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:
- 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.
- Diabetes mellitus is the most common secondary cause in adults.
- In the USA, the annual incidence among children is reported to be 2-7 cases per 100,000.
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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 (15%) - the most common cause in children.
- Focal segmental glomerulosclerosis (35% of nephrotic syndrome) - the most common cause of idiopathic nephrotic syndrome in adults.
- Membranous glomerular disease (33%).
- Membranoproliferative glomerulonephritis (14%).
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:
- 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.
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. 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.
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 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.
- Diet and fluids:
- 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.
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.
- 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%.
- Adult prognosis is variable and largely related to the underlying cause, its severity, progression and response to any treatment used to modify it.
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.
- Cohen EP et al; Nephrotic Syndrome, Medscape, Sep 2011
- Filler G, Young E, Geier P, et al; Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis. 2003 Dec;42(6):1107-13.
- Kitiyakara C, Kopp JB, Eggers P; Trends in the epidemiology of focal segmental glomerulosclerosis. Semin Nephrol. 2003 Mar;23(2):172-82.
- 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 E, Willis N, Craig J; Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001533.
- 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.
- Lane JC, Pediatric Nephrotic Syndrome, Medscape, May 2010
|Original Author: Dr Sean Kavanagh, Dr Richard Draper||Current Version: Dr Colin Tidy||Peer Reviewer: Dr Hayley Willacy|
|Last Checked: 19/08/2011||Document ID: 2505 Version: 23||© EMIS|
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