Francisco González-Martínez

Delayed mTOR Inhibition with Low Dose of Everolimus Reduces TGFβ Expression, Attenuates Proteinuria and Renal Damage in the Renal Mass Reduction Model

Background The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFβ expression in the 5/6 nephrectomy model in Wistar rats. Methods This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation. Results Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFβ observed in the remnant kidney model. Conclusion Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFβ mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin.

Presence of Pre-Existing HLA Antibodies in Renal Transplant Patients and its Impact During the First Year Post Transplant

Introduction Predictive value of donor specific antibody (DSA) for the ocurrence of antibody mediated rejection (AMR) and graft loss in the individual patient is variable. In Uruguay, these techniques for detecting antibodies began to be implemented since 2016.The objective of this study was to assess the impact of presenting pre-formed antibodies in the first year of kidney transplantation outcome. Materials and Methods Retrospective multi-centric study, which included adult patients who received a kidney transplant with a cadaveric donor between 1/1/16 and 4/30/17, in the 3 transplant centers of Uruguay. All patients underwent study of HLA class I and II antibodies and specificity study for determination of DSA, performed by solid-phase technique, Luminex. At the transplant, they had a negative cross-test due to microliphocytotoxicity. Comparison off the incidence of acute rejection (AR) and survival of grafts and patients were calculated between the groups of patients with and without preformed antibodies. Results Of 125 patients analyzed, 73% did not present preformed antibodies, while 27% were sensitized with the presence of anti-HLA antibodies both class I and/or class II. Of this 27% of patients, 11% had anti-HLA antibodies pre-transplant positive, both class I and/or class II without DSA, and 16% had DSA. Patients were divided into 3 groups, according to absence of antibodies (G1), presence of antibodies but without DSA-positive (G 2) and presence of antibodies with DSA-positive (G3). G2 and G3 had a significantly higher percentage of females (p = 0.002), retransplants (p = 0.001), time on dialysis (p = 0.01), higher PRA (p = 0.001) as well as a higher number of transfusions (p = 0.02), versus G1 patients. The 3 groups did not have induction differences nor maintenance immunosuppression. There was a significant difference in perioperative desensitization, with infusion of gamma globulin (G3 75% versus G1 and G2 4.6% and 8%, p = 0.001). Month follow-up of the groups was of G1, G2 and G3, 11 ± 5.12 ± 5 and 9 ± 5.5 months of mean respectively. The incidence of AR in G2 and G3 was 46% and 45% versus 15% G1, (p = 0.001). Diagnosis of AR was performed at 19 ± 17.16 ± 26 and 18 ± 32 days post transplant for groups G1, G2 and G3 respectively, without differences. Patients survival was similar between groups, with 1 death in each group, all due to sepsis. Censored by death graft survival at one year was 95% G1, 100% G2 and 93% G3 (p = ns). Conclusion Patients transplanted with preformed antibodies, were most frequently females, retransplant and had more time on dialysis. Although this group mostly received desensitization treatment, at 3 months it presents a higher acute rejection rate, but with similar renal graft survival at 1 year.