Potential Role of SGLT-2 Inhibitors in Improving Allograft Function and Reducing Rejection in Kidney Transplantation

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have demonstrated renoprotective and cardioprotective benefits beyond their antiglycemic effects. Their potential utility in kidney transplant recipients (KTRs) for preserving graft function and reducing rejection risk is currently under active investigation. Preliminary studies indicate that SGLT-2i therapy stabilizes estimated glomerular filtration rate (eGFR), decreases glomerular hyperfiltration, and improves metabolic outcomes in KTRs. Emerging clinical evidence also suggests that SGLT-2i may be associated with reduced rates of acute rejection, although direct immunosuppressive actions remain unclear. Experimental findings further suggest that SGLT-2i modulates gene regulation pathways involved in inflammation, oxidative stress, and fibrosis, contributing to improved allograft outcomes. Current safety data in KTRs are reassuring, without significant increases in urinary tract infections or adverse graft events. Nevertheless, long-term prospective studies specific to transplant populations are lacking. This review summarizes available evidence regarding the mechanisms of action, clinical efficacy, and safety profile of SGLT-2i in kidney transplantation, emphasizing their metabolic, hemodynamic, inflammatory, and immunomodulatory effects.

Keywords: immunosuppressant; mechanistic target of rapamycin (mTOR); rejection; signaling/signaling pathways.

FIGURE 1

Nutrient‐sensing pathways modulated by SGLT‐2 inhibitors. SGLT‐2 inhibitors create a low‐nutrient state by promoting glucosuria and natriuresis, activating AMPK, and inhibiting mTORC1 signaling. This metabolic shift suppresses cell proliferation, glycolysis, and pro‐inflammatory responses, mimicking calorie restriction and providing protection against hypertrophy and inflammation. AMPK, AMP‐activated protein kinase; GLUT, glucose transporter; mTORC1, mammalian target of rapamycin complex 1; SGLT‐2i, sodium–glucose cotransporter‐2 inhibitors.

FIGURE 2

Metabolic modulation of T‐cell activation by SGLT‐2 inhibition. High‐nutrient conditions (left) support robust glycolysis and glutaminolysis, stabilizing c‐Myc, enhancing IL‐2 production, and driving T‐cell proliferation. Under low‐nutrient conditions induced by SGLT‐2 inhibitors (right), reduced glycolysis and c‐Myc degradation limit metabolite availability, attenuating histone acetylation and cytokine production. This metabolic shift suppresses T‐cell activation and proliferation, promoting a less inflammatory, more quiescent or regulatory phenotype. c‐Myc, MYC proto‐oncogene; GLUT, glucose transporter; IFN‐γ, interferon‐gamma; IL‐17, interleukin‐17; IL‐2, interleukin‐2; mTORC1, mechanistic target of rapamycin complex 1; SGLT‐2i, sodium–glucose cotransporter‐2 inhibitors.

FIGURE 3

Nutrient‐driven epigenetic modulation in renal cells. High nutrient availability (glucose and amino acids) generates metabolites such as aKG, which can be converted into the oncometabolite 2HG via IDH1/2 enzymes. Elevated 2HG disrupts DNA/histone methylation and demethylation processes, causing aberrant gene expression. SGLT‐2 inhibitors reduce intracellular glucose, potentially limiting these epigenetic changes and maintaining normal gene expression in kidney cells. 2HG, 2‐hydroxyglutarate; aKG, α‐ketoglutarate; DNMT, DNA methyltransferase; GLUT, glucose transporter; HDMT, histone demethylase; HMT, histone methyltransferase; IDH1/2, isocitrate dehydrogenase 1/2; SGLT‐2i, sodium–glucose cotransporter‐2 inhibitors; TCA, tricarboxylic acid cycle; TET, ten–eleven translocation.

FIGURE 4

SGLT‐2 inhibition improves renal oxygenation and mitigates chronic hypoxia. SGLT‐2 inhibitors reduce proximal tubular oxygen consumption by limiting glucose and sodium reabsorption, enhancing oxygen availability in renal tissue. Increased erythropoietin production and hematocrit further improve oxygen delivery. Collectively, these mechanisms alleviate intrarenal hypoxia, reducing inflammation, fibrosis, and tubular injury, thereby promoting graft preservation. EPO, erythropoietin; Hct, hematocrit; RBC, red blood cell; SGLT‐2i, sodium–glucose cotransporter‐2 inhibitors.