Evaluation of diagnostic criteria for IgG4-related tubulointerstitial nephritis
Tang et al. Diagnostic Pathology
Evaluation of diagnostic criteria for IgG4- related tubulointerstitial nephritis
Xuanli Tang 0 1
Bin Zhu 1
Yunqin Hu 1
Yinghua Zhang 1
Xiaoling Zhu 1
Hongyu Chen 0 1
Yongjun Wang 1
0 Equal contributors
1 Department of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou hospital of traditional Chinese medicine , Hangzhou 310007 , China
Background: IgG4-TIN is the most common pattern of renal involvement in IgG4-related disease. There are several proposed diagnostic criteria of IgG4-TIN recently. Two of them proposed by the Mayo Clinic and JSN are predominant. However, histopathological criteria of the number of IgG4+ plasma cells and several histological features are still under discussion due to low amount of tissue in renal biopsy specimens and low frequency of this kind of specimens. We aimed to screen IgG4-TIN on archived renal biopsy samples and evaluated the application of two proposed diagnostic criteria. Methods: We selected 480 interstitial inflammation samples for light and electron microscopy and immunohistochemistry of CD138, IgG and IgG4 test. The Mayo Clinic proposed criteria diagnosed high-probability IgG4-TIN and JSN criteria confirmed IgG4-TIN. Results: Twelve high-probability IgG4-TIN were screened by histology, imaging, serology and other organ involvement according to the Mayo Clinic proposed criteria. The previous principal pathological diagnoses were IgAN (n=4), CreGN (n=4), tubulointerstitial nephritis (n=3) and LN (n=1). Three cases showed storiform fibrosis and a bird's eye pattern. The distribution of IgG4+ plasma cells was focal, multifocal or diffuse, with a mixed mild, moderate or strong stainingpattern. Their treatment and clinical outcomes varied depending on different levels of proteinuria, serum creatinine, eGFR and original glomerular disease presentation. Therefore, we applied strict histological criteria of storiform fibrosis and evenly distributed IgG4+ plasma cells by JSN to confirm typical IgG4-TIN. Two cases were finally diagnosed as real IgG4-TIN. One was previously diagnosed as idiopathic interstitial nephritis with rapid response to corticosteroid therapy. The other was CreGN with immune complex deposits, which had poor outcome and long-term hemodialysis. Conclusions: IgG4-TIN might present concurrently with glomerular disease. The proposed criteria by the Mayo Clinic is flexible, sensitive, and superior in the identification of early-stage or atypical IgG4-TIN, with enhanced risk of misdiagnosis as compared to the proposed criteria by JSN, which is stricter, more specific, and might overlook early-stage or atypical IgG4-TIN. We propose a new set of criteria to improve pathologist-derived diagnosis.
Diagnostic criteria; IgG4-related tubulointerstitial nephritis; IgG4; Pathological features; Immunohistochemistry
IgG4-RD is recognized as a systemic autoimmune
disease that is characterized by significant
lymphoplasmacytic infiltration of IgG4 positive plasma cells, with
obliterative phlebitis and storiform fibrosis leading to
organ swelling or nodular lesions [1–3]. It was first
recognized as sclerosing or AIP, which usually occurs with
multi-organ involvement. Single organ injury such as
kidney damage was reported occasionally [2–6].
IgG4TIN was the most common pattern of renal involvement
[7–11]. There were several proposed diagnostic criteria
of IgG4-TIN in recent years, most of which emphasized
histological features and rich IgG4+ plasma cells as
indispensable criteria [3, 11, 12]. Nevertheless, the suitable
cut-off values of IgG4+ plasma cells and the diagnostic
strength of other specific histopathologic features are
still debated in literature, also due to low amount of
tissue in renal biopsy specimens and low frequency of this
kind of specimens. In addition, IgG4 analysis in renal
biopsy was not routinely performed previously, thus
IgG4-TIN awareness was suffered and it would be easily
misdiagnosed, especially when the morphological
appearance was atypical. In this study, we retrospectively
screened IgG4-TIN from archived renal biopsy samples,
analyzed their clinical pathological characteristics and
evaluated the utility of two proposed diagnostic criteria to
identify their potential advantages and disadvantages.
Materials and Methods
Patients with sufficient acute or chronic interstitial
inflammation (the frequency of inflammatory cells that
were > 25 % within the cortical interstitium) by light
microscopy were enrolled in this study from April 2008
through December 2013, irrespective of the presence or
absence of glomerular disease. Altogether, 480 patients
who were first admitted as renal injury without any
remarkable medical history were studied following
approval by the ethical committees of Hangzhou Hospital
of Traditional Chinese Medicine.
HE-stained slides were reviewed by two pathologists.
Cases were selected by lightmicroscopy as having an
average plasma cell count of more than 5 plasma cells in
at least 3 HPF fields . Sections from the corresponding
paraffin-embedded tissue blocks were recut and
immunostained for the following antibodies: CD138 (#IR642; 1:50;
Dako Cytomation, Glostrup, Denmark), IgG (#A0423;
1:250; Dako Cytomation, Glostrup, Denmark) and IgG4
(#AU009; 1:500; Binding Site, Birmingham, UK). Antigen
was retrieved by EDTA solution as well as gastric enzyme,
and Elivision system was applied in IHC detection. The
positive cell counting was calculated as an average number
per HPF over three fields. Abundant plasma cells were
defined as more than 20/HPF. Suspected IgG4-TIN were
defined as IgG4 positive cells > 10/HPF or IgG4/IgG positive
cells >40 %.
Screening for high-probability IgG4-TIN
High-probability IgG4-TIN cases were screened according
to the criteria proposed by the Mayo Clinic as shown in
Table 1 . Clinical and laboratory features including age,
gender, microscopic hematuria (−, <3; ±, 3–10; + 11–20; 2
+, 21–40; 3+, 41–100; 4+, >100), 24-hour proteinuria,
albumin, SCr, eGFR and IgG levels were then analyzed. The
presence of eGFR was calculated by the mordification of
diet in renal disease (MDRD). Histological features,
determined on the basis of previous pathological studies of
IgG4-RD were reanalyzed [3, 9, 13–17]. Immune complex
deposits in TBM were observed by IgG test and electron
Confirmation of IgG4-TIN
The histological criterion proposed by JSN was much
stricter as shown in Table 1 . It emphasized that
Table 1 Two proposed criteria for IgG4-TIN by the Mayo Clinic and JSN
Other organ involvement Characteristic findings of IgG4-RD in other organs
The Mayo Clinic criteria
Plasma cell-rich TIN with >10 IgG4+ plasma cells/HPF field in
the most concentrated field (mandatory criterion)
TBM immune complex deposits by immunofluorescence,
immunohistochemistry, and/or electron microscopy
Small peripheral low-attenuation cortical nodules, round or
wedge-shapped lesions, or diffuse patchy involvement
Elevated serum IgG4 or total IgG level
The histologic feature and at least one other feature from
imaging, serology or other organ involvement
a. Dense lymphoplasmacytic infiltrate with >10 IgG4+
plasma cells/HPF and/or IgG4/IgG+ plasma cell ratio
of >40 %
b. Characteristic storiform fibrosis
Multiple low-density lesions on enhanced CT,
diffuse kidney enlargement, hypovascular solitary
nodule, hypertrophic lesion of the renal pelvic wall
Elevated serum IgG4 or total IgG level
Clinical or laboratory evidence of kidney damage
Characteristic findings of IgG4-RD in other organs
The histologic feature (a and b) and at least two of
other features from imaging, serology or other organ
storiform fibrosis was an essential criterion, and that
IgG4 positive cells should be marked and densely stained
[18, 19]. We followed this guideline to confirm
IgG4TIN since lesions were numerous in our study, including
many different glomerular diseases that might lead to a
misdiagnosis of the underlying condition. Therefore
confirmed IgG4-TIN was screened from a high-probability
IgG4-TIN group according to the criteria proposed by
Statistical analysis was performed with SPSS software
version 17.0. Normally distributed data were expressed as
mean ± SD. The clinical characteristics between two groups
were compared by Student’s t test. Categorical variables of
histological features between two groups were expressed as
percentages and were compared by Chi-square test or
Fisher’s exact test. Correlations were assessed by Spearman’s
rank correlation to estimate the relationship of the clinical
characteristics associated with IgG4 positive cells and the
stage of interstitial fibrosis. P-values less than 0.05 were
considered statistically significant.
Cases of suspected IgG4-TIN
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
Fig. 1 The procedure of screening cases
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.
Cases of high-probability IgG4-TIN
According to the proposed criteria of the Mayo Clinic
, 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.
Table 2 The comparison of clinical characteristics between
the high-probability IgG4-TIN group and excluded group in
abundant plasma cells samples
IgG4-TIN (n = 12) (n = 43)
1.04 (0.21 - 2.69) 3.12 (0.06 - 17.33) 0.043
492.8 (105–1832) 0.070
Female gender (n (%)) 6 (50 )
Albumin (35–55 g/L)
32.8 (25.7 - 42.1) 31.8 (15–46)
eGFR (80-120 ml/min) 23.6 (5.4 - 65.3)
29.5 (3.2 - 143.1)
Data are expressed as mean (minimum, maximum), number (frequency)
Table 4 Pathological features of confirmed IgG4-TIN, high-probability IgG4-TIN and both excluded groups in abundant plasma cells
Abundant plasma cells samples
IgG4-TIN (n = 12)
Inflammation infiltrating renal capsule
Inflammation infiltrating renal medulla
TBM immune complex deposits
Data are expressed as number (frequency); P value 1: High-probability IgG4-TIN compared to Excluded; P value 2: Confirmed IgG4-TIN compared to
unconfirmed; –: no statistics.
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;
Cases of confirmed IgG4-TIN
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 .
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 . 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  (Fig. 3), whereas there was only one
case that showed specific fibrosis in ten left cases, which
Fig. 2 Histological features and immunohistochemistry findings of case twelve. a) Multi-focal fibrosis with obliteration of several tubules (×40) HE.
b) Isolated glomeruli in the middle of fibrosis (×100) PAM. c) IgA deposits in mesengium (×200) IF. d) Multi-focally distributed plasma cells by
CD138 test (×100) IHC. e) Focally scattered IgG4 positive cells by IgG4 test (×100) IHC. f) IgG4 test (×200) IHC
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.
The epidemiology and etiology of IgG4-TIN remain
unclear. It has been hypothesized that autoimmune
disorders and allergic reactions might be the heterogeneous
causes [26–28]. However, this was opposed by several
researchers. They demonstrated that IgG4 antibody
inhibited activation of complement to suppress immune
reactivity. Moreover, a specific allergen was never
detected [29, 30]. Recently, it was reported that IgG4-TIN
was associated with a hematological disorder . Thus,
the pathogenesis of this disease remains unclear.
The characteristic histological features such as
storiform fibrosis and a bird’s-eye pattern were shown in
more than 90 % of IgG4-TIN cases by JSN [18, 32]. By
contrast, these presentations were shown in only 17.1 %
of cases in the Mayo Clinic . Therefore, several
studies tried to define the stages of fibrosis to achieve
consensus . In our study, most of the high-probability
IgG4-TIN cases showed that mild or moderate fibrosis
and the typical storiform pattern was rarely observed.
However, a bird’s-eye pattern was easier to find with
numerous plasma cell nests encircled in fibrosis . We
presumed that this was an early characteristic feature of
IgG4-TIN, which would progress to storiform fibrosis.
In addition, immune complex deposition in TBM was
reported to be more easily observed than specific fibrosis
[12, 19]. In the present study, immune complex
deposition was marginally more frequently observed than
specific fibrosis in the high-probability IgG4-TIN group,
although they all presented in the confirmed group.
Some common features, such as extension of lesions
Fig. 3 Pathological features of case five of histology, IHC and electron microscopy. a) Diffuse fibrosis with obliteration of most tubules and isolation of
glomeruli (×40) HE. b) Typical storiform fibrosis with abundant inflammation cells (×200) PAM. c) Rich collagen fibrosis and characteristic bird’s-eye
pattern (×200) Masson trichrome staining. d) Characteristic bird’s-eye pattern (×400) PAM. e) Abundant, evenly distributed, strong positive plasma cells
in interstitium by CD138 test (×100) IHC. f) Abundant strong stained and evenly distributed IgG4+ plasma cells (>50 per HPF) in interstitium and
tubular epithelial cells by IgG4 test (×200) IHC. g) Apparent TBM deposition of two tubules by IgG test (×200) IHC. h) Thickened TBM with scattered
electron dense immune complex deposits (×4000) EM
into renal capsules and eosinophil infiltration strongly
indicated IgG4-TIN; while tubulitis, peritubular
capillaritis, necrotizing angiitis and neutrophil infiltration were
negatively suggestive of IgG4-TIN [19, 25]. However, we
found that only tubulitis was more frequent in
highprobability IgG4-TIN than that in the excluded cases.
Eosinophil infiltration was demonstrated to reproducibly
be seen in IgG4-TIN [12, 13, 19], although it was not
significantly different from other TIN cases such as
allergic interstitial nephritis or acute CreGN in our study. This
might be explained by that the lesions seen in our cases
were much more variable, including many glomerular
Fig. 4 A new set of criteria of IgG4-TIN for pathologist
diseases with acute interstitial inflammation, thus both
eosinophil and neutrophil infiltration were non-specific.
The clinical and pathological evidence of unconfirmed
IgG4-TIN remain understudy. It’s unknown whether
IgG4-TIN is concurrent with or earlier than glomerular
lesions, or the second injury of glomerular diseases. In
previous studies, some pauci-immune CreGN, DN, LN
and MN met the criteria of IgG4 > 10 per HPF, but they
were not real IgG4-TIN [12, 17]. The fibrosis and
inflammatory lesions of these suspected cases were patchy
or segregated, and IgG4+ plasma cells were focally and
less densely distributed, which was different from the
IgG4-TIN. In our study, cases were selected irrespective
of glomerular disease, thus glomerular nephritis with
interstitial IgG4 positive cells was included in
highprobability IgG4-TIN, but their histological features had
remarkable differences. Moreover, their reaction to
treatment and prognosis varied considerably from each other.
Six cases recovered well from poor renal function, two
cases remained stable, and four cases progressed to end
stage renal disease requiring long-term hemodialysis.
Therefore we used the stricter criteria proposed by JSN
and finally confirmed two cases. One had acute
glomerular nephritis, which convinced us to believe that
IgG4-TIN could co-exist with glomerulonephritis,
wherein the prognosis was much worse and the patient
depended on long-term hemodialysis. Although ten left
high-probability cases met the proposed criteria by the
Mayo Clinic, their clinical manifestations, histological
features, treatment and prognosis varied from each
other. Thus, we currently consider them to be unreal
IgG4-TIN, although frequent follow-up will be necessary
to verify. The proposed criteria by the Mayo Clinic are
much looser and more sensitive, which makes it easier
to determine early-stage or atypical IgG4-TIN, although
it increases the risk of misdiagnosis. By contrast, the
proposed criteria by JSN are much stricter and more
specific, and yet early-stage or atypical IgG4-TIN might
be easily missed. Therefore, we propose a new set of
criteria for renal biopsy patients in Fig. 4, which would
enable the pathologist to make more accurate diagnosis.
Further, studies of more accumulated cases and
longterm follow-up are necessary for etiology and proposing
criteria of atypical IgG4-TIN.
IgG4-TIN is easily missed without IgG4 test at the time
of renal biopsy. The essential nature of increased IgG4
plasma cells is unclear and it will exist in various
kidney diseases meanwhile. Strict histological criteria are
helpful, and sometimes necessary in differentiation of
IgG4-RD: IgG4-related disease; AIP: Autoimmune pancreatitis;
IgG4TIN: IgG4-related tubulointerstitial nephritis; HE: Hematoxylin and
eosin; HPF: High power field; IHC: Immunohistochemistry; SCr: Serum
creatinine; eGFR: Estimated glomerular filtration rate; TBM: Tubular
basement membrane; JSN: The Japanese Society of Nephrology; IgAN: IgA
nephropathy, CreGN, Crescentic glomerulonephritis; TIN: Tubulointerstitial
nephritis; FSGS: Focal segmental glomerulous sclerosis; LN: lupus nephritis;
MN: Membranous nephropathy; SS: Sjogren Syndrome; ARF: Acute renal failure;
ANCA: Antineutrophil cytoplastic antibody; PAM: Periodic acid methenaming
silver stain; IF: Immunofluorescence; AAV: ANCA-associated vasculitis.
The authors declare that they have no competing interests.
TXL; participated in staining slides, statistical analysis and writing the article.
ZB; participated in designing study, clinical data collecting and article revise.
CRP; participated in doing electron microscopy. HYQ; participated in
diagnosis of IgG4-TIN. ZYH; participated in laboratory data collecting and
analysis. ZXL; participated in providing intellectual content and ethical
consent. CHY; participated in designing study and final approval of
submission. WYJ; participated in management of members of the study. All
authors read and approved the final manuscript.
This study was partially supported by the following: (1) Zhejiang medical and
health science and technology plan project (2011KYB081); (2) The clinical
speciality and special disease project of Hangzhou Science and Technology
bureau (20100733Q29); (3) The national natural science foundation of China
(81173426). Those funding sources had no involvement in the study design
or data collection. We thank Min Man and Zheng Jie who kindly provided
technical support, and Du Xin (Department of Nephrology, Nanjing First
Hospital, Nanjing Medical University) for providing excellent English
proofreading. We confirm that this article has not been simultaneously
reviewed or published elsewhere.
1Department of Nephrology (Key laboratory of Zhejiang province,
management of kidney disease), Hangzhou hospital of traditional Chinese
medicine, Hangzhou 310007, China. 2Department of Pathology, Zhejiang
Academy of Medical Science, Hangzhou 310007, China.
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