26th June 2023

Glomerulonephritides associated with nephrotic syndrome

Minimal Change Disease

Minimal change disease most often presents as nephrotic syndrome, and the majority of cases are idiopathic. It is the most common cause of nephrotic syndrome in children. It is caused by T cells releasing cytokines causing effacement of podocytes in the glomerulus leading to increased permeability.

Causes:

• Malignancy: Hodgkin’s lymphoma, thymoma
• Infection: Epstein-Barr virus (EBV)
• Drugs: NSAIDs and rifampicin

No change is seen on light microscopy and electron microscopy shows effacement of podocytes.

Management:

• Majority of cases are steroid responsive
• Cyclophosphamide is second line for steroid-resistant cases

Prognosis (rule of thirds):

• 1/3 have just one episode
• 1/3 have infrequent relapses
• 1/3 have frequent relapses which often stop before adulthood

Membranous glomerulonephritis

Commonest cause of nephrotic syndrome in older adults (>60 years of age). It is caused by immune complexes formed by an autoantibody binding to an antigen, which directly target the glomerular basement membrane (GBM). The immune complexes deposit in the subepithelial layer between the podocytes and the GBM. This leads to activation of the complement pathway, causing inflammation and subsequent damage to the podocytes and mesangial cells and results in increased permeability of the GBM. Areas of the GBM remain undamaged and become thickened. This causes the typical ‘spike and dome’ appearance seen on electron microscopy of membranous glomerulonephritis.

Causes:

• Idiopathic: associated with anti-phospholipase A2 antibodies
• Infection: Hepatitis B, malaria, syphilis
• Drugs: gold, penicillamine, NSAIDs, captopril
• Malignancy: Most commonly, solid tumours of the lung and colon. Also, prostate, lymphoma, and leukaemia.
• Autoimmune diseases: systemic lupus erythematosus, thyroiditis, rheumatoid arthritis

Management:

• First line treatment is with an ACE inhibitor or an angiotensin II receptor blocker. Evidence shows they reduce proteinuria and improve prognosis.
• Immunosuppression is reserved for patients with severe or progressive disease. Corticosteroids and another drug, such as cyclophosphamide, are often used. Corticosteroids alone are not effective.
• Anticoagulants are considered for high-risk patients due to the risk of venous thromboembolism in nephrotic syndrome. Membranous glomerulonephritis is the nephropathy most likely to cause renal vein thrombosis.

Prognosis (rule of thirds)

• 1/3 – spontaneous remission
• 1/3 – remain proteinuric
• 1/3 – develop end stage renal failure

Good prognostic features: female sex, young age at initial presentation, asymptomatic proteinuria at initial presentation.

Focal segmental glomerulosclerosis (FSGS)

In FSGS there is initial damage of the glomeruli leading to protein and lipids leaking out of the glomerulus. Protein and lipids then deposit in the glomeruli, damaging and scarring the glomeruli and increasing permeability of the basement membrane, resulting in nephrotic syndrome. FSGS leads to reduced kidney function and can progress to renal failure. It can also be complicated by the development of anaemia due to reduced production of erythropoietin.

Causes:

• Primary FSGS (idiopathic)
• Genetic
• Obesity (hypothesis that increased lipids can lead to FSGS)
• Obstructive sleep apnoea
• Sickle cell disease
• HIV
• Autoimmune diseases, including systemic lupus erythematosus and Alport’s syndrome
• Heroin, steroids

Management:

• 1st line – steroids
• 2nd line – immunosuppressants
• Lifestyle changes
• Treat underlying cause
• Stop medication or drug causing FSGS

Prognosis:

• If untreated, FSGS can lead to renal failure. It is very unlikely to go into spontaneous remission without treatment.