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The long-term prognosis of steroid-sensitive
nephrotic syndrome is relatively good. However, most patients experience
relapses in their clinical course. In this issue, Sinha, et al.
[1] report the prognosis of steroid-sensitive nephrotic syndrome in 1071
children, which is the largest retrospective cohort study to date. They
describe that approximately one-half of the patients developed
frequent-relapsing nephrotic syndrome (FRNS) or steroid-dependent
nephrotic syndrome (SDNS), consistent with the rates in previous
reports. FRNS and SDNS are critical issues for children, because of the
severe adverse effects of steroid treatment, and psychological issues
owing to long hospitalization, frequent hospital visits, and side
effects of treatment. Therefore, clarification of risk factors for a
frequent-relapsing course and its prevention are quite important. The
authors concluded that early onset (<4 years), lack of adequate initial
therapy (<8 weeks), and short duration of initial remission lasting <6
months are risk factors for a frequent-relapsing course. Among these,
the only one in which we can intervene is initial therapy. Although many
pediatric nephrologists think that initial steroid treatment at disease
onset may influence the future clinical course, the optimal length of
initial steroid therapy remains controversial. A standard basic initial
steroid therapy at primary onset was proposed by the International Study
of Kidney Disease in Children (ISKDC) more than 30 years ago. The
proposal was daily steroid therapy (60 mg/m2/d)
for 4 weeks followed by alternate-day treatment (40 mg/m2/2d)
for 4 weeks (original was 3 days of medication followed by 4 days off in
a week, but later modified). Thereafter, this protocol was revised in a
variety of ways to obtain a better prognosis.
The KDIGO (Kidney Disease: Improving Global Outcomes)
guideline recommends that oral prednisone should be administered as a
single daily dose starting at 60 mg/m2/d
or 2 mg/kg/d (maximum: 60 mg/d) for 4-6 weeks followed by alternate-day
medication at 40 mg/m2/2d or
1.5 mg/kg/2d (maximum: 40 mg/2d) with tapering of the dose for 2-5
months [2]. The published US guideline recommends that the initial
steroid therapy should be 2 mg/kg/d for 6 weeks followed by 1.5 mg/kg/2d
on alternate days for 6 weeks (maximum: 40 mg/2d) [3]. In the Cochrane
systematic review, it is stated that duration of therapy up to 7 months
appeared to be more effective than therapy for 2 months in achieving
sustained remission. In Japan, a randomized controlled trial (RCT)
comparing daily therapy for 4 weeks followed by alternate-day therapy
for 6 months with the standard 2-month therapy is ongoing. The results
of this RCT will provide some suggestions regarding the optimal mode of
initial steroid treatment. The duration of daily steroid therapy, i.e. 4
or 6 weeks, should also be evaluated by an RCT.
Although half of the 1071 patients progressed to
FRNS, 185 children had FRNS or SDNS and 42 had late steroid resistance
in long-term observation. However, 72% of FRNS patients were in
remission or had infrequent relapses with immunosuppressive agents or
low-dose steroid. Therefore, the long-term prognosis is relatively good.
However, a certain proportion of patients showed disease transition to
the adult form or a difficult clinical course resistant to existing
therapy. Such patients were likely to be complicated with severe
infection, resulting in high mortality in their study. Recently,
rituximab, an anti-CD20 antibody, has become an emerging therapy for
difficult nephrotic syndrome [5,6]. Rituximab allows such patients to
discontinue steroid treatment and dramatically reduces the number of
relapses. Rituximab can also induce remission in patients with
intractable steroid-resistant nephrotic syndrome. Although more clinical
experience is needed to establish a safe and effective mode of
administration, such new molecular target therapies will improve the
clinical course of childhood nephrotic syndrome in the future.
References
1. Sinha A, Hari P, Sharma PK, Gulati A, Kalaivani M,
Mantan M, et al. Disease Course in Steroid Sensitive Nephrotic
Syndrome. Indian Pediatr. 2012;49:881-7 .
2. Improving Global Outcomes (KDIGO)
Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for
Glomerulonephritis. Kidney Inter. 2012; 2: 139–274.
3. Gipson DS, Massengill SF, Yao L, Nagaraj S, Smoyer
WE, Mahan JD, et al. Management of childhood onset nephrotic
syndrome. Pediatrics. 2009;124: 747-57.
4. Hodson EM, Willis NS, Craig JC. Corticosteroid
therapy for nephrotic syndrome in children. Cochrane Database Syst Rev.
2007; 17:CD001533.
5. Gulati A, Sinha A, Jordan SC, Hari P, Dinda AK,
Sharma S, et al. Efficacy and safety of treatment with rituximab
for difficult steroid-resistant and dependent nephrotic syndrome:
multicentric report. Clin J Am Soc Nephrol. 2010;5:2207-12.
6. Ito S, Kamei K, Ogura M, Sato M, Fujimaru T,
Ishikawa T, et al. Maintenance therapy with mycophenolate mofetil
after rituximab in pediatric patients with steroid-dependent nephrotic
syndrome. Pediatr Nephrol. 2011; 26:1823-8.
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