Characterization of Slit2-C as a biomarker of disease activity in systemic lupus erythematosus and lupus nephritis
OA Version
Citation
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a high likelihood of renal involvement. There are several pathophysiological processes that remodel the kidney in lupus nephritis (LN). A kidney biopsy is the golden standard for classifying lupus nephritis. Commercially available clinical tests based on blood or urine specimens can provide indications about the disease progression of LN, but they are not always highly specific for SLE or LN. Therefore, there is a need to discover improved biomarkers that are specific to autoimmune and chronic kidney diseases. The ligand Slit2 binds to its receptor Robo, which is found in the kidney. Recent studies have shown that Slit2-Robo2 signaling is associated with podocyte effacement and detachment from the glomerular basement membrane (GBM). Furthermore, there is an increased expression of Robo2 in animal models of immune-mediated nephritis and acute kidney injury, as well as human kidney samples of membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Given these recent findings, it is of great interest to investigate whether altered Slit2 and Robo2 expression modulates disease activity in lupus nephritis, which is classically characterized by glomerulonephritis and impaired glomerular function. This thesis focuses on evaluating the C-terminus of the Slit 2 protein (Slit2-C) as a biomarker of disease activity in SLE and LN. Our hypothesis was that Slit2-C levels would be elevated in patients with severe LN, particularly in LN patients with chronic kidney disease (CKD). We found that Slit2-C in serum was significantly associated with SLE Disease Activity Index 2K (SLEDAI-2K) scores, low C3 complements, high platelet cell count, proteinuria, urine protein-to-creatinine ratio, hematuria, and NIH activity and chronicity indices in kidney biopsies. There was significantly elevated serum Slit2-C in Class IV+V LN compared to Class II, Class III, and Class IV LN. However, the healthy control and renal disease control had higher serum Slit2-C values than the majority of the LN cohort. Our results suggest that, in the setting of autoimmune kidney disease, Slit2-C is a sensitive biomarker of disease activity and renal damage. Interestingly, LN patients with CKD had lower levels of serum Slit2-C relative to non-CKD LN patients. There was no statistical significance between Slit2-C and estimated glomerular filtration rates (eGFR) or between Slit2-C and serum creatinine levels in LN patients. The majority of non-CKD LN patients in our study cohort presented with proteinuria yet normal eGFR. Further study is thereby warranted to determine the degree to which Slit2-C levels reflect the remodeling of both glomerular and non-glomerular structures in the kidney as a result of LN pathophysiology. Overall, the findings of our pilot study establish Slit2-C as a potential biomarker of disease activity and renal damage in SLE and LN. In contrast to the N-terminus of Slit2 and uncleaved Slit2, Slit2-C lacks the binding domain that activates the transmembrane Robo receptor. Comparative analyses with Slit2-N and uncleaved Slit2 will be instrumental for the comprehensive evaluation of Slit2 as a valid biomarker for autoimmune and chronic kidney diseases.
Description
2024