525 SGLT2 inhibition in non-diabetic CKD: results in experimental lupus nephritis

Abstract Background and Aims Sodium glucose cotransporter type 2 inhibitors (SGLT2i) potently attenuate cardiovascular morbidity and progression of CKD in patients with type 2 diabetes. It has been proposed that SGLT2 inhibition may also elicit renoprotective effects in non-diabetic CKD. The aim of this work is to evaluate whether the treatment with an SGLT2i improves kidney disease progression in a mouse model of lupus nephritis (LN). Method We performed a single center randomized controlled preclinical trial using female MRLlpr/lpr mice. The animals were randomly assigned to (1) vehicle or (2) empagliflozin (EMP, 10 mg/kg/day) treatment once signs of active systemic lupus erythematosus (SLE) appeared: proteinuria >100 mg/dL (++ in reactive strips) or lymphadenopathy in minimum 2 bilateral sites with proteinuria >30 mg/dL (+ in reactive strips). We included 13 mice per group that were treated during 4 weeks. Empagliflozin was given as an admix into standard chow diet. Reduction of urinary albumin to creatine ratio (UACR) was considered the primary endpoint whereas glomerular filtration rate (GFR), renal histology (LN activity/chronicity index, glomerulosclerosis, interstitial fibrosis) and SLE markers (total serum IgG, anti-dsDNA IgG, glomerular IgG deposits, lymph node weight, spleen weight) were considered secondary endpoints. Results After 4 weeks of treatment, no significant differences in fasting blood glucose levels were found between the experimental groups. As expected, empagliflozin administration notably inhibited SGLT2 in the tubular cells demonstrated by a significant increase of urinary glucose (p < 0.0001). This is consistent with the increased water intake observed in MRLlpr/lpr mice treated with empagliflozin (p < 0.0001). At the end of the experiment, vehicle treated MRLlpr/lpr mice showed a significant increase in UACR (p = 0.0012) consistent with LN progression that was not attenuated by empagliflozin. In line, empagliflozin did not modify GFR and LN activity/chronicity indexes, glomerulosclerosis or interstitial fibrosis in kidney. Finally, regarding SLE markers, 4-weeks empagliflozin treatment was not able to decrease total serum IgG, anti-dsDNA IgG, glomerular IgG deposits or lymph node weight. Only spleen weight was significantly decreased in empagliflozin treated MRLlpr/lpr mice (p = 0.003). Conclusion In our experimental setting, empagliflozin treatment reduced spleen weight suggesting a protective role in SLE in MRLlpr/lpr mice.