LAUSR

The nephroprotective efficacy of sodiumglucose cotransporter2 (SGLT2) inhibitors (SGLT2i) in patients with chronic kidney disease, with or without type 2 diabetes, has already been described. Although patients with autoimmune diseases were excluded from large renal outcome trials, the use of SGLT2i in antineutrophil cytoplasmic antibodyassociated vasculitis (AAV) and systemic lupus erythematodes (SLE) for nephroprotection has increasingly been emphasised. While SGLT2 was studied in diabetic nephropathy and IgA nephropathy (IgAN), the presence of SGLT2 specifically in renal vasculitis and lupus nephritis has not been described yet. In renal vasculitis and lupus nephritis, SGLT2 was detectable and predominantly localised to the tubulointerstitial as compared with the glomerular compartment (figure 1A). For comparative analysis, we next extracted transcriptome data sets for SGLT2 expression (encoded by SLC5A2), specifically from microdissected tubulointerstitial (31 healthy controls, 17 with diabetic nephropathy, 25 with IgAN, 21 with renal vasculitis and 32 with lupus nephritis) and glomerular compartments (21 healthy controls, 12 with diabetic nephropathy, 27 with IgAN, 23 with renal vasculitis and 32 with lupus nephritis, www.nephroseq.org, January 2022, University of Michigan, Ann Arbor, Michigan, online supplemental tables 1 and 2). In renal vasculitis and lupus nephritis, tubulointerstitial SLC5A2 mRNA expression was significantly higher as compared with the glomerular compartment (p<0.0001, figure 1B), with no sex differences for tubulointerstitial (p=0.7) or glomerular SLC5A2 expression (p=0.4, figure 1C). Interestingly, kidney function positively correlated with particularly tubulointerstitial SLC5A2 mRNA expression in renal vasculitis and lupus nephritis (figure 1D and online supplemental figure 1A,B). Compared with healthy control kidneys, a significant reduction of tubulointerstitial SLC5A2 mRNA expression levels was detectable in diabetic nephropathy (p=0.01), while IgAN, renal vasculitis and lupus nephritis did not significantly differ (p=0.6 for all comparisons, figure 1E and online supplemental figure 2A). In contrast, glomerular SLC5A2 was significantly reduced in diabetic nephropathy (p=0.0005), IgAN (p=0.0003), renal vasculitis and lupus nephritis (p<0.0001 for both comparisons, figure 1E). Interestingly, no association between kidney function and SLC5A2 was observed in diabetic nephropathy and IgAN (online supplemental figure 3A,B). Gene set enrichment analysis in the whole data set (including 201 tubulointerstitial and 199 glomerular compartments) linking SLC5A2 expression to potential signalling pathways revealed positive associations with lipid metabolism by peroxisome proliferatoractivated receptor (PPAR)-α and the tricarboxylic acid (TCA) cycle (figure 1F and online supplemental table 3). Glomerular SLC5A2 mRNA expression correlated with protein and fatty acid metabolism (figure 1F and online supplemental table 4). In summary, this comparative analysis revealed predominant tubulointerstitial expression of SGLT2 in renal vasculitis and lupus nephritis. Moreover, worse kidney function correlated with loss of tubulointerstitial SGLT2 expression particularly in renal vasculitis and lupus nephritis. Therefore, nephroprotection by SGLT2i could be effective especially once the initial phase of remission induction in renal vasculitis and lupus nephritis is achieved and kidney function stabilised. Finally, this is the first report linking SGLT2 to distinct metabolic signalling pathways in the kidney that could also be relevant for autoimmune diseases including AAV and SLE. In general, management of renal complications in AAV and SLE involves immunosuppressive and antiinflammatory treatment, and also an approach towards nephroprotection and cardiovascular risk reduction. SGLT2i exerts unequivocal nephroprotective effects by reducing glomerular hyperfiltration and albuminuria, tubular injury, loss of kidney function and incidence of acute kidney injury. These effects suggest that SGLT2i is an ideal therapeutic approach also for patients with AAV and SLE, especially when renal and cardiac complications already manifested. Because of limited information about treatment at time of kidney biopsy or detailed histopathology in the current study, we emphasise future studies regarding SGLT2, particularly in autoimmune diseases with renal involvement (including AAV and SLE).