Does Monosodium Urate Crystal Vascular Deposition Exist? Review of the Evidence
Angelo L. Gaffo
Round 1
Reviewer 1 Report
The proposed manuscript aims to critically review the experimental evidence relating to the presence or absence of monosodium urate crystals in vascular tissues. This is an interesting and controversial topic which has also been neglected in both clinical and pre-clinical research and which, as rightly pointed out by the authors, if confirmed could also have major implications in the clinic.
The work is rigorous and includes all the publications on the subject, discussing them in an adequate and rigorous manner. Everything is developed in a coherent and logical way.
The only two notes I would like to suggest, if the authors and the editor deem it appropriate, concern the following aspects:
1) There are no hints of hypotheses and effects from the physiopathological point of view relating to the extra-articular (and in particular vascular) deposition of Urate crystals either as a mechanism of possible formation or as a hypothetical causative mechanism for the onset of cardiovascular pathologies .
2) The study critically discusses the methodologies used, rightly highlighting their limits and reasons for confusion; however some of the studies cited also support histopathological evidence such as the presence of leukocyte infiltrate in the tissues in which the crystals are deposited and more. This aspect which, in my opinion, should be considered as equally important as the chemical-physical methods discussed, should be developed.
Author Response
The proposed manuscript aims to critically review the experimental evidence relating to the presence or absence of monosodium urate crystals in vascular tissues. This is an interesting and controversial topic which has also been neglected in both clinical and pre-clinical research and which, as rightly pointed out by the authors, if confirmed could also have major implications in the clinic.
The work is rigorous and includes all the publications on the subject, discussing them in an adequate and rigorous manner. Everything is developed in a coherent and logical way.
- We thank the reviewer for the kind comments.
The only two notes I would like to suggest, if the authors and the editor deem it appropriate, concern the following aspects:
1) There are no hints of hypotheses and effects from the physiopathological point of view relating to the extra-articular (and in particular vascular) deposition of Urate crystals either as a mechanism of possible formation or as a hypothetical causative mechanism for the onset of cardiovascular pathologies.
(A) We thank the reviewer for the suggestion. We added the following in the introduction section to support the rationale of asking ourselves whether these deposits exist or not : ‘Theoretically, urate can crystalize anywhere, and have been found beyond joints and their surroundings(10, 11). Urate formation is mediated by xanthine oxidase activity, which has been found to be high in atheroma plaques(4) where a higher urate level could in theory lead to a local urate crystallization process. Such vascular crystal deposition could generate local inflammation and lead to endoluminal obstruction such as the one occurring in atheroma, and cause cardiovascular events.’
2) The study critically discusses the methodologies used, rightly highlighting their limits and reasons for confusion; however some of the studies cited also support histopathological evidence such as the presence of leukocyte infiltrate in the tissues in which the crystals are deposited and more. This aspect which, in my opinion, should be considered as equally important as the chemical-physical methods discussed, should be developed.
(A) We understand the reviewer’s point and developed this point as recommended. However, as recently published in GUCDD journal by Mariano Andrès, cholesterol crystals in atheroma can also be responsible for this leukocyte infiltrate which is therefore quite unspecific. We added the following page 4: ‘Furthermore, the inflammatory response to MSU crystals mediated by the NLRP3 inflammasome is not specific as the same pathway is known to be activated by cholesterol crystals in atheroma plaques (4, 17, 18). The histopathological evidence of leukocyte infiltrate in vessel walls near crystals cannot ascertain their nature.’ And page 6 ‘Authors acknowledged how difficult crystal observation with polarized light microscopy is on tissue slices, and that typical MSU crystals were essentially found in the prostates which were also examined. The local cellular inflammatory infiltrate also varied from one site of crystal deposition to the other.’
Reviewer 2 Report
This is a very nice summary of the evidence for a controversial topic. Authors should be commended for performing this review. I have minor observations:
-Found the first phrase of the introduction confusing: it is open to debate if CV or renal disease could be the main issue. Also, is probably incorrect to say that gout has a high mortality per se, when it really is through its disease associations.
-When discussing the two hypothesis also there is lack of clarity: the first hypothesis mentions inflammation driven by MSU crystal deposition. Is this in joints and periarticular tissues as it is well-known in gout? I think so but this deserves clarification, as the second hypothesis mentions MSU deposition in vessels. As written the two hypotheses seems the same.
-Would consider adding the reference numbers in the manuscript to table 1.
-Page 5: why is “uric acid”, “symptomatic” in quotations?
Some confusing sentences in the introduction. Suggest another read and review.
Author Response
Reviewer 2
This is a very nice summary of the evidence for a controversial topic. Authors should be commended for performing this review.
- We thank the reviewer for the kind comment.
I have minor observations:
-Found the first phrase of the introduction confusing: it is open to debate if CV or renal disease could be the main issue. Also, is probably incorrect to say that gout has a high mortality per se, when it really is through its disease associations.
(A) We modified the first sentence for the following: ‘Beyond the excruciating joint pain it causes, the main issue with gout is its high association with comorbidities including cardiovascular diseases (CVD) which may explain the higher mortality of associated with the disease’
-When discussing the two hypothesis also there is lack of clarity: the first hypothesis mentions inflammation driven by MSU crystal deposition. Is this in joints and periarticular tissues as it is well-known in gout? I think so but this deserves clarification, as the second hypothesis mentions MSU deposition in vessels. As written the two hypotheses seems the same.
(A) We thank the reviewer for pointing this out, she/he is indeed correct. We modified this part of the introduction section and specified “in joints and peri-articular tissues” when needed for clarity.
-Would consider adding the reference numbers in the manuscript to table 1.
(A) We thank the reviewer and added the references inside Tables 1 and 2
-Page 5: why is “uric acid”, “symptomatic” in quotations?
(A) We removed the quotation of symptomatic as we had explained earlier what the authors had meant. For uric acid, we developed earlier in the revised version that the authors probably meant ‘urate’ as it is the basic soluble form found in the body (and not its acid form).
Comments on the Quality of English Language
Some confusing sentences in the introduction. Suggest another read and review.
- The sentences of the introduction were edited for clarity.
