Renal biopsy has been the gold standard for diagnosing and managing lupus nephritis (LN), but repeat biopsy exposes patients to another invasive procedure. Better noninvasive means for monitoring patients’ disease are needed, but a new study presented at the National Kidney Foundation’s 2022 Spring Clinical Meetings corroborates other recent research that current clinical biomarkers cannot reliably predict histologic class or activity of LN.

“Our findings suggest repeat biopsies did not show worse LN class or activity despite worsening of certain biomarkers when renal function was preserved,” investigators Kelly Liang, MD, of the University of Kansas Medical Center in Kansas City, and colleagues wrote. “Further studies are needed to determine which changes in clinical biomarkers are predictive of worse LN class and disease activity on repeat renal biopsy. There is an urgent need for novel noninvasive biomarkers to predict LN flares to guide therapy.”

Their findings are based on a study of 37 patients with LN, of whom 3 underwent a repeat biopsy. Of 37 LN patients, 31 had baseline creatinine values at initial biopsy. Biomarkers showed improvement in all patients between baseline and 12 months (mean creatinine, double-strand DNA antibodies, erythrocyte sedimentation rate, and C-reactive protein decreased and complement C3 and complement C4 increased). In the 3 patients who had a second renal biopsy, at least 3 clinical biomarkers were worse at the time of biopsy.

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Of the 3 patients, 2 had normal creatinine at repeat biopsy. All 3 patients had an initial biopsy showing combined proliferative and membranous (class 5) LN. Proliferative LN class fluctuated thereafter. Activity and chronicity indices also varied. In patient 1, LN class changed from 4+5 at diagnosis to 3+5, 3+5, 4+5, and 3+5 over 4 repeat biopsies. In patient 2, LN class changed from 3+5 to 2+5 on repeat biopsy. In patient 3, LN class changed from 2+5 to 3+5.

In a study of 220 patients with LN, published in Rheumatology, Andrea Fava, MD, of Johns Hopkins University in Baltimore, Maryland, and colleagues found that conversion from proliferative to membranous LN — or vice versa — occurs frequently. Patients with pure class 5 disease at first biopsy converted to proliferative LN in 41% of cases, the investigators reported. Conversely, among patients who had pure class 5 at a repeat biopsy, 52% previously had proliferative LN. New onset end-stage kidney disease (ESKD) occurred within 2 years in 9% of patients with pure class 5 in a repeat biopsy.

“[LN class conversion] can occur at any time in the course of disease, limiting the prognostic value of the first biopsy,” Dr Fava’s team pointed out.

In a paper published in the Clinical Journal of the American Society of Nephrology, Isabelle Ayoub, MD, and Brad H. Rovin, MD, of The Ohio State University in Columbus, Ohio, summarized the challenge of managing LN after the initial episode, which is generally informed by a kidney biopsy. This is difficult because proteinuria and estimated glomerular filtration rate, the currently available clinical biomarkers of kidney disease activity, “cannot accurately distinguish between ongoing inflammatory injury and chronic kidney damage.”

Their paper described the findings of a case series showing that blood tests for complement system fragments and autoantibodies did not accurately predict LN histology in 3 patients.

“Identifying and validating novel biomarkers that will help in the stratification, prognostication, and management of lupus nephritis are essential,” they wrote.

Although current clinical biomarkers fall short in their ability to predict LN activity, some progress is being made in identifying such biomarkers. For example, Dr Fava and collaborators analyzed the urinary proteomic profiles of 30 patients with LN and found that interleukin-16 (IL-16) was the second most expressed cytokine by most infiltrating immune cells in LN and it was found at key sites of kidney injury. In addition, treatment response correlated with a reduction in urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties.

“These findings implicate IL-16 in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker,” Dr Fava’s team concluded in a paper published in Arthritis & Rheumatology. If validated by other research, this study can help in designing a “liquid biopsy” of a patient’s urine sample, Dr Fava discussed in a video interview on the study.

Meanwhile, clinicians continue to wrestle with the appropriate proteinuria threshold for initial renal biopsy. A prospective study published in Rheumatology by corresponding author Jill P. Buyon, MD, of the NYU Grossman School of Medicine, New York, New York, and colleagues provides some guidance. In a study of 275 patients with LN, they found a high incidence of proliferative and membranous LN among those with low proteinuria. The vast majority of patients (92%) had class 3, 4, 5 or mixed LN. Urinary protein to creatinine ratio (UPCR) was less than 1.0 g/g in 54 patients and more than 1.0 g/g in 221 patients. The “low” UPCR group with class 3, 4, and/or 5 LN had a median activity index of 4.5 and a chronicity index of 3, despite 39% of these patients having an inactive sediment or normal serologies. Of this group, 79% had a UPCR of less than 0.5 g/g at 1 year. “These data support renal biopsy at thresholds lower than a UPCR of 1,” Dr Buyon’s team stated.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original references for a full list of authors’ disclosures.


  1. Liang L, Landsittel D, Li Y, Mongelli C, Bastacky S. Are changes in clinical biomarkers associated with changes in lupus nephritis pathology on repeat biopsy? Presented at the National Kidney Foundation 2022 Spring Clinical Meetings, Boston, Massachusetts, April 6-10, 2022. Poster 321.
  2. Fava A, Fenaroli P, Rosenberg A, et al. History of proliferative glomerulonephritis predicts end stage kidney disease in pure membranous lupus nephritis. Rheumatology. Published online October 19, 2021. doi:10.1093/rheumatology/keab775
  3. Ayoub I, Rovin BH. The use of serological tests in the care of patients with lupus nephritis. Clin J Am Soc Nephrol. 2022 Feb;17(2):305-307. doi:10.2215/CJN.13431021
  4. Fava A, Rao DA, Mohan C, et al. Urine proteomics and single cell transcriptomics identify IL-16 as a biomarker for lupus nephritis. Arthritis Rheumatol. 2021. doi:10.1002/art.42023
  5. Fava A. Urine proteomics and single cell transcriptomics identify IL-16 as a biomarker for lupus nephritis. Johns Hopkins Medicine. 2021. Accessed on April 15, 2022 at
  6. Carlucci PM, Li J, Fava A, et al. High incidence of proliferative and membranous nephritis in SLE patients with low proteinuria in the Accelerating Medicines Partnership. Rheumatology. Published online February 25, 2022. doi:10.1093/rheumatology/keac067