Renal - Glomerular disease

Question 1

Features of glomerular disease

Answer 1

• Reduced GFR - damage to glomerulus
• Proteinuria - protein leakage through glomerular basement membrane
• Haematuria - active glomerular injury, causing bleeding
• Hypertension - sodium and water retention, excess renin secretion
• Oedema - sodium and water retention

Glomerulonephritis means “inflammation of the glomerulus”

Question 2

Primary vs secondary glomerular disease

Answer 2

Primary = only if kidney is affected 
Secondary = kidney + other tissues 

Classified by clinical syndrome, histopathology, or underlying disease (diagnostic). If etiology unknown, then histopathological description (e.g. minimal change disease) serves as diagnosis

Question 3

Pathological classification of glomerular disease

Answer 3

Proliferative disease = abnormal proliferation of cells within glomerulus
- proliferation of macrophages within Bowman’s capsule gives appearance known as crescent

Mesangial disease = excess production of mesangial matrix

Membranous disease = glomerular basement membrane damaged and thickened

Membranoproliferative = both thickening of glomerular basement membrane and cellular proliferation usually of mesangial cells

Vasculitis = inflammation of blood vessels

Question 4

Classification based on number of glomeruli affected

Answer 4

Focal - disease affects only some glomeruli
Diffuse - disease affects ALL glomeruli
Segmental - disease affects only part of the glomerulus
Global - disease affects the whole glomerulus

Question 5

Clinical syndromes of glomerular disease

Answer 5

5 major clinical syndromes (different combinations of possible effects on the glomerulus)

1) Asymptomatic proteinuria or haematuria - mild glomerular damage
2) Acute glomerulonephritis - SAME as acute nephritic syndrome; haematuria, reduced GFR, sodium and water retention, and hypertension
3) Chronic glomerulonephritis - slow progressive glomerular damage; proteinuria, haematuria and hypertension
4) Rapidly progressive glomerulonephritis - syndrome of rapid renal failure; oliguria, haematuria and proteinuria (usually without other features of nephritic syndrome)
5) Nephrotic syndrome - heavy proteinuria leading to hypoalbuminaemia and oedema

Question 6

Clinical assessment of glomerular disease

Answer 6

History:

• Recent frank haematuria 1-2 days after URTI - IgA nephropathy
• Nephritic syndrome (haematuria, oedema, hypertension, oliguria) 1-3 weeks after infection - post streptococcal glomerulonephritis
• Haemoptysis + rapidly progressive glomerulonephritis - Goodpasture’s syndrome
• Skin + joint involvement + renal impairment suggest systemic inflammatory condition, e.g. SLE, RA or vasculitis

Examination:

• important to exam for skin, joint, lung and heart lesions + neurological complications, can indicate SLE or vasculitis or infection
• SLE and infective endocarditis –> cardiac valve lesions and glomerular disease
• obesity - focal segmental glomerulosclerosis

Question 7

Investigations in suspected glomerular disease

Answer 7

1) Urine
- Urinalysis - blood and protein
- MC&S - red cell casts = active glomerular injury and bleeding
- Biochemistry - measure serum albumin and quantify proteinuria with 24 hour urine collection OR spot urine protein/creatinine ratio or spot albumin/ creatinine ratio
- eGFR
- Serum creatinine and urea, ?creatinine clearance

2) Bloods:
- Biochemistry - electrolytes, urea, creatinine, glucose (exclude diabetes), immunoglobulins (exclude dysproteinaemias)
- Microbiology - exclude infection (culture, serology, anti-streptolysin O titres)
- Immunology:
AGBM = Goodpasture’s
ANCA = vasculitis (p-ANCA, or c-ANCA)
ANA, Anti dsDNA + low complement = SLE
Cryoglobulins = Cryoglobulinaemia

3) Lung function - only if pulmonary haemorrhage
- blood in alveoli absorbs CO used in gas transfer –> raised transfer coefficient

Question 8

What are the non proliferative glomerulonephridites?

Answer 8

Glomerulonephritis/ glomerular disease divided into proliferative and non proliferative. This is a pathological classification and are features of one or more of the clinical syndromes associated with glomerular disease.

Non proliferative glomerulonephritis - lack of proliferation of cells within the glomerulus, generally cause nephrotic syndrome. Disease affects the glomerular basement membrane.

Include:

1) MINIMAL CHANGE NEPHROPATHY
2) FOCAL SEGMENTAL GLOMERULOSCERLOSIS
3) MEMBRANOUS NEPHROPATHY

These conditions can cause nephrotic syndrome, asymptomatic proteinuria or haematuria (less common) and chronic glomerulonephritis (this can occur with most glomerulonephritis except minimal change and crescentic change).

Question 9

Minimal change nephropathy - definition and treatment

Answer 9

Accounts for 90% of nephrotic syndrome in children and 20% in adults.
Association with atopy in children (asthma, eczema etc) and often follows URTI

Minimal change - light microscopy and immunostaining are normal (i.e. resemble normal glomeruli), but electron microscopy shows fusion of podocyte foot processes.

Rx - steroids and ciclosporin if relapse. Renal impairment does not occur. NSAIDs can cause minimal change disease.

Question 10

Focal segmental glomerulosclerosis

Answer 10

Accounts for 15% of adult nephrotic syndrome and can also cause haematuria and hypertension. Focal (affecting some but not all glomeruli) and segmental (affecting only part of the glomerulus) scarring - scars contain immunoglobulin and complement.

Electron microscopy shows podocyte foot process fusion as in minimal change disease (2 conditions may be the result of essentially the same process).

Rx - steroids + cyclophosphamide or cyclosporin if relapse + antihypertensives + statins
Transplant often required - 50% progress to renal failure

Question 11

Which patients may be at risk of focal segmental glomerulosclerosis?

Answer 11

HIV - variant is associated
Obesity
Black patients - defect in CD2AP slit pore protein

Question 12

What is the etiology of membranous nephropathy? What does imaging show and how do patients respond to treatment?

Answer 12

MCC nephrotic syndrome in older patients. Slowly progressive. Can rarely manifest as asymptomatic proteinuria or haematuria.
Proteinuria and renal impairment.

Histology - thickening of glomerular basement membrane and subepithelial deposits
Immunofluorescence shows diffuse uptake of IgG

Usually idiopathic but can be secondary to malignancy, hepatitis B, SLE, or use of gold or penicillamine drugs

Some patients respond to steroids and chlorambucil or cyclophosphamide, but minority develop end stage renal disease. Rule of “thirds”

• 1/3 chronic membranous glomerulonephritis
• 1/3 go into remission
• 1/3 develop end stage renal failure

Question 13

Proliferative glomerulopathy

Answer 13

Diseases characterised by increased number of cells in the glomerulus.
Usually present with nephritic syndrome.
Dangerous! - can progress to end stage renal failure quickly over weeks - years.

Include:

1) IgA NEPHROPATHY
2) MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
3) POST INFECTIOUS GLOMERULONEPHRITIS
4) RAPIDLY PROGRESSING GLOMERULONEPHRITIS

Question 14

Membranoproliferative glomerulonephritis

Answer 14

Uncommon - young adults and children
Varied presentation - asymptomatic haematuria or proteinuria to the usual presentation of combined nephrotic and nephritic syndrome.

Most patients develop end stage renal failure, no useful treatment.

Mesangial cell proliferation, excess mesangial matrix and thickening of glomerular basement membrane. Most cases are type 1 with subendothelial deposits + mesangial immune deposits. Type 2 is rarer, there are immune deposits in the membrane.

Type 1 - SLE, infection, cryoglobulinaemia, low complement (C3 and C4)

Type 2 - antibodies that activate and deplete complement, some patients have partial lipodystrophy

Question 15

IgA nephropathy

Answer 15

Berger’s disease. MCC primary glomerular disease
Presentation - young man who develops macroscopic haematuria 1-2 days after URTI. Can also present with asymptomatic haematuria, proteinuria and renal impairment.

There is mesangial cell proliferation, increased mesangial matrix and IgA deposition in the mesangium. Patients often have raised IgA levels.

Treatment is usually unsuccessful - 1/3 of patients develop end stage renal disease and recurrence can occur AFTER transplantation

Question 16

How is IgA nephropathy related to HSP?

Answer 16

HSP - Henoch Schonlein purpura is a small vessel ANCA negative vasculitis that mainly affects children aged under 10. Typically there is a purpuric rash on the ankles, buttocks and elbows, abdominal pain, and renal disease. There is usually haematuria, proteinuria, fluid retention and renal impairment, sometimes with nephrotic syndrome. Histology is the same as IgA, but most children recover fully without treatment.

Question 17

Post infectious glomerulonephritis

Answer 17

Diffuse proliferative glomerulonephritis
Often follows streptococcal infection but can follow others, esp infective endocarditis.

Presentation is nephritic syndrome occuring several weeks after infection.

Endothelial and mesangial proliferation and glomerular infiltration by neutrophils and monocytes. There is deposition of complement, IgM and IgG on the basement membrane and in the mesangium. Electron microscopy shows subepithelial deposits. Antibiotics are given to eradicate any lingering infection, small number of patients develop end stage renal disease.

Question 18

What is rapidly progressing glomerulonephritis?

Answer 18

Also known as crescentic glomerulonephritis. Crescents are accumulations of macrophages in Bowman’s space and indicate severe glomerular disease. It carries a poor prognosis.

Any type of glomerulonephritis can progress to rapidly progressing glomerulonephritis, but some types are only ever present as RPGN. These include Goodpasture’s, and systemic vasculitis (e.g. microscopic polyangitis, Wegener’s). IgA nephropathy, HSP and cryoglobulinaemia can also progress to RPGN.

Question 19

What causes Goodpasture’s syndrome?

Answer 19

Antibodies against the C terminal of the alpha 3 chain of type 4 collagen in the glomerular basement membrane and the alveolar basement membrane in the lung. The antibody binds to these membranes, triggering inflammation. This causes rapidly preogressive crescentic glomerulonephritis with acute renal failure and lung haemorrhage. Patients are usually male with tissue type HLA-DR15. If untreated patients die of pulmonary haemorrhage or renal failure.

Question 20

Treatment for Goodpasture’s syndrome

Answer 20

Treatment involves plasma exchange to remove the antibodies and immunosuppression with steroids and cyclophosphamide to inhibit glomerular inflammation and reduce antibody production. If treated early, most patients recover and relapse is common.

Question 21

Primary vasculitis causing glomerular disease

Answer 21

Primary vasculitis is necrotising inflammation of blood vessels that can affect the kidney, lung, joints, skin and nervous system. They are classified according to size of the vessels affected or the presence of granulomata. The two small vessel diseases (and less commonly, Churg-Strauss syndrome) can cause a focal segmental proliferative glomerulonephritis with necrosis and crescent formation. Clinically, they often present as rapidly progressive glomerulonephritis. Histologically there is infiltration of the glomeruli by neutrophils, but not complement or immunoglobulin deposition.

Wegeners = ENT + renal 
MP = skin + renal + joint + lung disease

Question 22

Antibodies used to diagnose small vessel vasculitis

Answer 22

Small vessel vasculitis is either anti-neutrophil cytoplasmic antibody (ANCA) positive or negative.

Patients with Wegener’s have a cytoplasmic or c-ANCA reactivity against proteinase 3. Patients with microscopic polyangitis (and a subset of patients with PAN, and Churg-Strauss) have perinuclear or p-ANCA reactivity against myeloperoxidase.

Idiopathic rapidly progressive glomerulonephritis is a small vessel vasculitis affecting only the kidney. There is no ANCA but it is treated like other small vessel disorders.

Question 23

Treatment of vasculitis causing RPGN

Answer 23

Initially with steroids and cyclophosphamide. After several months, azothioprine is substituted for cyclophosphamide. Plasma exchange is sometimes used in the acute phase.

Question 24

How does SLE affect kidneys?

Answer 24

SLE is a multisystem disease that can affect the nervous system, joints, skin, kidneys and heart. The renal effects have been classified by WHO into 6 types. The renal presentation depends on the histological lesion. It is typically nephrotic syndrome or renal impairment and can be acute. There is usually ANAs or dsDNA antibodies and low complement levels. Typically, the ESR is raised. A raised CRP indicates infection.

Rx - steroids + cyclophosphamide or azothioprine
Plasma exchange is sometimes used

Question 25

Features of SLE

Answer 25

F>M
Skin - butterfly rash
Eyes - uveitis 
Joint inflammation
Heart - valve lesions 
Neurological/ psychiatric disease 
Anaemia 
Thrombosis

Question 26

What is cryoglobulinaemia?

Answer 26

Cryoglobulins and immunoglobulins that precipitate in the cold. They occur in inflammatory or neoplastic diseases, including myeloma, lymphoma multisystem autoimmune diseases and chronic infection. Plasma complement levels are usually low.

Typically, cryoglobulins cause a type 1 mesangiocapillary glomerulonephritis. Mixed essential cryoglobulinaemia is usually caused by hepatitis C infection.

Presentation is usually purpuric rash, arthralgia, peripheral neuropathy and glomerulonephritis.
Rx - plasma exchange

Question 27

Dysproteinaemias

Answer 27

Excess antibody production by benign or malignant plasma cells.

Malignant disease or myeloma can cause various renal problems, including glomerular deposition of amyloid fibrils, tubular toxicity from filtered light chains, which may form casts in the tubules (myeloma cast nephropathy) and mesangiocapillary glomerulonephritis resulting from glomerular deposition of light chains (light chain deposition disease). The presence of free immunoglobulin light chains (Bence Jones proteins) in the urine or monoclonal band in plasma raises the possibility of myeloma.

Question 28

How does rheumatoid arthritis and other collagen vascular diseases cause glomerular disease?

Answer 28

RA can cause amyloid deposition, mesangial proliferative glomerulonephritis, membranous nephropathy or a focal segmental glomerulonephritis with vasculitis and necrosis.

Systemic sclerosis or scleroderma is rarely associated with a crescentic glomerulonephritis. More commonly, there is hyperplasia of small renal arteries. Any additional vasospasm causes acute renal ischaemia. This “renal crisis” triggers renin release, which worsens the vasospasm and promotes severe hypertension.

Question 29

Drugs associated with glomerular disease

Answer 29

Gold, penicillamine - membranous nephropathy
Hydralazine - lupus like disease
NSAIDs - minimal change nephropathy, with nephrotic syndrome and sometimes interstitial nephritis

Question 30

Amyloidosis and glomerular disease

Answer 30

Amyloid protein is usually a combination of amyloid P protein with either antibody light chain (AL) amyloid or inflammatory amyloid A protein (AA). AL amyloid is typical or dysproteinaemias, whereas AA amyloid is typical of chronic inflammatory disease. Amyloid deposition damages kidney, liver, spleen, heart, tongue and nervous system.

Amyloidosis can cause proteinuria and nephrotic syndrome. Histologically, amyloid proteins can be visualised with Congo red or immunostaining in the glomeruli, the tubules and blood vessels. Rx is by treating underlying disease.

Question 31

Hereditary causes of glomerular disease

Answer 31

Thin basement membrane disease - asymptomatic microscopic haematuria

• inherited
• does not cause renal impairment

Alport’s disease - X linked mutation in the apha 5 chain of type 4 collagen (different to Goodpasture’s)

• causes proteinuria, haematuria and renal failure
• sensorineural deafness