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Published ahead of print on April 5, 2006
Clin J Am Soc Nephrol 1: 511-517, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.01120905
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Epidemiology and Outcomes

Steroid Treatment for Severe Childhood IgA Nephropathy: A Randomized, Controlled Trial

Norishige Yoshikawa*, Masataka Honda{dagger}, Kazumoto Iijima{ddagger}, Midori Awazu§, Shinzaburou Hattori||, Koichi Nakanishi*, Hiroshi Ito§; for the Japanese Pediatric IgA Nephropathy Treatment Study Group

* Department of Pediatrics, Wakayama Medical University, Wakayama; {dagger} Tokyo Metropolitan Hachiouji Children’s Hospital, Tokyo; {ddagger} Department of Nephrology, National Center for Child Health and Development, Tokyo; § Department of Pediatrics, Keio University School of Medicine, Keio; and || Kumamoto University School of Medicine, Kumamoto, Japan

Address correspondence to: Prof. Norishige Yoshikawa, Department of Pediatrics, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. Phone: +81-73-441-0632; Fax: +81-73-444-9055; E-mail: nori{at}wakayama-med.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
A previous trial showed that treatment of children with severe IgA nephropathy (IgAN) using prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduced the severity of immunologic renal injury and prevented any increase in the percentage of sclerosed glomeruli. This study compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (combination) with those of prednisolone alone in 80 children with newly diagnosed IgAN that showed diffuse mesangial proliferation. Patients were randomly assigned to receive either the combination or prednisolone alone for 2 yr. The primary end point was the disappearance of proteinuria, defined as urinary protein excretion <0.1 g/m2 per d, and the secondary end points were urinary protein excretion at the end of treatment, the change in the percentage of sclerosed glomeruli during the trial, and adverse effects. The two study groups were similar in terms of baseline characteristics. Thirty-nine of the 40 patients who received the combination and 39 of the 40 who received prednisolone completed the trial. Thirty-six (92.3%) of the 39 patients who received the combination and 29 (74.4%) of the 39 who received prednisolone reached the primary end point by the 2-yr follow-up point (P = 0.007 log-rank). The percentage of sclerosed glomeruli was unchanged in the patients who received the combination but increased from 3.1 ± 4.8 to 14.6 ± 15.2% in the prednisolone group (P = 0.0003). The frequency of adverse effects was similar in the two groups. It is concluded that combination treatment may be better for severe IgAN than treatment with prednisolone alone.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
IgA nephropathy (IgAN) is the most common variety of primary glomerulonephritis in the world today. It was initially considered a benign disease with a favorable prognosis, but then data from long-term follow-up studies revealed that the disease progressed to renal failure in 20 to 50% of adult patients (1,2). Although there has been a prevailing belief that the prognosis of IgAN is more benign in children, recent studies do not support this (3). Children who have IgAN and in whom diffuse mesangial proliferation is evident on renal biopsy have a high risk for progressive renal deterioration (4). On the basis of a multicenter, randomized trial, we reported previously that treatment of childhood IgAN with diffuse mesangial proliferation using prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduced the severity of immunologic renal injury and prevented any increase in the percentage of sclerosed glomeruli (5). Corticosteroids uncombined with other drugs have been widely used to treat IgAN in pediatric patients (6–8). However, it has not been clear whether similar effects can be obtained using prednisolone alone in children with severe IgAN.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
The study was a prospective, unblinded, randomized, controlled clinical trial that involved 20 Japanese pediatric renal centers (The Japanese Pediatric IgA Nephropathy Treatment Study Group). The study protocol was in accordance with the standards of the ethics committee at each center, and all patients’ parents gave informed consent to participate.

Patients
Patients were eligible for the study when they had a new diagnosis of having IgAN with diffuse mesangial proliferation by renal biopsy and when the following criteria were satisfied: (1) Age ≤15 yr at study entry, (2) no previous treatment with corticosteroids or immunosuppressive drugs, and (3) sufficient renal biopsy tissue available for histologic evaluation (minimum of 10 glomeruli).

The pathologist at each study center examined each renal biopsy specimen by light and immunofluorescence microscopy. The histologic sections were reviewed by two independent investigators who were unaware of the patients’ clinical data at entry into the study. A diagnosis of IgAN was based on the presence of IgA as the sole or predominant Ig in the glomerular mesangium without systemic disease (9). Diffuse mesangial proliferation was defined on the basis of the World Health Organization criteria (>80% of glomeruli showing moderate or severe mesangial cell proliferation, i.e., more than three cells per peripheral mesangial area) (10). Mesangial cell proliferation always was accompanied by increased mesangial matrix. The intensity of mesangial IgA deposits was graded semiquantitatively on a scale of 0 to 3+: 0, none; 1+, slight; 2+, moderate; and 3+, intense.

Study Design
After study eligibility was established and informed consent was obtained, patients were assigned randomly to one of the two treatment groups. Randomization was done by a sealed-envelope technique in blocks of four. The patients who were assigned to group 1 received prednisolone, azathioprine, warfarin, and dipyridamole treatment for 24 mo. Prednisolone was given orally at a dose of 2 mg/kg body wt per day (maximum 80 mg/d) every day in three divided doses for 4 wk, followed by 2 mg/kg every 2 d given as a single dose in the morning for 4 wk, 1.5 mg/kg every 2 d given as a single dose in the morning for 4 wk, and 1 mg/kg every 2 d given as a single dose in the morning for 21 mo. Azathioprine was given orally at a dose of 2 mg/kg body wt per day in a single morning dose for 24 mo. When a patient’s leukocyte count decreased to <4 x 109/L, azathioprine was discontinued until the leukocyte count increased to >4 x 109/L. Warfarin was given in a single morning dose to maintain the Thrombotest at 30 to 50% for 24 mo. Dipyridamole was given orally at a dose of 5 mg/kg body wt per day in three divided doses for a total dose of not more than 400 mg/d for 24 mo. The patients who were assigned to group 2 received prednisolone alone under the same treatment protocol as that for group 1. The use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers was prohibited.

On entry into the study, all patients underwent a physical examination, and their complete medical histories were obtained. Initial clinical and laboratory results were forwarded to the coordinating center. Patients were followed up once a month during the study. At each follow-up visit, the patients were asked about their symptoms and were monitored for any adverse effects of therapy. Tests and measurements that were carried out at each visit comprised blood count (including hemoglobin, white blood cells, and platelets), Thrombotest, serum creatinine, blood urea nitrogen, serum IgA concentration, urinary protein excretion, hemostix test, BP, body weight, and body height. Hypertension was defined as present when the systolic or diastolic BP exceeded the upper normal limit for Japanese healthy children (mean + 2 SD).

At the time of study enrollment, all patients were asked to undergo repeat renal biopsies at the end of treatment. Two independent investigators who were blinded to the treatment status reviewed the second biopsies. No arrangement was made about treatment after the end of the 24-mo study period, and this was left to the judgment of each physician.

Statistical Analyses
On the basis of the data of our previous randomized, controlled study (5), we decided that the primary end point was the disappearance of proteinuria, as defined by urinary protein excretion <0.1 g/m2 per d (11), and the secondary end points were urinary protein excretion at the end of treatment, change in the percentage of sclerosed glomeruli during the trial, and adverse effects. We predicted that the disappearance rate of proteinuria would be 65% in the combination group and 50% in the prednisolone alone group. Thirty-six patients were required for each study group, based on a selection design (12) in which the probability of correctly selecting the better treatment is 0.9 when it is superior by an absolute difference of 15% in the disappearance rate of proteinuria.

The results were analyzed with StatView J-4.02 software. The distribution of clinical and morphologic attributes between the treatment groups was examined by Fisher exact test. Continuous characteristics at the start of treatment were compared using the Mann-Whitney U test. Differences between study entry and study end in each treatment group were tested by the Wilcoxon signed rank test. The disappearance rate of proteinuria was analyzed by the Kaplan-Meier method, and the two groups were compared by intention-to-treat analysis by log-rank test. A two-tailed P < 0.05 was taken as the level of significance.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Between January 1994 and December 1998, 83 children received a new diagnosis of having IgAN that showed diffuse mesangial proliferation. All 83 children met the criteria for inclusion in the trial. Eighty of the 83 patients were willing to enter the study (Figure 1). Of these, 40 were assigned to group 1 (prednisolone, azathioprine, warfarin, and dipyridamole) and 40 were assigned to group 2 (prednisolone alone). The clinical and laboratory characteristics of the patients in the two groups were similar (Table 1). Twenty-three (57.5%) patients in group 1 and 27 (67.5%) in group 2 presented with asymptomatic proteinuria and microscopic hematuria detected by a school screening program.


Figure 1
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  		Figure 1. Trial profile.

 

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  		Table 1. Baseline characteristics

 
One patient in group 1 was lost to follow-up in the first month as a result of withdrawal of consent. Prednisolone was discontinued in four patients in group 2 as a result of adverse effects (three patients, in the 13th, 14th, and 21st months) and noncompliance (one patient in the 13th month). One of the three patients was lost to follow-up in the 22nd month. Three patients in group 1 did not complete the azathioprine therapy because of adverse effects (in the first, second, and 11th months) but completed the planned prednisolone, warfarin, and dipyridamole therapy. Thirty-nine patients each in groups 1 and 2 completed the 2 yr of treatment (Figure 1). All 40 patients in both groups were included in the Kaplan-Meier analysis of treatment effect (Figure 2).


Figure 2
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  		Figure 2. Disappearance of proteinuria as defined by urinary protein excretion <0.1 g/m2 per d.

 
Changes in Proteinuria, Hematuria, Renal Function, and Serum IgA Concentrations
At the end of the 2-yr treatment period, 36 (92.3%) of the 39 patients in group 1 and 29 (74.4%) of the 39 patients in group 2 reached the primary end point (urinary protein excretion <0.1 g/m2 per d). Kaplan-Meier analysis demonstrated that the disappearance rate of proteinuria was significantly higher in group 1 than in group 2 at the 2-yr follow-up point (log-rank P = 0.007; Figure 2). The difference in the disappearance rate of proteinuria between the two groups at the end of the 2-yr treatment period was 17.9% (95% confidence interval 1.8 to 34.0%).

Mean urinary protein excretion in group 1 was reduced from 1.29 g/m2 per d at the start of treatment to 0.10 g/m2 per d at the end (P < 0.0001), and that in group 2 was also reduced from 1.16 to 0.12 g/m2 per d (P < 0.0001; Table 2). The intergroup difference in the reduction of mean urinary protein excretion at the end of treatment was NS. The presence of blood in morning urine, quantified using dipsticks, a colorimetric test for hemoglobin (13), showed significant reduction in both groups (Table 2). The mean serum IgA concentration in group 1 decreased from 276 ± 118 mg/dl at the start of treatment to 194 ± 85 mg/dl at the end (P = 0.0001), and that in group 2 also decreased from 245 ± 109 to 194 ± 90 mg/dl (P = 0.0003). BP and creatinine clearance were normal at the end of the trial in all patients. The mean body mass indexes in both groups increased significantly even though they were within normal range during the study period (Table 2).


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  		Table 2. Effect of 2 yr of treatment

 
Changes in Pathologic Features
Thirty-two patients in group 1 and 30 in group 2 underwent repeat renal biopsies at the end of treatment (Table 2). The mean percentage of glomeruli that showed segmental or global sclerosis was unchanged in group 1 but increased from 3.1 ± 4.8% at the start of treatment to 14.6 ± 15.2% at the end of treatment in group 2 (P = 0.0003). The percentage of glomeruli that showed crescents was significantly reduced in both groups (P < 0.0001, respectively). The percentage of glomeruli that showed capsular adhesions was unchanged in both groups.

Immunofluorescence was not available for the repeat biopsy at the end of treatment for one patient each in groups 1 and 2. The initial renal biopsy revealed intense or moderate mesangial deposits of IgA in all patients. Mesangial IgA deposits became significantly less intense at the end of treatment in both groups (P = 0.006 and 0.03, respectively).

Adverse Effects
The adverse effects in both treatment groups are shown in Table 3. Ten patients in each group showed adverse effects, and the total number of cases of adverse effects that were observed in each group was 14. One patient in each group showed aseptic necrosis of the femoral head (as a result of prednisolone). Other adverse effects that affected group 1 patients were glaucoma (as a result of prednisolone; two patients), headache (as a result of dipyridamole; three patients), leukopenia (as a result of azathioprine; four patients), bleeding (one patient), anemia (as a result of azathioprine; one patient), and elevation of transaminase concentration (two patients). Other adverse effects as a result of prednisolone that affected group 2 patients were hypertension (five patients), glucosuria (three patients), glaucoma (two patient), cataract (two patients), and elevation of transaminase concentration (one patient). Hypertension was improved only by restricted sodium diet and tapering of prednisolone based on the study design without antihypertensive drugs. All of these adverse effects except for aseptic necrosis of the femoral head and cataract subsided after the treatment.


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  		Table 3. Adverse effects

 
Azathioprine was discontinued until the adverse effects subsided in two patients with leukopenia and one patient with elevation of transaminase concentration in group 1. However, these three patients completed the planned prednisolone, warfarin, and dipyridamole therapy. Prednisolone was discontinued in one patient with glucosuria and hypertension, one patient with glaucoma and hypertension, and one patient with glaucoma in group 2 by doctors in charge.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Like our previous randomized, controlled trial (5), this study showed that the combination therapy for 2 yr significantly reduced the level of urinary protein excretion, serum IgA concentration, and mesangial IgA deposition and prevented any increase of sclerosed glomeruli in children with newly diagnosed IgAN that showed diffuse mesangial proliferation. In contrast, treatment with prednisolone alone for 2 yr did not prevent a further increase of sclerosed glomeruli, although it reduced the level of urinary protein excretion, serum IgA concentration, and mesangial IgA deposition. Disappearance of proteinuria (primary end point) was observed in 36 (92.3%) of the 39 patients in the combination therapy group and in 29 (74.4%) of the 39 patients in the prednisolone alone group. Kaplan-Meier analysis demonstrated that the disappearance rate of proteinuria was significantly higher in group 1 than in group 2 at the 2-yr follow-up point (log-rank P = 0.007; Figure 2). The difference in the disappearance rate of proteinuria between the groups at the end of the 2-yr treatment period was 17.9% (95% confidence interval 1.8 to 34.0%). On the basis of the selection design (11), we therefore were able to select the combination treatment as the better of the two. This selection also was supported by the intergroup difference in the change in the percentage of sclerosed glomeruli during the trial. These findings suggest that combination treatment may be better for IgAN that shows diffuse mesangial proliferation than prednisolone monotherapy. Most of the patients who reached the primary end point did so within the first 12 mo (Figure 2). Therefore, we may be able to modify the duration and/or dose for prednisolone treatment to reduce adverse effects.

The most appropriate treatment for patients with IgAN is controversial. The present standard treatment is focused on two perspectives: Anti-inflammatory drugs to fight the systemic immune reaction and renal histologic activity, including corticosteroids and immunosuppressors, and antisclerogenic drugs to inhibit progressive renal fibrosis (14). The rationale for using prednisolone and azathioprine in IgAN is that corticosteroids and immunosuppressive agents reduce IgA production and minimize the abnormal immune response and inflammatory events after glomerular IgA deposition. Warfarin and dipyridamole are used to inhibit the mediators of glomerular damage. Corticosteroids, immunosuppressive agents, antiplatelet drugs, and anticoagulants have been used singly or in combination in children and adults with IgAN (7,15–19). However, clinical trials that were conducted in the early period have not provided convincing evidence of any beneficial effect of drugs (20,21).

Corticosteroids have been widely used to treat moderate to severe IgAN, particularly in pediatric patients. To date, information concerning not only the effectiveness but also the safety of corticosteroid therapy over a long time course has been largely defective. It has been difficult to assess the results of treatment trials with these agents in terms of preservation of renal function, as a result in part of wide variations in the length of therapy and the dosing regimens used and also to the use of corticosteroids in combination with other drugs (22). Recently, however, some evidence has been obtained for the role of corticosteroids in the treatment of IgAN (2,22). In adults with IgAN, an Italian prospective, randomized, controlled trial demonstrated that a 6-mo course of steroid treatment protected against deterioration of renal function with no notable adverse effects during follow-up (23). Recently, the long-term follow-up data of the trial showed that corticosteroids significantly reduced proteinuria and protected against renal function deterioration (24). With regard to children, our previous study (5) is the only randomized, controlled trial so far to have demonstrated that treatment that includes corticosteroid for 2 yr early in the course of disease reduces immunologic renal injury and prevents any further increase of glomerular sclerosis. Up to now, however, it has been unknown whether corticosteroid alone is sufficient for treatment of IgAN in children, and there has been no reliable evidence for its effectiveness in this group of patients (22).

The difference in the effectiveness between the two treatment regimens in our study was thought to be due to the total effect of azathioprine, warfarin, and dipyridamole. Although the exact mechanism by which this regimen prevents glomerular sclerosis remains unknown, immunosuppressive agents may play a major role. To investigate this issue, a controlled trial is currently in progress to compare the effects of prednisolone, immunosuppressive agents, warfarin, and dipyridamole with those of prednisolone and immunosuppressive agents in children with severe IgAN.

The beneficial effects of prednisolone, azathioprine, warfarin, and dipyridamole treatment were accompanied by relatively few serious adverse effects that were attributable specifically to the drugs, except for aseptic necrosis of the femoral head. Three patients did not complete the treatment because of adverse effects of azathioprine. However, these adverse effects subsided after withdrawal of azathioprine, and three of the patients completed the planned prednisolone, warfarin, and dipyridamole therapy. Aseptic necrosis of the femoral head was observed in one patient in each of the groups. This is a severe adverse effect with sequelae. To reduce its frequency and severity, we may be able to modify the corticosteroid regimen. Five of the 40 patients in group 2 (prednisolone alone) showed hypertension, but none of the 40 patients in group 1 (combination) did so. Dipyridamole therapy therefore may prevent the development of hypertension in children who receive prednisolone.

Our serial pathologic observations (25,26) have revealed that the extent of glomerulosclerosis increases with time in patients who show persistent proteinuria. In this study, treatment was started early in the course of disease because the duration of the disease before treatment was short and the extent of glomerulosclerosis was low as a result of the school screening program. Accumulated experience indicates that long-term corticosteroid and/or immunosuppressive treatment during the insidiously progressive stage of the disease does not confer any benefit in adult patients (27). Because of the variable rate of progression to renal failure and the probable multifactorial pathogenesis of IgAN, the effectiveness of any treatment can be evaluated properly only by a controlled trial.

In a controlled trial, it is important to select adequate end points. Although in a clinical trial of progressive IgAN the ultimate end point is development of chronic renal insufficiency, most pediatric patients do not develop it during the 2-yr study period (22). Our previous trial (5) and experience also support this. Therefore, studies of pediatric patients with IgAN may differ markedly from studies of adults with regard to the apparent risk for progressive disease and, hence, the need for therapy (22). For this reason, we decided that the primary end point of this study was the disappearance of proteinuria.

Although the 2-yr study period may be too short to confirm the long-term benefit of the prednisolone, azathioprine, warfarin, and dipyridamole regimen, the results obtained so far suggest that the combination therapy may slow the rate of progression to chronic renal failure, because it prevents the progression of glomerular sclerosis. After 2 yr of treatment, all of the patients are still being followed to examine the long-term effects of the combination treatment on the rate of progression to chronic renal failure.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Treatment of children with severe IgAN using prednisolone alone for 2 yr reduces the severity of immunologic renal injury but does not prevent any further increase of glomerular sclerosis. Therefore, treatment with prednisolone, azathioprine, warfarin, and dipyridamole for 2 yr early in the course of disease may be better than prednisolone alone for this group of patients.


   Acknowledgments
 
This study was supported in part by Health and Labor Sciences Research Grants (Research on Children and Families) by Japanese Ministry of Health Labor and Welfare.

The Japanese Pediatric IgA Nephropathy Treatment Study Group: Coordinating Committee: H. Ito (Tokyo), N. Yoshikawa (Wakayama); Statistics Committee: T. Kawamura (Nagoya); investigators: Y. Takekoshi (Sapporo); Y. Kondo (Sendai); K. Tamura (Mito); M. Honda, M. Ikeda, K. Iijima, M. Awazu (Tokyo); K. Yamaoka, K. Nakagawa (Osaka); S. Hattori, H. Nakazato, A. Furuse (Kumamoto); M. Ninomiya (Kagoshima).

We are grateful to Prof. Yasuo Ohashi and Dr. Nahoko Yata (Epidemiology and Preventive Health Science, Graduate School of Medicine, University of Tokyo) for helpful advice on the decision of sample size.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received September 26, 2005. Accepted February 13, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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