IgG4-related kidney disease

MINI-SYMPOSIUM: PATHOLOGY OF MEDICAL RENAL DISEASE

IgG4-related kidney diseaseLynn D Cornell

AbstractIgG4-related disease (IgG4-RD) is a recently recognized systemic immune-

mediated disease that can affect nearly any organ or tissue. The most

common manifestation in the kidney is IgG4-related tubulointerstitial

nephritis (IgG4-TIN), which can present as renal insufficiency, renal

mass lesions, or both. Histologically, IgG4-TIN is a plasma cell-rich inter-

stitial inflammatory infiltrate with mononuclear cells, eosinophils, and

increased IgG4þ plasma cells, along with expansile interstitial fibrosis

that often has a “storiform” appearance. Tubular basement membrane im-

mune complex deposits, best visualized on immunofluorescence staining,

are present in most cases. IgG4-TIN usually shows a rapid response to

steroid therapy. Glomeruli may be affected by IgG4-RD, usually in the

form of membranous glomerulonephritis; other glomerular lesions have

also been described. This review describes the different histopathologic

patterns of renal involvement by IgG4-RD, with associated clinical, radio-

graphic, and serologic features.

Keywords autoimmune pancreatitis; IgG4-related sclerosing disease;

immune complex; interstitial nephritis; membranous glomerulonephritis;

membranous nephropathy

Introduction

IgG4-related disease (IgG4-RD) is a recently recognized systemic

immune-mediated disease. IgG4-RD was first recognized in the

pancreas as a disease now termed autoimmune pancreatitis type I

(AIP). Other organs were noted to be involved with histopatho-

logic and clinical manifestations similar to AIP. AIP, or sclerosing

pancreatitis, was first described by Sarles et al. in 1961.1 These

authors surmised that sclerosing pancreatitis was an autoimmune

condition due to the presence of hypergammaglobulinemia in

some affected patients and the lack of evidence for an infection.

In 2001, Hamano et al. elucidated the link between IgG4 and

AIP: the hypergammaglobulinemia in AIP patients was largely

due to increased serum IgG4.2 Hamano and colleagues later

demonstrated tissue infiltration by IgG4þ plasma cells in the

pancreas in AIP.3 Thereafter, Kamisawa et al. expanded the

spectrum of AIP to a systemic disease by showing increased

IgG4þ plasma cells in AIP patients compared to controls in or-

gans and tissues other than the pancreas.4 These findings, sup-

plemented by IgG4 immunostaining of tissue, helped to identify

other organs involved by IgG4-RD.

Histologically, the fibroinflammatory lesions in different or-

gans often show striking histologic similarity.5 Some diseases,

including Mikulicz’s disease, Riedel’s thyroiditis, and some

cases of idiopathic hypocomplementemic tubulointerstitial

Lynn D Cornell MD Assistant Professor of Laboratory Medicine and

Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.

Conflicts of interest: none declared.

DIAGNOSTIC HISTOPATHOLOGY 19:5 166

nephritis,6e10 were previously thought to represent diseases of a

single organ system and now have become recognized as part of

IgG4-RD. The International Symposium on IgG4-related disease,

held in Boston, Massachusetts in October 2011, produced

consensus statements on the nomenclature and pathology of

IgG4-RD with its different organ manifestations.11,12

IgG4-related kidney disease (IgG4-RKD) is the term used to

refer to any or all patterns of renal involvement by IgG4-related

disease (IgG4-RD).12 As with other medical kidney diseases,

IgG4-RKD can be described in terms of changes to the different

“compartments” in the kidney: the tubules and interstitium,

the glomeruli, and the vessels. The most common pattern of

kidney involvement by IgG4-RD is IgG4-related tubulointerstitial

nephritis (IgG4-TIN). IgG4-TIN may be mass-forming and

detected on radiographic examination, or may be present clini-

cally as acute or progressive chronic renal insufficiency.

Glomerular disease, in particular membranous glomerulone-

phritis (MGN), may also be seen in IgG4-RD, with or without

concurrent IgG4-TIN.13 A lesion of the arteries, IgG4-related

plasma cell arteritis, has also been observed.14 The kidney may

also be affected by ureteral inflammatory pseudotumor or

retroperitoneal fibrosis.3,15,16 This article will review the different

patterns of renal involvement by IgG4-RD, with associated clin-

ical, radiographic, and serologic features.

IgG4-related tubulointerstitial nephritis

IgG4-TIN is a specific type of immune-mediated TIN that can be

distinguished from other types of TIN by clinical, radiographic,

laboratory, histopathologic, and immunophenotypic features.17

IgG4-TIN may present as masses evident on radiographic

studies, as acute or progressive chronic renal failure, or both.18

Tissue samples of mass lesions reveal TIN.19 IgG4-TIN patients

may have mild proteinuria and microscopic hematuria on uri-

nalysis. IgG4-TIN has been observed in IgG4-RD patients both

with and without pancreatic involvement, and some patients

appear to have renal involvement only. Saeki et al. and Raissian

et al. have collected data on the two largest biopsy series of IgG4-

TIN, at 23 and 35 cases respectively.18,20 These series showed

clinical and histologic features that have been encountered in

other organs affected by IgG4-RD: radiographic abnormalities,

plasma cell-rich inflammatory infiltrates with increased IgG4þplasma cells, elevated serum total IgG or IgG4, presence of other

organ involvement (either at the same time as renal involvement

or at another time), and rapid response to steroid therapy in most

patients.

Clinical features of IgG4-TIN

The average age of patients with IgG4-TIN is approximately 65

years, and most patients (w73e80%) are male.18,20,21 Patients in

IgG4-TIN studies represent a variety of racial and ethnic groups.

Most patients (57e76%) have acute or progressive chronic renal

failure. In the remaining patients, the primary indication for bi-

opsy or nephrectomy is a renal mass lesion. Many patients have

both kidney mass lesions and some degree of renal insufficiency.

There was other organ involvement by IgG4-RD in >80% of

patients in the Raissian et al. biopsy series, either concurrent

with or prior to the recognized IgG4-TIN. The most common

� 2013 Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.mpdhp.2013.02.002


extra-renal sites involved were the pancreas, liver, and salivary

or lacrimal glands.

Laboratory features of IgG4-TIN

Elevated serum total IgG and IgG4 has been observed inw70e80%

of patients with AIP22 and can be an indicator of IgG4-RD in the

appropriate clinical setting. Similarly, in IgG4-TIN, almost 80% of

patients with measurements available in a series of IgG4-TIN had

elevated serum total IgG or IgG4 levels. Of the subset that had

IgG4 subclass levels measured, 92% had elevated serum IgG4.18

Elevated serum IgG4 alone is not specific for IgG4-RD, however,

and so results of these serum studies should be interpreted

with caution.23 Other common laboratory features are hypo-

complementemia (56e78%of IgG4-TIN patients), peripheral blood

eosinophilia (33e48%), and positive ANA (w30%), which is usu-

ally low-titer.18,20
Figure 1 IgG4-related tubulointerstitial nephritis (IgG4-TIN). This biopsy is
from a 67-year-old woman with proteinuria (4 g/day), hematuria, and a
Radiographic features of IgG4-TIN serum creatinine of 1.2 mg/dl. The biopsy shows a multifocal TIN with
highly cellular areas with little fibrosis (arrowhead) and other areas with

increased fibrosis with a storiform pattern (arrow). In addition to IgG4-

TIN, the biopsy showed IgG4-related membranous glomerulonephritis,

which explains the heavy proteinuria. (Hematoxylin and eosin).

Renal radiographic involvement has been observed in 35% of

patients with AIP24; biopsy of such lesions reveals IgG4-TIN.19

Radiographic lesions of IgG4-TIN are best visualized on

contrast-enhanced CT scan. The lesions are commonly bilateral

and multiple and predominantly involve the renal cortex. Renal

parenchymal lesions can be variable, and can appear as small

peripheral cortical nodules, round or wedge-shaped lesions,

diffuse patchy involvement, or a large solitary mass.24 The

radiographic differential diagnosis of renal parenchymal lesions

includes lymphoma, vasculitis, pyelonephritis, and metastatic

cancer. Renal ultrasound may show markedly enlarged

kidneys.18

Biopsy features of IgG4-TIN

Figure 2 Higher magnification of the biopsy in Figure 1 reveals a pattern of

storiform fibrosis. Numerous eosinophils are present in the infiltrate (ar-

rows), along with plasma cells (arrowheads). (Hematoxylin and eosin).

By definition, IgG4-TIN shows a plasma cell-rich interstitial in-

flammatory cell infiltrate on light microscopic examination.

There is a spectrum of histologic appearances, ranging from

acute tubulointerstitial nephritis with minimal fibrosis, to an

intermediate pattern with some interstitial fibrosis but still a

marked inflammatory infiltrate, to a densely fibrotic, pauci-

cellular pattern with extensive tubular destruction and atro-

phy.18 (See Figure 1) The different degrees of fibrosis may

represent different stages of disease: on nephrectomy samples,

the innermost part of a mass lesion is more fibrotic, surrounded

by a more inflammatory lesion; and patients who have been

treated for a long history of other organ involvement show more

fibrotic and less inflammatory lesions. The fibrosis is expansile

and pushes the tubules apart. The fibrosis often has a “storiform”

pattern as seen in other organs involved by IgG4-RD.25 (Figure 2)

The interstitial infiltrate is composed of plasma cells, mono-

nuclear cells, and sometimes numerous eosinophils. The pres-

ence of many eosinophils may cause confusion with allergic TIN

due to a drug. Mild mononuclear cell tubulitis is seen, sometimes

also with occasional eosinophilic or plasma cell tubulitis. Gran-

ulomatous inflammation, neutrophils, and necrosis are absent. In

some cases, particularly those with extensive fibrosis, tubules are

destroyed and only fragments of tubular basement membranes

(TBMs) can be appreciated on PAS e or silver-stained sections.

(Figures 3 and 4) A lesion similar to IgG4-TIN, chronic sclerosing

pyelitis, an inflammatory mass that affects the renal pelvis, has

also been described.26


More than 80% of IgG4-TIN cases show focal or diffuse TBM

immune complex deposits, usually in the absence of glomerular

deposits. By immunofluorescence (IF), there is bright granular

TBM staining for IgG and kappa and lambda light chains, usually

for C3 with lesser intensity, and for C1q in w10% of cases.18

(Figure 5). Rarely, dim TBM granular IgA staining may also be

present. TBM deposits are found more frequently in specimens

with interstitial fibrosis, and the deposits are found only in areas

of the fibroinflammatory process and not in adjacent unaffected

areas.18 By electron microscopy, corresponding amorphous TBM

electron dense deposits are seen in cases with deposits seen by

IF.18 (Figure 6) Of interest, similar immune complex deposits are

seen in basement membranes in the pancreas affected by AIP,27

which also supports a common immune-mediated mechanism in

different organs in IgG4-RD. Glomeruli are negative by IF and

electron microscopy unless there is a concurrent immune



Figure 3 A Jones methenamine silver stain shows residual tubular base-

ment membranes (arrows) from tubules destroyed by the fibroinflamma-

tory infiltrate.

Figure 5 Immunofluorescence staining for IgG on a biopsy from a 76-year-

old man with a history of autoimmune pancreatitis shows granular

staining of tubular basement membranes (white arrows). There is also

granular interstitial staining for IgG (white arrowheads). A glomerulus

(black arrow) is negative for IgG. There was similar staining for kappa and

lambda light chains and for C3.


complex glomerulonephritis. The presence of TBM immune

complex deposits is a helpful diagnostic feature, as these deposits

are unusual outside of the setting of lupus nephritis.

As examined by Raissian et al., immunostaining for IgG4þplasma cells is helpful in distinguishing IgG4-TIN from other

types of plasma cell-rich interstitial inflammatory infiltrates that

could mimic IgG4-TIN clinically and histologically.18 Using a cut-

off point of focal moderate (11e30 IgG4þ cells/40x field)

to marked (>30 IgG4þ cells/40� field) increase in IgG4þ plasma

cells, similar to what is used in pancreatic specimens, this study

showed a sensitivity of 100% (95% confidence interval (CI),

0.9e1) and specificity of 92% (CI 0.86e0.95) for distinguishing

IgG4-TIN from other forms of TIN, after excluding cases of in-

flammatory infiltrates in pauci-immune necrotizing and cres-

centic glomerulonephritis, which also can show increased IgG4þplasma cells in a significant number of cases.18

In contrast to criteria used for evaluation of pancreatic spec-

imens stained for IgG4, the Raissian et al. study of kidney

Figure 4 Immunoperoxidase staining for IgG4 shows a marked increase in

IgG4þ plasma cells. No tubular basement membrane immune complex

deposits were identified in this biopsy by immunoperoxidase or immu-

nofluorescence, which does not exclude a diagnosis of IgG4-TIN.


biopsies only evaluated a single 40x field with the most

concentrated IgG4þ plasma cells to account for the usual small

size of kidney biopsies. Nephrectomy samples may require

evaluation of three high-magnification fields to avoid over-

diagnosis of IgG4-TIN,11 although other histopathologic fea-

tures are helpful and more readily seen in nephrectomy samples

or larger wedge biopsy specimens done for mass lesions.

Recently, in other organs, the IgG4þ to IgGþ plasma cell ratio

has been evaluated to help account for differences in the con-

centration of plasma cells.28 This ratio is particularly helpful in

cases with sparse inflammation, especially retroperitoneal

fibrosis. One study of kidney biopsies suggested an IgG4/IgGþplasma cell ratio of >40% to diagnose IgG4-TIN,29 although

lower ratios are probably acceptable depending on the tissue

sample size and other clinicopathologic features.

Figure 6 Electron microscopy on the biopsy in Figure 5 shows thickened

tubular basement membranes with amorphous electron dense deposits

(arrows). The glomeruli were free of immune complex deposits.




Diagnostic criteria for IgG4-TIN

Two papers have proposed diagnostic criteria for IgG4-TIN.18,21

Both of these put forward similar criteria that include histology,

serology, other organ involvement, and radiographic features.

(Table 1) Both papers emphasize the need to exclude other di-

agnoses that may show increased IgG4þ plasma cells, especially

granulomatosis with polyangiitis (Wegener), ChurgeStrauss syn-

drome, and plasma cell myeloma or lymphoproliferative disorders

with plasmacytic differentiation. The proposed clinicopathologic

criteria are similar to the HISORt criteria proposed for the diag-

nosis of AIP.30 One notable difference between the diagnosis of

AIP and IgG4-TIN is that IgG4-TIN does not use response to steroid

therapy as a diagnostic criterion, as response to steroid therapy

does not distinguish IgG4-TIN from interstitial nephritis due to

other causes.

Histopathologic differential diagnosis of IgG4-TIN

TIN in general is a disease pattern with heterogenous causes,

both immune and non-immune, both inherited and acquired.

The clinical presentation, laboratory results, radiographic find-

ings, and biopsy features should be considered in an attempt to

make a specific diagnosis. As opposed to glomerular diseases,

which are, for the most part, specific and well-defined in terms

of histologic, ultrastructural, and immunophenotypic features,

renal biopsies are sometimes diagnosed simply as TIN without a

Proposed diagnostic criteria for IgG4-TIN

Raissian et al. criteria for IgG4-TIN (Raissian et al., 2011)

Histology Plasma cell-rich tubulointerstitial nephritis with >1

Tubular basement membrane immune complex depo

microscopyb

Imaging Small peripheral low-attenuation cortical nodules, ro

Diffuse marked enlargement of kidneys

Serology Elevated serum IgG4 or total IgG level

Other organ

involvement

Includes autoimmune pancreatitis, sclerosing cholan

aortic aneurysm, lung involvement, retroperitoneal fi

Japanese Society of Nephrology criteria for IgG4-related kidney disease (tu

Clinical features Clinical or laboratory evidence of kidney damage, inc

serum IgG or IgE level or hypocomplementemia

Imaging Abnormal radiographic findings: Multiple low-density

hypovascular solitary kidney mass, hypertrophic lesio

Serology Elevated serum IgG4 or total IgG level

Histology C Dense lymphoplasmacytic infiltrate with >10 IgG4

C Characteristic storiform fibrosis

Other organ

involvement

Characteristic histologic findings of IgG4-RD in other

Diagnosis of IgG4-TIN requires the histologic feature of plasma cell-rich TIN with in

Serology, or other organ involvement categories.

“Definite” IgG4-related kidney disease occurs with three of the following: clinical feat

features (a & b); imaging, serology, or other organ involvement; or clinical features,

“Probable” and “possible” disease occurs with fewer criteria.a Mandatory criterion.b Supportive criterion, present in >80% of cases.

Table 1


more specific diagnosis indicating the underlying cause of this

disease pattern. Listed below are individual features that can be

seen in IgG4-TIN and the differential diagnosis of those features.

(Table 2)

Increased IgG4þ plasma cells. Increased IgG4þ plasma cells are

present in IgG4-TIN, but this feature is not specific for IgG4-RD.31

In kidney biopsies with interstitial inflammation related to pauci-

immune glomerulonephritis, w30% of cases show at least focal

moderate to marked increase in IgG4þ plasma cells.18 Increased

IgG4þ plasma cells have also been noted in granulomatosis with

polyangiitis (Wegener’s, GPA) affecting other organs.32 Histo-

logic features that suggest GPA are necrotizing or crescentic

glomerulonephritis, or neutrophils, karyorrhexis or necrosis

within areas of interstitial inflammation. (Figure 7) Neutrophils

are typically absent or very rare in IgG4-RD in any affected tissue,

including IgG4-TIN. The absence of a serum ANCA (or anti-

myeloperoxidase or -proteinase 3 antibodies) also helps to

exclude GPA or ANCA-related disease as a cause of the interstitial

inflammation.

Focally increased IgG4þ plasma cells can be seen in a few

other causes of interstitial inflammation; other clinical and his-

topathologic features usually can distinguish these from IgG4-

TIN. Chronic pyelonephritis resembles IgG4-TIN because it can

be mass-forming radiographically and can show plasma cell-rich

0 IgG4D plasma cells/hpf field in the most concentrated fielda

sits by immunofluorescence, immunohistochemistry, and/or electron

und or wedge-shaped lesions, or diffuse patchy involvement

gitis, inflammatory masses in any organ, sialadenitis, inflammatory

brosis

bulointerstitial nephritis) (Kawano et al., 2011)

luding abnormal renal function or abnormal urinalysis with elevated

lesions on contrast-enhanced CT scan, diffuse kidney enlargement,

n of the renal pelvic wall

þ plasma cells/hpf and/or IgG4/IgGþ plasma cell ratio of >40%

organs

creased IgG4þ plasma cells and at least one other feature from the Imaging,

ures, serology, and histologic features (a & b); imaging, serology, and histologic

serology, histologic features (a only), and other organ involvement.



Differential diagnosis of IgG4-TIN

Type of interstitial inflammation Potential similarities to IgG4-TIN Potential distinguishing features from IgG4-TIN

Mass-forming granulomatosis with

polyangiitis (Wegener) or ChurgeStrauss

syndrome

Similar radiographic features

Other organ involvement

May show increased IgG4þ plasma cells

Vascular inflammation

Neutrophils, necrosis, karyorrhexis

Necrotizing and crescentic glomerulonephritis

Positive serum ANCA (MPO or PR3)

Vascular involvement is necrotizing, without

plasma cells

Chronic pyelonephritis May show similar radiographic features

Plasma cell-rich infiltrate

Usually no increase in IgG4þ plasma cells

Neutrophils and neutrophilic cast may be

present

Positive urine culture

Inflammation adjacent to unsampled tumor Inflammation (less likely plasma cell-rich)

Mass lesion on imaging studies


Clinical/radiographic correlation

Acute allergic tubulointerstitial nephritis Many eosinophils

Peripheral eosinophilia


Usually not plasma cell-rich

Typically no TBM immune complex deposits

Not mass-forming

Hypocomplementemic tubulointerstitial

nephritis (some previously diagnosed cases

likely represent IgG4-TIN)

TBM immune complex deposits

Plasma cell-rich interstitial inflammation

Hypocomplementemia

No increase in IgG4þ plasma cells

Absence of systemic inflammatory disease

Tubulointerstitial nephritis associated with

Sj€ogren syndrome

TBM immune complex deposits


May show similar radiographic features

No increase in IgG4þ plasma cells

Salivary gland involvement has distinct

pathology from IgG4-RD6,38

Tubulointerstitial lupus nephritis TBM immune complex deposits


Positive serum ANA


Most cases show glomerular abnormalities by

light microscopy and glomerular immune

complex deposition by IF/EM

Not mass-forming

Lymphoma or plasma cell myeloma Rare cases composed of IgG4þ plasma cells

May show similar radiographic features

Patients may have lymphadenopathy

Monotypic staining for kappa or lambda light

chain

Histopathologic characteristics in other organs

Monomorphic infiltrate without tubulitis

Table 2


infiltrate on biopsy. Helpful features that favor chronic pyelo-

nephritis over IgG4-TIN are the presence of neutrophils or

neutrophilic casts, which may be focal, and a history of urinary

tract infections or positive urine cultures.

Other types of TIN show increased plasma cells, especially

autoimmune TIN, including TIN associated with Sj€ogren syn-

drome. Sj€ogren syndrome can mimic IgG4-RD clinically with

salivary gland involvement, but this disease is clinically and

histopathologically distinct from IgG4-RD.6 Notably, nearly all

cases of Sj€ogren syndrome-related TIN do not show increased

IgG4þ plasma cells.18

TBM immune complex deposits: TBM immune complex de-

posits are an especially helpful feature in IgG4-TIN because these

deposits are uncommon in the absence of immune complex

glomerulonephritis. The most common disease with TBM de-

posits is lupus nephritis. Lupus nephritis can show plasma cell-

rich tubulointerstitial inflammation and TBM immune complex

deposits, and so is in the differential diagnosis of IgG4-TIN. A

clinical history of systemic lupus erythematosus (SLE) is helpful


in making the diagnosis of lupus nephritis, but the pathologist

must exercise caution in patients who have been labeled with

SLE because of clinical and serologic features that could repre-

sent another immune-mediated disease. Patients with IgG4-RD

not uncommonly have a positive ANA. Lupus TIN typically is

accompanied by glomerular disease, which is usually not present

in IgG4-TIN, although membranous glomerulonephritis (MGN) is

a glomerular pattern seen in both SLE and IgG4-RD.13,33

Apparent lupus TIN with minimal glomerular deposits has

rarely been reported.34 A unique feature of IgG4-TIN is the

presence of TBM immune complex deposits only in areas of

interstitial inflammation (usually with fibrosis), whereas the

TBM deposits in lupus TIN may be present in areas with or

without inflammation.

Other types of TIN can show TBM immune complex deposits

without glomerular deposits. Like lupus nephritis, Sj€ogren syn-

drome is associated with systemic autoimmune disease. Sj€ogren

syndrome in the kidney shows TIN with increased plasma cells

and may show TBM deposits.35,36 Some patients diagnosed

clinically as Sj€ogren syndrome may actually have IgG4-RD in the



Figure 7 ANCA-associated disease can mimic IgG4-RD. This kidney biopsy

was of a mass lesion in a 55-year-old woman. Light microscopy revealed a

plasma cell-rich inflammatory infiltrate, but there also were areas of ne-

crosis, granulomatous inflammation, and neutrophils (arrow), features

that are not part of IgG4-related disease (hematoxylin and eosin, left

panel). An immunoperoxidase stain for IgG4 (right panel) showed a

marked increase in IgG4þ plasma cells, which initially led to an erroneous

diagnosis of IgG4-related disease. The patient had a positive anti-

myeloperoxidase antibody. This patient had a similar inflammatory lesion

in the heart.


form of chronic sclerosing sialadenitis, which shows increased

IgG4þ plasma cells and is a distinct clinicopathologic entity from

Sj€ogren syndrome.6,37 Only one of 14 cases of Sj€ogren syndrome-

associated TIN showed a focal moderate increase in IgG4þplasma cells in one study.18

TIN with TBM immune complex deposits without systemic

disease include idiopathic hypocomplementemic interstitial

nephritis with extensive tubulointerstitial deposits and giant cell

tubulitis with TBM immune deposits. Many cases of hypo-

complementemic interstitial nephritis likely represent IgG4-TIN,

as it was previously not widely recognized.9,38,39 Many of the

described patients were elderly males. Two patients in the largest

series of 8 biopsies had a history of sclerosing cholangitis, and so

cases may represent IgG4-RD.9

Giant cell tubulitis shows granular TBM staining for IgG, C3,

and kappa and lambda light chains by IF.40 This entity also

shows the unusual feature of giant cells surrounding tubules,

which is not seen in IgG4-TIN. Clinically, the patients described

had recently undergone heart valve replacement for rheumatic

heart disease; the authors propose that the giant cell tubulitis is

an allergic reaction to a drug.

BK polyomavirus tubulointerstitial nephritis (BK-TIN) can

show TBM deposits.41 The clinical setting of BK-TIN is different

from IgG4-TIN, however, in that this disease usually occurs in

renal allografts. A recent series of BK-TIN in the native kidney

had no cases with TBM deposits.42 IgG4-TIN has not been

described in allografts.

Anti-tubular basement membrane nephritis is a TIN that shows

TBM staining by IF, but the staining pattern is linear, as opposed

to the granular staining as seen in IgG4-TIN and other entities in

the differential diagnosis.43 Furthermore, in anti-TBM nephritis,

electron dense deposits are not seen in the TBM ultrastructurally.

Increased eosinophils: the presence of numerous eosinophils in

an interstitial infiltrate first raises the common possibility of


allergic TIN due to drug. Both IgG4-TIN and allergic TIN may

show peripheral eosinophilia as well. Even eosinophilic tubulitis

is sometimes seen in IgG4-TIN (LD Cornell, unpublished obser-

vation), as in allergic TIN. Indeed, some researchers speculate

that IgG4-RD is a chronic allergic reaction rather than a typical

“autoimmune” disease.44 That said, IgG4-TIN shows the char-

acteristic features of expansile interstitial fibrosis, plasma cell-

rich inflammation, and TBM deposits. Some cases of IgG4-TIN

show an acute TIN pattern without fibrosis or TBM deposits,

however; in these cases, a clinical history suggestive of IgG4-RD

is helpful, as is an immunoperoxidase stain for IgG4 to show

increased IgG4þ plasma cells.

Mass lesion with interstitial inflammation on biopsy: a sig-

nificant number of patients with IgG4-RD undergo biopsy or

nephrectomy for a renal mass lesion(s) with a clinical suspicion

of malignancy.18,19 Radiographic features of IgG4-TIN are

described elsewhere in more detail.24When the biopsy shows

only inflammation, the question arises as to whether the

inflammation is a reaction to an adjacent tumor, or if the

inflammation itself accounts for the mass. Inflammatory entities

that account for renal mass lesions include GPA (Wegener’s),

chronic pyelonephritis, and IgG4-TIN; all three can show

increased plasma cells but usually have other distinguishing

clinical and histologic features. The pathologist, radiologist, and

clinician should keep in mind the possibility of inflammation

adjacent to an unsampled tumor, in which case re-biopsy of the

mass is needed for diagnosis.

When should IgG4 staining be performed?

Biopsy features of expansile or “storiform” interstitial fibrosis,

acute TIN with increased plasma cells, TBM immune deposits, a

clinical history suggestive of IgG4-RD, or a renal mass lesion that

on biopsy shows interstitial inflammation should all prompt the

pathologist to stain for IgG4 to evaluate infiltrating plasma cells.

IgG4-related glomerular disease

Glomerular diseases have been described in IgG4-RD, mostly as

case reports or as part of IgG4-TIN case series. In a clinical series

of patients with IgG4-RD, 11/28 (39%) patients had some type of

glomerular lesion.21

IgG4-related membranous glomerulonephritis

MGN in the setting of IgG4-RD is referred to as “IgG4-related

MGN” (IgG4-MGN).12 MGN in general is a glomerular disease

pattern characterized by regularly-spaced subepithelial glomer-

ular basement membrane (GBM) immune complex deposits.

MGN may be primary (“idiopathic”) or may be secondary to a

number of conditions, including autoimmune diseases, neo-

plasms, medications, and infections.45 Of note, primary MGN is

also an IgG4-dominant disease.46,47

In two biopsy series of IgG4-TIN, MGN was present in w7%

of patients.18,20 MGN has also been noted in several case reports

of IgG4-RD.18,20,21,25,48e55 There is one published series of IgG4-

related MGN, which included 9 patients.13 All patients presented

with proteinuria, which was typically nephrotic-range. In this

series, 5 of 9 patients had concurrent IgG4-TIN on biopsy,

although TIN was sometimes focal. IgG4-TIN therefore does not




necessarily accompany IgG4-MGN. It should be noted that the

MGN pattern affects glomeruli diffusely and does not by itself

result in renal mass lesions like IgG4-TIN. IgG4-MGN should be

suspected in IgG4-RD patients with significant proteinuria. Pa-

tients with MGN on renal biopsy and IgG4-TIN or a clinical

history suggestive of extrarenal IgG4-RD should be evaluated for

IgG4-RD.

By light microscopy, the features of IgG4-MGN are similar to

primary MGN or MGN secondary to other diseases. Glomeruli

appear normal or show thickened capillary loops. Subepithelial

immune complex deposits can be seen on a trichrome stain, and

GBM “spikes” can sometimes be seen using silver or PAS stains.

One biopsy in the Alexander et al. series showed segmental

endocapillary hypercellularity in addition to the MGN pattern. By

IF, glomeruli typically show segmental or global granular GBM

staining for IgG, C3, and kappa and lambda light chains. In IgG4-

MGN, similar to primary MGN, the glomerular deposits contain

IgG4, as can be demonstrated by IF staining for IgG subclasses or

immunoperoxidase staining for IgG4 (the latter is a less sensitive

technique than IF). Immunostaining for the phospholipase A2

receptor, which is associated with primary MGN, was negative in

all 8 biopsies stained in the Alexander et al. series; this finding

argues that these cases represent a secondary MGN.13,56 Two of 9

patients had other glomerular disease in addition to IgG4-MGN:

one had IgA nephropathy, and another had nodular diabetic

glomerulosclerosis. Compared to IgG4-TIN, TBM deposits were

less common in IgG4-MGN, present in 33% of cases.13

Other IgG4-related glomerular lesions

Other glomerular diseases have been reported in IgG4-RD,

including IgA nephropathy/HenocheSch€onlein purpura, mem-

branoproliferative glomerulonephritis, and endocapillary prolif-

erative glomerulonephritis, sometimes with crescents.20,21,57e59

Minimal change disease has been reported in 3 of 116 IgG4-

RKD cases presented in regional meetings in Japan between

2004 and 2011 (Takako Saeki, personal communication). Pa-

thologists have sometimes observed a pattern of mesangial pro-

liferative glomerulonephritis with IgG-containing mesangial

immune complex deposits, without a more specific diagnosis, in

cases of IgG4-TIN.19,20 Diabetic glomerulosclerosis can be seen in

patients with IgG4-RD. Although diabetes mellitus is common in

the general population, diabetes is sometimes a manifestation of

AIP due to pancreatic endocrine insufficiency, and thus could

give rise to diabetic glomerulosclerosis.

IgG4-related vascular disease

IgG4 plasma cell arteritis was recently described in a patient with

concurrent IgG4-TIN on biopsy.14 The arteritis affected small and

medium-sized arteries and showed marked intimal, medial, and

adventitial inflammation with plasma cells and mononuclear

cells, with many IgG4þ plasma cells. No neutrophils, fibrinoid

necrosis of the arteries, or rupture of the elastica was present,

and so this is a distinctive type of arteritis.

Veins can be seen in nephrectomy specimens, but are usually

not present in kidney needle core biopsies. Venulitis similar to

that seen in other organs affected by IgG4-RD can sometimes be

seen in IgG4-TIN but is not necessary for diagnosis in the

kidney.11,19


IgG4-RKD: response to therapy

IgG4-TIN usually shows a rapid response to steroid therapy,

similar to other organs affected by IgG4-RD. In both larger IgG4-

TIN biopsy series, 90% of patients with elevated serum creati-

nine and who were treated with steroids showed decreased

creatinine at follow-up.18,20 A few patients were treated with

steroids plus other immunosuppressive drugs and also respon-

ded.18 TIN of any cause may respond to steroid therapy, but

IgG4-TIN tends to show a response even in cases with severe

interstitial fibrosis on the biopsy sample.18 This observation may

reflect the patchy nature of the infiltrate in IgG4-TIN, or it may

reflect a different process of fibrosis from other tubulointerstitial

diseases.

IgG4-TIN may relapse after treatment, similar to other organ

manifestations of IgG4-RD.60e62 A small case series described a

response to rituximab in IgG4-RD patients refractory to steroid

treatment,63 and one patient in the Raissian series of IgG4-TIN

who was steroid-dependent showed a response to rituximab

(unpublished data). Other studies of rituximab in IgG4-RD are

ongoing. Longer-term follow-up data will need to be collected on

IgG4-RD patients who have been treated with steroids or other

immunosuppressive agents.

IgG4-MGN has been recognized more recently, and so there is

less knowledge of response to treatment for this manifestation of

IgG4-RKD. In the Alexander et al. series of IgG4-MGN patients,

6 patients were treated with various immunosuppressive drugs.

All 6 patients showed decreased proteinuria and most showed

decreased serum creatinine at an average of 39 months follow-up

(range 4e184 months). One patient was not treated, progressed to

end-stage renal disease, and underwent kidney transplantation,

and had no clinical evidence of recurrent MGN more than 10 years

after transplant. While IgG4-TIN shows a brisk response to ther-

apy, IgG4-MGN likely has a different pathogenic mechanism. We

would not necessarily expect the same treatment response of

proteinuria, which may require reabsorption of immune complex

deposits and glomerular basement membrane remodeling.

Conclusion

IgG4-RKD can take a number of different forms. IgG4-TIN is a

plasma cell-rich TIN that may present as renal failure, renal mass

lesions, or both. IgG4-TIN is distinguished from other causes of

TIN by histologic, immunophenotypic, clinical, serologic, and

radiographic features. IgG4-RKD may also take the form of

glomerulonephritis, most commonly with a pattern of MGN,

which may or may not show concurrent IgG4-TIN. IgG4þ plasma

cell arteritis was recently described in the kidney, and is distinct

from other types of arteritis. IgG4-TIN typically shows a rapid

response to steroid or other immunosuppressive therapy, but less

is known about response of glomerular lesions to therapy. A

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IgG4-related kidney disease