Abbate, Rosanna

Bertoni, E.

Caroti, L.

Cellai, A. P.

Farsetti, S.

Fedi, Sandra

Larti, Aida

Marcucci, Rossella

Rogolino, A:

Rosso, G.

Salvadori, M.

Zanazzi, M.

English

Florence Research

20 December 2021Lower homocysteine levels in renal transplant recipients treated with everolimus: a possible link with a decreasedcardiovascular risk? / S. Farsetti; M. Zanazzi; L. Caroti; G. Rosso; A. Larti; R. Marcucci; S. Fedi; A: Rogolino; A.P. Cellai;R. Abbate; E. Bertoni; M. Salvadori. - In: TRANSPLANTATION PROCEEDINGS. - ISSN 0041-1345. - STAMPA. -42(2010), pp. 1381-1382.Original Citation:Lower homocysteine levels in renal transplant recipients treated with everolimus: apossible link with a decreased cardiovascular risk?Terms of use:Publisher copyright claim:(Article begins on next page)La pubblicazione è resa disponibile sotto le norme e i termini della licenza di deposito, secondo quanto stabilito dallaPolicy per l'accesso aperto dell'Università degli Studi di Firenze (https://www.sba.unifi.it/upload/policy-oa-2016-1.pdf)Availability:This version is available at: 2158/393411 since:Questa è la Versione finale referata (Post print/Accepted manuscript) della seguente pubblicazione:FLORERepository istituzionale dell'Università degli Studi diFirenzeOpen AccessLTCSRC(imcrclwAbaha©3Tower Homocysteine Levels in Renal Transplant Recipientsreated With Everolimus: A Possible Link With A Decreasedardiovascular Risk?. Farsetti, M. Zanazzi, L. Caroti, G. Rosso, A. Larti, R. Marcucci, S. Fedi, A. Rogolino, A.P. Cellai,. Abbate, E. Bertoni, and M. SalvadoriABSTRACTCardiovascular disease (CVD) is the main cause of morbidity and mortality in renaltransplant recipients. The incidence of CVD in this setting is approximately 5-fold greaterthan in age- and and gender-matched subjects. This excess cardiovascular risk is notcompletely explained by traditional cardiac risk factors. It has been well documented thatthese patients show greatly increased prevalence of both fasting and postmethionine-loading hyperhomocysteinemia (hHcy) compared with the general population. An immu-nosuppressive therapy based on everolimus has been demonstrated to reduce theincidence major adverse coronary events at 4 years compared with azathioprine amongheart transplant recipients. In contrast, scarce data are available on the impact ofeverolimus on emerging risk factors, such as homocysteine (Hcy), in renal transplantrecipients. The aim of this study was to evaluate the possibile impact of everolimuscompared with other immunosuppressive regimes among 132 stable recipients, including91 men and 41 women who were at least 1 year after transplant with stable renal functionand no clinical evidence of acute or chronic renal graft rejections. We compared 31subjects on everolimus immunosuppressive therapy (group A) versus 101 on immunosup-pressive therapy based on cyclosporine, steroids, and mycophenolate. The Hcy levels weresignificantly lower among group A patients compared with group B: 16.5  5 mol/L vs21.2  11 mol/L; P  .005. Hyper-Hcy, defined as Hcy levels 15 mol/L, was diagnosedin 18 out of 31 patients (51%) of group A and in 82 out of 101 patients (81%) of group B.This preliminary study demonstrates a favorable impact of everolimus on a marker ofatherothrombosis which is associated with a worse vascular prognosis.fwwPWyenTUAardiovascular disease (CVD) is the main cause ofmorbidity and mortality in renal transplant recipientsRTRs).1 Indeed, the incidence of CVD in RTRs is approx-mately 5-fold greater than in age- and and gender-7atched subjects. This excess cardiovascular risk is notompletely explained by the number of traditional cardiacisk factors to which RTRs are exposed. The greatly in-reased prevalence of both fasting and postmethionineoading hyperhomocysteinemia (hHcy) in RTRs comparedith the general population has been well documented.2–4n immunosuppressive therapy based on everolimus haseen demonstrated to reduce the incidence of 4-year majordverse coronary events compared with azathioprine ineart transplantation.5 On the other hand, no data arevailable on the impact of everolimus on emerging risk 52010 Published by Elsevier Inc.60 Park Avenue South, New York, NY 10010-1710ransplantation Proceedings, 42, 1381–1382 (2010)actors, such as Hcy, in RTRs. The aim of the present studyas to evaluate the possible impact of everolimus comparedith other immunosuppressive regimes on Hcy levels.ATIENTS AND METHODSe investigated 229 stable RTRs (150 male, 79 female) at least 1ear after transplant with stable renal function and no clinicalvidence of acute or chronic renal graft rejection episodes. Thirty-ine RTRs were on immunosuppressive therapy based on everoli-From Renal Unit (S.Fa., M.Z., L.C., G.R., A.L., E.B., M.S.),hrombosis Center (R.M., S.F., A.R., A.P.C., R.A.), Caregginiversity Hospital, Florence, Italy.Address reprint requests to Silvia Farsetti, MD, Renal Unit,zienda Ospedaliera Universitaria Careggi, V. le Pieraccini 18-0134, Firenze, Italy. E-mail: silvia.farsetti@email.it0041-1345/–see front matterdoi:10.1016/j.transproceed.2010.03.1121381moDdpbRNglg1oN5DSpristphsapleaAiamsSwggomompskmcamtsbrdttpuoRRCNptrScJa411382 FARSETTI, ZANAZZI, CAROTI ET ALus (group A), and 190 were on immunosuppressive therapy basedn triple therapy (cyclosporine, steroids, micophenolate; group B).Statistical analysis was performed by means of the SPSS package.ata are reported as mean  SD. The comparison betweenifferent groups was performed by a Mann-Whitney U test. Allrobability values were 2 tailed, with values of .05 considered toe statistically significant.ESULTSo significant differences were documented between the 2roups in the dialysis age, graft duration, or creatinineevels. Hcy levels were significantly lower in patients ofroup A compared with group B: 16.5  5 mol/L vs 21.2 1 mol/L; P  .005. Hyper-Hcy, defined as hHcy levels15 mol/L, was diagnosed in 23 out of 39 patients (58.9%)f group A and in 144 out of 190 patients (75.8%) of group B.o significant differences were found in vitamin B6 levels:.0  3.5 gram/L vs 4.4  3.4 gram/L.ISCUSSIONeveral studies have found increased levels of Hcy both inatients with end-stage renal disease and in RTRs with aecovered renal function.2–4 We previously demonstrated,n the same clinical setting of the present study, that vitaminupplementation reduces the carotid artery intima-mediahickness in renal transplant recipients with hHcy.6 In theresent paper, we confirmed the high prevalence of mildHcy in RTRs. Notably, this preliminary study demon-trates a favorable impact of everolimus on this marker oftherothrombosis which is associated with a worse vascularrognosis. The proliferation-signal inhibitor (PSI)/mamma-ian target of rapamycin (mTOR) inhibitors sirolimus andverolimus have shown considerable promise in reducingcute rejection episodes in renal transplant recipients.lthough PSIs are associated with an increase in hyperlip-demia, which is a major risk factor for atherosclerosis andssociated cardiovascular disease, recent studies with siroli-us have demonstrated protection from atheroma progres-ion in hyperlipidemic apolipoprotein E–deficient mice.irolimus and everolimus inhibit the mTOR signaling path-ay, inducing inhibition of gene transcription, reduced cellrowth and proliferation, reduced vascular endothelialttrowth factor production. In the endothelial cell, the effectf PSIs is reduced cell growth and proliferation. Further-ore, there may also be alterations in endothelial nitricxide synthase expression, changes in the ratio of matrixetalloproteinases (MMP) to tissue inhibitors of metallo-roteinases, MMP-2 and MMP-9 activation, reduced expres-ion of the positive cell-cycle regulator cyclin-dependentinase 2, proliferating-cell nuclear antigen, and proinflam-atory cytokines, and diminished expression of monocytehemotactic protein 1, which is associated with the attenu-tion of monocyte chemotaxis and reduced neointimalacrophage counts in sirolimus-fed mice.The potential protective role of mTOR inhibitors, par-icularly everolimus, in the processes that lead to athero-clerosis and cardiovascular events seems to be confirmedy the results of this preliminary study. Hcy levels, whichepresent an independent risk factor for cardiovascularisease, are significantly reduced in renal transplant pa-ients treated with everolimus compared with patientsreated with other immunosuppressive regimens. Largerrospective studies are needed to clarify the impact that these of everolimus may have on methionine metabolism andn morbidity and mortality from cardiovascular causes inTRs.EFERENCES1. Kasiske BL, Guijarro C, Massy Z, Wiederkeher MR, Ma JZ:ardiovascular disease after renal transplantation. J Am Socephrol 7:158, 19962. Bostom AG, Gohh RY, Beaulieu AJ: Determinants of fastinglasma total homocysteine levels among chronic stable renalransplant recipients. Transplantation 68:257, 19993. Marcucci R, Fedi S, Brunelli T, et al: High cysteine levels inenal transplant recipients. Transplantation 71:746, 20014. Ducloux D, Motte G, Challier B, Gibey R, Chalopin JM:erum total homocysteine and cardiovascular disease occurrence inhronic, stable renal transplant recipients: a prospective study.Am Soc Nephrol 11:134, 20005. Eisen HJ, Straling RC, Kobashigawa J: Incidence of MACEnd economic burden in de novo heart transplant recipients: a-year comparison of everolimus and azathioprine. Transplant Int8:PO–111, 20056. Marcucci R, Zanazzi M, Bertoni E, et al: Vitamin supplemen-ation reduces the progression of atherosclerosis in hyperhomocys-einemic renal transplant recipients. Transplantation 75:1551, 2003

Lower homocysteine levels in renal transplant recipients treated with everolimus: a possible link with a decreased cardiovascular risk?

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Lower homocysteine levels in renal transplant recipients treated with everolimus: a possible link with a decreased cardiovascular risk?

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