Q1 LONG ANSWER 10M ★ High-yield

Describe the mechanisms of glomerular injury. Differentiate the nephritic from the nephrotic syndrome and add a note on rapidly progressive glomerulonephritis.

Pathology · 2nd Professional — Para-Clinical

The Glomerular Filtration Barrier

Glomerular disease comprises disorders in which the primary injury is to the glomerulus, presenting as one of a small number of recognisable clinical syndromes.

Three layers of the filtration barrier — fenestrated endothelium, the glomerular basement membrane, and the visceral epithelial cells (podocytes) with their interdigitating foot processes and slit diaphragms
Two kinds of selectivity — size (the basement membrane) and charge (anionic heparan sulphate repels albumin, which is itself negatively charged)
Loss of charge selectivity gives selective proteinuria (albumin only, as in minimal change disease); loss of size selectivity gives non-selective proteinuria (albumin and larger globulins)

The Clinical Syndromes

Syndrome	Features
Nephritic syndrome	Haematuria with dysmorphic red cells and red cell casts, oliguria, hypertension, azotaemia, and mild proteinuria (under 3.5 g a day). "Inflammation"
Nephrotic syndrome	Heavy proteinuria over 3.5 g a day, hypoalbuminaemia, oedema, hyperlipidaemia and lipiduria. "Leakiness"
Rapidly progressive glomerulonephritis	Nephritic syndrome with loss of renal function over days to weeks; crescents on biopsy
Asymptomatic haematuria or proteinuria	Detected incidentally; IgA nephropathy, thin basement membrane disease
Chronic glomerulonephritis	Progressive scarring with chronic kidney disease

Feature	Nephritic	Nephrotic
Underlying process	Inflammation with proliferation	Increased permeability, often non-inflammatory
Proteinuria	Mild, under 3.5 g/day	Heavy, over 3.5 g/day
Haematuria	Marked, with red cell casts	Absent or minimal
Oedema	Mild; periorbital	Marked; may be anasarca
Blood pressure	Raised	Usually normal
Serum albumin	Normal or mildly low	Markedly low
Renal function	Impaired — azotaemia	Often preserved initially
Typical example	Post-streptococcal glomerulonephritis	Minimal change disease

CLINICAL PEARL

Red cell casts prove the bleeding is glomerular. A cast is moulded in a renal tubule, so red cells trapped within one must have entered the nephron at or above the tubule — that is, through the glomerulus. Blood from a stone, a tumour or an infection enters lower down and forms no casts. This single finding separates nephritic disease from urological bleeding at almost no cost.

Mechanisms of Glomerular Injury

Mechanism	Explanation	Examples
IN situ immune complex formation	Antibody binds an antigen already planted or intrinsic to the glomerulus	Membranous nephropathy (anti-PLA2R on the podocyte); Heymann nephritis
Circulating immune complex deposition	Complexes formed elsewhere lodge in the glomerulus; granular immunofluorescence — "lumpy bumpy"	Post-streptococcal glomerulonephritis, SLE, hepatitis B and C
Anti-GBM antibody	Antibody to type IV collagen; linear immunofluorescence	Goodpasture syndrome — lung and kidney together
Podocyte injury	Loss of foot processes and slit diaphragms; NO immune deposits	Minimal change disease, focal segmental glomerulosclerosis
Cell-mediated and pauci-immune	T cells and ANCA-activated neutrophils; few or NO deposits	ANCA-associated vasculitis
Non-immune	Metabolic, haemodynamic or deposition injury	Diabetic nephropathy, amyloidosis, hypertension

Histological Terms

Term	Meaning
Diffuse	All glomeruli involved
Focal	Some glomeruli involved
Global	The whole of an affected glomerulus
Segmental	Part of an affected glomerulus
Proliferative	Increase in cell number — mesangial, endocapillary or extracapillary
Crescent	Proliferation of parietal epithelial cells and macrophages in BOWMAN space, following rupture of the capillary wall and leakage of fibrin; the marker of severe injury
Membranous	Basement membrane thickening without proliferation
Sclerosis	Increase in matrix; scarring

Rapidly Progressive Glomerulonephritis

Type	Immunofluorescence	Causes
Type I — anti-GBM	Linear IgG along the basement membrane	Goodpasture syndrome (with lung haemorrhage); anti-GBM disease
Type II — immune complex	Granular ("lumpy bumpy")	Post-infectious, SLE, IgA nephropathy, Henoch–Schonlein purpura
Type III — pauci-immune	Little or NO staining	ANCA-associated — granulomatosis with polyangiitis, microscopic polyangiitis

Crescents in more than 50% of glomeruli define the entity; the proportion correlates with prognosis
A nephrological emergency — untreated, renal function is lost within weeks; treated early with steroids, cyclophosphamide or rituximab, and plasma exchange for anti-GBM disease, much can be salvaged

Applied Aspects

Urine microscopy is the cheapest and most informative test — dysmorphic red cells and red cell casts point to the glomerulus and change the whole direction of investigation
Renal biopsy is required for diagnosis in most glomerular disease, and must be examined by light microscopy, immunofluorescence and electron microscopy together — each answers a different question
Complement levels help — C3 is low in post-streptococcal glomerulonephritis, lupus nephritis and membranoproliferative disease; normal in IgA nephropathy, minimal change disease and anti-GBM disease
IgA nephropathy (Berger disease) is the commonest glomerulonephritis worldwide, presenting with haematuria during or within a day or two of an upper respiratory infection — "synpharyngitic" — unlike post-streptococcal disease, which follows after one to four weeks
In India, infection-related glomerulonephritis remains common, and chronic glomerulonephritis is a leading cause of end-stage renal disease in the young
Blood pressure control and ACE inhibition reduce proteinuria and slow progression in nearly all chronic glomerular disease, whatever the histology
The degree of proteinuria is the best single predictor of progression — better than the histological label — which is why reducing it is a treatment target in its own right
Interstitial fibrosis on biopsy predicts outcome better than the glomerular lesion, because it reflects irreversible damage already done

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