Nephrotic syndrome

Synonym: nephrosis

What is nephrotic syndrome?

Nephrotic syndrome is a clinical syndrome showing specific features of heavy proteinuria causing hypoalbuminaemia or hypoproteinaemia. It is caused by increased permeability of serum protein through the damaged basement membrane in the renal glomerulus.

Nephrotic syndrome is defined by the presence of:

• Heavy proteinuria (≥3.5 g/day); and

• Hypoalbuminaemia (serum albumin ≤30* g/L).¹

• Peripheral oedema.

*Some guidelines use a serum albumin threshold of ≤25 g/L.^{2 3}

As a result of heavy proteinuria and hypoalbuminaemia, nephrotic syndrome is frequently accompanied by dyslipidaemia, abnormalities in coagulation/fibrinolysis, reduced renal function, and immunological disorders.

Adult-onset nephrotic syndrome differs from childhood-onset in several important ways. Most importantly, nephrotic syndrome in adults is more aetiologically heterogeneous compared to children and treatment approaches therefore rely more heavily on the histological diagnosis provided by renal biopsy.⁴

Nephrotic syndrome epidemiology

• In children, the average worldwide incidence of nephrotic syndrome is 2-16.9 per 100,000. There is significant variability in both incidence and steroid responsiveness among various ethnic groups.⁵

• In adults, the annual incidence of nephrotic syndrome in adults is 3 per 100,000.

• In adults, 80-90% of cases of nephrotic syndrome are idiopathic. Focal segmental glomerulosclerosis (FSGS) and membranous nephropathy are the most common primary causes. Type 2 diabetes mellitus and systemic lupus erythematosus (SLE) are the most common secondary causes.³

• Minimal change disease accounts for 10-25% of cases of nephrotic syndrome in adults⁶ and 70-90% of cases in children.⁷

Causes of nephrotic syndrome

Nephrotic syndrome can be caused by a wide range of primary and secondary glomerular diseases. See also the separate Acute Nephritis, Interstitial Nephritides and Nephrotoxins and Glomerulonephritis articles.

Primary glomerular diseases

• Minimal change glomerular disease is the most common cause in children.

• Focal segmental glomerulosclerosis (FSGS) and membranous nephropathy are the most common causes of primary nephrotic syndrome in adults.

• Membranoproliferative glomerulonephritis primarily affects children and young adults; it presents with nephrotic or nephritic syndrome, or with asymptomatic renal disease.⁸

Secondary glomerular diseases^{3 9}

• Infection - eg, bacterial (including infective endocarditis, mycoplasma, leprosy and syphilis), viral (including HIV, hepatitis B and hepatitis C, Epstein-Barr virus, herpes zoster), and parasitic (including malaria, schistosomiasis, filariasis, toxoplasmosis).

• Immunological/inflammatory - eg, systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, Henoch-Schönlein purpura, vasculitides, sarcoidosis.

• Metabolic diseases - eg, diabetes mellitus, amyloidosis.

• Inherited disease - eg, Alport's syndrome (hereditary nephritis), congenital nephrotic syndrome (Finnish type), familial FSGS, sickle cell disease.

• Malignant disease - eg, multiple myeloma, melanoma, 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, pamidronate, diamorphine, interferon alfa, penicillamine, probenecid, heroin and many others.

• Toxins - eg, insect sting, snake bites, phytotoxins, poison ivy.

• Pregnancy - eg, pre-eclampsia.

• Transplant rejection.

Nephrotic syndrome symptoms and signs

Symptoms^{3 10}

• Symptoms of oedema: discomfort (abdominal, genital), increased work of breathing from pleural effusion.

• Symptoms of hypovolaemia/intravascular volume depletion: dizziness, abdominal cramps.

• Symptoms of infection: fever, nausea or vomiting, rash, abdominal pain.

• Some patients may notice frothiness of their urine.

• Hypercoagulability may manifest as venous or arterial thrombosis - eg, deep vein thrombosis, myocardial infarction.

• Patients may also report general fatigue, lethargy, poor appetite, weight gain (fluid associated) or weakness.

Signs

Clinical signs of nephrotic syndrome include:^{2 9 10}

• 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.

• Breathlessness: pleural effusion (occasionally, severely hypoalbuminaemic people may have pleural effusions or ascites), fluid overload (high jugular venous pressure).

• Breathlessness with chest pain: pulmonary embolism, myocardial infarction.

• Signs of hypovolaemia/intravascular volume depletion: tachycardia, cold peripheries, oliguria, reduced capillary refill time, hypotension (late sign).

• Dyslipidaemia: eruptive xanthomata, xanthelasmata.

• Signs of infection or systemic disease: eg, fever, rash, purpura, joint swelling.

• Muehrcke's lines: multiple transverse white lines on the nail, which are associated with hypoalbuminaemia. They disappear on applying pressure, hence the term 'apparent leukonychia' is also used to describe this finding.¹¹

Investigations^{2 3}

• 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 and electrolytes.

• LFTs (to exclude liver pathology); bone profile (calcium, phosphate, alkaline phosphatase).

• Fasting glucose

• Lipid profile

• Check for other systemic diseases and causes of nephrotic syndrome as clinically appropriate - for example:
  

  • ESR and CRP.

  • Immunoglobulins, serum and urine electrophoresis.

  • Autoimmune screen if an underlying autoimmune disease is suspected: autoantibodies and complement levels.

  • Hepatitis B and hepatitis C; HIV.

  • Thyroid function tests.

• Imaging should be guided by clinical assessment - for example, chest X-ray if pleural effusion or infection are suspected; abdominal ultrasound if ascites is present; renal ultrasound scan if GFR is reduced or there is suspected obstruction/to check the size and shape of the kidneys.

• Consider complications and investigate appropriately, for example:
  

  • 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.

  • 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. For example in children, since almost all cases are due to minimal change disease, renal biopsy can be reserved for specific indications. However in adults, where the causes are more heterogeneous, a biopsy is much more likely to be needed to obtain a definitive diagnosis. A nephrologist should always be consulted.

Nephrotic syndrome treatment and management^{2 3}

Management principles

The management of nephrotic syndrome involves managing oedema and other symptoms, identifying and treating the renal pathology and any underlying causes, and preventing or treating complications.

Oedema

• Oedema is treated according to its severity. Options include: a low salt diet, fluid restriction, loop diuretic, potassium sparing diuretic, and thiazide diuretic.

• Check weight daily 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 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.

Treating the renal pathology

• Corticosteroids are generally used as first line agents.

• Immunosuppressive therapies are also used and include calcineurin inhibitors (ciclosporin or tacrolimus), alkylating agents (cyclophosphamide and chlorambucil), levamisole, rituximab and mycophenolate mofetil.

• In adults with idiopathic membranous nephropathy, immunosuppressants may be effective at inducing remission and reducing progression to end stage renal failure, but their benefits must be balanced against their risks.¹²

• Steroids have been used widely for the treatment of adult-onset minimal change disease. Calcineurin inhibitors or enteric-coated mycophenolate sodium with low dose prednisolone may be more effective for inducing remission than prednisolone alone.¹³

• Most children will have minimal change nephrotic syndrome and will usually respond to a trial of steroid therapy under the direction of a renal specialist. Children with their first episode of nephrotic syndrome should be treated for two or three months with corticosteroids; there is no advantage to treating for any longer than this.¹⁴

• While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the mortality rate to around 3%, but they also have well recognised potentially serious adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and behavioural disturbances.¹⁴

• In children who do not respond to steroids, and in some adults, immunosuppressive therapies may be used. There is weak evidence that calcineurin inhibitors may increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide.¹⁵

• Rituximab may be a helpful addition in managing children with steroid-sensitive nephrotic syndrome (SSNS) who have relapses.¹⁶

Hypertension - angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers are often used in adults to manage hypertension associated with kidney disease, as they reduce proteinuria.

Hyperlipidaemia - this does not initially require treatment but may do so if prolonged.

Vaccination: children with nephrotic syndrome should have the pneumococcal vaccination, if they are not already vaccinated. Some children are also advised to be vaccinated against chickenpox between relapses.

Intravenous albumin and prophylactic anticoagulation are currently not recommended for routine use. Recommendations about prophylactic antibiotics, protection against steroid-induced gastric irritation, and calcium/ vitamin D supplementation vary.¹⁷

Referral and admission

Initial management should focus on investigating the cause, identifying complications and managing the symptoms of the disease.⁹ Most patients do not require acute hospitalisation. All patients should be referred urgently to a nephrologist for further investigation.⁹ 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 independently with therapy or with the condition in the family.

• Any features of a possible nephritic syndrome such as haematuria, hypertension and impaired renal function parameters.

Complications

Complications of nephrotic syndrome include:

• Decreased resistance to infections, due to urinary immunoglobulin loss.

• Increased risk of venous thromboembolism.¹⁸ Adults with membranous nephropathy are at particular risk.¹⁹

• 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.⁹

• Chronic kidney disease may occur as a result of an underlying cause - eg, amyloidosis or diabetes.⁹

• Steroid-resistant nephrotic syndrome is associated with a high risk of developing end-stage kidney disease²⁰ .

• 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.

• Nephrotic syndrome may trigger new, or worsen existing, hypothyroidism.²¹

• Anaemia may be seen in persistent nephrotic syndrome. It may be due to excess urinary losses of iron, transferrin and other substrates needed for erythropoiesis.²²

Prognosis

• Since the introduction of corticosteroids, the overall mortality of primary nephrotic syndrome has decreased dramatically from over 50% to approximately 2-5%.

• Corticosteroids have reduced the mortality rate in children to around 3%.¹⁴

• The 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.

• The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy but 80% experience a relapsing course.¹⁴

• Congenital nephrotic syndrome usually carries a very poor prognosis.

• The prognosis in adults is variable and largely related to the underlying cause, its severity, progression and response to any treatment used to modify it.

• About 50% of adults with idiopathic FSGS, willprogress to end-stage renal disease over five to 10 years.³