Epidemiology

• Nephrotic syndrome is a relatively rare but important manifestation of kidney disease.
• The incidence of nephrotic syndrome is about three new cases per 100 000 each year in adults.^[1]
• Diabetes mellitus is the most common secondary cause in adults.^[2]
• In the USA, the annual incidence among children is reported to be 2-7 cases per 100,000.^[3]

More common causes of the nephrotic syndrome

It can be caused by a wide range of primary (idiopathic) and secondary glomerular diseases. See also the separate articles Acute Nephritis and Nephrosis, Interstitial Nephritides and Nephrotoxins and Glomerulonephritis.

Primary glomerular diseases

• Minimal-change glomerular disease (15%) - the most common cause in children.^[4]
• Focal segmental glomerulosclerosis (35% of nephrotic syndrome) - the most common cause of idiopathic nephrotic syndrome in adults.^[5]
• Membranous glomerular disease (33%).
• Membranoproliferative glomerulonephritis (14%).

Secondary glomerular diseases^[1]

• Infection, eg HIV, hepatitis B and hepatitis C, mycoplasma, syphilis, malaria, schistosomiasis, filariasis, toxoplasmosis
• Collagen vascular diseases, eg systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, Henoch-Schönlein purpura, vasculitides.
• Metabolic diseases, eg diabetes mellitus, amyloidosis.
• Inherited disease, eg Alport's syndrome, hereditary nephritis, sickle cell disease.
• Malignant disease, eg multiple myeloma, leukaemia, lymphoma, carcinoma of breast, carcinoma of lung, carcinoma of colon and carcinoma of stomach.
• Drugs, eg non-steroidal anti-inflammatory drugs (NSAIDs), captopril, lithium, gold, diamorphine, interferon alfa, penicillamine, probenecid and many others.
• Toxins, eg bee sting, snake bites, phytotoxins.
• Pregnancy, eg pre-eclampsia.
• Transplant rejection.

Presentation

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, eg deep vein thrombosis, myocardial infarction.
• Recurrent infections and/or general fatigue, lethargy, poor appetite, weakness or episodic abdominal pain may cause presentation to a doctor.

Signs

Clinical signs of nephrotic syndrome include:^[1]

• Oedema (oedema of dependent parts or generalised oedema are the main clinical findings): periorbital oedema (facial oedema may be found in children), lower- limb oedema, oedema of the genitals, ascites.
• Tiredness.
• Leukonychia.
• Breathlessness: pleural effusion (occasionally, severely hypoalbuminaemic cases may have pleural effusions or ascites), fluid overload (high jugular venous pressure), acute kidney injury (acute renal failure).
• Breathlessness with chest pain: pulmonary embolism, myocardial infarction.
• Dyslipidaemia: eruptive xanthomata, xanthelasmata.

Investigations^[1]

• Urine dipstick analysis: proteinuria and check for microscopic haematuria.
• Midstream urine for microscopy, culture and sensitivities to exclude urinary tract infection.
• Quantify proteinuria using an early morning urinary protein:creatinine ratio or albumin:creatinine ratio.
• FBC and coagulation screen.
• Renal function tests.
• LFTs (to exclude liver pathology); bone profile (calcium, phosphate, alkaline phosphatase).
• Check for other systemic diseases and causes of nephrotic syndrome:
  • ESR and CRP.
  • Fasting glucose.
  • Immunoglobulins, serum and urine electrophoresis.
  • Autoimmune screen if an underlying autoimmune disease is suspected: autoantibodies and complement levels.
  • Hepatitis B and hepatitis C, and HIV.
• CXR and abdominal or renal ultrasound scan (especially if renal function is abnormal): to check for pleural effusion or ascites, the presence of two kidneys, the size and shape of the kidneys, and any urinary tract obstruction.
• Consider complications:
  • Lipids - hyperlipidaemia.
  • Doppler ultrasound of leg veins in suspected deep vein thrombosis.
  • Abdominal ultrasound, renal vein Doppler scan, venography of the inferior vena cava, CT and MRI scanning of the abdomen if renal vein thrombosis is suspected.
  • Ventilation-perfusion scan - 'VQ' nuclear medicine lung scan; CT, pulmonary angiography for pulmonary embolism.
• Renal biopsy under ultrasound; renal biopsy may be helpful to guide diagnosis and treatment, but is not indicated in all patients with nephrotic syndrome.^[2]

Management

Sodium and fluid restriction and high-dose diuretic treatment are indicated for most adults with nephrotic syndrome. Angiotensin-converting enzyme (ACE) inhibitors are also indicated for most adults with nephrotic syndrome. Steroids have been used widely for the treatment of adult-onset minimal change disease but the response rates to immunosuppressive agents in adult minimal change disease, especially steroids, are more variable than in children.^[6] Intravenous albumin, prophylactic antibiotics and prophylactic anticoagulation are currently not recommended.^[2]

The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy but over 70% experience a relapsing course.^[7] Children who fail to respond may be treated with immunosuppressive agents including calcineurin inhibitors (ciclosporin or tacrolimus) and with non-immunosuppressive agents such as ACE inhibitors. However, further evidence is needed to confirm the efficacy of ciclosporin and to evaluate other regimens for idiopathic steroid-resistant nephrotic syndrome, including high-dose steroids with ciclosporin.^[8] Eight-week courses of cyclophosphamide or chlorambucil and prolonged courses of ciclosporin and levamisole reduce the risk of relapse in children with relapsing steroid-sensitive nephrotic syndrome compared with corticosteroids alone.^[9]

Referral and admission

Initial management should focus on investigating the cause, identifying complications, and managing the symptoms of the disease.^[1] Most patients do not require acute hospitalisation. All patients should be referred urgently to a nephrologist for further investigation.^[1] Indications for acute admission include:

• Severe generalised oedema, particularly if pleural effusion/oedema is causing respiratory compromise.
• Tense scrotal/labial oedema.
• Complications of the nephrotic state (eg sepsis, pneumonia, myocardial infarction, deep vein thrombosis).
• Inability to comply with therapy/inability to cope with the condition in the family/independently.
• Any features of a possible nephritic syndrome such as haematuria, hypertension and impaired renal function parameters.

Management principles

• Diet and fluids:
  • Reduce salt intake in the diet (avoid processed foods and adding salt to food).
  • Give a diet with adequate calorific intake and sufficient protein content (1-2 g/kg daily).^[10]
  • Fluid restriction is not usually necessary (if severe enough to need this then the patient may need admission).^[10]
• Hyperlipidaemia - does not initially require therapy but may do so if prolonged.^[10]
• Oedema:
  • 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 the 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. Children in their first episode of nephrotic syndrome should be treated for at least three months with an increase in benefit for up to seven months of treatment.^[7]
• 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.^[10]

Complications

Complications of nephrotic syndrome include:^[3]

• Decreased resistance to infections, due to urinary immunoglobulin loss.
• Increased risk of arterial and venous thrombosis, due to loss of antithrombin III and plasminogen in the urine, combined with an increase in hepatic synthesis of clotting factors.
• Acute kidney injury may rarely occur as a spontaneous complication of nephrotic syndrome. Acute kidney injury may also be caused by excessive diuresis, interstitial nephritis due to use of diuretics or NSAIDs, sepsis or renal vein thrombosis.^[1]
• Chronic kidney disease may occur as a result of an underlying cause, eg amyloidosis or diabetes.^[1]
• Increased risk of osteitis fibrosa cystica and osteomalacia due to loss of vitamin D-binding protein and its complexes in the urine, through a combination of calcium malabsorption and secondary hyperparathyroidism.

Prognosis

• This is very variable depending on the underlying cause.
• Congenital nephrotic syndrome usually carries a very poor prognosis.
• Corticosteroids have reduced the mortality rate in children to around 3%.^[7]
• Outlook for the vast majority of children with minimal-change nephrotic syndrome is excellent, with good response to steroids, 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.