Age
n
2.5 %
50.0 %
97.5 %
3–5 months
18
0.14
0.20
0.26
6–8 months
19
0.14
0.22
0.31
9–11 months
31
0.14
0.22
0.34
1 year
70
0.16
0.23
0.32
2 years
73
0.17
0.24
0.37
3 years
88
0.21
0.27
0.37
4 years
81
0.20
0.30
0.40
5 years
96
0.25
0.34
0.45
6 years
102
0.25
0.34
0.48
7 years
85
0.28
0.37
0.49
8 years
56
0.29
0.40
0.53
9 years
36
0.34
0.41
0.51
10 years
44
0.30
0.41
0.57
11 years
58
0.35
0.45
0.58
Table 2
Between 12 and 16 years old in males and females. Reference values of serum creatinine in Japanese adolescents
Sex
|
Males
|
Females
|
||||||
---|---|---|---|---|---|---|---|---|
Age
|
n
|
2.5 %
|
50.0 %
|
97.5 %
|
N
|
2.5 %
|
50.0 %
|
97.5 %
|
12 years
|
15
|
0.40
|
0.53
|
0.61
|
54
|
0.40
|
0.52
|
0.66
|
13 years
|
30
|
0.42
|
0.59
|
0.80
|
38
|
0.41
|
0.53
|
0.69
|
14 years
|
17
|
0.54
|
0.65
|
0.96
|
40
|
0.46
|
0.58
|
0.71
|
15 years
|
15
|
0.48
|
0.68
|
0.93
|
22
|
0.47
|
0.56
|
0.72
|
16 years
|
30
|
0.62
|
0.73
|
0.96
|
27
|
0.51
|
0.59
|
0.74
|
eGFR (mL/min/1.73 m2) = 110.2 × (reference serum Cr/patient’s serum Cr) + 2.93
Reference serum Cr levels (Cr (mg/dL)) are shown by the following two equations of body length (Ht (m)):
Male patients: Cr = −1.259 Ht5 + 7.815 Ht4 – 18.57 Ht3 + 21.39 Ht2 – 11.71 Ht + 2.628
Female patients: Cr = −4.536 Ht5 + 27.16 Ht4 – 63.47 Ht3 + 72.43 Ht2 – 40.06 Ht + 8.778
A simple serum Cr-based eGFR formula for bedside use was also determined for Japanese children between the ages of 2 and 11 years ([6], PMID: 23564380):
eGFR (mL/min/1.73 m2) = 0.35 × Ht/Cr × 100
The Committee also reported reference values for serum cystatin C levels ([7], PMID: 23446519), a cystatin C-based equation for eGFR in Japanese children and adolescents ([8], PMID: 24253614), and reference values for serum β2 microglobulin (Table 3) ([9], PMID: 22797889).
Table 3
Reference values of serum β2 microglobulin levels in Japanese children
All subjects
|
Boys
|
Girls
|
||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Age
|
n
|
2.5 %
|
50 %
|
97.5 %
|
n
|
2.5 %
|
50 %
|
97.5 %
|
n
|
2.5 %
|
50 %
|
97.5 %
|
3–5 months
|
21
|
1.5
|
1.8
|
3.2
|
17
|
1.5
|
1.8
|
3.2
|
4
|
1.6
|
1.8
|
2.1
|
6–8 months
|
18
|
1.4
|
1.8
|
2.6
|
14
|
1.4
|
1.9
|
2.6
|
4
|
1.6
|
1.6
|
2.3
|
9–11 months
|
29
|
1.3
|
1.7
|
3.3
|
15
|
1.3
|
1.7
|
3.3
|
14
|
1.3
|
1.8
|
3.2
|
1 year
|
69
|
1.4
|
1.7
|
3.1
|
32
|
1.4
|
1.7
|
3.2
|
37
|
1.2
|
1.6
|
3.0
|
2 years
|
73
|
1.0
|
1.5
|
2.5
|
40
|
1.0
|
1.5
|
2.2
|
33
|
1.0
|
1.5
|
3.4
|
3 years
|
85
|
1.0
|
1.5
|
2.3
|
46
|
1.1
|
1.5
|
2.3
|
39
|
1.0
|
1.5
|
2.4
|
4 years
|
78
|
1.1
|
1.4
|
2.5
|
42
|
1.0
|
1.4
|
2.1
|
36
|
1.1
|
1.4
|
3.1
|
5 years
|
94
|
1.1
|
1.4
|
2.3
|
46
|
1.1
|
1.5
|
2.7
|
48
|
1.0
|
1.4
|
2.2
|
6 years
|
101
|
1.1
|
1.4
|
2.3
|
43
|
1.1
|
1.4
|
2.4
|
58
|
1.0
|
1.5
|
2.3
|
7 years
|
83
|
1.0
|
1.4
|
2.1
|
36
|
0.9
|
1.3
|
2.1
|
47
|
1.0
|
1.4
|
2.2
|
8 years
|
55
|
1.0
|
1.4
|
2.5
|
19
|
1.0
|
1.4
|
1.8
|
36
|
1.0
|
1.4
|
2.3
|
9 years
|
37
|
1.0
|
1.4
|
2.1
|
18
|
1.1
|
1.4
|
1.8
|
19
|
1.0
|
1.4
|
2.1
|
10 years
|
42
|
0.9
|
1.3
|
1.9
|
11
|
1.1
|
1.4
|
1.6
|
31
|
0.9
|
1.3
|
1.9
|
11 years
|
58
|
1.0
|
1.3
|
2.3
|
19
|
1.1
|
1.3
|
2.1
|
39
|
1.0
|
1.2
|
2.4
|
12 years
|
69
|
1.0
|
1.3
|
1.8
|
14
|
1.2
|
1.3
|
1.5
|
55
|
0.9
|
1.3
|
1.9
|
13 years
|
68
|
1.0
|
1.3
|
1.8
|
30
|
1.0
|
1.4
|
2.0
|
38
|
1.0
|
1.2
|
1.5
|
14 years
|
57
|
0.9
|
1.3
|
2.0
|
17
|
1.1
|
1.4
|
2.0
|
40
|
0.9
|
1.2
|
1.7
|
15 years
|
35
|
0.8
|
1.2
|
1.8
|
15
|
0.8
|
1.2
|
1.8
|
20
|
0.8
|
1.1
|
1.7
|
16 years
|
59
|
0.8
|
1.2
|
1.8
|
30
|
0.8
|
1.2
|
1.8
|
29
|
0.8
|
1.1
|
1.4
|
All ages
|
1,311
|
1.0
|
1.4
|
2.3
|
504
|
1.0
|
1.4
|
2.3
|
627
|
1.0
|
1.4
|
2.3
|
Japanese Children with Pre-dialysis CKD
Although several studies have described the epidemiology of pre-dialysis CKD in children in Western countries, few have focused on Asian children. It is important to be aware of differences in the epidemiology of CKD among people from different regions secondary to racial differences, variations in screening methods among medical institutions, and differences in school-screening programs. The Committee conducted a nationwide population-based survey of Japanese children aged 3 months to 15 years with pre-dialysis CKD to examine the prevalence of pediatric CKD in Japan. CKD was classified according to the previously noted criteria derived from the reference serum Cr levels in Japanese children (Tables 4 and 5). Data from 447 children was collected. When subdivided according to diagnostic criteria, 70.5 % of children had stage 3 CKD, 23.9 % stage 4 CKD, and 5.6 % stage 5 CKD. The estimated prevalence in Japanese children with CKD was 2.98 cases/100,000 children. Of 407 CKD cases with non-glomerular disease, 278 (68.3 %) had congenital anomalies of the kidney and urinary tract (Table 6) ([10], PMID: 23825101).
Table 4
Diagnostic criteria for chronic kidney disease (CKD) , stages 3–5, based on reference serum Cr levels (mg/dL) in Japanese children
Age
|
CKD stage 3
|
CKD stage 4
|
CKD stage 5
|
---|---|---|---|
<2 years
|
|||
3–5 months
|
0.41–0.80
|
0.81–1.60
|
≥1.61
|
6–8 months
|
0.43–0.84
|
0.85–1.68
|
≥1.69
|
9–11 months
|
0.47–0.92
|
0.93–1.84
|
≥1.85
|
1 year
|
0.47–0.92
|
0.93–1.84
|
≥1.85
|
2–12 years
|
|||
2 years
|
0.49–0.96
|
0.97–1.92
|
≥1.93
|
3 years
|
0.55–1.08
|
1.09–2.16
|
≥2.17
|
4 years
|
0.61–1.20
|
1.21–2.40
|
≥2.41
|
5 years
|
0.69–1.36
|
1.37–2.72
|
≥2.73
|
6 years
|
0.69–1.36
|
1.37–2.72
|
≥2.73
|
7 years
|
0.75–1.48
|
1.49–2.96
|
≥2.97
|
8 years
|
0.81–1.60
|
1.61–3.20
|
≥3.21
|
9 years
|
0.83–1.64
|
1.65–3.28
|
≥3.29
|
10 years
|
0.81–1.60
|
1.61–3.20
|
≥3.21
|
11 years
|
0.91–1.80
|
1.81–3.60
|
≥3.61
|
Table 5
Diagnostic criteria for stages 3–5 CKD based on reference serum Cr levels (mg/dL) in Japanese adolescents
CKD stage 3
|
CKD stage 4
|
CKD stage 5
|
|
---|---|---|---|
Males
|
|||
12 years
|
1.07–2.12
|
2.13–4.24
|
≥4.25
|
13 years
|
1.19–2.36
|
2.37–4.72
|
≥4.73
|
14 years
|
1.31–2.60
|
2.61–5.20
|
≥5.21
|
15 years
|
1.37–2.72
|
2.73–5.44
|
≥5.45
|
Females
|
|||
12 years
|
1.05–2.08
|
2.09–4.16
|
≥4.17
|
13 years
|
1.07–2.12
|
2.13–4.24
|
≥4.25
|
14 years
|
1.17–2.32
|
2.33–4.64
|
≥4.65
|
15 years
|
1.13–2.24
|
2.25–4.48
|
≥4.49
|
Table 6
Primary etiologies of stages 3–5 CKD in Japanese children aged 3 months to 15 years
Primary disease
|
Non-glomerular kidney disease (N = 407, 91.1 %)
|
Glomerular kidney disease (N = 35, 7.8 %)
|
Unclassified (N = 5, 1.1 %)
|
|||
---|---|---|---|---|---|---|
N
|
(%)
|
N
|
(%)
|
N
|
(%)
|
|
CAKUT
|
278
|
(68.3)
|
0
|
(0.0)
|
0
|
(0.0)
|
CAKUT with obstructive urologic malformationsa
|
60
|
(21.6)
|
0
|
(0.0)
|
0
|
(0.0)
|
CAKUT without obstructive urologic malformations
|
218
|
(78.4)
|
0
|
(0.0)
|
0
|
(0.0)
|
Cortical necrosis (perinatal period)
|
40
|
(9.8)
|
0
|
(0.0)
|
0
|
(0.0)
|
Polycystic kidney disease
|
20
|
(4.9)
|
0
|
(0.0)
|
0
|
(0.0)
|
Nephronophthisis
|
19
|
(4.7)
|
0
|
(0.0)
|
0
|
(0.0)
|
Drug induced
|
17
|
(4.2)
|
0
|
(0.0)
|
1
|
(20.0)
|
Other inherited kidney damage
|
10
|
(2.5)
|
1
|
(2.9)
|
0
|
(0.0)
|
Acute kidney injury
|
10
|
(2.5)
|
0
|
(0.0)
|
0
|
(0.0)
|
Neurogenic bladder
|
6
|
(1.5)
|
0
|
(0.0)
|
0
|
(0.0)
|
Other noninheritable character
|
4
|
(1.0)
|
2
|
(5.7)
|
0
|
(0.0)
|
Alport’s syndrome
|
0
|
(0)
|
8
|
(22.9)
|
0
|
(0.0)
|
Cystinosis
|
1
|
(0.2)
|
0
|
(0.0)
|
0
|
(0.0)
|
Wilms tumor
|
1
|
(0.2)
|
0
|
(0.0)
|
0
|
(0.0)
|
Chronic tubulointerstitial nephritis
|
1
|
(0.2)
|
0
|
(0.0)
|
0
|
(0.0)
|
Focal segmental glomerulosclerosis
|
0
|
(0.0)
|
8
|
(22.9)
|
0
|
(0.0)
|
Chronic glomerulonephritis
|
0
|
(0.0)
|
8
|
(22.9)
|
0
|
(0.0)
|
Congenital nephrotic syndrome
|
0
|
(0.0)
|
3
|
(8.6)
|
0
|
(0.0)
|
Hemolytic uremic syndrome
|
0
|
(0.0)
|
3
|
(8.6)
|
0
|
(0.0)
|
Systemic lupus erythematosus
|
0
|
(0.0)
|
2
|
(5.7)
|
0
|
(0.0)
|
Unknown
|
0
|
(0.0)
|
0
|
(0.0)
|
4
|
(80.0)
|
The Committee conducted a follow-up survey to determine the rate of disease progression in these patients. The study revealed that 12.5 % of children with pre-dialysis CKD progressed to end-stage kidney disease with a median follow-up of 1.49 years and that children with advanced (stage 4/5) CKD were particularly likely to progress (Table 7) ([11], PMID: 24516225).
Table 7
Risk factors for end-stage kidney disease (Cox regression model)
Variable
|
HR
|
95 % CI
|
P-value
|
---|---|---|---|
Sex
|
|||
Female
|
1.56
|
0.67–3.62
|
0.306
|
Male
|
1.00
|
–
|
–
|
Age
|
|||
Age <2 years (versus 2 years to the start of puberty)a
|
9.06
|
2.29–35.84
|
0.002
|
After puberty (versus 2 years to the start of puberty)a
|
4.88
|
1.85–12.85
|
0.001
|
Recognizable syndromeb
|
2.54
|
0.75–8.58
|
0.133
|
CKD stage
|
|||
CKD stage 4 (versus stage 3)
|
11.12
|
4.22–29.28
|
<0.001
|
CKD stage 5 (versus stage 3)
|
26.95
|
7.71–94.17
|
<0.001
|
CAKUT
|
0.60
|
0.25–1.47
|
0.261
|
Preterm delivery (<37 weeks)
|
1.33
|
0.50–3.53
|
0.562
|
Heavy proteinuriac
|
7.56
|
3.22–17.77
|
<0.001
|
Hypertensiond
|
0.53
|
0.19–1.46
|
0.219
|
Use of antihypertensive drugs
|
1.08
|
0.42–2.75
|
0.874
|
Development of Multicenter Clinical Trials in Japan
In the late 1980s, core members of the JSPN started multicenter clinical trials to develop evidence-based, effective, and safe treatments for pediatric kidney diseases, especially IgA nephropathy (IgAN) and nephrotic syndrome in children. A substantial number of clinical trials conducted by JSPN members brought about significant progress in the treatment of those diseases.
Multicenter Clinical Trials for IgA Nephropathy in Children
In 1990, the Japanese Pediatric IgA Nephropathy Treatment Study Group was established to develop better treatments for IgAN in children (President: Norishige Yoshikawa).
From 1990 to 1993, a randomized controlled trial of combined therapy for newly diagnosed, severe childhood IgA nephropathy was defined as showing diffuse mesangial proliferation in the renal biopsy. In this trial, the efficacy and safety of 2 regimens (prednisolone, azathioprine, heparin–warfarin, and dipyridamole vs. heparin–warfarin, and dipyridamole) were compared in patients with newly diagnosed severe childhood IgA nephropathy showing diffuse mesangial proliferation. The results indicated that treatment of children with severe IgAN with prednisolone, azathioprine, heparin–warfarin, and dipyridamole for 2 years early in the course of the disease reduced immunologic renal injury and prevented increases in sclerosis of glomeruli ([12], PMID: 9890315). A retrospective long-term follow-up study of patients enrolled in the study was carried out to evaluate the long-term effectiveness of combined therapy in children with IgAN showing diffuse mesangial proliferation. The results suggested that 2-year combined therapy not only ameliorated the activity of the acute phase of nephritis but also improved the long-term outcome of severe childhood IgAN ([13], PMID: 21493743).
A randomized controlled trial that compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (in combination) with those of prednisolone alone in 80 children with newly diagnosed IgAN showing diffuse mesangial proliferation was conducted from 1994 to 1998. The results suggested that combination treatment may be better for severe IgAN than treatment with prednisolone alone ([14], PMID: 17699253).
From 1998 to 2001, a pilot trial in which mizoribine instead of azathioprine was administered as part of the combination therapy for treating 23 children with severe IgAN, and evaluating the efficacy and safety was carried out. The results suggested that the efficacy and safety of the mizoribine combination appeared acceptable for treating children with severe IgAN ([15], PMID: 18224343). A prospective single-arm pilot trial was also conducted in which lisinopril (0.4 mg/kg per day) was administered as the therapeutic treatment to 40 children with mild IgAN with proteinuria (morning urinary protein/creatinine ratio ≥0.2 g/g). The results suggested that the efficacy and safety of lisinopril were acceptable for the treatment of children with mild IgAN ([16], PMID: 18825420).
Multicenter Clinical Trials for Childhood Nephrotic Syndrome
In 1998, the Japanese Study Group of Renal Disease in Children (JSRDC) was established (President: Masataka Honda). This study group was contiguously developed out of the Study Group for Treatment for Childhood Nephrotic Syndrome in Japan, which was founded by Hiroshi Ito and Norishige Yoshikawa in 1987. The JSRDC has carried out multicenter clinical trials and long-term follow-up studies mainly for nephrotic syndrome.
A prospective open-label multicenter trial to evaluate the efficacy and safety of treating children with frequently relapsing nephrotic syndrome (FRNS) with cyclosporine (Sandimmune) (JSRDC05) revealed that treatment with cyclosporine for 2 years in a dosage that maintained the trough level between 80 and 100 ng/mL for the first 6 months and 60 and 80 ng/mL for the next 18 months was an effective and relatively safe treatment for children with FRNS ([17], PMID: 18305467). A prospective follow-up study after the JSRDC05 trial (2-year treatment with cyclosporine) was carried out to investigate cyclosporine dependency after its discontinuation. The results suggested that children with FRNS who received cyclosporine were at high risk of relapse after discontinuation, particularly those who experienced relapse during cyclosporine treatment ([18], PMID: 22837276). Additionally, to evaluate the safety and efficacy of microemulsified cyclosporine (Neoral), a prospective multicenter trial was conducted according to the previously established protocol described above using microemulsified cyclosporine instead of conventional cyclosporine (Sandimmune) (JSRDC07). The results suggested that microemulsified cyclosporine administered according to the treatment protocol was safe and effective in children with FRNS ([19], PMID: 20530497).
To evaluate the efficacy and safety of a 12-month course of cyclosporine in children with steroid-resistant nephrotic syndrome (SRNS) , a prospective multicenter trial was conducted (JSRDC08). The results showed that a high remission rate was achieved using a combined cyclosporine–prednisolone treatment regimen in children with SRNS who had minimal change/diffuse mesangial proliferation and a combined cyclosporine–prednisolone plus methylprednisolone pulse therapy regimen in children who had focal segmental glomerulosclerosis ([20], PMID: 19714370). A prospective 5-year follow-up study of this patient cohort revealed that many children required ongoing immunosuppression treatment, although SRNS treatment with cyclosporine provided high renal survival and remission rates ([21], PMID: 23314441).
The Pediatric Mizoribine Study Group in Japan, founded by Kazuo Yoshioka and Sunao Maki, conducted a double-blind placebo-controlled multicenter trial to evaluate the efficacy and safety of mizoribine in children with FRNS. This was the first ICH-GCP-based multicenter clinical trial for childhood nephrotic syndrome in Japan. The results suggested that mizoribine significantly decreased the relapse rate and prolonged the remission period in the subgroup consisting of patients aged 10 years or younger ([22], PMID: 10886577).
In 2003, a large multicenter clinical trial study group consisting of approximately 150 institutes in Japan, called the Japanese Study Group of Kidney Disease in Children (JSKDC) , was established (President: Norishige Yoshikawa 2003–2013, Kazumoto Iijima 2014–). This study group is supported by a grant from the Ministry of Health, Labour and Welfare of Japan and has conducted several ICH-GCP-based clinical trials for chronic kidney diseases, especially for nephrotic syndrome in children.
An open-label, multicenter, randomized phase II trial was conducted to identify the better of two protocols for treating children with FRNS using microemulsified cyclosporine (JSKDC03). This trial showed that the C2 monitoring higher target regimen in which the target C2 level was 600–700 ng/mL for the first 6 months and 450–550 ng/mL for the next 18 months was better than the lower target regimen in which the target C2 level was 450–550 ng/mL for the first 6 months and 300–400 ng/mL for the next 18 months ([23], PMID: 24262503).
The JSKDC conducted a multicenter, randomized, non-inferiority, open-label trial in which prednisolone treatment for 2 months (International Study of Kidney Disease in Children: ISKDC regimen) was compared with treatment for 6 months in children with a first episode of idiopathic nephrotic syndrome (JSKDC04). The results suggested that 2 months of initial prednisolone therapy were not inferior to 6 months of initial therapy with an increasing cumulative dose [24].
In 2008, nine core centers of JSKDC organized a study group called the rituximab for Childhood-Onset Refractory Nephrotic Syndrome (RCRNS) Study Group . The RCRNS Study Group conducted the first multicenter, double-blind, randomized, placebo-controlled trial of rituximab therapy for childhood-onset complicated FRNS/steroid-dependent nephrotic syndrome (SDNS) with a 1-year observation period to evaluate its efficacy and safety in patients with childhood-onset complicated FRNS/SDNS. This trial was an investigator-initiated clinical trial that sought to gain approval from the Japanese government to make rituximab available for patients with childhood-onset complicated FRNS/SDNS and proved that rituximab is effective and safe, at least for 1 year, for the treatment of childhood-onset complicated FRNS/SDNS ([25], PMID: 24965823).
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Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, Miura K, Aya K, Nakanishi K, Ohtomo Y, Takahashi S, Tanaka R, Kaito H, Nakamura H, Ishikura K, Ito S, Ohashi Y, On behalf of Rituximab for Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study Group. Rituximab for the treatment of childhood-onset complicated frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2014;384:1273-81. doi:10.1016/S0140-6736(14)60541-9. Epub 2014 Jun 22. PMID: 24965823.