US Pharm. 2014;39(5):HS2-HS8.
ABSTRACT: Pediatric patients with nephrotic syndrome (NS) can
exhibit proteinuria, hypoalbuminemia, edema, and dyslipidemia. Morbidity
and mortality associated with nephrotic syndrome, including progression
to end-stage renal disease (ESRD), are reduced with treatment.
Idiopathic NS occurs more often than NS from secondary causes in
pediatric patients. Corticosteroids are used first-line to induce
remission and are effective in most pediatric patients. Inadequate
response to corticosteroids dictates the need for adjunctive or
alternative therapies such as alkylating agents, calcineurin inhibitors,
mycophenolate mofetil, and rituximab. These strategies are useful for
patients who do not remit with steroids, who frequently relapse, or who
Pediatric patients with nephrotic syndrome (NS) have increased
glomerular filtration barrier permeability, resulting in clinical
features such as proteinuria, hypoalbuminemia, edema, and dyslipidemia.1,2
The annual incidence and prevalence of NS in children are two to seven
cases per 100,000 and 12 to 16 cases per 100,000, respectively.2
In children, idiopathic NS (INS) occurs more often than NS from to
secondary causes such as diabetes and systemic lupus erythematosus.3
With biopsy, INS can be diagnosed by histopathologic type to predict
treatment success and prognosis, although the treatment strategy is
unlikely to differ.
ETIOLOGY, DIAGNOSIS, AND OUTCOMES
The most prevalent pathology of INS in children is minimal-change
disease (MCD). A much smaller, but rising, percentage of INS is
attributed to focal segmental glomerulosclerosis (FSGS). Diffuse
mesangial hypercellularity, membranous nephropathy,
membranoproliferative glomerulonephritis, and immunoglobulin A (IgA)
nephropathy are less common.4 Symptom onset in patients with MCD commonly occurs from 2 to 6 years of age.2 Corticosteroid responsiveness is the most significant prognostic factor in INS.2
Children with steroid-sensitive nephrotic syndrome (SSNS) are more
likely to have favorable long-term outcomes, whereas those with
steroid-resistant nephrotic syndrome (SRNS) have comparatively lower
renal survival rates.1 Approximately 90% of pediatric patients with INS achieve complete remission (CR) (TABLE 1) with corticosteroids and are classified as having SSNS (TABLE 2).2
Therefore, renal biopsy is not required for all children, owing to the
high likelihood of response to initial and subsequent courses of
Renal biopsy is indicated in children with SSNS who fail to respond
to corticosteroids after one or more remissions or who have
deteriorating renal function while receiving calcineurin inhibitors
(CNIs), despite dose reduction.1 High suspicion of other
etiologies, such as FSGS based on older age or the higher prevalence in
African or African American individuals, may warrant biopsy. Pediatric
patients with SRNS (TABLE 2) should undergo biopsy to exclude
secondary causes of NS and to evaluate severity. Secondary causes also
can be excluded through medical history, physical examination,
laboratory tests, and imaging. Although genetic mutations have been
identified in some children with SRNS and FSGS, routine evaluation is
not recommended because of the high cost and lack of utility with regard
to prognosis and treatment modification at this point.
In children, proteinuria is defined as urine protein excretion ≥40 mg/m2/h, a protein-creatinine ratio (PCR) ≥2,000 mg/g, an albumin-creatinine ratio ≥300 mg/dL, or 3+ on urine dipstick.1
In the absence of overt clinical symptoms, nephrotic-range proteinuria
is generally defined as urine PCR ≥2,000 mg/g. Quantification of
proteinuria is used as a surrogate marker of outcomes and is important
for assessing prognosis and treatment response.
COMPLICATIONS AND ASSOCIATED THERAPIES
In addition to proteinuria, other complications of glomerular
disease, such as hypertension, edema, thrombosis, and infection, should
be treated to reduce associated morbidity and mortality. Adequate
dietary protein intake (0.8-1.0 g/kg/day) should be maintained and is
optimally utilized in conjunction with a high-carbohydrate diet.1
For children with IgA nephropathy, an ACE inhibitor (ACEI) or
angiotensin receptor blocker (ARB) is suggested for proteinuria between
0.5 and 1 g/day per 1.73 m2.1 For other pediatric
INS etiologies, renin-angiotensin system blockade is not recommended for
proteinuria independent of hypertension. However, an ACEI or ARB is
recommended first-line for children with hypertension regardless of the
degree of proteinuria.5 The target blood pressure for
children with glomerulonephritis is <50th percentile for both
systolic and diastolic pressure for age and sex.5
Although it is debated whether a reduction in hyperlipidemia
positively impacts renal function, children with NS should typically be
classified and treated as high-risk patients owing to the association
with cardiovascular (CV) disease.1 Childhood lipid levels are representative of future lipid levels and CV events in a general pediatric population.6
In children with chronic kidney disease, it is recommended that lipid
levels be evaluated annually owing to the influence of growth and
development. Statins are typically not recommended for dyslipidemia in
children with NS, owing to inadequate assessment of clinically relevant
outcomes and long-term safety data in this population. Emphasis is
placed on therapeutic lifestyle changes, including dietary fat
restriction and weight loss, when appropriate.
Additional dietary modifications include moderate sodium restriction in patients with edema associated with NS.1
Diuretic therapy may also be required, although even patients with a
normal glomerular filtration rate may be resistant to diuretics. Loop
diuretics are used most commonly and may be given in combination with
thiazide diuretics or metolazone to augment effects. Intravenous (IV)
diuretic therapy may be needed in patients who are unresponsive to oral
therapy from possible effects of intestinal-wall edema on
gastrointestinal absorption. Pediatric patients receiving diuretic
therapy should be monitored cautiously because of the increased risk of
hypovolemia in this population.
Thrombophilic risks should be considered in children with NS.1
Although venous thromboembolism (VTE) occurs in only 3% of pediatric NS
cases, it may be associated with significantly increased morbidity and
mortality.7 Serum albumin <2.5 g/dL has been associated
with an increased risk of thrombosis in adults, although this
association was not found in a large cohort of pediatric patients.1,7
Risk factors for VTE development in children include worsening
proteinuria and histologic evidence of membranous nephropathy and/or
class V lupus nephritis. No definitive recommendations have been made
concerning the pharmacologic prevention of VTE in pediatric patients
with NS. Nonpharmacologic risk-reduction strategies should be
implemented, and pharmacologic prophylaxis may be considered in
Children with NS should be immunized for prevention of infection, including the pneumococcal influenza vaccination.1,8
Live vaccines are contraindicated while patients are receiving
immunosuppressants and should be deferred until the prednisone dose is
<1 mg/kg daily (<20 mg/day) or 2 mg/kg on alternate days (<40
mg on alternate days).1,8
TREATMENT OF INS
Although the exact mechanism is unknown, corticosteroid therapy has
been highly effective for pediatric NS for nearly 5 decades, with as few
as 20% of patients failing to respond.1,9,10 Greater success with corticosteroids occurs in NS that is due to MCD than in NS that is due to FSGS.10
Randomized, controlled trials (RCTs) have not established
corticosteroid dosing; however, the International Study of Kidney
Disease in Children recommends oral prednisone 60 mg/m2/day or 2 mg/kg/day (maximum dose 60 mg/day) once daily for 4 to 6 weeks, followed by 40 mg/m2 or 1.5 mg/kg (maximum 40 mg on alternate days) every other day for 2 to 5 months, with tapering.1,11,12 Alternatively, prednisolone may be given at the same doses.1
Clinical studies correlate longer and higher doses of corticosteroids
with higher rates of remission and a lower incidence of relapse; thus,
regimens with corticosteroid exposure less than what is presented should
not be used.13 Nevertheless, extended-duration dosing (i.e., 6 months) results in relapse in nearly 40% of patients.13
Results from two currently registered placebo-controlled trials
evaluating corticosteroid administration for durations of 20 weeks and
24 weeks are anticipated.
Children who relapse after initially responding to corticosteroids
will likely respond to corticosteroids again and should be treated with a
subsequent dose of oral prednisone 60 mg/m2 or 2 mg/kg (maximum 60 mg/day) until CR has been maintained for 3 days.1
Thereafter, alternate-day dosing of corticosteroids should be continued
for 4 weeks. Although adverse effects (AEs) in clinical trials did not
increase with longer durations (i.e., 5-7 months) of corticosteroid
therapy compared with a shorter duration (i.e., 2 months), repetitive
treatments could reasonably be expected to increase the risk of weight
gain, growth impediments, hypertension, hyperglycemia, bone loss,
psychological disorders, and adrenal suppression.13 Children who do not remit after corticosteroid therapy are classified as SRNS and are at greater risk for mortality and ESRD.10 Low-quality evidence supports the use of high-dose corticosteroids in SRNS.1
Additionally, children with SSNS can be deemed late nonresponders,
usually within the first year, if they exhibit resistance or partial
response to a minimum of 4 weeks of full-dose corticosteroids; these
patients may derive benefit from nonsteroidal therapies.14
Nonsteroidal agents may be used in pediatric patients to reduce
exposure to corticosteroids, thereby decreasing related AEs, or when
steroid resistance is demonstrated. These medications, which are
referred to as corticosteroid-sparing agents when used for
frequent-relapsing NS (FRNS) or steroid-dependent NS (SDNS), include
alkylating agents, CNIs, mycophenolate mofetil (MMF), and rituximab.
Predictors of FRNS include initial remission time ≥9 days and first
relapse in ≤6 months.15 Recommendations related to the use of these agents for FRNS and SDNS, as well as data for SRNS, are presented below.
Alkylating Agents (Cyclophosphamide, Chlorambucil): Alkylating
agents can reduce relapse in pediatric NS by 24% to 72% up to 5 years
after remission, consequently lowering corticosteroid exposure in
patients with SSNS classified as FRNS or SDNS.1,16 Although
these agents’ immunosuppressant effects are well known, the exact
mechanism in NS has not been defined. The use of oral cyclophosphamide
(2 mg/kg/day) for 8 to 12 weeks (maximum cumulative dose 168 mg/kg) or
oral chlorambucil (0.1-0.2 mg/kg/day) for 8 weeks (maximum cumulative
dose 11.2 mg/kg) in children is supported by moderate-quality evidence.1
Although hemorrhagic cystitis is unlikely to occur when recommended
doses are used, patients should be in remission prior to
cyclophosphamide initiation in order to tolerate large volumes of fluid
and produce adequate urine output to protect against the risk of this
disorder.1 Subsequent exposure to alkylating agents is not
recommended, owing to the risk of dose-dependent gonadal toxicity (in
both males and females). Reduced sperm counts have been reported with
cumulative doses of cyclophosphamide >200 to 300 mg/kg and
chlorambucil 8 to 10 mg/kg.1 Cyclophosphamide, which is metabolized through glutathione S-transferase, may be more efficacious in patients expressing this polymorphism.17 Chlorambucil may be associated with a higher risk of cancer, seizures, and bacterial infections versus cyclophosphamide.1,18
Current recommendations include no role for alkylating agents in SRNS,
based on limited evidence suggesting that the risks far outweigh the
CNIs (Cyclosporine, Tacrolimus): The recommended
doses of CNIs for pediatric NS are oral cyclosporine 4 to 5 mg/kg/day
(starting dose) divided twice daily and oral tacrolimus 0.1 mg/kg/day
(starting dose) divided twice daily for 12 months.1 Given
their relatively similar efficacy, there is no order of preference in
using alklyating agents versus CNIs for FRNS or SDNS.1 However, unlike alkylating agents, CNIs may be used as initial therapy for SRNS. If
the patient fails to achieve partial remission or CR at 6 months,
discontinuation of the CNI may be considered; otherwise, the CNI should
be continued for at least 12 months.1 Most studies have
examined CNIs given in addition to low-dose corticosteroids for SRNS;
however, superiority has not been established between CNI monotherapy
and CNI in combination with corticosteroids.1 AEs associated with CNIs include hypertension, renal impairment, and hyperkalemia.1,10 Diabetes mellitus also has been associated with tacrolimus use in children.1
Monitoring for trough levels of 80 to 150 ng/mL for cyclosporine and 5
to 10 ng/mL for tacrolimus may be targeted to minimize nephrotoxicity.1
Although most studies on SRNS have been performed using cyclosporine,
tacrolimus is an alternative for patients unwilling to experience
hypertrichosis and gum hypertrophy, which are associated with long-term
(>1 year) cyclosporine use.10 CNIs are very expensive, and
although not currently recommended, one study demonstrated that using
50% less cyclosporine provided similar efficacy and safety via
coadministration of ketoconazole 1.5 mg/kg/day as a metabolic inhibitor
MMF: Although MMF is probably less effective
than CNIs, a few small pediatric studies show promising results with MMF
in maintenance of remission from SDNS and FRNS, with minimal AEs.1 Oral MMF doses used in studies were 1,200 mg/m2/day or about 30 mg/kg/day in two divided doses.1
The high cost of MMF is likely to be a limitation, and therapy should
not be discontinued sooner than 12 months to avoid the risk of relapse.
In SRNS, MMF is an option for patients who fail to achieve remission
with CNI and steroids.1,10
Rituximab: Of all the alternative agents,
rituximab has the most limited evidence for use in SDNS, SRNS, and FRNS.
Studies have used rituximab 375 mg/m2 IV once weekly for 1
to 4 weeks. Rituximab is believed to work by acting on the B cell, but
it may have a more direct effect on the podocyte itself in FSGS.20
Current guidelines recommend rituximab only in children with SDNS who
have continuing frequent relapses despite optimal combinations of
prednisone and corticosteroid-sparing agents, and/or who have serious
AEs from therapy.1 The high cost also must be considered.
Based on the lack of RCTs and the concern over AEs, rituximab is not
recommended for SRNS.1
Other Agents: Moderate-quality evidence supports
the use of levamisole 2.5 mg/kg on alternate days for 1 year to reduce
the risk of relapse in pediatric SSNS.1 However, the manufacturer voluntarily discontinued production of levamisole partly due to the risk of agranulocytosis.1,21
Consequently, outside of veterinary use, the drug is no longer
available in the United States. Aside from corticosteroids,
adrenocorticotropic hormone (H.P. Acthar Gel) is the only FDA-approved
agent for the treatment of NS without uremia of the idiopathic type or
due to lupus erythematosus.9,22
Galactose, adalimumab, and thiazolidinediones are potential future therapeutic options for pediatric NS.10
Until larger trials evaluate these agents’ utility, no dosing
strategies or targeted populations can be recommended. Mizoribine and
azathioprine are not recommended because RCTs show no additional benefit
of either drug over placebo in FRNS or SDNS.1
Corticosteroids continue to be the mainstay of treatment for
pediatric NS and have a high degree of success, although relapse often
occurs. Steroid-sparing agents are available for pediatric patients
experiencing frequent relapses or steroid dependence. Alkylating agents,
CNI, MMF, and rituximab are beneficial in SSNS, whereas fewer options
exist for SRNS. A limited number of RCTs demonstrate varying benefit
with each of these agents, and an accompanying set of disadvantages such
as short-term and long-term AEs, cost, and required monitoring for each
drug class must be considered.
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22. H.P. Acthar Gel (repository corticotropin injection) product
information. Union City, CA: Questcor Pharmaceuticals, Inc; January
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