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Validation of the 2019 ACR/EULAR criteria for IgG4-related disease in a Japanese kidney disease cohort: a multicentre retrospective study by the IgG4-related kidney disease working group of the Japanese Society of Nephrology
  1. Takako Saeki1,
  2. Tasuku Nagasawa2,
  3. Yoshifumi Ubara3,
  4. Yoshinori Taniguchi4,
  5. Motoko Yanagita5,
  6. Shinichi Nishi6,
  7. Michio Nagata7,
  8. Yutaka Yamaguchi8,
  9. Takao Saito9,
  10. Hitoshi Nakashima10,
  11. Mitsuhiro Kawano11
  1. 1Department of Internal Medicine, Nagaoka Red Cross Hospital, Nagaoka, Japan
  2. 2Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, Sendai, Japan
  3. 3Nephrology Center, Toranomon Hospital, Minato-ku, Japan
  4. 4Department of Endocrinology, Metabolism, Nephrology and Rheumatology, Kochi University, Kochi, Japan
  5. 5Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  6. 6Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
  7. 7Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  8. 8Yamaguchi’s Pathology Laboratory, Chiba, Japan
  9. 9Sanko Clinic, Fukuoka, Japan
  10. 10Medical Corporation, Souseikai, Fukuoka, Japan
  11. 11Department of Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
  1. Correspondence to Dr Takako Saeki, Department of Internal Medicine, Nagaoka Red Cross Hospital, Nagaoka 940-2085, Japan; saekit{at}

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IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect various organs. The kidney is one of the organs most frequently affected and IgG4-related tubulointerstitial nephritis (TIN) is the most dominant feature.1 However, several radiologically characteristic lesions within the kidney have also been shown to be diagnostic for IgG4-RD affecting the kidney, in the setting of definitively diagnosed IgG4-related lesions in extrarenal organs.2 Therefore the term ‘IgG4-related kidney disease (IgG4-RKD)’ has been proposed as a comprehensive term for the renal lesions associated with IgG4-RD.2 3

In 2011, the IgG4-RKD working group of the Japanese Society of Nephrology proposed diagnostic criteria for IgG4-RKD.4 Recently, we validated those criteria in a Japanese kidney cohort and developed a revised version.5 On the other hand, the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-RD (the ACR/EULAR criteria) were proposed in 2019.6 According to the latter criteria, exclusion criteria should be applied first to any potential IgG4-RD case. Then, inclusion criteria consisting of eight weighted domains are applied to any case that does not satisfy any of the exclusion criteria, and if the total inclusion points score is ≥20, the case can be classified as ‘IgG4-RD’. We validated the ACR/EULAR criteria in the Japanese kidney cohort used in our validation study for IgG4-RKD 2011.5 Briefly, the cohort comprised Japanese patients diagnosed as having renal injury on the basis of urinalysis, radiographic findings and/or function tests between April 2012 and May 2019, in whom serum IgG4 values and/or data for immunohistological staining of IgG4 in renal biopsy samples were known and for whom sufficient clinical information was available. These patients were classified as IgG4-RD or mimickers based on the ACR/EULAR criteria, and the results were evaluated by expert opinion.

Among the 105 patients included, the expert panel diagnosed 55 as true IgG4-RKD and 50 as mimickers. One patient in each group was used for validation of the ACR/EULAR criteria. The clinical and renal pathological features of each group are shown in table 1. In the IgG4-RKD group, renal biopsy was performed in 51 patients and IgG4-TIN was evident in 48 of them (tissue samples being inadequate in 3). Of the 48 patients with biopsy-proven IgG4-RKD, 34 had extrarenal lesions. Among 14 patients who had only renal lesions, 13 had at least one of the following items: storiform fibrosis demonstrated by renal biopsy, hypocomplementaemia or bilateral renal cortex low-density areas demonstrated by radiology. In seven patients for whom renal histology confirmation was not possible (unavailable in four and inadequate in three), diagnosis of IgG4-RKD was based on radiologically evident bilateral renal cortex low-density areas, in the setting of biopsy-proven IgG4-related extrarenal lesions (n=6) or a definite diagnosis of autoimmune pancreatitis (n=1).

Table 1

Data are available on reasonable request

Four of the 55 IgG4-RKD patients and 24 of the 50 mimickers had exclusion criteria. Of the remaining cases, 50 of 51 IgG4-RKD patients and 1 of 26 mimickers had an inclusion criterion score of ≥20 points (figure 1 and online supplemental table 1). One IgG4-RKD patient, whose autoimmune pancreatitis was the focal swelling type, was misclassified as non-IgG4-RKD. As a result, 50 of the 55 IgG4-RKD patients were classified as IgG4-RKD and 49 of the 50 mimickers were classified as non-IgG4-RKD (sensitivity 90.9%, specificity 98.0%, positive predictive value 98.0% and negative predictive value 90.7%).

Figure 1

Performance of the American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease in a Japanese kidney cohort. ANCA, antineutrophil cytoplasmic antibody; IgG4-RKD, IgG4-related kidney disease; MPO, myeloperoxidase; PR-3, proteinase 3.

Many IgG4-RKD patients had extrarenal lesions and IgG4-positive cell-rich TIN associated with other diseases was effectively excluded on the basis of exclusion criteria. In conclusion, the ACR/EULAR criteria showed an excellent test performance for IgG4-RKD in Japanese patients, although further validation studies of other racial groups will be necessary.


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  • Handling editor Josef S Smolen

  • Contributors All authors made contributions to the conception and design of this study. TSaeki, TN and MK performed the data analysis. TSaeki and MK wrote the manuscript. TSaeki, YU, YT, MY, HN and MK collected the data. All authors contributed to reviewing the manuscript and approved the final version for publication.

  • Funding This work was supported in part by the committee of the Japanese Society of Nephrology and MHLW Research Programme on Rare and Intractable Diseases (grant number JPMH20FC1040).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study protocol was initially approved by the ethics committee of Fukuoka University Hospital (reference number 2017M174) and subsequently by the boards of the collaborating institutions.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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