IgG4-Related Kidney Disease and IgG4-Related Retroperitoneal Fibrosis: An Update on Diagnosis and Treatment

Abstract

Renal involvement of IgG4-related disease (IgG4-RD), collectively termed IgG4-related kidney disease (IgG4-RKD), most commonly manifests as tubulointerstitial nephritis (TIN) but can also manifest as membranous glomerulonephritis (MGN) and acute interstitial nephritis (AIN) as a histologic subtype of IgG4-related TIN (IgG4-TIN). IgG4-related retroperitoneal fibrosis (IgG4-RPF) can cause obstructive kidney disease with or without active parenchymal IgG4-RKD. IgG4-RD is a clinicopathological diagnosis, requiring correlation of clinical, laboratory, radiological, and histological findings to identify features of IgG4-RD and rule out mimickers. Histopathologic features of IgG4-RD in tissue include a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, typically accompanied by so-called “storiform” fibrosis. Important mimics of IgG4-RKD include infection, malignancy, antineutrophil cytoplasmic autoantibody (ANCA)-associated disease, idiopathic multicentric Castleman disease, Rosai-Dorfman-Destombes disease and Sjögren Disease (SjD). Mimickers of IgG4-RPF include lymphoma, Erdheim-Chester disease, and idiopathic RPF. IgG4-RKD and IgG4-RPF are responsive to the systemic therapies used for IgG4-RD in general. Corticosteroids are the traditional first line therapy; however, B cell–targeted therapies, including rituximab, inebilizumab, and obexelimab are more potent and less toxic than steroids. Further trials are currently being conducted on newer medications that target signaling pathways and immune cells involved in the pathogenesis of IgG4-RD. Early recognition and treatment are critical to prevent irreversible organ damage. This review summarizes the current understanding of the pathogenesis, clinical spectrum, diagnostic approach, and management strategies for IgG4-RD, IgG4-RKD, and IgG4-RPF.

Overview of IgG4-RD

IgG4-RD is an immune-mediated fibro-inflammatory disease characterized by infiltration of involved organs by IgG4-positive plasma cells and tissue fibrosis, with elevated serum IgG4 in about two-thirds of patients.^1,2 The most commonly affected organs include the pancreas, bile duct, salivary and lacrimal glands, lymph nodes, retroperitoneum, lungs, and kidneys. Radiographically, IgG4-RD often mimics autoimmune disease, malignancy, infection, and other inflammatory or autoimmune conditions.³

What we now recognize as IgG4-RD was described over the years in various individual organ system manifestations at different times, first as Mikulicz disease (bilateral salivary gland enlargement) in the late 1880s.⁴ The link of IgG4 to these various disparate presentations was made by Japanese researchers in 2001 who noted elevated serum IgG4 antibody levels in patients with sclerosing (type I autoimmune) pancreatitis.⁵ The prevalence of IgG4-RD has been estimated to be approximately 5.3 per 100,000 people in the United States but is rising because of increased recognition.⁶ The disease typically affects middle-aged to elderly people with a male predominance.^7,8 It remains unknown what causes the disease activation, leading to the typical histopathologic lesion.

Whether triggered by autoimmunity, infection, or molecular mimicry, in IgG4-RD, there is an oligoclonal expansion of IgG4-positive, mature and activated plasma cells.⁹ The antibodies produced by these cells have been shown to be reactive to multiple autoantigen targets.^9,10 There is tissue infiltration by both IgG4-positive plasma cells and CD4-positive helper T cells, and it is proposed that these cells activate local cells within the tissue to promote profibrotic cytokine release that results in fibrosis within the infiltrated tissue.⁹

IgG4-RD is a heterogeneous disease that can affect nearly any organ. The most common manifestations include lymphadenopathy, lacrimal and salivary gland swelling, autoimmune pancreatitis, retroperitoneal fibrosis, and biliary sclerosis.¹¹ Lymphadenopathy is common in IgG4-RD, but is a nonspecific feature. Renal involvement, collectively referred to as IgG4-RKD, is present in approximately 20% of patients. In the kidney, most patients (> 75%) present with acute kidney injury or chronic kidney disease; other presenting features can include proteinuria (owing to IgG4-MGN), or renal mass lesion(s).^12,13 Approximately half of patients with IgG4-TIN have hypocomplementemia; this feature is more common among patients with kidney disease than with other organ manifestations of IgG4-RD.¹¹ Because IgG4-RPF is a common cause of obstructive renal disease, it is also discussed in this review; the focus of this paper will be on diagnosis and management of IgG4-RKD.

IgG4-RKD and IgG4-RPF

The 2 primary ways by which IgG4-RD affects the kidneys are direct cellular infiltration of renal parenchymal tissue (IgG4-TIN and IgG4-MGN) and ureteral obstruction from fibroinflammatory retroperitoneal lesions (IgG4-RPF). In Table 1, we summarize the key pathogenic mechanisms, clinical and histopathologic findings, and important disease mimickers of IgG4-RKD. The most common and well-recognized renal manifestation of IgG4-RD is TIN (i.e., IgG4-TIN), predominantly seen in males with a mean age of 65 years.^14,15 IgG4-TIN is by definition a plasma cell–rich TIN, usually with increased IgG4-positive plasma cells. The association of TIN with IgG4-RD was first noted in case reports in 2004 when patients with autoimmune pancreatitis were found to have TIN.^16,17 The first small case series more fully defining this association and describing the histopathologic appearance of IgG4-TIN was published in 2007, followed by larger tissue-based series several years later.18, 19, 20 AIN, a histologic subtype of IgG4-TIN, has recently been characterized in approximately 10% of IgG4-TIN cases, although this subtype is likely underdiagnosed.¹² Rarely, nonnecrotizing arteritis can be seen in IgG4-TIN.^12,21

Table 1.

Renal and peri-renal features of IgG4-related disease

Subtype	Clinical features	Epidemiology	Imaging	Histology and immunophenotype	Key mimics
IgG4-TIN	Frequent extra-renal IgG4-RD (∼80%); middle-aged to elderly; male > female	∼80% of IgG4-RKD pts	Abnormal in ∼50%: Hypoattenuated, rounded, wedge-shaped lesions on CT	Plasma cell–rich TIN; expansile or “storiform” interstitial fibrosis; tubular atrophy; IgG4+/IgG plasma cell ratio >0.4 in 60% of cases; TBM immune deposits in >80%; rare glomerular pseudocrescents; rare nonnecrotizing arteritis	ANCA-associated interstitial inflammation; SjD–associated TIN; Castleman’s disease–associated TIN; IgM plasma cell TIN; TINU; other autoimmune and plasma cell–rich TIN
IgG4-AIN	Same as above (histologic subtype of IgG4-TIN)	∼10% of IgG4-TIN	(as above)	Plasma cell–rich interstitial infiltrate; minimal interstitial fibrosis/tubular atrophy (<10%); increased IgG4+ plasma cells on IHC; few or no TBM deposits by IF	(as above)
IgG4-MGN	Frequent extra-renal features; frequent concurrent IgG4-TIN	∼7-15% of IgG4-RKD patients	Radiographic abnormalities less common than IgG4-TIN	Subepithelial immune deposits along GBM; IF staining positive for IgG, C3, kappa and lambda; TBM deposits by IF only with concurrent TIN	Primary/idiopathic MGN (anti-PLA2R associated); other causes or secondary MGN
IgG4-RPF	May have concurrent renal disease, flank/abdominal pain, malaise, anorexia, and lower extremity edema	∼25% of patients with IgG4-related disease	Retroperitoneal, periaortic, periureteric fibrosis on CT/ MRI with or without ureteric obstruction	Swirling “cartwheel” fibrosis; endophlebitis; perivascular dense lymphoplasmacytic infiltrate; IgG4+/IgG plasma cells > 0.4	Idiopathic RPF; ANCA-associated periureteral fibrosis; drugs (methyldopa, β-blockers); infection (TB, histoplasma); radiotherapy; Erdheim-Chester disease; other histiocytosis; lymphoma

AIN, acute interstitial nephritis; ANCA, antineutrophil cytoplasmic autoantibody; anti-PLA2R, antiphospholipase A2 receptor; CT, computed tomography; GBM, glomerular basement membrane; IF, immunofluorescence; IgG4-RD, IgG4-related disease; IHC, immunohistochemistry; MGN, membranous glomerulonephritis; MRI, magnetic resonance imaging; RPF, retroperitoneal fibrosis; SjD, Sjogren’s disease; TB, tuberculosis; TBM, tubular basement membrane; TIN, tubulointerstitial nephritis; TINU, TIN with uveitis.

Although less common than TIN, IgG4-RD can manifest as glomerular involvement, typically as a pattern of MGN. IgG4-MGN accounts for approximately 7% to 16% of IgG4-RD.^12,15,20 In addition, 56% of biopsies showing MGN have concurrent IgG4-TIN. IgG4-MGN is, for the most part, not associated with anti–phospholipase A2 receptor antibodies, compatible with this being a secondary MGN.^22,23 Other glomerular diseases described in association with IgG4-RD include IgA nephropathy and diabetic glomerulosclerosis.^12,24

Retroperitoneal fibrosis (i.e., IgG4-RPF), is seen in 9.6% to 27% of patients with IgG4-RD. IgG4-RPF lesions can present as periaortic or periureteric lesions, or as a plaque in the retroperitoneal space. In cases of IgG4-RPF with periaortic involvement, patients may develop inflammatory abdominal aortic aneurysms.²⁵ IgG4-RD causing aortitis, periaortitis, and periarteritis, involving the abdominal aorta, thoracic aorta, and iliac arteries is well-recognized both with and without retroperitoneal fibrosis.²⁶ Lesions can cause both dilatation or stenosis of the affected blood vessel.²⁷ Mass effect caused by the lesion on anatomical structures in the retroperitoneal space, as well as inflammation, can lead to the clinical symptoms of the patient. IgG4-RPF can typically present with flank, back, or abdominal pain, as well as malaise, fever, anorexia, weight loss, and lower limb edema.²⁸ About one-third of patients with IgG4-RPF have unilateral or bilateral obstructive uropathy and hydronephrosis,²⁹ which can result in acute or chronic kidney injury.²²

Another complication and clinical finding can be thrombosis and edema, if the lesion affects the venous system. Rarely, narrowing of the iliac artery can result in limb claudication.²⁷

Serologic Markers of IgG4-RD

A number of laboratory findings can suggest the presence of IgG4-RD, and some of these findings help differentiate between the phenotypic variants of IgG4-RD.² Helpful investigations include a complete blood count, creatinine, liver enzymes, C-reactive protein, Igs (including IgG subclasses), serum protein electrophoresis, antinuclear antibody, ANCA (or antimyeloperoxidase and anti–proteinase 3), serum complement (C3 and C4), urine analysis, as well as urine albumin-to-creatinine ratio and protein-to-creatinine ratio.²

Laboratory features suggestive of IgG4-RD include eosinophilia, polyclonal hypergammaglobulinemia on serum protein electrophoresis, elevation in serum IgE and IgG4, and hypocomplementemia.³⁰ C-reactive protein is usually normal or low (< 30  mg/l) because of what is felt to be relatively low-grade immune activity.¹⁴ Polyclonal hypergammaglobulinemia is sometimes attributed to the elevated serum IgG4 levels seen in this disease as well as other IgG subclasses.³⁰ Serum ANCA (antimyeloperoxidase or anti–proteinase 3) are generally negative in IgG4-RD; and in fact, such positive antibodies are an exclusion criterion in IgG4-RD classification criteria.^31,32 ANCA-associated disease can mimic IgG4-RD clinically, radiographically, and histopathologically, including in the kidney.³³ Clinicians should be aware of the laboratory test methodology, because a positive antinuclear antibody can yield a false-positive ANCA by indirect immunofluorescence (IF); antimyeloperoxidase and anti–proteinase 3 assays are more specific.^34,35 A positive antinuclear antibody, usually low-titer, is present in approximately 30% of patients with IgG4-RKD.^12,19 Interestingly, the presence of serum anti-C1q antibodies in patients with IgG4-RD is strongly associated with renal disease activity and with the presence of cutaneous small-vessel vasculitis.³⁶ In addition, it is important to understand the laboratory’s method for measuring serum IgG4, because markedly elevated levels can produce a falsely low result due to a prozone effect in some assays.³⁷

In IgG4-RKD, IgG4-TIN will usually present with an increase in creatinine along with the above findings, depending on the underlying phenotype. Mild proteinuria, in the absence of concurrent glomerular disease, can be seen in IgG4-TIN,³⁸ possibly related to polyclonal hypergammaglobulinemia or due to “tubular proteinuria” in the setting of TIN. Heavier proteinuria, particularly in the nephrotic range, is more likely due to IgG4-MGN.^12,13 With IgG4-RPF, an increase in creatinine can correlate with ureteric obstruction seen on imaging (ultrasound, computed tomography [CT] or magnetic resonance imaging), as ureteric obstruction, hydronephrosis, RPF, and other radiologic findings of IgG4-RD lesions in other organs.

Radiologic Findings

Radiologic imaging findings in IgG4-RD can vary depending on the organs involved. Typically, there is evidence of diffuse or localized organ swelling of or mass-like lesion(s) in ≥1 organs.³⁹ In IgG4-RKD, radiographic abnormalities are present in about half of patients who undergo biopsy, and a mass lesion is the primary indication for kidney biopsy (less commonly partial or total nephrectomy) in 15% of patients, although the percentages likely vary depending on the clinical practice focus on medical kidney disease versus kidney tumors. The most common imaging finding is hypoattenuated, rounded, wedge-shaped lesions in the renal parenchyma on CT (Figure 1).^40,41 RPF, typically diagnosed by CT or magnetic resonance imaging, can be seen as a soft tissue mass surrounding tissues in the retroperitoneal space, including the aorta, renal pelvis, and ureters (Figure 2).27, 40, 41, 42 Hydroureteronephrosis may be present if the RPF is causing outlet obstruction of the pelvis and ureteric system. 18ˆF-fluorodeoxyglucose positron emission tomography/CT is very sensitive for staging patients with multiorgan disease, because the involved organs often demonstrate low to moderate fluorodeoxyglucose avidity; however, in most cases, CT of the neck to pelvis is sufficient for staging.⁴³ Patients with lacrimal gland swelling should undergo CT head to assess for orbital pseudo-tumor.

Figure 1.

Renal IgG4 imaging. (a) Axial portal venous phase computed tomography CT showing patchy cortical hypoattenuation of the posterior interpolar region of the left kidney. Note is made of intrahepatic biliary dilatation in the right hepatic lobe (black arrowhead) and bulky pancreatic head (thick white arrow) (suggesting IgG4-related cholangitis and pancreatitis, respectively). (b) Axial portal venous phase computed tomography of the same patient 5 years later showing progressive hypoattenuating cortical areas in both kidneys. (c) and (d) Axial and MIP oblique coronal excretory phase computed tomography demonstrating bilateral enhancing parapelvic soft tissue with obliteration of renal sinus fat (curved arrows).

Figure 2.

Retroperitoneal fibrosis related to IgG4 disease. (a) Axial portal venous computed tomography demonstrating enhancing periaortic soft tissue, (b) with increased uptake on fluorodeoxyglucose positron emission tomography scan. (c) Axial T2 weighted sequence at the level of lower pole of the kidneys showing intermediate signal periaortic soft tissue, (d) with moderate enhancement on post-contrast T1- weighted sequence. (e) Axial arterial phase computed tomography performed 5 years later showing reduced periaortic soft tissue. (f) Coronal arterial phase computed tomography showing aneurysmal dilatation of infrarenal aorta. Incidental note is made of left ureteric double-J stent (white arrow) for hydroureteronephrosis secondary to retroperitoneal fibrosis.

In the abdomen, there can be involvement of the pancreas, biliary tree, or mesentery, with pancreatic involvement being the most classical. A diffusely enlarged pancreas with loss of pancreatic clefts and the presence of a peripancreatic hypoattenuating halo are the usual findings.^41,44 Biliary disease presents with sclerosing cholangitis, showing biliary duct wall thickening and strictures on enhanced imaging.⁴⁰

Histopathology of IgG4-RD

Although clinical, serologic, and radiologic assessment can be helpful in raising the suspicion for IgG4-RD and identifying possible biopsy targets, often a tissue biopsy and histopathologic confirmation are necessary to make a definitive diagnosis of IgG4-RD.³² A kidney biopsy, particularly one for “medical” (nontumor) purposes, including IF staining and electron microscopy, can also help exclude malignancy and other possible mimickers of the disease.²⁴ A diagnosis of IgG4-TIN can also be made on biopsies targeted at a mass lesion; in this case, cytopathology evaluation alone may be insufficient, and needle core biopsies are needed for the purpose of adequate evaluation of tissue structures and for IgG4 immunostaining.

The classic 3 characteristic histopathologic manifestations of IgG4-RD are remarkably similar in the lesions localized in different organs. They are as follows: lymphoplasmacytic infiltration, “storiform” fibrosis, and obliterative phlebitis.⁴⁵ However, the kidney shows a somewhat different phenotype, notably with the absence of phlebitis, and “storiform” fibrosis is not always present. IgG4-RD lacks necrosis/karyorrhexis or granulomas, the presence of which essentially excludes a diagnosis of IgG4-RD and instead raises the possibility of ANCA-associated disease.²⁴

The lymphoplasmacytic tissue infiltration is often dense, consisting mainly of mononuclear cells and polyclonal plasma cells, with scattered eosinophils.^45,46 This cellular infiltration is accompanied by characteristic so called “storiform” fibrosis seen in IgG4-RD, although this histologic description is not necessarily reproducible. Immunohistochemistry shows increased IgG4-positive plasma cells (> 11/high power microscopic field in the 3 most severely affected areas, with some differences between organs and specimens involved).⁴⁶ An IgG4-to-IgG ratio of ≥0.4 (40%) has been proposed as a diagnostic criterion; this ratio is more useful in cases or organs involved that show more fibrosis and less inflammation.⁴⁵ The IgG4-to-IgG plasma cell ratio is not usually useful in the evaluation of kidney biopsy infiltrates, which tend to show more inflammation than some other manifestations such as IgG4-RPF.¹²

Renal Histopathologic Findings in IgG4-RKD and IgG4-RPF

Most patients with IgG4-RKD present with kidney dysfunction with or without a mass lesion; therefore, the usual route to a tissue diagnosis is via a needle biopsy with tissue sent for examination by light microscopy (with special stains), IF, and electron microscopy. However, the diagnosis can be made on a biopsy of a mass lesion that only had tissue submitted in formalin fixative for light microscopy because of the clinical suspicion of neoplasm.

In IgG4-TIN (Figure 3), light microscopy shows a plasma cell-rich TIN, often including several eosinophils. Tubulitis is present, mostly with mononuclear cells but can also include plasma cells and eosinophils. Immunoperoxidase staining (immunohistochemistry) shows at least focal moderate (11–30/40× microscopic high power field) or marked (> 30/high power field) increase in IgG4-positive plasma cells, present in a single needle biopsy field in the most concentrated area, in >90% of cases.¹² Expansile (pushing apart the tubules) or so-called “storiform” fibrosis, sometimes called a “bird’s eye” pattern, can be seen accompanying the inflammatory infiltrate, although this histologic feature is not necessarily present or a reproducible feature. Granulomas or numerous neutrophils are not present in IgG4-TIN. Obliterative phlebitis is not seen in the kidney. Nonnecrotizing arteritis can be seen rarely, in about 5% of cases, but is likely overlooked when mild.¹² On IF, granular staining for IgG, kappa, lambda, with lesser staining for C3, and occasionally also staining for C1q and/or IgA can be seen in the tubular basement membranes (TBM).⁴⁷ Corresponding amorphous electron dense deposits are seen in TBM by electron microscopy.

Figure 3.

Typical biopsy features of IgG4-related tubulointerstitial nephritis. A “typical” case of IgG4-related tubulointerstitial nephritis shows a plasma cell-rich tubulointerstitial nephritis pattern with expansile (pushing apart tubules) fibrosis and thickened tubular basement membranes (hematoxylin & eosin, upper left panel); numerous eosinophils (arrows) can be present, as seen in this example, and could cause confusion with an allergic drug reaction. An immunoperoxidase stain for IgG4 in this case shows increased IgG4+ plasma cells (upper right panel). Some cases show so called “storiform” (reminiscent of a woven mat) or “bird’s eye” (reminiscent of a cut of maple wood) pattern of interstitial fibrosis, as shown in this example (periodic acid-Schiff, middle left panel). Occasionally, an immunoperoxidase stain for IgG4 done to evaluate interstitial plasma cells will reveal granular glomerular basement membrane staining (arrow) of membranous glomerulonephritis, although immunofluorescence staining is more sensitive to detect immune complex glomerulonephritis (middle right panel). Immunofluorescence staining for IgG shows granular tubular basement membrane deposits as well as interstitial deposits in majority of cases of IgG4-tubulointerstitial nephritis in areas of interstitial fibrosis and tubular atrophy (IgG immunofluorescence, lower left panel); note the negative staining glomerulus on the left. Electron microscopy shows corresponding amorphous electron dense deposits in the tubular basement membranes (arrows) (lower right panel).

IgG4-AIN is a histologic subtype of IgG4-TIN that was only recently recognized. IgG4-AIN (Figure 4) is a plasma cell–rich TIN with, by definition, absent or minimal interstitial fibrosis and tubular atrophy (< 10%), and usually has absent or very focal TBM deposits by IF.¹² IgG4-AIN is likely underdiagnosed, in part because of the absence of TBM deposits, and also because diagnosis requires the pathologist to order an IgG4 stain to evaluate the plasma cells and likely requires knowledge of other organ involvement. For this reason, we recommend performing IgG4 immunoperoxidase staining in all cases of plasma cell–rich TIN if another clear cause of TIN is not apparent; however, the presence of increased IgG4-positive plasma cells alone is not specific and must be interpreted in the full clinicopathologic context.

Figure 4.

Recently recognized biopsy features of IgG4-related tubulointerstitial nephritis. Acute interstitial nephritis pattern: diffuse dense interstitial inflammation with minimal interstitial fibrosis (Masson trichrome, upper panel); higher magnification shows a plasma cell-rich infiltrate (hematoxylin & eosin, left middle panel), and immunoperoxidase staining for IgG4 shows a marked increase in IgG4+ plasma cells (right middle panel). The acute interstitial nephritis pattern is more difficult to diagnose as IgG4-related tubulointerstitial nephritis, because it does not show the peculiar expansile fibrosis characteristic of IgG4-related tubulointerstitial nephritis, and it also often does not show tubular basement membrane immune complex deposits using immunofluorescence. Arteritis: A rare finding on biopsy, this example shows plasma cells and mononuclear cells within the thickened intima of an artery (hematoxylin & eosin, lower panel). Note the absence of fibrinoid necrosis and karyorrhexis, which if present would exclude a diagnosis of IgG4-related kidney disease and would instead be suggestive of antineutrophil cytoplasmic autoantibody–associated disease.

Another histologic pattern in the kidney biopsy that can be seen associated with IgG4-TIN is a glomerular “pseudocrescent” or “interstitial crescent”, which may mimic a true crescent as seen in glomerulonephritis. However, pseudocrescents represent glomerular “capsulitis” with reactive epithelial cells akin to tubulitis but affecting Bowman’s capsule and lining parietal epithelial cells. Particularly when (nonnecrotizing) arteritis is present, the pathologist must be careful to recognize IgG4-TIN and not misdiagnose pauci-immune focal crescentic glomerulonephritis.

Less common than IgG4-TIN is IgG4-MGN. A membranous nephropathy pattern of injury is defined as regularly spaced subepithelial deposits along the glomerular basement membranes; this pattern can be seen on light microscopy, IF, and electron microscopy.⁴⁸ On IF, these deposits are positive for IgG, C3, kappa, and lambda, and the deposits are IgG4-dominant (similar to primary membranous nephropathy), but negative for phospholipase A2 receptor.⁴⁹ No antigen associated with IgG4-MGN has been identified. IgA nephropathy and diabetic glomerulosclerosis are the other most common glomerular diseases in IgG4-RD.¹²

Histopathologic assessment of RPF caused by IgG4-RD shows findings similar to those seen in other involved extrarenal tissue, including lymphoplasmacytic infiltration, “storiform” fibrosis, and increased IgG4-positive plasma cells. Because RPF involvement tends to be more fibrotic and less inflammatory, the IgG4-to-IgG positive plasma cell ratio (at >0.4) is more useful for diagnosis with this pattern of organ involvement.

Diagnostic and Classification Criteria for IgG4-RD

The 2012 International consensus criteria set the gold standard for histopathological findings in IgG4-RD.⁴⁶ However, IgG4-RD is ultimately a clinicopathological diagnosis; clinicians must combine clinical, laboratory, radiological, and histological findings to make a diagnosis and exclude mimics. To this end, the 2019 American College of Rheumatology and European League Against Rheumatism classification criteria for IgG4-RD are helpful entry, inclusion, and exclusion criteria for the diagnosis of IgG4-RD.³¹ Although designed for research classification, they can be helpful in clinical care. For patients to be considered for IgG4-RD they would need to meet the entry criteria, which require clinical or radiologic involvement of ≥1 organ typically affected by this disease (pancreas, bile duct, kidneys, retroperitoneum, lung, aorta, pachymeninges, orbits, thyroid, lacrimal or other major salivary gland), or pathologic evidence of an inflammatory process accompanied by lymphoplasmacytic infiltrate in one of these same organs.³¹

The exclusion criteria must be absent and can be divided into clinical, serologic, radiologic, and histopathologic categories. They include a fever and a lack of response to glucocorticoids (GCs) (clinical); leukopenia and thrombocytopenia with no alternative explanation, peripheral eosinophilia, positive ANCA, anti-dsDNA, RNP, Smith, Ro or La antibodies, or cryoglobulinemia (serologic); radiologic findings suspicious for malignancy or infection, especially if rapid radiologic progression, or splenomegaly (radiologic); histopathologic evidence of malignancy, necrosis, necrotizing vasculitis, primarily granulomatous inflammation, or features consistent with a macrophage or histiocytic disorder (histopathologic); and a known diagnosis of idiopathic multicentric Castleman disease, inflammatory bowel disease (if only pancreas or bile duct involvement) or Hashimoto thyroiditis (if only thyroid involvement).³¹

There are weighted inclusion criteria which are based on histopathologic, serologic, and specific organ findings.³¹ Provided that the entry criteria are met, no exclusion criteria are met, and the total points assigned based on the inclusion criteria are ≥ 20, then a diagnosis of IgG4-RD is likely.³¹ Although these classification criteria are helpful, further work is needed to more clearly define the histopathologic and immunophenotypic features of IgG4-RD across different tissues, including the kidney and retroperitoneum, and to distinguish IgG4-RD from its mimics.

Clinical diagnostic criteria for IgG4-RKD were originally proposed in 2011⁵⁰ and later revised in 2020.⁵¹ Kidney injury can manifest as decreased renal function or abnormal urine studies, or IgG4-RKD may be seen incidentally on imaging studies performed for other reasons.⁵² Histologic criteria for IgG4-TIN, including an evaluation of the utility of IgG4 immunoperoxidase staining, were proposed in 2011.¹⁹ Specific renal radiologic findings, elevated serum IgG4 levels (≥ 135 mg/dl), classic renal histopathologic findings, and extrarenal histopathologic, radiologic, and clinical findings can aid in the diagnosis. Depending on the constellation of findings, a definite, probable, and possible diagnosis can be made.⁵¹ Still, further work is needed to update and standardize the histopathologic diagnostic criteria for IgG4-RD, including IgG4-RKD, to reflect advances in understanding of the disease spectrum, overlap, and mimickers, since the 2012 pathology consensus paper.⁴⁶ A general diagnostic algorithm for suspected IgG4-RKD and RPF is presented in Figure 5.

Figure 5.

An approach to suspected IgG4-RKD and RPF. AIN, acute interstitial nephritis; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic autoantibody; anti-MPO, antimyeloperoxidase antibody; anti-PLA2R, antiphospholipase A2 receptor; anti-PR3, anti–proteinase 3 antibody; CRP, C-reactive protein; ECD, Erdheim-Chester disease; GBM, glomerular basement membrane; IgG4-RD, IgG4-related disease; IgG4-RKD, IgG4-related kidney disease; iMCD, idiopathic multicentric Castleman disease; MGN, membranous glomerulonephritis; PHGG, polyclonal hypergammaglobulinemia; RDD, Rosai-Dorfman-Destombes disease; RPF, retroperitoneal fibrosis; SjD, Sjogren’s disease; SPEP, serum protein electrophoresis; TBM, tubular basement membrane; TIN, tubulointerstitial nephritis; TINU, TIN and uveitis; UACR, urine albumin-to-creatinine ratio; UPCR, urine protein-to-creatinine ratio.

Mimickers of IgG4-RKD and IgG4-RPF

There are a number of diseases that can resemble or be confused with IgG4-RD clinically, radiologically, and on histopathology. The tumefactive nature of IgG4-RD radiologically raises the possibility of malignancy, inflammation due to other autoimmune processes, infection, or hematologic disease.⁵³ There are, however, some diseases that can be difficult to differentiate from IgG4-RD even with appropriate investigation.

One inflammatory disease that closely mimics IgG4-RD is ANCA-associated disease. ANCA disease can affect multiple organs, including the retroperitoneum and kidney, and can give rise to mass lesions.^33,54,55 Histologically, ANCA-associated inflammation is usually plasma cell–rich; can show extensive fibrosis; and in about one-third of cases, can show increased IgG4-positive plasma cells, including often a diffuse marked increase in IgG4-positive plasma cells. Distinguishing features include giant cells or granulomatous inflammation (which essentially excludes a diagnosis of IgG4-RD), karyorrhexis, and numerous neutrophils, although these entities are not always histologically distinguishable.³³ Serum testing for antimyeloperoxidase and anti–proteinase 3 helps to evaluate for the possibility of ANCA associated disease.

IgG4-RKD renal lesions seen on imaging can be mistaken for malignancy, other autoimmune inflammatory disease, infection or pyelonephritis, lymphoma, and infarction.⁵⁶ IgG4-RPF mimickers include idiopathic RPF, infection (tuberculosis, histoplasmosis) and drug-related RPF, radiation therapy injury and trauma or surgical scarring.⁵⁷ Tissue samples for pathology, including staining for IgG4 to evaluate plasma cells, can help establish the diagnosis.

Renal mimickers of IgG4-TIN include SjD, idiopathic multicentric Castleman disease, Rosai-Dorfman-Destombes disease, TIN with uveitis, drug-induced TIN, as well as other causes of TIN (particularly autoimmune causes).²⁴ Various clinical, serologic, and histopathologic characteristics can help differentiate IgG4-TIN from its many mimickers, including the number of IgG4-positive plasma cells, C-reactive protein level, the presence of autoantibodies, and the clinical presentation of the disease. Similarly, the IgG4-AIN pattern can resemble other more common causes of AIN (drug-induced and autoimmune) but can be differentiated from these causes by the presence of increased plasma cells, and in particular, increased IgG4-positive plasma cells, along with a clinical history compatible with IgG4-RD.^12,24

Among the classical autoimmune diseases, SjD is a mimic of IgG4-RD.^2,58 SjD often presents with salivary and lacrimal gland involvement and may cause plasma cell–rich TIN. Indeed, before it was recognized and defined, IgG4-TIN has in the past been misattributed as SjD-associated TIN.^59,60 On kidney biopsy, IgG4-TIN is more likely than SjD to show TBM-immune deposits. Investigations will show polyclonal hypergammaglobulinemia and hypocomplementemia and may show normal to elevated C-reactive protein levels. However, there may be a positive antinuclear antibody, anti-Ro and anti-La antibodies, which are not typically seen in IgG4-RD.⁵⁸ One previously named entity, idiopathic hypocomplementemic interstitial nephritis with extensive tubulointerstitial deposits, is now recognized as representing IgG4-TIN.

IgG4-MGN has similar histologic and immunophenotypic features as primary membranous nephropathy, but whereas most cases of primary disease are associated with anti-phospholipase A2 receptor antibodies, IgG4-MGN is not. About half of IgG4-MGN cases show concurrent IgG4-TIN, and so this feature can help establish the diagnosis if present; otherwise, a clinical history of IgG4-RD is needed to attribute the MGN to IgG4-RD.²³

Treatment of IgG4-RKD and IgG4-RPF

Although the pathophysiology of IgG4-RD, including IgG4-RKD and IgG4-RPF, is not fully understood, it is an immune-mediated disease that involves lymphocyte and fibro-inflammatory activation that generally responds very well to immunosuppressive therapy.⁶¹ This typically involves systemic immunosuppressive therapy with steroids and other disease-modifying antirheumatic drugs.⁶² Although conservative measures may be required for symptom management in cases of nephrotic syndrome in IgG4-MGN (e.g., salt restriction and diuresis) and surgical or mechanical (stenting) management to relieve obstruction in IgG4-RPF, renal involvement of IgG4-RD generally responds well to systemic therapy in most cases.⁶³ Despite the high rate of response to treatment in IgG4-RD, relapses are common, indicating a need for therapies that achieve more durable disease control. A summary of systemic therapies and the evidence behind these therapies in the treatment of IgG4-RD is shown in Table 2.

Table 2.

Systemic therapies for IgG4-related disease

Treatment, reference	Study design	Patient population	End point and response	Notable side effects or toxicity, notes on renal outcomes
Prednisone [glucocorticoid] Masaki et al.64	Phase II, single-arm trial	N = 61 Median age = 62 yrs Japan	End points: complete remission, response rate, relapse rate, adverse effects - 65.9% of patients with definite IgG4-RD achieved complete remission - overall response rate was 93.2% - 14.6% of patients relapsed during the 5-yr maintenance period	High frequency of glucose intolerance reported - No renal outcomes reported
Thalidomide Chen et al.65	Randomized, placebo-controlled trial - steroids & thalidomide vs. steroids & placebo	n = 57	End points: relapse rate at 12 mos, remission rates, adverse effects - 13.8% vs. 67.8% relapse rate for thalidomide group vs. placebo - 75.8% vs. 32.2% remission rate for thalidomide group vs. placebo	35/57 experienced adverse effects, most were mild or moderate - no renal outcomes reported
Cyclophosphamide (CYC) Yunyun et al.66	Nonrandomized, controlled trial - steroid monotherapy vs. CYC & steroids	n = 102 Median age GI: 49.72 yrs, GII: 53.52 yrs	End points: relapse rates, response rates, remission rates, adverse effects - 38.5% relapse rate in steroid monotherapy - 12.0% relapse rate for CYC and steroid combination treatment	2% experienced liver toxicity - No difference in renal outcomes between the 2 groups
Mycophenolate mofetil (MMF) Yunyun et al.67	Randomized, controlled trial - steroid monotherapy vs. MMF & steroids	n = 69 mean age: GI: 55.34 yrs, GII: 56.76 yrs	End points: response rates, relapse rates, remission rates, adverse effects - 20.59% vs. 40.0% relapse rate in combined group vs. monotherapy - 76.47% vs. 51.42% remission rate in combined group vs. monotherapy	No severe side effects reported- No difference in renal outcomes between the 2 groups
B cell depletion
Rituximab (RTX) [CD20 Mab] Carruthers et al.68	Phase II, single-arm trial	n = 30 Mean age = 61 yrs USA	End points: IgG4-RD RI declines by $\ge 2$ points when compared with baseline, no disease flare-ups before month 6, no need for steroids during months 2–6 - 77% achieved primary outcome; 60% achieved complete remission within 12 mos	2/30 (6.7%) patients experienced serious infections requiring hospitalization - No renal outcomes reported
Obexelimab [CD19 Mab] Perugino et al.69	Phase II, single-arm trial	N = 15 Median age = 63 yrs USA	End point: number of patients whose IgG4-RD RI decreased by ≤2 from baseline in 169 d - 80% of patients reached primary end point; 93% of patients met end point at some time	13/15 (87%) experienced adverse effects, most were mild or moderate and due to initial treatment - No renal outcomes reported
Inebilizumab Stone et al.70,71	Phase III randomized, placebo-controlled trial - Inebilizumab vs. placebo	N = 135 Mean age = 58.2 yrs 22 countries (80 sites)	End points: treatment of first flare after taken off steroids, annual flare rate, flare-free, treatment-free remission (52 wks), flare-free, steroid-free remission (52 wks) - Inebilizumab reduced risk of flare by 87%; 60% vs. 10% flares in placebo vs. intervention - 57% vs. 22% flare-free, treatment-free remission of intervention vs. control	12/68 (18%) experienced serious adverse events - No renal outcomes reported

IgG4-RD, IgG4-related disease.

Historical Standard-GCs and Disease-Modifying Antirheumatic Drugs

Possibly the first reported case of IgG4-RD treated with GC therapy was in 1995 when Japanese researchers treated autoimmune pancreatitis associated with hyperglobulinemia successfully with steroids.²⁴ GCs are now a mainstay and first-line therapy in patients with IgG4-RD, usually with good response to therapy and induction of remission.²⁴ The consensus recommendation for induction therapy in IgG4-RKD is that approximately 30 to 40 mg/d of oral prednisone should be initiated in affected patients for 2 to 4 weeks, by which time patients usually show a response, which is then followed by a gradual taper-off of GC.⁷² Notably, in cases of IgG4-TIN, the response to GC therapy is typically rapid and substantial, and the degree of fibrosis present should not discourage treatment.^19,73 In cases of IgG4-RPF, moderate- to high-dose prednisone is indicated, based on expert opinion, with dosing of 1 mg/kg (≤80 mg) for 4 weeks, with tapering of 0.5 mg/kg in the second month, and 0.25 mg/kg in the third and fourth months. The remainder of tapering off prednisone continues for 6 to 12 months.⁷⁴ The use of a higher steroid induction regimen for IgG4-RPF is informed by previous evidence demonstrating its efficacy in idiopathic RPF.⁷⁵ However, with the addition of steroid-sparing agents, such conventional synthetic disease-modifying antirheumatic drugs or B cell depletion therapy, tapering can be done more quickly. In the case of inebilizumab, steroids were tapered off in 8 weeks, after the first dose of inebilizumab.⁷²

Some disease-modifying antirheumatic drugs, such as cyclophosphamide, mycophenolate, and thalidomide have been trialed in the management of IgG4-RD, with mostly favorable recurrence and remission rates (Table 2).65, 66, 67

B Cell–Depleting Therapies

B cell–depleting therapy, initially using rituximab, has been found to be an effective treatment strategy of IgG4-RD, including in those with steroid-refractory disease.⁷⁶ Rituximab is a monoclonal antibody, which targets CD20 surface antigens present on mature B cells, leading to cell depletion and thereby interrupting B cell differentiation into plasmablasts and plasma cells, reducing antibody production and downstream immune activation.⁷⁷

In 2015, an open-label trial demonstrated the efficacy of rituximab alone, without GC, in the treatment of IgG4-RD, with a 97% disease response and 60% achieving remission at 1 year.⁶⁸ A longer period of remission has been shown with rituximab maintenance therapy.⁷⁸ Rituximab dosing in IgG4-RD is similar to other autoimmune diseases, administered i.v. in 2 separate 1-g doses 15 days apart. A 2024 systematic review and meta-analysis of rituximab therapy in IgG4-RD demonstrated an 88.5% initial response rate, in which the majority of patients were steroid-resistant, with a 16.9% relapse rate.⁷⁹ Maintenance rituximab significantly reduced relapse rates to 2.8%, compared with 21.5% in those treated with induction rituximab only, although there was significant heterogeneity in the maintenance regimen. The most common adverse events seen related to rituximab were infections and infusion reactions. In this study, the adverse event rate was 31.6%, with a 3.9% serious adverse event rate. Although IgG4-RD appears to respond well to rituximab, use of this therapy was limited in availability because of the off-label use and the high cost associated with this medication.⁸⁰

An important monoclonal antibody therapy that has been studied in IgG4-RD and other autoimmune diseases is inebilizumab.⁷⁰ This medication targets the CD19 cell surface antigen, which is also present on a wide range of B cell populations. Targeting CD19 has been proposed as a more effective approach to autoimmune disease therapy given the presence of CD19 on early progenitor B cells through plasmablasts and some plasma cells, which lack CD20 expression.^81,82

Results from the MITIGATE trial, a randomized placebo-controlled trial assessing the efficacy of inebilizumab versus placebo in patients with IgG4-RD treated with a GC taper, showed lower disease flare rates and higher complete remission rates in the inebilizumab group.⁷⁰ Inebilizumab was administered i.v. at 300 mg doses given 15 days apart and then at 26 weeks during a 52-week period. Expectedly, lymphopenia and infection were the most common adverse events associated with inebilizumab in this trial. Inebilizumab has since been approved in the United States by the US Food and Drug Administration in April 2025 for the treatment of IgG4-RD.

Obexelimab is another monoclonal antibody targeting B cells that may show promise as a treatment for patients with IgG4-RD.⁶⁹ Obexelimab acts by targeting CD19 on B cells, similar to inebilizumab, but has the added effect of binding to the Fc gamma IIb receptor, thereby disrupting B cell signaling. An open-label, phase 2 pilot study, testing obexelimab in patients with IgG4-RD, showed that 14 of the 15 patients enrolled in the study responded to therapy, although 13 had an adverse event to obexelimab.⁶⁹ A phase 3, double-blind, placebo-controlled trial (i.e., INDIGO, NCT05662241) is currently being conducted to look at the efficacy of obexelimab in approximately 190 patients with active IgG4-RD.⁸³ Obexelimab will be given as a weekly 250 mg subcutaneous dose over the course of 1 year and has the advantage of subcutaneous rather than i.v. administration.

Other Emerging Therapies

There are other monoclonal antibodies that do not directly target B cells, which are emerging as potential therapies for IgG4-RD. Dupilumab is a monoclonal antibody, approved for use in type 2 inflammatory disease, such as asthma, nasal polyps, and atopic dermatitis, that inhibits interleukin (IL)-4 and IL-13 signaling by targeting the IL-4 receptor alpha.^84,85 Because IL-4 is involved in the signaling and class switching of IgM to IgG4 antibodies in IgG4-RD and IL-13 plays a key role in fibrosis, it is felt that inhibiting these pathways using dupilumab may be beneficial to patients with this disease.⁸⁴ Some efficacy of dupilumab in IgG4-RD has been shown in case reports of patients who incidentally also had severe asthma or nasal polyps.^85,86

Rilzabrutinib is a Bruton tyrosine kinase inhibitor that is being studied in IgG4-RD. This was proposed as a possible therapy for IgG4-RD because Bruton tyrosine kinase plays an important role in the activation, differentiation, and maturation of immune cells, including B cells, monocytes, macrophages, neutrophils , eosinophils and mast cells.^71,87 A recent open-label, phase 2 clinical trial showed that rilzabrutinib given as a 400 mg oral tablet twice daily over 52 weeks prevented disease relapse in 70% of patients during that period.⁷¹

Efgartigimod is an altered human IgG1 fragment that binds to the neonatal Fc receptor on circulating IgG antibodies, reducing overall IgG levels in the body.⁸⁸ A phase 2, open-label study (NCT07025330) is being conducted on efgartigimod (a drug approved for use in myasthenia gravis)⁸⁹ in patients with IgG4-RD.

Conclusion

In summary, IgG4-RD is a systemic fibro-inflammatory disease that can affect the kidneys directly through IgG4-RKD and through obstruction caused by IgG4-RPF. IgG4-RKD typically presents as IgG4-TIN but can also be associated with MGN. IgG4-AIN is a histologic subtype of IgG4-TIN with minimal or absent tubular atrophy, interstitial fibrosis, or TBM deposits. Diagnosis of IgG4-RKD relies on a combination of characteristic clinical, serologic, radiologic, and histopathologic features. Treatment of IgG4-RKD is the same as treatment of systemic IgG4-RD, and involves immunosuppression, typically induction with GCs as first-line, and may include B cell–depleting agents such as rituximab or inebilizumab for induction and maintenance therapy. Further studies are underway to identify additional agents that may be used in the treatment of IgG4-RD.

Disclosure

LYCC has received speaker’s fees from Amgen and Recordati Rare Diseases. LDC works as a consultant for Amgen and Argenx. SCW has received speaker’s fee and has been a consultant for Amgen. All the other authors declared no competing interests.