattern (Proliferative)

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1. Acute Postinfectious (Post-streptococcal) GN

• Trigger: Group A beta-hemolytic Streptococcus (throat or skin infection); 1-3 weeks after pharyngitis, 3-6 weeks after impetigo
• Pathogenesis: Immune complex deposition; subepithelial "humps" on EM
• IF: Granular IgG + C3 in GBM and mesangium ("starry sky")
• Labs: Low C3 (complement consumed), ASO titer elevated, hematuria
• Prognosis: >95% of children recover; adults have a worse prognosis
• Treatment: Supportive; penicillin for active infection; antihypertensives, diuretics

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2. Rapidly Progressive (Crescentic) GN (RPGN)

• Induction: Pulse methylprednisolone (10-15 mg/kg/day IV x 3 days) then prednisone 1 mg/kg/day + cyclophosphamide (IV 15 mg/kg q2-3 weeks or oral 1.5-2 mg/kg/day) OR rituximab (375 mg/m² weekly x 4 doses)
• Avacopan (C5a receptor inhibitor, 30 mg BD for 52 weeks) as adjunctive therapy in severe disease to reduce steroid exposure
• Plasmapheresis: Consider if creatinine >5.7 mg/dL, dialysis-dependent, or diffuse alveolar hemorrhage
• Maintenance: Azathioprine 1.5 mg/kg/day or rituximab 500 mg at months 6, 12, 18 for 18 months to 4 years

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3. IgA Nephropathy (Berger Disease)

• Most common primary GN worldwide
• Pathogenesis: Mesangial deposition of poorly galactosylated IgA1 + IgG anti-IgA1 antibodies; complement activation
• Presentation: Recurrent macroscopic hematuria (often concurrent with upper respiratory infections - "synpharyngitic"), or persistent microscopic hematuria ± proteinuria
• IF: IgA dominant or co-dominant in mesangium
• EM: Mesangial electron-dense deposits
• Treatment: ACE inhibitors/ARBs for proteinuria; corticosteroids in selected patients; newer therapies include targeted-release budesonide (TRF-budesonide), sparsentan, and SGLT2 inhibitors

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4. Membranoproliferative GN (MPGN)

• Presentation: Mixed nephritic/nephrotic picture
• LM: Mesangial proliferation, GBM thickening and "splitting" (tram-track appearance)
• Type I: Immune complex-mediated (HBV, HCV, SLE) - subendothelial deposits; IF: IgG + C3 + C1q + C4
• Dense Deposit Disease (Type II): Alternative complement pathway dysregulation; C3 only on IF; dense osmiophilic intramembranous deposits on EM

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Summary Table: Primary Glomerulonephritides

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Secondary GN (Associated With Systemic Diseases)

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Complement Levels as a Diagnostic Clue

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General Management Principles

1. Treat the underlying cause where possible (antibiotics for infection, antivirals for HBV/HCV)
2. Supportive measures: Salt/water restriction, antihypertensives (ACE-I/ARBs preferred for their antiproteinuric effect), loop diuretics
3. Immunosuppression: Indicated for immune-mediated GN - options include corticosteroids, cyclophosphamide, rituximab, mycophenolate mofetil, azathioprine, calcineurin inhibitors (for nephrotic types like membranous/FSGS)
4. Monitoring: Serial creatinine, urinalysis, proteinuria quantification, ANCA/anti-GBM titers where relevant
5. Renal biopsy: Essential for definitive diagnosis and guiding treatment in most cases of GN

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• Robbins, Cotran & Kumar Pathologic Basis of Disease, Ch. 20, pp. 815-842
• Goldman-Cecil Medicine, Ch. 107, pp. 1255-1260
• Comprehensive Clinical Nephrology, 7th Edition
• Brenner and Rector's The Kidney, 2-Volume Set

Recent evidence note: A 2025 meta-analysis (PMID: 40721561) confirms the efficacy and safety of targeted-release budesonide (TRF-budesonide) for IgA nephropathy. A 2024 systematic review (PMID: 39423662) highlights the evolving role of innate immunity and the gut-kidney axis in IgA nephropathy pathogenesis.

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What Was Covered

1. Definition

2. Classification

• Etiological: Primary vs. Secondary (with full secondary cause table)
• Histopathological: MCD, FSGS, Membranous Nephropathy, MPGN, IgA - with age frequency breakdown
• Steroid Response: SSNS, SRNS, FRNS, SDNS (clinical classification)

3. Pathogenesis (7 mechanisms)

4. Individual Diseases

5. Clinical Features

6. Investigations

7. Management

• General: diet, edema (underfill vs. overfill algorithm), anti-proteinuric strategy, lipid control, anticoagulation, infection prevention
• Disease-specific: MCD protocol, FSGS protocol, Membranous Nephropathy risk-based algorithm (with image)
• Special populations

8. Flowcharts & Algorithms

• Pathogenesis flow
• Edema management algorithm
• MCD treatment algorithm with relapse pathways
• Membranous Nephropathy risk-stratified algorithm (textbook image)
• Master Roadmap flowchart from presentation to final management

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NEPHROTIC SYNDROME

Long Answer Question (LAQ) - Examination Standard

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INTRODUCTION

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1. DEFINITION

"Nephrotic syndrome is defined as more than 3.5 g of proteinuria in 24 hours, with serum albumin level less than 3.5 g/dL accompanied by hyperlipidemia and clinically apparent edema." — NKF Primer on Kidney Diseases, 8th Edition, p. 189

"The manifestations of the syndrome include massive proteinuria with the daily loss of 3.5 g or more, hypoalbuminemia with plasma albumin levels less than 3 g/dL, generalized edema, and hyperlipidemia and lipiduria." — Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 843

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2. INCIDENCE AND EPIDEMIOLOGY

• Annual incidence in children: 2-7 per 100,000; prevalence 16 per 100,000
• Male:Female ratio in children = 2:1 (this equalises in adults)
• Peak age in children: 2-6 years (preschool age); median age of onset 2.5 years
• In children under 10 years, Minimal Change Disease (MCD) accounts for 70-90% of cases
• In adults, Focal Segmental Glomerulosclerosis (FSGS) and Membranous Nephropathy (MN) are most common
• Diabetic nephropathy is the most common cause of NS globally (secondary cause)
• (Brenner & Rector's The Kidney; Campbell Walsh Wein Urology, 3-Volume Set)

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3. AETIOLOGY AND CLASSIFICATION

A. PRIMARY (Idiopathic) Nephrotic Syndrome

B. SECONDARY Nephrotic Syndrome

C. CLINICAL CLASSIFICATION (Used in Paediatrics)

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4. PATHOGENESIS

Step-by-Step Pathogenic Cascade

PRIMARY INSULT
(immune, toxic, genetic, metabolic)
          ↓
PODOCYTE INJURY
(foot process effacement, slit diaphragm disruption,
 nephrin/podocin dysfunction, anti-nephrin antibodies)
          ↓
LOSS OF GLOMERULAR FILTRATION BARRIER
          ↓
MASSIVE PROTEINURIA (>3.5 g/day)
     ↙        ↘         ↘          ↘
HYPO-       EDEMA    HYPER-       HYPER-
ALBUMIN-             LIPIDEMIA    COAG-
EMIA                              ULABILITY

A. Mechanism of Proteinuria

• The normal GBM acts as both a size barrier (filters proteins > 68 kDa) and a charge barrier (negatively charged proteoglycans repel anionic albumin)
• In NS, podocyte foot process effacement disrupts the filtration slit - proteins cross freely
• Selective proteinuria: mainly albumin (low MW) = MCD; indicative of good steroid response
• Non-selective proteinuria: albumin + globulins = FSGS, MN; indicates worse prognosis

B. Mechanism of Hypoalbuminemia

• Urinary albumin losses exceed hepatic synthetic capacity
• Increased renal catabolism of filtered albumin
• Reduced nutritional intake (anorexia from bowel edema)

C. Mechanism of Oedema

D. Mechanism of Hyperlipidemia and Lipiduria

• ↓ oncotic pressure → stimulates hepatic lipoprotein synthesis (VLDL, LDL ↑)
• ↓ lipoprotein lipase activity → impaired peripheral lipid clearance
• ↓ HDL (small molecule, easily filtered)
• Lipiduria: lipoproteins leak into urine → absorbed by tubular cells → shed as oval fat bodies ("Maltese cross" birefringence on polarised light microscopy)
• Long-term hyperlipidemia accelerates cardiovascular disease

E. Mechanism of Hypercoagulability

Risk of renal vein thrombosis, DVT, and pulmonary embolism - highest in membranous nephropathy. Risk is greatest when albumin < 2.0 g/dL and proteinuria > 10 g/day. (Brenner & Rector's The Kidney, Box 31.3; NKF Primer, 8th Ed., p. 190)

F. Susceptibility to Infection

• Loss of IgG → hypogammaglobulinemia
• Loss of complement factor B and properdin → impaired opsonization
• Loss of properdin → reduced alternative complement pathway activity
• T-cell dysfunction (particularly in MCD)
• Common organisms: Streptococcus pneumoniae (spontaneous bacterial peritonitis), Staphylococcus aureus, gram-negative organisms

G. Other Protein Losses and Their Consequences

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5. PATHOLOGY OF INDIVIDUAL DISEASES

A. Minimal Change Disease (MCD)

• MCD is a diagnosis of exclusion - all other causes must be ruled out
• The effacement diminishes as proteinuria resolves with treatment

B. Focal Segmental Glomerulosclerosis (FSGS)

• NOS (Not Otherwise Specified) - most common
• Perihilar variant - adaptive/secondary
• Cellular variant - active lesion
• Tip variant - better prognosis, steroid-responsive
• Collapsing variant - worst prognosis; HIV-associated (HIVAN), COVID-19-associated

C. Membranous Nephropathy (MN)

• Anti-PLA2R antibodies positive in 70-80% of primary MN - diagnostic and prognostic
• Rule of thirds: 1/3 spontaneous remission, 1/3 persistent proteinuria, 1/3 progress to ESKD

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6. CLINICAL FEATURES

Symptoms

Signs

Paediatric-Specific Features

• Periorbital oedema may be the only presenting sign initially
• Often mistaken for allergic periorbital oedema (diagnosis is delayed)
• Symptoms often follow an upper respiratory infection (URTI) trigger
• Abdominal pain may indicate spontaneous bacterial peritonitis (SBP)

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7. COMPLICATIONS

Mnemonic: "IT-CAKE" (I-nfection, T-hrombosis, C-ardiovascular, A-KI, K-idney progression, E-ndocrine)

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8. INVESTIGATIONS

TIER 1 - CONFIRM DIAGNOSIS

TIER 2 - ESTABLISH AETIOLOGY (SEROLOGICAL WORKUP)

TIER 3 - ASSESS COMPLICATIONS

TIER 4 - RENAL BIOPSY

• Age 1-8 years
• Pure nephrotic syndrome (no haematuria, no hypertension, normal GFR, normal complement)
• No systemic features

• Age < 1 year (suspect congenital NS - genetic)
• Age > 8-10 years (MCD less likely; MN, FSGS more likely)
• Macroscopic haematuria
• Persistent hypertension
• Hypocomplementemia (low C3/C4)
• Steroid resistance (SRNS)
• Systemic features (rash, arthritis, etc.)

1. Light microscopy (H&E, PAS, Jones silver, Masson trichrome)
2. Immunofluorescence (IgG, IgA, IgM, C1q, C3, C4)
3. Electron microscopy (deposit location, foot process effacement extent)

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9. DIFFERENTIAL DIAGNOSIS

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10. MANAGEMENT

OVERALL FRAMEWORK

┌─────────────────────────────────────────────┐
│          NEPHROTIC SYNDROME                 │
│                                             │
│ STEP 1: Confirm diagnosis                   │
│ STEP 2: Assess & treat complications        │
│ STEP 3: General/supportive care (ALL)       │
│ STEP 4: Determine aetiology (biopsy/serology│
│ STEP 5: Disease-specific immunosuppression  │
│ STEP 6: Monitor & manage relapse            │
└─────────────────────────────────────────────┘

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A. GENERAL (NON-SPECIFIC) MANAGEMENT

1. Diet

• Sodium restriction: < 2 g NaCl/day (reduces oedema and enhances diuretics)
• Protein: 0.8-1.0 g/kg/day (excessive protein worsens proteinuria; restriction aids anti-proteinuric measures)
• Fluid restriction: Only if hyponatremia (serum Na < 130 mEq/L) is present
• Low saturated fat, complex carbohydrate: Addresses hyperlipidemia

2. Oedema Management

OEDEMA MANAGEMENT
        ↓
Assess volume status:
MCD → likely UNDERFILL
FSGS/MN/Diabetic → likely OVERFILL
        ↓
ORAL LOOP DIURETIC (Furosemide 40-80 mg/day)
        ↓
INADEQUATE RESPONSE?
Add thiazide (metolazone 2.5-5 mg) → sequential nephron blockade
        ↓
STILL RESISTANT?
IV furosemide ± spironolactone (secondary hyperaldosteronism)
Note: IV albumin + furosemide is controversial and NOT routinely recommended
        ↓
CAUTION: In underfill patients (MCD) → aggressive diuresis risks AKI/hypovolemia

"Hypoalbuminemia reduces the binding of furosemide to plasma proteins and thereby enlarges its volume of distribution. A more logical approach to diuretic resistance is to limit albuminuria with an ACE inhibitor, ARB, or both." - Brenner & Rector's The Kidney, p. 2277

3. Anti-Proteinuric Strategy (RAAS Blockade)

• ACE inhibitors (enalapril, ramipril) OR ARBs (losartan, irbesartan) - first-line
• Reduce intraglomerular pressure → reduce proteinuria by 30-50%
• Slow CKD progression independently of BP effect
• Target urine protein < 1 g/day; ideally < 0.5 g/day
• Monitor: serum creatinine (acceptable rise ≤ 30% from baseline), serum K+ (hyperkalemia)
• Emerging: SGLT2 inhibitors (empagliflozin, dapagliflozin) - additive anti-proteinuric and renoprotective effects

4. Hyperlipidemia

• Statins: atorvastatin 10-40 mg or rosuvastatin 10-20 mg/night (first-line)
• Target LDL < 100 mg/dL; reduces cardiovascular risk
• Fibrates for severe hypertriglyceridemia (caution if using with statins - myopathy)
• Lipid-lowering alone does NOT treat underlying proteinuria

5. Anticoagulation

THROMBOSIS RISK IN NS
        ↓
HIGH RISK → Prophylactic anticoagulation
  (Membranous nephropathy + albumin < 2.0-2.5 g/dL + proteinuria > 10 g/day)
        ↓
WARFARIN: Target INR 2.0-3.0 OR LMWH (enoxaparin)
Note: DOACs (rivaroxaban, apixaban) - altered protein binding in NS - use cautiously
        ↓
ESTABLISHED THROMBOSIS: Full anticoagulation × 6-12 months

6. Infection Prevention

• Pneumococcal vaccination (PCV13 + PPSV23) before starting immunosuppression
• Children: Oral penicillin V 125 mg BD prophylaxis during active disease (SBP prevention)
• Co-trimoxazole prophylaxis during high-dose steroids/cyclophosphamide (PCP pneumonia)
• Low threshold for antibiotics in any febrile NS patient
• Varicella vaccination if non-immune before immunosuppression
• Avoid live vaccines during immunosuppression

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B. DISEASE-SPECIFIC MANAGEMENT

MCD / Steroid-Sensitive NS - Treatment Protocol

FIRST EPISODE OF NS IN CHILD (typical features = empirical treatment)
                    ↓
PREDNISOLONE: 60 mg/m²/day (max 60 mg/day) OR 2 mg/kg/day (max 60 mg)
                 × 4-6 weeks daily
                    ↓
Then: alternate-day prednisolone × 4-6 weeks, then taper and stop
                    ↓
                 8 WEEKS
              ↙            ↘
    REMISSION             NO REMISSION
    (protein clears)      (SRNS)
         ↓                    ↓
    Taper & stop          RENAL BIOPSY
                          + re-evaluate
                          Consider CNI,
                          rituximab
         ↓
    RELAPSE? (proteinuria returns)
         ↓
INFREQUENT RELAPSE          FREQUENT RELAPSE / SDNS
(<2 in 6 months)            (≥2 relapses in 6 months)
         ↓                         ↓
Repeat prednisolone         STEROID-SPARING AGENTS:
course                      1. Cyclophosphamide 2 mg/kg/day × 8-12 wks
                            2. Mycophenolate mofetil (MMF) 800-1200 mg/m²/day
                            3. Calcineurin inhibitor (CNI):
                               Cyclosporine 4-5 mg/kg/day OR
                               Tacrolimus 0.1-0.15 mg/kg/day
                            4. Rituximab 375 mg/m² IV × 1-4 doses
                            5. Levamisole (in some guidelines)

"Corticosteroids will induce a remission in the vast majority of children with nephrotic syndrome... Almost 50% of children with SSNS will experience multiple relapses." — Campbell Walsh Wein Urology, 3-Volume Set, p. 460

FSGS - Treatment Protocol

Membranous Nephropathy - Risk-Stratified Treatment

• Low risk: Preserved GFR, protein < 3.5 g/day, albumin > 3.0 g/dL → Monitor; 30% spontaneous remission
• Moderate risk: Protein 4-8 g/day, preserved GFR, anti-PLA2R > 50 RU/mL → Rituximab (preferred) or calcineurin inhibitor
• High risk: Protein > 8 g/day OR declining GFR OR albumin < 2.5 g/dL OR anti-PLA2R > 150 RU/mL → Rituximab OR Ponticelli regimen (alternating methylprednisolone + chlorambucil/cyclophosphamide monthly × 6 months)

Congenital Nephrotic Syndrome (CNS)

• Immunosuppression is NOT effective (genetic basis)
• Conservative: Na/fluid restriction, IV albumin + loop diuretics
• Hypercaloric diet, thyroid hormone replacement (TBG loss)
• Prophylaxis for thrombosis and infection
• Ultimately: bilateral nephrectomy + dialysis + renal transplantation (Campbell Walsh Wein Urology, 3-Volume Set, p. 462)

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11. MONITORING RESPONSE TO TREATMENT

• Complete remission: Urine protein < 0.3 g/day × 3 months
• Partial remission: ≥ 50% reduction AND protein < 3.5 g/day
• Relapse: Return of proteinuria > 3.5 g/day (or > 2+ on dipstick × 3 days) after remission
• Steroid resistance: No remission after 16 weeks full-dose steroids (adult) / 8 weeks (child)

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12. PROGNOSIS

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SUMMARY TABLE: NEPHROTIC SYNDROME AT A GLANCE

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STANDARD TEXTBOOK REFERENCES

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EXAMINER'S CHECKLIST - WHAT PROFESSORS LOOK FOR

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