A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases

Round 1

Reviewer 1 Report

Tubulointerstitial kidney disease as a cause of chronic kidney disease through mechanisms that lead to interstitial fibrosis and tubular atrophy has unpredictable evolution. Knowledge of genetic influences is of paramount importance to assist in the development of the possible course of the disease. The identification of deleterious genes that may influence the prognosis of the disease, differentiating harmful courses from those with a better prognosis. The present work has this purpose. In the future, this information may be important when gene therapy becomes a reality.

Author Response

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Reviewer 2 Report

In this review, this review explores the expanding repertoire of genes associated with TKD and the range of phenotypic manifestations they may cause. Additionally, it highlights the emerging evidence for the involvement of modifier genes that bridge the gap between seemingly rare monogenic TKDs and polygenic non-proteinuric CKDs. Overall, this manuscript is well written and informative. For this reason, I have some minor suggestions to improve the manuscript:

1. In the introduction, some sentences are quite long and complex, which might make it harder for readers to follow the information. Try to break down long sentences into shorter ones to improve readability. .

2. Some statements reference specific studies or data, but there are no direct citations for these claims. It would be helpful to include references for such statements to support the information presented.

Author Response

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Reviewer 3 Report

Reviewing the manuscript entitled, “A role for genetic modifiers in tubulointerstitial kidney dis-eases” by Leggatt GP et al., this is a review article focusing on genetic modification of tubulointerstitial kidney diseases (TKD). The authors also describe associations with polygenic abnormalities, focusing on single-gene abnormalities, which has the potential to become an important review in future TKD. Therefore, the authors should address the following concerns.

 Table 1 indicates the clinical entities and phenotypic descriptors constituting tubulointerstitial kidney diseases (TKD). However, in spite of allocating many pages, descriptions of the diseases shown in Table 1 are scarce. It's hard to understand what this table means. In addition, the table itself is difficult to read. Some disease names, phenotypes and gene names overlap. The authors need to modify it.

 The order of the genes described in Table 2 does not match the order of the genes described, making it extremely difficult to read. The author should clearly add which gene in Table 2 the described gene is. And the authors should describe genes listed in Table 2 but not described in the text as “other” or desired.

Table 2 indicates monogenic causes of TKD and evidence of modifier genes. And it contains many autosomal recessive genes such as renal tubular dysgenesis. On the other hand, figure 1 does not have a category called autosomal recessive TKD. It is difficult to understand the relationship between Tables 1 and 2 through Figure1.

 All figures are small and hard to read.

Author Response

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