The View of Pediatric Nephrotic Syndrome as a Podocytopathy

Round 1

Reviewer 1 Report

Overall, the article “The view of Nephrotic Syndrome as a Podocytopathy” is interesting to read, thorough with literature, and well drafted. However, there are few suggestions to the authors as mentioned below –

·      Table/s listing critical characteristics associated with different kinds of NS, possibly pathology, causes, diagnosis - validated biomarkers, available therapeutics/treatment, might be provided for better understanding of the readers.

·      Representative histological images might be used from published literature as a reference and cited while explaining section 2.4 “Histological classifications for focal segmental glomerular sclerosis” and again tabulated version of the text will aid in improving review understanding.

·      Line 94 – Authors mentioned slit diaphragm proteins “….. possibly Neph1”, cross check with literature for experimentally validated component proteins of slit diaphragm.

·      Lines 129-132 – Rewrite “When the syndrome begins in school age of adolescence, the possibility of NS secondary to systemic diseases must be considered [17] MCNS and Focal segmental glomerulosclerosis (FSGS) are the most common histological forms of primary NS” to make it understandable / easy to follow.

·      Line 187 – donor might be used instead of “donator” as its widely used terminology, similarly recipient instead of receiver.

·      Line 221 - FS or FP ?

Though well drafted, but at places basic punctuation’s / grammar needs fixing for instance, ".......remain present in the babie's circulation" – line 375.

Author Response

We would like to thank the reviewer. Please, see letter attached. 

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors have written a very comprehensive overview of nephrotic syndrome and the relationship between podocyte injury and proteinuria. Strengths of the paper include the thoroughness of the literature review and summary of relevant genetic and pathophysiological principals.  I do find that it is very long and challenging to get through. 

My suggestions are as follows:

1. Remove all mention of secondary causes of podocytopathies (lupus, diabetes, secondary FSGS etc).  I have attached a file with examples of potential areas of the paper to be removed.  The pathophysiology of secondary FSGS and secondary causes of proteinuria are much different than genetic and idiopathic and add unnecessary length and complexity for the reader.

The editors could also consider asking the authors to split this into two papers: one focusing on idiopathic and primary FSGS and MCD, the other focusing on genetic and congenital nephropathies since it is such a complex topic. 

2.  Page 1 Line 30 - Peak age of incidence is at 2-3 years old - please specify which disease you are referring to here (e.g. childhood nephrotic syndrome? minimal change disease?) and add a citation that supports this statement. 

3. Under heading pathophysiological mechanisms (section 2.1) I do not agree with the statement NS has an insidious onset and is frequently delayed.  Many patients present with rapid onset of edema and proteinuria. Please use a citation to support this statement if not revising. 

4. Under section 2.2 podocyte foot processes: Define integrin complexes upon first mention 

5. Under section 2.3 Histopathology of common types of nephrotic syndrome.  This includes a lot of extra information that is not actually related to the histopathology (e.g. frequency of diagnosis, primary circulating factor of FSGS).  Move this to other portions of the paper (e.g. under pathophysiology) or remove. 

Section 2.3.3: FSGS

Focus on primary and genetic FSGS here (not secondary). Instead of summarizing the case report of FSGS recurrence after transplant, find and cite an article looking at the frequency and outcomes of FSGS recurrence after transplant as it is a well known and defined entity that does not require such a detailed explanation. 

Comments for author File: Comments.pdf

The English language was easy to follow, no concerns. 

Author Response

We would like to thank the reviewer. Please refer to the letter attached.

Author Response File: Author Response.pdf

Reviewer 3 Report

The authors are attempting to compile the current literature surrounding Nephrotic syndrome and bring forth the idea that considering NS as a podocytopathy will lead to a better understanding. While the manuscript is written well in terms of readability, the following points raise serious concerns overall.

Major Concerns:

1.       Figure 1 is redrawn from another review article that the authors cite with the figure with no additional updates. You should not redraw a figure from another review article as is. Either the authors need to obtain proper permission to reuse the figure (which it doesn’t seem to have) or make their figure based on the current knowledge based on original research articles. The authors frame the section the figure belongs to as an “update on molecular anatomy and effacement”, yet the figure and the section are based on the paper they are citing from that was published 20 years ago. This is misleading as well.

2.       Many of the citations are other review articles including some of the reviews written by the senior author. If the authors are trying to mention a particularly novel idea another review has brought to attention, it should be cited as “reviewed by 1”. If the authors are trying to cite a scientific finding, the original manuscript by itself or together with the review should be cited; “2, reviewed by 1” or “2” (If the original article is 2 and the review article is 1). In any case, the citation of the original research manuscript is necessary. Please examine the review articles you are citing for the original articles. Much work has been done in this area in recent years that can be cited. Original articles including but not limited to PMID: 36454699, PMID: 34894725, PMID: 37866673, PMID: 37880610, PMID: 34569252, PMID: 34459222, PMID: 34423678 are recent and can be cited instead.

Author Response

We would like to thank the reviewer. Please see attached letter. 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

I believe authors have sufficiently addressed the comments/concerns, therefore I recommend the manuscript for publication.

Reviewer 2 Report

I believe the authors have addressed the reviewers comments adequately. 

Reviewer 3 Report

The concerns I had were adequately answered.