Approach

The main treatment goals are inducing and maintaining complete remission with resolution of proteinuria and edema, as well as minimizing serious adverse effects of therapy. ​​​Children >1 year of age who have nephrotic syndrome (NS) are initially treated empirically with corticosteroids for minimal change disease (MCD), whereas those <1 year of age require confirmation of the diagnosis with kidney biopsy and/or genetic testing before treatment is started.[2] Adults also require a kidney biopsy to confirm the diagnosis prior to treatment.[3]

Initial presentation

Corticosteroid therapy is considered the mainstay of therapy and is the initial treatment given to all patients, unless there are contraindications.[3] A child with NS has an 85% to 90% chance of attaining complete remission of proteinuria within 4-6 weeks of corticosteroid therapy (corticosteroid-sensitive nephrotic syndrome or SSNS).[2]​ In adults with MCD, the response to corticosteroids may take much longer than in children.[25][27]​​​

Landmark trials in the 1970s, due to efforts by the International Study of Kidney Disease in Children (ISKDC), defined the initial role of corticosteroid therapy in MCD.[20] Although the initial therapeutic approach has largely remained unchanged, the duration of corticosteroid treatment in children at onset of NS is debated. In the US, the National Kidney Foundation quality initiative program recommends flexibility in the duration of the initial treatment course of corticosteroids (8 or 12 weeks), depending on the child's response and clinical characteristics.[28]​ The Kidney Disease Improving Global Outcomes (KDIGO) guidelines make a similar recommendation.[3] One meta-analysis concluded that the 8-week regimen for a first episode of SSNS may not be equally effective as the 12-week regimen.[29]​ In one UK study, clinical outcomes did not improve when the initial course of corticosteroid treatment was extended from 8 to 16 weeks in children with SSNS. However, the extended treatment course was associated with an increase in quality of life.[30]​ One Cochrane review concluded that there is no benefit of prolonging corticosteroid therapy in children beyond 2-3 months in the first episode of SSNS.[31] [ Cochrane Clinical Answers logo ] ​​ In adults, high-dose corticosteroid treatment for MCD should be given for no longer than 16 weeks.[3]

In patients in whom corticosteroids are contraindicated, an immunosuppressant may be given for initial therapy, such as cyclophosphamide or a calcineurin inhibitor (e.g., cyclosporine, tacrolimus).[3]

In children, NS is considered to be corticosteroid-resistant (SRNS) if there is not a complete response within 4 weeks of treatment.[3]​ If partial remission is observed, continuation of the oral corticosteroid or a switch to a high-dose intravenous corticosteroid may be considered for a further 2 weeks, as some patients may be late responders.[3][32]​​​​​​ SRNS is an indication for kidney biopsy.[3][32]​​​​​ Genetic testing for a monogenic cause of NS is recommended, as immunosuppression may not be beneficial in some of these cases.[3][28]​​​​ Treatment of SRNS in children has improved in the last decade but remains challenging. Most patients do not remain free of proteinuria and may show progressive kidney damage. In children with a nongenetic form of NS, treatment with a calcineurin inhibitor enhances remission rates.[3][32][33]​ If genetic and/or histopathology assessment is not available, immediate immunosuppressive treatment with a calcineurin inhibitor may be started.[32]​ If calcineurin inhibitors are not available, cyclophosphamide may be used.[32]

Most published studies on SRNS are in children but in practice, treatment of SRNS is similar for adults. In adults with MCD, only 50% respond to corticosteroid treatment by 4 weeks, with 80% achieving remission by 16 weeks.[25]​ Between 10% and 20% of adults with MCD are corticosteroid-resistant (defined as no response to 16 weeks of corticosteroid treatment).[1][3]​ Repeat biopsy is likely to show lesions of focal segmental glomerulosclerosis, which reflects a pathologic shift in the course of the disease.[1][3][25]​​ See Focal segmental glomerulosclerosis.

To minimize the risk of osteoporosis, ensure adequate dietary calcium intake, or start calcium supplementation in those with inadequate intake, in all children treated with corticosteroids.[2]​ Vitamin D levels should be assessed in patients with frequently-relapsing or corticosteroid-dependent NS and supplementation guided by serum levels.[2][3]

Relapse

Relapse is the reappearance of nephrotic-range proteinuria; in children, this is defined as dipstick ≥ 3+ for 3 consecutive days.[3]​ Around 70% to 80% of children with SSNS will have at least one relapse and up to 50% will have frequent relapses or become dependent on corticosteroids to maintain remission.[2] Infrequent relapses (<2 relapses per 6 months within 6 months of disease onset or <4 relapses per 12 months in any subsequent 12-month period) may be treated with corticosteroids in both children and adults.[3]​ Patients with a recent diagnosis who present in relapse are treated similarly to the initial presentation but are converted to the lower corticosteroid dose when the urine has been free of protein for 3 days. They are then tapered off or maintained on this dose for 4 weeks or more, depending on the patient's history of relapses and incidence of adverse effects from corticosteroids.

In children with SSNS who subsequently fail to respond to corticosteroids, a kidney biopsy is indicated.[3]​ 

Corticosteroid-sparing therapy is recommended for:[3][28]​

  • patients with frequently relapsing NS (≥2 relapses per 6 months within 6 months of disease onset or ≥4 relapses per 12 months in any subsequent 12-month period) who develop serious corticosteroid-related adverse effects (e.g., growth failure, significant weight gain, hypertension, diabetes, osteoporosis, behavioral concerns, or cataracts)

  • patients who are corticosteroid-dependent (relapses occur during corticosteroid tapering or within 2 weeks of corticosteroid discontinuation).

Corticosteroid-sparing agents are ideally initiated while the patient is in remission with corticosteroid treatment and include the following options: cyclophosphamide, mycophenolate, rituximab, or a calcineurin inhibitor.[2][3]​ There is no clear efficacy of one agent over the other and the decision for use is based on issues such as resources, adherence, adverse effect profile, and patient preferences.[3]​​[27][28][34]​ After patients start the corticosteroid-sparing agent, the corticosteroid is often tapered and stopped, or tapered to the lowest possible dose.

The Kidney Disease Improving Global Outcomes (KDIGO) guideline also recommends levamisole (an anthelmintic agent) as a corticosteroid-sparing option; however, this drug has been withdrawn in some countries (including the US) due to concerns about severe adverse effects, but it may still be available in some locations.[35]

Management of edema

The mainstay in the management of edema includes a low-salt diet and evaluation of the patient’s fluid status, with restriction of fluid intake if fluid overloaded.[1][2]​​​​​​ Depending on the stage of MCD, the rate of progression of hypoproteinemia, and the absolute levels of plasma oncotic pressure, functional hypovolemia may develop, which stimulates hemostatic mechanisms and secondary sodium retention.[36] Fluid restriction is equivalent to daily output plus insensible water losses.​

In the presence of massive anasarca or significant respiratory distress, hypertonic albumin and furosemide should be considered.[36] Furosemide is given intravenously with each albumin infusion to promote diuresis.[36] Blood pressure and respiratory status should be closely monitored during these infusions, as hypertension, worsening respiratory distress, and hypercoagulability can occur with aggressive diuresis.[36] Although albumin and diuretic therapy results in fluid removal and weight loss in children with NS, this effect is transient unless remission of proteinuria occurs.[36]

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