Nationwide survey on current treatments for IgA nephropathy in Japan
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A wide variety of treatments, including tonsillectomy and steroid pulse therapy (TSP), are performed for the various stages of IgA nephropathy (IgAN) in Japan. However, the current status of treatments for IgAN patients in Japan is still unclear. The objective of the present study was to investigate the current status of treatments for IgAN patients.
A nationwide survey was conducted in 2008 by sending questionnaires to the 1,194 teaching hospitals of the Japanese Society of Nephrology (JSN) via Progressive Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan.
Among the total 376 hospitals (31.4 %) that responded, 188 hospitals (66.2 % in the internal medicine departments) performed TSP, out of which 137 hospitals (61.4 %) had begun to perform TSP in the period from 2004 to 2008. The following two major steroid pulse protocols in TSP were used: (1) three cycles over 3 consecutive weeks and (2) three cycles every 2 months. Approximately 68 % of pediatric hospitals (68 hospitals) performed combination therapy with prednisolone, azathioprine, heparin-warfarin and dipyridamole. The clinical remission rates for hematuria and proteinuria after TSP tended to be higher than those following other corticosteroid therapies. Almost all hospitals prescribed antiplatelet agents and renin angiotensin system inhibitor (RAS-I).
In addition to popular treatments such as antiplatelet agents and RAS-I, TSP is becoming a standard treatment for adult IgAN patients in Japan.
KeywordsIgA nephropathy Nationwide survey Questionnaire survey Tonsillectomy and steroid pulse therapy
IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis in the world, and is recognized as one of the major causes of end-stage kidney disease (ESKD) [1, 2, 3, 4, 5]. Although IgAN was initially believed to represent a benign condition, recent studies  have shown that 30–40 % of patients progress to ESKD within 10–25 years from its apparent onset. Therefore, treatment strategies to decrease the risk of IgAN progressing to ESKD would have substantial health benefits . However, disease-specific therapy for IgAN patients has not been established because the pathogenesis of IgAN is still a matter of debate.
As annual check-ups including urinalysis are well established in Japan, patients in various stages of IgAN can be managed and are provided a wide variety of treatments. Oral corticosteroid, steroid pulse therapy, tonsillectomy and steroid pulse therapy (TSP), antihypertensive agents, immunosuppressants, antiplatelet agents and anticoagulants are listed in the regional guidelines of Japan .
Corticosteroid therapy is now a popular treatment for IgAN patients after being first reported by Kobayashi . Although the clinical value of intravenous steroid pulse therapy was demonstrated by Pozzi et al , no consensus exists for the corticosteroid dose and administration route (oral or intravenous infusion). TSP has recently become a popular standard treatment in Japan. However, the current status of IgAN treatment in Japan is still unclear because no nationwide study has been conducted. Thus, we conducted a nationwide survey using a questionnaire through the Progressive Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan.
A total of 376 hospitals (31.4 %) (Internal Medicine 284; Pediatrics 92) responded. The mean number of beds in these hospitals was 581.
Tonsillectomy and steroid pulse therapy (TSP)
Steroid pulse therapy without tonsillectomy
Number of hospitals for each treatment
Total (%) n = 376
Internal medicine (%) n = 284
Pediatrics (%) n = 92
Steroid pulse monotherapy
Oral corticosteroid monotherapya
Routine examinations, concomitant drugs, and adverse effects for each treatment
Routine examination (hospitals, %)
Concomitant drugs (hospitals, %)
Adverse effects (hospitals, %)
General blood examination (221, 99.1),
Blood pressure (202, 90.6),
Ophthalmologic examination (108, 48.4),
Bone densitometry (107, 48.0),
Upper gastrointestinal endoscopy (40, 17.9),
Bone metabolism maker (20, 9.0)
H2 blocker or proton-pump inhibitor (207, 92.8),
Antiplatelet agent (157, 70.4),
Vitamin D3 (91, 40.8),
Vitamin K2 (15, 6.7)
Steroid-induced diabetes (32, 14.3),
Steroid-induced psychosis (17, 7.6),
Moon face (12, 5.4), Steroid osteoporosis (6, 2.7),
Postoperative pain (6, 2.7),
Bleeding (5, 2.2), Loss of taste (3, 1.3)
Steroid pulse monotherapy
General blood examination (147, 76.6),
Blood pressure (135, 70.3),
Ophthalmologic examination (75, 39.0),
Bone densitometry (74, 38.5),
Upper gastrointestinal endoscopy (28, 14.6),
Bone metabolism maker (16, 8.3)
H2 blocker or proton-pump inhibitor (137, 71.4),
Antiplatelet agent (22, 11.5),
Vitamin K2 (13, 6.8)
Steroid-induced diabetes (13, 6.8),
Steroid-induced cataract (7, 3.6),
Pneumonia (5, 2.6),
Moon face (4, 2.1),
Central obesity (4, 2.1)
Oral corticosteroid monotherapy*
General blood examination (128, 69.6),
Blood pressure (116, 63.0),
Bone densitometry (56, 30.4),
Ophthalmologic examination (55, 29.9),
Upper gastrointestinal endoscopy (20, 10.9),
Bone metabolism maker (15, 8.2)
H2 blockers or proton-pump inhibitors (111,
60.3), bisphosphonates (74, 40.2), Vitamin D3 (56, 30.4),
Antiplatelet agents (26, 14.1),
Vitamin K2 (9, 4.9)
Steroid-induced diabetes (11, 6.0),
Steroid-induced cataract (5, 2.7),
Steroid-induced psychosis (4, 2.1),
Moon face (3, 1.6),
Steroid-induced osteoporosis (3, 1.6)
Oral corticosteroid monotherapy (including combination therapy)
A total of 184 hospitals (48.9 %) performed oral corticosteroid monotherapy (Table 2). Most of the hospitals (149, 81.0 %) performed this therapy for less than 10 patients annually, and only 10 hospitals performed it for more than 11 patients. The most frequent initial dose in the internal medicine and pediatric departments was 21–40 and 1–2 mg/kg/day, respectively. The most frequent duration of medication was 24 months (54 hospitals, 28.7 %), and the duration of medication varied in each hospital. Seventy-four hospitals (40.2 %) had tapering criteria, and 68 hospitals (68.5 % in pediatric hospitals) provided a combination therapy of prednisolone, azathioprine, heparin-warfarin and dipyridamole. The most cited indication for this therapy was the proteinuria grade (140 hospitals; 76.1 %). Other indications included histological findings (129 hospitals, 70.1 %), disease activity (93 hospitals, 50.5 %), hematuria grade (31 hospitals, 16.8 %) and duration from onset (19 hospitals, 10.3 %). The most frequent clinical remission rate of hematuria was 40–60 % (Fig. 2), and that of proteinuria was 0–20 % (Fig. 3). Table 3 shows the routine examinations performed before oral corticosteroid monotherapy, concomitant drugs and adverse effects.
Renin-angiotensin system inhibitor (RAS-I)
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.  in 2001. Many clinical studies on TSP have been reported from Japan since 2001 [12, 13, 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 . 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, 12, 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. . Another is in which steroid pulses are administrated three times every 2 months, based on previous report by Pozzi et al. . 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 . A number of studies by Japanese groups [17, 18, 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 . 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.  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.  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 . 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 . Previous studies including meta-analysis [24, 25, 26, 27] reported beneficial effects of anti-platelet agents for IgAN. Therefore, antiplatelet agents are listed in the Japanese regional guidelines . In fact, the national health insurance covers dipyridamole for glomerulonephritis and dilazep hydrochloride for IgAN. On the contrary, Fleoge et al.  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 . 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 . Because several studies, including randomized controlled trials [31, 32, 33], have reported the effectiveness of RAS-I for IgAN, recent guidelines  recommend this therapy for IgAN. Tomino et al.  and Moriyama et al.  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 . 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.
We thank the fellows of the Japanese Society of Nephrology who responded to our questionnaire. This study was supported by a grant in a part by Grants-in Aid for Progressive Renal Diseases Research, and Clinical Research of Secondary Screening of Hematuria by Novel Noninvasive Biomarker for IgA nephropathy, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan.
Conflict of interest
The authors have declared that no Conflict of interest exists.
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