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Pediatric Nephrotic Syndrome Treatment & Management

  • Author: Jerome C Lane, MD; Chief Editor: Craig B Langman, MD  more...
 
Updated: May 16, 2016
 

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 selected 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.[46]

Highlights of these guidelines include the following[46] :

  • 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 alternate 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 alternate 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.[47]

Chronic hyperlipidemia has been linked to increased risk of atherosclerosis and coronary artery disease.[28] 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.[20]

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.[47]

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.[8, 47, 48]

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.[47]

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.[47]

Thromboembolism

Initial treatment of thromboembolic complications includes thrombolysis with anticoagulants (such as heparin) and/or fibrinolytic agents (ie, tissue plasminogen activator, streptokinase, urokinase).[22] For secondary prevention, warfarin is often prescribed for a period of as long as 6 months.[28]

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.[22]

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.[27]

A study by Rheault et al that looked to determine the incidence, epidemiology, and hospital outcomes associated with acute kidney injury in children hospitalized with nephrotic syndrome found that acute kidney injury occurred in 58.6% of 336 children and 50.9% of 615 hospitalizations. Risk factors for acute kidney injury included steroid-resistant nephrotic syndrome, infection, and nephrotoxic medication exposure.[49]

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Corticosteroid Therapy

Initial therapy

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.[50]

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.[35, 42]

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 alternate days for 4 weeks. Subsequent studies demonstrated that a longer alternate-day maintenance period of 6 weeks resulted in a lower rate of relapse.[35]

Thus, the general consensus now is daily induction steroid treatment for 6 weeks, followed by alternate-day maintenance therapy for another 6 weeks.[42] After 6 weeks of alternate day treatment, steroids may be stopped or slowly tapered over a variable length of time.

Longer duration of alternate-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 alternate day steroids for 6 months could reduce the subsequent relapse rate by 33% compared with shorter alternate-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 alternate day steroid treatment still needed to be conducted.[51]

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 alternate days for 2–5 months, with a minimum total duration of treatment of 12 weeks.[46]

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 alternate days for 4 weeks. Steroids may then be stopped or gradually tapered.[46, 42]

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Diuretic Therapy

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.

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Antihypertensive Therapy

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.

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Home Monitoring

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.

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Frequently Relapsing and Steroid-Dependent Disease

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.[46]

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.[52]

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.[52] 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 alternate days and tapered over 3 or more months.[46] 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.[28] Additionally, a higher incidence of infections and leukopenia may be seen with chlorambucil compared with CYP.[53] 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.[54] However, a subsequent randomized trial did not reach this same conclusion,[55] 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 alternate-day low-dose corticosteroids and enalapril.[56]

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.[56] Thus, TAC therapy is a promising alternative 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.[57]

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.[58]

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.[28, 42]

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.[59] 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.[58] 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 alternate days.[28]

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 alternate 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.[60]

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.[61]

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.[46, 62]

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Steroid-Resistant Disease and Focal Segmental GS

The most frequently recommended treatment for FSGS and SRNS is CSA. Approximately 36% of children with SRNS may achieve remission with this agent.[63] CSA is dosed as for FRNS and SDNS. However, higher doses and trough levels may be required to achieve remission in SRNS and FSGS.[28] TAC may be effective as well, although studies are limited at this time.[64] Most studies to date have shown no clear benefit to the use of alkylating agents in FSGS and SRNS.[43]

A recent, retrospective study of children with SRNS treated with TAC examined 19 children with a mean follow-up of 55 months. Complete remission was achieved in 58% of patients, partial remission in 32%, and no response in 9%. Sustained remission was achieved in 58% of patients, but only in 50% of those with FSGS. Forty percent of patients with FSGS progressed to end-stage kidney disease.

In a nonrandomized study of in children with SRNS, approximately half responded to MMF. Of 34 patients treated with CSA prior to MMF, 20% achieved complete remission, 39% achieved partial remission, and 41% had no response. Among 18 patients treated only with MMF, 27% achieved complete remission, 33% partial remission, and 40% had no response.[65] The MMF regimen used in this study was 500-600 mg/m2 body surface area/d or 18 mg/kg/d [maximum 1 g] for a minimum of 6 mo.

In the largest, prospective, randomized trial to date in pediatric FSGS, 138 children and adults (aged 2-40 years) were randomized to treatment with CSA or MMF with dexamethasone (dexa). Thirty-three percent of patients treated with MMF/dexa and 45% of patients treated with CSA achieved partial or complete remission, which was not statistically different in response rate. There was no difference between the 2 treatment arms in the rate of sustained remission.[66]

A controversial treatment involves high-dose, intravenous methylprednisolone tapered over 78 weeks, in combination with alternate-day oral prednisone; CYP or chlorambucil is added if remission is not achieved in the first 10 weeks. The authors reported a 52% remission rate in SRNS.[67] However, subsequent studies using this protocol have not duplicated the initial success. The risk of steroid toxicity and infection, as well as lack of sufficient evidence for the effectiveness of this protocol, have dampened enthusiasm for this treatment.

The use of an ACE inhibitor (eg, enalapril), either alone or in combination with an ARB (eg, losartan), has been shown to reduce proteinuria in FSGS/SDNS and should be considered in all patients, even in the absence of hypertension. Accordingly, ACE inhibitors and ARB should be considered as preferred agents in patients with hypertension. ACE inhibitor and ARB treatment may also have a renoprotective effect and slow progression of renal disease by inhibiting pathways of fibrosis.[64]

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Investigational Treatments

The following treatments have been studied in nephrotic syndrome, but cannot be routinely recommended:

  • Rituximab
  • Plasmapheresis
  • Galactose
  • Zinc

Rituximab

Rituximab (Rituxan) 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 SRNS.

A prospective trial of 12 patients with SDNS, who were given a single dose of rituximab (375 mg/m2 body surface area) demonstrated a reduction in the number of relapses and use of steroids.[68] However, 75% of patients relapsed within 1 year, and 7 patients were given a second dose of rituximab. No serious adverse effects were reported.

A multicenter trial in which 22 patients with SDNS or CSA-dependent nephrotic syndrome were given 2-4 weekly doses of rituximab (375 mg/m2) demonstrated complete remission in all 15 patients, who were free of proteinuria at the time of rituximab administration. Only 3 of 7 patients who were still nephrotic at the time of administration achieved remission.[69]

An open-label, randomized, controlled, noninferiority trial was recently performed, in which 54 children with steroid– and/or calcineurin inhibitor–dependent INS were randomized to either standard treatment (prednisone/calcineurin-inhibitor) or rituximab in addition to low-dose prednisone and calcineurin inhibitor. Three months after randomization, proteinuria was 70% lower in patients treated with rituximab compared with standard therapy; relapse occurred in 18.5% in the rituximab group and 48% in the standard treatment group. At 3 months, 63% of the rituximab group was drug free, compared with 4% in the standard treatment group. It was concluded that rituximab with low-dose prednisone and calcineurin inhibitor was noninferior to standard therapy in maintaining short-term remission in children with steroid– and calcineurin inhibitor–dependent INS.[70]

Only a small number of patients with SRNS treated with rituximab have been reported in the literature to date. In these 4 small studies, rituximab was administered in 1-4 weekly doses (375 mg/m2) with resultant remission of proteinuria in some patients.[71] However, these studies are too small to draw any general conclusions about the use of rituximab in SRNS.

A recent nonrandomized cohort study examined the efficacy of rituximab in pediatric patients with SDNS and SRNS. Patients were treated with 2-4 doses of intravenous rituximab. In 24 patients with SDNS, sustained remission of proteinuria was achieved in 83% at 12 months and 71% at approximately 17 months of follow-up. In 33 patients with SRNS, at 6 months of follow-up, 27% had complete remission, 21% had partial remission, and 51% had no response. At approximately 22 months of follow-up, 21% of patients with SRNS had complete remission and 24% had partial remission.[72]

Rituximab has been associated with fatal pulmonary interstitial fibrosis.[73] Rituximab has also been associated with hypogammaglobulinemia and a subsequent need for intravenous immunoglobulin administration. Additionally, progressive multifocal leukoencephalopathy has been reported in a patient with lupus nephritis treated with rituximab.[71]

Given the lack of adequate, controlled trials and the potential for severe adverse consequences, routine use of rituximab cannot be recommended at this time. Further studies are needed to examine the safety and efficacy of rituximab. The 2012 KDIGO guidelines recommend that rituximab be considered only for children with SDNS or FRNS with poor response to steroids and steroid-sparing agents or who have significant adverse effects from such therapy.[46]

Plasmapheresis

Because of the evidence of immunological mechanisms and presumed circulating factors in the pathophysiology of nephrotic syndrome, plasmapheresis has been attempted in patients with treatment-resistant FSGS and SRNS. To date, a few case reports and small series have showed some efficacy in reducing proteinuria in patients with FSGS or SRNS treated with plasmapheresis or immunoadsorption.[74]

Routine use of plasmapheresis or immunoadsorption in SRNS and FSGS cannot be recommended at this time. However, evidence suggests that plasmapheresis might be effective in treating recurrence of proteinuria in patients with FSGS who have received a kidney transplant.[75]

Galactose

Some patients with FSGS have been found to have an incompletely characterized circulating permeability factor (FSPF) that has been associated with recurrence of FSGS after kidney transplantation. Galactose has a high affinity for FSPF. An adult patient with FSPF-positive FSGS who was treatment-resistant was placed on galactose (10 g orally twice daily).[76] He achieved complete remission of proteinuria within 7 months and, 2 years later, remained in complete remission (on a higher dose of 15 g orally twice daily).

In a recent report, 2 children with SRNS and poor response to TAC achieved partial remission of proteinuria after treatment with galactose. Galactose currently is being studied as part of the Novel Therapies in Resistant Focal Segmental Glomerulosclerosis (FONT2) clinical trial for FSGS and in another prospective trial for children with SRNS.[62]

Further studies are needed before routine use of galactose can be recommended, and safety and efficacy in children is unknown.

Zinc

A study examined oral zinc supplementation (10 mg daily) of children with SSNS.[77] The authors found a trend in reduction of relapse frequency and an increase in remission length. However, the study was underpowered to show statistical significance.

Further studies are needed before routine use of zinc supplementation can be recommended.

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Side Effects of Drug Therapy

Corticosteroids

Behavioral changes, increased appetite, and Cushingoid signs (rounded, or "moon" facies) are common during the first 6 weeks of daily therapy but usually begin to subside during the alternate-day maintenance therapy period and, if steroids are successfully discontinued, usually disappear completely within 3-6 months

If longer periods of steroid therapy are required, the risk of complications increases. Complications of long-term steroid therapy may include the following:

  • Infection
  • Obesity
  • Growth delay
  • Osteopenia
  • Avascular necrosis of the hip
  • Cataracts
  • Hypertension
  • Hyperglycemia
  • Nephrolithiasis
  • Hyperlipidemia

Nutritional counseling and an exercise regimen may help to limit weight gain during steroid therapy. Consideration should be given to monitoring of bone density by dual energy X-ray absorptiometry (DEXA) in patients on long-term steroids.

Diuretics

Loop diuretics (furosemide, bumetanide) commonly cause hypokalemia and contraction alkalosis. Serum electrolytes should be monitored and electrolyte abnormalities treated as indicated.

Metolazone may augment these side effects. The use of potassium-sparing diuretics (spironolactone, amiloride) may help to limit hypokalemia.

Albumin

Infusion of 25% albumin can result in pulmonary edema, congestive heart failure and acute kidney injury. It should be used cautiously, sparingly, and only in those patients with hemoconcentration and/or diuretic-resistant edema. Slow infusion of 1 g/kg as a continuous infusion over 24 hours might help to limit complications.

Calcineurin inhibitors

CSA and TAC can cause increased susceptibility to infection, direct nephrotoxicity, hyperkalemia, and hypertension. CSA can also cause hirsutism and gingival hyperplasia, whereas TAC can cause impaired glucose tolerance and overt diabetes.

Alkylating agents

CYP, chlorambucil, and nitrogen mustard can cause dose-related infertility (including azoospermia, oligospermia, and amenorrhea), nausea, and hair loss. The risk of infertility rises above a cumulative CYP dose of 200 mg/kg . Hair loss, when it occurs, is usually mild and not cosmetically significant in the doses used for most types of INS.

Alkylating agents can also cause myelosuppression and increased susceptibility to infection. CYP can cause hemorrhagic cystitis and increased incidence of bladder malignancy.

Mycophenolate mofetil

Side effects of MMF include cramps, diarrhea, GI distress, myelosuppression, and increased susceptibility to infection.

Antihypertensive agents

Side effects of blood pressure medications are numerous and can include the following:

  • Hyperkalemia and acute kidney failure (ACE inhibitors, ARBs)
  • Hypotension
  • Bradycardia (beta-blockers)
  • Fatigue
  • Sedation (clonidine)
  • Electrolyte disturbances (diuretics)
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Indications for Hospital Admission

Admitting all patients with new-onset nephrotic syndrome to the hospital is not necessary. Individually address the decision on whether to admit the child or to investigate and initiate treatment on an outpatient basis.

Possible medical indications for admission include the following:

  • Anasarca, especially when resistant to outpatient therapy and/or accompanied by respiratory compromise, massive ascites or scrotal/perineal or penile edema
  • Significant hypertension
  • Anuria or severe oliguria
  • Peritonitis, sepsis, or other severe infection
  • Significant respiratory infection
  • Significant azotemia

Hospital admission may be necessary because of social reasons and often is useful on initial presentation of idiopathic nephrotic syndrome (INS) in order to provide intensive education of the family regarding INS and long-term management at home.

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Diet and Activity

A sodium-restricted diet should be maintained while a patient is edematous and until proteinuria remits. Thereafter, a normal diet can be followed. During severe edema, careful and modest fluid restriction may be appropriate, but the patient must be monitored closely for excessive intravascular volume depletion.

Protein restriction is not indicated, except in cases of acute or chronic kidney failure when severe azotemia is present. Even then, protein restriction should be done carefully as to avoid impaired somatic growth.

A normal activity plan is recommended. Because viral respiratory illnesses are often associated with relapses of nephrotic syndrome, keeping children with INS away from those who have obvious respiratory tract infections may be beneficial. However, children should not be kept out of school and should have as normal a routine as possible.

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Vaccination

Yearly influenza vaccination is recommended to prevent serious illness in the immunocompromised patient, as well as to prevent this possible trigger of relapse.

Pneumococcal vaccination should be administered to all patients with INS upon presentation. Vaccination should be repeated every 5 years while the patient continues to have relapses.

Routine childhood vaccines with live virus strains are contraindicated during steroid therapy and for a minimum of 1 month afterward.[78] Care must be taken in administering live viral vaccines to children in remission from FRNS, who might need to restart steroid therapy shortly after vaccination.

Because of the high risk of varicella infection in the immunocompromised patient, postexposure prophylaxis with varicella-zoster immune globulin is recommended in the nonimmune patient. Patient with varicella-zoster infection should be treated with acyclovir and carefully monitored.[28] Varicella immunization is safe and effective in patients with INS who are in remission and off steroid treatment (with the usual precautions for administering live viral vaccines to patients who have received steroids).[79]

Routine non-live viral vaccines should be administered according to their recommended schedules. Despite the former belief that routine immunization can trigger relapse of nephrotic syndrome, no solid evidence supports this, and the risk of these preventable childhood illnesses exceeds the theoretical, unproven risk for triggering relapses.

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Consultations and Long-Term Monitoring

Consultations

Because of the complexity of care of INS in all but the simplest of cases, the lack of strong clinical evidence supporting treatment options, and the great deal of experience required in successfully managing these patients, care of the patient with INS should always be performed in consultation with a pediatric nephrologist.

In cases that have initially been managed by the primary care specialist, referral to a pediatric nephrologist is mandatory in cases of FRNS, SDNS, SRNS, secondary nephrotic syndrome, and situations in which a kidney biopsy is necessary.

Referral to a pediatric nephrologist is mandatory for all children with nephrotic syndrome whose symptoms fail to respond to initial therapy (complete remission of proteinuria); in most of these patients, a percutaneous renal biopsy is indicated, and an alternative treatment plan may be desirable.

As with all chronic illnesses, many psychosocial issues may need to be addressed, including behavior, adherence to medication, adequate parental/caretaker supervision, medical insurance, missed work and school due to hospitalizations and outpatient visits, and many other important issues. Consultation with social workers and mental health care workers may be useful.

Long-term monitoring

Ambulatory monitoring of the child's condition and response to treatment is a very important aspect of the overall management of nephrotic syndrome.

Home monitoring of urine protein and fluid status is an important aspect of management. Parents and/or caregivers should be trained to monitor first morning urine proteins at home with urine dipstick. Weight should be checked every morning as well and a home logbook should be kept recording the patient’s daily weight, urine protein, and steroid dose if the child is receiving steroids.

Families and patients are instructed to call for any edema, weight gain, or urine testing 2+ or more for protein for more than 2 days. Rapid detection of relapse of proteinuria by home testing of urine can allow early initiation of steroid treatment before edema and other complications develop. Urine testing at home is also useful in monitoring response (or nonresponse) to steroid treatment.

A study by Ishikura et al indicated that children with frequently relapsing nephrotic syndrome (FRNS) commonly suffer relapses following 2 years of cyclosporine treatment but nonetheless have a favorable prognosis with regard to renal function and overall survival. In the study, 46 patients who had participated as children in an earlier study, in which they had received 2 years of cyclosporine treatment, were followed up after a median period of 10.3 years subsequent to the start of that treatment. It was found that 23 (50%) of the patients either had continued to experience frequent relapses over the follow-up period or else were on immunosuppressant therapy. None of the patients in the second study, however, suffered renal dysfunction or a lethal event during the follow-up period.[80, 81]

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Contributor Information and Disclosures
Author

Jerome C Lane, MD Associate Professor of Pediatrics, Northwestern University, The Feinberg School of Medicine; Attending Physician, Department of Pediatrics, Division of Kidney Diseases, Ann & Robert Lurie Children's Hospital of Chicago

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children's Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, International Society of Nephrology

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Raptor Pharmaceuticals; Eli Lilly and Company; Dicerna<br/>Received grant/research funds from NIH for none; Received grant/research funds from Raptor Pharmaceuticals, Inc for none; Received grant/research funds from Alexion Pharmaceuticals, Inc. for none; Received consulting fee from DiCerna Pharmaceutical Inc. for none.

Acknowledgements

Laurence Finberg, MD Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine and Stanford University School of Medicine

Laurence Finberg, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Adrian Spitzer, MD Clinical Professor Emeritus, Department of Pediatrics, Albert Einstein College of Medicine

Adrian Spitzer, MD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Pediatric Society, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).
 
 
 
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