Lupus Nephritis from Bench to Bedside

Applying the latest ACR guideline to the diagnosis & treatment of lupus nephritis

CHICAGO—During ACR Convergence 2025, three lupus experts presented a session titled, Bench to Bedside in the Diagnosis and Treatment of Lupus Nephritis. The talk highlighted new biomarkers for lupus nephritis and a practical approach on how to apply the 2024 ACR Guideline for the Screening, Treatment and Management of Lupus Nephritis to patients refractory to treatment.

Novel Urinary Biomarkers

Dr. Fava

Andrea Fava, MD, assistant professor of medicine and director of Lupus Translational Research at Johns Hopkins School of Medicine, Baltimore, spoke on applying promising new data from the AMP program clinically.

Lupus nephritis carries a 20% risk of end-stage kidney disease within 20 years. Current practice patterns include serial screening for proteinuria. “We react with a kidney biopsy if proteinuria is above a ‘magic threshold’ of 500 mg per 24 hours,” Dr. Fava said.

However, the use of proteinuria as a measure of disease activity has several limitations. Dr. Fava explained how proteinuria has been shown to have no correlation with inflammation, is a lagging indicator and cannot distinguish treatable inflammation from chronic damage.

Michelle Petri, MD, MPH

A plenary given at ACR Convergence 2025 by Michelle Petri, MD, from Johns Hopkins School of Medicine demonstrated among patients with SLE and proteinuria from 0.25–0.499g/g nearly half had evidence of actionable lupus nephritis (21% had Class III/IV +/- V and 25% with Class V) even despite proteinuria below the 500 mg threshold.¹

Dr. Fava also highlighted in a study of patients with systemic lupus erythematosus (SLE) nephritis treated for three years and in complete renal remission who underwent repeat kidney biopsy. In the study, 20% of patients in proteinuric remission for greater than one year still had persistent histologic activity.²

Dr. Fava discussed his work in urine proteomics, quantifying over 1,000 proteins in the urine and identifying ones that correlated with intra-renal immunologic activity.³ Urinary biomarkers of immunologic response, such as interleukin 16, CD163 and CD206, decreased in responders and predicted one-year response, suggesting effective immunosuppression reduces intrarenal inflammation early.

Many urine protein biomarkers outperform proteinuria in predicting poor long-term outcomes (Fig. 1, below). Urinary tenascin C was a novel marker discovered—and involved in matrix remodeling—whose persistence along with other markers emerged as a robust predictor of kidney function loss in lupus nephritis. A 12-protein panel and urinary proteomics-based score were presented, which outperformed UPCR and helped stratify high-risk individuals, regardless of the proteinuria response.⁴

“Since these urinary biomarkers parallel intrarenal inflammation and predict future GFR, they could detect early treatment responses or failures, and in a few years, allow us to make earlier treatment changes in nephritis patients more precisely,” Dr. Fava said. “This can help inform tapering of immunosuppression, serve as surrogate endpoints in clinical trials and better identify lupus nephritis before proteinuria.”

Approach to Patients with Inadequate Response

Dr. Maria Dall’Era

Next, Maria Dall’Era, MD, Jean S. Engleman Distinguished Professor of Medicine and chief of the Division of Rheumatology at the University of California, San Francisco, presented an approach on how to apply the 2024 ACR Lupus Nephritis Guideline to patients who experience an inadequate response to treatment or have refractory lupus nephritis.

The guideline defines inadequate renal response as no complete response or partial response by 6–12 months. Refractory lupus nephritis is defined as failing two different, appropriate, six-month therapy courses.⁶

Dr. Dall’Era reviewed a checklist of key considerations when encountering patients with lupus nephritis with inadequate response. These include assessing adherence (i.e., therapeutic drug level monitoring), confirming appropriate dosing, confirming accuracy of the UPCR, assess for non-immunologic mechanisms and consider alternative diagnoses or repeat kidney biopsy.

“Medication dose and patient adherence should be assessed regularly throughout treatment, particularly as an important first step in evaluating inadequate response or refractory lupus nephritis,” Dr. Dall’Era said.

Non-immunologic mechanisms that can cause ongoing proteinuria due to hyperfiltration or CKD progression include high salt intake, being overweight, hypertension and high protein diet. “Your patient might have an increased level of proteinuria due to hyperfiltration from a high salt meal the night before,” she said.

A repeat kidney biopsy can also be informative, particularly to exclude alternative etiologies of kidney dysfunction, such as thrombotic microangiopathy, other vascular lesions (arteriosclerosis), aPL nephropathy, lupus podocytopathy or fibrosis or chronicity without ongoing activity. Repeat kidney biopsy can be considered if there is partial response, a presumptive flare, CKD progression, or prior to withdrawal of immunosuppression.⁷

Dr. Dall’Era also mentioned complement-mediated thrombotic microangiopathy (TMA), formerly termed atypical hemolytic uremic syndrome. “It is important to recognize, as it is being increasingly diagnosed amongst our patients with SLE— and it requires anti-complement therapy in addition to standard therapies for SLE,” she said.

Treating Refractory Lupus Nephritis

Dr. Anca D. Askanase

Anca Askanase, MD, professor of medicine at Columbia University School of Medicine, New York, presented the final segment on therapeutic options for refractory lupus nephritis. Per the ACR Guideline, for patients with SLE who have proteinuria of >0.5g (or a UPCR >0.5g/g) and/or impaired kidney function not otherwise explained, they conditionally recommend performing a percutaneous kidney biopsy.

For patients with active, newly diagnosed or flare of Class III/IV (with or without concomitant Class V) lupus nephritis, the guideline conditionally recommends therapy with a triple immunosuppressive regimen consisting of pulse IV glucocorticoids followed by oral glucocorticoid taper plus: 1) mycophenolic acid analog (MPAA) plus belimumab; 2) MPAA plus calcineurin inhibitor (CNI); or 3) EuroLupus low-dose cyclophosphamide (CYC) plus belimumab followed by MPAA substituted for CYC after CYC is complete (fig. 2, below).

“An MPAA-based regimen is preferred over a cyclophosphamide-based regimen,” Dr. Askanase said. For high-grade proteinuria (≥3g/g), MPAA plus CNI is preferred, over belimumab-based regimen. For patients with significant extra-renal manifestations, belimumab is preferred over CNI. Given CYC and CNI was not studied in randomized controlled trials, it was not recommended as part of the guideline.

Dr. Askanase finally briefly reviewed the data from the randomized controlled trials of voclosporin (AURORA 1), belimumab (BLISS-LN) and obinutuzumab (NOBILITY). In subgroup analyses of the voclosporin trial, patients with class III and IV lupus nephritis had better odds ratio response, as compared to those with pure class V.⁸

For belimumab (BLISS-LN), subgroup analyses suggested patients with class III or IV lupus nephritis did better than Class III + V or IV + V and better than pure Class V.⁹ “Additionally, patients with high-grade proteinuria [UPC >3] did less well than those with lower proteinuria,” she said. “In contrast, in the obinutuzumab subgroup analysis, patients with higher grade proteinuria [UPC >3] did better than those with lower grade proteinuria.”

In Summary

This session provided attendees a practical approach to the application of the 2024 ACR Guideline for Lupus Nephritis. The role of urinary protein biomarkers to better predict treatment response and prognosis was discussed, which may be entering our clinics in a few short years.

“We define response to lupus nephritis in a proteinurocentric way,” Dr. Fava said. “Better biomarkers are coming. In the meantime, don’t let proteinuria fool you.”

Mithu Maheswaranathan, MD, is an assis­tant professor of medicine in the Division of Rheumatology at Duke University School of Medicine, Durham, N.C.

References

1. Petri M, Fava A, Atta M, et al. Redefining when to biopsy the kidney in patients with SLE [abstract: 0772]. Arthritis Rheumatol. 2025;77(suppl 9).
2. De Rosa M, Azzato F, Toblli JE, et al. A prospective observational cohort study highlights kidney biopsy findings of lupus nephritis patients in remission who flare following withdrawal of maintenance therapy. Kidney Int. 2018 Oct;94(4):788–794.
3. Fava A, Buyon J, Magder L, et al. Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis. JCI Insight. 2024 Jan 23;9(2):e172569.
4. Lee CY, Taghavi S, Zhang S, et al. Urinary Tenascin C Predicts Kidney Function Loss in Lupus Nephritis [abstract 0851]. Arthritis Rheumatol. 2025 Oct;77(suppl 9).
5. Fava A, Concoff A, O’Malley T, et al. A urinary biomarker panel to predict the probability of histologically active lupus nephritis [abstract 1642]. Arthritis Rheumatol. 2024 Oct; 76(suppl 9).
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7. Anders HJ. Re-biopsy in lupus nephritis. Ann Transl Med. 2018 Nov;6(suppl 1):S41.
8. Arriens C, Teng YKO, Ginzler EM, et al. Update on the efficacy and safety profile of voclosporin: An integrated analysis of clinical trials in lupus nephritis. Arthritis Care Res. 2023 Jul;75(7):1399–1408.
9. Rovin BH, Furie R, Teng YKO, et al. A secondary analysis of the belimumab international study in lupus nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. Kidney Int. 2022 Feb;101(2):403–413.
10. Furie RA, Rovin BH, Garg JP, et al. Efficacy and safety of obinutuzumab in active lupus nephritis. N Engl J Med. 2025 Apr 17;392(15):1471–1483.