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Clinical trials with sodium-glucose co-transporter 2 inhibitors (SGLT2i) have demonstrated to slow the progression of CKD by reducing hyperfiltration and proteinuria. However, SGLT2i have shown anti-inflammatory properties that are not well explained so far. The aim of this study is to analyse the gene expression of IL-1β and NLRP3 with the use of dapagliflozin added to standard of care therapy (SoC), compared to isolate SoC in inactive lupus nephritis (LN) patients.
The present cross-over RCT (RBR-3vcg568) included adults with chronic and inactive LN class III or IV(+/-V), proteinuria >500mg/24h and eGFR >20ml/min in maintenance therapy. RAASi should be stable >4w. We exclude patients with recurrent urinary infections, biopsy with active LN (AI>2), use of induction therapy in the last 12mo, including CNI, and prednisone >20mg/d. Patients are randomized to receive dapagliflozin 10mg or not, on top of SoC therapy. Total RNA from PBMC was extracted for cDNA synthesis before and 24 weeks after the use of dapagliflozin + SoC or isolate SoC. For both groups we performed gene expression of IL-1β and NLRP3 using qPCR Taqman® probes with the GAPDH and ACTB genes to normalize the data. Wilcoxon rank test was used to compare gene expression of matched pairs on baseline and 6 months (mo) after intervention. Statistical analysis was performed using GraphPad Prism 8.0 software and differences were considered significant when p<0.05.
From 94 screened class III or IV(+/-V) LN patients in maintenance therapy, we excluded 67 due to active LN, low proteinuria or low eGFR. We have included 27 chronic LN patients that were randomized 1:1. Baseline characteristics and labs of 14 patients that had minimum of 6 mo of follow-up are described in table 1. We analysed gene expression of IL-1β and NLRP3 from 9 patients in dapa + SoC and 5 patients from SoC groups at baseline and 6mo. Baseline characteristics and labs are described in table 1. After 6 mo of dapagliflozin there was a significant decrease in IL-1β gene expression (FC = -2.21 ± 0.42; p= 0.017), but no significant increased expression in the control group (FC = +1.59 ± 0.76; p= 0.31). NLRP3 expression was not significantly different after 6 mo in dapa group (FC=-1.07 ± 0.42; p= 0.73) and in control group (FC= -2.02 ± 0.32; p=0.15).
We demonstrated reduced gene expression of IL-1 β, but no change in NLRP3 expression after 6 months of dapagliflozin on top of SoC maintenance therapy for LN with residual proteinuria. Further tests should help to clarify anti-inflammatory pathways related to use of SGLT2 inhibitors.