PONE-D-19-16719

Enhancement of solute clearance using pulsatile push-pull dialysate flow for the Quanta SC+: a novel clinic-to-home haemodialysis system

PLOS ONE

Dear Professor Buckberry,

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Pasqual Barretti, Ph.D., MD

Academic Editor

PLOS ONE

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We note that one or more of the authors are employed by a commercial company: Quanta Dialysis Technologies Ltd & EXcorLab GmbH.

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Additional Editor Comments (if provided):

Authors must fully answer the questions of the reviewers, in particular of the reviewer 1. After my reading of the text my decision is major revision

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Although it is known that the Push / pull mode is advantageous for clearances because of anti-fouling, it is highly novel that the Push / pull mode is incorporated into a home hemodialysis machine and put into practical use.

・Figs. should be as clear as possible.

・Add the number of original data number and standard deviation to the table and Fig.

Reviewer #2: Buckberry CH and coworkers are submitting a study assessing the potential benefit of adding convective clearance to the SC+ hemodialysis system developed by Quanta. By modifying the time pressure algorithm of filling/emptying cassette chambers they generate a push-pull like flow. As proof of concept they developed an invitro study showing that new algorithm was able to generate this alternate push-pull flow by US. They moved subsequently to a prototype with bench testing of various solute clearances (fluorescein-tagged dextran of various molecular weight) thereafter with invitro blood simulation (conductivity as surrogate of urea, myoglobin and B2M) and compared the modified SC+ to a predilution HDF model using conventional HD and predilution HDF system (high flux filter and Nikkiso DBS5 machine). In brief, the authors showed that their modified SC+ system ensured push-pull flow increasing instantaneous clearances by 10 to 15% and compared favorably with that achieved using pre-dilution HDF with a substitution fluid flow rate of 60 ml/min with the same dialyzer and marker molecules in blood simulated experiment. Interestingly clearance values using the push-pull method on the SC+ system, were maintained over the duration of treatment.

This is an interesting concept based on invitro studies taking benefits of minimal changes and time pressure algorithm modification in an existing innovative hemodialysis device. Now, the study raises several concerns that need to be addressed for clarification and better understanding:

1. This is a proof of concept study and not a clinical validation study meaning that further clinical trials in vivo are required to confirm their findings.

2. It is not clear why the modified SC+ with push-pull flow was compared with predilution HDF since my understanding of the algorithm modification is correct, it should be better suited to be compared with postdilution HDF. Internal filtration process associated with push-pull flow regime is mimicking postdilution action and not predilution.

3. In the study design, it not clear to me why solute clearances of modified SC+ developing push-pull like flow were not compared with standard SC+ algorithm machine. In other words, purely diffusive HD versus added convective component. Such design would have been better understood for showing the added value of the new algorithm.

4. Blood based invitro study is confusing and not necessarily correct since some clearance measurements are performed in a single-pass for small molecules and others in a recirculating pass for larger molecules. It would have been preferable to perform them in the same mode based on tank recirculation with log transformation time concentration decline to obtain a true overall clearance based on the slope decline. Furthermore, there is no mass balance calculation from blood and dialysate side to validate clearance calculation.

5. Surprisingly, solute clearances obtained in predilution HDF mode with DBS5 machine are lower over the all spectrum of markers than those obtained in pure hemodialysis. This is struggling and should be explained since it is not in line with the known fact that solute clearances are higher in HDF in particular for larger molecular compounds. One can suspect something went wrong with sampling due to predilution mode or calculations or both. In this setting one can expect clearances higher by about 30 ml/min through molecular weight spectrum.

6. From a presentation and wording perspective, introduction and discussion are too long and more related to the benefits of home therapy using the SC+ device. This is not the topic of this study. The authors should stay focused on the aim of the study which is to show some benefits on solute clearances by adding a convective component with a modified algorithm. In addition, the authors referred to benefits of using internal transport phenomenons using MCO membrane in term of solute clearances in standard HD. If this is the case, why not using MCO membrane in standard HD, instead of this modified new algorithm intended to increase convective clearances? How does it compare? What are benefits and risks of combining them?

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Reviewer #1: No

Reviewer #2: No

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Enhancement of solute clearance using pulsatile push-pull dialysate flow for the Quanta SC+: a novel clinic-to-home haemodialysis system

PONE-D-19-16719R1

Dear Dr. Buckberry,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Pasqual Barretti, Ph.D., MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I agree with the reviewers. I believe that the authors address all questions and the manuscript has improved a lot, being able to be published.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Thank you for having addressed my concerns, even if sometimes you were not able to provide the precise or adequate answer. It reads better and more scientifically exact now.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No