IgG4-Related Kidney Disease

Introduction

IgG4-related disease (IgG4-RD) is a rare yet clinically significant systemic fibroinflammatory disorder marked by the infiltration of IgG4+ plasma cells.¹ IgG4-RD affects various peculiar organs, such as the pancreas, lacrimal and salivary glands, orbits, kidneys, retroperitoneum, and aorta. It can mimic autoimmune diseases and malignancies both clinically and histopathologically, such as Sjogren disease, sarcoidosis, ANCA-associated vasculitis, and lymphoma, making the diagnosis challenging.^1,2

Kidney involvement occurs in 7%–25% of patients with IgG4-RD³ and may present as obstructive uropathy due to retroperitoneal fibrosis, tubulointerstitial nephritis (TIN), and glomerular lesions, particularly membranous nephropathy. The kidney parenchyma is a significant target in IgG4-RD, with plasma cell–rich TIN being the most common presentation of IgG4-related kidney disease. TIN due to IgG4-RD presents with low-grade proteinuria and mostly insidiously progressive acute or chronic kidney failure, and histopathological confirmation of IgG4+ plasma cell–rich TIN is key for diagnosis.^3,4

Case Presentation

A 63-year-old man with a history of obesity, hypertension, prediabetes, hyperlipidemia, and fatty liver disease was referred for worsening of baseline kidney function and albuminuria. A year prior, he had an excision of a submandibular salivary gland because of a mass initially attributed to cervical lymphadenopathy. The pathological analysis revealed chronic sialadenitis with nodular lymphoid cell infiltrate and acinar atrophy without evidence of malignancy. Over the subsequent months, the patient developed unexplained weight loss and systemic lymphadenopathy. Computed tomography of the chest, abdomen, and pelvis showed subpleural nodules in the right lung, bilateral iliac and retroperitoneal lymphadenopathy, and two 15-mm complex cysts in the right kidney. A positron emission tomography scan revealed hypermetabolic lymph nodes, raising concerns for lymphoma. A lymph node biopsy showed nonspecific polymorphous lymphocytes, ruling out lymphoma. The patient's baseline creatinine was 1.24 mg/dl, urine protein–creatinine ratio was 190 mg/g, urine albumin–creatinine ratio was 48 mg/g, and hemoglobin A1c was 5.7 six months before. These respectively increased to 2.67 mg/dl, 313, 112 mg/g, and 6.2 at presentation. Serological workup was negative for anti-Ro, anti-La, anti-nuclear antibody, ANCA, serum protein electrophoresis/immunofixation, and Quantiferon-TB Gold but notable for low C3 at 57 mg/dl (reference range: 82–167 mg/dl), low C4 at 3 mg/dl (reference range: 12–38 mg/dl), and high IgG4 at 968 mg/dl (normal 2–96 mg/dl). His complete blood count, bilirubin, and pancreatic enzymes were normal. A kidney biopsy revealed diffuse IgG4-positive plasma cell–rich tubulointerstitial inflammation (Figure 1, A and C) with a storiform or bird's-eye pattern (Figure 1B) and granular IgG deposits in the tubular basement membrane, mesangium, and Bowman's capsule (Figure 1, D–G). On the basis of clinical and histopathological features, a diagnosis of IgG4-RD was established. The patient was initiated on 30 mg prednisone daily for 4 weeks, leading to improved creatinine at 1.4 mg/dl; normalization of C3, C4, and IgG4 levels; and remission of lymphadenopathy. Prednisone was gradually tapered over 3 months and subsequently discontinued.

Figure 1.

Kidney pathology of the patient. (A) H&E staining showing diffuse, severe plasma cell–rich tubulointerstitial inflammation with prominent expansile interstitial fibrosis and tubular atrophy (200× magnification). (B) Jones silver stain showing storiform or bird's-eye fibrosis (200× magnification). (C) Numerous IgG4⁺ plasma cells (>10 per high-power field; 200× magnification). IF staining showing (D) diffuse strong granular staining of tubular basement membranes for IgG, kappa, and lambda (100× magnification) and (E) granular staining for IgG within glomerular mesangium and Bowman's capsule. Electron microscopy showing (F) electron-dense deposits (white arrows) in the tubular basement membranes (1500× magnification) and (G) mesangium (6000× magnification). H&E, hematoxylin and eosin.

Diagnostic Challenge in IgG4-RD

IgG4-RD can manifest with clinical and histopathological features of autoimmune diseases and malignancies, leading to a diagnostic challenge for clinicians.⁵ Diagnosis requires a high index of suspicion and thorough evaluation integrating clinical, radiological, and laboratory assessments.⁵ Although an elevated serum IgG4 level can be associated with IgG4-RD, it is neither sufficiently sensitive nor specific for diagnosis because it can be observed in various other conditions.¹ The final diagnosis can only be made by delineating characteristic histopathological findings of plasma cell–rich inflammation and storiform fibrosis in the appropriate clinical scenario.¹ It is crucial to exclude certain malignancies, autoimmune diseases, and inflammatory disorders that can manifest with similar clinical and histopathological features. American College of Rheumatology/European League Against Rheumatism 2019 guidelines suggest using a classification system and require a score of 20 or more, with appropriate organ involvement and the absence of exclusion criteria; however, these criteria are intended for classification purposes and not for confirming a diagnosis.^1,6

In the kidneys, TIN is the most common manifestation of IgG4-RD. Although plasma cell–rich infiltration is a hallmark of IgG4-RD, it could also be associated with multiple disease processes, including ANCA-associated vasculitis, Sjogren syndrome, IgM plasma cell interstitial nephritis, TIN with uveitis syndrome, sarcoidosis, and SLE.⁷ Thus, it is fundamental that these patients are evaluated considering overall clinical presentation along with pathological findings. Lymphoma and monoclonal cell infiltration should also be ruled out with immunohistochemistry or immunofluorescence.⁷ Certain serum laboratory findings can aid in diagnosis. Approximately 90% of patients with IgG4-RD who present with TIN have elevated serum IgG and IgG4.⁷ Over half of these patients, including our case, demonstrate hypocomplementemia.⁷ These laboratory findings are more commonly associated with kidney involvement than with other organs in IgG4-RD.⁷

Management of IgG4-Related Kidney Disease

The pathogenesis of IgG4-RD entails activated B cells and plasmablasts as well as T-lymphocytes; therefore, IgG4-RD is usually responsive to immunosuppressive treatment, and early intervention can prevent significant organ damage.¹ Glucocorticoid monotherapy has a well-established efficacy,¹ typically starting with a high dose (i.e., 0.6 mg/kg) for 2–4 weeks, followed by tapering within the subsequent 8 weeks.⁸ Approximately 20% of patients can relapse upon tapering steroids. Dwindling levels of serum complements could be a valuable biomarker for predicting relapse in patients with IgG4-RD–presenting TIN.³

While glucocorticoids remain the first-line treatment of IgG4-RD, upon tapering, most patients will experience a disease relapse. B-cell depletion with rituximab, a monoclonal anti-CD20, or newer agents such as inebilizumab are effective to prevent disease relapses.^9,10 Notably, in the MITIGATE trial of inebilizumab versus placebo, kidney disease was recorded in over one third of trial participants. The most commonly affected organs in the MITIGATE trial included the pancreas (51.9%), lymph nodes (49.6%), submandibular glands (48.9%), and lacrimal glands (38.5%), followed by kidney involvement reported in 34.1% of patients.¹⁰ Earlier initiation of B-cell depletion should be considered if there are contraindications to higher cumulative doses of glucocorticoids or patients develop glucocorticoid-related side effects.⁹ We opted for treatment with steroids, given the anticipated short duration of the therapy, while closely monitoring the patient's comorbidities. The patient demonstrated excellent tolerance to the treatment, with his weight remaining unchanged and a hemoglobin A1c of 6.3 recorded 2 months after the complete cessation of steroid therapy.

Patient Protections

The authors declare that they have obtained written consent from the patient reported in this article.

Supplementary Material

cjasn-20-588-s001.pdf ^{(1.4MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C181.

Funding

None.

Author Contributions

Data curation: Vince Ha.

Supervision: Sayna Norouzi.

Validation: Hae Yoon Grace Choung, Vince Ha, Sayna Norouzi.

Visualization: Sayna Norouzi.

Writing – original draft: Niloufar Ebrahimi.

Writing – review & editing: Amir Abdipour, Hae Yoon Grace Choung, Orhan Efe, Andreas Kronbichler, Sayna Norouzi, Arvind Singh, William Whittier.