Japanese Clinical Practice Guidelines for IgA Nephropathy: Difference from KDIGO Guidelines

The purpose of the Clinical Guidelines for IgA Nephropathy 2014 was to define evidence-based clinical guidelines that reflect the clinical situation of IgAN in Japan. This guideline is developed to provide answers to clinical questions (CQs) that nephrologists may encounter in the clinical practice for the treatment of IgAN. Each answer is shown as a statement, and recommendation grades based on the evidence-based levels are noted for each statement in the treatment section (Table 15.1). It was not aimed at creating an exhaustive textbook but at supporting clinical decisions by answering questions raised by nephrologists in clinical practice and establishing a standard treatment. With the aim of comprehensively supporting nephrologists in the treatment of IgAN in clinical settings, the Clinical Guidelines for IgA Nephropathy 2014 Advisory Committee independently evaluated the results of principal randomized parallel-group clinical trials published to date (Figs. 15.2 and 15.3) and presented the scheme of indications for preventive intervention of renal dysfunction progression in this guideline (Fig. 15.4). Now, the indications of therapeutic interventions of IgAN are mainly based on GFR and urinary protein level in this guideline and also the evidence-based practice guideline for the treatment of chronic kidney disease (CKD) [4]. The Clinical Guidelines for IgA Nephropathy 2014 also describe the characteristics and treatment of pediatric IgAN.

The Clinical Guidelines for IgA Nephropathy 2014 comprehensively covers the concept, diagnosis, pathology, epidemiology, and adverse effects of treatment, as well as the standard treatment of IgAN (Table 15.2), actively presenting the data obtained from Japanese patients in figures and tables. IgAN can be definitely diagnosed when kidney biopsy results show IgA deposition within the renal glomerular mesangium. However, glomerular IgA deposition can occur in normal kidneys. Thus, Japanese guidelines define IgAN as follows: IgAN is a disease characterized by urinary findings suggestive of glomerulonephritis; predominantly, IgA is deposited in the glomeruli, with no evidence of other underlying diseases. Glomerular hematuria and proteinuria are urinary findings that suggest glomerulonephritis.

Pathological lesions which are commonly seen in IgAN are shown in the figure panels. Differences in pathological classification between the Japanese severity classification and the Oxford classification are described in detail. The Clinical Guidelines for IgA Nephropathy 2014 has a supplemental material section that contains structured abstracts of the clinical trials published to date.

In Japan, the major potential treatment modalities for adult IgAN are the use of renin-angiotensin system (RAS) blockers, corticosteroids, nonsteroidal immunosuppressive agents, antiplatelet agents, and n-3 fatty acids (fish oil) and tonsillectomy (with corticosteroid pulse therapy). Based on the results of several randomized controlled trials (RCTs), we evaluated the reduction of proteinuria and preservation of kidney function in response to the therapeutic interventions (Figs. 15.2 and 15.3). Because the entry criteria of the majority of the RCTs included GFR and urinary protein levels, the indications of these therapeutic interventions are mainly based on GFR and urinary protein level in this guideline. Age and renal histological lesions may potentially provide clinically useful information on indications of these therapeutic interventions. Interventions to optimize blood pressure, salt intake, lipid and glucose metabolism, body weight, and smoking habits should be considered, if necessary (Fig. 15.4).

Although both the Japanese Clinical Guidelines for IgA Nephropathy 2014 and Chap. 10 in the KDIGO Clinical Practice Guidelines for Glomerulonephritis evaluated indications for intervention for IgAN based mainly on the results of RCTs, they have some differences. One of the major differences is the usage of different criteria to determine the strength of intervention recommendations. The KDIGO guidelines do not indicate an intervention if its efficacy has not been demonstrated in RCTs, whereas the Japanese guidelines indicate that such an intervention be used as second-line therapy if non-RCTs or cohort studies suggested the efficacy of the intervention.

Another major difference is the strength of the recommendations for RAS blockers and corticosteroids. The Japanese guidelines position both RAS blockers and corticosteroids as first-line therapy for IgAN patients with CKD stages G1–G2 and urinary protein levels >1.0 g/day. By contrast, the KDIGO guidelines indicate corticosteroids for patients with persistent proteinuria at urinary protein levels ≥1 g/day despite treatment with RAS blockers, because of a concern about adverse effects due to corticosteroid administration.

Tonsillectomy is not recommended for patients with IgAN, unless for tonsil-related diseases, in the KDIGO guidelines. The Japanese guidelines state that tonsillectomy combined with steroid pulse therapy may improve urinary findings in patients with IgAN and lower the progression of renal dysfunction. This may also be considered a treatment option, as the RCT conducted by the Progressive Renal Dysfunction Research Group of the MHLW reported that tonsillectomy combined with steroid pulse therapy was found to be more effective than steroid pulse therapy alone in reducing urinary protein [5]. To establish more amount of substantial evidence, the superiority of tonsillectomy combined with steroid pulse therapy should be further investigated. No RCT of tonsillectomy alone has been conducted. Previous studies may have shown the long-term efficacy of tonsillectomy in cases of IgAN. Therefore, according to the current clinical practices in Japan, tonsillectomy alone may also be considered as a treatment option.

We summarize the recommendation grades of the Japanese guidelines in Table 15.3. The Clinical Guidelines for IgA Nephropathy 2014 was developed in accordance with the Japanese clinical practice for the treatment of IgAN. Publishing a comprehensive practice guideline suitable for Japanese clinical practice may provide an optimum treatment and encourage new clinical trials based on clinical questions.