REVIEWS

IgG4-related disease and the kidney

Frank B. Cortazar and John H. Stone
Abstract | IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that involves
almost every organ system. In this Review, we summarize current knowledge of IgG4-RD and its most
frequent manifestations in the kidney—IgG4-related tubulointerstitial nephritis (TIN) and membranous
glomerulonephropathy (MGN). Diagnosis of IgG4-RD relies on histopathology: the typical features are a dense
lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions
stain positively for IgG4. IgG4-related TIN bears the hallmark pathological findings of IgG4-RD; distinctive
radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary
to IgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have
roles in the pathophysiology of IgG4-RD, but the details of these roles remain unclear. The IgG4 molecule itself
is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response.
Fibrosis might be caused by activation of innate immune cells by polarized CD4+ T cells. Glucocorticoids are
the standard initial treatment for IgG4-RD, but their long-term adverse effects and the high frequency of relapse
and renal damage associated with use of this treatment has prompted a search for more effective options.
B-cell depletion and the targeting of plasmablasts are both promising approaches.
Cortazar, F. B. & Stone, J. H. Nat. Rev. Nephrol. advance online publication 30 June 2015; doi:10.1038/nrneph.2015.95

Introduction
IgG4-related disease (IgG4‑RD) is a fibroinflammatory
condition that has emerged in the past 15 years and is
characterized by tumefactive lesions and two hallmark
histological features: a lymphoplasmacytic infiltrate
that is enriched with IgG4+ plasma cells, and stori­form
fibrosis.1 The disease often presents with multiple organ
involvement and is often, but not always, associ­ated with
an elevated serum level of IgG4. Such elevated concen-
trations of IgG4 were first noted in 2001, in patients
with sclerosing pancreatitis; this condition is now rec-
ognized as falling within the IgG4‑RD spectrum and
is known as type 1 (IgG4-related) autoimmune pan-
creatitis.2 Type 2 auto­immune pancreatitis has distinct
clinical and pathological features.3 Frequent extrapan-
creatic involvement in type 1 autoimmune pancreatitis
led to the realization in 2003 that IgG4‑RD is a systemic
disease.4 Eponymous diseases that were all previously
regarded as discrete clinical entities, such as Mikulicz
disease, Küttner tumour and Riedel thyroiditis, are now
recognized as part of the spectrum of IgG4‑RD, as the
pathology observed across organs in each disease is
strikingly similar.1
IgG4‑RD can affect nearly every organ system, includ-
Nephrology Unit ing the pancreas, biliary tree, aorta, lung, salivary and
(F.B.C.), Rheumatology lacrimal glands, thyroid, pachymeninges and kidney.
Unit (J.H.S.),
Massachusetts
Clinically apparent renal involvement seems to occur in
General Hospital, approximately 15% of patients.5 Intrinsic renal involve-
55 Fruit Street, Boston, ment of IgG4‑RD encompasses two distinct entities
MA 02114, USA.
that together comprise IgG4-related kidney disease
Correspondence to:
J.H.S.
jhstone@ Competing interests
mgh.harvard.edu The authors declare no competing interests.
(IgG4‑RKD): tubulointerstitial nephritis (TIN) and
membranous glomerulonephropathy (MGN). Prompt
evaluation and treatment of these entities are essen-
tial because of the increased morbidity and mortal-
ity that is associated with the development of chronic
kidney disease. In this Review, we provide an over-
view of IgG4‑RD and describe the clinicopathological
features of IgG4-related TIN and MGN secondary to
IgG4‑RD. We also briefly review IgG4-related retro-
peritoneal fibrosis (RPF), an inflammatory condition
on the IgG4‑RD disease spectrum that often centres on
the periaortic region and can entrap ureters, leading
to hydronephrosis and renal injury. Finally, we discuss
treatment approaches to IgG4‑RD, including the
current use of glucocorticoids and the promising results
obtained with rituximab treatment, and highlight new
research that aims to elucidate the pathogenesis of this
systemic disease.
Overview of IgG4‑RD
A defining feature of IgG4‑RD is that the histological
appearance of affected tissue is similar regardless of
the organ from which it originates.1 The predominant
morpho­logical observation is a dense lymphoplasmacytic
infiltrate that is rich in IgG4+ plasma cells (Figure 1). This
lymphoplasmacytic infiltrate is enmeshed by irregu-
larly whorled storiform fibrosis.6,7 Obliterative phlebi-
tis, which results in destruction of the venous wall and
lumen, is another lesion that is commonly observed
in IgG4‑RD (Figure 1d).6 Some variation in pathology
exists between organs. For example, obliterative phlebitis
is universally present in type 1 autoimmune pancreatitis

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REVIEWS
Key points
■■ IgG4-related disease (IgG4‑RD) is a systemic disease that can affect almost
every organ system, including the kidney
■■ Diagnosis of IgG4‑RD is based on characteristic pathology: a lymphoplasmacytic
infiltrate enriched with IgG4+ plasma cells, and storiform fibrosis
■■ Serum IgG4 levels are elevated in most patients with IgG4‑RD, but are neither
sufficiently sensitive nor sufficiently specific to enable diagnosis of the disease
■■ IgG4-related tubulointerstitial nephritis is the most common form of IgG4-
related kidney disease; the condition is characterized by unique findings on
contrast-enhanced CT and the hallmark pathology of IgG4‑RD
■■ Membranous glomerulonephropathy secondary to IgG4‑RD is a rare
manifestation of IgG4‑RD that is not associated with antibodies against the
secretory phospholipase A2 receptor
■■ Glucocorticoids are the standard therapy for IgG4‑RD, but frequent relapses and
adverse effects limit their use; B-cell depletion is an alternative approach
a b
c d
Figure 1 | Typical pathological features of IgG4‑related disease in the lung,
retroperitoneum and mediastinum. a | Low magnification Nature Reviews | Nephrology
of lymphoplasmacytic
infiltrate in a lung biopsy sample from a patient. Diffuse cellular infiltrates are
interwoven with extensive storiform fibrosis. Haematoxylin and eosin staining,
magnification ×100. b | High magnification of lymphoplasmacytic infiltrate (white
arrows) and storiform fibrosis (black arrows). Haematoxylin and eosin staining,
magnification ×400. c | A biopsy sample from the retroperitoneum of a patient with
IgG4-related retroperitoneal fibrosis, immunostained to identify IgG4+ plasma cells
(brown-stained nuclei). Germinal centres are also evident (arrows). Magnification
×400. d | Obliterative phlebitis in a lung biopsy sample from a patient with fibrosing
mediastinitis. The lumen of the vein (black arrows) is almost completely obliterated
by the lymphoplasmacytic infiltrate (grey arrows). Haematoxylin and eosin staining,
magnification ×400. Images courtesy of V. Deshpande, Massachusetts General
Hospital, Boston, USA.
but is seen less frequently in some organs—including the
kidney in IgG4‑RKD—than in others. Eosinophilic infil-
tration occurs in approximately 50% of IgG4‑RD cases,
regardless of the organ involved.6
IgG4+ plasma cells
No number of IgG4+ plasma cells within a biopsy sample
is sufficient to make a diagnosis of IgG4‑RD without his-
tological findings that support the diagnosis. Neither the
number of IgG4+ plasma cells per high-power field (hpf)
nor the ratio of IgG4+ to IgG+ plasma cells is specific for
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the diagnosis of IgG4-RD.8 Rather, the presence of hall-
mark morphological features in the right clinical context
allows the pathologist and clinician to reach the diag-
nosis in collaboration. A high number of IgG4+ plasma
cells per hpf and an elevated IgG4+:IgG+ plasma cell ratio
supports the diagnosis of IgG4‑RD, but careful clinico-
pathological correlation and sound clinical judgement
must be exercised in the diagnosis of IgG4‑RD.
Variation between patients and organs also prevents
IgG4+ plasma cell concentrations from being a reliable
diagnostic marker of IgG4‑RD. For example, fewer IgG4+
plasma cells might be expected in biopsy samples from
patients with RPF than in samples from patients without
RPF because the pathology of this condition at the time
of biopsy is predominantly fibrotic, possibly as a result of
a longer subclinical phase than other forms of IgG4‑RD,
but the reason is uncertain. In patients with RPF, as few
as 10 IgG4+ plasma cells per hpf might be considered
sufficient to support a diagnosis of IgG4-RD, particu-
larly if the remainder of the clinical and pathological
features are consistent with that diagnosis. A much
higher number of IgG4+ plasma cells per hpf is usually
seen in biopsy samples of the major salivary glands, lac-
rimal glands, pancreas, lungs, kidneys, and many other
organs in patients with IgG4‑RD. Such variation has led
to proposals that a diagnosis of IgG4-RD should be con-
sidered only if >10–50 IgG4+ plasma cells per hpf are
found in biopsy samples, depending on the particular
organ involved.6–8 A finding of >30 IgG4+ plasma cells
per hpf is considered to have reasonable specificity for
type 1 autoimmune pancreatitis, whereas a finding of >10
IgG4+ plasma cells per hpf has reasonable specificity for
IgG4-related TIN,8,9 although precise specificities have
not been quantified.
The IgG4+:IgG+ plasma cell ratio can also be a useful
metric for diagnosis. In most documented cases of
IgG4‑RD, this ratio is >40%, a value that has been pro-
posed as a criterion for diagnosis across all organs.8 The
IgG4+:IgG+ plasma cell ratio can be particularly helpful
in the setting of advanced fibrosis, when the paucity
of cells makes large concentrations of IgG4 + plasma
cells unlikely.
Serum IgG4 concentrations
Diagnosis of IgG4‑RD
Analysis of serum IgG4 levels is often the first diagnostic
test ordered when IgG4‑RD is suspected. Concentrations
of serum IgG4 that are 6–8-fold higher than the normal
upper limit (~0.86–1.35 g/l) strongly suggest the diag-
nosis. Some patients with multiorgan disease exhibit
dramatic elevations in serum IgG4 concentration,
­occasionally as high as 40–50 g/l.10
Milder elevations of IgG4 levels are common in
a variety of conditions, many of which can mimic
IgG4‑RD. Bronchiectasis, biliary diseases, pancreatic
cancer, and vasculitides, such as granulomatosis with
polyangiitis (formerly known as Wegener granuloma-
tosis) and eosinophilic granulomatosis with poly­angi­
itis (formerly known as Churg–Strauss syndrome), all
fit this category.11 The high frequency with which mild
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a Heavy chain
Cys Cys Cys Cys
Pro Pro Pro Pro
Ser Ser Ser Ser
Light chain
Cys Cys Cys Cys
b
Recombination
Symmetric IgG4 antibodies Asymmetric IgG4 antibodies
Figure 2 | Fab arm exchange among IgG4 antibodies. aNature Reviews
| The heavy | Nephrology
chains of
IgG4 antibodies switch between interchain and intrachain disulphide-bonded
configurations. Intrachain disulphide-bonded IgG4 consists of noncovalently
associated ‘half-molecules’ that can dissociate from one another. b | Dissociation
of the two halves of the IgG4 antibodies allows recombination to produce
asymmetric, bispecific antibodies. Modified from Mahajan, V. S. et al. Annu. Rev.
Pathol. 9, 315–347 (2014) with permission from Annual Review of Pathology ©
by Annual Reviews, http://www.annualreviews.org.
to moderate elevations of serum IgG4 concentrations
are observed in patients with diagnoses other than
IgG4‑RD greatly limits the utility of IgG4 concentration
for diagnosis. In a 2014 study, the upper limit of IgG4
levels considered to be normal was doubled relative to
the standard; this approach raised the specificity of the
assay from 60% to 91%, but decreased the sensitivity to
an unacceptably low 35%.12
Furthermore, a normal serum IgG4 level does not
exclude diagnosis of IgG4‑RD. When IgG4‑RD was
first identified, diagnosis of the condition was linked
with elevated serum IgG4 concentrations. Consequently,
many subsequent studies have given disproportionate
importance to serum IgG4 concentrations in diagno-
sis.2 This bias has increased the reported prevalence
of elevated serum IgG4 concentrations and led to an
undue influence of serum IgG4 concentrations on
the diagnosis.
Two studies that were performed at one medical centre
provide a striking demonstration that serum IgG4 con-
centration is not a reliable indicator for diagnosis of
IgG4-RD.12,13 In the first, all cases of elevated serum IgG4
concentrations recorded at the Massachusetts General
Hospital over a 10‑year period were reviewed.12 65 of 72
patients with IgG4‑RD had elevated serum IgG4 con-
centrations (mean 4.05 g/l, range 1.40–20.0 g/l), giving
a sensitivity of 90%. By contrast, a second review of
125 patients who had histopathologically confirmed
IgG4‑RD found that only 55% of patients with active
disease had an elevated serum IgG4 concentration before
the initiation of treatment.13 In the first study, the posi-
tive predictive value of an elevated serum IgG4 concen-
tration was only 34%.12 In both studies, elevated serum
IgG4 concentrations correlated with the presence of
multi­organ disease. These findings confirm that reliance
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REVIEWS
on serum IgG4 concentrations for diagnosis of IgG4-RD
is fraught with pitfalls.
In summary, a substantial elevation in serum IgG4
level can suggest a diagnosis of IgG4-RD, but is not
diagnostic in itself. Furthermore, a notable minority of
patients with histopathologically confirmed disease have
normal IgG4 blood concentrations.
Treatment outcomes
A second consideration with respect to serum IgG4 con-
centration is whether the IgG4 concentration, if elevated
at baseline, is a useful measure of the response to treat-
ment and/or a predictor of disease relapse. Insight comes
from a large retrospective study that evaluated the treat-
ment of type 1 autoimmune pancreatitis with gluco-
corticoids across 17 centres in Japan.14 Despite a nearly
universal clinical response and a decline in serum IgG4
levels in all patients following treatment, serum
IgG4 levels remained elevated above normal in 63%
of cases. Although disease relapse was more common
among patients with persistently elevated serum IgG4
levels  (30%) than among patients whose  serum
IgG4 levels reduced to normal (10%), 30% of the patients
who experi­enced relapse had normal serum IgG4 levels
at the time of relapse. The lack of a consistent associ­ation
between IgG4 levels and the risk of relapse has been
­confirmed in another similar study.15
The prozone or ‘hook’ effect—which leads to low
meas­urements of serum antigen levels (IgG4 in this
case)—when in fact there is a large excess of antigen
relative to the reagent antibody, can lead to spuriously
low measurements of serum IgG4 levels. Nephelometry
assays are particularly prone to this error. In one report,
spuriously low measurements of serum IgG4 levels
caused by the prozone effect were recorded for 10 of 38
patients with biopsy-confirmed IgG4‑RD.10 This error
in measurement can be avoided by the appropriate dilu-
tion of serum samples, which ensures that the reagent
antibody remains in excess of the antigen of interest.
Assays that are designed to detect higher serum IgG4
concentrations have the potential to prevent this problem
in the future.
In summary, serum IgG4 concentrations correlate only
loosely with disease activity, and are imperfect predic-
tors of the need for additional treatment. Appropriate
dilutions should be performed to ensure that the
prozone effect does not result in spurious reports of low
serum IgG4.
Pathophysiology
The role of IgG4
IgG4 itself is unlikely to drive the pathogenesis of
IgG4‑RD. The IgG4 molecule has unique chemical
properties that distinguish it from other immunoglobu-
lin subclasses and make it more suited to downregulat-
ing inflammation than to inducing inflammation. The
immunoglobulin classes and subclasses are defined by
the sequences of their heavy chain constant domains.
The IgG4 antibody exhibits weak binding to comple-
ment component C1q and Fcγ receptors because of the
REVIEWS
TFH
Autoantigen
Antigen-specific IgG4
IL-4
Plasma- IL-10
blasts
or B cells Differentiation
Short-lived
Class II pMHC antigen plasma cell
T-cell receptor Adhesion molecule
CD4+
cytotoxic
T cell
Perforin
Granzyme A/B IFN-γ, TGF-β
Granulysin Fibroblast
Cytotoxicity
Fibrosis
Figure 3 | The possible pathophysiology of IgG4-related disease. Nephrology
A CD4+| cytotoxic
Nature Reviews
T cell might act as a critical mediator of fibrosis by secreting cytokines such as IFN‑γ
and TGF‑β. These cytokines induce the recruitment and activation of fibroblasts.
Secretion of IL‑4 and IL‑10 by TFH cells and other cells might promote class-
switching of IgG antibodies to IgG4 and differentiation of B cells into plasma cells.
Antigen presentation, presumably in the presence of class II MHC molecules by
autoreactive B cells and perhaps other cells, is probably required to maintain the
activated state of the CD4+ cytotoxic T cell. The T cell and antigen-presenting cells
interact via adhesion molecules. Abbreviations: pMHC, peptide-MHC; TFH, T follicular
helper; TGF‑β, transforming growth factor β. Modified from Mahajan, V. S. et al. Annu.
Rev. Pathol. 9, 315–347 (2014) with permission from Annual Review of Pathology ©
by Annual Reviews, http://www.annualreviews.org.
amino acid sequence in its CH2 domain.16,17 The result
is an attenuated ability to activate the classic comple-
ment pathway and participate in antibody-dependent
­cell-mediated cytotoxicity.17
Another unique feature of IgG4 is its ability to
form ‘half-antibodies’ through the process of Fab arm
exchange, which results in IgG molecules that have two
different binding specificities (Figure 2).17 Amino acid
variation at the hinge region of IgG4 allows reduction
of the disulphide bonds that join the two halves of an
IgG4 molecule, leading to their recombination to form
asymmetric antibodies that consist of half-­antibody
fragments directed against different antigens.16,17 The
consequence is a reduced ability to crosslink anti-
gens and form immune complexes, although the
extent to which this recombination occurs in vivo
remains unclear.
Taken together, the properties of the IgG4 mol-
ecule suggest that it would suppress inflammation.
Indeed, the IgG4 response has been shown to develop
after chronic antigen exposure as part of a tolerogenic
response.17 IgG4 might, therefore, act as a noninflam-
matory ‘antigen sink’, the purpose of which is to mop up
antigen through its monovalent binding in a process that
dampens inflammation.
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The role of T cells
Although humoral immunity has frequently been
regarded as the major contributor to the pathophysi-
ology of IgG4‑RD owing to high serum IgG4 concen-
trations in many patients, T cells could ultimately be
implicated in disease pathogenesis. The CD4+ T cell is
in fact the most abundant cell within IgG4‑RD lesions.
In addition, high serum concentrations of circulat-
ing plasma­blasts in patients with IgG4‑RD demon-
strate intense somatic hypermutation, a hallmark of
interaction with T cells within the germinal centres
of lymph nodes. 18 Detailed genetic studies have not
yet been undertaken with populations of sufficient
size to produce meaningful results, so the HLA associ­
ations of IgG4‑RD remain incompletely characterized.
Conflicting reports have implicated type 1 T helper
(T H 1) cells and type  2 T  helper (T H 2) cells in the
­pathophysiology of IgG4‑RD.19,20
IL‑4 and IL‑10 have been suggested to be the cyto-
kines that drive the switch of IgG antibodies to the IgG4
subclass, but the precise molecular details of how T cells
participate in this process remain unclear.21 Some polar-
ized T cells, perhaps TH1 or TH2 cells, might drive the
storiform fibrosis and obliterative phlebitis observed in
IgG4‑RD. A separate T follicular helper cell response
might be responsible for generating the IgG4 phenotype
that helps define the disease.
Memory CD4+ T cells, which probably have a major
role in orchestrating IgG4‑RD, could be sustained by
the continuous presentation of antigen by B cells, which
would explain the clinical improvement observed follow-
ing B-cell depletion. Either the same antigen or an event
triggered by fibrosis could lead to a parallel T follicular
helper cell response that induces the development of ger-
minal centres within lymph nodes (and other involved
organs), generating IgG4-secreting plasma­blasts and
long-lived plasma cells. The fact that B-cell depletion
does not lead to the complete normalization of serum
IgG4 concentrations implies the existence of long-
lived plasma cells. These cells presumably return to the
bone marrow and continue to produce IgG4, albeit at
­substantially diminished levels.22,23
In summary, the pathology observed in IgG4‑RD
might be associated with two parallel processes
(Figure 3). First, a polarized CD4+ T-cell population that
is yet to be fully characterized probably activates innate
immune cells, including macrophages, myofibroblasts
and fibroblasts. Actions of this cellular network would
lead to the characteristic fibrosis observed in IgG4‑RD.
Second, a compensatory feedback loop could involve
generation of IgG4-secreting plasmablasts, plasma cells,
and IgG4 antibodies. The result of this feedback loop
might in part be downregulation of the overall inflam-
matory response. Many details of these overarching
­processes remain to be elucidated.
Unique pathology of the kidney
The kidney is unique among the organs affected by
IgG4‑RD because two types of histopathology have
been described in this organ. IgG4-related TIN exhibits
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the classic pathological features of IgG4‑RD, although
obliterative phlebitis is observed less frequently in the
kidney than in other organs.8 However, MGN second-
ary to IgG4‑RD represents a novel manifestation of
IgG4‑RD, in which lymphoplasmacytic infiltrate and
storiform fibrosis need not be present for diagnosis. This
­dichotomous pathology is discussed in detail below.
IgG4‑related TIN
TIN is the most common renal manifestation of
IgG4‑RD. The majority of data regarding this entity are
derived from two biopsy series: a Japanese cohort of 23
patients and an American cohort of 35 patients.5,9
Clinical features
The average age at diagnosis of IgG4‑related TIN is
approximately 65 years.5,9 Patients with TIN are pre-
dominantly male, reflecting the overall demographics of
IgG4‑RD.1,5,9 In the vast majority of cases, IgG4‑related
TIN is diagnosed in the setting of known extrarenal
IgG4‑RD.5,9 For example, 22 of 23 patients in the study
from Japan exhibited extrarenal disease manifestations,
the most common of which were sialadenitis (83%),
lymphadenopathy (44%), type 1 autoimmune pancreati-
tis (39%) and dacryoadenitis (30%).5 Renal involvement
became evident because of progressive renal decline
or the discovery of characteristic radiological features
detected during evaluation of extrarenal IgG4‑RD.5,9
In the series from the USA, acute or progressive renal
failure was the impetus for renal biopsy in approximately
75% of patients.9 The other 25% of patients underwent
biopsy for evaluation of a mass lesion that in most cases
was detected incidentally by imaging.9
Laboratory features
In cases of renal failure associated with IgG4‑RD, the rise
in serum creatinine level is typically insidious but can be
rapidly progressive. As is the case for other causes of TIN,
the degree of proteinuria is variable, but nephrotic-range
proteinuria is rare;5,9 the presence of nephrotic-range pro-
teinuria in a patient with IgG4‑related TIN strongly sug-
gests concomitant MGN, a second renal lesion that is
associated with IgG4‑RD.9 Urinalysis in IgG4‑related
TIN typically reveals mild to moderate proteinuria and
occasionally the presence of white blood cells.5 Mild
haema­turia can be observed in rare cases, but red blood
cell casts are characteristically absent.5 Elevated total
serum concentrations of IgG and IgG4 have been found
in nearly all cases of IgG4‑RKD reported to date, but the
strength of this association needs to be evaluated in larger
series of patients.5,9
Approximately 60% of patients with IgG4‑related
TIN have hypocomplementaemia, with low CH50
values in the total haemolytic complement assay and
low levels of complement C3 and complement C4.5,9
Hypocomplementaemia is not characteristic of most
patients with IgG4‑RD, so this finding indicates that
careful scrutiny for IgG4‑related TIN is appropri-
ate. The condition known as hypocomplementemic
immune complex TIN—which is characterized by C3
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REVIEWS
Kidney Kidney
Vertebral
body
Figure 4 | CT scan of the kidneys in a patient
Reviewswith
Nature | Nephrology
IgG4‑related tubulointerstitial nephritis. Multiple cortical,
hypodense lesions are visible (arrows).
and C4 hypocomplementaemia, an interstitial infiltrate
rich in plasma cells, and IgG staining along tubular
basement membranes—probably represents previously
unrecognized cases of IgG4‑related TIN.24,25 Peripheral
eosinophilia, a common finding among many aeti-
ologies of TIN, is noted in approximately 40% of cases
associated with IgG4‑RD.5,9,25 Serum from patients with
IgG4‑related TIN is often weakly positive for antinuclear
antibodies, but negative for specific antibodies, such as
those associated with systemic lupus erythematosus
and Sjögren syndrome (for example, antibodies against
double-stranded DNA or the Sm, Ro or La antigens).5,9
Radiological features
Contrast-enhanced CT is used to identify radiographic
abnormalities in IgG4‑related TIN.26 If contrast enhance-
ment is used, up to 80% of patients with the condition
exhibit characteristic findings of the disease, but the risk
of contrast nephropathy must be considered carefully in
patients with renal insufficiency.5,9 The most common
finding is multiple, often bilateral, hypodense lesions,
which are observed in ~40% of patients (Figure 4).5,9 The
lesions predominantly involve the renal cortex and have
been characterized into four morphological patterns:
peripheral cortical nodules <1 cm in diameter; well-
defined or poorly defined round lesions; wedge-shaped
lesions; and diffuse, patchy lesions.26 Thickening of the
renal pelvis has also been described.5 Biopsy samples
of these lesions show the classic histological features of
IgG4‑related TIN.26 The differential diagnoses for such
radiographic findings include pyelonephritis, embolic
disease, lymphoma and metastatic solid tumours.
Diffuse bilateral renal enlargement is seen in approxi-
mately 20% of patients with IgG4‑related TIN. Mass
lesions that mimic renal cell carcinoma are often
observed;5,9,27 nephrectomies for presumed renal cell
carcinoma sometimes yield a diagnosis of IgG4‑related
TIN.28 Therefore, IgG4‑related TIN should be consid-
ered in the differential diagnosis of renal cell carcinoma.
Classic but subtle extrarenal manifestations of IgG4‑RD
REVIEWS
a b
c d
Figure 5 | Renal pathology in IgG4‑related tubulointerstital nephritis.
Nature Reviews | Nephrology
a | Lymphoplasmacytic infiltrate within the renal interstitium, with abundant
eosinophils (circled). Strongly evident among the cellular infiltrate are interlacing
fibrils of storiform fibrosis (arrows). Haematoxylin and eosin staining, magnification
×100. b | High-power view of IgG4-related tubulointerstitial nephritis, showing
eosinophils (circled) and storiform fibrosis (arrows). Haematoxylin and eosin
staining, magnification ×400. c | Renal fibrosis following serial recurrences of
IgG4-related tubulointerstitial nephritis. Despite apparent clinical effectiveness
of glucocorticoid treatment, poorly controlled treatment has led to progressive
renal fibrosis (white arrows), glomerular obsolescence (black arrows) and
permanent renal damage, placing the patient at major risk of end-stage renal
disease. Trichrome stain, magnification ×400. d | IgG4 immunostaining in a patient
with active IgG4‑related tubulointerstitial nephritis. Examples of IgG4+ cells are
circled. Magnification ×400. Images courtesy of V. Deshpande, Massachusetts
General Hospital, Boston, USA.
(for example, salivary or lacrimal gland enlargement)
might be overlooked in the preoperative evaluation.
Although serum IgG4 levels are an imperfect diagnos-
tic test (see above), a substantially elevated serum IgG4
value should also heighten suspicion of IgG4‑RD.15
Renal pathology
Examination of tissue affected by IgG4‑related TIN by
light microscopy reveals a lymphoplasmacytic inter-
stitial infiltrate that can be either diffuse or multifocal
(Figure 5).9,29 Eosinophils, which are frequently observed
in other aetiologies of TIN, are also characteristic of
IgG4‑related TIN (Figures 5a and 5b).29 Whereas in some
cases a dense cellular infiltrate with minimal fibrosis is
observed, other cases are characterized by prominent
expansile interstitial fibrosis.9 One plausible hypoth-
esis is that these different patterns are determined by
the chronicity of the lesion (that is, the fibrotic lesions
might result from more prolonged disease), but other
undefined variables might also contribute. Patients with
a fibrotic interstitium typically demonstrate the hallmark
storiform fibrosis of IgG4‑RD.5,29 A mild mononuclear
tubulitis is frequently observed, but severe tubulitis is
more likely to be seen if TIN is drug-induced.29 Poorly
controlled disease seems to lead to progressive renal
fibrosis, glomerular obsolescence and/or permanent
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renal damage in many cases, and occasionally to
­end-stage renal disease (Figure 5c).
Immunofluorescence studies have confirmed the depo-
sition of immune complexes in the tubular basement
membrane in more than 80% of cases of IgG4‑related
TIN.9 The complexes invariably stain positively for IgG,
for kappa and lambda light chains without monoclonal
restriction, and also (in most cases) for complement
C3. 9,30,31 Complement component C1q deposition is
observed in approximately 15% of cases. The locations
of immune complex deposits correspond to the areas
affected by TIN, as seen by light microscopy; deposits are
not present within parenchyma that, from haematoxylin
and eosin staining, does not seem to be involved.9 These
findings strongly resemble the pathology observed in
­hypocomplementemic immune complex TIN.24
Immunostaining of tissue affected by IgG4‑related
TIN typically reveals an increased number of IgG4+
plasma cells (>10 per hpf; Figure 5d) and an increased
IgG4+:IgG+ plasma cell ratio (>40%) relative to healthy
tissue. A study that defined elevated levels of IgG4 +
plasma cells as >10 cells per hpf had a sensitivity of 100%
and specificity of 92% for differentiating IgG4‑related
TIN from other aetiologies of a tubulointerstitial
plasma­c ytic infiltrate. 9 Pauci-immune glomerulo­
nephritis, in which tissue can also be enriched with
IgG4+ plasma cell infiltrates,9 was the exception to this
rule. Among 15 patients with pauci-immune glomerulo­
nephritis whose renal biopsy samples were assessed
for IgG4+ plasma cells, six (40%) had at least 10 IgG4+
plasma cells per hpf. Fortunately, pauci-immune glo-
merulonephritis is distinguishable from IgG4‑related
TIN by the presence of necrotizing glomerulonephri-
tis and positive anti­neutro­phil cytoplasmic antibody
­serology in the majority of cases.9
Diagnostic criteria
Two sets of diagnostic criteria have been proposed for
IgG4‑related TIN, each of which is based on a combi-
nation of pathological findings, imaging, serology and
clinical features.9,32 Both sets require exclusion of all
other diseases, particularly antineutrophil cytoplasmic
antibody-associated vasculitis, which can lead to the
presence of a lymphoplasmacytic infiltrate. Criteria pro-
posed by Raissian et al.9 require a TIN with >10 IgG4+
plasma cells per hpf in addition to either characteristic
imaging findings (see the discussion of radiological fea-
tures, above), elevated serum IgG4 or total IgG, or evi-
dence of extrarenal IgG4–RD. The more complex criteria
proposed by Kawano et al.32 stratify patients with features
of IgG4‑related TIN into one of three ­categories: definite,
probable, and possible.
MGN secondary to IgG4‑RD
MGN is the only glomerular lesion that can be reliably
attributed to IgG4‑RD. It is important to distinguish
between the MGN secondary to IgG4‑RD and idiopathic
MGN, which is a separate disorder.33 MGN secondary to
IgG4‑RD was observed in approximately 7% of patients
included in the two largest biopsy series of IgG4‑RKD
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 REVIEWS

a b c

*
* *

20 μm

Figure 6 | Renal pathology in MGN secondary to IgG4‑RD. a | Glomerulus from a patient with MGN secondary
Nature to| IgG4‑RD
Reviews Nephrology
and nephrotic-range proteinuria, but which appears normal. The lack of glomerular basement thickening underscores the
importance of immunofluorescence and electron microscopy for the diagnosis of early MGN. b | Immunofluorescence
micrograph of a glomerulus from a patient with MGN secondary to IgG4‑RD following incubation with an antibody that binds
specifically to the heavy chain of IgG. Fine granular staining is evident along the glomerular basement membrane (arrows).
c | Electron micrograph that shows discrete subepithelial deposits (arrows) and effacement of the visceral epithelial cells
(asterisks). Abbreviations: IgG4‑RD, IgG4‑related disease; MGN, membranous glomerulonephropathy. Images courtesy of
H. Rennke, Brigham & Women’s Hospital, Boston, USA.

published to date,5,9 and a series of nine cases of MGN
secondary to IgG4‑RD provides the basis for current
understanding of this condition. Further studies of MGN
secondary to IgG4‑RD will be a welcome a­ ddition to
the literature.
Clinical and laboratory features
MGN secondary to IgG4‑RD seems to occur predomi-
nantly in older males, as is true for IgG4-related TIN.34
Seven of the nine patients included in the series had
known extrarenal manifestations of IgG4‑RD at the time
of diagnosis of MGN.34 Almost all patients presented
with nephrotic-range proteinuria (mean 8.3 g daily) and
low serum albumin concentrations (mean 20 g/l); serum
creatinine levels were elevated in 75% of patients (mean
194 μmol/l, range 70.7–583.4 μmol/l).34 Five of the nine
patients had concomitant TIN that was identified in
renal biopsy samples; in these patients, TIN was probably
the primary driver of renal dysfunction because renal
dysfunction correlated with the degree of TIN sever-
ity.35 Serum IgG4 concentrations were elevated in all
five patients in whom it was measured.34 The impetus
for biopsy was proteinuria in seven patients and acute
kidney injury in the other two.34
Diffuse bilateral renal enlargement attributable to
IgG4‑RKD was detected in only one of seven patients
with the condition and who underwent renal imaging.34
This finding is in contrast to imaging findings in patients
with IgG4‑related TIN, ~70% of whom exhibited
charac­teristic radiographic features of the condition.5,9
Intravenous contrast dye was necessary to detect the
hypodense cortical lesions found in the patients with
IgG4-related TIN, whereas patients in the MGN series
might not have received intravenous contrast owing to
the presence of significant renal dysfunction. The data
presented might therefore underestimate the frequency
of radiographic findings.
Renal pathology
Experience to date of MGN secondary to IgG4‑RD sug-
gests that a substantial subset of cases—five out of nine
in the largest series—have concomitant IgG4‑related
TIN. 34 All biopsy samples in this series exhibited
subepithelial deposits in a membranous pattern when
examined by immunofluorescence and electron micros-
copy (Figure 6).34 Immunofluorescence staining for IgG
subclasses was performed on samples from four patients,
and IgG4 was the predominant immunoglobulin in three
of the samples.
Interestingly, IgG4 is also the predominant immuno­
globulin present in idiopathic MGN. A study published
in 2009 found that the secretory phospholipase A2 recep-
tor (PLA2R) is the target antigen in the majority of cases
of idiopathic MGN; 33 circulating antibodies against
PLA2R were present in approximately 70% of patients
with the condition. The staining of biopsy samples for
glomerular deposits of anti-PLA2R antibodies seems
to be more sensitive than the detection of serum anti-
PLA2R antibodies in idiopathic MGN. 36 However,
in a study of renal biopsy samples from eight patients
with MGN secondary to IgG4‑RD, none of the samples
showed positive staining for anti-PLA2R antibodies.34
Assays for antibodies against PLA2R are not helpful
in distinguishing between idiopathic MGN and MGN
secondary to IgG4‑RD because as many as 30% of
patients with idiopathic MGN are negative for this anti-
body. However, other features help differentiate between
these two entities. Many patients with MGN second-
ary to IgG4‑RD have both extrarenal manifestations
of IgG4‑RD and IgG4-related TIN that is detectable in
biopsy samples, whereas patients with idiopathic MGN
have neither.34 Furthermore, serum levels of IgG4 are
typically elevated in MGN secondary to IgG4‑RD but
not in idiopathic MGN.34
One pathophysiological consideration in MGN sec-
ondary to IgG4‑RD is whether the inciting antigen is
endogenous to the podocyte or a result of circulating
immune complex deposition. Certain histological fea-
tures might help distinguish between these two possi-
bilities. In idiopathic MGN, the antigen is endogenous
to the podocyte, and the corresponding immune com-
plexes are therefore confined to the subepithelial space.33
By contrast, secondary forms of MGN (for example,
those caused by drugs, infections, autoimmune diseases
and malignancies) are a result of circulating immune
complexes or circulating free antigen that lead to in situ

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© 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
immune complex formation.29 In this case, random
deposition of the circulating immune complexes in the
glomerulus often results in the localization of immune
complexes in the subendothelial space and mesangium
in addition to the subepithelial space.37,38
Three of the nine biopsy samples from the series of
patients with MGN secondary to IgG4‑RD exhibited
mesangial or subendothelial deposits in addition to sub-
epithelial deposits.9 Heterogenous mechanisms are prob-
ably responsible for the different pathological features
observed. More cases of MGN secondary to IgG4‑RD
need to be studied to determine the degree to which its
pathophysiology is shared with that of other types of sec-
ondary MGN. Determining whether the target antigen
in MGN secondary to IgG4‑RD is localized to the podo-
cyte, as it is in idiopathic MGN, could provide impor-
tant insight into the pathogenesis of some features of
IgG4‑RKD and possibly into other organ m ­ anifestations
of IgG4‑RD.
Retroperitoneal fibrosis
RPF is characterized by the development of fibro­
inflammatory tissue in the periaortic and peri-iliac retro­
peritoneum,39 a process that tends to encase the ureters
and adjacent structures.39 Pain in the back, abdomen
or flank is the most common presenting symptom.39
Ureteral obstruction that leads to renal failure is often
present at diagnosis. In a series of 53 patients with RPF,
hydronephrosis and elevated serum creatinine levels
(>106.1 μmol/l) were noted at diagnosis in 55% and
66% of patients, respectively.40 Treatment of obstruction
with percutaneous nephrostomy tubes, ureteral stents
or open surgery is sufficient to prevent acute develop-
ment of end-stage renal disease in most cases, but many
patients experience chronic kidney disease as a result of
the refractory nature of RPF or the failure to detect the
lesion while it is still amenable to immunosuppression.41
A variety of secondary causes of RPF have been rec-
ognized, including infection, radiation therapy, medi-
cations, malignancies and trauma.39 However, before
the recognition of IgG4‑RD, most cases of RPF were
regarded as idiopathic.42 In a retrospective assessment
of 23 patients who were diagnosed with idiopathic RPF
at the Massachusetts General Hospital,43 histopathologi-
cal findings led to diagnosis of IgG4‑RD in 13 patients
(57%) on the basis of classic IgG4‑RD histology and an
IgG4+:IgG+ plasma cell ratio >40%. Extraretroperitoneal
manifestations of IgG4‑RD were frequently observed in
the same patients, and also helped with diagnosis. No
currently recognized clinical or radiographic features
reliably differentiate between IgG4‑related RPF and RPF
that has no other disease association. Greater scrutiny of
the pathological details observed in cases of RPF could
lead to more precise c­ lassification of RPF subsets.
Treatment
IgG4‑related disease
The optimal treatment for IgG4‑RD is unknown. To date,
no randomized clinical trials have evaluated the com-
parative effectiveness of different treatment regimens.
8  |  ADVANCE ONLINE PUBLICATION
© 2015 Macmillan Publishers Limited. All rights reserved
Current approaches to the management of the disease
are based on observational case series, and the decision
to treat is based on symptoms and the organ systems
involved. Renal involvement of IgG4‑RD is organ threat-
ening, so prompt treatment is indicated with the goal
of suppressing inflammation before the development of
marked fibrosis.44,45
Glucocorticoids are currently the first-line treatment
for IgG4‑RD.45 Most data on the use of glucocorticoids
are derived from the treatment of type 1 autoimmune
pancreatitis and have been extrapolated to the treat-
ment of extrapancreatic IgG4‑RD. Treatment of type 1
autoimmune pancreatitis with glucocorticoids typi-
cally results in a symptomatic response within 2 weeks
and remission within 2–3 months.14,45 However, many
patients experience relapse as glucocorticoid treatment
is reduced or discontinued, and the optimal approach
to ensure maintenance of remission remains unclear.14,45
In a large cohort of patients with type 1 autoimmune
pancreatitis, 34% of patients experienced relapse after
withdrawal of glucocorticoids.45 This finding probably
underestimates the true number of relapses, as patients
often have recurrent manifestations of IgG4‑RD many
years after presentation.
Prolonged treatment with glucocorticoids is particu-
larly problematic in IgG4‑RD because the condition
tends to afflict middle-aged to elderly individuals who
are already are at increased risk of osteoporosis, dia­betes
mellitus and complications after infections. For this
reason, there is interest in steroid-sparing therapeutic
agents for IgG4‑RD, particularly in the subset of patients
with refractory or recurrent disease. Azathioprine and
mycophenolate mofetil (MMF) have been used in
the treatment of patients with relapsing type 1 auto­
immune pancreatitis, but only a limited amount of
data suggests true efficacy in the absence of concurrent
glucocorticoid treatment.46
Treatment with rituximab to induce B-cell depletion
has yielded promising results.22,23,45 In one report, four
patients with various manifestations of IgG4‑RD, includ-
ing aortitis, type 1 autoimmune pancreatitis, sialadenitis
and orbital pseudotumour, responded dramatically to
rituximab therapy and were able to discontinue gluco-
corticoid therapy.22 IgG4 levels decreased by 65% within
2 months of rituximab therapy, and levels of other IgG
subclasses did not decline. This finding suggests that
rituximab might interfere with repletion of short-lived
­plasmablasts and plasma cells that produce IgG4.18,47
These findings were corroborated by a study that
included 10 patients with IgG4‑RD that was refractory
to prednisone.23 With rituximab treatment, a marked
improvement was observed in all but one patient, and
all patients were able to discontinue glucocorticoids
entirely. Six patients exhibited durable responses after
initial treatment with rituximab and did not require
additional therapy over a mean follow-up period of
9.6 months (range 4–14 months). Clinical flares that
required retreatment with rituximab were associated
with an increase in serum IgG4 levels following B-cell
reconstitution. This phenomenon suggests that IgG4
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levels could be used to follow disease activity in patients
who have elevated serum IgG4 concentrations at baseline
and are treated with rituximab but not glucocorticoid
maintenance therapy. However, subsequent studies of
patients with IgG4‑RD treated with rituximab suggest
that blood plasmablast concentrations are a more useful
biomarker than are serum IgG4 concentrations in this
setting.18,47 Further investigation is needed to establish
the optimal use of rituximab in IgG4‑RD and to test the
methods used to follow clinical responses.
IgG4‑related TIN
Published experience of treating IgG4‑RD with renal
involvement is limited to a few case series. In a Japanese
biopsy series of IgG4‑related TIN, 21 of 23 patients
were treated with prednisolone monotherapy.5 11 of
these patients had serum creatinine concentrations
≤114.9 μmol/l before treatment, and renal involvement
was detected on the basis of radiographic abnormalities
more frequently than on the basis of renal insufficiency.
Serum creatinine concentrations improved or stabilized
at 1 month after treatment in all patients except one,
whose condition progressed to end-stage renal disease.
In the Mayo Clinic TIN series, all 21 patients who were
treated received prednisone, and two patients received
concomitant MMF. 9 19 (90%) of these patients had
serum creatinine concentrations >1.6 μmol/l before
treatment (mean 3.5 μmol/l). One patient’s condition
progressed to a stage that required dialysis, but the
remainder exhibited stable or improved renal function,
with a mean post-treatment serum creatinine concen-
tration of 1.7 μmol/l after follow-up periods that varied
in length. Two patients responded to prednisone but
relapsed following glucocorticoid withdrawal.
Data on long-term outcomes of IgG4-related TIN
treatment are available from a retrospective analysis
of 40 patients.44 These patients were treated with pred-
nisolone at an initial dose of 20–60 mg daily. A subset
of 20 patients had a pretreatment estimated glomeru-
lar filtration rate (eGFR) <60 ml/min/1.73 m2 (mean
32.5 ± 16.2 ml/min/1.73 m2) and a follow-up period of at
least 12 months. Treatment in this subgroup was initiated
with a mean prednisolone dose of 36.0 ± 9.5 mg daily. At
a mean follow-up of 54.5 months, all but one patient
remained on some maintenance dose of prednisolone
(mean 6.0 ± 3.7 mg daily). At the end of the follow-up
period, the mean eGFR had significantly improved to
44.4 ± 11.0 ml/min/1.73 m2. Despite these favourable
clinical responses, 60% of patients who underwent CT
imaging during follow-up exhibited evidence of notable
renal atrophy. This atrophy was observed even in patients
who seemed to respond well to prednisolone therapy.
A retrospective study of drug-induced allergic inter-
stitial nephritis suggests that early recognition of the
condition and treatment with glucocorticoids attenuates
the degree of interstitial fibrosis.48 Furthermore, histol-
ogy of tissue from patients with IgG4‑related TIN and
treated with glucocorticoids demonstrated a reduction of
cellular infiltrate, but subsequent development of inter-
stitial fibrosis.49 Taken together, these findings support
NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION  |  9
© 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
early treatment of IgG4‑related TIN, with the goal of
­preventing renal fibrosis.
One of many unanswered questions is whether
patients with radiographic abnormalities associated with
IgG4‑related TIN but no obvious clinical renal impair-
ment require immunosuppressive therapy. In a cohort
of 14 patients with eGFR >60 ml/min/1.73 m2 (mean
83.4 ± 14 ml/min/1.73 m2) and abnormalities detected
by imaging, treatment with glucocorticoids led to
improvements in the abnormalities detected by imaging
and no change in eGFR after a mean follow-up period of
42.4 ± 17.0 months.44 Patients were treated with a mean
initial prednisolone dose of 36.8 ± 13.3 mg daily, which
was tapered gradually over the course of 12 months to
a maintenance dose of 5.5 ± 3.3 mg daily. Whether renal
function would have deteriorated without treatment is
unknown, because data on the untreated natural course
of IgG4‑related TIN are sparse. Close monitoring of renal
function is essential if a conservative (non-treatment)
strategy is selected. However, given that renal atrophy
is known to occur in many patients with IgG4‑related
TIN, treatment even in the absence of overt clinical renal
dysfunction is reasonable.
Relapse of renal dysfunction following steroid taper-
ing or withdrawal is frequently observed among patients
with IgG4‑related TIN. In the largest cohort of patients
who were treated with glucocorticoids, 20% experi-
enced a relapse in either the kidney or another organ
system while on maintenance therapy (median 5 mg
daily). The mean follow-up period in that study was
only 44 months.44 An alternative therapy is desirable for
patients who are at high risk of complications of long-
term glucocorticoid therapy (for example, people with
glucose intolerance or osteoporosis at baseline) and those
with relapsing disease.
Although not yet studied specifically in patients
with IgG4‑related TIN, B-cell depletion with rituximab
might yield a durable response that obviates the need
for extended glucocorticoid therapy in some cases. This
hypothesis requires confirmation in rigorous trials.44
MGN secondary to IgG4‑RD
Treatment of MGN secondary to IgG4‑RD is typically
directed against the underlying systemic disorder rather
than the renal lesion, although treatment regimens exist
that target the kidney lesion in MGN associated with sys-
temic lupus erythematosus.50 Experience of treatment of
MGN secondary to IgG4‑RD is limited to a retrospective
analysis of seven patients who were followed for a mean
period of 39 months (range 4–184 months).34 Four of
those patients had concomitant IgG4‑related TIN identi-
fied by biopsy. Treatment approaches varied: two patients
received prednisone; two initially received prednisone
alone and subsequently received prednisone with MMF;
one received prednisone, cyclophosphamide and an
angiotensin-converting-enzyme inhibitor; one received
an angiotensin-converting-enzyme inhibitor followed by
rituximab and MMF; and one patient was not treated.
Treatment led to a decline in proteinuria from a mean
baseline of 8.8 g daily (range 3.5–16 g daily) to 1.2 g
REVIEWS

daily (range 0–3.1 g daily) and an associated improve-
ment in the mean serum creatinine concentration from
221.0 μmol/l (range 70.7–583.4 μmol/l) to 123.8 μmol/l
(range 70.7–221.0 μmol/l).
The heterogeneity of treatment in this series under-
scores the lack of available clinical evidence, and the
small numbers preclude firm conclusions about the com-
parative efficacies of different regimens. Extrapolation
of data from other chronic kidney diseases associated
with proteinuria (>500 mg daily) indicate that such
patients should be treated with an inhibitor of the renin–­
angiotensin system.51 Patients with nephrotic-range pro-
teinuria should be screened for dyslipidaemia and treated
with statin therapy if concentrations of low-density
­lipoproteins are elevated.52
Conclusions and next steps
IgG4‑RD is now recognized as a link between many
clinical entities that were previously regarded as
unique, organ-specific disorders; many of these enti-
ties have been recognized by physicians for more than
100 years. The medical literature on IgG4‑RD has grown
rapidly over the past decade, but current understand-
ing of IgG4‑RKD is largely based on fewer than 100
patients. Descriptions of larger numbers of patients with
IgG4‑RKD are essential for obtaining a full picture of
this entity. The entity of MGN secondary to IgG4‑RD,
which is substantially less common than IgG4‑related
TIN, remains particularly unexplored.
The antigenic trigger for IgG4‑RD remains unidenti­
fied, and the direct role (if one exists) of the IgG4
molecule itself remains unclear. Although serum
IgG4 concentrations are elevated in the majority of
patients—often dramatically so—IgG4 levels have clear
shortcomings as a disease biomarker. Recent findings
suggest that plasmablast concentrations have potential
as a biomarker that could help with diagnosis, gauging
disease activity, and determining the optimal timing of
treatment. Further studies that focus on IgG4+ plasma-
blasts are required to determine whether flow cytom-
etry assays for these cells are superior to measurement of
plasmablast concentrations for these purposes. The high
degree of somatic hypermutation observed in circulat-
ing plasmablasts in IgG4‑RD suggests an important role
for T cells in shaping the B-cell responses, but studies of
T cells in IgG4‑RD are still only at an early stage.
The propensity of IgG4‑RKD to flare following the ces-
sation of glucocorticoid treatment poses a major chal-
lenge for clinicians, particularly considering that the
patient population at risk of this disease often has consid-
erable comorbidities (for example, old age and pancre-
atic damage) that render ongoing glucocorticoid therapy
undesirable. Moreover, the observation that kidneys
that are affected by IgG4‑RD often undergo fibrosis and
atrophy, even after seemingly positive clinical responses,
raises questions about the optimal strategies for remis-
sion induction and maintenance. B-cell depletion is a
promising therapy but requires further investigation
before its full role and optimal use are understood.
Review criteria
PubMed was searched for full-text English-language
papers published online up to May 2014 using the
following terms: “IgG4‑related disease AND (kidney
OR renal).” References included in the manuscript
were chosen at the authors’ discretion based on their
relevance to the subject of the Review.

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disease. N. Engl. J. Med. 366, 539–551 (2012).
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pancreatitis. N. Engl. J. Med. 344, 732–738
(2001).
3. Deshpande, V. et al. Subclassification of
autoimmune pancreatitis: a histologic
classification with clinical significance.
Am. J. Surg. Pathol. 35, 26–35 (2011).
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5. Saeki, T. et al. Clinicopathological characteristics
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19. Zen, Y. et al. Th2 and regulatory immune
reactions are increased in immunoglobin G4-
related sclerosing pancreatitis and cholangitis.
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20. Okazaki, K. et al. Autoimmune-related
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and a Th1/Th2-type cellular immune response.
Gastroenterology 118, 573–581 (2000).
21. Zen, Y. & Nakanuma, Y. Pathogenesis of IgG4-
related disease. Curr. Opin. Rheumatol. 23,
114–118 (2011).
22. Khosroshahi, A., Bloch, D. B., Deshpande, V. &
Stone, J. H. Rituximab therapy leads to rapid
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improvement in IgG4-related systemic disease.
Arthritis Rheum. 62, 1755–1762 (2010).
23. Khosroshahi, A. et al. Rituximab for the
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10 consecutive patients. Medicine (Baltimore)
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24. Vaseemuddin, M., Schwartz, M. M., Dunea, G.
& Kraus, M. A. Idiopathic hypocomplementemic
immune‑complex‑mediated tubulointerstitial
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25. Baker, R. J. & Pusey, C. D. The changing profile
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26. Takahashi, N., Kawashima, A., Fletcher, J. G. &
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27. Cornell, L. D. et al. Pseudotumors due to IgG4
immune-complex tubulointerstitial nephritis
associated with autoimmune pancreatocentric
disease. Am. J. Surg. Pathol. 31, 1586–1597
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28. Alkhasawneh, A. & Allan, R. W. IgG4
inflammatory pseudotumor of the kidney.
Case Rep. Urol. 2012, 919087 (2012).
29. Yoshita, K. et al. Light-microscopic
characteristics of IgG4-related tubulointerstitial
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tubulointerstitial nephritis. Nephrol. Dial.
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30. Kawano, M. et al. Immunohistochemical
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nephritis: detailed analysis of 20 Japanese
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Acknowledgements
The authors thank Vikram Deshpande from the
Massachusetts General Hospital, Boston, USA, for
providing Figures 1 and 5, and Helmut Rennke from
the Brigham & Women’s Hospital, Boston, USA, for
providing Figure 6.
Author contributions
Both authors researched data for the article, made
substantial contributions to discussions of the
content, wrote the article and reviewed and/or edited
the manuscript before submission.