Pediatric Nephrotic Syndrome Treatment & Management

Updated: Mar 04, 2020
  • Author: Jerome C Lane, MD; Chief Editor: Craig B Langman, MD  more...
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Treatment

Approach Considerations

A trial of corticosteroids is the first step in the 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 1-12 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, for human immunodeficiency virus [HIV], hepatitis B and C viruses)

  • 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 12 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 complement levels (C3, C4)

  • 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.

Children older than 12 years require a kidney biopsy because of the rising incidence of focal segmental glomerulosclerosis (FSGS) and other causes of nephrosis in that age range.

The Kidney Disease: Improving Global Outcomes (KDIGO) group released guidelines that address management of steroid-sensitive nephrotic syndrome in children aged 1-18 years. [63]

Highlights of these guidelines include the following [63] :

  • Definition of nephrotic syndrome: Edema, urine protein:creatinine ratio ≥2 mg/mg; 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/m2/day or 2 mg/kg/day (maximum, 60 mg/day) for 4-6 weeks. After 4-6 weeks, switch to 40 mg/m2 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/m2/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/m2 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 the lowest dose to maintain remission or use corticosteroid-sparing agents, including alkylating agents, levamisole, calcineurin inhibitors, and 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. [64]

Chronic hyperlipidemia has been linked to an increased risk of atherosclerosis and coronary artery disease. [41] 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. [33]

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

Children with INS have been effectively treated with probucol, but this agent has been associated with a 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. [64]

Small studies have shown that simvastatin and lovastatin are well tolerated and effective in childhood INS. Total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were reduced by 42%, 44%, and 46%, respectively. No changes in proteinuria, hypoalbuminemia, or progression of renal disease were noted. [18, 64, 65]

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. [64]

Long-term safety studies regarding statins in pediatrics are lacking, and the routine use of statins was not recommended by an expert panel. The only drugs recommended by the panel were bile acid sequestrants. [64]

Thromboembolism

Initial treatment of thromboembolic complications includes thrombolysis with anticoagulants (such as heparin) or fibrinolytic agents (ie, tissue plasminogen activator, streptokinase, urokinase). [35] For secondary prevention, warfarin is often prescribed for a period of as long as 6 months. [41]

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, steroid-dependent nephrotic syndrome [SDNS], and SRNS). However, adequate controlled trials examining the use of aspirin have not been performed. [35]

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 the remission of nephrotic syndrome, correction of intravascular volume contraction, or (in patients with acute interstitial nephritis) removal of the inciting agent. [40]

Rheault et al looked at the incidence, epidemiology, and hospital outcomes associated with acute kidney injury in children hospitalized with nephrotic syndrome and 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 SRNS, infection, and nephrotoxic medication exposure. [66]

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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/day (2 mg/kg/day), with a maximum of 60 mg, daily for 4 weeks. Traditionally, the total daily dose was split into 2 doses. However, a single daily dose of steroids has efficacy equal to split dosing and fewer adverse effects. [67]

The 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. [63]

Studies since the ISKDC 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. [48, 59]

Earlier 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. [48]

Thus, the general consensus is daily induction steroid treatment for 6 weeks, followed by alternate-day maintenance therapy for another 6 weeks. [59] After 6 weeks of alternate-day treatment, steroids may be stopped or slowly tapered over a variable length of time.

A Cochrane review suggested that after the initial daily steroid induction phase, continuation of alternate-day steroid therapy for 6 months could reduce the subsequent relapse rate by 33% compared with a shorter alternate-day regimen. [68] However, several randomized controlled trials failed to show a benefit of extended 6-month steroid therapy versus 2-3 months of treatment; therefore, the 6-month steroid regimen is no longer recommended. [56]

Treatment of infrequent relapses

For infrequent relapses (1 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 the initial presentation. Prednisone, 2 mg/kg/day (60 mg/m2/day), 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. [63, 59]

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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/day), 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 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.

Because ACE inhibitors and ARBs can cause birth defects, adolescent women who are taking these agents must be counseled regarding the 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 a 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 the patient is 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. [63]

The current KDIGO guidelines recommend that in FRNS and SDNS, prednisone be prescribed at 2 mg/kg/day (60 mg/m2/day) 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. [63] A steroid-sparing agent, such as those listed below, can be considered once proteinuria is in remission.

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. Commonly used steroid-sparing agents are alkylating agents, calcineurin inhibitors, levamisole, mycophenolate mofetil, and rituximab.

Alkylating agents

Cyclophosphamide (CYP) is the predominant alkylating agent used in the treatment of FRNS and SDNS. CYP offers the benefit of possible sustained remission after a defined course of treatment, although with the possible risk of infertility and other adverse effects.

In a Cochrane meta-analysis, CYP was found to have significantly reduced the risk of relapse at 6-12 months and 12-24 months compared with steroid treatment alone. [69]

CYP (2 mg/kg daily) is given orally for 8-12 weeks. An early study found that a 12-week course was more effective than an 8-week course in producing sustained remission of nephrotic syndrome. [70] However, a subsequent randomized trial did not reach the same conclusion, [71]  and a Cochrane report found no benefit to extending the duration of CYP treatment beyond 8 weeks. Intravenous CYP, given monthly for 6 months, was as effective at 1 year as oral CYP in the Cochrane report. [72]

A meta-analysis reported remission rates following treatment with CYP to be 72% after 2 years and 36% after 5 years for patients with FRNS, and 40% and 24%, respectively, for those with SDNS. [73]

Patients treated with CYP must have weekly complete blood cell 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 (CNI)

Calcineurin inhibitors (eg, cyclosporin A [CSA] and tacrolimus [TAC]) are useful steroid-sparing agents. These agents can also be used in children who fail to respond to, or subsequently relapse after, treatment with CYP, or in children whose families object to the use of CYP. There appears to be no difference in efficacy at 1 year between CSA and CYP. [72]

CNIs 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 CNI-induced nephrotoxicity and fibrosis.

CSA has traditionally been the CNI most frequently used. However, limited studies suggest that TAC may be as effective as CSA. A 2-year prospective, uncontrolled trial demonstrated no difference between CSA and TAC in relapse at 1 and 2 years in children with FRNS and SDNS. [74] A single-center, randomized controlled trial by Choudhry et al found that TAC (0.1-0.2 mg/kg/day) and CSA (5-6 mg/kg/day) had 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. [75]

The use of TAC reduces the risk of gingival hyperplasia and hirsutism associated with CSA, although nephrotoxicity is a risk with TAC as well as CSA. [75] It is the author's practice to use TAC in order to avoid the adverse effects of CSA.

Cyclosporin A

CSA treatment is started at 3-5 mg/kg/day 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 have a better correlation with AUC. [76]

Kidney function and drug levels must be carefully monitored because of 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. [41, 59]

Tacrolimus

TAC is started at a dose of 0.1 mg/kg daily divided every 12 hours and adjusted to keep the trough level at about 5-10 ng/mL. [77] Our practice is to use the lowest possible dose that sustains remission and to aim for a trough level of about 3-5 ng/mL. TAC trough levels correspond better to AUC than CSA trough levels, allowing better determination of dosing and exposure with TAC than with CSA. [76] As with CSA, continuing low-dose steroid therapy is often necessary to maintain remission, although some patients may eventually be able to discontinue steroids.

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. Adverse effects include leukopenia, hepatic dysfunction, agranulocytosis, vasculitis, and encephalopathy. Levamisole is prescribed at a dose of 2.5 mg/kg given on alternate days. [41]

Mycophenolate mofetil

Mycophenolate mofetil (MMF) has been increasingly used in FRNS and SDNS because it has fewer adverse effects than CYP, CSA, and TAC. [78] Although small studies have shown 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. [79]  However, a multicenter, randomized, open-label study of 60 children with FRNS no difference in relapses at 2 years between MMF and CSA. [80]

MMF might be a useful steroid-sparing agent in stable patients (without excessive edema, need for hospitalization, and other serious complications) whose families wish to avoid the possible adverse effects of CYP, CSA, and TAC. However, the 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 cell counts should be monitored for bone marrow suppression, and liver function tests should occasionally be performed to monitor for hepatic toxicity.

MMF 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 SRNS. [81]

Rituximab

Rituximab is a chimeric anti-CD20 antibody that results in depletion of B cells. 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. The usual dosing schedule is 2-4 weekly doses of rituximab (375 mg/m2 per dose).

A study by Basu et al that included 176 pediatric patients with SDNS reported a higher 12-month relapse-free survival rate in the rituximab group than in the TAC group (90.0% vs 63.3%) as well as a lower 12-month cumulative corticosteroid dose in the rituximab group. [82]

Kamei et al examined the long-term outcomes and safety of rituximab treatment to prevent relapses of complicated FRNS and SDNS in 51 children and reported that 94% of patients in the study developed relapses during the observation period (median, 59 months); the 50% relapse-free survival was 261 days. Fifty-nine percent of the patients developed SDNS, 86% required re-administration of immunosuppressive agents, and 43% received additional rituximab treatment. [83]

In an open-label, randomized, controlled, noninferiority trial, 54 children with steroid- or CNI-dependent INS were randomized to either standard treatment (prednisone/CNI) or rituximab in addition to low-dose prednisone and a CNI. Three months after randomization, proteinuria was 70% lower in patients treated with rituximab than in those who received standard therapy; relapse occurred in 18.5% of the rituximab group and 48% of the standard treatment group. At 3 months, 63% of the rituximab group was drug free, compared with 4% of the standard treatment group. It was concluded that rituximab with low-dose prednisone and a CNI was noninferior to standard therapy in maintaining short-term remission in children with steroid- and CNI-dependent INS. [8]

A multicenter, randomized, controlled trail in 48 children with FRNS or SDNS demonstrated a significantly longer median relapse-free period for rituximab (267 days) than for placebo (101 days). [9]

The adverse effects of rituximab are rare but potentially serious. Risks include Pneumocystis jirovecii pneumonia, pulmonary fibrosis, and progressive multifocal leukoencephalopathy. [78]  

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Steroid-Resistant Disease and Focal Segmental GS

Genetic considerations play an important role in the treatment of SRNS and FSGS; approximately 30% of children with SRNS may have a single-gene cause of their disease. [3] Monogenic SRNS and FSGS are generally unresponsive to immunosuppressive medications, and identification of monogenic cases may avoid unnecessary treatment.

Calcineurin inhibitors (CSA and TAC) are the mainstay of treatment for SRNS and FSGS. In response to CNI treatment, SRNS without a clear genetic link may show complete remission in up to 60% of patients and partial remission in 19% of patients. [56] In one study, the response rate (complete and partial remission) to CSA for non-genetic SRNS was 68% versus 17% (partial remission only) for genetic SRNS. [84]  In a study by Büscher et al, 60% of patients with non-genetic SRNS achieved complete remission and another 19% had partial remission with CSA treatment, compared with 16% of patients with genetic SRNS who had only partial remission. [85]

The efficacy of TAC seems similar to that of CSA. As mentioned above, TAC may have the advantage of avoiding the gingival hyperplasia and hypertrichosis associated with CSA. [75]

Initial dosing recommendations for CSA and TAC in SRNS and FSGS are similar to those for FRNS and SDNS: CSA, 3-5 mg/kg/d divided every 12 hours; TAC, 0.1 mg/kg daily divided every 12 hours. Higher doses may be needed in SRNS and FSGS, and the dose may need to be titrated up carefully until a response is seen or adverse effects warrant a reduction in dose or discontinuation of treatment. [41]

An early, controversial protocol involved high-dose, intravenous methylprednisolone tapered over 78 weeks, in combination with alternate-day oral prednisone; CYP or chlorambucil was added if remission was not achieved in the first 10 weeks. The authors reported a 52% remission rate in SRNS. [86] However, subsequent studies using this protocol have not duplicated the initial success. The risk of steroid toxicity and infection, as well as the lack of sufficient evidence for the effectiveness of this protocol, has dampened enthusiasm for this treatment.

Most studies have shown no clear benefit to the use of alkylating agents in FSGS and SRNS. [60, 87]

In a nonrandomized study of 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. [88] The MMF regimen used in this study was 500-600 mg/m2/day or 18 mg/kg/day (maximum, 1 g) for a minimum of 6 months.

In the largest prospective, randomized trial to date in pediatric FSGS, 138 children and adults (aged 2-40 years) received 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. No difference was noted between the 2 treatment arms in the rate of sustained remission. [89]

The data are limited regarding the efficacy of rituximab in SRNS and FSGS. Case series indicate that rituximab may be effective in SRNS. [56] However, in an open-label, randomized, controlled trial in 31 children with SRNS resistant to steroids and CNI, no reduction in proteinuria was observed with the addition of rituximab. [10]

Two randomized trials in SRNS have shown a reduction in proteinuria with enalapril or fosinopril. Therefore, ACE inhibitors or ARBs should be considered for all patients with SRNS and FSGS, except when limited by hyperkalemia or significantly reduced kidney function. [56] Additionally, ACE inhibitor and ARB treatment may also have a renoprotective effect and slow progression of renal disease by inhibiting pathways of fibrosis. [90]

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Investigational Treatments

Plasmapheresis, galactose, zinc, and monoclonal antibodies other than rituximab have been studied in nephrotic syndrome but cannot be routinely recommended.

Plasmapheresis

Because of the evidence of immunologic 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 shown some efficacy in reducing proteinuria in patients with FSGS or SRNS treated with plasmapheresis or immunoadsorption. [91]

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. [92]

Galactose

Some patients with FSGS 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 given galactose (10 g orally twice daily). [93] 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 one small study, 7 children with SRNS and positive FSPF activity were treated with oral galactose (0.2 g/kg twice daily) for 16 weeks. Despite a decrease in FSPF, no reduction in proteinuria was demonstrated. [94]

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

Zinc

A study examined oral zinc supplementation (10 mg daily) in children with SSNS. [95] The authors found a trend in the reduction of relapse frequency and an increase in remission length. However, the study was underpowered to show statistical significance.

In a study of 60 children with SSNS, patients were randomized to receive zinc or placebo in addition to standard treatment for 6 months. Patients treated with zinc demonstrated a 43% reduction in relapses compared with those who received placebo. [96]

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

Monoclonal antibodies beyond rituximab

Ofatumumab (OFA), a new humanized anti-CD20 antibody that depletes B cells in a similar manner to rituximab, is currently under investigation for the treatment of childhood INS.

In one study, 4 of 5 children with rituximab-resistant SRNS achieved complete remission over 12 months of follow-up after treatment with OFA (300 mg/1.73 m2 for the first week, followed by 5 weekly infusions [2 g/1.73 m2 each]). [97]

In another study, 4 children with SRNS unresponsive to multiple drugs, including rituximab, were treated with OFA (300 + 700 mg/1.73 m2, 2 weeks apart). One patient achieved stable remission at 12 months of follow-up, whereas another child had only transient remittance of proteinuria; the other 2 children had no response. [98] In a later study, the same group treated 2 patients allergic to rituximab and induced stable remission after 12 months of follow-up following treatment with a single dose (750 mg/1.73 m2) of OFA. [99]  

Wang et al treated 5 childhood INS patients (4 with SRNS and one with post-transplant recurrence of FSGS) with OFA (300 mg/1.73 m2 for the first week, followed by 4 or 5 weekly infusions of 2 g/1.73 m2). Three patients achieved complete remission, and 1 patient had partial remission. [100]

A double-blind, randomized, controlled superiority trial is underway to compare OFA with rituximab in children who have SDNS and CNI-dependent NS. [101]

Other biologic therapies that have been investigated include the following:

  • Abatacept (an inhibitor of the T-cell costimulatory molecule B7-1 [CD80])
  • Adalimumab (a monoclonal antibody against tumor necrosis factor alpha)
  • Fresolimumab (a monoclonal antibody against transforming growth factor beta)

There are no data to support the efficacy or use of these agents at this time. [102]

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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 typically 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 corticosteroid therapy are required, the risk of complications increases. Complications of long-term steroid therapy may include the following:

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 who are receiving long-term corticosteroid therapy.

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 adverse 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. Albumin should be used cautiously, sparingly, and only in those patients with hemoconcentration or diuretic-resistant edema. Slow infusion of 1 g/kg as a continuous infusion over 24 hours might help to limit complications.

Calcineurin inhibitors

Cyclosporin A (CSA) and tacrolimus (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

Cyclophosphamide (CYP) 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

The adverse effects of MMF include cramps, diarrhea, gastrointestinal distress, myelosuppression, and increased susceptibility to infection.

Rituximab

The adverse effects of rituximab are rare but potentially serious. Risks include Pneumocystis jirovecii pneumonia, pulmonary fibrosis, and progressive multifocal leukoencephalopathy. [78]  

Antihypertensive agents

Blood pressure medications have numerous adverse effects, which 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 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 tract 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 so 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 (23-valent and heptavalent) 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. [103] 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. Patients with varicella-zoster infection should be treated with acyclovir and carefully monitored. [41] 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). [104]

Routine non-live viral vaccines should be administered according to their recommended schedules. Although it was formerly believed that routine immunization can trigger a relapse of nephrotic syndrome, no solid evidence supports this belief, and the risk of preventable childhood illnesses exceeds the theoretical, unproven risk of 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 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 of 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.

Ishikura et al found that children with 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. Twenty-three (50%) of the patients either had continued to experience frequent relapses over the follow-up period or else were receiving immunosuppressant therapy. None of the patients in the second study, however, suffered renal dysfunction or a lethal event during the follow-up period. [105]

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