PONE-D-22-03854A convenient online desalination tube coupled with mass spectrometry for the direct detection of iodinated contrast media in untreated human spent hemodialysatesPLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: N/A

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: This manuscript present a very interesting work using Mass sprectrometry for the detection of biomomolecules in body fluids.

First of all, as chemist, I think it would be interesting to report not only the structures of the molecules detected in MS and indicated in table 1, but also of the ioversol and especially at least a proposal for the structure of the products ion at m/z 588.8 .

Please write correctly the formula of sulfate and phospate ions (Line 270)

Authors are also asked to pay attention to the visual quality of the figures, as they are blurry and sometimes difficult to read

Finnaly please check the style of the references so that they match to the guideline for authors corresponding to the journal

Reviewer #2: This manuscript presents an interesting application using a desalination tube fitted online to the mass spectrometer to analyze directly untreated human spent hemodialysates for the presence of hemodialisates. The technique used for sample clean-up is based on ion exchange; the concept of inline sample clean up prior to LC-MS of biomolecular solutions dates back to 2003 (Ref 5) and there is a report using a desalination tube for online LC-MS analysis published in 2021 (Ref 12).

This manuscript is well prepared, with current references and the findings are very interesting. The introduction and approach to sample preparation are thorough.

Please find below a couple of comments, questions and concerns:

1. In figures 2 and 3, the Intensity is expressed in %units. Regarding Patient #1: how do you know that CHDF “consistently removed the metabolites such as creatinine, L-cartinine, TMAP and iohexol with time”(lines 207-208)? Were you using an internal standard? It is difficult to estimate a decreasing trend when the Y-axis units are expressed in %.

2. Iohexol was not detected in patient #1 until after 24h of initiating CHDF (line 201). In patients #2 and #3 ioversol is detected in a higher concentration in the first couple of hours; ioversol signal decreases over time with the lowest concentration after 24h (lines 238-242).

Both iohexol and ioversol are contrasting agents. Why would you see such an opposite behaviour and what does it say about the use of these two contrasting agents?

3. In Patient #1, a range of metabolites such as creatinine, L-carnitine, TMAP are detected (lines 202-204). Were these metabolites observed in Patients #2 and #3? Can you comment on their signal levels with increase in time after the start of CHDF in Patients #2 and #3? Do these trends compare to what was observed in Patient #1?

4. What is the desalination efficiency of these tubes in terms of removing the excess inorganic salts ? Are there any reference studies that address this question?

5. Ioversol standards were infused via the online desalination tube into the TW MS/MS for method optimization. Can you comment if there was any loss of ioversol during the desalination tube stage? Were you able to establish a concentration range for the ioversol signal detected in the different samples?

6. How does the signal intensity for ioversol or iohexol help with determining and establishing the maximum and/ or safe levels of these contrasting agents in hemodialysates? Is there a known limit of detection for ioversol or iohexol in hemodialysates when using these instruments?

7. Lines 256-267, 277-279, 304-314 in the Discussion section contain review type’ information that would best fit in the Introduction section.

Although the findings are important for this application, there is not enough data for a full research article. So I suggest resubmitting as a communications article or major revision to add more data and address most concerns expressed here.

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Reviewer #1: No

Reviewer #2: No

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A convenient online desalination tube coupled with mass spectrometry for the direct detection of iodinated contrast media in untreated human spent hemodialysates

PONE-D-22-03854R1

Dear Dr. Sato,

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

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Kind regards,

Joseph Banoub, Ph,D., D. Sc., FCIC, FRSC

Academic Editor

PLOS ONE

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