Potential Renal Damage Biomarkers in Alport Syndrome—A Review of the Literature

Round 1

Reviewer 1 Report

In general I thought this was a very interesting and novel review. Was this a systematic review – of so probably needs this spelled out more clearly…

 

I think though that the Abstract needs to have a summary of the results in it – it currently reads like an Introduction. Gene names should be in italics. My understanding is that collagen IV represents about 70% of the dry weight of the GBM – not 50%. In the Abstract, ‘encode’ is probably better than ‘codif’y. In the Introduction – also I am not sure that pathogenic variants affect the retinal pigment epithelium – but rather than membranes in the retina. It is no longer correct to state that Alport syndrome occurs in one in 5000 individuals – the manuscript in 2021 JASN from Gibson demonstrates that X-linked disease occurs in about one in 2000 and AD Alport syndrome or heterozygous variants in COL4A3 or COL4A4 occur in about 100.

 

Digenic Alport syndrome is best interpreted using the inheritance of the underlying variants – so for COL4A5 plus a COL4A3 variant, it must include X-linked inheritance.

 

I think that the diagnosis of Alport syndrome now depends on genetic evidence and not on three of the four clinical criteria – which excluded AD disease anyway.

 

It would be helpful if the conclusion actually recommended the tests that are most helpful and the studies that still need to be undertaken.  

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

Gomes and colleagues have written a concise review of the current understanding of the pathogenesis of Alport syndrome and the published literature on biomarkers of kidney disease progression in patients with this condition.  I think the authors serve a useful purpose by compiling the various Alport biomarker studies in a single resource.

The manuscript contains a number of minor typographical and grammatical errors that should be corrected.  There are also some misconceptions that should be addressed, and several relevant publications that are not cited.  These are enumerated below.

1.  Page 4, lines 167-171: This paragraph is unclearly written and somewhat misleading in regards to Alport syndrome (AS), and omits relevant literature specific to AS.  In lines 170-171, referring to estimated GFR and albuminuria, the authors state that "these conventional biomarkers only increase when significant renal function has been lost and kidney damage is advanced."  First, eGFR decreases rather than increases. Second, a study of biomarkers and kidney pathology in dogs with X-linked AS (Benali et al, Vet Pathol, 2016;53:803-812) showed that albuminuria precedes the appearance of multiple pathological indicators of glomerular and tubulointerstitial injury.  It has also been demonstrated that in boys with AS that eGFR, expressed as creatinine clearance, remains normal until there is detectable expansion of interstitial volume, and that eGFR is inversely correlated with interstitial volumes (Kashtan et al, Pediatr Nephrol, 1988;12:269-274).

2.  There are a number of typographical errors in Table 1:

2018 study, column 4:  "at de same group" needs correction

2020 study, column 2:  "1 AS pediatric patients" is likely incorrect

2022 study, column 4:  UMCP-1 should be uMCP-1

3.  Page 6, lines 228-229:  The sentence "in 38 patients with longitudinal follow-up, a significantly correlation observed with both variables, uEDF/cr and eGFR, decresead with age". This sentence needs to be revised, and decreased should be spelled correctly.

4.  Page 6, line 252:  The second "and" should be deleted.

5.  Page 7, line 267:  "was" should be "were"

6.  Page 7, line 268:  "GMB" should be "GBM"

7.   Page 7, MicroRNA section:  A relevant publication that is not included is another study of miRNA-21 in dogs with XLAS (Clark et al, Vet Pathol, 2019;56:93-105).

8.  Page 8, line 336:  "fundi" should be "funding"

9.  I think it would be useful for the authors to distinguish biomarkers that may reliably indicate a higher risk of kidney disease progression (eg uMCP-1, HMGB1, TGFb-1) from those that appear when renal damage is already established (eg miRNA-21, uEGF).  The way a biomarker is used in clinical practice could be influenced by whether the biomarker is predictive or confirmative of kidney damage.

 

Author Response

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Author Response File: Author Response.docx