The authors of a new article published in Kidney International discussed developments in lupus nephritis (LN) management that could change clinical practice. These include incorporating new immunosuppressive therapies, using kidney biopsies for management and not just diagnosis, applying molecular technologies to interrogate biopsies, and examining novel LN biomarkers.
“This is a unique time for the lupus community,” Brad H. Rovin, MD, of The Ohio State University Wexner Medical Center in Columbus, Ohio, and colleagues wrote. “After years of struggling, two new LN drugs have been approved and additional promising therapies are on the horizon.”
New Immunosuppressive Therapies
The medical community is investigating how best to use newly approved belimumab, a monoclonal antibody that inhibits B cell activating factor, and voclosporin, a calcineurin inhibitor, to treat LN, the authors explained. Currently, there are no biomarkers or patient characteristics to identify which patients will benefit from using a voclosporin- or belimumab-based regimen compared with standard care in proliferative or proliferative plus membranous LN. The long-term safety and efficacy of these drugs are not known yet.
Obinutuzumab, a humanized monoclonal anti-CD20 antibody that may offer more effective B cell depletion, is undergoing testing in a phase 3 randomized controlled trial and may become another option. Anifrolumab, a type 1 interferon receptor antagonist recently approved for moderate to severe systemic lupus erythematosus, is also being evaluated for LN. Reducing or eliminating glucocorticoids is a major goal.
Using Kidney Biopsies in LN Management
Most patients with lupus are considered for a kidney biopsy once proteinuria of 500 mg/d or more persists. Dr Rovin and colleagues believe chronic damage occurs before this threshold and advocated for earlier biopsy and treatment to improve outcomes. Along with diagnosing LN, biopsy may identify podocytopathy and/or thrombotic microangiopathy.
According to the authors, additional kidney biopsies during management could be useful, especially because there may be discordance between proteinuria and LN activity. In patients with ongoing proteinuria, a repeat kidney biopsy showing no renal immune activity may support immunosuppressive treatment withdrawal, they noted. In treatment responders, biopsy findings, such as persistent histologic activity, may help inform the decision to continue therapy.
Molecular Interrogation of the Kidney Biopsy
Routine histologic evaluation of the kidney biopsy does not capture the underlying heterogeneity of LN pathogenesis, according to Dr Rovin and colleagues. Molecular interrogation of the biopsy may provide further insights. The authors discussed the use of regional, single-cell, and spatial transcriptional profiling to characterize the distinct gene expression profiles in responders vs nonresponders to LN treatment.
Several novel candidate biomarkers may prove useful in LN, according to the authors. Plasma cell signatures and CD163 from M2c macrophages reflect LN activity and may be detectable in urine. With respect to novel chronicity and prognostic biomarkers, the pro-inflammatory chemokine monocyte chemotactic protein-1 (MCP-1) may represent the transition from inflammation and fibrosis to chronic kidney damage. Patients unresponsive to treatment also have upregulation of genes encoding extracellular matrix proteins, such as TIMP-1, serine protease inhibitors (serpins), TNF receptors, and collagens. Serpin A3 may correlate with interstitial fibrosis severity. Circulating TNF receptor 2 levels and urinary epidermal growth factor correlate with the chronicity index.
“An understanding that LN is not simply an autoimmune process that involves the kidney, but also a chronic kidney disease that needs immune and non-immune management to preserve kidney function is taking hold,” the authors concluded.
Mejia-Vilet JM, Malvar A, Arazi A, Rovin BH. The lupus nephritis management renaissance. Kidney Int. Published online October 3, 2021. doi:10.1016/j.kint.2021.09.012