PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Nephrotic syndrome is also known as nephrosis and is defined by the presence of proteinuria, oedema, hyperlipidaemia, and hypoalbuminaemia. It has serious complications and must be on the differential diagnosis for any patient presenting with new-onset oedema. A thorough assessment for the underlying cause of nephrotic syndrome is essential. The diagnostic criteria for nephrotic syndrome are:
- Proteinuria greater than 3-3.5 g/24 hours or spot urine protein:creatinine ratio of >300-350 mg/mmol.
- Serum albumin <25 g/L.
- Peripheral oedema.
- Severe hyperlipidaemia (total cholesterol often >10 mmol/L) is often present.
- Nephrotic syndrome is a relatively rare but important manifestation of kidney disease.
- The incidence of nephrotic syndrome is about 3 new cases per 100,000 each year in adults.
- In adults, diabetes mellitus is the most common secondary cause, and focal segmental glomerulosclerosis and membranous nephropathy are the most common primary causes.
- Minimal change disease accounts for 10%-25% of cases of nephrotic syndrome in adults.
- The incidence of minimal change disease is higher in children with a reported incidence of 2 per 100,000 per year in Caucasian children and higher rates in Arabian and Asian children.
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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 - the most common cause in children.
- Focal segmental glomerulosclerosis - the most common cause of idiopathic nephrotic syndrome in adults.
- Membranous glomerular disease.
- Membranoproliferative glomerulonephritis - primarily affects children and young adults; presents with nephrotic or nephritic syndrome, or with asymptomatic renal disease.
Secondary glomerular diseases
- 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.
- 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.
Clinical signs of nephrotic syndrome include:
- 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 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.
- 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.
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. Intravenous albumin, prophylactic antibiotics and prophylactic anticoagulation are currently not recommended.
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.
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.
Vaccination: children with nephrotic syndrome should have the pneumococcal vaccination. Some children are also advised to have vaccination against chickenpox between relapses.
Referral and admission
Initial management should focus on investigating the cause, identifying complications, and managing the symptoms of the disease. Most patients do not require acute hospitalisation. All patients should be referred urgently to a nephrologist for further investigation. 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.
- 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).
- Fluid restriction is not usually necessary (if severe enough to need this then the patient may need admission).
- Hyperlipidaemia - does not initially require therapy but may do so if prolonged.
- 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.
- 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.
- A number of new drugs, including rituximab, galactose and antifibrotic agents, are under investigation for the treatment of idiopathic focal and segmental glomerulosclerosis in adults.
Complications of nephrotic syndrome include:
- 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. Adults with membranous nephropathy are at particular risk.
- 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.
- Chronic kidney disease may occur as a result of an underlying cause - eg, amyloidosis or diabetes.
- 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.
- 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%.
- 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%.
- 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.
- Adult prognosis is variable and largely related to the underlying cause, its severity, progression and response to any treatment used to modify it.
- For adults with idiopathic focal and segmental glomerulosclerosis, treatment may achieve complete or partial remission of proteinuria in 50-60% of patients and protect them from end-stage renal disease, but the remaining patients are resistant to currently available drugs.
Further reading & references
- Hull RP, Goldsmith DJ; Nephrotic syndrome in adults. BMJ. 2008 May 24;336(7654):1185-9.
- Kodner C; Nephrotic syndrome in adults: diagnosis and management. Am Fam Physician. 2009 Nov 15;80(10):1129-34.
- Hogan J, Radhakrishnan J; The treatment of minimal change disease in adults. J Am Soc Nephrol. 2013 Apr;24(5):702-11. doi: 10.1681/ASN.2012070734. Epub 2013 Feb 21.
- McGrogan A, Franssen CF, de Vries CS; The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011 Feb;26(2):414-30. doi: 10.1093/ndt/gfq665. Epub 2010 Nov 10.
- Alchi B, Jayne D; Membranoproliferative glomerulonephritis. Pediatr Nephrol. 2010 Aug;25(8):1409-18. doi: 10.1007/s00467-009-1322-7. Epub 2009 Nov 12.
- Palmer SC, Nand K, Strippoli GF; Interventions for minimal change disease in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD001537.
- Hodson EM, Willis NS, Craig JC; Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD003594.
- Hodson EM, Willis NS, Craig JC; Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD002290.
- Hodson E, Willis N, Craig J; Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001533.
- Ponticelli C, Graziani G; Current and emerging treatments for idiopathic focal and segmental glomerulosclerosis in adults. Expert Rev Clin Immunol. 2013 Mar;9(3):251-61. doi: 10.1586/eci.12.109.
- Kerlin BA, Ayoob R, Smoyer WE; Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease. Clin J Am Soc Nephrol. 2012 Mar;7(3):513-20. doi: 10.2215/CJN.10131011. Epub 2012 Feb 16.
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.
Dr Sean Kavanagh
Dr Colin Tidy
Dr Adrian Bonsall