Review Highlights Urgency for New Lupus Nephritis Research

Outcomes for patients with lupus nephritis, which can lead to irreversible renal impairment, can be improved with better measures to evaluate risk and detect early disease, along with new treatments, say researchers writing in Nature Reviews Rheumatology.

In this review, Anne Davidson, M.B.B.S, and Naomi Maria, Ph.D., of the Feinstein Institute for Medical Research in Manhasset, New York, discuss avenues to diagnostic and therapeutic advances for patients with lupus nephritis, a condition that remains an unmet medical need.

In patients with lupus nephritis, which affects around 80 percent of adolescents and 40 percent of adults with systemic lupus erythematosus (SLE), the risk of end-stage renal disease (ESRD) has not improved in the United States in the past 20 years, with immunosuppressive therapies failing to reverse  the condition in more than half of treated patients. The situation in compounded by poor access to health care and poor treatment adherence.

DIAGNOSIS

While genetic factors confer risks of lupus nephritis development and progression, the condition cannot be currently diagnosed with genetic testing. Several genetic polymorphisms are associated with the onset of lupus nephritis, but each polymorphism contributes only a small increase to risk. Further, methods are needed to detect early glomerular injury so that therapies that preserve glomerular structure and function in patients with lupus nephritis can be used. Meanwhile, many types of immune cells are found in the kidneys of patients with lupus nephritis, and both single-cell and enhanced microscopic analyses of renal tissues have produced new information about the progression to chronic kidney disease (CKD), but a better understanding of how each infiltrating cell type contributes to renal injury is needed.

Lupus nephritis is currently diagnosed with biopsy prompted by a change in the patient’s clinical status, such as hematuria.

However, “analysis of renal tissue is not always an accurate indicator of renal outcome, and samples taken by biopsy from patients in full clinical remission can show ongoing inflammation,” the authors wrote. “Meeting the need for effective therapies in lupus nephritis requires biomarkers for disease risk, as well as for response to therapy.”

Clinical data from patients with lupus nephritis can be integrated with biomarkers, including changes in circulating cells, inflammatory mediator concentrations, urinary proteins or molecular signatures in renal tissue, to help predict prognosis and treatment response. A decrease in proteinuria to <0.7–0.8 g/dl by one year after diagnosis is currently the best predictor of long-term outcome.

See "Treatment" next page.

TREATMENT

Standard immunosuppressive treatments have a high non-response rate in lupus nephritis and no biologic drugs are approved for the condition. However,  belimumab (Benlysta, GSK), which is approved for the treatment of SLE, is on track for regulatory submission for lupus nephritis after meeting its primary and secondary endpoints in a late-stage trial.

Meanwhile, the IL-12–IL-23 inhibitor ustekinumab and the type I interferon receptor antagonist anifrolumab have shown benefit in SLE, with a trial of the latter in lupus nephritis progressing. The combination of mycophenolate mofetil with either calcineurin antagonists tacrolimus or voclosporin has also shown potential, while the B cell-depleting agent obinutuzumab has achieved F.D.A. breakthrough status for development and review on the basis of a successful phase 2 study in lupus nephritis.

In addition to these immune-modulating therapies, an improved understanding of tubulointerstitial injury leading to CKD along with renal repair are leading to potential strategies aiming to preserve renal function and prevent fibrosis. Moreover, since patients with SLE have a high risk of premature cardiovascular disease, and CKD increases cardiovascular risk, lifestyle modification, angiotensin-converting enzyme inhibitors, statins and hypertension control to decrease this risk should be tested in patients with lupus nephritis.

Further, since poor outcome in lupus nephritis is associated with non-white patient ethnicity in the United States, the socioeconomic disparities that might affect lifestyle choices and medication adherence need to be understood and addressed by clinicians.

REFERENCE

Naomi I. Maria, Anne Davidson. “Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy.” Nature Reviews Rheumatology. March 19, 2020. DOI: https://doi.org/10.1038/s41584-020-0401-9