Updated Pathways in Cardiorenal Continuum after Kidney Transplantation
Round 1
Reviewer 1 Report
I have reviewed the manuscript “Novel pathways in cardiorenal continuum after kidney transplantation”. The subject is relevant and stimulating to the field. The manuscript is well-written and easy to follow.
Novelty – Although the authors do address relatively less known pathways of disease -with truly interesting and provocative scientific gaps- in cardiorenal continuum after kidney transplantation , I am afraid the described pathways are not novel by definition. Instead, I think this review could be targeted to update on the subject by bring up together recent studies on such pathways. I would suggest to downplay the title and aims wording of the manuscript, as to align better with what could actually be offered -within a relatively short deadline- considering its present form.
Comprehensive revision of clinical evidence - In line with the previous comment, further revision of clinical literature is needed. While I think the authors made a good job delving with several mechanisms and compressing the literature into a reasonably sized manuscript, it should be underscored that it lacks a comprehensive revision of clinical evidence supporting actual translation of such pathways of disease (or its rectification) into short and long-term outcomes post kidney transplant.
Figure 1 – Some pathways do not make sense to me in the way they are presented. E.g., vascular remodeling leads to age?, early vascular ageing leads to AGE?
Author Response
Reviewer #1
Comments and Suggestions for Authors
I have reviewed the manuscript “Novel pathways in cardiorenal continuum after kidney transplantation”. The subject is relevant and stimulating to the field. The manuscript is well-written and easy to follow.
Novelty – Although the authors do address relatively less known pathways of disease -with truly interesting and provocative scientific gaps- in cardiorenal continuum after kidney transplantation , I am afraid the described pathways are not novel by definition. Instead, I think this review could be targeted to update on the subject by bring up together recent studies on such pathways. I would suggest to downplay the title and aims wording of the manuscript, as to align better with what could actually be offered -within a relatively short deadline- considering its present form.
Dear Reviewer#1,
Thank you for your time spent in revising our paper. In concordance with your suggestion, we have toned down the title and aims of this manuscript. Instead of “Novel” we used “Updated” in the title.
Comprehensive revision of clinical evidence - In line with the previous comment, further revision of clinical literature is needed. While I think the authors made a good job delving with several mechanisms and compressing the literature into a reasonably sized manuscript, it should be underscored that it lacks a comprehensive revision of clinical evidence supporting actual translation of such pathways of disease (or its rectification) into short and long-term outcomes post kidney transplant.
We agree that the absence of evidence-based literature might undermine some of our hypothesis. However, as clinicians working in kidney transplantation field, we have observed specific signals that are interesting and can stimulate future research. We have already initiated research projects in line with the proposed pathways, though, it is to early to interpret the results.
Figure 1 – Some pathways do not make sense to me in the way they are presented. E.g., vascular remodeling leads to age?, early vascular ageing leads to AGE?
Figure 1 has been corrected. The arrows reflecting on the direction of proposed pathways were inserted. To avoid misinterpretation, we deleted already known risk factor- “age”- from the picture.
Reviewer 2 Report
The Authors have investigated an important clinical problem: characterizing and treating pathologic cardiovascular processes occurring in kidney transplant recipients in their manuscript, “Novel pathways in cardiorenal continuum after kidney 2 transplantation”. I congratulate the Authors for this very well-written manuscript describing clinically relevant and particularly timely findings.
Author Response
Dear Reviewer#2,
We appreciate your input in revising and commenting on our paper.
Reviewer 3 Report
The article is very well written, the topic is innovative and scientifically sound. .
My only concern is Fig. 1 (Proposed pathways for impaired cardiorenal continuum after kidney transplantation) that could be improved to clarify which factors are donor-related and which are recipient-related
Author Response
Dear Reviewer#3,
Thank you for important point you have raised. We have clarified the title of Figure 1, since here we present only recipient related proposed pathways.
“Proposed pathways for impaired cardiorenal continuum after kidney transplantation in kidney transplant recipient”.
Round 2
Reviewer 1 Report
Concerning my first comment: "...I would suggest to downplay the title and aims wording of the manuscript, as to align better with what could actually be offered -within a relatively short deadline- considering its present form". I am afraid the revision of the authors was solely focused on downplaying the wording of the title (yet not the wording of the aims), but they did not actually level up the content of the manuscript to what "could actually be offered -within a relatively short deadline- considering its present form".
Thus, the revision I asked for is still missing. As mentioned earlier, appropriate revision of the available clinical evidence is lacking in this manuscript.
I did not ask for authors' evidence. Certainly, it may derive from currently available literature published by others, but it must be appropriately published to allow scrutiny before being cited. I am afraid it is not scientifically correct to rely on a comment by the authors stating that they have "observed specific signals that are interesting and can stimulate future research". Those signals are to be described, discussed and peer-reviewed before they can be included in a Review paper.
This way of proceeding in scientific publishing is not correct.
If the authors decide to perform the revision of the available clinical evidence and include it in the manuscript I will be happy to go over an (actually) revised version of the manuscript.
Author Response
Dear Reviewer,
We appreciate your criticism.
Your raised concerns were discussed with other co-authors. To our opinion the part of the paper that needed clarification was about Shrunken Pore Syndrome. We worked on that and added some sentences:
“The recently recognized GFR-marker cystatin C shows higher correlation to cardiovascular disease than creatinine47 . There are several explanatory models to this. One is the Shrunken pore syndrome (SPS)….”
” The evidence on changes in levels of various molecules, like those observed in SPS, are limited. Lower cystatin C and beta2-microglobulin based eGFR´s are shown to be superior to creatinine-based kidney function in predicting cardiovascular events and delayed graft function [61] as reported by the large Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) study. Additionally, increased concentration of gelatinases (MMP‐2 or gelatinase A), stromelysin (MMP‐3) and osteoprotegrin has been linked to both chronic transplant nephropathy[62] and SPS [49] albeit the absence of kidney failure [53].”
We have also revised the last paragraph and changed it to:
Indeed, SPS with normal measured glomerular filtration [53] does not ameliorate cardiovascular risk. Both living and deceased kidney donors with preexisting SPS could supposedly contribute to CVD and CV risk after kidney transplantation [63]. Hence, the use of cystatin C in renal transplantation needs further studies [59], especially if tubular injury co-occurs [64].
The changes in the introduction were also made:
“There is enough evidence supporting the fact that left ventricular function and left ventricular hypertrophy improves after kidney transplantation[9] .However, the impairement of vascular structure after kidney transplantation remains unchanged and might even worsen[10,11]. The pathophysiological mechanisms behind vascular remodeling observed in the posttransplant period include atherosclerosis, arteriosclerosis and the cardiorenal syndrome. For example, activation of the complement system [12-15], low-grade inflammation [2], and structural and functional changes of the glomerular filtration barrier [3] (Fig.1) – are the hallmarks of posttransplant changes in cardiovascular and renal continuum. We aim to critically review pathways that might help to better understand pathophysiological mechanisms and develop new treatment options for improving cardiovascular health after kidney transplantation. “
Best regards,
Agne Laucyte-Cibulskiene
