Introduction 1 2 3 4 4 5 6 4 In the study reported here, we investigated data from 500 children with IgA-N to determine whether the long-term outcome has improved in Japanese children with IgA-N. Methods Patients The medical history of children under the age of 20 years who underwent routine renal biopsies at Kobe University and Wakayama Medical University hospitals between January 1976 and December 2004 were analyzed retrospectively. Clinical data and follow-up information were obtained from the medical records, and if needed, further complementary information was obtained by telephone contact with the patients, family members and or physicians. 7 8 Renal survival was defined as the period from the time of apparent disease onset to end-stage renal disease (ESRD) requiring renal replacement therapy. Given the change of policy for treating IgA-N patients in the early 1990s, we divided the study period when the initial renal biopsy had been performed into two time periods: 1976–1989 (early period) and 1990–2004 (late period). Treatment 5 6 1 Table 1 Treatment in three randomized controlled trials for childhood IgA nephropathy with diffuse mesangial proliferation Period 1990–1993 (first RCT) 1994–1998 (second RCT) 2001–present (third RCT) Group 1 Prednisolone Prednisolone (as in group 1 in the first period) Prednisolone   2 mg/kg/day, 4 weeks   2 mg/kg/day, 4 weeks   2 mg/kg/2 days, 4 weeks   2 mg/kg/2 days, 4 weeks   1.5 mg/kg/2 days, 4 weeks   1.5 mg/kg/2 days, 4 weeks   1 mg/kg/2 days, 21 months   1 mg/kg/2 days, 9 months     0.5 mg/kg/2 days, 12 months Azathioprine Azathioprine (as in group 1 in the first period) No azathioprine   2 mg/kg/day, 24 months Dipyridamole Dipyridamole (as in group 1 in the first period) Dipyridamole   5 mg/kg/day, 24 months   6–7 mg/kg/day, 24 months Heparin No heparin    APTT 60 s, 28 days  Warfarin Warfarin Warfarin   TT 30–50%, 23 months   TT 30–50%, 24 months   TT 20–50%, 24 months   Mizoribine     4 mg/kg/day, 24 months Group 2 Heparin-Warfarin   Dipyridamole (as in group 1)    Prednisolone (as in group 1) Prednisolone (as in group 1)   Mizoribine (as in group 1) TT, Thrombotest; APTT, activated partial thromboplastin time; RCT, randomized controlled trial For the treatment of children with mild IgA-N showing focal mesangial proliferation we started a RCT by the JPIGANTS in 1990. During this trial (1990–1993) about half of the children with mild IgA-N in our hospitals received Sairei-to, a Chinese herb, for 24 months, and the other half received no medication. We began to use ACEIs for treatment of mild IgA-N with focal mesangial proliferation as the first choice from the beginning of 2000. Statistical analyses U 9 10 11 p Results Patients Between 1976 and 2004, 1759 children underwent a first renal biopsy examination at the Kobe University and Wakayama Medical University hospitals. Among these, 500 Japanese children (28.4%; 279 boys and 221 girls) were diagnosed as having IgA-N: 219 in 1976–1989 and 281 in 1990–2004. There was no evident change in the number of patients per year between the early (1976–1989) and late (1990–2004) periods. The median patient age at diagnosis was 10.9 years (range 2.5–19.6 years), and the median follow-up period for the patients overall was 5.9 years (range 1.3–20.5 years). 2 2 Table 2 Baseline characteristics Characteristic Number of patients (%) p n n n Sex (M/F) 279/221 132/87 147/134 0.08 Age at diagnosis, year, median [range] 10.9 [2.5–19.6] 10.1 [3.4–16.8] 11.6 [2.5–19.6] < 0.001 Initial presentation Asymptomatic proteinuria and hematuria 384 (76.8%) 150 (68.5%) 234 (83.3%) < 0.001 Macroscopic hematuria 93 (18.6%) 60 (27.4%) 33 (11.7%) < 0.001 Edema 23 (4.6%) 9 (4.1%) 14 (5.0%) 0.67 2   <1 361 (72.2%) 146 (66.7%) 215 (76.5%) 0.008   ≥1 139 (27.8%) 73 (33.3%) 66 (23 .5%)  2   <60 13 (2.6%) 3 (1.4%) 10 (3.6%) 0.16   ≥60 487 (97.4%) 216 (98.6%) 271 (96.4%)  Renal biopsy at diagnosis    Diffuse mesangial proliferation 171 (34.2%) 63 (28.8%) 108 (38.4%) 0.03    Focal mesangial proliferation 329 (65.8%) 156 (71.2%) 173 (61.6%)  Treatment 3 Table 3 Change of initial treatment for IgA nephropathy in Japanese children Treatment Focal mesangial proliferation Diffuse mesangial proliferation n n n n No treatment 96 (61.6%) 23 (13.2%) 19 (30.2%) 1 (0.9%) Antiplatelet and/or anticoagulant 35 (22.4%) 2 (1.2%) 14 (22.2%) 7 (6.5%) Prednisolone, (± antiplatelet and/or anticoagulant) 4 (2.6%) 6 (3.5%) 7 (11.1%) 25 (23.1%) Prednisolone + immunosuppressant, (± antiplatelet and/or anticoagulant) 7 (4.5%) 8 (4.6%) 19 (30.2%) 74 (68.5%) Chinese herb (Sairei-to) 14 (9.0%) 46 (26.5%) 4 (6.3%) 0 (0.0%) ACEI and/or ARB 0 (0.0%) 88 (50.9%) 0 (0.0%) 1 (0.9%) ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker Renal survival 4 1 4 p 1 4 Table 4 Actuarial renal survival analysis of 500 children with IgA nephropathy   Initial renal biopsy year Number of patients 10-year renal survival 15-year renal survival 20-year renal survival p a Total 1976–2004 500 96.4% 84.5% 73.9%  Total 1976–1989 219 94.0% 80.1% 70.1% 0.008 1990–2004 281 98.8% 98.8% – Diffuse mesangial proliferation 1976–1989 63 78.5% b – 0.0003 1990–2004 108 97.8% b – Focal mesangial proliferation 1976–1989 156 100.0% 97.7% – 0.5 1990–2004 173 100.0% 100.0% – a p b Fig. 1 95% CI  2 3 p 2 4 p 3 4 Fig. 2 Kaplan-Meier plot of renal survival stratified by the initial biopsy year for children with severe IgA nephropathy showing diffuse mesangial proliferation  Fig. 3 Kaplan-Meier plot of renal survival stratified by the initial biopsy year for children with mild IgA nephropathy showing focal mesangial proliferation  5 2 2 5 Table 5 Univariate and multivariate analysis of the prognostic value of factors for end-stage renal disease-free survival Factor Univariate Multivariate HR 95% CI p HR 95% CI p Mesangial proliferation focal; diffuse 10.92 2.80–72.46 <0.001 10.27 2.42–70.75 0.001 2 5.27 1.65–19.77 0.01 2.14 0.57–8.78 0.26 2 14.12 2.11–57.41 0.01 5.58 0.74–30.22 0.09 Initial renal biopsy year 1976–1989; 1990–2004 0.14 0.01–0.74 0.02 0.08 0.004–0.43 0.002 CI, Confidence interval; HR, hazard ratio; CCl, creatinine clearance Discussion Although this was a retrospective study, the data seem to provide unique and valuable information about IgA-N in children for several reasons. First, the study subjects were a complete non-selected cohort of patients with IgA-N from among all children who underwent first renal biopsy examinations at Kobe University and Wakayama Medical University hospitals between 1976 and 2004. Five hundred children with IgA-N participated in our study, which to our knowledge is the largest series used to investigate the outcome of IgA-N in children to date. Furthermore, these patients were diagnosed histologically by a single investigator (N.Y.) based on the same criteria during the whole study period. Renal biopsy criteria were also unchanged during the whole study period. Therefore, the cohort in the present study is considered to have been rigidly homogeneous in terms of the analysis of the disease outcome. 12 2 13 5 5 6 14 4 9 11 15 p 5 6 3 2 13 14 16 18 5 6 5 6 4 1 2 1 2 The median follow-up period of the patients overall was 5.9 years (range 1.3–20.5 years). Although this is a considerably long period, it may not be sufficiently long for the follow-up of IgA-N, which has a slow progressive course. Since the elapsed time from apparent disease onset to ESRD was used to evaluate the disease outcome, chronic renal insufficiency before ESRD was not considered in our study. Thus, we do not know whether the observed improvement of outcome means a complete cure of the disease or merely a delay of the disease course. Further follow-up of the cohort for a long period is therefore important. One aspect which we should consider in our study is the possibility that at least some of the differences in outcome between the early and late groups may be due to general changes in care that have occurred over time. Such changes are frequently not recognized, such as a gradually greater awareness of managing marginally raised blood pressure, among others. In conclusion, this study has demonstrated a substantial improvement of long-term renal survival in Japanese children with IgA-N. On the basis of the results of this study we were unable to provide the reason for this improved outcome directly; however, it is likely that adequate management using a strict policy of treatment may have been responsible.