IgG4-related kidney disease

Seminars in Diagnostic Pathology (2012) 29, 245-250
IgG4-related kidney disease
Lynn D. Cornell, MD
From the Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
Minnesota.
KEYWORDS
Interstitial nephritis;
Immune complex;
IgG4-related disease;
Membranous
glomerulonephritis;
Membranous
nephropathy
IgG4-related kidney disease is a term that refers to any form of renal involvement by IgG4-related
disease (IgG4-RD), a recently recognized systemic immune-mediated disease. The most common renal
manifestation is IgG4-related tubulointerstitial nephritis (IgG4-TIN), which presents as acute or chronic
renal insufficiency, renal mass lesions, or both. On biopsy, IgG4-TIN shows a plasma cell–rich
interstitial inflammatory infiltrate with increased IgG4⫹ plasma cells, along with expansile interstitial
fibrosis; tubular basement membrane immune complex deposits are common. IgG4-TIN usually shows
a brisk response to immunosuppressive therapy. Glomeruli may be affected by IgG4-RD, usually in the
form of membranous glomerulonephritis. Other patterns of glomerular disease include IgA nephropathy, membranoproliferative glomerulonephritis, and endocapillary or mesangioproliferative immune
complex glomerulonephritis. IgG4-related plasma cell arteritis has also been observed in the kidney.
This review describes the histopathologic and immunophenotypic patterns of renal involvement by
IgG4-RD, with associated clinical, radiographic, and serologic features.
© 2012 Elsevier Inc. All rights reserved.
IgG4-related kidney disease (IgG4-RKD) is the term
used to refer to any pattern of renal involvement by IgG4related disease (IgG4-RD).1 As with other medical kidney
diseases, IgG4-RKD can be described in terms of changes to
the different “compartments” in the kidney: the tubules and
interstitium, the glomeruli, and the vessels. In the kidney,
IgG4-RD manifests most commonly as tubulointerstitial
nephritis (TIN), which may be mass forming and detected
on radiographic examination. Glomerular disease, in particular membranous glomerulonephritis (MGN), may also be
seen in IgG4-RD, with or without concurrent IgG4-related
TIN (IgG4-TIN). A lesion of the arteries, IgG4-related
plasma cell arteritis, has also been observed.2 The kidney
may also be affected by extrarenal manifestations of IgG4RD, including ureteral inflammatory pseudotumor or retroperitoneal fibrosis.3-5 This article will review the different
patterns of renal involvement by IgG4-RD, with associated
clinical, radiographic, and serologic features.
Clinical presenting features of IgG4-RKD
IgG4-TIN in the kidney may present as masses evident on
radiographic studies, as acute or progressive chronic renal
failure, or both.6 Tissue samples of radiographic lesions
reveal TIN.7 Patients with TIN may have mild proteinuria
and microscopic hematuria on urinalysis, and those with
MGN usually present with heavy proteinuria or nephrotic
syndrome.8 IgG4-related retroperitoneal fibrosis or ureteral
inflammatory pseudotumor may lead to renal failure due to
obstruction.3-5
IgG4-related tubulointerstitial disease
Address reprint requests and correspondence: Lynn D. Cornell,
MD, Division of Anatomic Pathology, Department of Laboratory Medicine
and Pathology, Mayo Clinic, Rochester, MN 55905.
E-mail address: cornell.lynn@mayo.edu.
IgG4-TIN, the most commonly recognized pattern of
renal involvement by IgG4-RD, is a specific type of immune-mediated TIN that can be distinguished from other
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246
Seminars in Diagnostic Pathology, Vol 29, No 4, November 2012
types of TIN by clinical, radiographic, laboratory, histologic, and immunophenotypic features.9 IgG4-TIN has been
observed in IgG4-RD patients both with and without pancreatic involvement; in some patients the disease is confined
to the kidney. A lesion similar to IgG4-TIN, chronic sclerosing pyelitis, an inflammatory mass that affects the renal
pelvis, has also been described.10 Raissian et al and Saeki et
al have collected data on the two largest biopsy series of
IgG4-TIN at 35 and 23 cases, respectively.6,11 Both of these
series showed many of the clinical and histologic features
that have been encountered in other organs affected by
IgG4-RD, namely, radiographic tumoral lesions, plasma
cell–rich inflammatory infiltrates with increased IgG4⫹
plasma cells, elevated total IgG or IgG4 levels in the serum,
presence of other organ involvement, and rapid response to
steroid therapy in most patients. Features specific to the
kidney are detailed below.
Clinical features of IgG4-TIN
The average age of patients with IgG4-TIN is 65 years;
most (⬃80%) are male. The Saeki et al study from Japan
included only Japanese patients; the Raissian series from
North America included patients from other racial and ethnic groups, although the majority of cases were Caucasian.6,11 Most patients (57%-76%) had acute or progressive
chronic renal failure. In the remaining patients, the primary
indication for biopsy or nephrectomy was a renal mass
lesion. Many patients had both renal failure and kidney
mass lesions. Other organs were involved by IgG4-RD in
⬎80% of patients in the Raissian et al biopsy series, either
concurrently or before the recognition IgG4-TIN. The most
common extrarenal sites involved were the pancreas, liver,
and salivary or lacrimal glands.
Laboratory features of IgG4-TIN
Similar to autoimmune pancreatitis, almost 80% of
IgG4-TIN patients had elevated serum total IgG or IgG4
levels.12 Not all of these patients had serum IgG subclass
levels measured; of the subset that did, 92% had an
elevated serum IgG4.6 Elevated serum IgG4 alone is not
specific for IgG4-RD, and the results of these serum
studies should be interpreted with caution.13 Other common laboratory features are decreased serum C3 and/or
C4 levels (56%-78% of IgG4-TIN patients), peripheral
blood eosinophilia (33%-48%), and low-titer positive
anti-nuclear antibody (⬃30%).6,11
Radiographic features of IgG4-TIN
Radiographic lesions of IgG4-TIN are best visualized on
contrast-enhanced computed tomography scan. The lesions
are commonly bilateral and multiple and predominantly
involve the renal cortex. Renal parenchymal lesions can be
classified as small peripheral cortical nodules, round or
wedge-shaped lesions, diffuse patchy involvement, or a
large solitary mass.14 The radiographic differential diagnosis of renal parenchymal lesions includes lymphoma, vasculitis, pyelonephritis, and metastatic cancer.
Histologic, immunophenotypic, and ultrastructural
features of IgG4-TIN
By light microscopy, IgG4-TIN shows a plasma cell–rich
interstitial inflammatory cell infiltrate. There is a spectrum
of histologic appearances, ranging from acute TIN with
minimal fibrosis, to an intermediate pattern with some interstitial fibrosis but a marked inflammatory infiltrate, to a
densely fibrotic paucicellular pattern with extensive tubular
destruction and atrophy.6 The fibrosis is expansile, pushing
apart the tubules, and often has a “storiform” pattern as seen
in other organs involved by IgG4-RD.15 Along with plasma
cells and mononuclear cells, some tissue specimens show
numerous eosinophils and thus may be confused with allergic TIN due to a drug. Focal mild mononuclear cell tubulitis
is seen in most cases, and eosinophilic or plasma cell
tubulitis may also be seen. In some cases, tubules are
destroyed and only fragments of tubular basement membranes (TBMs) can be appreciated on periodic acid-Schiff
(PAS)- or silver-stained sections (Figure 1).
By immunofluorescence, ⬎80% of cases show focal or
diffuse TBM immune complex deposits, which stain for
IgG and kappa and lambda light chains, usually for C3,
albeit lesser intensity, and in approximately 10% of cases,
for C1q in approximately 10% of cases.6 TBM deposits are
found more frequently in specimens with interstitial fibrosis. Deposits are found only in areas of the fibroinflammatory process and not in adjacent unaffected areas.6
Specimens with deposits seen by immunofluorescence
show corresponding amorphous TBM electron-dense deposits by electron microscopy.6 Glomeruli are negative by
immunofluorescence and electron microscopy unless there
is a concurrent immune complex glomerulonephritis.
Immunostaining for IgG4⫹ plasma cells is helpful in
distinguishing IgG4-TIN from other types of plasma cell–
rich tubulointerstitial inflammatory infiltrates that could
mimic IgG4-TIN clinically and histologically.6 Using a
cutoff of focal moderate (11-30 IgG4⫹ cells/40⫻ field) to
marked (⬎30 IgG4⫹ cells/40⫻ field) increase in IgG4⫹
plasma cells, the authors of one study found a sensitivity of
100% (95% confidence interval: 0.9-1) and specificity of
92% (95% confidence interval: 0.86-0.95) for distinguishing
IgG4-TIN from other forms of TIN, after excluding cases of
inflammatory infiltrates in pauci-immune necrotizing and
crescentic glomerulonephritis.6
In kidney biopsies with interstitial inflammation related
to pauci-immune glomerulonephritis, approximately 30% of
cases showed a focal moderate to marked increase in
IgG4⫹ plasma cells6; others have made this observation
in the kidney as well.16 Similar findings have been noted in
granulomatosis with polyangiitis (Wegener’s granulomatosis) affecting other organs.17 The absence of a serum antineutrophil cytoplasmic antibody (or anti-myeloperoxidase
or -proteinase 3 antibodies) and necrotizing or crescentic
glomerulonephritis on the tissue specimen helps to exclude
pauci-immune glomerulonephritis as a cause of the interstitial inflammation. Focally increased IgG4⫹ plasma cells
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Cornell
IgG4-Related Kidney Disease
247
Figure 1 IgG4-TIN in a young man who presented with acute renal failure. The kidneys were markedly enlarged bilaterally on
ultrasound examination. On biopsy, there is a marked interstitial inflammatory cell infiltrate with expansile fibrosis (left panel; Jones
methenamine-silver). An IgG4 immunoperoxidase stain shows a marked increase in IgG4⫹ plasma cells (middle panel). By
immunofluorescence, there is TBM and interstitial granular staining for IgG, whereas a glomerulus is negative for immune complex
deposition (right panel); a similar staining pattern was also seen for IgG4 and for kappa and lambda light chains (data not shown).
(Color version of figure is available online.)
were seen in a few other causes of interstitial inflammation,
including chronic pyelonephritis; these other causes usually
can be distinguished on clinical and histopathologic
grounds. Notably, nearly all cases of Sjögren syndromerelated TIN did not show increased IgG4⫹ plasma cells.
Clinicians and pathologists should keep in mind that IgG4
plasma cell staining alone is not diagnostic of IgG4-RD.
Diagnosis of IgG4-TIN
Recent publications from Japan and North America have
proposed diagnostic criteria for IgG4-TIN.6,18 Both propose
a multimodal approach to the diagnosis (Tables 1 and 2).
Table 1
Both articles emphasize the need to exclude other diagnoses
that may show increased IgG4⫹ plasma cells, in particular
granulomatosis with polyangiitis, Churg–Strauss syndrome,
and plasma cell myeloma or lymphoproliferative disorders
with plasmacytic differentiation.
Table 2
RKD18
Japanese Society of Nephrology criteria for IgG4-
Clinical
features
Proposed diagnostic criteria for IgG4-TIN
Histology
Imaging
Serology
Other organ
involvement
Plasma cell–rich TIN with ⬎10 IgG4⫹
plasma cells/hpf field in the most
concentrated field*
TBM immune complex deposits by
immunofluorescence,
immunohistochemistry, and/or electron
microscopy†
Small peripheral low-attenuation cortical
nodules, round or wedge-shaped lesions,
or diffuse patchy involvement
Diffuse marked enlargement of kidneys
Elevated serum IgG4 or total IgG level
Characteristic findings of IgG4-RD in
other organs
Raissian et al histologic criteria for IgG4-TIN.6
Diagnosis of IgG4-TIN requires the histologic feature of plasma
cell–rich TIN with increased IgG4⫹ plasma cells and at least one other
feature from the imaging, serology, or other organ involvement categories.
*Mandatory criterion.
†Supportive criterion, present in ⬎80% of cases.
Imaging
Serology
Histology
Other organ
involvement
Clinical or laboratory evidence of kidney
damage, including abnormal renal
function or abnormal urinalysis with
elevated serum IgG or IgE level or
hypocomplementemia
Abnormal radiographic findings:
Multiple low-density lesions on
contrast-enhanced computed
tomography scan, diffuse kidney
enlargement, hypovascular solitary
kidney mass, hypertrophic lesion of the
renal pelvic wall
Elevated serum IgG4 or total IgG level
a. Dense lymphoplasmacytic infiltrate
with ⬎10 IgG4⫹ plasma cells/hpf and/
or IgG4/IgG⫹ plasma cell ratio of
⬎40%
b. Characteristic storiform fibrosis
Characteristic histologic findings of
IgG4-RD in other organs
“Definite” IgG4-RKD occurs with three of the following: clinical
features, serology, and histologic features (a and b); imaging, serology, and histologic features (a and b); imaging, serology, or other
organ involvement; or clinical features, serology, histologic features (a
only), and other organ involvement.
“Probable” and “possible” disease occurs with fewer criteria.
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248
Seminars in Diagnostic Pathology, Vol 29, No 4, November 2012
IgG4-related glomerular disease
Glomerular diseases have been described in patients with
IgG4-RD, mostly in the form of case reports or as a part of
IgG4-TIN case series. In a clinical series of Kawano et al,
11 of 28 (39%) patients were reported to have some type of
glomerular lesion.18
IgG4-related MGN
MGN is a glomerular disease pattern characterized by
subepithelial glomerular basement membrane (GBM) immune complex deposits, and may be a primary (“idiopathic”) disease or secondary to a number of conditions,
including autoimmune diseases, infections, medications,
and neoplasms.19 MGN in the setting of IgG4-RD is referred to as “IgG4-related MGN” (IgG4-MGN)1 although it
is recognized that primary MGN is also an IgG4-dominant
disease.20,21
In the two largest series of IgG4-TIN, MGN was present
in approximately 7% of patients, and this form of glomerular disease has been noted in several case reports as
well.6,11,15,18,22-28 Patients with IgG4-MGN all presented
with proteinuria, typically nephritic range. IgG4-MGN thus
should be suspected in IgG4-RD patients with significant
proteinuria, and conversely, patients with MGN on renal
biopsy, and an appropriate clinical history should be evaluated for IgG4-RD.8
Histopathologically, in IgG4-MGN, the glomeruli appear
normal or show thickened glomerular capillary loops on
H&E-stained sections (Figure 2). GBM “spikes” can sometimes be seen using silver or PAS stains, and subepithelial
immune complex deposits may be seen on a trichrome stain.
One biopsy in our series showed segmental endocapillary
hypercellularity in addition to the MGN pattern.8 By immunofluorescence, glomeruli typically show segmental or
global granular GBM bright staining for IgG, C3, and both
kappa and lambda light chains. Immunofluorescence staining for IgG subclasses or immunoperoxidase staining for
IgG4 revealed that the glomerular deposits contained IgG4.
Immunostaining for the phospholipase A2 receptor (a finding typically seen in primary MGN) was negative in all 8
biopsies stained, which argues that this is a secondary
MGN.8,29 In our series, 5 of 9 patients (56%) showed
concurrent IgG4-TIN on biopsy. Compared with IgG4-TIN,
TBM deposits were less common in IgG4-MGN, present in
33% of cases.8
Other IgG4-related glomerular lesions
Other glomerular diseases have been variably reported in
IgG4-RD, including IgA nephropathy, Henoch-Schönlein purpura, and membranoproliferative glomerulonephritis.11,18,30-32
A few cases of endocapillary proliferative glomerulonephritis,
sometimes with crescents, have been described.11,18,27,32 In the
setting of IgG4-TIN, nephropathologists have occasionally observed a pattern of mesangial proliferative glomerulonephritis
with IgG-containing mesangial immune complex deposits,
without a more specific diagnosis.7,11 Diabetic glomerulosclerosis may be identified in cases of autoimmune pancreatitis
with pancreatic endocrine insufficiency. In addition, there have
been three cases of minimal change disease among 116 IgG4RKD cases presented in regional meetings in Japan between
2004 and 2011 (Takako Saeki, personal communication).
IgG4-related vascular disease
Plasma cell–rich renal arteritis has recently been described in a patient with IgG4-TIN.2 This lesion affected
small and medium-sized arteries on a biopsy, with marked
intimal, medial, and adventitial inflammation by plasma
cells and lymphocytes (Figure 3). Many IgG4⫹ plasma
cells were present in the arterial wall. Neither fibrinoid
Figure 2 IgG4-MGN in an elderly woman with heavy proteinuria at 4 g/d. By light microscopy, the glomeruli appear normal (left panel;
Jones methenamine-silver). Immunofluorescence shows global granular GBM staining for IgG (middle panel). No TBM deposits were
identified despite presence of concurrent IgG4-TIN in some areas. Electron microscopy shows small subepithelial electron-dense deposits
(arrows, right panel). (Color version of figure is available online.)
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Cornell
IgG4-Related Kidney Disease
249
has a different pathogenic mechanism and thus would not be
expected to show the same rapid treatment response with
respect to proteinuria.
Conclusions
Figure 3 IgG4-related renal arteritis in an elderly man with
acute on chronic renal failure. A representative artery shows severe
arteritis with numerous plasma cells in the intima, media, and
adventitia, without fibrinoid necrosis (hematoxylin and eosin). An
immunoperoxidase stain for IgG4 showed numerous IgG4⫹
plasma cells in the arterial lesion. Image courtesy of Dr Shree
Sharma and Dr Vivette D’Agati, Columbia University. (Color
version of figure is available online.)
necrosis of the arteries nor rupture of the elastica was
present, and neutrophils were not identified in the lesions.
Veins are usually not present in kidney needle core
biopsies but can be seen in nephrectomy specimens. Venulitis, similar to that seen in other organs affected by IgG4RD, can sometimes be seen in IgG4-TIN, but is not necessary for diagnosis.7
IgG4-RKD and response to therapy
Similar to other organ manifestations of IgG4-RD, IgG4TIN also usually shows a swift response to steroid therapy.
In both major series of IgG4-TIN, 90% of patients with
elevated serum creatinine at presentation who were treated
with steroids showed decreased creatinine at follow-up.
Although TIN of any cause may respond to steroid therapy,
IgG4-TIN tends to show a response even in cases with
severe interstitial fibrosis on the biopsy sample. IgG4-TIN
may relapse after treatment, similar to other organ manifestations of IgG4-RD.33,34 A small case series described a
response to rituximab in IgG4-RD patients refractory to
steroid treatment.35 We have also encountered one steroiddependent patient with IgG4-TIN who showed a response to
rituximab (Cornell LD, unpublished data). Long-term follow-up data are needed to assess the impact of immunosuppressive therapy on IgG4-TIN.
In a series of IgG4-MGN patients, six patients were
treated with various immunosuppressive drugs. All six patients showed decreased proteinuria and most showed decreased serum creatinine at an average of 39-month follow-up (range: 4-184 months). Although IgG4-TIN shows a
swift response to therapy, we hypothesize that IgG4-MGN
The kidney can be affected by IgG4-RD in a variety of
patterns. IgG4-TIN, the most common renal manifestation
of IgG4-RD, is a plasma cell–rich immune-mediated disease that may present as renal failure, renal mass lesions, or
both. IgG4-TIN may be distinguished from other forms of
TIN by histologic, immunophenotypic, clinical, serologic,
and radiographic features. Glomerular disease may also be
seen in IgG4-RD, most commonly with a pattern of MGN,
although the glomerular disease may not be accompanied by
IgG4-TIN. IgG4⫹ plasma cell arteritis has recently been
described in the kidney. IgG4-TIN typically shows a swift
response to steroid therapy; refractory patients may respond
to rituximab.
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