Nationwide survey on current treatments for IgA nephropathy in Japan

A wide variety of treatments for IgAN exist in Japan because various stages of disease can be observed and managed. The current treatment situation has been unclear until now because no nationwide study has been conducted regarding IgAN treatment. The present study assessed the precise situation of treatment for IgAN in Japan.

TSP was first reported by Hotta et al. [11] in 2001. Many clinical studies on TSP have been reported from Japan since 2001 [12‐14]. Miura et al. conducted a multicenter retrospective cohort study, and reported that TSP was effective for patients with early-stage IgAN if performed within 5 years of onset and for those who have daily proteinuria <1.1 g and serum creatinine <1.5 mg/dl [15]. However, the details of TSP (protocols, indication, clinical remission rate, etc.) varied in each report, and the current TSP situation was thus unclear. Our results show that almost 70 % of internal medicine hospitals performed TSP. Almost 40 % of hospitals always added combined steroid pulse therapy with tonsillectomy. Moreover, almost 60 % hospitals began TSP in the period between 2004 and 2008 (Fig. 1), indicating that TSP spread through Japan quickly and has become the major therapeutic approach for IgAN in the last decade. We also observed that the clinical remission rates for both hematuria and proteinuria following TSP tended to be higher than those resulting from steroid pulse without tonsillectomy or oral corticosteroid monotherapy (Figs. 2, 3). This may be one of the main reasons for the quick spread of this therapy in Japan. In previous reports, TSP protocols have varied. In particular, the number of steroid pulses given during TSP varied in each report [11‐13]. Our results showed that there are two major protocols for TSP in Japan. One is a protocol in which the steroid pulses are administrated three times, with a steroid pulse every week, on the basis of the original report by Hotta et al. [11]. Another is in which steroid pulses are administrated three times every 2 months, based on previous report by Pozzi et al. [10]. We did not find a clear difference in clinical efficacy between two methods.

The Japanese Pediatric IgA Nephropathy Treatment Study Group advocated combination therapy for childhood IgAN in their 2008 guideline [16]. A number of studies by Japanese groups [17‐19] have reported beneficial outcomes in childhood IgAN using the combination therapy with prednisolone, azathioprine, heparin-warfarin and dipyridamole. The rationale for this treatment is as follows; (1) corticosteroids and immunosuppressive agents reduce serum IgA production and minimize the abnormal immune response and inflammatory events following glomerular IgA deposition, and (2) heparin-warfarin and dipyridamole are used to inhibit the mediators of glomerular damage [17]. Our results demonstrated that 68 hospitals (68.5 % of pediatric hospitals) performed the combination therapy, suggesting that combination therapy is a standard therapy for pediatric IgAN in Japan. Pozzi et al. [20] recently demonstrated that clinical outcomes in adults are not different between treatment with corticosteroids alone and corticosteroids with oral azathioprine. In contrast, Kamei et al. [21] reported that the combination therapy improves the long-term outcome in childhood IgAN. Because these two studies enrolled different populations, this difference may provide a clue of the indications for this treatment.

A recent meta-analysis showed that the use of corticosteroids IgAN patients is associated with a significant decrease in the risk of ESKD and urinary protein excretion [22]. Although the practice pattern (with or without tonsillectomy, immunosuppressants, etc) was not standardized, almost 70 % hospitals were found to perform corticosteroid therapy. Consequently, one can conclude that corticosteroid therapy has become standard in Japan. In particular, TSP and combination therapy are popular in internal medicine and pediatric departments, respectively.

Intraglomerular coagulation, either through local activation of blood coagulation or impaired removal by the fibrinolytic system, has been proposed as one of the factors causing glomerular injury in IgAN [23]. Previous studies including meta-analysis [24‐27] reported beneficial effects of anti-platelet agents for IgAN. Therefore, antiplatelet agents are listed in the Japanese regional guidelines [8]. In fact, the national health insurance covers dipyridamole for glomerulonephritis and dilazep hydrochloride for IgAN. On the contrary, Fleoge et al. [28] did not recommend using antiplatelet agents in patients with IgAN because most studies on antiplatelet agents are often combined with immunosuppressants and were retrospective and nonrandomized. Moreover, the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis concluded that there is no benefit for antiplatelet agents alone because patients received other concomitant therapies in Japanese studies [29]. Our results suggest that almost all Japanese hospitals (351, 93.4 %) prescribed antiplatelet agents for IgAN. It is thought that Japanese nephrologists prescribe these drugs based on previous studies and for compliance with regional guidelines. In future, we need to confirm the effects of antiplatelet agents in a large cohort study from Japan.

RAS-I is effective for glomerular hypertension, podocyte injury and tubulointerstitial injury, and thus is prescribed for glomerulonephritis. Amelioration of glomerular injury and fibrosis by ARB has been demonstrated in animal models of IgAN [30]. Because several studies, including randomized controlled trials [31‐33], have reported the effectiveness of RAS-I for IgAN, recent guidelines [29] recommend this therapy for IgAN. Tomino et al. [34] and Moriyama et al. [35] reported the beneficial effects of IgAN in Japan. Furthermore, our results revealed that almost all hospitals (371, 98.7 %) prescribed RAS-I for IgAN, indicating that RAS-I is a popular treatment in Japan. The combination of ACE-I and ARB has antiproteinuric effects greater than monotherapy in normotensive IgAN [36]. The present study revealed that 218 hospitals (58.8 %) prescribed ACE-I and ARB concurrently. The indications for concurrent use are proteinuria and blood pressure, suggesting that they aim to renoprotect through antiproteinuric effects.

Our study has several limitations. First, there was a possibility of selection bias. The response rate was only 31.4 % of 1,194 hospitals. Those hospitals tended to be large hospitals; thus, our results could not reflect the treatments in small hospitals and clinics. Second, a possibility for measurement bias regarding clinical efficacy existed. Because we did not strictly define “clinical remission” in this study, treatment efficacy depended on the judgment of each hospital. Third, the questionnaire asked about all treatments in each hospital; thus, we could not analyze and estimate the priority of the treatments. Fourth, the questionnaire surveyed all IgAN stages, but it is well known that IgAN has a heterogeneous disease course; therefore, treatments may depend on stage. In future, we need to conduct an investigation of the treatments for each stage of IgAN.

In conclusion, corticosteroid therapy, along with antiplatelet agents and RAS-I therapy, has become a standard treatment for IgAN in Japan. Although we observed that the corticosteroid therapy protocol varied, TSP is becoming a standard treatment, at least for adult IgAN. Further studies are required to compare the efficacy of each treatment and to determine the standard therapy for each stage of IgAN.