The nephrotic syndrome is a renal disorder characterised by heavy urinary protein losses. It is the final clinical presentation of both primary renal pathology and systemic pathologies which affect the kidney.
The nephrotic syndrome is defined by:
- combination of heavy proteinuria (protein: creatinine ratio greater than 200 mg/mmol)
- hypoalbuminemia (less than 25 g/L)
- and generalized oedema
- particularly periorbital oedema
This triad is commonly accompanied by hyperlipidaemia.
Whilst the definition appears clear, there are a number of points worth consideration:
- with increasing age patients are more vulnerable to severe proteinurea and hypoalbuminaemia
- the level of hypoalbuminaemia at which oedema develops varies between individuals and with age
- other measures of renal function such as urea and creatinine, are usually normal
- renal failure may develop
- although the nephrotic syndrome has long thought to be due to protein loss resulting in a low albumin and low plasma oncotic pressure, patients may have a normal or increased plasma volume (this would suggest that there is not a simple relation between salt retention and renin concentration in many patients (1))
With respect to nephrotic synndrome (NS) in children:
- approximately 80% of cases of childhood NS have minimal change disease (MCD)
- NS is commonest glomerular disease of childhood with a median age at presentation of 4 years
- epidemiology (3):
- incidence is 2 to 7/100,000 children, with a prevalence of 16/100,000
- marked differences in the incidence of nephrotic syndrome depending on ethnicity with proportions ranging from 1.15 to 16.9/100,000 children with the highest incidence in children from south Asia
- most children have MCD in which changes on light microscopy are minor or absent and respond to corticosteroid agents
- histological variant seen and the response to immunosuppressive treatment varies with ethnicity
- steroid - sensitive nephrotic syndrome (SSNS) is less common in African and African-American children, and in South Africa only 7.2% of 236 African children had SSNS compared with 62% of 286 Indian children
- childhood nephrotic syndrome is classified into steroid-sensitive nephrotic syndrome (SSNS), steroid-resistant nephrotic syndrome (SRNS), congenital and infantile nephrotic syndrome (0 to 12 months) and nephrotic syndrome secondary to other diseases including Henoch Schonlein nephritis, systemic lupus erythematosus and hepatitis B nephropathy
- more common in males than females (ratio 3:2)
- over 90% of cases with MCD will respond to steroid therapy, but 70% of these will develop a relapsing course
- steroid responsiveness is the most important determining factor in the long-term prognosis of NS
- conditions such as focal segmental glomerulosclerosis (FSGS) and mesangiocapillary glomerulosclerosis (MCGN) account for the remaining 20% of cases of NS
- tend to present in the older child and the majority do not respond to oral steroid therapy alone
- assumed that MCD and FSGS are immune mediated; there is controversy as to whether they are part of a spectrum or separate disorders
- serum IgG levels are low and IgM levels are often raised
- routine renal biopsy is not performed at presentation
- this is because the majority of children have MCD and are likely to respond to corticosteroid
- atypical features in a child:
- age less than 12 months or greater than 12 years
- persistent hypertension or impaired renal function
- gross haematuria
- low plasma C3
- hepatitis B or C positive
- most children with primary nephrotic syndrome respond to corticosteroid therapy within four weeks
- there is no benefit of prolonging prednisone therapy beyond two to three months in the first episode of SSNS (3)
- in children who fail to respond to corticosteroids, kidney biopsy is performed to determine pathology
- rituximab is a valuable additional agent for managing children with steroid-dependent nephrotic syndrome (4)
With respect to NS in adults (5):
- MCD accounts for only 10 to 25 percent of cases of nephrotic syndrome in adults
- patients over age 16 are generally treated after kidney biopsy that shows MCD
- initial therapy is with steroids
- adults tend to respond more slowly, with more than 25 percent of responders taking three to four months or longer to undergo complete remission
- approximately 50 to 75 percent of glucocorticoid-responsive adults will have a relapse, and frequent relapses occur in 10 to 25 percent
- steroid-dependence is seen in 25 to 30 percent
- adults with MCD are oedematous and often hypertensive
- first-line therapy is a salt-free diet and diuretics for fluid removal
- if antihypertensive therapy is still required, use of an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) seems a reasonable option for blood pressure reduction, and may have the added benefit of reducing urinary protein excretion
- there are no randomized trials to guide the optimal therapy of relapse
- second line possible agents include cyclosporin and cyclophosphamide
- cyclosporin combined with low dose prednisolone may be used to achieve relapse
- review (65 studies, n=3807) found strengthened evidence that immunosuppressive therapy (IST) is probably superior to non-IST in inducing remission and reducing progression to end stage kidney disease (6)
Reference:
- (1) Lancet (1995); 346 (8969):148-52.
- (2) Dolon MN, Gill D. Management of nephrotic syndrome. Paediatrics and Child Health 2002:369-374.
- (3) Hahn D, Samuel SM, Willis NS, Craig JC, Hodson EM. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database of Systematic Reviews 2020, Issue 8. Art. No.: CD001533. DOI: 10.1002/14651858.CD001533.pub6.
- (4) Larkins NG, Liu ID, Willis NS, Craig JC, Hodson EM. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database of Systematic Reviews 2020, Issue 4. Art. No.: CD002290. DOI: 10.1002/14651858.CD002290.pub5.
- (5) UptoDate - Treatment of minimal change disease in adults (September 2012)
- (6) von Groote TC, Williams G, Au EH, Chen Y, Mathew AT, Hodson EM, Tunnicliffe DJ. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database of Systematic Reviews 2021, Issue 11. Art. No.: CD004293. DOI: 10.1002/14651858.CD004293.pub4.