26th June 2023

Glomerulonephritides associated with mixed nephrotic and nephritic syndrome

Membranoproliferative (mesangiocapillary) glomerulonephritis

Membranoproliferative glomerulonephritis (MPGN) can present as either nephritic or nephrotic syndrome. Common symptoms include:

• Proteinuria
• Haematuria
• Oedema
• Hypoalbuminaemia

Type I MPGN (most common) is associated with either activation of the classical complement pathway triggered by circulating immune complexes, which can be caused by chronic infections such as hepatitis B, or hepatitis C, or inappropriate activation of the alternate complement pathway leading to increased breakdown of complement protein C3 to C3a and C3b. These immune complexes or complement proteins deposit in the subendothelial layer, causing recruitment and accumulation of inflammatory cells, which release oxidants and proteases. These damage the endothelium and cause thickening of the glomerular basement membrane which can lead to proliferation of mesangial cells and mesangial interposition. This can result in splitting of the basement membrane and cause a ‘tram-track’ appearance of the basement membrane on light microscopy.

Causes:

• Cryoglobulinaemia
• Hepatitis B
• Hepatitis C
• Bacterial endocarditis
• Alpha-1-antitrypsin deficiency
• Systemic lupus erythematosus

Type II MPGN (also called ‘dense deposit disease’) is caused by C3-nephritic factor stabilising C3-convertase which leads to prolonged and increased cleavage of C3 into C3a and C3b. The result is circulating C3a and C3b deposits in the basement membrane. This causes inflammation of the basement membrane and low levels of C3 (which is used to aid in the diagnosis). Electron microscopy shows intramembranous immune complex deposits with ‘dense deposits’.

Causes:

• Partial lipodystrophy (associated with subcutaneous tissue loss from the face)
• Factor H deficiency

Type III MPGN is associated with immune complexes or complement; both are deposited in the subepithelial and subendothelial layer of the glomerulus.

Causes:

• Hepatitis B and C

Steroids may be effective for the management of all three types; however, a renal transplant may be required if the nephropathy is left untreated or is resistant to steroids.

Post-streptococcal glomerulonephritis (PSGN)

PSGN is caused by infection by group A beta-haemolytic streptococcus bacteria. This leads to the development of immune complexes, which deposit in the glomeruli, causing inflammation. It can present as nephrotic or nephritic syndrome but is one of the most common causes of nephritic syndrome in children. It is categorised as a type III hypersensitivity reaction and occurs 1-4 weeks after the initial infection. PSGN is associated with diffuse proliferative glomerulonephritis, and electron microscopy shows dense subendothelial ‘humps’ caused by immune complex deposits.

Lupus Nephritis

In systemic lupus erythematosus (SLE), the DNA in the cells becomes damaged and in some cells this damage is so extensive that the cell undergoes apoptosis. This leads to the release of parts of the nucleus which, in SLE, the immune system treats as antigens. This results in the body creating antibodies against these ‘nuclear antigens’; these antibodies are called antinuclear antibodies (ANA).

These antibodies bind to the antigens forming antigen-antibody complexes, which can deposit in various places in the body, including the kidneys and particularly the glomerulus, leading to a type III hypersensitivity reaction resulting in inflammation, and this is termed lupus nephritis. Lupus nephritis is further categorised into

Type I – Normal kidney

Type II – Mesangial proliferative glomerulonephritis

Type III – Focal proliferative glomerulonephritis, where one nephron or a segment of nephrons are affected.

Type IV – Diffuse proliferative glomerulonephritis, where all or almost all nephrons in both kidneys are affected. The most common lupus nephritis. Renal biopsy shows endothelial and mesangial proliferation in a characteristic wire loop appearance. Subendothelial immune complex deposits are seen on electron microscopy.

Type V – Diffuse membranous glomerulonephritis

Type VI – Sclerosing glomerulonephritis

Management:

• Treat hypertension with ACE inhibitors as first line.
• Glucocorticoids with mycophenolate or cyclophosphamide.
• Mycophenolate is usually preferred to azathioprine as there is less risk of developing end stage renal disease.