Lupus nephritis (LN) remains one of the most severe manifestations of systemic lupus erythematosus (SLE), carrying substantial risks of chronic kidney disease, end-stage renal disease, and premature mortality. Historically governed by high-dose corticosteroids and cytotoxic regimens, the therapeutic landscape of LN is undergoing a rapid evolution.

In this interview with Full Stack Medicine, Samir Parikh, MD, Clinical Professor of Internal Medicine in the Division of Nephrology at The Ohio State University, Wexner Medical Center, reviewed the latest therapeutic approvals, emerging pipeline mechanisms, clinical utility of repeat renal biopsies, and strategies for optimizing multidisciplinary collaboration.

The Expanding Armamentarium

The recent FDA approval of obinutuzumab marks a notable milestone in targeted B-cell depletion for LN. Unlike first-generation type 1 anti-CD20 antibodies like rituximab, obinutuzumab exhibits distinct molecular and pharmacodynamic properties that translate into superior clinical efficacy.

“The difference between obinutuzumab and rituximab is greater antibody-dependent cytotoxicity, better B-cell depletion in tissues, and better overall peripheral B-cell depletion,” Dr. Parikh explained. “Obinutuzumab, added to background therapy of mycophenolate and steroid, was superior to standard of care.”

This clinical benefit was established in the phase 3 REGENCY trial, which also offered key mechanistic insights through pre- and post-treatment biopsy substudies. Dr. Parikh highlighted that many patients achieved histologic remission even before complete clinical remission was apparent.

“Sometimes, proteinuria may not come down as fast as the inflammatory injury goes away in some settings, or proteinuria may stay because of other reasons like glomerular sclerosis. The fact that you're arresting the intrarenal inflammation, turning off the disease, and refining that by second biopsy was pretty exciting to see.”

Beyond obinutuzumab, additional agents are undergoing late-stage evaluation. These include anifrolumab, a type I interferon receptor antagonist currently in phase 3 for LN; ianalumab, an anti-BAFF receptor monoclonal antibody that arrests B-cell maturation; and novel agents targeting plasma cells via anti-CD38 mechanisms to deplete the long-lived and short-lived plasma cells responsible for autoantibody production.

Shifting Treatment Paradigms and Cellular Targets

With recent additions to the clinical toolkit—including voclosporin, belimumab, and obinutuzumab—clinicians are operating within an altered treatment paradigm centered on earlier control and steroid-sparing approaches.

“We're using less corticosteroids, which is fantastic for patients, which leads to less side effects and without sacrificing outcomes,” noted Dr. Parikh. “We are moving the needle a little bit with overall clinical response, but we still have some work to do. We're still seeing a 50% complete clinical response rate or less after a year's worth of treatments.”

Because SLE is inherently polyclonal and polygenic, future therapeutic success will likely depend on targeting multiple cell lineages simultaneously. Dr. Parikh pointed to T- and B-cell bispecific antibodies, CAR T-cell therapies, and CAR NK-cell platforms aimed at providing a profound “immune reset.” While autologous CAR T approaches present clinical hurdles regarding toxicity, cost, and lymphodepletion, emerging off-the-shelf allogeneic platforms and bispecific engagers offer promising avenues for broader clinical application.

Navigating the Role of Repeat Kidney Biopsies

While primary renal biopsy remains foundational for confirming LN and excluding secondary etiologies, the indication for repeat biopsies is gaining renewed attention. Routine laboratory biomarkers often fail to differentiate active intrarenal inflammation from chronic irreversible damage.

“Proteinuria can be a biomarker of active disease or chronic disease or both. Complement levels may normalize, but LN can still go on,” Dr. Parikh stated. “Unfortunately, repeating histology and getting histologic information may be helpful to help guide our treatment decisions longitudinally.”

Dr. Parikh outlined three key clinical scenarios where a repeat biopsy provides high diagnostic yield:

Refractory or ambiguous clinical trajectories: When proteinuria fails to improve despite intensive therapy, a repeat biopsy distinguishes unresolved inflammatory activity (which warrants treatment modification) from evolving glomerulosclerosis or concurrent pathology such as thrombotic microangiopathy.
Planned immunosuppression withdrawal: In patients demonstrating sustained clinical response (such as 30 months of stability with at least 12 months of complete clinical remission), repeat histology helps evaluate subclinical activity. Observational data indicate that persistent histologic inflammation at the time of tapering predicts subsequent renal flare.
Pre-pregnancy counseling: Because LN predominantly affects women of childbearing age, clarifying whether residual proteinuria represents active disease or quiescent scarring is critical for assessing maternal-fetal risks prior to conception.

Strengthening Multidisciplinary Care and Access

As treatment algorithms grow more complex, active participation in continuing medical education and multidisciplinary coordination between nephrology, rheumatology, primary care, and pharmacy is essential. Dr. Parikh emphasized that partnering directly with patients to navigate disease education, minimize chronic therapy burdens, and expand access to specialized care remains fundamental to improving long-term outcomes.

Key Takeaways

The FDA approval of obinutuzumab introduces enhanced peripheral and tissue B-cell depletion, demonstrating superiority over standard background therapy in the REGENCY trial.
Histologic resolution often precedes complete clinical proteinuria reduction; repeat biopsies can clarify whether residual proteinuria reflects persistent inflammation or chronic structural damage.
Current therapeutic strategies focus on minimizing corticosteroid exposure while combining targeted biologics to improve complete renal response rates and prevent future flares.
Emerging therapies—including anti-CD38 plasma cell depleters, bispecific T-cell engagers, and CAR cell therapies—aim to address the polygenic, multi-cell nature of SLE through deeper immune resets.
Repeat biopsy should be considered during refractory disease, prior to immunosuppressive withdrawal, and as part of pre-pregnancy planning in female patients.
Coordinated multidisciplinary management and expanded patient access to specialized clinics are crucial to eliminating healthcare disparities in lupus nephritis.

About Dr. Parikh

Samir Parikh, MD, is a Clinical Professor of Internal Medicine at The Ohio State University Wexner Medical Center. He specializes in nephrology, including the treatment of glomerulonephritis, vasculitis, systemic lupus erythematosus, acute kidney injury, and chronic renal insufficiency. Dr. Parikh’s research focuses on identifying new disease biomarkers and optimizing the use of kidney biopsy to personalize management decisions in kidney diseases. He has served as principal investigator for numerous trials of new therapies for lupus nephritis and other glomerular diseases.

Insights Into the Future of Lupus Nephritis Care