26th June 2023

Glomerulonephritis

Physiology and Pathophysiology of the glomerulus

Physiology of the glomerulus

Glomerulonephritis is caused by inflammation of the glomerulus. The glomerulus is involved in ultrafiltration of the blood (filtration under pressure), regulating renal blood flow and maintenance of systemic blood pressure. The glomerulus is a bundle of capillaries contained within Bowman’s capsule, and together they make up the renal corpuscle. The renal corpuscle filters blood – this happens when blood travels from the afferent arteriole into the glomerulus under pressure. The fenestrated endothelial cells of the glomerular capillaries and podocytes allow water, ions, and small molecules from the bloodstream to flow into Bowman’s capsule and out into the proximal convoluted tubule to eventually be excreted in the urine. Larger molecules, such as proteins and blood cells, are normally unable to pass through the glomerulus and therefore remain within the blood.

Pathophysiology of the glomerulus

In glomerulonephritis, the glomerulus becomes damaged; this can occur due to multiple reasons including immune cells, antibodies, complement proteins, immune complexes, hypertension, and sclerosis. This helps to explain the common presentations of glomerulonephritis which are: asymptomatic proteinuria and haematuria; nephrotic syndrome; nephritic syndrome; rapidly progressive glomerular disease; and chronic kidney disease.

Nephrotic Syndrome

Consists of a triad of:

• Heavy proteinuria (>3.5g/day)
• Hypoalbuminemia
• Oedema

Proteinuria develops due to disruption to the filtering process of the glomerulus, caused by damage to the endothelial cells and podocytes. This results in the passage of proteins into the urine. This process also causes albumin (a protein) to incorrectly pass out of the bloodstream, causing hypoalbuminaemia. Oedema is secondary to low serum albumin, loss of oncotic pressure and retention of sodium and water by the distal nephron.

Patients with nephrotic syndrome are hypercoagulable due to the loss of antithrombin proteins, particularly antithrombin III, in the urine. This increases the risk of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and renal vein thrombosis. Hyperlipidaemia is very common and causes an increased risk of cardiovascular disease. There is also an increased risk of bacterial infection, most commonly cellulitis, due to urinary immunoglobulin loss. Hypocalcaemia can also occur due to the loss of vitamin D and binding protein in the urine.

Nephritic Syndrome

Patients typically present with haematuria (both macroscopic and microscopic), hypertension, proteinuria, and sterile pyuria. It is caused primarily by inflammation and damage to the glomerular capillary.

Types of Glomerulonephritis

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.

Glomerulonephritides associated with nephritic syndrome

IgA Nephropathy (Berger’s disease)

IgA nephropathy, also known as Berger’s disease, is a type III hypersensitivity disorder caused by IgA immune complexes which deposit in the mesangium of the glomerulus. The mesangium is a matrix of cells that helps support the capillary loops, therefore, when this is damaged, it results in leakage of red blood cells leading to haematuria. It is the most common nephropathy worldwide and develops during infection of the mucosal lining, either of the respiratory tract or the gastrointestinal tract.

Associated Conditions:

• Coeliac disease
• Dermatitis herpetiformis
• Henoch-Schoenlein purpura (HSP) (there is significant pathological overlap with HSP and IgA)
• Alcoholic cirrhosis

Histology:

• Light microscopy – mesangial proliferation
• Electron microscopy – immune deposits in the mesangium
• Immunofluorescence – IgA immune complexes

Management:

• Control blood pressure – ACE inhibitors commonly used, which also reduce proteinuria
• Steroids – prevent immune complex formation.
• If isolated haematuria with no significant proteinuria, often no treatment is required, and renal function just needs to be monitored.

Prognosis:

• Approximately twenty-five percent of patients develop end stage renal failure.
• Frank haematuria with little or no proteinuria is a good prognostic factor
• Poor prognostic factors include
  • Male gender
  • Proteinuria (particularly >2 grams/day)
  • Hypertension
  • Smoking
  • Hyperlipidaemia

Rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritis (RPGN), also known as crescenteric glomerulonephritis, is caused by cell proliferation due to inflammation of the glomerulus, which leads to splitting or breaking of the glomerular basement membrane. This damage to the glomerular basement membrane allows larger molecules, such as inflammatory mediators, plasma proteins and fibrin, to pass into Bowman’s space. This leads to increased recruitment of monocytes and macrophages and increased proliferation of parietal epithelial cells, causing thickening. This results in the characteristic crescent-moon shaped glomeruli seen in RPGN, which can be visualised on electron microscopy. The glomeruli become significantly damaged, causing a decrease in renal function, and this can quickly progress to renal failure.

There are three types of RPGN categorised by what causes the original damage to the glomerular basement membrane and can be differentiated using immunofluorescence.

Type I

• Anti-glomerular basement membrane (Anti-GBM) antibodies cause damage to the glomerular basement membrane.
• Associated with Goodpasture’s syndrome
• Immunofluorescence shows linear IgG deposits along the basement membrane

Type II

• Caused by immune complexes
• Associated with post-streptococcal glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, Henoch-Schoenlein purpura.
• Immunofluorescence – granular appearance of immune complexes

Type III

• Anti-neutrophil cytoplasmic antibody (ANCA) cause damage to the glomerular basement membrane
• Associated with
  • Granulomatosis with polyangiitis (GPA, Wegener’s granulomatosis) – cANCA
  • Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome)
  • Microscopic polyangiitis – pANCA
• Immunofluorescence – no changes (pauci-immune disease process, therefore no anti-GBM antibodies and no immune complexes).

Management:

Treatment options are the same for all three types and treatment should be initiated early to prevent a poor prognosis and development of renal failure.

• Anticoagulants – to protect against thromboembolism due to loss of fibrin
• Plasmapheresis
• Immunosuppressants
• Dialysis
• Transplant

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.