QuestionSBA
QuestionChoice
This patient has no risk factors for heart failure. It would be reasonable to check BNP levels as it has a high negative predictive value for heart failure, but, in this context, testing for proteinuria is more pertinent
32294
b
Serum brain natriuretic peptide (BNP)
QuestionChoice
An ECHO to assess for heart failure would usually be performed after checking serum BNP levels
32295
c
Echocardiogram (ECHO)
QuestionChoice
Hypothyroidism is a rare cause of generalised oedema. This patient does not have any other symptoms of hypothyroidism which makes it less likely
32296
d
Check thyroid function
QuestionChoice
Checking renal function is vital given the likely diagnosis of nephrotic syndrome. However, renal function can be normal in the early stages of nephrotic syndrome and therefore the most important initial test is to check for proteinuria
32297
e
Check renal function
QuestionChoice
Chronic hepatitis C infection is a risk factor for membranoproliferative glomerulonephritis (MPGN). This can present with features of nephrotic syndrome, which include generalised oedema, hypoalbuminaemia and proteinuria. Nephrotic syndrome is also a pro-thrombotic state, and the recent DVT raises further suspicion in this context. The next best investigation is therefore a bedside urine dipstick to assess for proteinuria. If there is proteinuria, then this should be quantified using a UPCR. Nephrotic range proteinuria is > 3.5g/day which is equivalent to a UPCR value of 350 mg/mmol
32293
a
Urine dipstick +/- urinary protein:creatinine ratio (UPCR)
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lol

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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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Quesmed Tutorial: Paediatric Nephrology
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A 45-year-old man with a history of hepatitis C with liver cirrhosis presents to his General Practitioner (GP) with increasing swelling of his legs, causing him discomfort when he walks. He denies any other symptoms including cough or shortness of breath.

He is currently on anticoagulation for an unprovoked deep-vein thrombosis (DVT) that occurred one month ago. Liver function tests at that point were at baseline.

On examination, his JVP is not raised with heart and lung sounds normal. The abdomen is soft and non-tender with no palpable masses. There is bilateral pitting oedema to the knees bilaterally.

Which of the following is the most appropriate initial investigation?
a