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Evaluating, Diagnosing, and Managing IgG4-RD in Nephrology

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Released: October 18, 2026

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IgG4-related disease (IgG4-RD) is a systemic immune-mediated condition that can affect the kidneys and other organs, potentially leading to progressive inflammation, fibrosis, and irreversible organ damage. Diagnosing and managing IgG4-RD requires a systematic and multidisciplinary approach to patient care. Learn how IgG4-RD generally presents in nephrology, the importance of ruling out key mimicking diseases and assessing multiorgan involvement, as well as evidence-based treatment strategies to prevent relapse and irreversible organ damage.

Jai Radhakrishnan
Jai Radhakrishnan
IgG4 RD in Nephrology

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IgG4-related disease (IgG4-RD) is a systemic, fibroinflammatory condition that can affect almost every organ in the body, including the kidneys. Therefore, it is essential that healthcare professionals (HCPs) in nephrology recognize IgG4-RD early, accurately diagnosis it, and appropriately treat patients to prevent irreversible organ damage and improve quality of life.

IgG4-RD was first recognized in patients with type 1 autoimmune pancreatitis. Over the years, case studies have reported multiorgan involvement that often goes beyond the pancreas to the lymph nodes, salivary glands, kidneys, lungs, and aorta, among others.

What is shared across multiorgan involvement is the histology of IgG4-RD. You will often see dense lymphoplasmacytic infiltration or mass-forming lesions with inflammation and storiform fibrosis on biopsy. Another criterion used to diagnose this disease is a preponderance of IgG4-staining plasma cells in the involved organs. But every organ has different thresholds regarding how many of these cells are needed to suspect IgG4-RD.

HCPs should biopsy the involved organ to confirm the diagnosis of IgG4-RD. There are also additional clues like inflammatory biomarkers, organ dysfunction biomarkers, and raised IgG levels that can support this diagnosis. Although these diagnostic criteria help HCPs suspect or establish a high probability of disease, an IgG4-RD diagnosis ultimately rests on biopsy in most cases.

Ruling Out Differential Diagnoses:
When it comes to ruling out differential diagnoses to confirm IgG4-RD, the biggest concern, particularly with mass-forming lesions, is malignancy. Many times, an organ like a kidney is preemptively removed because malignancy is suspected, only for HCPs to find out that the issue was IgG4-RD.

Other differential diagnoses include infection and vasculitis. Many infectious diseases and vasculitis disorders can overlap with or confuse the clinical picture in patients with IgG4-RD. This is why HCPs should always obtain a serum IgG4 level, as it provides a good baseline for monitoring disease activity. The caveat here is that many patients, including those with predominantly fibrotic disease in the retroperitoneum and biliary tract, may have normal IgG4 levels. IgG4 levels can also be elevated in other conditions, including certain autoimmune diseases and malignancies.

Regardless of patients’ IgG4 levels, it is the pattern that matters most, not the number. Key histologic features of IgG4-RD that pathologists should look for include storiform fibrosis, obliterative phlebitis, and dense infiltrate of IgG4-positive plasma cells. These are essential clues that bring IgG4-RD to the forefront and rule out your differential diagnoses.

Moving Toward Steroid-Sparing Therapy:
Historically, most patients with IgG4-RD were treated with glucocorticoid therapy, and treatment courses varied depending on the organs involved and patients’ response. Many actually required long-term glucocorticoid therapy to achieve disease control, but the expected toxicities with prolonged use do not make this treatment strategy ideal.

Then came B-cell–depleting therapy. Rituximab was first used off label after showing efficacy in managing IgG4-RD, leading to a reduction in steroid therapy exposure for patients. Inebilizumab was later approved in April 2025 as the first therapy indicated to treat IgG4-RD in adults.

Despite this, most patient cases require glucocorticoid therapy at induction to help bridge them to systemic therapy. The idea here is to control patients’ acute inflammation with glucocorticoids and use B-cell–depleting therapy as the main maintenance approach to consolidate remission treatment and prevent relapse.

The availability of systemic therapy has truly changed the way we manage this chronic disease because steroid-sparing treatment is crucial. B-cell–depleting therapy provides a way to reduce or potentially avoid prolonged steroid exposure.

Monitoring Disease Activity and Treatment Response:
HCPs should monitor patients’ inflammatory biomarkers, including complement, C-reactive protein, erythrocyte sedimentation rate, and IgG4 levels, at baseline and during treatment to track response. If these biomarkers are not improving with treatment, the disease may still be active, and HCPs should recalibrate treatment plans. Similarly, if these biomarkers are controlled and eventually start rising again, patients may be at increased risk for relapse.

Depending on the suspected organs involved, imaging also plays an important role in diagnosing and monitoring treatment response. If patients have mass-forming lesions, shrinking these with treatment should be a priority.

From a nephrology perspective, monitoring kidney function with the estimated glomerular filtration rate, proteinuria, and urinalysis is critical. However, it can be difficult to distinguish a chronic fibrotic process from ongoing inflammation. In select cases, especially when patients’ kidney function is not improving, a repeat biopsy may be necessary to determine whether the current therapy is controlling the inflammation. This can help HCPs determine whether patients should stop, continue, or intensify their therapy.

Importance of Preserving Quality of Life:
Although there are no good long-term studies on quality of life, HCPs must ensure that patients with a delayed diagnosis, including those at high risk of relapse, do not develop irreversible organ damage due to the fibrotic nature of this disease. This can include biliary strictures, chronic kidney disease, or retroperitoneal fibrosis that leads to chronic obstruction. These complications can significantly affect patients’ quality of life.

This is why it is essential to not only treat IgG4-RD early and aggressively to help patients achieve remission but to prevent relapse through careful monitoring and treatment adjustments.

Leveraging Multidisciplinary Care to Ensure Access:
IgG4-RD is truly a multidisciplinary disease. If nephrology is controlling patients' kidney disease and they develop salivary gland or ocular involvement, worsening liver function tests, and/or respiratory symptoms with abnormal chest imaging, we must involve the appropriate specialists. There are experts for each organ system, and we must identify them and refer patients appropriately.

A multidisciplinary approach can also help in ensuring access to treatment. It is well known that IgG4-RD therapies outside glucocorticoids are expensive. In addition, rituximab is often difficult to obtain for many patients because it is not FDA-approved for this disease. I have sometimes had to resort to using other therapies that may not be as effective, and many patients are consequently kept on glucocorticoid therapy for a long time. A multidisciplinary team can help you link patients to resources so they can access and afford their much-needed therapies.

With the FDA approval of inebilizumab, access to systemic therapy has certainly become easier, too. Hopefully, this will continue to improve as emerging therapies in the pipeline become available.

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How often do you receive referrals for patients with IgG4-RD and kidney involvement? You can get involved in the conversation by answering the poll question and posting a comment below.

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