IgG4-Related Kidney Disease: Why It’s Missed and How to Treat It

In an interview with Pharmacy Times, Jai Radhakrishnan, MD, MBBS, MS, FASN, professor of medicine at Columbia University Medical Center and clinical director of the nephrology division at NewYork-Presbyterian Hospital, discussed his oral abstract at the American Society of Nephrology’s Kidney Week 2026, in Denver, Colorado, a post hoc subgroup analysis of the phase 3 MITIGATE trial (NCT04540497) of inebilizumab (Uplinza; Amgen) in patients with IgG4-related disease (IgG4-RD) and active kidney involvement.

Radhakrishnan said kidney involvement is often missed because it is largely asymptomatic, can mimic lymphoma, kidney cancer, or lupus, and gets fragmented across specialties; diagnosis requires biopsy with IgG4 staining. In MITIGATE, 40 of 135 patients had active kidney disease at baseline. In this subgroup, inebilizumab reduced flare risk by 92% vs placebo, and 57% of treated patients reached flare-free, steroid-free complete remission vs 21% with placebo. Patients receiving inebilizumab needed a mean of 58 mg of additional prednisone over the year versus about 1755 mg with placebo. Because every flare leads to nephron loss, he said, preventing flares protects long-term kidney function, though the findings are exploratory.

For pharmacists, he emphasized screening for hepatitis B, tuberculosis, and immunoglobulin levels before therapy, updating vaccines beforehand, infusion premedication, and monitoring for infections, including urinary tract infections.

Pharmacy Times: Why is kidney involvement in IgG4-related disease so often missed or misdiagnosed?

Jai Radhakrishnan, MD, MBBS, MS, FASN: Kidney disease is mostly asymptomatic. The most common kidney lesion is tubulointerstitial nephritis, which presents as a slowly rising creatinine, usually a bland urine, and no other symptoms. The kidney involvement gets noticed when the provider sends the kidney function tests on routine labs in a patient with systemic symptoms. Other kidney presentations may be seen on imaging; cortical lesions or a solitary renal mass can be mistaken for lymphoma, pyelonephritis, or even kidney cancer, and some patients have lost a kidney to surgery for suspected malignancy.

From a lab standpoint, high IgG and low complement levels may point clinicians toward other autoimmune diseases, [such as] lupus. Retroperitoneal fibrosis causing hydronephrosis may get treated by a urologist with urinary diversion procedures, and the systemic disease behind it never gets picked up.

Lastly, there is the problem of fragmentation, which is seen with any multisystem disease (problem connecting the dots). In our analysis of the MITIGATE placebo arm, kidney flares often came with disease in other organs, most commonly the salivary glands, lymph nodes, pancreas, and biliary tree, and new disease sometimes showed up in organs that had never been affected before.

The only way to confirm IgG4-RD is to do a biopsy. Even then, the physician needs to ask for IgG4 staining.

Pharmacy Times: What do the MITIGATE kidney subgroup findings mean for patients with IgG4-related disease?

Radhakrishnan: In MITIGATE, 40 of 135 patients, roughly 30%, had active kidney disease at baseline. Thus, this is not an incidental issue. The results were important in that inebilizumab cut the risk of flare by 92% compared with placebo. Only 2 of 21 patients on inebilizumab flared over the year, versus 12 of 19 on placebo, and neither of those two flares involved the kidney. The annualized flare rate fell by about 90%. And 57% of treated patients reached flare-free, steroid-free complete remission at one year, compared with 21% on placebo.

The other finding is that placebo patients with kidney involvement flared a bit sooner than the overall placebo group, with a median of about 211 days versus 246. Kidney patients may be a higher-risk group, and they seem to benefit at least as much from treatment. In terms of kidney outcomes, every flare leads to nephron loss. In the placebo arm, creatinine, BUN, and proteinuria all rose during kidney flares and improved once the flare was treated. Although reassuring in the short term, repeated rounds of inflammation lead to fibrosis, which does not reverse. Preventing flares is really about protecting kidney function over the long run. This is noted in many other autoimmune/inflammatory kidney diseases.

There are limitations to the study. This was a post hoc analysis of 40 patients, so the findings are exploratory.

Pharmacy Times: How could inebilizumab help reduce reliance on corticosteroids in these patients?

Radhakrishnan: Steroids clearly work well in IgG4-related disease as initial therapy. The problem is that as the dose comes down, many patients flare, and many end up on steroid maintenance for years. Long-term steroids can lead to diabetes, bone loss, infections, weight gain, and cataracts. In MITIGATE, all patients were treated with the same 8-week steroid taper. Subsequently, in the kidney subgroup, patients on inebilizumab needed an average of 58 mg of additional prednisone over the year. Patients on placebo needed about 1,755 mg, which is a very significant difference.

The interpretation is that steroids do play an important role for induction, with B-cell depletion doing the maintenance work.

Pharmacy Times: What should pharmacists monitor and counsel on for patients receiving inebilizumab?

Radhakrishnan: Before the first dose, patients should be screened for hepatitis B, quantitative immunoglobulin levels, and tuberculosis. Regarding vaccines, live vaccines are contraindicated during treatment, so the time to update immunizations is before therapy starts. Every infusion should be preceded by premedication with a corticosteroid, an antihistamine, and an antipyretic, with observation during/post-infusion.

Infections need to be looked for. Check for active infection before every dose and hold the infusion if the pt shows signs of infection. In our kidney patients, urinary tract infections were more common with inebilizumab than with placebo, 19% versus 5%. Lymphopenia was also frequent. Patients should know to report fever, urinary symptoms, or respiratory symptoms early. Over time, immunoglobulin levels should be monitored, since they can decline with continued treatment. Women who could become pregnant should talk about family planning, because B-cell depletion can affect the infant.

Pharmacy Times: Is there anything else you’d like to add?

Radhakrishnan: First, I’d ask clinicians to keep this diagnosis in mind. Think of it in an older male with unexplained interstitial nephritis, high IgG, low complement, or a history of pancreatitis or salivary gland swelling—always ask the pathologist for IgG4 staining in such patients. Secondly, there are many unanswered questions: How long to continue therapy, how inebilizumab compares with CD-20 depleting therapy (eg rituximab), and what are the long-term kidney outcomes.