QuestionSBA
QuestionChoice
This is most likely to cause diabetic glomerulosclerosis, which shows Kimmelsteil-Wilson nodules (nodules of hyaline material) on biopsy
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b
Diabetes mellitus
QuestionChoice
This woman has nephrotic syndrome, characterised by oedema, proteinuria and hypoalbuminaemia. The thickened glomerular basement membrane with subepithelial deposits is characteristic of membranous nephropathy as a cause of her nephrotic syndrome. Causes of membranous nephropathy include autoimmune disease and infection such as hepatitis B and hepatitis C. A renal biopsy would show a spike and dome pattern on a silver stain
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a
Hepatitis B virus
QuestionChoice
This is most likely to cause focal segmental glomerulosclerosis, which would show focal scarring and areas of collagen sclerosis
32076
d
HIV
QuestionChoice
This is most likely to cause mesangiocapillary glomerulonephritis, which may lead to nephrotic or nephritic syndrome. This would appear as double contouring of the capillary walls or a "tram track" appearance on electron microscopy
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e
Cryoglobulinaemia
QuestionChoice
This is most likely to cause minimal change glomerulonephritis, the most common cause of nephrotic syndrome in children. This would appear as podocyte effacement on electron microscopy
32075
c
Lithium
QuestionComment
19% seriously?? jesus you guys need to spend more time on the wards
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Ok Tom 
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Big mo
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Shhh let Tom have his moment, they don’t come by often
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Colonel Kernel
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Tom
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I got this right but I though HIV could also cause membranous nephropathy?
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more often it causes focal segmental glomerulosclerosis?
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TNF Beta 
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Poisoned Lyme 
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# Summary

Nephrotic syndrome refers to the clinical triad of proteinuria, hypoalbuminemia and peripheral oedema. It occurs due to increased permeability of the glomerular basement membrane, which occurs either due to a variety of both primary (idiopathic) or secondary diseases. Renal biopsy is the key investigation to differentiate between causes and should be considered in all adults. Other investigations include a urine dip and protein:creatinine ratio, LFTs for albumin and investigations for an underlying cause such as myeloma or diabetes. First-line management is usually with steroids; other immunosuppressants may need to be added. Management options for oedema include lifestyle changes (low salt diet, fluid restriction) and/or diuretics.

# Definition

Nephrotic syndrome occurs when there is excessive loss of protein in the urine, leading to hypoalbuminemia and peripheral oedema. Other resulting features include hyperlipidaemia, abnormal coagulation and immunodeficiency. 

# Aetiology

The common underlying pathology leading to nephrotic syndrome is damage to the glomerular basement membrane leading to excessive leakage of protein into the urine.

There are a wide variety of conditions that may lead to nephrotic syndrome which may be classified as either primary (idiopathic) or secondary (due to another underlying disease) - these include:

- **Minimal change disease** causes the majority of cases of nephrotic syndrome in young children
- It is usually idiopathic but may rarely be associated with lymphoma or NSAID use
- Glomeruli are normal under light microscopy
- Electron microscopy shows diffuse effacement of the podocyte food processes
- Steroid responsiveness is characteristic
- **Focal segmental glomerulosclerosis** may be primary or secondary to conditions including HIV, extensive nephron loss or drugs (e.g. heroin)
- Biopsy shows sclerosis of segments of the glomerular tuft, only affecting some glomeruli
- **Membranous nephropathy** is the leading cause of nephrotic syndrome in older people
- Biopsy shows thickening of the glomerular basement membrane without cellular proliferation
- A classic "spike and dome" appearance is described where subepithelial immune deposits are interspersed with new basement membrane growth
- Most cases are primary; usually associated with PLA2R antibodies
- Others may be secondary to malignancy, infections, autoimmune disease or drugs
- **Membranoproliferative glomerulonephritis** is also referred to as membranoproliferative glomerulonephritis
- It can present with nephrotic or nephritic syndrome
- It may be idiopathic or secondary to infections such as hepatitis C or systemic lupus erythematosus
- **Diabetic nephropathy** may affect patients with longstanding type 1 or 2 diabetes
- It tends to be a progression from microalbuminuria, especially if untreated
- Patients are at risk of end-stage renal disease
- Biopsy shows thickening of the glomerular basement membrane, mesangial expansion and Kimmelstiel-Wilson nodules
- **Amyloidosis**, especially AA amyloid due to chronic inflammation
- AL amyloid (due to light chain deposition) and hereditary amyloidosis can also cause nephropathy
- On biopsy, amyloid deposits stain with Congo red and display apple green birefringence under polarized light
- **Multiple myeloma** can present with a variety of renal manifestations, with proteinuria and renal insufficiency the most common
- Nephrotic syndrome occurs in a minority of cases and may be due to a number of underlying mechanisms
- **Lupus nephritis** i.e. renal involvement due to systemic lupus erythematosus
- Class V (membranous lupus nephritis) is the most likely to cause nephrotic syndrome
- This is characterised histologically by subepithelial immune complex deposition
- **Medications** are a rarer cause of nephrotic syndrome, including:
- Bisphosphonates
- NSAIDs
- D-penicillamine
- Probenecid
- Tolbutamide

# Classification

The diagnosis of nephrotic syndrome requires the presence of all of:

- Proteinuria > 3.5 grams/24 hours
- Serum albumin < 30 grams/litre
- Peripheral oedema

# Signs and Symptoms

**Symptoms include:**

- Frothy urine due to proteinuria
- Swelling of the face and body
- Weight gain due to fluid retention
- Fatigue
- Lethargy
- Anorexia

**Signs include:**

- Oedema - typically peripheral and periorbital
- Muehrcke's lines refers to paired white transverse lines across the nails that may occur secondary to hypoalbuminemia
- Signs of hyperlipidaemia such as xanthelasma (yellow plaques over the eyelids)
- Signs of pleural effusion e.g. dull bases to percussion with decreased air entry

Patients may also present with signs and symptoms of complications e.g. infection, thrombosis.

# Differential Diagnosis

- **Heart failure** is a common cause of peripheral oedema; typically however patients cannot lie flat due to breathlessness and so facial oedema is unusual; proteinuria is not a feature
- **Cirrhosis** is commonly complicated by fluid accumulation, usually in the form of ascites; although ascites may occur in nephrotic syndrome it is less common than fluid accumulation in the peripheries and face; proteinuria is not a feature
- **Chronic kidney disease** may present with fluid retention, especially in patients with end-stage renal disease - it may coexist with nephrotic syndrome however renal function is often preserved
- **Medications** may cause peripheral oedema including calcium channel blockers, NSAIDs and corticosteroids

# Investigations

**Bedside tests:**

- **Urine dipstick** looking for proteinuria; glycosuria may be present in diabetes but haematuria is not usually seen
- **Urine protein:creatinine ratio** should be over 2 or **24 hour urine collection** should show proteinuria >3.5g/day

**Blood tests:**

- **LFTs** to confirm hypoalbuminemia
- **U&Es** for renal function (significant impairment is unusual)
- **FBC** may show anaemia in persistent nephrotic syndrome
- **Vitamin D** may be low as this is lost in urine
- **Bone profile** may show hypocalcemia secondary to decreased calcium absorption due to vitamin D deficiency
- **Coagulation screen** is usually normal although there is a hypercoagulable state wiht increased risk of thromboembolism
- **HbA1c** or **fasting glucose** for diabetes
- **Lipid profile** often shows dyslipidemia
- **CRP** and **ESR** may be raised due to an underlying inflammatory, malignant or infectious process
- **Myeloma screen** i.e. immunoglobulins and serum protein electrophoresis if myeloma is suspected
- **Autoimmune screen** e.g. for suspected systemic lupus erythematosus (antinuclear antibody, complement levels etc.)
- **Infection screen** i.e. hepatitis B and C serology, HIV testing

**Imaging tests:**

- **Chest X-ray** if there are clinical signs of pleural effusion
- **US KUB** (kidneys, ureters and bladder) if there is renal impairment to assess for obstruction and any structural abnormalities of the kidneys
- Imaging may be required to diagnose complications, such as a **CT pulmonary angiogram** for suspected pulmonary embolism or **doppler ultrasound** of the limbs for suspected deep vein thrombosis

**Special tests:**

- **Renal biopsy** is the key investigation to diagnose the cause of nephrotic syndrome - this is important both for prognosis and to guide management 
- Biopsy is usually indicated in adults, however in children there are specific indications e.g. if not responsive to steroids

# Management

**Conservative:**

- Restrict salt intake to <2g/day
- Fluid restriction to <1.5L/day 
- Weight should be monitored, with a target of 1-2 kg weight loss per day until the patient reaches their predicted "dry weight" (i.e. weight when not oedematous)
- Dietary changes (e.g. avoiding a high protein diet, limiting fat intake) may be advised and dietician input may be indicated
- Mechanical thromboprophylaxis (TEDS) to reduce risk of venous thromboembolism

**Medical:**

- **Corticosteroids** are usually first-line for management of nephrotic syndrome - these should be weaned after remission is achieved
- Other immunosuppressive drugs (e.g. ciclosporin, cyclophosphamide, mycophenolate mofetil or rituximab) may be added as steroid sparing agents or for severe or refractory cases
- Diuretics are used to treat significant peripheral oedema, usually furosemide but potassium sparing and thiazide diuretics may be added as adjuncts
- Risk of thromboembolism should be assessed and prophylactic anticoagulation considered
- Antihypertensives may be required to maintain a normal blood pressure; ACE inhibitors and angiotensin II receptor blockers may also help to reduce proteinuria
- Ensure patients are up to date with vaccinations (however live vaccines should not be given to patients who are immunocompromised)
- In some cases hyperlipidaemia may require treatment with statins 
- Patients taking steroids may require co-administration of proton pump inhibitors for gastric protection and consideration of bone protection

**Surgical:**

- If nephrotic syndrome results in end-stage renal failure, renal replacement therapy may be required either with dialysis or renal transplantation

# Complications

- **Increased risk of infection** as immunoglobulins are lost in urine
- **Venous thromboembolism** due to urinary loss of anti-thrombotic proteins such as antithrombin III
- **Hyperlipidaemia** due to increased hepatic production of lipoproteins to compensate for hypoalbuminemia - this may also present with lipiduria (which may cause urine to appear milky) 
- **Acute kidney injury** may occur due to excessive diuresis or renal vein thrombosis
- **Chronic kidney disease** may occur secondary to the underlying cause of nephrotic syndrome (e.g. diabetes, amyloidosis)
- **Medication side-effects** especially with chronic steroid use (e.g. osteoporosis, psychiatric effects)
- **Hypothyroidism** due to urinary losses of T4 and T3 with their binding proteins
- **Vitamin D deficiency** as this is also lost in urine
- **Anaemia** may result from persistent nephrotic syndrome as iron bound to transferrin and erythropoietin are lost in urine

# Prognosis

Prognosis varies between subtypes, for example minimal change disease rarely progresses to end-stage renal failure (1% of cases), whereas 50% of patients with FSGS will do over 5-10 years.

Mortality has been greatly reduced with the use of steroids and immunosuppression.

Relapses are common and may require repeated courses of steroids or escalation to other immunosuppressive medications.

# References

[KDIGO Guidelines on Glomerular Diseases](https://kdigo.org/guidelines/gd/)

[Patient UK - Nephrotic syndrome](https://patient.info/doctor/nephrotic-syndrome-pro)

[Radiopaedia - Nephrotic syndrome](https://radiopaedia.org/articles/nephrotic-syndrome?lang=gb)
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Hepatitis B infection is associated with membranous nephropathy (MN), a kidney disorder characterized by the thickening of the glomerular basement membrane. The association occurs due to immune complex deposition in the kidneys, which can lead to proteinuria and nephrotic syndrome.
A 53 year old lady is admitted with a 2 week history of bilateral lower limb swelling. Albumin is 21g/L (normal range 35-50 g/L) and she has proteinuria of 6.5g/24h. She is referred to the nephrologist who decides to get a renal biopsy. This reveals a diffusely thickened glomerular basement membrane with IgG and C3 subepithelial deposits.

Which of the following is the most likely underlying cause of her condition?
a