Nephrotic Syndrome

See also:
Acute Renal Failure
Chronic Renal Failure
Acute Nephritis and Nephrosis
Interstitial Nephritides and Nephrotoxins
Glomerulonephritis

Nephrotic syndrome is a pattern of presentation of renal disease, rather than a single pathological entity or diagnosis. Nephrotic syndrome is also known as nephrosis and is defined by the presence of nephrotic-range proteinuria, oedema, hyperlipidemia, and hypoalbuminaemia. It has serious complications and must be on the differential diagnosis for any patient presenting with new onset oedema.¹

It comprises the following elements:

• Stimulation of the liver to increase synthesis of all plasma proteins (including the lipoproteins), due to their low level in the blood.
• Reduction of lipoprotein catabolism due to reduced levels of lipoprotein lipase in blood.

Nephrotic syndrome is a relatively rare but important manifestation of kidney disease.
In the US, its annual incidence among children is reported to be 2–7 cases per 100,000.³ Incidence varies among adults depending on the incidence of underlying causes for the condition, particularly diabetes mellitus. Nephrotic syndrome has an incidence of around three new cases per 100 000 each year in adults.¹

It can be caused by a wide range of primary (idiopathic) and secondary glomerular diseases.

Primary renal diseases

• Minimal-change nephrotic syndrome (~85% of childhood cases)
• Focal segmental glomerulosclerosis (~9% of childhood cases)
• Mesangial proliferative glomerulonephritis (~2% of childhood cases)
• Membranous nephropathy (~3% of childhood cases)
• Membranoproliferative glomerulonephritis

Secondary renal diseases

• Postinfectious causes, e.g. Group-A beta-haemolytic streptococci, TB, malaria, syphilis, viruses such as VZV, HBV, HIV, infectious mononucleosis
• Collagen vascular diseases, e.g. SLE, rheumatoid arthritis, polyarteritis nodosa, Henoch-Schönlein purpura, vasculitides
• Metabolic diseases, e.g. diabetes mellitus, amyloidosis
• Inherited disease, e.g. Alport's syndrome, hereditary nephritis, sickle cell disease
• Malignant disease, e.g. multiple myeloma, leukaemia, lymphoma, carcinoma of breast/lung/colon/stomach
• Medications, e.g. NSAIDs, captopril, lithium, gold, diamorphine, interferon-alpha, penicillamine, probenecid and many others
• Toxins, e.g. bee sting, snake bites, phytotoxins
• Pregnancy, e.g. pre-eclampsia
• Transplant rejection

Symptoms

• In children facial swelling is a common presenting feature, with periorbital oedema often being the first evidence that something is wrong; oedema may progress to involve the whole body.
• Adults tend to present with peripheral oedema affecting the ankles and legs, which may progress to involve the whole body.
• Some patients may notice frothiness of their urine.
• Hypercoagulability may manifest as venous or arterial thrombosis, e.g. DVT, MI.
• Recurrent infections and/or general fatigue, lethargy, poor appetite, weakness or episodic abdominal pain may cause presentation to a doctor.

Signs

• Oedema of dependent parts or generalised oedema are the main clinical findings.
• Facial oedema may be found in children.
• Occasionally, severely hypoalbuminaemic cases may have pleural effusions or ascites.
• Urinalysis will reveal gross proteinuria.
• Hypertension and haematuria are not usually found but may affect a minority of cases.

The aim of investigations is to find the underlying cause, direct future management, establish a baseline of severity and monitor response to treatment. The initial sequence is:¹

• Confirm proteinuria present: urine dipstick positive
• Check for concomitant invisible (microscopic) haematuria: urine dipstick positive
• Exclude urine infection:urine microscopy/culture and sensitivity
• Measure amount of proteinuria:
  • Early morning urinary protein:creatinine ratio or albumin:creatinine ratio (mg/mmol)
  • Typically >300-350 mg/mmol in nephrotic syndrome
• Basic blood testing:
  • Full blood count and coagulation screen
  • Renal function including plasma creatinine and estimated glomerular filtration rate
  • Liver function tests to exclude concomitant liver pathology
  • Bone profile—corrected (for albumin) plasma calcium
• Check for other systemic diseases and causes of nephrotic syndrome:
  • C reactive protein and erythrocyte sedimentation rate
  • Glucose
  • Immunoglobulins, serum and urine electrophoresis
  • Autoimmune screen if an underlying autoimmune disease is suspected—antinuclear antibody (ANA), anti-double stranded DNA antibody (dsDNA), and complement values (C3 and C4)
  • Hepatitis B and C and HIV (after obtaining informed consent)
• Chest x ray and abdominal or renal ultrasound scan (especially if renal function is abnormal):
  • To check for pleural effusion or ascites
  • To check for the presence of two kidneys, their size and shape, and the absence of obstruction
  • To exclude malignancy and exclude other causes of oedema
• Be vigilant for complications such as thromboembolism:
  • Doppler ultrasound of leg veins in suspected deep vein thrombosis
  • Abdominal ultrasound, renal vein Doppler scan, venography of the inferior vena cava, computed tomography and magnetic resonance imaging of the abdomen if renal vein thrombosis is suspected
  • V/Q nuclear medicine lung scan, computed tomography pulmonary angiography for pulmonary embolism
• Investigate the underlying renal and systemic cause of nephrotic syndrome:
  • Renal biopsy under ultrasound (to assess size and structural condition of kidneys)
  • Obstructed or small kidneys may contraindicate renal biopsy
  • Make histological preparations for light microscopy, immunofluoresence or immunoperoxidase, electron microscopy

Most cases will require renal biopsy to determine the exact underlying cause of the condition; children under 8 years old usually have minimal-change nephrotic syndrome and so may be spared this investigation, especially if they are steroid-responsive. Adults with an obvious cause (e.g. diabetes with evidence of other complications) may be spared a biopsy at the discretion of a renal specialist. Other investigations to diagnose less usual causes such as abdominal fat/gingival biopsy to detect amyloidosis may be needed in place of or in addition to a renal biopsy.

Initial management should focus on investigating the cause, identifying complications, and managing the symptoms of the disease.¹ All patients should be referred to a nephrologist for further investigation, which often includes a renal biopsy.¹

• Most cases do not require acute hospitalisation.
• Reduce salt intake in diet (avoid processed foods and adding salt to food).
• Give diet with adequate calorific intake and sufficient protein content (1–2 g/kg daily).⁴
• Hyperlipidaemia – does not initially require therapy but may do so if prolonged.⁴
• Fluid restriction is not usually necessary (if severe enough to need this then may need admission).⁴
• Referral to a renal service for urgent outpatient assessment is advisable, to confirm the mode of presentation and direct any future investigations/therapy.
• Oedema is treated through diuretic therapy with furosemide (~1 mg/kg/day) ± spironolactone (~2 mg/kg/day).
• Check weight regularly to assess response to diuretics and ensure fluid retention is not worsening, or that patient is over-diuresed.
• Patients with very low albumin levels may not respond to diuretics and may require admission to receive intravenous albumin therapy.
• Some children with severe oedema may be prescribed antibiotic prophylaxis against infection and this should usually be on the advice of a renal specialist.
• Most children will have minimal-change nephrotic syndrome and usually respond to a trial of steroid therapy under the direction of a renal specialist.
• Other forms of nephrotic syndrome are less treatment responsive; ACE inhibitors are frequently used in adults to some effect.
• In children who do not respond to steroids, and in some adults, treatment may be with other immunomodulatory drugs such as cyclophosphamide, ciclosporin, tacrolimus and levamisole.⁴

• This is highly variable depending on the underlying cause.
• Congenital nephrotic syndrome usually carries a very poor prognosis.
• Outlook for the vast majority of children with minimal-change nephrotic syndrome is excellent; response to steroids is the norm, although there may be relapses and a need to use alternative immunomodulatory drugs. Since the introduction of corticosteroids, the overall mortality of primary nephrotic syndrome has decreased dramatically from over 50% to approximately 2-5%.
• Adult prognosis is variable and largely related to the underlying cause, its severity, progression and response to any treatment used to modify it.