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The International Society of Nephrology/Renal Pathology Society (ISN/RPS) lupus nephritis (LN) classification is under reconsideration, given challenges with inter-rater reliability and resultant inconsistent relationship with treatment response. Integration of molecular classifiers into histologic evaluation can improve diagnostic precision and identify therapeutic targets. This study described the relationship between histological and molecular phenotypes and clinical responses in LN. Renal compartmental mRNA abundance was measured in 54 biopsy specimens from LN patients and correlated to ISN/RPS classification and individual histologic lesions. A subset of transcripts was also evaluated in sequential biopsies of a separate longitudinal cohort of 36 patients with paired samples obtained at the time of flare and at follow up. Unsupervised clustering based on mRNA abundance did not demonstrate a relationship with the (ISN/RPS) classification, nor did univariate statistical analysis. Exploratory analyses suggested a correlation with individual histologic lesions. Glomerular FN1 (fibronectin), SPP1 (secreted phosphoprotein 1), and LGALS3 (galectin 3) abundance correlated with disease activity and changed following treatment. Exploratory analyses suggested relationships between specific transcripts and individual histologic lesions, with the important representation of interferon-regulated genes. Our findings suggested that the current LN classification could be refined by the inclusion of molecular descriptors. Combining molecular and pathologic kidney biopsy phenotypes may hold promise to better classify disease and identify actionable treatment targets and merits further exploration in larger cohorts.

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) lupus nephritis (LN) classification is under reconsideration, given challenges with inter-rater reliability and resultant inconsistent relationship with treatment response. Integration of molecular classifiers into histologic evaluation can improve diagnostic precision and identify therapeutic targets. This study described the relationship between histological and molecular phenotypes and clinical responses in LN. Renal compartmental mRNA abundance was measured in 54 biopsy specimens from LN patients and correlated to ISN/RPS classification and individual histologic lesions. A subset of transcripts was also evaluated in sequential biopsies of a separate longitudinal cohort of 36 patients with paired samples obtained at the time of flare and at follow up. Unsupervised clustering based on mRNA abundance did not demonstrate a relationship with the (ISN/RPS) classification, nor did univariate statistical analysis. Exploratory analyses suggested a correlation with individual histologic lesions. Glomerular FN1 (fibronectin), SPP1 (secreted phosphoprotein 1), and LGALS3 (galectin 3) abundance correlated with disease activity and changed following treatment. Exploratory analyses suggested relationships between specific transcripts and individual histologic lesions, with the important representation of interferon-regulated genes. Our findings suggested that the current LN classification could be refined by the inclusion of molecular descriptors. Combining molecular and pathologic kidney biopsy phenotypes may hold promise to better classify disease and identify actionable treatment targets and merits further exploration in larger cohorts.

Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus (SLE) and a major driver of morbidity and mortality. Proliferative forms of LN are typically managed with immunosuppressive therapy, with the aim of attenuating renal inflammation and preserving kidney function.1 Unfortunately, despite several clinical trials of LN conducted over the past 30 to 40 years, none has translated into new Food and Drug Administration (FDA)−approved therapies. Multiple issues in clinical trial design likely contributed to these negative outcomes, such as confounding background medications (especially high-dose glucocorticoids), trial duration, and the choice of trial endpoints. Most trials incorporated composite endpoints to define clinical response based on proteinuria and kidney function. Kidney function was generally assessed as a change in estimated glomerular filtration rate or serum creatinine (sCr) as compared to the patients’ values at trial entry.2 Thresholds were then chosen to define the extent of the clinical response (complete, partial, or no response). However, evidence supporting these thresholds is not robust. For example, most studies used a proteinuria cutoff of <0.3 to 0.5 g/d to describe complete response; however, a post hoc analysis of 2 large LN trials demonstrated that proteinuria levels of <0.7 to 0.8 g/d after 1 year of treatment predicted favorable long-term kidney outcomes, suggesting that a less stringent proteinuria cutoff may be reasonable. Similarly, an sCr value <15% above baseline has often been required for complete response in LN trials.S1−S5 However, day-to-day variations in sCr measurements are routinely observed in clinical practice in patients with and without chronic kidney disease, even when measured within a 24-hour period.3 To determine a threshold of kidney function that accounts for expected day-to-day variations, we investigated the fluctuation of sCr in a cohort of patients with LN who were complete renal responder