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IgG4-related kidney disease – A review
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Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
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Review
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IgG4-related kidney disease – A review
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Dinesh Pradhan a , Niharika Pattnaik b , Russell Silowash a , Sambit Kumar Mohanty c,∗
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University of Pittsburgh Medical Center, Pittsburgh, PA, USA Kalinga Hospital, Bhubaneswar, India c CORE Diagnostics, Gurgaon, India b
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Article history: Received 16 December 2014 Received in revised form 5 March 2015 Accepted 25 March 2015
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Keywords: IgG4 Kidney disease
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Contents
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IgG4-related disease (IgG4-RD) is a recently recognized systemic autoimmune disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive plasma cells in multiple organs. The condition was first described as a disease of the pancreas, and has since been recognized in various organ systems including the kidneys. IgG4 related kidney disease (IgG4-RKD) signifies any form of renal involvement by IgG4-RD. The most common renal involvement by IgG4-RD is tubulointerstitial nephritis. Glomerular disease, in particular membranous glomerulonephritis, may also be seen. Other co-existent glomerular diseases such as IgA nephropathy, membranoproliferative glomerulonephritis, and mesangioproliferative immune complex glomerulonephritis may be identified. IgG4-related plasma cell arteritis has also been noted in the kidney. As with IgG4-RD in general, IgG4 related kidney disease (IgG4-RKD) usually occurs in middle-aged to elderly men. Common findings in IgG4-RKD are plasma cellrich interstitial inflammatory infiltrate either in a focal or diffuse pattern with increased IgG4+ plasma cells, expansile swirling interstitial fibrosis, high levels of serum IgG and IgG4, hypocomplementemia, high serum IgE levels and/or peripheral blood eosinophilia. By immunofluorescence, most of the cases show IgG4 dominant tubular basement membrane immune complex deposits. Similar to IgG4-RD, IgG4RKD often shows a rapid response to steroid therapy. In this review, we discuss the current knowledge on IgG4-RKD and its clinical relevance. © 2015 Elsevier GmbH. All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and radiologic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathologic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Macroscopic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microscopic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IgG4-TIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IgG4-related glomerular lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IgG4-related vascular lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunophenotypic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Direct immunofluorescence findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ultrastructural features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author. Tel.: +91 9711689262. E-mail address: [email protected] (S.K. Mohanty). http://dx.doi.org/10.1016/j.prp.2015.03.004 0344-0338/© 2015 Elsevier GmbH. All rights reserved.
Please cite this article in press as: D. Pradhan, et al., IgG4-related kidney disease – A review, Pathol. – Res. Pract (2015), http://dx.doi.org/10.1016/j.prp.2015.03.004
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Introduction
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IgG4-related disease (IgG4-RD) is a recently recognized systemic autoimmune disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells in multiple organs [1,2]. The diagnosis of IgG4-related disease depends on the characteristic morphologic appearance, which includes a dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and increased numbers of IgG4+ plasma cells. Deshpande et al. [3] nevertheless stresses careful clinicopathologic correlation, which cannot be superseded by the morphologic criteria alone. This systemic disease was first recognized as a disease of the pancreas [sclerosing lymphoplasmacytic pancreatitis also referred as autoimmune pancreatitis (AIP)] by Sarles et al. in 1961 [4]. IgG4RD disease has now been described in nearly every organ system, including the kidney, liver (sclerosing cholangitis, pseudotumor), gallbladder (IgG4-related cholecystitis), salivary and lacrimal glands (chronic sclerosing sialadenitis/Kuttner’s tumor; dacryoadenitis; Mikulicz disease), lung and pleura (interstitial pneumonitis, inflammatory pseudotumor, fibrinous pleuritis), orbit (pseudotumor), breast (sclerosing mastitis, inflammatory pseudotumor), retroperitoneum (retroperitoneal fibrosis), cardiovascular system (periaortitis; inflammatory aortic aneurysm; pericarditis), lymph nodes (lymphadenopathy with various histologic patterns), skin (cutaneous pseudolymphoma), pituitary gland (infundibulohypophysitis), thyroid (Riedel thyroiditis; Hashimoto thyroiditis), and prostate (prostatitis) [5–16]. The fibroinflammatory lesions show remarkable histologic similarity in these different organs [3,17]. Renal involvement in IgG4-RD in any form is collectively referred to as IgG4-related kidney disease (IgG4-RKD) [18–20]. The most common renal involvement by IgG4-RD is in the form of plasma cell rich tubulointerstitial nephritis (IgG4-TIN). Other renal manifestations and associations of IgG4-RD include membranous glomerulonephritis (MGN) with or without IgG4-TIN, IgA nephropathy, membranoproliferative glomerulonephritis, mesangioproliferative immune complex glomerulonephritis, sclerosing pyelitis, IgG4-related plasma cell arteritis and hydronephrosis associated with IgG4 related retroperitoneal fibrosis or ureteral inflammatory pseudotumor [1,18–21]. To date, sporadic case reports and occasional series of IgG4-RD have been described in the literature. In this review, we discuss the recent literature related to IgG4-RD as it affects the kidney.
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Clinical and radiologic features
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IgG4-RKD like other IgG4-RD is found mostly in older men. It presents commonly as acute or progressive chronic renal failure, radiographic mass lesion, or both [22]. The mean serum creatinine in the Raissian et al. [22] biopsy series, was lower in patients with renal tissue specimens obtained primarily for mass lesions compared to those biopsied for renal failure (1.4 mg/dl versus 4.2 mg/dl, respectively). Patients with IgG4-TIN alone may have mild proteinuria and microscopic hematuria; those with concurrent membranous glomerulonephritis present with heavy proteinuria or nephrotic syndrome. Other patients may present with obstruction related to retroperitoneal fibrosis or ureteral inflammatory pseudotumor [18,20]. Over 80% of patients in the Raissian et al. [22] biopsy series had other organ involvement, either concurrently or prior to the recognized renal involvement. The most common extrarenal sites affected were the pancreas, liver and salivary or lacrimal glands [22]. IgG4-TIN is commonly bilateral and multiple. These lesions predominantly involve the renal cortex. Diffuse swelling of bilateral kidneys or patchily distributed hypoattenuated mass lesions may be evident on imaging [1]. Renal
parenchymal lesions as best seen on contrast enhanced computed tomography (CT) scan can be classified as a large solitary mass, small multiple peripheral cortical nodules, wedge shaped or round lesions, or diffuse patchy involvement [23]. The mass lesion appears hypoattenuated on contrast-enhanced CT and is not visible on noncontrast-enhanced CT. Lymphoma, pyelonephritis, metastases, or vasculitis may simulate this condition radiologically and so renal biopsy becomes important [23]. Laboratory features Almost 80% of patients with IgG4-RKD, have hypergammaglobulinemia or elevated serum total IgG and/or IgG4 levels [1,24]. The finding of an elevated serum IgG4 alone is not specific for IgG4RD, as 5% of the normal population and 10% of pancreatic cancer patients have an elevated serum IgG4 level [25]. Other common laboratory features are hypocomplementemia (decreased serum C3 and/or C4 levels), a high serum IgE level, and peripheral blood eosinophilia (33–48%) [1,22]. Some patients have a positive antinuclear antibody (ANA, in about 30%), mostly with low titer levels [1,22].
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Pathologic features
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IgG4-RKD is mostly diagnosed on renal biopsies and so gross findings have not been studied extensively. Microscopic features IgG4-RKD can be described histologically as changes to the different compartments in the kidney, including the tubules and interstitium, the glomeruli, and the vessels. IgG4-TIN IgG4-RKD displays a diffuse or multifocal TIN with increased plasma cells, as well as a mononuclear cell-rich interstitial inflammatory infiltrate (Figs. 1 and 2) [20]. There is a spectrum of microscopic appearances, which include acute TIN with minimal fibrosis, an intermediate pattern with some interstitial fibrosis and a marked inflammatory infiltrate, and a densely fibrotic, paucicellular pattern with extensive tubular destruction and atrophy [22].
Fig. 1. Microscopic picture of IgG4-related kidney disease (IgG4-RKD): renal parenchyma showing interstitial plasma cell rich chronic inflammatory infiltrate; the tubules are histologically unremarkable (hematoxylin–eosin, original magnification 200×).
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Fig. 2. High power view of the renal interstitial chronic inflammatory infiltrate, which has a predominance of plasma cells (hematoxylin–eosin, original magnification 400×). Fig. 4. IgG4-related kidney disease (IgG4-RKD) showing strong immunoreactivity for IgG4 in the interstitial plasma cells (IgG4, original magnification 400×).
stained sections. Glomerular basement membrane (GBM) spikes may occasionally be seen using silver or PAS stains, and subepithelial immune complex deposits may at times be seen on a trichrome stain [20]. 5 of 9 IgG4-MGN patients (56%) showed concurrent IgG4TIN on biopsy [20]. Other glomerular diseases have been variably reported in IgG4-RD, including IgA nephropathy, IgA vasculitis and membranoproliferative glomerulonephritis. A few cases of endocapillary proliferative glomerulonephritis, at times with crescents, have been described. Diabetic glomerulosclerosis may be noted in cases of AIP with pancreatic endocrine insufficiency. In addition, three cases of minimal change disease have been found among 116 IgG4-RKD cases presented in regional meetings in Japan between 2004 and 2011 [20].
Fig. 3. Periodic acid–Schiff (PAS) stain highlighting the basement membrane of tubules. (PAS, original magnification 400×).
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In the fibrotic interstitium collagen fibers exhibit a swirling or storiform pattern as seen in other involved organs involved by IgG4-RD [1]. The fibrosis is expansile, pushing apart the tubules. Focal, mild mononuclear cell tubulitis is commonly seen, but eosinophilic or plasma cell tubulitis is not uncommon. Tubules rarely may be destroyed, and periodic acid–Schiff (PAS) (Fig 3) or silver stains are required to appreciate the fragments of tubular basement membranes (TBMs). At times, numerous eosinophils may be seen admixed with the lymphoplasmacytic interstitial infiltrate, raising the possibility of allergic TIN. IgG4-related glomerular lesions Glomeruli appear normal on light microscopy in most IgG4RKD cases. In a clinical series of Kawano et al. [26], 11 out of 28 (39%) patients of IgG4-RKD were reported to have some type of glomerular lesion. MGN in the setting of IgG4-RD is referred to as IgG4-related MGN (IgG4-MGN). Immunostaining for the phospholipase A2 receptor (immunoreactivity typically seen in primary MGN) was negative in all biopsies stained, which confirms the diagnosis of a secondary MGN. In the two largest series of IgG4TIN, MGN was present in approximately 7% of patients [1,22]. Histopathologically, IgG4-MGN glomeruli appear normal or show thickened glomerular capillary loops on hematoxylin and eosin
IgG4-related vascular lesions Vessels are generally unremarkable in IgG4-RKD [1,22]. Plasma cell-rich renal arteritis has recently been described in a patient with IgG4-TIN [21]. This lesion affected small- and medium-sized arteries on a biopsy, with marked lymphoplasmacytic infiltration of the intima, media, and adventitia. Many IgG4+ plasma cells were present in the arterial wall. However, neither fibrinoid necrosis of the arteries nor rupture of the elastica was seen, nor neutrophils were present in the lesions. Venulitis, similar to other IgG4-RD, may sometimes be seen in IgG4-TIN [20]. Immunophenotypic features Raissian et al. [22] examined the concentration of IgG4+ plasma cells (Fig. 4) in IgG4-TIN and its mimickers and found a sensitivity of 100% and specificity of 92% using a cut-off of moderate (11–30 IgG4+ cells/40× field) to marked (>30 IgG4+ cells/40× field) increase in IgG4+ plasma cells for distinguishing IgG4-TIN from other forms of TIN. The only exception was inflammatory infiltrate in pauci-immune necrotizing and crescentic glomerulonephritis wherein approximately 30% of cases showed a moderate increase in IgG4+ plasma cells. Similar findings have been noted in granulomatosis with polyangiitis affecting other organs [22]. These immunohistochemical false positives may be ruled out by taking other clinical, radiographic, and laboratory features into consideration. IgG4+/IgG+ plasma cell ratio is a more powerful tool than IgG+ plasma cell counts in establishing the diagnosis of IgG4-related
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disease [3]. Some researchers have suggested an IgG4+/IgG+ plasma cell ratio of >40% as a comprehensive cutoff value for diagnosing IgG4-RKD [26]. To increase precision, IgG4+ and IgG+ cells can be counted using the printed photographs of the same microscopic field at 40× objective lens, especially when the count of such cells is very high [3]. Because the IgG4+ cell distribution may be patchy, counting only areas of intense IgG4 focus may be more representative [3]. Few studies of other potential tissue biomarkers have been done in IgG4-RD. FOXP3+ regulatory T cells are known to be increased in IgG4-RD. However, the diagnostic value of FOXP3 immunostaining is limited because its specificity is lower than that of IgG4 immunostaining [3]. As T helper cell 2(Th2)-dominant immune reaction in IgG4-RD is known, immunostaining for Th2type cytokines or chemokines is another potential tool, but reliable antibodies that work on paraffin-embedded sections are not commercially available [3]. IgG4 immunostain: the monoclonal antibody of IgG4 (most commonly used, clone HP6025) is preferable to polyclonal one because plasma cells are more clearly stained. Antigen retrieval with proteinase or heat treatment assists in producing high-contrast signals. Background staining is occasionally strong probably due to permeating serum IgG4 or secreted proteins from infiltrating plasma cells [3].
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Direct immunofluorescence findings
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By immunofluorescence, most of the cases show TBM immune complex deposits, with focal or diffuse granular staining for IgG. Immunofluorescence staining for IgG subclasses reveals IgG4dominant TBM deposits. The deposits are also positive for kappa and lambda light chains (indicating polyclonality), C3 with lesser intensity, and occasionally for C1q (about 10% cases) [22]. 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 [22]. Glomeruli are negative by immunofluorescence, unless there is a concurrent MGN [1]. By immunofluorescence, IgG4-MGN typically shows segmental or global granular GBM bright staining for IgG, C3, and both kappa and lambda light chains. Immunofluorescence staining for IgG subclasses reveal that the glomerular deposits contain IgG4. Compared with IgG4-TIN, TBM deposits were less common in IgG4-MGN, present in only 33% of cases [20]. Ultrastructural features TBM deposits seen by immunofluorescence show corresponding amorphous electron-densedeposits by electron microscopy [22]. Glomeruli typically are free of deposits, unless there is a concurrent MGN, in which case there are numerous subepithelial electrondense deposits [22]. Diagnosis The diagnostic criteria proposed in two large series give an overview of IgG4-RKD. Raissin et al. [22] in a large series has proposed the diagnostic criteria of IgG4-related TIN. The histologic criteria of plasma cell-rich TIN with more than 10 IgG4+ plasma cells/high power field (hpf) in the most concentrated field is kept as a mandatory criteria, while TBM immune complex deposits by immunofluorescence, immunohistochemistry, and/or electron microscopy present in more than 80% of biopsy qualifies as a supportive criterion. Diagnosis of IgG4 TIN requires histologic criteria along with one other feature on serology (elevated serum IgG4 or total IgG level), imaging (small peripheral low-attenuation cortical nodules, round or wedge-shaped lesions, diffuse patchy involvement and/or diffuse marked enlargement of kidneys) or other
organ involvement [22]. The Japanese Society of Nephrology also places an emphasis on histologic criteria for diagnosing IgG4RKD [26]. Dense lymphoplasmacytic infiltration with infiltrating IgG4 positive plasma cells in more than 10/hpf and/or IgG4/IgG positive plasma cells ratio of more than 40% on immunohistochemistry is kept as the major criteria for diagnosing IgG4-RKD, along with characteristic storiform fibrosis surrounding nests of lymphocytes and/or plasma cells. Other criteria of importance include serology [elevated serum IgG4 level (IgG4 ≥ 135 mg/dl)], imaging (multiple low-density lesions on enhanced computed tomography, diffuse kidney enlargement, hypovascular solitary mass in the kidney and/or hypertrophic lesion of renal pelvic wall without irregularity of the renal pelvic surface), clinical (presence of some kidney damage, as manifested by abnormal urinalysis, urine markers, or decreased kidney function with either elevated serum IgG levels, hypocomplementemia, or elevated serum IgE levels), and/or other organ involvement with similar histologic features [26]. Other laboratory features like hypocomplementemia, hypergammaglobulinemia, elevated IgE, eosinophilia, and positive ANA may be used as minor criteria, but more studies are needed to elaborate these parameters. Deshpande et al. [3] has suggested that the terminology of IgG4-RD to any organ be conferred when the histologic criteria of dense lymphoplasmacytic infiltrate, storiform-type fibrosis and/or obliterative phlebitis are met along with increased IgG4+ plasma cells (>10 on biopsy specimens) and IgG4/IgG positive plasma cell ratio more than 40%. Differential diagnosis IgG4-RKD is not a distinct histopathologic entity and should be suspected in all biopsies with significant interstitial inflammation rich in plasma cells and in which clinical, radiologic, and laboratory features point toward this disorder. These lesions may be seen in pauci-immune glomerulonephritis, autoimmune TIN, lupus nephritis, chronic pyelonephritis, idiopathic hypocomplementemic TIN, TIN associated with Sjogren’s syndrome, and granulomatosis with polyangiitis. As mentioned earlier, most cases of pauci-immune glomerulonephritis (30%) and granulomatosis with polyangiitis in the Raissian et al. [22] series showed a moderate increase in IgG4+ plasma cells. However, the absence of necrotizing or crescentic glomerulonephritis on the tissue specimen helps to exclude pauci-immune glomerulonephritis as a cause of the interstitial inflammation. Similarly, the absence of serum anti-neutrophil cytoplasmic antibodies (or antimyeloperoxidase or antiproteinase 3 antibodies) excludes granulomatosis with polyangiitis. Notably Sjogren’s syndrome-related TIN has predominantly IgG4 negative plasma cells and thus can be excluded. Lupus nephritis has characteristic wire loop lesions, anti-nuclear antibody, and double stranded DNA positivity. Chronic pyelonephritis and autoimmune nephritis can be distinguished by other clinical and histopathologic features. Idiopathic hypocomplementemic TIN shares most of the clinical and histologic features of IgG4-RKD, and also reveals similar immunofluorescence and electron microscopy findings such as hypocomplementemia, positivity for serum anti nuclear antibody, anti-neutrophil cytoplasmic antibodies and/or rheumatoid antibody in some cases. IgG4/IgG positive plasma cell ratio more than 40% and typical storiform fibrosis have not been demonstrated [15]. However, more cases needs to be studied to elaborate their sharp distinction and to determine if they belong to the same entity. Treatment and prognosis IgG4-TIN shows a favorable response to steroid therapy in most cases, like other IgG4-RD. The Saeki et al. [1] series showed rapid
Please cite this article in press as: D. Pradhan, et al., IgG4-related kidney disease – A review, Pathol. – Res. Pract (2015), http://dx.doi.org/10.1016/j.prp.2015.03.004
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improvement in creatinine levels following treatment with steroids in 18 out of 19 (>90%) patients within 4 weeks. Similar result has been shown in the Raissian et al. [22] series, wherein 17 of 19 (∼90%) patients showed rapid response. Although TIN of any cause may respond to steroid therapy, IgG4-TIN tends to show a more brisk response, even in cases with severe interstitial fibrosis on the biopsy. Few cases of relapse in IgG4-RD have been known to occur. Response to rituximab in IgG4-RD patients refractory to steroid treatment has been seen in a small series [30], as well as in one patient each in the Raissian and Cornell series [20,22]. However, long term follow up data for these patients is required to give a definitive opinion. In an IgG4-MGN series, six patients were treated with various immunosuppressive drugs. All of them showed decreased proteinuria and most showed decreased serum creatinine at an average of 39-month follow-up [20]. However, IgG4-MGN appears to show lesser response to treatment as compared to IgG4-TIN. Dialysis or renal transplantation may be needed in the presence of highly active or immunosuppression resistant disease.
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Conclusion
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In conclusion, IgG4-RKD is the renal manifestation of a systemic autoimmune disease, usually in the form of plasma cell-rich TIN with immune complex deposits. MGN may also be seen in IgG4-RD, with or without concurrent TIN. IgG4-related plasma cell arteritis has recently been described in the kidney. The fibroinflammatory manifestations in IgG4-RKD (including TIN) generally show a brisk response to steroid therapy; refractory patients may respond to rituximab. Long term follow-up data of these patients will be needed for future management. The pathogenesis and role of IgG4 in this disorder remains elusive and will need further research.
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Uncited references
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[27–29].
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References
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[1] T. Saeki, S. Nishi, N. Imai, et al., Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis, Kidney Int. 78 (2010) 1016–1023. [2] H. Takahashi, M. Yamamoto, C. Suzuki, Y. Naishiro, Y. Shinomura, K. Imai, The birthday of a new syndrome: IgG4 related diseases constitute a clinical entity, Autoimmun. Rev. 9 (2010) 591–594. [3] V. Deshpande, Y. Zen, J.K. Chan, et al., Consensus statement on the pathology of IgG4-related disease, Mod. Pathol. 25 (2012) 1181–1192. [4] H. Sarles, J.C. Sarles, R. Muratore, C. Guien, Chronic inflammatory sclerosis of the pancreas – an autonomous pancreatic disease, Am. J. Dig. Dis. 6 (1961) 688–698. [5] T. Kamisawa, N. Funata, Y. Hayashi, et al., A new clinicopathological entity of IgG4-related autoimmune disease, J. Gastroenterol. 38 (2003) 982–984.
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[6] V. Deshpande, S. Chicano, D. Finkelberg, et al., Autoimmune pancreatitis: a systemic immune complex mediated disease, Am. J. Surg. Pathol. 30 (2006) 1537–1545. [7] V. Deshpande, M. Mino-Kenudson, W. Brugge, G.Y. Lauwers, Autoimmune pancreatitis: more than just a pancreatic disease? A contemporary review of its pathology, Arch. Pathol. Lab. Med. 129 (2005) 1148–1154. [8] S. Kitagawa, Y. Zen, K. Harada, et al., Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner’s tumor), Am. J. Surg. Pathol. 26 (2005) 783–791. [9] Y. Zen, Y. Kasahara, K. Horita, et al., Inflammatory pseudotumor of the breast in a patient with a high serum IgG4 level: histologic similarity to sclerosing pancreatitis, Am. J. Surg. Pathol. 29 (2005) 275–278. [10] W. Cheuk, J.K. Chan, IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity, Adv. Anat. Pathol. 17 (2010) 303–332. [11] Y. Li, E. Nishihara, K. Kakudo, Hashimoto’s thyroiditis: old concepts and new insights, Curr. Opin. Rheumatol. 23 (2011) 102–107. [12] J.R. Stone, Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease, Curr. Opin. Rheumatol. 23 (2011) 88–94. [13] B. Shrestha, H. Sekiguchi, T.V. Colby, et al., Distinctive pulmonary histopathology with increased IgG4-positive plasma cells in patients with autoimmune pancreatitis: report of 6 and 12 cases with similar histopathology, Am. J. Surg. Pathol. 33 (2009) 1450–1462. [14] J.T. Geyer, V. Deshpande, IgG4-associated sialadenitis, Curr. Opin. Rheumatol. 23 (2011) 95–101. [15] N. Kambham, G.S. Markowitz, N. Tanji, M.M. Mansukhani, A. Orazi, V.D. D’Agati., Idiopathic hypocomplementemic interstitial nephritis with extensive tubulointerstitial deposits, Am. J. Kidney Dis. 37 (2001) 388–399. [16] A. Khosroshahi, J.H. Stone, A clinical overview of IgG4-related systemic disease, Curr. Opin. Rheumatol. 23 (2011) 57–66. [17] Y. Zen, Y. Nakanuma, IgG4-related disease: a cross-sectional study of 114 cases, Am. J. Surg. Pathol. 34 (2010) 1812–1819. [18] L.D. Cornell, IgG4-related kidney disease, Curr. Opin. Nephrol. Hypertens. 21 (2012) 279–288. [19] L.D. Cornell, IgG4-related tubulointerstitial nephritis, Kidney Int. 78 (2010) 951–953. [20] L.D. Cornell, IgG4-related kidney disease, Semin. Diagn. Pathol. 29 (2012) 245–250. [21] S.G. Sharma, H.L. Vlase, V.D. D’Agati., IgG4-related tubulointerstitial nephritis with plasma cell rich renal arteritis, Am. J. Kidney Dis. 61 (2013) 638–643. [22] Y. Raissian, S.H. Nasr, C.P. Larsen, et al., Diagnosis of IgG4-related tubulointerstitial nephritis, J. Am. Soc. Nephrol. 22 (2011) 1343–1352. [23] N. Takahashi, A. Kawashima, J.G. Fletcher, S.T. Chari, Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings, Radiology 242 (2007) 791–801. [24] R.P. Sah, S.T. Chari, Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis, Curr. Opin. Rheumatol. 23 (2011) 108–113. [25] A. Ghazale, S.T. Chari, T.C. Smyrk, et al., Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer, Am. J. Gastroenterol. 102 (2007) 1646–1653. [26] M. Kawano, T. Saeki, H. Nakashima, et al., Proposal for diagnostic criteria for IgG4-related kidney disease, Clin. Exp. Nephrol. 15 (2011) 615–626. [27] M. Van der Neut Kolfschoten, J. Schuurman, M. Losen, et al., Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange, Science 317 (2007) 1554–1557. [28] T. Rispens, P. Ooievaar-De Heer, E. Vermeulen, et al., Human IgG4 binds to IgG4 and conformationally altered IgG1 via Fc–Fc interactions, J. Immunol. 182 (2009) 4275–4281. [29] A. Nirula, S.M. Glaser, S.L. Kalled, F.R. Taylora, What is IgG4? A review of the biology of a unique immunoglobulin subtype, Curr. Opin. Rheumatol. 23 (2011) 119–124. [30] A. Khosroshahi, D.B. Bloch, V. Deshpande, J.H. Stone, Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4related systemic disease, Arthritis Rheum. 62 (2010) 1755–1762.
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Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
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Review
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IgG4-related kidney disease – A review
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Dinesh Pradhan a , Niharika Pattnaik b , Russell Silowash a , Sambit Kumar Mohanty c,∗
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University of Pittsburgh Medical Center, Pittsburgh, PA, USA Kalinga Hospital, Bhubaneswar, India c CORE Diagnostics, Gurgaon, India b
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Article history: Received 16 December 2014 Received in revised form 5 March 2015 Accepted 25 March 2015
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Keywords: IgG4 Kidney disease
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Contents
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IgG4-related disease (IgG4-RD) is a recently recognized systemic autoimmune disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive plasma cells in multiple organs. The condition was first described as a disease of the pancreas, and has since been recognized in various organ systems including the kidneys. IgG4 related kidney disease (IgG4-RKD) signifies any form of renal involvement by IgG4-RD. The most common renal involvement by IgG4-RD is tubulointerstitial nephritis. Glomerular disease, in particular membranous glomerulonephritis, may also be seen. Other co-existent glomerular diseases such as IgA nephropathy, membranoproliferative glomerulonephritis, and mesangioproliferative immune complex glomerulonephritis may be identified. IgG4-related plasma cell arteritis has also been noted in the kidney. As with IgG4-RD in general, IgG4 related kidney disease (IgG4-RKD) usually occurs in middle-aged to elderly men. Common findings in IgG4-RKD are plasma cellrich interstitial inflammatory infiltrate either in a focal or diffuse pattern with increased IgG4+ plasma cells, expansile swirling interstitial fibrosis, high levels of serum IgG and IgG4, hypocomplementemia, high serum IgE levels and/or peripheral blood eosinophilia. By immunofluorescence, most of the cases show IgG4 dominant tubular basement membrane immune complex deposits. Similar to IgG4-RD, IgG4RKD often shows a rapid response to steroid therapy. In this review, we discuss the current knowledge on IgG4-RKD and its clinical relevance. © 2015 Elsevier GmbH. All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and radiologic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathologic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Macroscopic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microscopic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IgG4-TIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IgG4-related glomerular lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IgG4-related vascular lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunophenotypic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Direct immunofluorescence findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ultrastructural features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author. Tel.: +91 9711689262. E-mail address: [email protected] (S.K. Mohanty). http://dx.doi.org/10.1016/j.prp.2015.03.004 0344-0338/© 2015 Elsevier GmbH. All rights reserved.
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Introduction
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IgG4-related disease (IgG4-RD) is a recently recognized systemic autoimmune disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells in multiple organs [1,2]. The diagnosis of IgG4-related disease depends on the characteristic morphologic appearance, which includes a dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and increased numbers of IgG4+ plasma cells. Deshpande et al. [3] nevertheless stresses careful clinicopathologic correlation, which cannot be superseded by the morphologic criteria alone. This systemic disease was first recognized as a disease of the pancreas [sclerosing lymphoplasmacytic pancreatitis also referred as autoimmune pancreatitis (AIP)] by Sarles et al. in 1961 [4]. IgG4RD disease has now been described in nearly every organ system, including the kidney, liver (sclerosing cholangitis, pseudotumor), gallbladder (IgG4-related cholecystitis), salivary and lacrimal glands (chronic sclerosing sialadenitis/Kuttner’s tumor; dacryoadenitis; Mikulicz disease), lung and pleura (interstitial pneumonitis, inflammatory pseudotumor, fibrinous pleuritis), orbit (pseudotumor), breast (sclerosing mastitis, inflammatory pseudotumor), retroperitoneum (retroperitoneal fibrosis), cardiovascular system (periaortitis; inflammatory aortic aneurysm; pericarditis), lymph nodes (lymphadenopathy with various histologic patterns), skin (cutaneous pseudolymphoma), pituitary gland (infundibulohypophysitis), thyroid (Riedel thyroiditis; Hashimoto thyroiditis), and prostate (prostatitis) [5–16]. The fibroinflammatory lesions show remarkable histologic similarity in these different organs [3,17]. Renal involvement in IgG4-RD in any form is collectively referred to as IgG4-related kidney disease (IgG4-RKD) [18–20]. The most common renal involvement by IgG4-RD is in the form of plasma cell rich tubulointerstitial nephritis (IgG4-TIN). Other renal manifestations and associations of IgG4-RD include membranous glomerulonephritis (MGN) with or without IgG4-TIN, IgA nephropathy, membranoproliferative glomerulonephritis, mesangioproliferative immune complex glomerulonephritis, sclerosing pyelitis, IgG4-related plasma cell arteritis and hydronephrosis associated with IgG4 related retroperitoneal fibrosis or ureteral inflammatory pseudotumor [1,18–21]. To date, sporadic case reports and occasional series of IgG4-RD have been described in the literature. In this review, we discuss the recent literature related to IgG4-RD as it affects the kidney.
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Clinical and radiologic features
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IgG4-RKD like other IgG4-RD is found mostly in older men. It presents commonly as acute or progressive chronic renal failure, radiographic mass lesion, or both [22]. The mean serum creatinine in the Raissian et al. [22] biopsy series, was lower in patients with renal tissue specimens obtained primarily for mass lesions compared to those biopsied for renal failure (1.4 mg/dl versus 4.2 mg/dl, respectively). Patients with IgG4-TIN alone may have mild proteinuria and microscopic hematuria; those with concurrent membranous glomerulonephritis present with heavy proteinuria or nephrotic syndrome. Other patients may present with obstruction related to retroperitoneal fibrosis or ureteral inflammatory pseudotumor [18,20]. Over 80% of patients in the Raissian et al. [22] biopsy series had other organ involvement, either concurrently or prior to the recognized renal involvement. The most common extrarenal sites affected were the pancreas, liver and salivary or lacrimal glands [22]. IgG4-TIN is commonly bilateral and multiple. These lesions predominantly involve the renal cortex. Diffuse swelling of bilateral kidneys or patchily distributed hypoattenuated mass lesions may be evident on imaging [1]. Renal
parenchymal lesions as best seen on contrast enhanced computed tomography (CT) scan can be classified as a large solitary mass, small multiple peripheral cortical nodules, wedge shaped or round lesions, or diffuse patchy involvement [23]. The mass lesion appears hypoattenuated on contrast-enhanced CT and is not visible on noncontrast-enhanced CT. Lymphoma, pyelonephritis, metastases, or vasculitis may simulate this condition radiologically and so renal biopsy becomes important [23]. Laboratory features Almost 80% of patients with IgG4-RKD, have hypergammaglobulinemia or elevated serum total IgG and/or IgG4 levels [1,24]. The finding of an elevated serum IgG4 alone is not specific for IgG4RD, as 5% of the normal population and 10% of pancreatic cancer patients have an elevated serum IgG4 level [25]. Other common laboratory features are hypocomplementemia (decreased serum C3 and/or C4 levels), a high serum IgE level, and peripheral blood eosinophilia (33–48%) [1,22]. Some patients have a positive antinuclear antibody (ANA, in about 30%), mostly with low titer levels [1,22].
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IgG4-RKD is mostly diagnosed on renal biopsies and so gross findings have not been studied extensively. Microscopic features IgG4-RKD can be described histologically as changes to the different compartments in the kidney, including the tubules and interstitium, the glomeruli, and the vessels. IgG4-TIN IgG4-RKD displays a diffuse or multifocal TIN with increased plasma cells, as well as a mononuclear cell-rich interstitial inflammatory infiltrate (Figs. 1 and 2) [20]. There is a spectrum of microscopic appearances, which include acute TIN with minimal fibrosis, an intermediate pattern with some interstitial fibrosis and a marked inflammatory infiltrate, and a densely fibrotic, paucicellular pattern with extensive tubular destruction and atrophy [22].
Fig. 1. Microscopic picture of IgG4-related kidney disease (IgG4-RKD): renal parenchyma showing interstitial plasma cell rich chronic inflammatory infiltrate; the tubules are histologically unremarkable (hematoxylin–eosin, original magnification 200×).
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Fig. 2. High power view of the renal interstitial chronic inflammatory infiltrate, which has a predominance of plasma cells (hematoxylin–eosin, original magnification 400×). Fig. 4. IgG4-related kidney disease (IgG4-RKD) showing strong immunoreactivity for IgG4 in the interstitial plasma cells (IgG4, original magnification 400×).
stained sections. Glomerular basement membrane (GBM) spikes may occasionally be seen using silver or PAS stains, and subepithelial immune complex deposits may at times be seen on a trichrome stain [20]. 5 of 9 IgG4-MGN patients (56%) showed concurrent IgG4TIN on biopsy [20]. Other glomerular diseases have been variably reported in IgG4-RD, including IgA nephropathy, IgA vasculitis and membranoproliferative glomerulonephritis. A few cases of endocapillary proliferative glomerulonephritis, at times with crescents, have been described. Diabetic glomerulosclerosis may be noted in cases of AIP with pancreatic endocrine insufficiency. In addition, three cases of minimal change disease have been found among 116 IgG4-RKD cases presented in regional meetings in Japan between 2004 and 2011 [20].
Fig. 3. Periodic acid–Schiff (PAS) stain highlighting the basement membrane of tubules. (PAS, original magnification 400×).
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In the fibrotic interstitium collagen fibers exhibit a swirling or storiform pattern as seen in other involved organs involved by IgG4-RD [1]. The fibrosis is expansile, pushing apart the tubules. Focal, mild mononuclear cell tubulitis is commonly seen, but eosinophilic or plasma cell tubulitis is not uncommon. Tubules rarely may be destroyed, and periodic acid–Schiff (PAS) (Fig 3) or silver stains are required to appreciate the fragments of tubular basement membranes (TBMs). At times, numerous eosinophils may be seen admixed with the lymphoplasmacytic interstitial infiltrate, raising the possibility of allergic TIN. IgG4-related glomerular lesions Glomeruli appear normal on light microscopy in most IgG4RKD cases. In a clinical series of Kawano et al. [26], 11 out of 28 (39%) patients of IgG4-RKD were reported to have some type of glomerular lesion. MGN in the setting of IgG4-RD is referred to as IgG4-related MGN (IgG4-MGN). Immunostaining for the phospholipase A2 receptor (immunoreactivity typically seen in primary MGN) was negative in all biopsies stained, which confirms the diagnosis of a secondary MGN. In the two largest series of IgG4TIN, MGN was present in approximately 7% of patients [1,22]. Histopathologically, IgG4-MGN glomeruli appear normal or show thickened glomerular capillary loops on hematoxylin and eosin
IgG4-related vascular lesions Vessels are generally unremarkable in IgG4-RKD [1,22]. Plasma cell-rich renal arteritis has recently been described in a patient with IgG4-TIN [21]. This lesion affected small- and medium-sized arteries on a biopsy, with marked lymphoplasmacytic infiltration of the intima, media, and adventitia. Many IgG4+ plasma cells were present in the arterial wall. However, neither fibrinoid necrosis of the arteries nor rupture of the elastica was seen, nor neutrophils were present in the lesions. Venulitis, similar to other IgG4-RD, may sometimes be seen in IgG4-TIN [20]. Immunophenotypic features Raissian et al. [22] examined the concentration of IgG4+ plasma cells (Fig. 4) in IgG4-TIN and its mimickers and found a sensitivity of 100% and specificity of 92% using a cut-off of moderate (11–30 IgG4+ cells/40× field) to marked (>30 IgG4+ cells/40× field) increase in IgG4+ plasma cells for distinguishing IgG4-TIN from other forms of TIN. The only exception was inflammatory infiltrate in pauci-immune necrotizing and crescentic glomerulonephritis wherein approximately 30% of cases showed a moderate increase in IgG4+ plasma cells. Similar findings have been noted in granulomatosis with polyangiitis affecting other organs [22]. These immunohistochemical false positives may be ruled out by taking other clinical, radiographic, and laboratory features into consideration. IgG4+/IgG+ plasma cell ratio is a more powerful tool than IgG+ plasma cell counts in establishing the diagnosis of IgG4-related
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disease [3]. Some researchers have suggested an IgG4+/IgG+ plasma cell ratio of >40% as a comprehensive cutoff value for diagnosing IgG4-RKD [26]. To increase precision, IgG4+ and IgG+ cells can be counted using the printed photographs of the same microscopic field at 40× objective lens, especially when the count of such cells is very high [3]. Because the IgG4+ cell distribution may be patchy, counting only areas of intense IgG4 focus may be more representative [3]. Few studies of other potential tissue biomarkers have been done in IgG4-RD. FOXP3+ regulatory T cells are known to be increased in IgG4-RD. However, the diagnostic value of FOXP3 immunostaining is limited because its specificity is lower than that of IgG4 immunostaining [3]. As T helper cell 2(Th2)-dominant immune reaction in IgG4-RD is known, immunostaining for Th2type cytokines or chemokines is another potential tool, but reliable antibodies that work on paraffin-embedded sections are not commercially available [3]. IgG4 immunostain: the monoclonal antibody of IgG4 (most commonly used, clone HP6025) is preferable to polyclonal one because plasma cells are more clearly stained. Antigen retrieval with proteinase or heat treatment assists in producing high-contrast signals. Background staining is occasionally strong probably due to permeating serum IgG4 or secreted proteins from infiltrating plasma cells [3].
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By immunofluorescence, most of the cases show TBM immune complex deposits, with focal or diffuse granular staining for IgG. Immunofluorescence staining for IgG subclasses reveals IgG4dominant TBM deposits. The deposits are also positive for kappa and lambda light chains (indicating polyclonality), C3 with lesser intensity, and occasionally for C1q (about 10% cases) [22]. 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 [22]. Glomeruli are negative by immunofluorescence, unless there is a concurrent MGN [1]. By immunofluorescence, IgG4-MGN typically shows segmental or global granular GBM bright staining for IgG, C3, and both kappa and lambda light chains. Immunofluorescence staining for IgG subclasses reveal that the glomerular deposits contain IgG4. Compared with IgG4-TIN, TBM deposits were less common in IgG4-MGN, present in only 33% of cases [20]. Ultrastructural features TBM deposits seen by immunofluorescence show corresponding amorphous electron-densedeposits by electron microscopy [22]. Glomeruli typically are free of deposits, unless there is a concurrent MGN, in which case there are numerous subepithelial electrondense deposits [22]. Diagnosis The diagnostic criteria proposed in two large series give an overview of IgG4-RKD. Raissin et al. [22] in a large series has proposed the diagnostic criteria of IgG4-related TIN. The histologic criteria of plasma cell-rich TIN with more than 10 IgG4+ plasma cells/high power field (hpf) in the most concentrated field is kept as a mandatory criteria, while TBM immune complex deposits by immunofluorescence, immunohistochemistry, and/or electron microscopy present in more than 80% of biopsy qualifies as a supportive criterion. Diagnosis of IgG4 TIN requires histologic criteria along with one other feature on serology (elevated serum IgG4 or total IgG level), imaging (small peripheral low-attenuation cortical nodules, round or wedge-shaped lesions, diffuse patchy involvement and/or diffuse marked enlargement of kidneys) or other
organ involvement [22]. The Japanese Society of Nephrology also places an emphasis on histologic criteria for diagnosing IgG4RKD [26]. Dense lymphoplasmacytic infiltration with infiltrating IgG4 positive plasma cells in more than 10/hpf and/or IgG4/IgG positive plasma cells ratio of more than 40% on immunohistochemistry is kept as the major criteria for diagnosing IgG4-RKD, along with characteristic storiform fibrosis surrounding nests of lymphocytes and/or plasma cells. Other criteria of importance include serology [elevated serum IgG4 level (IgG4 ≥ 135 mg/dl)], imaging (multiple low-density lesions on enhanced computed tomography, diffuse kidney enlargement, hypovascular solitary mass in the kidney and/or hypertrophic lesion of renal pelvic wall without irregularity of the renal pelvic surface), clinical (presence of some kidney damage, as manifested by abnormal urinalysis, urine markers, or decreased kidney function with either elevated serum IgG levels, hypocomplementemia, or elevated serum IgE levels), and/or other organ involvement with similar histologic features [26]. Other laboratory features like hypocomplementemia, hypergammaglobulinemia, elevated IgE, eosinophilia, and positive ANA may be used as minor criteria, but more studies are needed to elaborate these parameters. Deshpande et al. [3] has suggested that the terminology of IgG4-RD to any organ be conferred when the histologic criteria of dense lymphoplasmacytic infiltrate, storiform-type fibrosis and/or obliterative phlebitis are met along with increased IgG4+ plasma cells (>10 on biopsy specimens) and IgG4/IgG positive plasma cell ratio more than 40%. Differential diagnosis IgG4-RKD is not a distinct histopathologic entity and should be suspected in all biopsies with significant interstitial inflammation rich in plasma cells and in which clinical, radiologic, and laboratory features point toward this disorder. These lesions may be seen in pauci-immune glomerulonephritis, autoimmune TIN, lupus nephritis, chronic pyelonephritis, idiopathic hypocomplementemic TIN, TIN associated with Sjogren’s syndrome, and granulomatosis with polyangiitis. As mentioned earlier, most cases of pauci-immune glomerulonephritis (30%) and granulomatosis with polyangiitis in the Raissian et al. [22] series showed a moderate increase in IgG4+ plasma cells. However, the absence of necrotizing or crescentic glomerulonephritis on the tissue specimen helps to exclude pauci-immune glomerulonephritis as a cause of the interstitial inflammation. Similarly, the absence of serum anti-neutrophil cytoplasmic antibodies (or antimyeloperoxidase or antiproteinase 3 antibodies) excludes granulomatosis with polyangiitis. Notably Sjogren’s syndrome-related TIN has predominantly IgG4 negative plasma cells and thus can be excluded. Lupus nephritis has characteristic wire loop lesions, anti-nuclear antibody, and double stranded DNA positivity. Chronic pyelonephritis and autoimmune nephritis can be distinguished by other clinical and histopathologic features. Idiopathic hypocomplementemic TIN shares most of the clinical and histologic features of IgG4-RKD, and also reveals similar immunofluorescence and electron microscopy findings such as hypocomplementemia, positivity for serum anti nuclear antibody, anti-neutrophil cytoplasmic antibodies and/or rheumatoid antibody in some cases. IgG4/IgG positive plasma cell ratio more than 40% and typical storiform fibrosis have not been demonstrated [15]. However, more cases needs to be studied to elaborate their sharp distinction and to determine if they belong to the same entity. Treatment and prognosis IgG4-TIN shows a favorable response to steroid therapy in most cases, like other IgG4-RD. The Saeki et al. [1] series showed rapid
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improvement in creatinine levels following treatment with steroids in 18 out of 19 (>90%) patients within 4 weeks. Similar result has been shown in the Raissian et al. [22] series, wherein 17 of 19 (∼90%) patients showed rapid response. Although TIN of any cause may respond to steroid therapy, IgG4-TIN tends to show a more brisk response, even in cases with severe interstitial fibrosis on the biopsy. Few cases of relapse in IgG4-RD have been known to occur. Response to rituximab in IgG4-RD patients refractory to steroid treatment has been seen in a small series [30], as well as in one patient each in the Raissian and Cornell series [20,22]. However, long term follow up data for these patients is required to give a definitive opinion. In an IgG4-MGN series, six patients were treated with various immunosuppressive drugs. All of them showed decreased proteinuria and most showed decreased serum creatinine at an average of 39-month follow-up [20]. However, IgG4-MGN appears to show lesser response to treatment as compared to IgG4-TIN. Dialysis or renal transplantation may be needed in the presence of highly active or immunosuppression resistant disease.
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In conclusion, IgG4-RKD is the renal manifestation of a systemic autoimmune disease, usually in the form of plasma cell-rich TIN with immune complex deposits. MGN may also be seen in IgG4-RD, with or without concurrent TIN. IgG4-related plasma cell arteritis has recently been described in the kidney. The fibroinflammatory manifestations in IgG4-RKD (including TIN) generally show a brisk response to steroid therapy; refractory patients may respond to rituximab. Long term follow-up data of these patients will be needed for future management. The pathogenesis and role of IgG4 in this disorder remains elusive and will need further research.
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[1] T. Saeki, S. Nishi, N. Imai, et al., Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis, Kidney Int. 78 (2010) 1016–1023. [2] H. Takahashi, M. Yamamoto, C. Suzuki, Y. Naishiro, Y. Shinomura, K. Imai, The birthday of a new syndrome: IgG4 related diseases constitute a clinical entity, Autoimmun. Rev. 9 (2010) 591–594. [3] V. Deshpande, Y. Zen, J.K. Chan, et al., Consensus statement on the pathology of IgG4-related disease, Mod. Pathol. 25 (2012) 1181–1192. [4] H. Sarles, J.C. Sarles, R. Muratore, C. Guien, Chronic inflammatory sclerosis of the pancreas – an autonomous pancreatic disease, Am. J. Dig. Dis. 6 (1961) 688–698. [5] T. Kamisawa, N. Funata, Y. Hayashi, et al., A new clinicopathological entity of IgG4-related autoimmune disease, J. Gastroenterol. 38 (2003) 982–984.
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[6] V. Deshpande, S. Chicano, D. Finkelberg, et al., Autoimmune pancreatitis: a systemic immune complex mediated disease, Am. J. Surg. Pathol. 30 (2006) 1537–1545. [7] V. Deshpande, M. Mino-Kenudson, W. Brugge, G.Y. Lauwers, Autoimmune pancreatitis: more than just a pancreatic disease? A contemporary review of its pathology, Arch. Pathol. Lab. Med. 129 (2005) 1148–1154. [8] S. Kitagawa, Y. Zen, K. Harada, et al., Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner’s tumor), Am. J. Surg. Pathol. 26 (2005) 783–791. [9] Y. Zen, Y. Kasahara, K. Horita, et al., Inflammatory pseudotumor of the breast in a patient with a high serum IgG4 level: histologic similarity to sclerosing pancreatitis, Am. J. Surg. Pathol. 29 (2005) 275–278. [10] W. Cheuk, J.K. Chan, IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity, Adv. Anat. Pathol. 17 (2010) 303–332. [11] Y. Li, E. Nishihara, K. Kakudo, Hashimoto’s thyroiditis: old concepts and new insights, Curr. Opin. Rheumatol. 23 (2011) 102–107. [12] J.R. Stone, Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease, Curr. Opin. Rheumatol. 23 (2011) 88–94. [13] B. Shrestha, H. Sekiguchi, T.V. Colby, et al., Distinctive pulmonary histopathology with increased IgG4-positive plasma cells in patients with autoimmune pancreatitis: report of 6 and 12 cases with similar histopathology, Am. J. Surg. Pathol. 33 (2009) 1450–1462. [14] J.T. Geyer, V. Deshpande, IgG4-associated sialadenitis, Curr. Opin. Rheumatol. 23 (2011) 95–101. [15] N. Kambham, G.S. Markowitz, N. Tanji, M.M. Mansukhani, A. Orazi, V.D. D’Agati., Idiopathic hypocomplementemic interstitial nephritis with extensive tubulointerstitial deposits, Am. J. Kidney Dis. 37 (2001) 388–399. [16] A. Khosroshahi, J.H. Stone, A clinical overview of IgG4-related systemic disease, Curr. Opin. Rheumatol. 23 (2011) 57–66. [17] Y. Zen, Y. Nakanuma, IgG4-related disease: a cross-sectional study of 114 cases, Am. J. Surg. Pathol. 34 (2010) 1812–1819. [18] L.D. Cornell, IgG4-related kidney disease, Curr. Opin. Nephrol. Hypertens. 21 (2012) 279–288. [19] L.D. Cornell, IgG4-related tubulointerstitial nephritis, Kidney Int. 78 (2010) 951–953. [20] L.D. Cornell, IgG4-related kidney disease, Semin. Diagn. Pathol. 29 (2012) 245–250. [21] S.G. Sharma, H.L. Vlase, V.D. D’Agati., IgG4-related tubulointerstitial nephritis with plasma cell rich renal arteritis, Am. J. Kidney Dis. 61 (2013) 638–643. [22] Y. Raissian, S.H. Nasr, C.P. Larsen, et al., Diagnosis of IgG4-related tubulointerstitial nephritis, J. Am. Soc. Nephrol. 22 (2011) 1343–1352. [23] N. Takahashi, A. Kawashima, J.G. Fletcher, S.T. Chari, Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings, Radiology 242 (2007) 791–801. [24] R.P. Sah, S.T. Chari, Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis, Curr. Opin. Rheumatol. 23 (2011) 108–113. [25] A. Ghazale, S.T. Chari, T.C. Smyrk, et al., Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer, Am. J. Gastroenterol. 102 (2007) 1646–1653. [26] M. Kawano, T. Saeki, H. Nakashima, et al., Proposal for diagnostic criteria for IgG4-related kidney disease, Clin. Exp. Nephrol. 15 (2011) 615–626. [27] M. Van der Neut Kolfschoten, J. Schuurman, M. Losen, et al., Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange, Science 317 (2007) 1554–1557. [28] T. Rispens, P. Ooievaar-De Heer, E. Vermeulen, et al., Human IgG4 binds to IgG4 and conformationally altered IgG1 via Fc–Fc interactions, J. Immunol. 182 (2009) 4275–4281. [29] A. Nirula, S.M. Glaser, S.L. Kalled, F.R. Taylora, What is IgG4? A review of the biology of a unique immunoglobulin subtype, Curr. Opin. Rheumatol. 23 (2011) 119–124. [30] A. Khosroshahi, D.B. Bloch, V. Deshpande, J.H. Stone, Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4related systemic disease, Arthritis Rheum. 62 (2010) 1755–1762.
Please cite this article in press as: D. Pradhan, et al., IgG4-related kidney disease – A review, Pathol. – Res. Pract (2015), http://dx.doi.org/10.1016/j.prp.2015.03.004
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