Approach Considerations

A trial of corticosteroids is the first step in treatment of idiopathic nephrotic syndrome (INS) in which kidney biopsy is not initially indicated. Thus, patients may be considered for steroid treatment prior to kidney biopsy if they meet all of the following criteria:

Age 1-8 years

Normal kidney function

No macroscopic (gross) hematuria

No symptoms of systemic disease (fever, rash, joint pain, weight loss)

Normal complement levels

Negative antinuclear antibody (ANA) assay

Negative viral screens (ie, HIV, hepatitis B and C)

No family history of kidney disease

Kidney biopsy should be performed prior to any immunosuppressive treatment, including steroids, in patients who meet one or more of the following criteria:

Age younger than 1 year or older than 8 years

Presence of recurrent gross hematuria

Relevant family history of kidney disease

Symptoms of systemic disease

Positive viral screens

Additional criteria are laboratory findings possibly indicative of secondary nephrotic syndrome or INS other than minimal change nephrotic syndrome (MCNS), such as the following:

Sustained elevation in serum creatinine levels

Low C3/C4 levels

Positive ANA findings

Positive anti–double-stranded DNA antibody assay

In these cases, histology guides treatment, and steroids may or may not be indicated depending on the underlying etiology.

In ed preadolescent patients older than 8 years (≤12 y), empirical steroid treatment can be considered prior to kidney biopsy; however, this should occur only under the care of a pediatric nephrologist experienced with nephrotic syndrome. Children older than 12 years require a kidney biopsy due to the rising incidence of focal segmental glomerulosclerosis (FSGS) and other causes of nephrosis in that age range.

In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) group released guidelines that address management of steroid-sensitive nephrotic syndrome in children aged 1–18 years.[48]

Highlights of these guidelines include the following[48]

Definition of nephrotic syndrome: Edema, urine protein:creatinine ratio ≥2000 mg/g; urine protein ≥300 mg/dL, dipstick urine protein 3+, hypoalbuminemia ≤2.5 mg/L

Initial treatment: Oral prednisone, starting as a daily dose of 60 mg/m 2/day or 2 mg/kg/day (maximum, 60 mg/day) for 4–6 weeks. After 4–6 weeks, switch to 40 mg/m 2 or 1.5 mg/kg (maximum, 40 mg) on nate days for 2–5 months with tapering, with a minimum total duration of treatment of 12 weeks

Treatment of infrequent relapse (1 relapse in 6 months or 1-3 relapses in 12 months): Administer initial treatment dose (60 mg/m 2/day or 2 mg/kg/day) until urinary protein is negative for 3 days; after urine is negative for protein for 3 days, change prednisone to 40 mg/m 2 or 1.5 mg/kg (maximum, 40 mg) on nate days for 4 weeks, then stop or taper dose

Treatment of frequent relapse (2 relapses in 6 months or ≥4 relapses in 12 months): Continue infrequent relapse treatment for 3 months at lowest dose to maintain remission or use corticosteroid-sparing agents, including alkylating agents, levamisole, calcineurin inhibitors, mycophenolate mofetil

The treatment of steroid-sensitive INS, steroid-dependent and frequently-relapsing INS, steroid-resistant nephrotic syndrome (SRNS) and FSGS are discussed in detail below. The treatment of membranoproliferative glomerulonephritis (MPGN), membranous nephropathy (MN), congenital nephrotic syndrome, and secondary nephrotic syndrome (eg, lupus nephritis and vasculitis) are beyond the scope of this article.

Hyperlipidemia

Lipid abnormalities generally resolve when nephrotic syndrome is in remission. Dietary modification does not appear to be effective in limiting hyperlipidemia during active nephrotic syndrome.[49]

Chronic hyperlipidemia has been linked to increased risk of atherosclerosis and coronary artery disease.[30] Chronic hyperlipidemia has also been associated with progression of renal disease. However, the small studies to date of lipid-lowering agents in pediatric INS have not shown an improvement in proteinuria or progression of renal disease.[22]

Dyslipidemias in adults with nephrotic syndrome have been successfully treated with the following:

Statins (simvastatin, lovastatin)

Fibrates (gemfibrozil)

Bile-acid binding resins (cholestyramine)

Probucol

Children with INS have been effectively treated with probucol, but this agent has been associated with prolonged QT interval and is not available in the United States. Gemfibrozil has also been shown to be effective in childhood nephrotic syndrome in small studies.[49]

Small studies have shown that simvastatin and lovastatin are well tolerated and effective in childhood INS. Total cholesterol, triglycerides, and LDL cholesterol were reduced by 42%, 44%, and 46%, respectively. No changes in proteinuria, hypoalbuminemia, or progression of renal disease were noted.[10, 49, 50]

In order to monitor for treatment-associated rhabdomyolysis, children treated with statins should have creatine kinase measured prior to initiating therapy and every 6-12 weeks during treatment. Patients and families should be instructed to report muscle soreness, tenderness, or pain. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels should be measured before initiating treatment and about every 3 months thereafter to monitor for liver toxicity.[49]

Long-term safety studies regarding statins in pediatrics are lacking, and routine use of statins were not recommended by an expert panel in 2004. The only drugs recommended at this time by the panel were bile acid sequestrants.[49]

Thromboembolism

Initial treatment of thromboembolic complications includes thrombolysis with anticoagulants (such as heparin) and/or fibrinolytic agents (ie, tissue plasminogen activator, streptokinase, urokinase).[24] For secondary prevention, warfarin is often prescribed for a period of as long as 6 months.[30]

Empiric prophylactic anticoagulation is not routinely indicated in INS. Some practitioners advocate the use of long-term, low-dose aspirin in patients with chronic nephrotic syndrome (eg, frequently relapsing nephrotic syndrome, SDNS, SRNS). However, adequate controlled trials examining the use of aspirin have not been performed.[24]

Acute kidney failure

Acute kidney failure may rarely result from complications of INS, from the underlying disease, or from drug therapy. In most cases, acute kidney failure is reversible with remission of nephrotic syndrome, correction of intravascular volume contraction, and/or (in patients with acute interstitial nephritis) removal of inciting agent.[29]

Exclude active infection or other contraindications before starting steroid therapy.

The original International Study of Kidney Disease in Children (ISKDC) protocol recommended induction therapy with oral prednisone or prednisolone at 60 mg/m2/d (2 mg/kg/d), with a maximum of 60 mg, daily for 4 weeks. Traditionally, the total daily dose was split into two doses. However, a single daily dose of steroids has efficacy equal to split dosing and fewer side effects.[51]

Subsequent studies have shown that a longer period of initial steroid treatment (6 weeks rather than 4 weeks) reduces the subsequent rate of relapse. Thus, the general consensus now is to prescribe the initial daily steroids for 6 weeks.[37, 44]

Original guidelines recommended that induction therapy be followed with maintenance therapy with oral prednisone or prednisolone at 40 mg/m2 (or 1.5 mg/kg), with a maximum of 40 mg, given as a single dose on nate days for 4 weeks. Subsequent studies demonstrated that a longer nate-day maintenance period of 6 weeks resulted in a lower rate of relapse.[37]

Thus, the general consensus now is daily induction steroid treatment for 6 weeks, followed by nate-day maintenance therapy for another 6 weeks.[44] After 6 weeks of nate day treatment, steroids may be stopped or slowly tapered over a variable length of time.

Longer duration of nate-day steroid treatment may further reduce the number of children with subsequent relapses. A meta-analysis concluded that, after the initial daily steroid induction phase, continuation of nate day steroids for 6 months could reduce the subsequent relapse rate by 33% compared with shorter nate-day treatment. No adverse effects were noted with the longer steroid treatment, although the authors cautioned the adequate randomized controlled trials comparing shorter versus long-term nate day steroid treatment still needed to be conducted.[52]

The 2012 KDIGO clinical practice guidelines recommend prednisone dosed at 60 mg/m2/day (2 mg/kg/day) given daily for 4–6 weeks, followed by 40 mg/m2 (1.5 mg/kg) given on nate days for 2–5 months, with a minimum total duration of treatment of 12 weeks.[48]

Treatment of infrequent relapses

For infrequent relapses (one relapse within 6 months of initial response, or 1-3 relapses in any 12-month period), steroids are resumed, although for a shorter duration than treatment during initial presentation. Prednisone, 2 mg/kg/d (60 mg/m2/d), is given as a single morning dose until the patient has been free of proteinuria for at least 3 days. Following remission of proteinuria, prednisone is reduced to 1.5 mg/kg (40 mg/m2) given as a single dose on nate days for 4 weeks. Steroids may then be stopped or gradually tapered.[48, 44]

Diuretic therapy may be beneficial, particularly in children with symptomatic edema. Loop diuretics, such as furosemide (starting at 1-2 mg/kg/d) may improve edema; their administration, however, should be handled with care because plasma volume contraction may already be present, and hypovolemic shock has been observed with overly aggressive therapy.

Metolazone may be beneficial in combination with furosemide for resistant edema. Patients must be monitored carefully on this regimen. If the child is sent home on diuretic therapy, the family must have clear guidelines about discontinuing therapy when edema is no longer present and careful communication with the family should continue.

When a patient presents with anasarca and signs of intravascular volume depletion (such as a high hematocrit, indicative of hemoconcentration), consideration should be given to administration of 25% albumin, although this is controversial. Rapid administration of albumin can result in pulmonary edema.

The author's practice has been to administer 25% albumin at a dose of 1 g/kg body weight given as a continuous infusion over 24 hours. Intravenous albumin may be particularly useful in diuretic-resistant edema and in patients with significant ascites and/or scrotal, penile or labial edema. Caution should be used when administering albumin. In addition to pulmonary edema, albumin infusion can result in acute kidney injury and allergic reaction.

Antihypertensive therapy should be given when hypertension is present and particularly if it persists, but caution should be exercised. In some patients, the hypertension will respond to diuretics. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) may also contribute to reducing proteinuria but should be used cautiously in the presence of acute kidney failure or volume depletion because they can worsen kidney function in these settings.

ACE inhibitors and ARBs can cause birth defects, so adolescent women who are taking these agents must be counseled regarding use of birth control, and pregnancy testing should be considered before starting these agents.

Calcium channel blockers and beta-blockers may also be used as first-line agents for hypertension.

Home monitoring of urine protein and fluid status is an important aspect of management. All patients and parents should be trained to monitor first morning urine proteins at home with urine dipstick. Urine testing at home is also useful in monitoring response (or non-response) to steroid treatment.

Weight should be checked every morning, as well, and a home logbook should be kept recording the patient’s daily weight, urine protein levels, and steroid dose if being treated. Families and patients are instructed to call for any edema, weight gain, or proteinuria of 2+ or more for more than 2 days.

Frequently relapsing nephrotic syndrome (FRNS) is defined as steroid-sensitive nephrotic syndrome (SSNS) with 2 or more relapses within 6 months, or 4 or more relapses within a 12-month period. Steroid-dependent nephrotic syndrome (SDNS) is defined as SSNS with 2 or more consecutive relapses during tapering or within 14 days of stopping steroids.[48]

With frequent courses of steroids or prolonged corticosteroid treatment, the risk of steroid toxicity is increased. Therefore, in FRNS and SDNS, the general practice is to change therapy to a steroid-sparing agent once remission of proteinuria has been achieved.

A Cochrane meta-analysis demonstrated that in children with SSNS, cyclophosphamide (CYP) and chlorambucil reduced the rate of relapse compared with treatment with prednisone alone. No difference in relapse rate was noted between CYP and chlorambucil. No difference in efficacy was noted between intravenous and oral CYP. Cyclosporine (CSA) was as effective as CYP and chlorambucil. No difference in relapse rate was noted between mycophenolate mofetil (MMF) and CSA.[53]

For FRNS and SDNS, the clinical evidence is inadequate to support a preferred method of treatment. Therefore, practitioners must rely on their clinical experience and discuss the potential advantages and disadvantages of each treatment with families and patients.[53] Given the complexity of management in these cases and the importance of clinical experience, patients should be referred to a pediatric nephrologist if this has not already been done.

The current KDIGO 2012 guidelines recommend that in FRNS and SDNS, prednisone treatment be prescribed at 2 mg/kg/d (60 mg/m2/d) as a single morning dose until the patient has been free of proteinuria for at least 3 days. Following remission of proteinuria, prednisone is reduced to 1.5 mg/kg (40 mg/m2) given as a single dose on nate days and tapered over 3 or more months.[48] A steroid-sparing agent, such as those listed below, can be considered once proteinuria is in remission.

Alkylating agents

Alkylating agents (e.g., cyclophosphamide [CYP], chlorambucil, nitrogen mustard) offer the benefit of possible sustained remission after a defined course of treatment, although with the possible risk of infertility and other side effects (see Side Effects of Drug Therapy).

An increased risk of seizures is noted with chlorambucil.[30] Additionally, a higher incidence of infections and leukopenia may be seen with chlorambucil compared with CYP.[54] Because of these risks, and the need to give nitrogen mustard intravenously, CYP has generally been the preferred alkylating agent.

CYP (2 mg/kg daily) is given orally for 8-12 weeks. An influential study found that a 12-week course was more effective than an 8-week course in producing sustained remission of nephrotic syndrome.[55] However, a subsequent randomized trial did not reach this same conclusion,[56] and the optimal duration of CYP treatment is still unclear at this time.

Patients must have weekly complete blood counts to monitor for leukopenia. Patients must also maintain adequate hydration and take CYP in the morning (not at bedtime) to limit the risk of hemorrhagic cystitis. Families must be counseled to report gross hematuria, fever, or severe illness.

Calcineurin inhibitors

Calcineurin inhibitors (e.g., cyclosporin A [CSA], tacrolimus [TAC]) are useful steroid-sparing agents. These agents can also be used in those children who fail to respond to, or subsequently relapse after, treatment with CYP, or in children whose families object to the use of CYP.

Calcineurin inhibitors have disadvantages: prolonged courses of treatment are needed, nephrotic syndrome tends to recur when treatment is stopped, and nephrotoxic injury may occur. Consideration should be given to kidney biopsy after prolonged treatment to monitor for calcineurin inhibitor–induced nephrotoxicity and fibrosis.

Limited studies are available regarding the effectiveness of TAC compared with CSA. A single-center study by Choudhry et al in 41 patients with idiopathic SRNS found that TAC (0.1-0.2 mg/kg/d) or CSA (5-6 mg/kg/d) have similar efficacy in inducing remission in patients with idiopathic SRNS at 6 months and 1 year when combined with nate-day low-dose corticosteroids and enalapril.[57]

Relapse was significantly greater with CSA than with TAC; in addition, TAC decreased blood cholesterol levels to a greater extent and resulted in fewer incidents of nephrotoxicity that necessitated discontinuance than CSA. Cosmetic adverse effects (e.g., hypertrichosis, gum hypertrophy) were significantly more frequent with CSA.[57] Thus, TAC therapy is a promising native to CSA because of the lower relapse risk and lack of cosmetic adverse effects.

In a recent noncontrolled, open-label, prospective study, children with frequently relapsing (FRNS), steroid-dependent (SDNS), or steroid-resistant INS (SRNS) were treated with either CSA (3–4 mg/kg/day, divided into 2 doses over 12-h intervals, trough blood level target of 100–150 ng/mL) or TAC (50–150 μg/kg/day, divided into 2 doses over 12-h intervals, trough blood target of 5–12 ng/mL). All patients were treated with a tapering schedule of prednisone. TAC was more effective than CSA in inducing remission of proteinuria in SRNS. No difference in efficacy was noted between CSA and TAC for patients with FRNS or SDNS. No difference in the relapse rate was noted in any group between TAC and CSA. As in the previous study, adverse effects (nephrotoxicity and hirsutism) were lower with TAC versus CSA.[58]

Cyclosporin A

CSA treatment is started at 3-5 mg/kg/d divided every 12 hours; doses are adjusted for trough concentrations of 50–125 ng/mL. However, trough levels correlate poorly with area-under-the-curve (AUC) pharmacokinetics and may not represent true exposure to CSA. levels obtained 2 hours after administration (C2) have better correlation with AUC.[59]

Kidney function and drug levels must be carefully monitored due to the risk of CSA-induced nephrotoxicity.

Low-dose steroids are continued for a variable length of time. As many as 40% of patients may need to remain on steroids during CSA treatment to maintain remission.[30, 44]

Tacrolimus

TAC is started at a dose of 0.1 mg/kg daily divided every 12 hours and adjusted to keep trough level about 5-10 ng/mL.[60] Our practice is to use the lowest possible dose that sustains remission and to aim for a trough level of around 3-5 ng/mL. TAC trough levels correspond better to AUC than CSA, allowing better determination of dosing and exposure with TAC than with CSA.[59] As with CSA, continuing low-dose steroids is often necessary to maintain remission, although some patients may eventually be able to discontinue steroid treatment.

Levamisole

Levamisole is an anthelmintic drug that has immune-modulating effects and can be effective in reducing the relapse rate in FRNS. However, it is unavailable in the United States. Side effects include leukopenia, hepatic dysfunction, agranulocytosis, vasculitis, and encephalopathy. Levamisole is prescribed at a dose of 2.5 mg/kg given on nate days.[30]

Mycophenolate mofetil

Although small studies have shown mycophenolate mofetil (MMF) to be effective in reducing the number of relapses in FRNS and SDNS, adequate randomized controlled trials still need to be performed. One study of 33 patients, using a 6-month course of MMF with tapering dose nate day steroids, achieved a 75% remission rate, which persisted in 25% of patients after discontinuation of MMF. Additionally, this study demonstrated an improvement in relapse rate from once every 2 months to once every 14.7 months.[61]

Thus, MMF might be a useful steroid-sparing agent in stable patients (without excessive edema, need for hospitalizations and without other serious complications) whose families wish to avoid the possible side effects of CYP, CSA, or TAC. However, response to MMF varies and is less reliable than other treatments.

MMF is started at a dose of 600 mg/m2 twice daily. Complete blood counts should be monitored for bone marrow suppression, and liver function tests should occasionally be performed to monitor for hepatic toxicity.

A study concluded that mycophenolate mofeti may be an effective and safe maintenance therapy to consider as an additive immunosuppressant after induction with rituximab in maintaining remission among children with refractory steroid-resistant nephrotic syndrome.[62]

Rituximab

There has been increasing interest in the use of rituximab in INS. Rituximab is a chimeric, anti-CD20 antibody that results in depletion of B cells. Isolated reports and small studies have examined the use of rituximab in SDNS and FRNS. However, inadequate evidence exists at this time to recommend the routine use of rituximab in INS. In experienced hands, rituximab may be considered in children with SDNS or FRNS in whom other treatments have failed or those with cumulative toxicity of other steroid-sparing agents. See below (under Investigational Treatments) for further information regarding rituximab.[48, 63]