Reviewer ’s report  
 
Title:  First clinica l experience in 14 patients treated with ADVOS: A study on feasibility, safety 
and efficacy of a new type of albumin dialysis  
 
Version: 0 Date: 25 Jul 2016 
 
Reviewer:  Vincenzo  Palmieri  
 
Reviewer’s report:  
 
The description of the pr otocol for the inclusion of patients is rather complicated. It seems that a 
part of the patients have been evaluated prospectively and another set of patients on a 
retrospective basis. The authors should be more explicit and to clarify this point, that cou ld 
represent another limitation of the study.  
 
The authors should also explain the meaning of the sentence (enclosed in the paragraph on the 
"Patients"): "After the run -in phase, the studies HEPATICUS -1 and HEPATICUS -2 have not 
been continued due to lack of  feasibility of the trial -concept." What do the authors mean? Is this 
lack of feasibility due to some specific reasons? Does this "lack of feasibility" explain the very 
long time passed from the time of the run -in phase (2012) and the time of submission of  the 
paper? This long interval seems really unreasonable since the median follow up of the patients 
has last no more than 28 days. In the conclusion the authors say that their study demonstrates the 
"feasibility" of the ADVOS procedure, but the just mentio ned sentence seems to be in contrast 
with this conclusion. All these aspects have to be elucidated by the authors.  
 
The authors have to explain the reason by which the transplantation was not an option for most 
of the patients enclosed in the study (12/14) even if the MELD score was in the range values 
pertinent for this purpose.  
 
In the paragraph on the Endpoints, it is not clear how many hours or days after the ADVOS they 
performed the evaluation of the effect of the treatment on the biochemical parameters . 
 
In the table 3, please correct the title "Treatment time (19)".  
 
What is the reason of the so huge differences in the time of duration of each session? When is it 
time to interrupt each treatment?  
 
In the same way, what is the reason of the so huge differe nces in the number of session?  
 
The evaluation of the effectiveness of the procedure in the elimination of bilirubin, creatinine 
and BUN has been done ONLY on the first session of treatment for each patient: this means that 
no conclusion may be drawn on th e existence of any correlation between the effect of the 
ADVOS on the biochemical parameters and the 28d survival. So, the aim of the study is properly 
the evaluation of the immediate effect (and not effectiveness) of the ADVOS on these 
parameters. This re present a critical limitation of the entire study and has to be well emphasized.  
"Seven of 14 patients had undergone renal replacement therapy before the first ADVOS 
treatment." Is it possible to argue any effect of this undefined nephrology treatment on t he effect 
of the ADVOS?  
 
The authors describe some "correlation" among variables but in the Statistical section, no test of 
correlation has been mentioned.  
 
The authors describe correlation among baseline values of biochemical variables and absolute or 
relative changes after the ADVOS procedure: it is not clear whether the "Delta" that they 
describe in the table 3 is referred to one or to the second type of change.  
 
In conclusion, this study seems to be interesting but it has several methodological limitations  
only in part recognized by the authors. Main limitation is that it is simply a study on the effect 
(and not effectiveness) and brief term safety of the procedure. No information are available on 
feasibility and on effectiveness (that means potential effec t on the survival). Some concerns arise 
also on the safety, since the outcome has been very poor in terms of very short term survival.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the  necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.   
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the  editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understand that my name wil l be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available und er an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title:  First clinica l experience in 14 patients treated with ADVOS: A study on feasibility, safety 
and efficacy of a new type of albumin dialysis  
 
Version: 0 Date: 25 Jul 2016 
 
Reviewer:  Vincenzo  Palmieri  
 
Reviewer’s report:  
 
The description of the pr otocol for the inclusion of patients is rather complicated. It seems that a 
part of the patients have been evaluated prospectively and another set of patients on a 
retrospective basis. The authors should be more explicit and to clarify this point, that cou ld 
represent another limitation of the study.  
 
The authors should also explain the meaning of the sentence (enclosed in the paragraph on the 
"Patients"): "After the run -in phase, the studies HEPATICUS -1 and HEPATICUS -2 have not 
been continued due to lack of  feasibility of the trial -concept." What do the authors mean? Is this 
lack of feasibility due to some specific reasons? Does this "lack of feasibility" explain the very 
long time passed from the time of the run -in phase (2012) and the time of submission of  the 
paper? This long interval seems really unreasonable since the median follow up of the patients 
has last no more than 28 days. In the conclusion the authors say that their study demonstrates the 
"feasibility" of the ADVOS procedure, but the just mentio ned sentence seems to be in contrast 
with this conclusion. All these aspects have to be elucidated by the authors.  
 
The authors have to explain the reason by which the transplantation was not an option for most 
of the patients enclosed in the study (12/14) even if the MELD score was in the range values 
pertinent for this purpose.  
 
In the paragraph on the Endpoints, it is not clear how many hours or days after the ADVOS they 
performed the evaluation of the effect of the treatment on the biochemical parameters . 
 
In the table 3, please correct the title "Treatment time (19)".  
 
What is the reason of the so huge differences in the time of duration of each session? When is it 
time to interrupt each treatment?  
 
In the same way, what is the reason of the so huge differe nces in the number of session?  
 
The evaluation of the effectiveness of the procedure in the elimination of bilirubin, creatinine 
and BUN has been done ONLY on the first session of treatment for each patient: this means that 
no conclusion may be drawn on th e existence of any correlation between the effect of the 
ADVOS on the biochemical parameters and the 28d survival. So, the aim of the study is properly 
the evaluation of the immediate effect (and not effectiveness) of the ADVOS on these 
parameters. This re present a critical limitation of the entire study and has to be well emphasized.  
"Seven of 14 patients had undergone renal replacement therapy before the first ADVOS 
treatment." Is it possible to argue any effect of this undefined nephrology treatment on t he effect 
of the ADVOS?  
 
The authors describe some "correlation" among variables but in the Statistical section, no test of 
correlation has been mentioned.  
 
The authors describe correlation among baseline values of biochemical variables and absolute or 
relative changes after the ADVOS procedure: it is not clear whether the "Delta" that they 
describe in the table 3 is referred to one or to the second type of change.  
 
In conclusion, this study seems to be interesting but it has several methodological limitations  
only in part recognized by the authors. Main limitation is that it is simply a study on the effect 
(and not effectiveness) and brief term safety of the procedure. No information are available on 
feasibility and on effectiveness (that means potential effec t on the survival). Some concerns arise 
also on the safety, since the outcome has been very poor in terms of very short term survival.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the  necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.   
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the  editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understand that my name wil l be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available und er an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title:  First clinica l experience in 14 patients treated with ADVOS: A study on feasibility, safety 
and efficacy of a new type of albumin dialysis  
 
Version: 0 Date: 25 Jul 2016 
 
Reviewer:  Vincenzo  Palmieri  
 
Reviewer’s report:  
 
The description of the pr otocol for the inclusion of patients is rather complicated. It seems that a 
part of the patients have been evaluated prospectively and another set of patients on a 
retrospective basis. The authors should be more explicit and to clarify this point, that cou ld 
represent another limitation of the study.  
 
The authors should also explain the meaning of the sentence (enclosed in the paragraph on the 
"Patients"): "After the run -in phase, the studies HEPATICUS -1 and HEPATICUS -2 have not 
been continued due to lack of  feasibility of the trial -concept." What do the authors mean? Is this 
lack of feasibility due to some specific reasons? Does this "lack of feasibility" explain the very 
long time passed from the time of the run -in phase (2012) and the time of submission of  the 
paper? This long interval seems really unreasonable since the median follow up of the patients 
has last no more than 28 days. In the conclusion the authors say that their study demonstrates the 
"feasibility" of the ADVOS procedure, but the just mentio ned sentence seems to be in contrast 
with this conclusion. All these aspects have to be elucidated by the authors.  
 
The authors have to explain the reason by which the transplantation was not an option for most 
of the patients enclosed in the study (12/14) even if the MELD score was in the range values 
pertinent for this purpose.  
 
In the paragraph on the Endpoints, it is not clear how many hours or days after the ADVOS they 
performed the evaluation of the effect of the treatment on the biochemical parameters . 
 
In the table 3, please correct the title "Treatment time (19)".  
 
What is the reason of the so huge differences in the time of duration of each session? When is it 
time to interrupt each treatment?  
 
In the same way, what is the reason of the so huge differe nces in the number of session?  
 
The evaluation of the effectiveness of the procedure in the elimination of bilirubin, creatinine 
and BUN has been done ONLY on the first session of treatment for each patient: this means that 
no conclusion may be drawn on th e existence of any correlation between the effect of the 
ADVOS on the biochemical parameters and the 28d survival. So, the aim of the study is properly 
the evaluation of the immediate effect (and not effectiveness) of the ADVOS on these 
parameters. This re present a critical limitation of the entire study and has to be well emphasized.  
"Seven of 14 patients had undergone renal replacement therapy before the first ADVOS 
treatment." Is it possible to argue any effect of this undefined nephrology treatment on t he effect 
of the ADVOS?  
 
The authors describe some "correlation" among variables but in the Statistical section, no test of 
correlation has been mentioned.  
 
The authors describe correlation among baseline values of biochemical variables and absolute or 
relative changes after the ADVOS procedure: it is not clear whether the "Delta" that they 
describe in the table 3 is referred to one or to the second type of change.  
 
In conclusion, this study seems to be interesting but it has several methodological limitations  
only in part recognized by the authors. Main limitation is that it is simply a study on the effect 
(and not effectiveness) and brief term safety of the procedure. No information are available on 
feasibility and on effectiveness (that means potential effec t on the survival). Some concerns arise 
also on the safety, since the outcome has been very poor in terms of very short term survival.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the  necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.   
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the  editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understand that my name wil l be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available und er an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
assistant