Klotho Deficiency in Severe COVID-19: A Unifying Hypothesis
Round 1
Reviewer 1 Report
In the manuscript “Klotho Deficiency in Severe COVID-19: A Unifying Hypothesis”, Campos-Obando and colleagues propose a possible importance of Klotho in the pathogenesis of COVID-19. The authors hypothesize tha Klotho deficiency might be a trigger associated with COVID-19 severity in different contexts, including ageing. The concept is good, although highly speculative. At the end, the authors discuss 2 findings in pre-clinical studies that more solidly support the hypothesis. The article is in general well written and reasonably organized, and the idea is intriguing. I have in general minor suggestions to strengthen the manuscript, but one major comment must be addressed.
Major:
Again, Metformin and Statins have their effects mediated by other players beside Klotho. The authors must add a brief paragraph for each treatment discussing possible Klotho-independent effects of those treatments. For example, statins change cholesterol levels, what might change membrane dynamics and impair viral infection and replication, explaining all the effects discussed in this review. The authors must also present the findings that support Klotho-independent effects.
Minor:
A more solid introduction is required to fully conceptualize the cell biology of Klotho. A description of Klotho structure, with the domains, as well as its functional roles would be beneficial. How is Klotho involved in ageing? Does it require its canonical role in phosphate transport? How Klotho promotes intracellular signaling? How Klotho is detected in plasma? What is the relation of AKI and serum Klotho levels? Distal tubule secretion of Klotho is the major source of plasma Klotho pools? Those questions will better support the basic aspects of the central player in the review.
In the 5th paragraph, line 74 the authors state “These data suggest that both chronic and acute Klotho deficiency increases the risk for COVID-19 severity and mortality.” This is a clear overstatement based on the reference and results discussed up to that point. The authors should consider softening this statement or presenting data that would more strongly support this hypothesis: Is there evidence that Klotho deficiency enhances viral infection susceptibility in murine models or in patients, not necessarily COVID-19? Reconstitution of Klotho rescues this phenotype? Is there a correlation between Klotho levels and COVID-19 outcome?
The authors should present figures to synthesize the findings discussed. The authors could create a table summarizing the findings from clinical and pre-clinical data, for example.
Check for typos across the text, such as inflamaasome (line 87).
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The manuscript is interesting, well written and gives important advances in the understanding of pathophysiology of COVID-19, suggesting new possibilities of treatment.
In their manuscript the authors suggest that low Klotho levels may play a key role in severe COVID-19, and that increasing Klotho levels could have a beneficial effect in the treatment of the disease. The study is very interesting and well written. However, it is now clear that there is a relationship between the presence of insulin resistance and the worsening trend of COVID-19, so much so that a better prognosis has been demonstrated in patients taking metformin. Furthermore, low levels of Klotho are known to be present in insulin resistant individuals. Therefore, the authors should discuss these relationships in more detail, because the basis of their findings may be the presence of insulin resistance in patients with low Klotho levels.
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
The concerns raised were promptly answered by the authors, and the manuscript was greatly improved.
No comments
Reviewer 2 Report
The authors have revised the manuscript according to the reviewer's suggestions
The manuscript has been revised by the authors according to the reviewr's suggestions
