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Introduction
IgG4-related disease (IgG4‑RD) is a fibroinflammatory (IgG4‑RKD): tubulointerstitial nephritis (TIN) and
condition that has emerged in the past 15 years and is membranous glomerulonephropathy (MGN). Prompt
characterized by tumefactive lesions and two hallmark evaluation and treatment of these entities are essen-
histological features: a lymphoplasmacytic infiltrate tial because of the increased morbidity and mortal-
that is enriched with IgG4+ plasma cells, and storiform ity that is associated with the development of chronic
fibrosis.1 The disease often presents with multiple organ kidney disease. In this Review, we provide an over-
involvement and is often, but not always, associated with view of IgG4‑RD and describe the clinicopathological
an elevated serum level of IgG4. Such elevated concen- features of IgG4-related TIN and MGN secondary to
trations of IgG4 were first noted in 2001, in patients IgG4‑RD. We also briefly review IgG4-related retro-
with sclerosing pancreatitis; this condition is now rec- peritoneal fibrosis (RPF), an inflammatory condition
ognized as falling within the IgG4‑RD spectrum and on the IgG4‑RD disease spectrum that often centres on
is known as type 1 (IgG4-related) autoimmune pan- the periaortic region and can entrap ureters, leading
creatitis.2 Type 2 autoimmune pancreatitis has distinct to hydronephrosis and renal injury. Finally, we discuss
clinical and pathological features.3 Frequent extrapan- treatment approaches to IgG4‑RD, including the
creatic involvement in type 1 autoimmune pancreatitis current use of glucocorticoids and the promising results
led to the realization in 2003 that IgG4‑RD is a systemic obtained with rituximab treatment, and highlight new
disease.4 Eponymous diseases that were all previously research that aims to elucidate the pathogenesis of this
regarded as discrete clinical entities, such as Mikulicz systemic disease.
disease, Küttner tumour and Riedel thyroiditis, are now
recognized as part of the spectrum of IgG4‑RD, as the Overview of IgG4‑RD
pathology observed across organs in each disease is A defining feature of IgG4‑RD is that the histological
strikingly similar.1 appearance of affected tissue is similar regardless of
IgG4‑RD can affect nearly every organ system, includ- the organ from which it originates.1 The predominant
Nephrology Unit ing the pancreas, biliary tree, aorta, lung, salivary and morphological observation is a dense lymphoplasmacytic
(F.B.C.), Rheumatology lacrimal glands, thyroid, pachymeninges and kidney. infiltrate that is rich in IgG4+ plasma cells (Figure 1). This
Unit (J.H.S.),
Massachusetts
Clinically apparent renal involvement seems to occur in lymphoplasmacytic infiltrate is enmeshed by irregu-
General Hospital, approximately 15% of patients.5 Intrinsic renal involve- larly whorled storiform fibrosis.6,7 Obliterative phlebi-
55 Fruit Street, Boston, ment of IgG4‑RD encompasses two distinct entities tis, which results in destruction of the venous wall and
MA 02114, USA.
that together comprise IgG4-related kidney disease lumen, is another lesion that is commonly observed
Correspondence to: in IgG4‑RD (Figure 1d).6 Some variation in pathology
J.H.S.
jhstone@ Competing interests exists between organs. For example, obliterative phlebitis
mgh.harvard.edu The authors declare no competing interests. is universally present in type 1 autoimmune pancreatitis
Treatment outcomes
A second consideration with respect to serum IgG4 con-
centration is whether the IgG4 concentration, if elevated
Recombination 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-
Symmetric IgG4 antibodies Asymmetric IgG4 antibodies
corticoids across 17 centres in Japan.14 Despite a nearly
universal clinical response and a decline in serum IgG4
Figure 2 | Fab arm exchange among IgG4 antibodies. aNature Reviews
| The heavy | Nephrology
chains of levels in all patients following treatment, serum
IgG4 antibodies switch between interchain and intrachain disulphide-bonded IgG4 levels remained elevated above normal in 63%
configurations. Intrachain disulphide-bonded IgG4 consists of noncovalently
of cases. Although disease relapse was more common
associated ‘half-molecules’ that can dissociate from one another. b | Dissociation
of the two halves of the IgG4 antibodies allows recombination to produce among patients with persistently elevated serum IgG4
asymmetric, bispecific antibodies. Modified from Mahajan, V. S. et al. Annu. Rev. levels (30%) than among patients whose serum
Pathol. 9, 315–347 (2014) with permission from Annual Review of Pathology © IgG4 levels reduced to normal (10%), 30% of the patients
by Annual Reviews, http://www.annualreviews.org. who experienced relapse had normal serum IgG4 levels
at the time of relapse. The lack of a consistent association
to moderate elevations of serum IgG4 concentrations between IgG4 levels and the risk of relapse has been
are observed in patients with diagnoses other than confirmed in another similar study.15
IgG4‑RD greatly limits the utility of IgG4 concentration The prozone or ‘hook’ effect—which leads to low
for diagnosis. In a 2014 study, the upper limit of IgG4 measurements of serum antigen levels (IgG4 in this
levels considered to be normal was doubled relative to case)—when in fact there is a large excess of antigen
the standard; this approach raised the specificity of the relative to the reagent antibody, can lead to spuriously
assay from 60% to 91%, but decreased the sensitivity to low measurements of serum IgG4 levels. Nephelometry
an unacceptably low 35%.12 assays are particularly prone to this error. In one report,
Furthermore, a normal serum IgG4 level does not spuriously low measurements of serum IgG4 levels
exclude diagnosis of IgG4‑RD. When IgG4‑RD was caused by the prozone effect were recorded for 10 of 38
first identified, diagnosis of the condition was linked patients with biopsy-confirmed IgG4‑RD.10 This error
with elevated serum IgG4 concentrations. Consequently, in measurement can be avoided by the appropriate dilu-
many subsequent studies have given disproportionate tion of serum samples, which ensures that the reagent
importance to serum IgG4 concentrations in diagno- antibody remains in excess of the antigen of interest.
sis.2 This bias has increased the reported prevalence Assays that are designed to detect higher serum IgG4
of elevated serum IgG4 concentrations and led to an concentrations have the potential to prevent this problem
undue influence of serum IgG4 concentrations on in the future.
the diagnosis. In summary, serum IgG4 concentrations correlate only
Two studies that were performed at one medical centre loosely with disease activity, and are imperfect predic-
provide a striking demonstration that serum IgG4 con- tors of the need for additional treatment. Appropriate
centration is not a reliable indicator for diagnosis of dilutions should be performed to ensure that the
IgG4-RD.12,13 In the first, all cases of elevated serum IgG4 prozone effect does not result in spurious reports of low
concentrations recorded at the Massachusetts General serum IgG4.
Hospital over a 10‑year period were reviewed.12 65 of 72
patients with IgG4‑RD had elevated serum IgG4 con- Pathophysiology
centrations (mean 4.05 g/l, range 1.40–20.0 g/l), giving The role of IgG4
a sensitivity of 90%. By contrast, a second review of IgG4 itself is unlikely to drive the pathogenesis of
125 patients who had histopathologically confirmed IgG4‑RD. The IgG4 molecule has unique chemical
IgG4‑RD found that only 55% of patients with active properties that distinguish it from other immunoglobu-
disease had an elevated serum IgG4 concentration before lin subclasses and make it more suited to downregulat-
the initiation of treatment.13 In the first study, the posi- ing inflammation than to inducing inflammation. The
tive predictive value of an elevated serum IgG4 concen- immunoglobulin classes and subclasses are defined by
tration was only 34%.12 In both studies, elevated serum the sequences of their heavy chain constant domains.
IgG4 concentrations correlated with the presence of The IgG4 antibody exhibits weak binding to comple-
multiorgan disease. These findings confirm that reliance ment component C1q and Fcγ receptors because of the
IgG4‑related TIN
Kidney Kidney
TIN is the most common renal manifestation of
Vertebral
IgG4‑RD. The majority of data regarding this entity are body
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
Figure 4 | CT scan of the kidneys in a patient
Reviewswith
approximately 65 years.5,9 Patients with TIN are pre- Nature | Nephrology
IgG4‑related tubulointerstitial nephritis. Multiple cortical,
dominantly male, reflecting the overall demographics of hypodense lesions are visible (arrows).
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 and C4 hypocomplementaemia, an interstitial infiltrate
from Japan exhibited extrarenal disease manifestations, rich in plasma cells, and IgG staining along tubular
the most common of which were sialadenitis (83%), basement membranes—probably represents previously
lymphadenopathy (44%), type 1 autoimmune pancreati- unrecognized cases of IgG4‑related TIN.24,25 Peripheral
tis (39%) and dacryoadenitis (30%).5 Renal involvement eosinophilia, a common finding among many aeti-
became evident because of progressive renal decline ologies of TIN, is noted in approximately 40% of cases
or the discovery of characteristic radiological features associated with IgG4‑RD.5,9,25 Serum from patients with
detected during evaluation of extrarenal IgG4‑RD.5,9 IgG4‑related TIN is often weakly positive for antinuclear
In the series from the USA, acute or progressive renal antibodies, but negative for specific antibodies, such as
failure was the impetus for renal biopsy in approximately those associated with systemic lupus erythematosus
75% of patients.9 The other 25% of patients underwent and Sjögren syndrome (for example, antibodies against
biopsy for evaluation of a mass lesion that in most cases double-stranded DNA or the Sm, Ro or La antigens).5,9
was detected incidentally by imaging.9
Radiological features
Laboratory features Contrast-enhanced CT is used to identify radiographic
In cases of renal failure associated with IgG4‑RD, the rise abnormalities in IgG4‑related TIN.26 If contrast enhance-
in serum creatinine level is typically insidious but can be ment is used, up to 80% of patients with the condition
rapidly progressive. As is the case for other causes of TIN, exhibit characteristic findings of the disease, but the risk
the degree of proteinuria is variable, but nephrotic-range of contrast nephropathy must be considered carefully in
proteinuria is rare;5,9 the presence of nephrotic-range pro- patients with renal insufficiency.5,9 The most common
teinuria in a patient with IgG4‑related TIN strongly sug- finding is multiple, often bilateral, hypodense lesions,
gests concomitant MGN, a second renal lesion that is which are observed in ~40% of patients (Figure 4).5,9 The
associated with IgG4‑RD.9 Urinalysis in IgG4‑related lesions predominantly involve the renal cortex and have
TIN typically reveals mild to moderate proteinuria and been characterized into four morphological patterns:
occasionally the presence of white blood cells.5 Mild peripheral cortical nodules <1 cm in diameter; well-
haematuria can be observed in rare cases, but red blood defined or poorly defined round lesions; wedge-shaped
cell casts are characteristically absent.5 Elevated total lesions; and diffuse, patchy lesions.26 Thickening of the
serum concentrations of IgG and IgG4 have been found renal pelvis has also been described.5 Biopsy samples
in nearly all cases of IgG4‑RKD reported to date, but the of these lesions show the classic histological features of
strength of this association needs to be evaluated in larger IgG4‑related TIN.26 The differential diagnoses for such
series of patients.5,9 radiographic findings include pyelonephritis, embolic
Approximately 60% of patients with IgG4‑related disease, lymphoma and metastatic solid tumours.
TIN have hypocomplementaemia, with low CH50 Diffuse bilateral renal enlargement is seen in approxi-
values in the total haemolytic complement assay and mately 20% of patients with IgG4‑related TIN. Mass
low levels of complement C3 and complement C4.5,9 lesions that mimic renal cell carcinoma are often
Hypocomplementaemia is not characteristic of most observed;5,9,27 nephrectomies for presumed renal cell
patients with IgG4‑RD, so this finding indicates that carcinoma sometimes yield a diagnosis of IgG4‑related
careful scrutiny for IgG4‑related TIN is appropri- TIN.28 Therefore, IgG4‑related TIN should be consid-
ate. The condition known as hypocomplementemic ered in the differential diagnosis of renal cell carcinoma.
immune complex TIN—which is characterized by C3 Classic but subtle extrarenal manifestations of IgG4‑RD
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 subepithelial deposits in a membranous pattern when
secondary to IgG4‑RD provides the basis for current examined by immunofluorescence and electron micros-
understanding of this condition. Further studies of MGN copy (Figure 6).34 Immunofluorescence staining for IgG
secondary to IgG4‑RD will be a welcome a ddition to subclasses was performed on samples from four patients,
the literature. and IgG4 was the predominant immunoglobulin in three
of the samples.
Clinical and laboratory features Interestingly, IgG4 is also the predominant immuno
MGN secondary to IgG4‑RD seems to occur predomi- globulin present in idiopathic MGN. A study published
nantly in older males, as is true for IgG4-related TIN.34 in 2009 found that the secretory phospholipase A2 recep-
Seven of the nine patients included in the series had tor (PLA2R) is the target antigen in the majority of cases
known extrarenal manifestations of IgG4‑RD at the time of idiopathic MGN; 33 circulating antibodies against
of diagnosis of MGN.34 Almost all patients presented PLA2R were present in approximately 70% of patients
with nephrotic-range proteinuria (mean 8.3 g daily) and with the condition. The staining of biopsy samples for
low serum albumin concentrations (mean 20 g/l); serum glomerular deposits of anti-PLA2R antibodies seems
creatinine levels were elevated in 75% of patients (mean to be more sensitive than the detection of serum anti-
194 μmol/l, range 70.7–583.4 μmol/l).34 Five of the nine PLA2R antibodies in idiopathic MGN. 36 However,
patients had concomitant TIN that was identified in in a study of renal biopsy samples from eight patients
renal biopsy samples; in these patients, TIN was probably with MGN secondary to IgG4‑RD, none of the samples
the primary driver of renal dysfunction because renal showed positive staining for anti-PLA2R antibodies.34
dysfunction correlated with the degree of TIN sever- Assays for antibodies against PLA2R are not helpful
ity.35 Serum IgG4 concentrations were elevated in all in distinguishing between idiopathic MGN and MGN
five patients in whom it was measured.34 The impetus secondary to IgG4‑RD because as many as 30% of
for biopsy was proteinuria in seven patients and acute patients with idiopathic MGN are negative for this anti-
kidney injury in the other two.34 body. However, other features help differentiate between
Diffuse bilateral renal enlargement attributable to these two entities. Many patients with MGN second-
IgG4‑RKD was detected in only one of seven patients ary to IgG4‑RD have both extrarenal manifestations
with the condition and who underwent renal imaging.34 of IgG4‑RD and IgG4-related TIN that is detectable in
This finding is in contrast to imaging findings in patients biopsy samples, whereas patients with idiopathic MGN
with IgG4‑related TIN, ~70% of whom exhibited have neither.34 Furthermore, serum levels of IgG4 are
characteristic radiographic features of the condition.5,9 typically elevated in MGN secondary to IgG4‑RD but
Intravenous contrast dye was necessary to detect the not in idiopathic MGN.34
hypodense cortical lesions found in the patients with One pathophysiological consideration in MGN sec-
IgG4-related TIN, whereas patients in the MGN series ondary to IgG4‑RD is whether the inciting antigen is
might not have received intravenous contrast owing to endogenous to the podocyte or a result of circulating
the presence of significant renal dysfunction. The data immune complex deposition. Certain histological fea-
presented might therefore underestimate the frequency tures might help distinguish between these two possi-
of radiographic findings. bilities. In idiopathic MGN, the antigen is endogenous
to the podocyte, and the corresponding immune com-
Renal pathology plexes are therefore confined to the subepithelial space.33
Experience to date of MGN secondary to IgG4‑RD sug- By contrast, secondary forms of MGN (for example,
gests that a substantial subset of cases—five out of nine those caused by drugs, infections, autoimmune diseases
in the largest series—have concomitant IgG4‑related and malignancies) are a result of circulating immune
TIN. 34 All biopsy samples in this series exhibited complexes or circulating free antigen that lead to in situ
immune complex formation.29 In this case, random Current approaches to the management of the disease
deposition of the circulating immune complexes in the are based on observational case series, and the decision
glomerulus often results in the localization of immune to treat is based on symptoms and the organ systems
complexes in the subendothelial space and mesangium involved. Renal involvement of IgG4‑RD is organ threat-
in addition to the subepithelial space.37,38 ening, so prompt treatment is indicated with the goal
Three of the nine biopsy samples from the series of of suppressing inflammation before the development of
patients with MGN secondary to IgG4‑RD exhibited marked fibrosis.44,45
mesangial or subendothelial deposits in addition to sub- Glucocorticoids are currently the first-line treatment
epithelial deposits.9 Heterogenous mechanisms are prob- for IgG4‑RD.45 Most data on the use of glucocorticoids
ably responsible for the different pathological features are derived from the treatment of type 1 autoimmune
observed. More cases of MGN secondary to IgG4‑RD pancreatitis and have been extrapolated to the treat-
need to be studied to determine the degree to which its ment of extrapancreatic IgG4‑RD. Treatment of type 1
pathophysiology is shared with that of other types of sec- autoimmune pancreatitis with glucocorticoids typi-
ondary MGN. Determining whether the target antigen cally results in a symptomatic response within 2 weeks
in MGN secondary to IgG4‑RD is localized to the podo- and remission within 2–3 months.14,45 However, many
cyte, as it is in idiopathic MGN, could provide impor- patients experience relapse as glucocorticoid treatment
tant insight into the pathogenesis of some features of is reduced or discontinued, and the optimal approach
IgG4‑RKD and possibly into other organ m anifestations to ensure maintenance of remission remains unclear.14,45
of IgG4‑RD. In a large cohort of patients with type 1 autoimmune
pancreatitis, 34% of patients experienced relapse after
Retroperitoneal fibrosis withdrawal of glucocorticoids.45 This finding probably
RPF is characterized by the development of fibro underestimates the true number of relapses, as patients
inflammatory tissue in the periaortic and peri-iliac retro often have recurrent manifestations of IgG4‑RD many
peritoneum,39 a process that tends to encase the ureters years after presentation.
and adjacent structures.39 Pain in the back, abdomen Prolonged treatment with glucocorticoids is particu-
or flank is the most common presenting symptom.39 larly problematic in IgG4‑RD because the condition
Ureteral obstruction that leads to renal failure is often tends to afflict middle-aged to elderly individuals who
present at diagnosis. In a series of 53 patients with RPF, are already are at increased risk of osteoporosis, diabetes
hydronephrosis and elevated serum creatinine levels mellitus and complications after infections. For this
(>106.1 μmol/l) were noted at diagnosis in 55% and reason, there is interest in steroid-sparing therapeutic
66% of patients, respectively.40 Treatment of obstruction agents for IgG4‑RD, particularly in the subset of patients
with percutaneous nephrostomy tubes, ureteral stents with refractory or recurrent disease. Azathioprine and
or open surgery is sufficient to prevent acute develop- mycophenolate mofetil (MMF) have been used in
ment of end-stage renal disease in most cases, but many the treatment of patients with relapsing type 1 auto
patients experience chronic kidney disease as a result of immune pancreatitis, but only a limited amount of
the refractory nature of RPF or the failure to detect the data suggests true efficacy in the absence of concurrent
lesion while it is still amenable to immunosuppression.41 glucocorticoid treatment.46
A variety of secondary causes of RPF have been rec- Treatment with rituximab to induce B-cell depletion
ognized, including infection, radiation therapy, medi- has yielded promising results.22,23,45 In one report, four
cations, malignancies and trauma.39 However, before patients with various manifestations of IgG4‑RD, includ-
the recognition of IgG4‑RD, most cases of RPF were ing aortitis, type 1 autoimmune pancreatitis, sialadenitis
regarded as idiopathic.42 In a retrospective assessment and orbital pseudotumour, responded dramatically to
of 23 patients who were diagnosed with idiopathic RPF rituximab therapy and were able to discontinue gluco-
at the Massachusetts General Hospital,43 histopathologi- corticoid therapy.22 IgG4 levels decreased by 65% within
cal findings led to diagnosis of IgG4‑RD in 13 patients 2 months of rituximab therapy, and levels of other IgG
(57%) on the basis of classic IgG4‑RD histology and an subclasses did not decline. This finding suggests that
IgG4+:IgG+ plasma cell ratio >40%. Extraretroperitoneal rituximab might interfere with repletion of short-lived
manifestations of IgG4‑RD were frequently observed in plasmablasts and plasma cells that produce IgG4.18,47
the same patients, and also helped with diagnosis. No These findings were corroborated by a study that
currently recognized clinical or radiographic features included 10 patients with IgG4‑RD that was refractory
reliably differentiate between IgG4‑related RPF and RPF to prednisone.23 With rituximab treatment, a marked
that has no other disease association. Greater scrutiny of improvement was observed in all but one patient, and
the pathological details observed in cases of RPF could all patients were able to discontinue glucocorticoids
lead to more precise c lassification of RPF subsets. entirely. Six patients exhibited durable responses after
initial treatment with rituximab and did not require
Treatment additional therapy over a mean follow-up period of
IgG4‑related disease 9.6 months (range 4–14 months). Clinical flares that
The optimal treatment for IgG4‑RD is unknown. To date, required retreatment with rituximab were associated
no randomized clinical trials have evaluated the com- with an increase in serum IgG4 levels following B-cell
parative effectiveness of different treatment regimens. reconstitution. This phenomenon suggests that IgG4
levels could be used to follow disease activity in patients early treatment of IgG4‑related TIN, with the goal of
who have elevated serum IgG4 concentrations at baseline preventing renal fibrosis.
and are treated with rituximab but not glucocorticoid One of many unanswered questions is whether
maintenance therapy. However, subsequent studies of patients with radiographic abnormalities associated with
patients with IgG4‑RD treated with rituximab suggest IgG4‑related TIN but no obvious clinical renal impair-
that blood plasmablast concentrations are a more useful ment require immunosuppressive therapy. In a cohort
biomarker than are serum IgG4 concentrations in this of 14 patients with eGFR >60 ml/min/1.73 m2 (mean
setting.18,47 Further investigation is needed to establish 83.4 ± 14 ml/min/1.73 m2) and abnormalities detected
the optimal use of rituximab in IgG4‑RD and to test the by imaging, treatment with glucocorticoids led to
methods used to follow clinical responses. improvements in the abnormalities detected by imaging
and no change in eGFR after a mean follow-up period of
IgG4‑related TIN 42.4 ± 17.0 months.44 Patients were treated with a mean
Published experience of treating IgG4‑RD with renal initial prednisolone dose of 36.8 ± 13.3 mg daily, which
involvement is limited to a few case series. In a Japanese was tapered gradually over the course of 12 months to
biopsy series of IgG4‑related TIN, 21 of 23 patients a maintenance dose of 5.5 ± 3.3 mg daily. Whether renal
were treated with prednisolone monotherapy.5 11 of function would have deteriorated without treatment is
these patients had serum creatinine concentrations unknown, because data on the untreated natural course
≤114.9 μmol/l before treatment, and renal involvement of IgG4‑related TIN are sparse. Close monitoring of renal
was detected on the basis of radiographic abnormalities function is essential if a conservative (non-treatment)
more frequently than on the basis of renal insufficiency. strategy is selected. However, given that renal atrophy
Serum creatinine concentrations improved or stabilized is known to occur in many patients with IgG4‑related
at 1 month after treatment in all patients except one, TIN, treatment even in the absence of overt clinical renal
whose condition progressed to end-stage renal disease. dysfunction is reasonable.
In the Mayo Clinic TIN series, all 21 patients who were Relapse of renal dysfunction following steroid taper-
treated received prednisone, and two patients received ing or withdrawal is frequently observed among patients
concomitant MMF. 9 19 (90%) of these patients had with IgG4‑related TIN. In the largest cohort of patients
serum creatinine concentrations >1.6 μmol/l before who were treated with glucocorticoids, 20% experi-
treatment (mean 3.5 μmol/l). One patient’s condition enced a relapse in either the kidney or another organ
progressed to a stage that required dialysis, but the system while on maintenance therapy (median 5 mg
remainder exhibited stable or improved renal function, daily). The mean follow-up period in that study was
with a mean post-treatment serum creatinine concen- only 44 months.44 An alternative therapy is desirable for
tration of 1.7 μmol/l after follow-up periods that varied patients who are at high risk of complications of long-
in length. Two patients responded to prednisone but term glucocorticoid therapy (for example, people with
relapsed following glucocorticoid withdrawal. glucose intolerance or osteoporosis at baseline) and those
Data on long-term outcomes of IgG4-related TIN with relapsing disease.
treatment are available from a retrospective analysis Although not yet studied specifically in patients
of 40 patients.44 These patients were treated with pred- with IgG4‑related TIN, B-cell depletion with rituximab
nisolone at an initial dose of 20–60 mg daily. A subset might yield a durable response that obviates the need
of 20 patients had a pretreatment estimated glomeru- for extended glucocorticoid therapy in some cases. This
lar filtration rate (eGFR) <60 ml/min/1.73 m2 (mean hypothesis requires confirmation in rigorous trials.44
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 MGN secondary to IgG4‑RD
with a mean prednisolone dose of 36.0 ± 9.5 mg daily. At Treatment of MGN secondary to IgG4‑RD is typically
a mean follow-up of 54.5 months, all but one patient directed against the underlying systemic disorder rather
remained on some maintenance dose of prednisolone than the renal lesion, although treatment regimens exist
(mean 6.0 ± 3.7 mg daily). At the end of the follow-up that target the kidney lesion in MGN associated with sys-
period, the mean eGFR had significantly improved to temic lupus erythematosus.50 Experience of treatment of
44.4 ± 11.0 ml/min/1.73 m2. Despite these favourable MGN secondary to IgG4‑RD is limited to a retrospective
clinical responses, 60% of patients who underwent CT analysis of seven patients who were followed for a mean
imaging during follow-up exhibited evidence of notable period of 39 months (range 4–184 months).34 Four of
renal atrophy. This atrophy was observed even in patients those patients had concomitant IgG4‑related TIN identi-
who seemed to respond well to prednisolone therapy. fied by biopsy. Treatment approaches varied: two patients
A retrospective study of drug-induced allergic inter- received prednisone; two initially received prednisone
stitial nephritis suggests that early recognition of the alone and subsequently received prednisone with MMF;
condition and treatment with glucocorticoids attenuates one received prednisone, cyclophosphamide and an
the degree of interstitial fibrosis.48 Furthermore, histol- angiotensin-converting-enzyme inhibitor; one received
ogy of tissue from patients with IgG4‑related TIN and an angiotensin-converting-enzyme inhibitor followed by
treated with glucocorticoids demonstrated a reduction of rituximab and MMF; and one patient was not treated.
cellular infiltrate, but subsequent development of inter- Treatment led to a decline in proteinuria from a mean
stitial fibrosis.49 Taken together, these findings support baseline of 8.8 g daily (range 3.5–16 g daily) to 1.2 g
daily (range 0–3.1 g daily) and an associated improve- shortcomings as a disease biomarker. Recent findings
ment in the mean serum creatinine concentration from suggest that plasmablast concentrations have potential
221.0 μmol/l (range 70.7–583.4 μmol/l) to 123.8 μmol/l as a biomarker that could help with diagnosis, gauging
(range 70.7–221.0 μmol/l). disease activity, and determining the optimal timing of
The heterogeneity of treatment in this series under- treatment. Further studies that focus on IgG4+ plasma-
scores the lack of available clinical evidence, and the blasts are required to determine whether flow cytom-
small numbers preclude firm conclusions about the com- etry assays for these cells are superior to measurement of
parative efficacies of different regimens. Extrapolation plasmablast concentrations for these purposes. The high
of data from other chronic kidney diseases associated degree of somatic hypermutation observed in circulat-
with proteinuria (>500 mg daily) indicate that such ing plasmablasts in IgG4‑RD suggests an important role
patients should be treated with an inhibitor of the renin– for T cells in shaping the B-cell responses, but studies of
angiotensin system.51 Patients with nephrotic-range pro- T cells in IgG4‑RD are still only at an early stage.
teinuria should be screened for dyslipidaemia and treated The propensity of IgG4‑RKD to flare following the ces-
with statin therapy if concentrations of low-density sation of glucocorticoid treatment poses a major chal-
lipoproteins are elevated.52 lenge for clinicians, particularly considering that the
patient population at risk of this disease often has consid-
Conclusions and next steps erable comorbidities (for example, old age and pancre-
IgG4‑RD is now recognized as a link between many atic damage) that render ongoing glucocorticoid therapy
clinical entities that were previously regarded as undesirable. Moreover, the observation that kidneys
unique, organ-specific disorders; many of these enti- that are affected by IgG4‑RD often undergo fibrosis and
ties have been recognized by physicians for more than atrophy, even after seemingly positive clinical responses,
100 years. The medical literature on IgG4‑RD has grown raises questions about the optimal strategies for remis-
rapidly over the past decade, but current understand- sion induction and maintenance. B-cell depletion is a
ing of IgG4‑RKD is largely based on fewer than 100 promising therapy but requires further investigation
patients. Descriptions of larger numbers of patients with before its full role and optimal use are understood.
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 Review criteria
TIN, remains particularly unexplored. PubMed was searched for full-text English-language
The antigenic trigger for IgG4‑RD remains unidenti papers published online up to May 2014 using the
fied, and the direct role (if one exists) of the IgG4 following terms: “IgG4‑related disease AND (kidney
molecule itself remains unclear. Although serum OR renal).” References included in the manuscript
IgG4 concentrations are elevated in the majority of were chosen at the authors’ discretion based on their
relevance to the subject of the Review.
patients—often dramatically so—IgG4 levels have clear
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Acknowledgements
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providing Figures 1 and 5, and Helmut Rennke from
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the Brigham & Women’s Hospital, Boston, USA, for
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providing Figure 6.
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