Evaluation of diagnostic criteria for IgG4-related tubulointerstitial nephritis

The procedure of screening cases is shown in Fig. 1. Herein, 480 samples with sufficient interstitial inflammation that accounted for 24.2 % of total renal biopsy specimens were selected in our study. After re-observing these specimens by light microscopy, 55 cases demonstrating abundant plasma cells were screened. Furthermore, 21 cases of suspected IgG4-TIN were screened from the previous group by CD138, IgG and IgG4 test, which accounted for 38.2 % of abundant plasma cell cases and 4.4 % of sufficient inflammation cases. The average number of CD138, IgG and IgG4 positive cells were 75.8 ± 34.9, 34.0 ± 21.3 and 19.9 ± 13.3 respectively. Their predominant pathological diagnoses were IgAN, CreGN and TIN respectively, whilst others were FSGS, LN, MN and SS.

According to the proposed criteria of the Mayo Clinic [12], twelve cases were screened at least for one other feature from the imaging, serology, or other organ involvement, which accounted for 57.1 % of suspected cases of IgG4-TIN. The average age was 52 years (range, 30 to 76 years). Six cases were male and the other six were female. Patients were much older (p < 0.01) whereas the incidence of proteinuria was lower (p < 0.05) than that of excluded cases (please see Table 2). In addition, Table 3 showed clinical and pathological features of twelve cases. Ten cases (or 83.3 %) had increased serum IgG levels; three cases (or 25 %) showed diffuse enlargement of both kidneys, six cases (or 50 %) presented with pulmonary interstitial fibrosis and one case had lymph node enlargement. All but one of the cases manifested acute (n = 6) or chronic (n = 5) renal failure.

Originally, nine cases were diagnosed with glomerular diseases and three cases were diagnosed with TIN pathologically. Both CreGN and IgAN were predominant glomerular diseases among them. The others were idiopathic TIN, drug-induced TIN and LN (Table 3). Most of their histological features were non-specific; however, storiform fibrosis and a bird’s eye pattern were significantly more frequent than that in the excluded cases (p < 0.01; Table 4). Moreover, IgG4+ plasma cells were focal, multi-focal or evenly distributed, with mild, moderate or strongly stained mixed expression patterns (Fig. 2). Fibrosis was mild or moderate with multifocal distribution. The stage of interstitial fibrosis ranged from 0 to 2, and most cases were in stage 1. It was neither significantly correlated with the number of IgG4+ cells (r = 0.433, P = 0.160) nor TBM immune complex deposits (r = 0.426, P = 0.167). Both the number of IgG4 positive cells and the stage of interstitial fibrosis had no significant correlation with clinical laboratorial characteristics (age, hematuria, proteinuria, albumin, SCr and eGFR) (P > 0.05). Tubulitis presented with significant differences between both groups, though it was not included into specific features of IgG4-TIN (p < 0.05; Table 4). Moreover, IgG or electron dense deposits in TBM were more frequently observed in the high-probability cases than excluded cases (p < 0.05; Table 4).

In the high-probability IgG4-TIN group, all 12 cases presented with substantial histological differences, including the stage of fibrosis, the number of IgG4 positive cells and their distribution. Their treatment and clinical outcomes were absolutely different, and were dependent, at least in part, on proteinuria, serum creatinine, eGFR and presence of original glomerular disease. Therefore, we applied strict morphological criterion by JSN to confirm the diagnosis of IgG4-TIN and found three cases that met it. Two cases (case 5 and case 11) met all criteria of histology, imaging, serology and other organ involvement. The left case (case 10) met all criteria but the imaging criterion.. The histological feature of this case, such as storiform fibrosis, was mild and distributed focally. Moreover, IgG4 positive cells were unevenly distributed and moderately stained. Therefore, we checked through the finding of more references, in which it was recommended to identify the presence of dense, diffuse infiltrates of IgG4 positive cells >50/HPF, which were highly specific [20‐24]. Moreover, an immunohistochemical study of IgG4-TIN from JSN showed the average number of IgG4 positive cells was 43.8/HPF [5]. Besides, Houghton DC and Troxell ML presented that the distribution of IgG4 positive cells were even and uniform in IgG4-TIN, while they were focal or multi-focal in various settings of interstitial nephritis [17]. Finally, we put the remained one case in the high-probability IgG4-TIN group, from which two cases were finally confirmed as IgG4-TIN. One of IgG4-TIN manifested ARF and the principal pathological diagnosis was immune complex CreGN. His serum ANCA was negative, which had no proof of AAV. The serum IgG4 level had decreased rapidly after a large dose of corticosteroid treatment, whereas his serum creatinine hardly decreased and hemodialysis was finally applied. Another case displayed chronic renal failure and the previous diagnosis was idiopathic TIN. Serum IgG4 level was undetectable at this time. Large dose of corticosteroids was prescribed and serum creatinine had decreased to normal level by one half month later. Both cases presented with a diffuse bird’s-eye pattern and focal storiform features [25] (Fig. 3), whereas there was only one case that showed specific fibrosis in ten left cases, which had significant difference (P < 0.01; Table 4). Moreover, IgG4+ plasma cells were presented at a frequency of more than 50 per HPF, which appeared as an evenly strong staining pattern with diffuse infiltration of the renal interstitium, while it was multifocal in left cases. No tubular necrosis was observed in confirmed cases, though it was frequently shown in the left cases.