This study demonstrated several important findings as follows: (1) there was no significant difference in the complete remission rate of proteinuria and hematuria at 12 months after the initiation of SP therapy between the ISP and CSP group, (2) the remission of proteinuria occurred faster in the CSP group than in the ISP group, and (3) there were no severe side effects in the ISP and CSP groups.
It is well known that SP therapy is one of the useful therapies for IgAN. The mechanisms of the efficacy are considered to be due to the suppression of systemic cytokine production and IgA production in plasma cells and the local suppression of inflammatory cell infiltration into mesangial and tubulointerstitial areas. In addition, several meta-analyses demonstrated that SP therapy could halt the progression of kidney dysfunction . However, we should be concerned about the use of steroids because there are various side effects, especially when the high-dose or long-term administration of steroids is performed [9, 10, 21]. Although intensive high-dose steroid administration for the purpose of early remission is CSP, while intermittent high-dose steroid administration for the purpose of lessen adverse effects is ISP, it is difficult to decide which protocol is preferable for patients with IgAN. Currently, there are no randomized controlled trials and only one observational study that directly compared the efficacy of SP therapy between these two protocols . Therefore, we retrospectively compared the therapeutic and adverse effects on those with IgAN between these two SP protocols. Our study showed that there was no difference in proteinuria and hematuria remission rates between the ISP and CSP groups at 12 months. The previous study reported that the remission rates for proteinuria and hematuria were significantly higher in the CSP group than in the ISP group . Although our results are inconsistent with theirs, their study differed from ours in several points. The study mentioned that the treatment period was shorter and the total dose of steroids was lesser in the ISP group than in the CSP group. On the other hand, in our study, there was no statistically significant difference in the treatment duration and the total dose of steroids between the two groups. Furthermore, the use of renin–angiotensin–aldosterone system inhibitors did not also significantly differ between the two groups at 12 months.
Although the KDIGO guideline does not recommend tonsillectomy for Caucasian patients with IgAN, the reports from the Asian region demonstrated that the combination of SP therapy and tonsillectomy reduced proteinuria compared to SP monotherapy [7, 15]. In our study, the CSP group included a significantly higher number of patients that underwent tonsillectomy compared to the ISP group. Therefore, we adjusted the differences in clinical characteristics, including tonsillectomy, using propensity score matching. Subsequently, the remission rates of proteinuria and hematuria did not significantly differ between the two groups even after the statistical adjustments. In addition, stratified analysis by histological grade revealed that the effects of SP therapy on IgAN were similar between the two groups. Taking these results into account, we speculated that the effects of SP therapy on IgAN at 12 months were comparable between the CSP and ISP groups regardless of whether or not the patients in the groups had undergone tonsillectomy.
The histological grade is one of the crucial factors influencing the clinical course of IgAN [17,18,19]. In the previous study, approximately 60% of all the study participants were classified as histological grade 1, and most of the study patients had conserved kidney function. Therefore, the previous study seemed to include mainly patients with mild IgAN. There is a possibility that these differences could contribute to the discrepancy in the results between the previous study and our study. On the other hand, we evaluated the histological grade according to the JSN and Oxford classification. Upon comparing the histological grade based on these two classifications, both results were similar.
Interestingly, our study showed that the remission rate of proteinuria at 2 months was significantly higher in the CSP group than in the ISP group, suggesting that CSP could lead to early remission of proteinuria. To date, no study has been reported on the comparison of the clinical course between the two SP protocols. However, there are several studies on the number of sessions of SP therapy, and three session of SP therapy were reported to have a higher remission rate of urinary findings than did one or two sessions of SP therapy . Considering the nature of SP therapy, as the dose of steroids administered in the first month is high in the CSP group, earlier remission of proteinuria would be obtained in this group than in the ISP group. It has been reported that the earlier remission of proteinuria led to the kidney prognosis [13, 22] and this seems to be a crucial point. To achieve the early suppression of inflammation, it could be better to choose CSP, especially for the clinically severe cases of IgAN. As our study did not include the severe cases of RPGN or NS, to resolve this issue, it is necessary to conduct a future study that includes such patients.
When choosing SP therapy, the adverse effects and length of hospitalization should be considered. Since the adverse effects of steroid therapy have been shown in several previous reports, they have been recognized as profound issues [15, 23]. As expected, these previous studies have reported that SP therapy led to the amelioration of urinary findings and slowing down the progression of kidney dysfunction; however, it also significantly increased the risk for adverse events [10, 21]. As for the assessment of the side effects, we also examined the infections, impaired glucose tolerance, and the change in BMD. However, no serious adverse effects were observed in both groups. No infections occurred during our study, as they were considered as a critical issue in the STOP-IgAN and TESTING trials [10, 21]. It was speculated that this discrepancy could result from the differences in clinical characteristics, race, doses and route of administration steroids, and the medical systems. In fact, many previous studies showed that SP therapy had only a few serious side effects, suggesting that it may be safe as long as it is performed under optimal medical management [22, 24,25,26,27,28]. In addition, the length of hospitalization which influences medical expenses would become inevitably long when choosing CSP. Our results showed that there was no significant difference in the therapeutic effects between the ISP and CSP groups. Considering these findings, it would be preferable to choose the ISP therapy (except for severe cases).
This study had several limitations. First, to adjust for differences in clinical characteristics, we performed propensity score matching analysis. However, the number of study patients was relatively small, and thereby, there was a possibility that we could not perform statistically sufficient adjustments. Second, the observation period was considered to be relatively short to assess the course of kidney function and kidney prognosis after SP therapy. In addition, mid-term evaluation was also not performed. A mid-term and long-term study are needed to resolve this issue in the future. Third, as mentioned above, our study did not include patients in clinically severe conditions such as those with RPGN or NS. To demonstrate the differences in therapeutic effect between ISP and CSP in such patients, a well-designed study including clinically severe patients should be carried out in the future.