14.2 Nephrotic and Nephritic Syndromes & Primary Glomerular Disease

Glomerular diseases represent a core test domain in MRCP(UK) Part 1. Candidates must possess detailed knowledge of clinical syndromes (nephrotic vs. nephritic), distinct histological patterns on light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM), and guideline-directed immunosuppressive regimens.

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1. Nephrotic Syndrome vs. Nephritic Syndrome

Glomerular pathologies typically present along a spectrum bounded by two quintessential clinical syndromes:

Nephrotic Syndrome

Defined by a classical diagnostic triad:

1. Heavy Proteinuria: > 3.5 g/24 hours (or urinary protein-to-creatinine ratio [PCR] > 300 mg/mmol; albumin-to-creatinine ratio [ACR] > 220 mg/mmol).
2. Hypoalbuminaemia: Serum albumin < 30 g/L (often < 20 g/L).
3. Peripheral Pitting Oedema: Dependent pitting oedema driven by secondary sodium and water retention (overfill hypothesis via renal ENaC upregulation by plasmin in filtrate) alongside reduced intravascular oncotic pressure (underfill hypothesis).

Secondary Complications of Nephrotic Syndrome:

• Hypercoagulability & Thromboembolism: Urinary filtration loss of endogenous anticoagulants (antithrombin III, protein C, and protein S), coupled with compensatory hepatic hyper-synthesis of prothrombotic factors (fibrinogen, factors V and VIII) and thrombocytosis. Venous thromboembolism is most common in membranous nephropathy, specifically predisposing to renal vein thrombosis (manifesting as sudden flank pain, macroscopic haematuria, worsening proteinuria, or sudden decline in renal function; confirmed via CT or Doppler ultrasound). Prophylactic anticoagulation (e.g. low-molecular-weight heparin or direct oral anticoagulants) is indicated when serum albumin falls below 20–25 g/L in high-risk patients.
• Hypercholesterolaemia & Dyslipidaemia: Diminished plasma oncotic pressure triggers generalized hepatic protein synthesis, markedly elevating total cholesterol, LDL, and apolipoprotein B, accompanied by defective peripheral clearance via lipoprotein lipase downregulation. Lipiduria yields oval fat bodies and "Maltese cross" birefringence under polarized light microscopy.
• Infection Risk: Urinary loss of low-molecular-weight immunoglobulins (chiefly IgG) and alternative complement pathway components (Factor B). Patients are uniquely vulnerable to encapsulated bacterial infections, classically Streptococcus pneumoniae (spontaneous bacterial peritonitis, lobar pneumonia, and sepsis). Pneumococcal and seasonal influenza vaccinations are mandatory.

Nephritic Syndrome

Characterized by acute, aggressive endocapillary glomerular inflammation and disruption of the glomerular filtration barrier:

• Haematuria with Active Urinary Sediment: Dysmorphic red blood cells (acanthocytes) and pathognomonic red blood cell casts.
• Sub-nephrotic Proteinuria: Typically 0.5–3.0 g/24 hours.
• Hypertension: Driven by impaired sodium and fluid excretion.
• Oliguria & Elevated Serum Creatinine: Secondary to reduction in total functional filtration surface area.

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2. Primary Glomerular Diseases

Minimal Change Disease (MCD)

• Epidemiology: Responsible for > 80% of nephrotic syndrome in young children (< 10 years) and 10–15% in adults.
• Aetiology: Mostly idiopathic (primary T-cell immune dysregulation generating circulating permeability factors targeting nephrin/podocin). Secondary triggers: NSAID use, Hodgkin lymphoma and other lymphoproliferative malignancies (paraneoplastic cytokine storm), lithium, and atopy.
• Renal Biopsy Features:
  • Light Microscopy (LM): Completely normal glomerular architecture ("nil disease"); tubules may contain reabsorbed lipid droplets.
  • Immunofluorescence (IF): Completely negative (no immune complex or complement deposition).
  • Electron Microscopy (EM): Pathognomonic diffuse, uniform effacement (flattening/fusion) of podocyte visceral epithelial foot processes.
• Clinical Presentation & Management: Abrupt onset of profound nephrotic syndrome with selective proteinuria (primarily albumin). Highly responsive to high-dose oral corticosteroids (oral prednisolone 1 mg/kg/day, up to 60–80 mg daily for 4–16 weeks). Over 90% achieve complete remission. Frequent relapses or steroid-dependent disease are managed with cyclophosphamide, calcineurin inhibitors (tacrolimus, ciclosporin), or rituximab.

Focal Segmental Glomerulosclerosis (FSGS)

• Epidemiology: The commonest cause of primary nephrotic syndrome in adults of African descent. Strongly associated with homozygous risk alleles in the APOL1 gene (which encodes apolipoprotein L1, offering evolutionary protection against Trypanosoma brucei rhodesiense African sleeping sickness at the expense of accelerated podocyte lysosomal swelling and lysis).
• Aetiology:
  • Primary: Circulating permeability factor (e.g. suPAR).
  • Secondary: Hyperfiltration from reduced nephron mass (unilateral renal agenesis, reflux nephropathy, morbid obesity), HIV-associated nephropathy (HIVAN) (characterised by the aggressive collapsing variant of FSGS), intravenous heroin abuse, and sickle cell nephropathy.
• Renal Biopsy Features:
  • LM: Sclerosis involving a portion of the capillary tuft (segmental) in some, but not all, glomeruli (focal), predominantly initiating in juxtamedullary nephrons. Often displays hyalinosis and adhesion to Bowman's capsule.
  • IF: Non-specific trapping of IgM and C3 within sclerotic segments.
  • EM: Extensive podocyte foot process effacement with focal areas of podocyte detachment from the underlying bare basement membrane.
• Management: Poor response to corticosteroids compared to MCD (< 30–50% complete response). Calcineurin inhibitors (tacrolimus), RAAS blockade, and SGLT2 inhibitors. High allograft recurrence: Recur in 30–40% of renal allografts post-transplantation, often within hours to days of engraftment due to the circulating permeability factor.

Membranous Nephropathy (MN)

• Epidemiology: The commonest cause of primary nephrotic syndrome in Caucasian adults (peak incidence between 40 and 60 years).
• Pathogenesis: In 70–80% of primary cases, circulating autoantibodies (chiefly IgG4) target the M-type phospholipase A2 receptor (anti-PLA2R) on the visceral podocyte surface. Autoantibodies against thrombospondin type-1 domain-containing 7A (THSD7A) account for another 3–5%. In situ immune complex formation activates complement, forming the sublytic membrane attack complex (C5b-9) which injures the podocyte.
• Secondary Causes (~20–25%): Solid organ malignancies (carcinomas of the lung, prostate, colon, stomach, and breast; age > 60 mandates thorough malignancy screening), infections (Hepatitis B, Hepatitis C, syphilis), autoimmune disease (Systemic Lupus Erythematosus Class V), and drugs (NSAIDs, penicillamine, gold).
• Renal Biopsy Features:
  • LM: Diffuse, uniform thickening of the glomerular basement membrane (GBM) without prominent cellular proliferation.
  • Silver Methenamine Stain: Classic "spike and dome" appearance (subepithelial projections of basement membrane "spikes" extending between non-staining immune deposits).
  • IF: Diffuse, uniform granular capillary loop deposition of IgG and C3.
  • EM: Subepithelial electron-dense immune deposits nestled along the external surface of the lamina densa beneath effaced podocytes.
• Management: High rate of spontaneous complete or partial remission (~30%); initial conservative management with ACEi/ARB, statins, and BP control for 6 months. For high-risk disease (persistent severe proteinuria, rising anti-PLA2R titres, or declining eGFR): targeted B-cell depletion with rituximab is now first-line under KDIGO guidelines; alternative is the cyclical Ponticelli regimen (alternating months of cyclophosphamide and oral/IV steroids).

IgA Nephropathy (Berger's Disease)

• Epidemiology: The most common primary glomerulonephritis worldwide, especially prevalent in East Asian populations.
• Pathophysiology: Multi-hit pathogenesis: genetically susceptible individuals produce excessive circulating galactose-deficient IgA1 (gd-IgA1). Endogenous IgG or IgA autoantibodies recognize the exposed hinge-region O-glycans, forming circulating immune complexes that deposit in the glomerular mesangium, triggering mesangial cell proliferation and extracellular matrix secretion.
• Clinical Presentation: Recurrent episodes of visible, macroscopic haematuria developing synchronously with or 1–2 days after an upper respiratory tract or gastrointestinal viral infection ("synpharyngitic" macroscopic haematuria). Between acute episodes, patients exhibit asymptomatic microscopic haematuria with variable proteinuria. Normal serum complement levels (C3 and C4 are typically normal).
• Renal Biopsy Features:
  • LM: Mesangial hypercellularity and expanded mesangial matrix.
  • IF (Diagnostic Gold Standard): Intense, predominant granular mesangial deposition of IgA (frequently co-depositing with C3).
  • EM: Dense immune-type deposits confined to the mesangial matrix.
  • Oxford Classification (MEST-C Score): Evaluates Mesangial hypercellularity (M), Endocapillary hypercellularity (E), Segmental glomerulosclerosis (S), Tubular atrophy/interstitial fibrosis (T), and Crescents (C).
• Therapy: Optimized supportive therapy with ACEi or ARBs titrated to achieve systolic BP < 120 mmHg and proteinuria < 0.5–0.75 g/day; SGLT2 inhibitors (dapagliflozin); targeted-release formulation oral budesonide (Nefecon, acts locally on ileal Peyer's patches); systemic corticosteroids in persistent high-risk disease.

Post-Streptococcal Glomerulonephritis (PSGN)

• Epidemiology & Timing: Immune complex-mediated glomerulonephritis developing 1 to 3 weeks following Group A beta-haemolytic streptococcal (Streptococcus pyogenes) pharyngitis, or 3 to 6 weeks following streptococcal impetigo/pyoderma.
• Clinical Signs: Classical acute nephritic syndrome: "smoky" or "cola-coloured" urine, facial and periorbital oedema, hypertension, and oliguria.
• Serological Features: Elevated antistreptolysin O titre (ASOT) (in pharyngitis) or anti-DNase B (in impetigo); markedly depressed serum C3 with normal or mildly low C4 (due to alternative complement pathway consumption). C3 levels normalize spontaneously within 6 to 8 weeks; failure to normalize beyond 8 weeks mandates renal biopsy to exclude C3 glomerulopathy or lupus nephritis.
• Renal Biopsy Features:
  • LM: Diffuse, global endocapillary proliferative and exudative glomerulonephritis with heavy neutrophilic infiltration.
  • IF: Coarse granular capillary loop and mesangial deposition of C3 and IgG ("starry sky" appearance).
  • EM: Characteristic large, subepithelial dome-shaped electron-dense "humps".
• Prognosis & Management: Spontaneous resolution occurs in > 95% of children and the majority of adults. Supportive therapy: salt and water restriction, loop diuretics for hypertension and circulatory overload.

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