Dyslipidemia in Transplant Patients: Which Therapy?

Round 1

Reviewer 1 Report

The paper is an interesting review about the management of dyslipidemia in transplant recipients, focusing especially on metabolic effect of immunosuppressant drugs, hypolipidemic drugs and the interaction between them.

The abstract and introduction are well written.

The paragraph “role of dyslipidemia in atherosclerosis” provides a deep understanding of the different lipoproteins class and their role in formation mechanisms of atherosclerotic plaques.

Even if the paper is focused on atherosclerosis and cardiovascular effects of dyslipidemia in transplant patients, a small mention should be made about other effects and consequences of increased circulating lipids (i.e. thrombotic disorders, changes in circulating adipokines, oxidative stress, kidney dysfunction secondary to lipotoxicity).

In line 249 a lower incidence of PTDM in patients treated with tacrolimus is mentioned but more recent results are in contrast with sentence. Torres et al (Torres A, Hernández D, Moreso F, Serón D, Burgos MD, Pallardó LM, Kanter J, Díaz Corte C, Rodríguez M, Diaz JM, Silva I, Valdes F, Fernández-Rivera C, Osuna A, Gracia Guindo MC, Gómez Alamillo C, Ruiz JC, Marrero Miranda D, Pérez-Tamajón L, Rodríguez A, González-Rinne A, Alvarez A, Perez-Carreño E, de la Vega Prieto MJ, Henriquez F, Gallego R, Salido E, Porrini E. Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus. Kidney Int Rep. 2018 Jul 11;3(6):1304-1315. doi: 10.1016/j.ekir.2018.07.009. PMID: 30450457; PMCID: PMC6224662.) have demonstrated that even though a cyclosporine-based regimen is associated with a less incidence of PTDM, the best balance between PTDM and acute rejection incidence is reached in a tacrolimus-based immunosuppression regimen (FK+MMF+steroid). 

Moreover, the systematic review and meta-analysis of Kotha et al (Kotha S, Lawendy B, Asim S, Gomes C, Yu J, Orchanian-Cheff A, Tomlinson G, Bhat M. Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients: Systematic review and meta-analysis. World J Transplant. 2021 Oct 18;11(10):432-442. doi: 10.5500/wjt.v11.i10.432. PMID: 34722172; PMCID: PMC8529944.)analyze the incidence of PTDM in patients treated with tacrolimus, cyclosporine and sirolimus. The results of this meta-analysis are in contrast with what has been stated: the overall incidence of PTDM was higher in tacrolimus and sirolimus regimens than in cyclosporine one. 

Line 407: it can “be” used.

Line 412: several factors “should” be taken into consideration.

Line 447-448: Dyslipidemia, one “of” the most.

Discussion and conclusion are clear.

Figures and tables are well designed.

In conclusion the paper “Dyslipidemia in transplant patients: which therapy” offers clear and simple information about the management of transplant recipients with dyslipidemia. It needs minor revisions.

Author Response

We thank the reviewer for her/his precious comments and suggestions. We improved the quality of the manuscript accordingly. In details, we added references to other effects caused by increased lipid levels and we discussed the references indicated by the reviewer on the effects of tacrolimus on PTDM (Kotha S. et al.  World J Transplant. 2021; Torres A. et al.  Kidney Int Rep. 2018). Moreover, we corrected grammar mistakes within the manuscript.

Reviewer 2 Report

In this review, Iannuzzo  et al. summarized the recent literature about dyslipidemia in solid-organ transplanted patients.

This review is very well written and exhaustive.

Here are my concerns:

-       Page 1: the authors should define “IHD”

-       Page 2: other risk factors identified: chronic kidney disease should be added as it is an important atherosclerosis risk factor. There is a large amount of article the authors may cite (Recio-Mayoral A, et al. Atherosclerosis. 2011. PMID: 21414625 …). It is only shortly discussed page 3.

-       Prediction of risk factor using traditional CVD risks factors differs in chronic kidney disease patients as compared to the general population (Mansell H., Stewart S.A., Shoker A. Validity of Cardiovascular Risk Prediction Models in Kidney Transplant Recipients. ScientificWorldJournal. 2014;2014:750579. Weiner D.E., Tighiouart H., Elsayed E.F., Griffith J.L., Salem D.N., Levey A.S., Sarnak M.J. The Framingham Predictive Instrument in Chronic Kidney Disease. J. Am. Coll. Cardiol. 2007;50:217). As such an extent that the benefit of hypocholesterolemic drugs have failed to prove a survival benefit in hemodialysis patients. This point should be discussed for kidney transplanted patients or solid organ transplanted patients with chronic kidney disease.

-       For comparison of tacrolimus and CsA , this article may be included : A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Vincenti F

-       For mTOR inhibitors : the metaanalyse of Karpe (PMID: 28730648) in 2017 may be included.

-       Also this randomized trial of Pascual  : 16861942

-       New immunosuppression drugs may be discussed even if the literature is missing : because it is a key point of future investigations (belatacept, tocilizumab…)

-       Table 2 should add information’s of risk and benefit, gradual risk of induction and efficacy to help clinicians to choose

Author Response

We thank the reviewer for her/his precious comments and suggestions. We improved the quality of the manuscript accordingly. In details,

1. we defined the acronym “IHD”
2. we clarified the role of CKD as independent risk factor for atherosclerosis,
3. We included and discussed the following suggested references (Mansell H. et al. ScientificWorld Journal. 2014; Weiner D.E. et al. J. Am. Coll. Cardiol. 2007; Vincenti F. et al. 2002; Karpe KM. et al. Cochrane Database Syst Rev. 2017; Pascual J. et al.  Transplantation. 2006).
4. We discussed the role of new immunosuppression drugs by adding the following sentence: “Currently, there is little evidence about the role of monoclonal and polyclonal antibodies. Therefore, it is difficult to address this topic in the present review: although these drugs currently have a greater risk for graft failure compared to previously cited immunosuppressants ¹⁰⁵, they showed a lower incidence of cardiovascular effects ¹⁰⁶ and may also prove effective in the future as rescue therapies for immunosuppressants-induced nephrotoxicity ¹⁰⁷ or late allograft rejection ¹⁰⁸.”
5. We improved the quality of Table 2 by adding the efficacy of lipid lowering agents