• Lupus Nephritis
• Therapeutics
• Autoimmunity

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition characterised by heterogeneous clinical features. The patients with SLE are known to have an increased risk of cardiovascular events, due to both traditional and disease-specific risk factors, including inflammation, endothelial dysfunction, accelerated atherosclerosis and lupus nephritis (LN). Since chronic kidney disease (CKD) is per se one of the strongest CV risk factors, any manoeuvres to prevent CKD progression, including reduction of albuminuria and prevention of estimated glomerular filtration decline, will likely have profound influences on patient outcomes.1 2

All patients with LN have by definition CKD, since they display albuminuria to varying degrees. While albuminuria is a classical sign of renal damage, a substantial portion of patients will also have structural and functional impairment of their kidney function as hallmark of CKD, that is, glomerular hyperfiltration and albuminuria. In the past, renin–angiotensin–aldosterone system inhibitors (RAASi) has already conferred nephroprotective potential in patients with LN; however, a substantial residual renal risk remains in all forms of CKD. In the last few years, novel treatment strategies are therefore required to further decrease proteinuria and to slow kidney function decline.3

Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have recently been demonstrated to exert profound cardio and nephroprotection in large cardiovascular outcome trials. An initial drop of eGFR after SGLT-2i administration (2–5 mL/min) is detected during the first weeks of treatment reflecting a reduction of intraglomerular pressure. A similar effect was observed with mineralocorticoid receptor blockers and ACE inhibitor.4 SGLT2i inhibits the sodium proton exchanger, further increasing the delivery of sodium to the loop of Henle, which results in activation of TGF feedback response with consequent attenuation of glomerular hyperfiltration. They reduce progression of CKD including albuminuria and improve outcomes in heart failure patients with and without type 2 diabetes on top of angiotensin-blocking agents.5 Since many aetiologies of non-diabetic nephropathy are characterised by intraglomerular hypertension, we hypothesise that SGLT2i acutely decrease GFR and proteinuria in patients without diabetes at risk of progressive kidney function loss via a glucose independent haemodynamic mechanism. Furthermore, distinct complications of SLE may also seem to be amenable to the therapeutic potential with SGLT2i such as the increased occurrence of pulmonary hypertension, metabolic syndrome and increased blood pressure.6 Patients with LN were excluded from such studies due to potential necessities of acute immunosuppression.7

The aim of this study was to analyse the effect of SGLT2i in patients with LN in chronic and stable treatment with immunosuppression and residual proteinuria.

Five patients with histologically confirmed LN on immunosuppressive therapy with mean proteinuria of 2.2 g/day had empaglifozin 10 mg/day added. Within 8 weeks of starting treatment, the patients experienced a dramatic decrease in proteinuria (49.9%) with minimal change in glomerular filtration rate (table 1, online supplemental figure 1).

This pilot trial evaluates the antiproteinuric and nephroprotective effect of SGLT2i in patients with LN. Landmark studies have unequivocally demonstrated the renoprotective effect of SGLT2i in addition to the standard of care (RAASi) in different chronic proteinuric nephropathies. For this reason, we believe that these drugs combined with RAASi may be an effective alternative in the management of residual proteinuria in patients with lupus nephropathy with adequate immunosuppression due to their nephroprotective and cardioprotective effects. Prospective randomised studies are needed to demonstrate the potential beneficial effect of SGT2 inhibitors in patients with LN.