Overall Statement: This is a review manuscript which authors tried to contextualize the current systemic treatments in 2018 for metastatic clear cell renal cell carcinoma and their association with the Hypoxia-Inducible Factors (HIF) Pathway. Besides that, authors enhanced the possible role of Selenium in the mentioned pathway and highlighted the base-line expression of some genes and miRNA linked to the HIF-Pathway.

Specific Comments:

a) Title, Abstract and Keywords: 1 - In title, authors enhanced their intention to write about the HIF-Pathway and the role of Selenium in ccRCC. Assuming that it is preferable to avoid abbreviations in the title, please change HIF to Hypoxia-Inducible Factors. 2 - Reading the abstract after read the whole manuscript, I noted that authors set a specific topic about the base-line expression of some genetic biomarkers. It would be interesting to add a related phrase in the abstract section. 3 - Authors mentioned seven keywords. Despite the fact that it in accordance with journal guidelines, I would suggest to change some of them. The keywords "VEGF", "mTOR inhibitors", and in particular "PD-L1 are not fully related to the objectives of this review. I would change or at least add the term "biomarker expression". However, this is just a suggestion.

b) Introduction 4 - Authors did a good job in stating the epidemiological profile of ccRCC in 2018. As a highlighted trial this year, authors correctly cited the CARMENA trial. However, due the several other studies criticizing some points of this mentioned trial, I would suggest to write a counterpoint in this section. 5 - Minor point: On the sentence "RCC is the most lethal genitourinary cancer given its disease course is largely asymptomatic and incidentally found in more than half of new cases"(Page 3; Lines 3-4), this phrase doesn't sound correct. Please review it.

c) As a review manuscript, authors divided the sections according to the respective issues. In this way, there are no Materials and Methods section. Clearly, this is not a systematic review and authors did not follow any guidelines in the review process. Databases, repositories and searched terms were not stated. If authors followed any kind of methodology for this review, please explain.

6 - Please do not use abbreviations in the head sections.

7 - MAJOR Point: I would like to mention an important issue in the section "Base-line Transcription and Translation in ccRCC Cell Line". Authors made an analysis with the genes HIF-1alfa, HIF-2alfa, and PD-L1, and with the miRNAs hsa-miR-155, and hsa-miR-210. It was analyzed their baseline expression in four ccRCC cell lines (Stated as 786-O, RC2, RCC4 and RCC4 cells transfected with wild-type von Hippel-Lindau). It is crucial to determine how this analysis was made. 8 - Why did authors choose these mentioned cell lines? 9 - How did authors achieved these results?

10 - Related to the regulation of HIF activation, the loss of VHL gene function is also a known step in this process. Please, add these information in the section "Role of HIF in Renal Cell Carcinogenesis"

11 - In this line, it would be valuable to complement this previous section with some statements about the relationship of Erythropoietin (EPO). I would suggest to cite the study from Ferreira et al (2017): Ferreira DB, Costa WH, Abreu-Clavijo D, et al. Tissue Expression of Erythropoietin Predicts Survival Rates in Clear Cell Renal Cell Carcinoma. Kidney Cancer 2017;1:143-149. doi 10.3233/KCA-170013

12 - Please review your abbreviations. The first time you use them, spell out the full term before the abbreviation in parenthesis

d) Conclusions: - In this sections, you need to state what do you conclude related to the primary goals of the study. In this way, you should add your comments about the possible role of Selenium in the HIF pathway.

e) Figures and Tables Adequate for the purpose of the manuscript

f) References Clearly stated

FINAL COMMENTS: Considering that treatment of advanced ccRCC actively changes throughout recent years, this manuscript is a valuable opportunity to highlight this issue. My suggestion for the editor is that it should be considered only after MAJOR REVIEWS.