25 Molecular signatures in kidney biopsies and their relationship to clinical activity

Abstract

<h3></h3> Initiated to molecularly deconstruct lupus nephritis (LN), the Accelerating Medicines Partnership (AMP) is a public-private consortium involving the National Institutes of Health, pharmaceutical companies, and lupus investigators across fifteen clinical sites collecting urine, blood, skin biopsies, and kidney biopsies from patients with LN. Almost 500 lupus patients have been enrolled in the AMP and their phentopyic data and specimens have been collected and applied to various technologies to provide insights into disease pathogenesis with the aim of facilitating more personalized medicine. Through several phases of AMP (technical preparation, pilot enrollment, and large-scale enrollment), 475 patients undergoing a clinically indicated percutaneous kidney biopsy consented to provide tissue for research. Overall, the rate of serious adverse events was 3.8%, consistent with that reported for standard procedures, supporting the safety of the procedure.¹ The cohort is largely female and minority dominant. For nearly two thirds of the patients, this was a repeat biopsy. It was noted that the level of proteinuria did not predict histology class and most patients with a urine protein/creatinine ratio (UPCR) &lt;1 had histology showing Class III, IV, V or mixed LN with accompanying activity and chronicity, despite an inactive sediment or normal serologies.² These AMP data reinforced the consideration of renal biopsy at thresholds UPCR &lt;1. For patients with UCPR &gt;1, overall complete response rates were only 25%. Lower chronicity, but not activity, associated with complete response with proliferative histology being more responsive than membranous. The earlier phases of AMP have yielded informative results based on single cell RNA sequencing. In brief, 21 subsets of leukocytes in LN were identified including multiple populations of myeloid cells, T cells, natural killer cells, and B cells.³ Cells expressed both pro-inflammatory and inflammation-resolving responses. Local activation of B cells correlated with an age-associated B-cell signature. Progressive stages of monocyte differentiation were evident. The majority of cells expressed a Type I interferon (IFN) response. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, which implicates a potential central role in cell trafficking. Kidney epithelial cells and M2-like macrophages may be coordinating traffic of immune cells infiltrating the kidney. A high Type I IFN response signature and fibrotic signature in tubular cells were each associated with non-responsiveness to therapy.⁴ Analysis of tubular cells from patients with proliferative, membranous, and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histological differences. Complete transcriptomic analysis of a larger dataset from 156 patients is underway. <h3>References</h3> Deonaraine KK, <i>et al</i>. Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the accelerating medicines partnership RA/SLE network. <i>Lupus Sci Med</i> 2021 Aug;<b>8</b>(1):e000522. Carlucci PM, <i>et al</i>. High incidence of proliferative and membranous nephritis in SLE patients with low proteinuria in the accelerating medicines partnership. <i>Rheumatology (Oxford)</i> 2022 Feb 25:keac067. Arazi A, <i>et al.</i> The immune cell landscape in kidneys of patients with lupus nephritis. <i>Nat Immunol</i> 2019 Jul;<b>20</b>(7):902–914. Der E. <i>et al</i>. Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. <i>Nat Immunol</i> 2019 Jul;<b>20</b>(7):915–927. <h3>Learning Objectives</h3> Explain how AMP data confirm need for consideration of renal biopsy in patients with thresholds UPCR &lt;1 Discuss AMP RNA sequencing results based on the analysis of immune cells and resident kidney cells such as the tubules, endothelium and fibroblasts Describe the importance of collecting such data in the development of personalized medicine for patients with LN