Ultrastructure

The barrier separating blood from the lumen of the matrix nephron consists of 3 layers:

Mesangial cells have three functions:

These layers form a complicated sieve controlling glomerular permeability. Wide pores (70–100 nm) in the endothelium allow all components to reach the basement membrane.

The basement membrane produced by the endothelium and epithelium has a strong anionic (negative) charge which repels major plasma proteins (also anionic). It has a central dense layer (lamina densa).

The epithelial cells are attached to the basement membrane by foot processes, separated by ‘slit pores’ 30–60 nm in diameter.

Filtration

The glomerular filtrate is virtually protein free plasma. Its rate of production is dependent upon:

Variation in any of these factors affects the output of urine. Diminished urinary output results from a reduction in renal blood flow as in shock, from an increase in osmotic pressure as in haemoconcentration, or from obstruction to the outflow of urine.

Aetiology

Pathology – There is generalised thickening of capillary basement membrane.

Tuft enlarges

Glomeruli not hypercellular

Specific silver staining of the basement membrane shows a typical pattern.

Immunofluorescence reveals deposition of IgG in the capillary walls.

Electron microscope findings explain this appearance.

In the later stages there is a massive increase in basement membrane material.

Silver staining shows

Tubular changes – In the early stages, protein droplets and lipid globules appear in the tubular epithelium. If the disease progresses there is atrophy of the tubules and interstitial fibrosis.

Prognosis – In about 25% of patients the disease remits spontaneously, the remainder continuing to have proteinuria and in 40% chronic renal failure eventually supervenes.

Aetiology

Complement activation is a feature of both forms. In Type 1 this is due to immune complexes by the classical pathway (p.99). In Type 2 there is activation by the alternative pathway by an autoantibody which stabilises C3 converting enzyme. Serum C3 is low in both forms.

Clinical Features

Children and young adults are usually affected. They present with the nephrotic syndrome (50%), the nephritic syndrome or asymptomatic haematuria or proteinuria.

In half of patients there is progression to renal failure (with hypertension) within a decade. The disease often recurs in the subsequently transplanted kidney.

Focal Segmental Glomerulosclerosis (FSGS)

In this pattern of disease, a segment of glomerulus undergoes sclerosis without inflammation, but with an increase in mesangial matrix.

Originally regarded as a variant of minimal change nephropathy, primary FSGS presents as with haematoma or nephrotic syndrome with progression to chronic renal failure. It may recur within a transplanted kidney.

Secondary FSGS may complicate a variety of preexisting conditions including those reflux nephropathy and intravenous drug use.

Mechanism

IgA immune complexes in blood → Glomeruli → Often focal deposition → Activation of complement (C3) → Often focal damage

Shows deposits of IgA and C3 within the mesangium: the capillary loops are not usually affected.

Immunofluorescence

Note: The focal deposition is dependent on the molecular size of the complex and failure of mesangial clearance.

Henoch–Schönlein purpura has similar renal changes but also skin rash and gastrointestinal symptoms.

Localisation of Complexes

This depends on the size of the complexes, their shape and electrical charge, and their ability to penetrate the basement membrane.

Other factors modifying the pathological changes are:

Note: In addition to its damaging consequences, complement activation does solubilise complexes allowing their disposal. Thus complement deficiency may predispose to immune complex disease, e.g. in systemic lupus erythematosus (SLE).

Who Classification

Parasitic Glomerulopathies

The kidney and particularly the glomeruli are damaged in many parasitic infections in the tropics. Malaria and schistosomiasis are especially important.