Comparison of clinicopathological features between patients with and without hypocomplementemia in IgG4-related kidney disease

Immunoglobulin G4–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 (IgG4-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 [2], and several glomerular lesions (especially membranous glomerulonephritis [3]) have been described as associated with IgG4-RD. Therefore the term ‘IgG4-related kidney disease’ (IgG4-RKD) has been proposed as a comprehensive term for the renal lesions associated with IgG4-RD [4]. Although the pathogenesis of IgG4-RD has not been fully clarified, the involvement of acquired immunity and innate immunity has been reported [5]. However, few studies have focused on the role of the complement in IgG4-RD, even though hypocomplementemia is a clinical feature. In IgG4-RD, the overall reported frequency of hypocomplementemia is 20–40%, and in patients with kidney disease it is 50–70% [1, 4, 6]. Indeed, hypocomplementemia is a useful diagnostic marker for IgG4-RKD [2] and has been reported as a potential predictor of relapse in IgG4-RKD [7, 8]. Herein we retrospectively examined the clinicopathological features of 60 patients with IgG4-RKD, collected from the institutions associated with the Japan IgG4-RKD working group between December 2010 and May 2019, with reference to the presence of hypocomplementemia. All of them were classified as having definite or probable IgG4-RKD according to the diagnostic criteria for IgG4-RKD 2020 [9] and/or as definite IgG4-RD according to the 2019 ACR/EULAR classification criteria [2]. Of the 60 patients, 11 had been included in the previous study [7]. Hypocomplementemia was defined as low C3 and/or low C4 and/or low CH50 levels compared with normal levels at each institution. Renal tissues were obtained by needle biopsy in all patients. The evaluated items pertaining to histologic features were as follows (Supplementary data, Table S1): extent of interstitial inflammation (grade 0–3), extent of interstitial fibrosis (grade 0–3), storiform fibrosis, the number of IgG4-positive cells per high-power field (grade 0–4), the ratio of IgG4-positive cells to IgG-positive cells (grade 1–9), membranous glomerulonephritis and deposition of IgG or complement along the renal tubular basement membrane (TBM). The study was approved by the ethics committee of Fukuoka University Hospital. Table 1 shows a comparison of clinicopathological features between the patients with and without hypocomplementemia. Hypocomplementemia was evident in 70% of the patients. There were no significant intergroup differences in age, male predominance, frequencies of allergy and extrarenal involvement or the number of extrarenal involved organs. In terms of laboratory findings, serum levels of IgG, and total IgG − IgG4, were significantly higher (P = .001 and .000, respectively) in the hypocomplementemia group. There were no significant intergroup differences in the levels of serum IgG4. The estimated glomerular filtration rate (eGFR; ml/min/1.73 m2) at diagnosis of IgG4-RKD tended to be lower in the hypocomplementemia group, although not to a significant degree (P = .076). Serum C3 levels were positively correlated with serum C4 and CH50 levels (r = 0.756, P < .01 and r = 0.785, P < .01, respectively). Levels of C3, C4 and CH50 were inversely correlated with IgG levels (r = −0.652, P < .01; r = −0.589, P < .01; and r = −0.491, P < .01, respectively) and the total IgG − IgG4 value (r = −0.717, P < .01; r = −0.705, P < .01; and r = −0.612, P < .01, respectively). There was no correlation between C3, C4 and CH50 levels and IgG4 levels (r = −0.256, P = .050; r = −0.105, P = .429; and r = −0.114, P = .389, respectively). Clinicopathological features of patients with IgG4-RKD. HC: hypocomplementemia; IgE: immunoglobulin E; IQR: interquartile range. aSemiquantitative score of the extent of interstitial inflammation (grade 0–3). bSemiquantitative score of the extent of interstitial fibrosis (grade 0–3). cSemiquantitative score of the number of IgG4-positive cells per high-power field (grade 0–4). dSemiquantitative score of the ratio of IgG4-positive cells:IgG-positive cells (or CD38-positive cells) (grade 1–9). Clinicopathological features of patients with IgG4-RKD. HC: hypocomplementemia; IgE: immunoglobulin E; IQR: interquartile range. aSemiquantitative score of the extent of interstitial inflammation (grade 0–3). bSemiquantitative score of the extent of interstitial fibrosis (grade 0–3). cSemiquantitative score of the number of IgG4-positive cells per high-power field (grade 0–4). dSemiquantitative score of the ratio of IgG4-positive cells:IgG-positive cells (or CD38-positive cells) (grade 1–9). Renal pathology was evaluated in 53 of the 60 patients. For direct immunofluorescence studies, we evaluated 47 specimens. Light microscopy demonstrated renal interstitial inflammation with IgG4-positive plasma cells in all cases examined. In the hypocomplementemia group, light microscopy demonstrated a significantly broader extent of renal interstitial inflammation (P = .035). There was no significant intergroup difference in other parameters. Levels of C3 and CH50 were inversely correlated with the extent of interstitial inflammation (r = −0.388, P = .005 and r = −0.279, P = .045). Immunofluorescence revealed a tendency for a high frequency of IgG or complement (C3 or C1q) deposition on the TBM in the patients with hypocomplementemia, although this was not statistically significant (P = .062). C1q deposition on the TBM was evident only in the hypocomplementemia group [6/15 (40%) versus 0/3 (0%) TBM deposition-positive cases] (Supplementary data, Table S2). To our knowledge, the present study is the largest cohort study to have compared the clinicopathological features of IgG4-RKD patients with and without hypocomplementemia. In 2018, Wang et al. [10] reported that the serum level of C3 was negatively correlated with the serum level of IgG4 and the interstitial fibrosis score in 17 patients with IgG4-RKD. The present study demonstrated that hypocomplementemia in IgG4-RKD was associated with elevated serum levels of IgG subclasses other than IgG4. Similar findings have been obtained in previous studies of IgG4-RKD [7] and were confirmed in the present larger cohort of patients. In histology, hypocomplementemia in IgG4-RKD was associated with a significantly broader extent of renal interstitial inflammation and C1q deposition on the TBM. These observations provide a new perspective on IgG4-RKD in that types of IgG other than IgG4 may result in hypocomplementemia, and that complement activation may be related to progression of renal interstitial inflammation mainly via the classical pathway. Because IgG4 is unable to bind C1q complement, it has been speculated to insufficiently activate the classical complement pathway [11]. Yamaguchi et al. [12] demonstrated that renal deposits were all positive for IgG4, but also positive for other subclasses (mainly IgG1 and occasionally IgG3) in IgG4-TIN. Nagamachi et al. [13] reported a patient with IgG4-TIN who showed definitive complement activation via the classical pathway in serological and histological examinations. Difficulty with the statistical evaluation of histological features of biopsy samples was a major limitation of the present study. In IgG4-TIN, renal interstitial inflammation is not distributed diffusely [14]. In addition, immune-complex deposition in the TBM is mainly evident in areas affected by fibro-inflammatory change and not in areas that are unaffected [12, 15]. Therefore, histological findings may vary significantly among biopsy samples, especially when needle biopsy is used. The significance of low complement in the clinical course and outcomes of patients with IgG4-RKD remains to be clarified. A study with a larger cohort will be necessary to better understand the contribution of the complement system in IgG4-RKD. This work was supported in part by the committee of the Japanese Society of Nephrology and MHLW Research Program on Rare and Intractable Diseases (grant JPMH20FC1040). This study is one of the projects of the IgG4-RKD Working Group in the Japanese Society of Nephrology. We thank members of institutions affiliated to the IgG4-RKD Working Group as follows: I. Narita, Y. Wada, H. Sato, M. Sudo and N. Imai (Niigata University); M. Iwano and N. Takahashi (Fukui University); K. Yahata (National Hospital Organization Kyoto Medical Center); H. Imamaki (Hirakata Kohsai Hospital); Y. Tanaka and S. Kubo (University of Occupational and Environmental Health); A. Kawakami and M. Kitamura (Nagasaki University); N. Honma (Niigata Prefectural Shibata Hospital) and E. Kohno (Nagaoka Chuo General Hospital). None declared. All authors made contributions to the conception and design of this study, contributed to reviewing the manuscript and approved the final version for publication. T.S., T.N. and M.K. performed the data analysis. T.S. and M.K. wrote the manuscript. T.S., Y.U., Y.T., M.Y., H.N. and M.K. collected the data. The data underlying this article will be shared upon reasonable request to the corresponding author. The authors have no conflicts of interest to declare. The results presented in this article have not been published previously in whole or part, except in abstract format.