Polimorfismos en el gen del VEGF pueden asociarse a desarrollo de proteinuria en pacientes trasplantados renales tratados con inhibidores m-TOR

Résumé

A calcineurin inhibitor (CNI)–based regimen is the cornerstone of immunosuppressive therapy after kidney transplantation. However, the nephrotoxic effect of CNIs and certain deleterious effects on the patient can limit long-term graft survival and contribute to greater morbidity and death in the patient with a functioning graft. M-TOR inhibitors (mTORi) were postulated as an alternative alone or in combination with CNI to minimize cumulative exposure to them. Although they have shown less immunosuppressive potency, they are especially useful in certain clinical settings, thanks to their antiproliferative and antiviral properties. However, they have a high discontinuation rate and one of the main causes of discontinuation is proteinuria, a marker of kidney damage associated with lower graft and patient survival. While the physiopathogenic mechanisms of post-mTORi proteinuria are not clearly understood, the Vascular Endothelial Growth Factor (VEGF) appears to play an important role in this complication. VEGF is a complex pleiotropic protein involved in the function and survival of endothelial and podocyte cells. To this end, it acts through the intracellular PI3K-Akt signaling cascade, which subsequently activates the mTOR pathway. MTORi, therefore, interfere with the activity of VEGF, in addition to reducing its production. In another vein, the VEGF gene is highly polymorphic, and several of its Single Nucleotide Polymorphisms (SNPs) have been linked to altered protein production. Post-mTORi proteinuria does not appear systematically, so it is possible that the genotypic or phenotypic basis of the subject increases his susceptibility to it. The SNPs of the VEGF gene could influence the development of post-mTORi proteinuria, given the implications they have on its protein expression. Objectives: To analyze if the Single Nucletotide Polymorphysms of the VEGF gene -2578 C> A, -1154 G> A and -936 C> T influence the development of proteinuria one year after introducing mTORi treatment in kidney transplant recipients, both in conversion therapy and in combination with a CNI. As secondary objectives, to evaluate the incidence of these SNPs in the two populations analyzed; to study the evolution of renal function and proteinuria according to the VEGF SNPs; to evaluate which factors are predictors of post-mTORi proteinuria; and to analyze the impact of proteinuria on renal graft and patient survival in the short-term...