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Next Lesson - Diabetic Nephropathy
Core
Glomerular disease is a disease of the kidney affecting either the glomerulus itself or the tubules, interstitium or vascular structures surrounding it. It mainly affects the glomerulus but pathology to any part of one nephron can cause damage to other parts of it, for example, if the glomerulus is damaged it can reduce the blood supply to the rest of the nephron resulting in ischaemia of that nephron.
In glomerular disease, the glomerulus can either become blocked, leading to renal failure and a decreased glomerular filtration rate (GFR), or it can leak, resulting in proteinuria and/or haematuria.
The pathology of the glomerular injury determines the clinical presentation.
Glomerulonephritis is inflammation of the glomeruli and it is caused by a number of different conditions. Four major structures are affected in glomerulonephritis: the capillary endothelium, the glomerular basement membrane, mesangial cells and podocytes. It often involves the immune system, with deposition of immune complexes in the glomerulus, either subepithelial or subendothelial, which then initiate an immune response causing inflammation.
Diagram – The glomerulus within the renal corpuscle
Creative commons source by Shypoetess [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
The cause of glomerulonephritis is diagnosed based on the clinical presentation and histological appearance of the glomerulus, and can then be classified as either primary or secondary GN. Primary GN only affects the kidney, while secondary GN is either kidney disease that becomes systemic disease or originates outside the kidney and then affects the kidney.
We can decide which conditions are likely in a presenting patient by looking at the clinical presentation and seeing which features support each diagnosis. The following is a list of presentations and features for different diagnoses:
- Asymptomatic Proteinuria and/or Haematuria – usually caused by IgA nephropathy, systemic lupus erythematosus (SLE) and focal segmental glomerulosclerosis.
- Proteinuria is the presence of excess protein in the urine.
- Haematuria is the presence of blood in the urine.
- Chronic Glomerulonephritis – this is where there has been ongoing inflammation for a long period of time. IgA nephropathy, SLE and any previously treated glomerulonephritis can cause chronic glomerulonephritis.
- Acute Glomerulonephritis – in acute GN there is sudden inflammation of the glomerulus, and this is usually caused by a nephritic syndrome (this will be discussed below). Nephritic syndromes include IgA nephropathy, SLE, post-infectious GN and ANCA-vasculitis.
- Rapidly Progressive Glomerulonephritis (RPGN) – in rapidly progressive GN there is a rapid loss of renal function which is associated with the formation of epithelial crescents in glomeruli histologically. Causes of RPGN include ANCA-vasculitis, anti-glomerular basement membrane disease, post-infectious GN and SLE.
- Nephrotic Syndrome – this will be talked about further in this article. Causes of nephrotic syndrome include minimal change disease, focal segmental glomerulosclerosis and SLE.
Nephrotic vs Nephritic Syndrome
Glomerulonephritis presents mainly as two syndromes, nephrotic syndrome and nephritic syndrome. These are not diagnoses but help to determine the cause of GN.
Nephrotic syndrome is where there is podocyte, subepithelial or glomerular basement membrane (GBM) damage causing disruption to the glomerular filtration barrier, allowing proteins to leak through and be excreted with urine. This leads to a triad of:
- Proteinuria > 350 mg/mmol or > 3.5g per day. Proteinuria of > 350 mg/mmol alone is nephrotic range proteinuria.
- Hypoalbuminaemia
- Oedema – hypoalbuminaemia from protein excretion leads to a lower oncotic pressure in the blood vessels causing fluid to leak out into the extracellular space.
This triad is can be accompanied by other features as well:
- High cholesterol
- Normal blood pressure
- Normal serum creatinine concentration
- Hypercoagulable state – there is a loss of antithrombin-III and proteins C and S through the damaged glomerulus, as well as a rise in fibrinogen levels which causes a hypercoagulable state. This can predispose the patients to thrombosis.
- Immunocompromised – patients with nephrotic syndrome may become immunocompromised due to the loss of immune proteins from the body.
- Low total thyroid level – this is due to the loss of thyroid-binding globulin through the damaged glomerulus resulting in a lower total thyroxine level but a normal free thyroxine level.
Nephrotic syndrome causes can be split into primary or secondary; primary only affects the kidney, while secondary is either kidney disease that becomes systemic or originates outside the kidney and then affects the kidney. This article will go into further depth on these conditions.
- Primary causes of nephrotic syndrome include minimal change disease, membranous glomerulonephritis and focal segmental glomerulosclerosis.
- Secondary causes of nephrotic syndrome include diabetes, SLE, amyloidosis, connective tissue disorders, and myeloma.
- Diabetes and amyloidosis will cause nephrotic syndrome but do not cause glomerulonephritis, with diabetes being the most common cause of nephrotic syndrome.
Nephrotic syndrome is managed by treating the underlying condition. Some features of nephrotic syndrome need to be treated to avoid complications while the definitive diagnosis is either being treated or investigated.
- Oedema should be treated using a large dose of diuretics (e.g. furosemide). Restricting salt and fluid can also help to treat oedema.
- Proteinuria can be reduced by giving a patient an ACE inhibitor (e.g. ramipril) which has an anti-proteinuric effect. Caution must be used if the patient is intravascularly depleted or if the renal function deteriorates acutely.
- Hypoalbuminaemia – if the patient has a serum albumin level of less than 20g/dL there is a high risk of venous thromboembolism and so they should be started on an anticoagulant, for example, a low-molecular-weight heparin (e.g. enoxaparin).
- Hypercholesterolaemia – generally if the underlying disease is treated, the serum cholesterol levels will decrease. If the patient is suffering from long-term nephrotic syndrome then give the patient cholesterol-lowering drugs (e.g. atorvastatin) to protect them from atherosclerosis.
- If the patient has high blood pressure then this should be treated with either an ACE inhibitor or an angiotensin receptor blocker and aim for the BP to be less than 140/90 mmHg.
Complications of nephrotic syndrome include:
- Increased risk of infection
- Venous thromboembolism
- Progression of chronic kidney disease
- Hypertension
- Hyperlipidaemia
Nephritic syndrome is inflammation affecting the glomerulus and endothelium. Damage to the endothelium also causes an inflammatory response which further damages the glomerulus. Inflammation disrupts the glomerular basement membrane resulting in the loss of the filtration barrier and impairment of renal function. In nephritic syndrome, there is a triad of:
- Haematuria
- Decreased glomerular filtration rate – there is renal impairment and oliguria (decreased urine output)
- Hypertension
Other features of nephritic syndrome include:
- Proteinuria of < 3 g/day – the level of proteinuria will be less than in nephrotic syndrome.
- The onset of nephritic syndrome may be either acute or rapidly progressive (RPGN)
- Renal failure – nephritic syndrome can lead to renal failure which will present as increased serum urea and increased serum creatinine. This is also known as azotaemia.
- Red cell casts – seen if a urine sample is sent for histological analysis.
Causes of nephritic syndrome include:
- Anti-GBM disease (Goodpasture’s disease)
- ANCA-associated vasculitis
- IgA nephropathy – this can also present as nephrotic syndrome.
- Post-infectious – rare in the UK. More common in children than in adults. Can present as nephrotic syndrome.
- Systemic lupus erythematosus – this can also present as nephrotic syndrome.
Management of nephritic syndrome is similar to nephrotic syndrome as it is mainly about treating the underlying cause. While the underlying cause is being treated, clinical features and risk factors can also be treated:
- Blood pressure control – use an ACE inhibitor (e.g. ramipril) or an angiotensin receptor blocker (e.g. losartan) as long as the renal function is normal and does not decrease. Restrict salt and water intake as well.
- Proteinuria – use an ACE inhibitor (e.g. ramipril) to reduce the proteinuria if renal function allow.
- Treatment of oedema – the same as for nephrotic syndrome, i.e. large dose diuretics (e.g. furosemide), if there is adequate renal function.
- Reduce cardiovascular disease risk – stop smoking, diet changes (e.g. reduce salt). If the patient is at risk then a cholesterol-lowering drug, e.g. a statin (e.g. atorvastatin) can be given.
- Renal dialysis – this can be used in the short term depending on the cause of nephritic disease. More information on renal dialysis can be found in our article about chronic kidney disease.
A useful way to remember the difference between nephrotic syndrome and nephritic syndrome is that nephrotic has an ‘O’ in it and so causes oedema, while nephritic has an ‘I’ in it and so causes inflammation.
Minimal Change Glomerulonephritis
Minimal change glomerulonephritis/disease is a condition that is common in childhood and adolescence. The disease is characterised by minimal changes to the histological appearance of the glomerulus. Examination through an electron microscope will reveal the loss of foot processes of podocytes resulting in the loss of the filtration barrier and nephrotic syndrome. It is caused by a circulating factor that damages the podocytes but there is no immune complex deposition.
Most cases are idiopathic but other causes include non-steroidal anti-inflammatory drugs, rifampicin, Hodgkin’s lymphoma and thymoma.
There is usually no progression to renal failure with minimal change disease, unlike most other glomerular diseases.
Features of minimal change disease include heavy proteinuria, nephrotic syndrome and ankle oedema. It is treated using corticosteroids and usually resolves but minimal change disease can recur if the steroids are stopped. If the disease does not respond to steroids, then an immunosuppressant may be used.
Management will also include the general treatment for nephrotic syndrome.
- As minimal change disease is the most likely cause of nephrotic syndrome in children, there is no need to biopsy children unless treatment fails.
- With minimal change disease, 1/3rd will get better, 1/3rd will have infrequent relapses and 1/3rd will have frequent relapses until adulthood.
Focal Segmental Glomerulosclerosis (FSGS)
Focal segmental glomerulosclerosis is a glomerular disease caused by a circulating factor that damages podocytes. It doesn’t affect all glomeruli and does not damage all parts of the glomerulus. FSGS presents as nephrotic syndrome, e.g. ankle oedema and proteinuria, and mainly occurs in adults. These circulating factors remain even if the patient has a kidney transplant, meaning the transplanted kidney can also be affected by FSGS.
FSGS can be idiopathic or can have a cause, for example, malignancy, medication, HIV, heroin, Alport’s syndrome, or infection.
Focal segmental glomerulosclerosis is treated using steroids and immunosuppressants, though it is less responsive to steroids than minimal change disease. The treatment will also include the general treatment for nephrotic syndrome.
FSGS can cause glomerulosclerosis (scarring of the glomerulus) if not treated. This means FSGS can progress to renal failure, as if left untreated, the scarring causes the GFR to decrease as less substances can be filtered which ultimately results in renal failure.
Membranous Glomerulonephritis (MGN)
Membranous glomerulonephritis is the most common cause of nephrotic syndrome in adults. It is caused by immune complex deposition in the glomerulus, either through an autoimmune process or secondary to another pathology. Examples include SLE, Hepatitis B virus and malignancy. Histologically the membranes appear thick and have an abnormal glomerular basement membrane.
The pathophysiology of membranous glomerulonephritis is as follows:
- An antigen is found in the glomerulus, either as a result of an autoimmune cause or another pathology. The antigen is typically found at the podocytes, so this is where the damage to the glomerulus occurs.
- IgG is produced by the body against the antigen and is filtered by the glomerulus.
- IgG then binds to the antigen in the glomerulus and causes an inflammatory response resulting in damage to the filtration barrier that causes nephrotic syndrome.
- The antigen-antibody complex formed between IgG and the antigen cannot be filtered by the glomerulus so remains there. This has the unfortunate effect of targeting the immune response at the glomerulus.
The treatment of MGN is through immunosuppression and corticosteroids, including the general treatment of nephrotic syndrome. With the treatment of MGN, one-third of patients recover, one-third stay the same and one-third deteriorate.
IgA nephropathy is a common glomerulonephritis that can occur at any age, and classically presents with visible or invisible haematuria. It is caused by IgA deposition in the mesangium of the glomerulus resulting in an inflammatory response causing mesangial damage. It is the most common cause of nephritic syndrome.
The histological features and the course of the disease can vary and the patient may have proteinuria instead of haematuria, so it can either present as nephritic syndrome or nephrotic syndrome.
IgA nephropathy is commonly predisposed by mucosal infections as IgA protects mucosal membrane. If a patient has an upper respiratory tract infection there may be over-activation of IgA causing it to be deposited in the glomerulus. This then results in an inflammatory response and damage.
IgA nephropathy presents with visible/invisible haematuria and/or proteinuria, an increased serum IgA concentration and a normal serum C3/C4 concentration, typically with a recent history of an upper respiratory tract infection within the past 1-2 days. The haematuria may be recurrent or IgA nephropathy may be picked up on the first presentation of haematuria.
There is no effective treatment for IgA nephropathy and 25-30% of patients will progress to end-stage renal failure within 20-25 years. However, it is managed using ACE inhibitors or angiotensin receptor blockers to control the proteinuria and hypertension, and reduce the progression of the disease.
Prognostic markers for the disease can help predict the course of the disease:
- Good Prognosis – frank haematuria.
- Poor Prognosis – male, proteinuria, hypertension, smoking, hyperlipidaemia.
This article will cover two main hereditary nephropathies: thin glomerular basement membrane nephropathy and Alport syndrome.
Thin Glomerular Basement Membrane Nephropathy
Thin glomerular base membrane nephropathy is also known as benign familial nephropathy. In this hereditary condition the glomerular basement membrane is thin which causes the kidneys to leak a small amount of blood resulting in an isolated haematuria.
There are typically no symptoms with this condition.
Treatment for thin GBM nephropathy is mainly supportive, with the symptoms being treated instead of the condition itself. The renal function is monitored but it typically has a benign course and so does not progress to renal failure.
Alport syndrome is a genetic disease caused by an X-linked genetic mutation leading to the production of abnormal collagen IV. In the kidneys it causes dysfunction of the glomerular basement membrane that results in haematuria and eventually renal failure.
Alport syndrome is associated with deafness as collagen IV is found in the cochlea which plays an important role in hearing. There are also visual disturbances as Alport syndrome affects the lens of the eye.
Alport syndrome typically presents with haematuria in childhood or adolescence, sensorineural hearing loss and eye disorders.
Treatment is mainly supportive, like with thin GBM nephropathy, but renal replacement therapy can be used to manage patients who develop renal failure. Patients can also undergo a renal transplant if they develop renal failure, but this may lead to anti-glomerular basement membrane disease.
Granulomatosis with Polyangiitis
Granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis, is an immune vasculitis where there is necrotising granulomatous inflammation in small and medium-sized blood vessels around the body. It mainly affects small arterioles and so often affects the kidneys and lungs causing a pulmonary-renal syndrome.
Circulating antibodies against white cells cause endothelial damage to blood vessels resulting in vasculitis and the inflammation seen in the disease. In this disease there is no immune complex deposition in the kidneys.
Patients can present with symptoms such as fatigue, arthralgia, myalgia, weight loss, cough, haemoptysis, shortness of breath, haematuria, hypertension, epistaxis, hearing loss, abdominal pain and a flat or saddled nose due to collapse of the nasal septum.
- Patients are most likely to present with systemic symptoms of the disease rather than solely renal symptoms.
- Patients can present after they develop pulmonary haemorrhage. This can be seen on a CT scan and will present with haemoptysis (coughing up blood).
- This condition usually affects people aged 45-60 years.
- Investigations can reveal a positive result for anti-neutrophil antibodies in 90%, e.g. cANCA, pANCA.
- Renal biopsy will reveal the presence of epithelial crescents in Bowman’s capsule.
Treatment for granulomatosis with polyangiitis is steroids, immunosuppression and plasma exchange. The condition has a good prognosis if caught early on with a median survival of 8-9 years. Granulomatosis with polyangiitis causes a rapidly progressive glomerulonephritis in 80% of patients which rapidly results in renal failure if not treated quickly.
ANCA-Associated Vasculitis is a term used to describe a group of conditions where there is destruction and inflammation of small blood vessels. This group includes granulomatosis with polyangiitis and microscopic polyangiitis.
Goodpasture’s Disease (Anti-Glomerular Basement Membrane Disease)
Goodpasture’s disease is an uncommon condition caused by antibodies targeting the alpha-3 chain of type IV collagen in the glomerular basement membrane. Type IV collagen is also present in the alveolar basement membrane, so Goodpasture’s disease can affect the lungs as well, though it is more difficult for the antibodies to get to the alveolar basement membrane.
- The IgG antibodies are deposited in the basement membrane resulting in acute and rapid inflammation of the glomerulus.
- IgG antibodies also cause inflammation and damage to the alveolar membrane. This damage can result in pulmonary haemorrhage and haemoptysis.
- Patients are more at risk of pulmonary haemorrhage if they smoke, have a lower respiratory tract infection, have pulmonary oedema, are a young male or have inhaled hydrocarbons.
Goodpasture’s disease can rapidly progress to glomerulonephritis and renal failure so needs to be recognised and treated quickly. It usually affects people aged 20-30 years or 60-70 years, and will present with an acute onset nephritic syndrome.
Signs and Symptoms:
- Shortness of breath
- Epistaxis (nose bleeding)
- Cough – may have haemoptysis (coughing up blood)
- Pallor and malaise
- Hepatomegaly
- Hypertension
- Abnormal renal function
Investigations will show haematuria and proteinuria on a urine dipstick. Blood tests may show the presence of anti-GBM antibodies. Renal biopsy will show linear IgG deposits along the glomerular basement membrane.
Treatment of Goodpasture’s disease is with immunosuppression, steroids and plasmapheresis. Plasmapheresis is where a patient undergoes dialysis of the plasma to remove the anti-GBM antibodies in the blood. The treatment will also include treating the nephritic syndrome to prevent the progression of the disease.
Vasculitis is the term used for a group of systemic disorders that cause inflammation of blood vessels. The different disorders are categorised depending on the size of the blood vessel they affect, so they will be classified as large vessel, medium vessel or small vessel vasculitis.
Vasculitis is associated with anti-neutrophil cytoplasmic antibody (ANCA), which attacks the endothelial lining of the glomerulus resulting in inflammation and causing holes to form.
If vasculitis affects the kidneys it causes a rapidly progressive glomerulonephritis that can progress to renal failure if not treated early. There is no immune complex or antibody deposition in the kidney, but the endothelial wall inflammation causes segmental necrosis resulting in holes in the glomerulus.
Two types of vasculitides that affect the kidney include:
- Microscopic Polyangiitis – a small vessel vasculitis that usually causes mild respiratory symptoms and will not cause renal symptoms.
- Blood tests will show a raised serum ANCA and a renal biopsy will show segmental necrotising glomerulonephritis.
- Microscopic polyangiitis is treated with immunosuppression.
- Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss) – this is a small vessel vasculitis. These patients will typically have asthma and/or allergic rhinitis previously and present with purpura, peripheral neuropathy, sinusitis and dyspnoea.
- Blood tests will show a raised serum ANCA and eosinophilia, and a renal biopsy will show focal segmental necrotising glomerulonephritis.
- It is treated with immunosuppression.
Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus is an auto-immune systemic disease that affects multiple organ systems, including the kidney. There are many patterns of renal disease with SLE and it can cause either nephritic or nephrotic syndrome. It is an important diagnosis to look out for and to have as a differential if a patient presents with either nephrotic or nephritic syndrome.
Post-Streptococcal Glomerulonephritis
Post-streptococcal glomerulonephritis is a glomerular disease that occurs mainly in children aged 3-12 years, weeks after a group A β-haemolytic streptococcal infection. It mainly causes a nephritic syndrome.
It will typically present weeks after an infection, such as tonsillitis, pharyngitis, impetigo and cellulitis. Glomerular disease will be seen 1-2 weeks after tonsillitis or pharyngitis and 3-4 weeks after impetigo or cellulitis.
Investigations will show anti-streptococcal antibodies, a low C3/complement level and immune complex deposition (IgG, IgM and C3).
Post-streptococcal glomerulonephritis is usually self-limiting and so the treatment is mainly supportive, using ACE inhibitors or angiotensin receptor blockers for the proteinuria and hypertension. Post-streptococcal glomerulonephritis can progress to end-stage renal failure, and if this happens then renal replacement therapy is given to the patient.
Edited by: Dr. Tom Bradley
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