Review Reports

Round 1

Reviewer 1 Report

This is a review article addressing an important post renal transplant complication which is hyperlipidemia. At times this can be present pre transplant and at times post-transplant but importantly this needs to be treated effectively and efficiently to decrease morbidity and mortality associated with the disease leading to renal failure and also renal transplants. 

 

The article flows well. It first talks about the causes of dyslipidemia in renal transplant patients how it is associated with the disease, procedure and then medications. It goes on to talk about the newer medications that are being used now which have lesser of an impact on lipid metabolism.

My comments for the authors are:

• While the lipid metabolism is well known, it isn’t on the reader’s mind. If you could draw a descriptive diagram and mark the different steps at which the different agents work would be great. It would be high yield as well.

 

Easy read as a review and I feel it is wholesome and informative.

 

 

Author Response

1. We appreciate the reviewer’s suggestion to create a descriptive diagram representing target points for lipid-lowering drugs, however, we believe this topic is comprehensively described in the text. The aim of our review is to present a broader context of dyslipidemia causes, development, and treatment after kidney transplantation, rather than a thorough analysis of the drug pharmacokinetics.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Dyslipidemia in renal transplant recipients

The authors review lipid metabolism and drugs available for treatment, as well as their interaction with common immunosuppressive drugs.

Page 3, Line 81:  “Adjustment of immunosuppressive therapy and the chance of drug interaction should have been taken into account to minimize the competing risk of allograft rejection and CVD development.”  The tense of this sentence does not make sense.  Perhaps you mean to say …drug interaction should be taken into account to minimize…

Line 88: Please discuss the effects of glucocorticoids by dose.  Today, most centers that continue prednisone have the dose decreased to 5 mg a day by a month after transplant.  Historically, it had been much higher.  Does 5 mg of prednisone still have a significant effect on lipid dysregulation?  Can you expand on this?

Line 111: Can you comment on the overall effect of mTORi s in most patients?  Does the dyslipidemia or endothelial protective effect seem to dominate in most humans?  That is, is CAD increased as expected with the degree of dyslipidemia or not?

Line 230:  “Concomitant statin prescription with CNI, particularly cyclosporine, must be 230

avoided due to reported rhabdomyolysis cases [9,67].”  Many transplant centers use statins with cyclosporine.  They use pravastatin or very low doses of other statins and watch carefully for rhabdomyolysis.  You mention above that the statins can be used at low doses in RTRs, especially if not on cyclosporine.  This statement that you cannot use statins with CNIs does not appear consistent with multiple other statements you make.

Line 308: Is there any reason not to suggest pravastatin and rosuvastatin ahead of the other statins?

 

 

Author Response

Reviewer 2

1. According to reviewer’s suggestion we changed the sentence as follow:

“Immunosuppression plays an important role in preserving the graft, however, medication schemes should be optimized in order to prevent dyslipidemia and drug-drug interactions causing worsening of CVD.

2. We expanded the topic of steroids as follow:

“Steroid withdrawal is associated with significantly reduced cholesterol concentrations, and slight weight reduction but may be responsible for the higher rate of early acute graft rejection. It also depends on immunosuppressive agents and dosage used in treatment protocol [30,31]. Moreover, steroid avoidance and steroid maintenance therapy have comparable outcomes on lipid profiles in immunologically low-risk RTRs [32].”

3. We supplemented our work with the information about mTOR inhibitors influence on CVD incidence in renal transplant recipients:

“However, due to the inconclusive results of the randomized controlled trials on mTOR inhibitors and their influence on the CVD, an unequivocal advantage of anti-inflammatory effects over dyslipidemic potential cannot be proven [46,47].”

4. According to reviewer’s suggestion we changed the sentence as follow:

“Concurrent treatment with statins and CNI, particularly cyclosporine, should be conducted with caution with lower doses of statins due to reported cases of rhabdomyolysis [9,73,74].”

5. We want clarify that, the order in which statins are mentioned in “Conclusion” does not represent the favorable order in which they should be prescribed. Moreover, in subparagraph 6.1.1. we emphasize the high safety profile of pravastatin and rosuvastatin.

 

Author Response File: Author Response.pdf