Submited on: 21 Sep 2017 12:27:22 AM GMT
Published on: 25 Sep 2017 09:30:38 AM GMT
Convincing in vitro, less convincing in vivo
Posted by Dr. Reto Krapf on 25 Sep 2017 02:09:35 PM GMT Reviewed by Author Invited Reviewers

  • What are the main claims of the paper and how important are they?

    The authors present convincing in vitro data using state of the art methodology. The data provide strong evidence for a gain of function mutation of the thick ascending limb Na/K/2Cl cotransporter. This is to the authors and mine knoweldge the first description in a human subject

  • Are these claims novel? If not, please specify papers that weaken the claims to the originality of this one.

    The report is novel.

  • Are the claims properly placed in the context of the previous literature?

    Yes. The selection of the cited literature is adequate and the discussion is well written

  • Do the results support the claims? If not, what other evidence is required?

    The in vitro evidence for a gain of function is quite convincing. I am far less sure about the human data and the claim that this mutation is responsible for the "cyclic edema" observed in this case:

    First, 24 h urine data in a patient apparently under her self selected regular diet, reflect primarily dietary intake. The renin/aldo levels (were they determined with the patient lying, sitting or standing") would be compatible with slight volume expansion at that single time point, however, an increase in NKCC2 activity would not be expected to result in chronicly low 24h urinary NaCl, Ca and mg excretion rates. It would be interesting to study this patient under metabolic diet conditions going from low to high dietary NaCl intake and tracking the effects on urinary excretion rates (including fractional exretion rates), blood pressure and renin/aldo levels. The *furosemide" test described by the authors should contain infos on dosage, administration route etc. This metabolic study would also allow tracking of the blood pressure effect. I did not find any blood pressure value in the paper! Was the patient hypertensive? How do the authors explain the cyclicity? Any clues that this young lady migh be bulimic?

  • If a protocol is provided, for example for a randomized controlled trial, are there any important deviations from it? If so, have the authors explained adequately why the deviations occurred?

    Not applicable

  • Is the methodology valid? Does the paper offer enough details of its methodology that its experiments or its analyses could be reproduced?

    See my comments under "do the results support the claim", but could not go furhter due to space limit. I do not think that the authors have proven that the mutation is functionally severe enough to explain the clinical observation.

  • Would any other experiments or additional information improve the paper? How much better would the paper be if this extra work was done, and how difficult would such work be to do, or to provide?

    see above

  • Is this paper outstanding in its discipline? (For example, would you like to see this work presented in a seminar at your hospital or university? Do you feel these results need to be incorporated in your next general lecture on the subject?) If yes, what makes it outstanding? If not, why not?

    This paper is very interesting, with a diligent metabolic workup it might become outstanding.

  • Other Comments:


  • Competing interests:
  • Invited by the author to review this article? :
  • Have you previously published on this or a similar topic?:
  • References:
  • Experience and credentials in the specific area of science:

    I am an academic nephrology with longstanding Research experience in electrolyte and acid-base regulation.

  • How to cite:  Krapf R .Convincing in vitro, less convincing in vivo[Review of the article 'A Gain of Function NKCC2 Mutation in a Patient with Chronic Cyclic Edema ' by Kurtz I].WebmedCentral 2017;8(9):WMCRW003365
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