Summary:
This is a review article focusing on the interactions between the renal (acute and chronic) and cerebrovascular pathological states. The authors elucidate the several mechanisms by which renal dysfunction could potentially contribute to stroke presentations and discuss the therapeutic options.

Specific Comments:
1. Abstract:

a) The overall gist of the abstract is present, but there are areas for instance, that lack continuity and are not grammatically aligned. The first sentence (lines 1-2) of the abstract is on stroke as an event which is followed by Line 3 “In particular, both acute kidney injury and chronic kidney disease (CKD) are associated with an increased risk of stroke and cerebrovascular events”.

b) Lines 4-5, “The underlying mechanistic approach between impaired renal function and stroke is yet to be explored” The way this sentence is structured implies that not much work has been done in this arena when in reality the next few sentences discusses about the work that contradict this statement.

c) Lines 9-11 : “Also, unique risk factors like bone mineral metabolism, uremic toxins, and anemia, along with the process of dialysis in CKD patients, eventually increases the risk of stroke.” Can the authors describe why anemia is catergorized as a unique risk factor while they state it as a traditional risk factor in the introduction? Grammatical modifications are also needed for this sentence.

1. Introduction:

a) Page 3 Lines 4-6 “It can be broadly divided into five subtypes, namely ischemic, hemorrhagic, transient ischemic attack, cryptogenic stroke and brain stem stroke(association; Bhattacharya et al., 2013)”
The classfication of stroke into ischemic, hemorrhagic, TIA, and then as cryptogenic stroke and brainstem stroke does not follow any particular pattern. The first two are the different clinical varieties of stroke, followed by a TIA that is an ischemic stroke variant and then cryptogenic stroke which is one of the etiologies of ischemic stroke and finally brainstem stroke that is based on location. Can the authors elaborate on the basis of this classification?
Also, they provided a citation in this context by “Bhattacharya, P., Pandey, A.K., Paul, S., Patnaik, R. & Yavagal, D.R. (2013) Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents. PLoS One, 8, e73481.” Can the authors clarify on the applicability of this article here? Of note, this article was also a self-citation and was retracted from the journal due to similarities with prior publications. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073481

b) Lines 20-23, Page 3 “Also, non-traditional risk factors like hyperhomocysteinemia, oxidative stress, inflammatory mediators, prothrombotic factors and cardiovascular causes like thromboembolism, atherosclerosis or renal causes like intradialytic hypotension (Brouns & De Deyn, 2004; Viggiano et al., 2019).”
This sentence ends abruptly without a clear meaning.

c) Page 4 lines 1-2, “A strong basis for cerebrorenal interactions is due to the anatomic, hemodynamic and vasoregulatory similarities of their vascular beds.”
Can the authors explain their rationale/basis on how the simiariies lead to cerebro-renal interactions?

d) Lines 15-18, Page 4 “mechanistic effect of various factors of kidney disease such as gut-derived toxins, atherosclerosis, cerebral small vessel disease, platelet dysfunction, and hyperphosphatemia, hyperlipidemia, hyperglycemia, etc. on the risk and pathophysiologic consequence on cerebrovascular diseases like stroke.” Grammatical corrections needed. Can the authors clarify on the information in this sentence where they categorize “cerebral small vessel disease under the factors of kidney disease” but then imply their effect on the risk and pathophysiological consequence of cerebrovascular diseases like stroke?

3) Mechanisms:

a)Page 5, line 1: The authors state “ Studies have reported that women suffer from anemia more often as compared to men (Kanic et al., 2018).” Can the authors describe the relevance of gender differences with regards to the context of this topic?

b) Page 5, lines 9-11 “Erythropoiesis stimulating agents (ESA) are used in the management of anemia and the detrimental outcomes of blood transfusions like secondary iron overload, infections and sensitization (Eschbach, 1989).” Can the authors clarify the meaning of this sentence especially in the setting of the current review?

d) Page 5 Lines 17-19 “specific uremic-induced inhibitors of erythropoiesis leads to anemia(Babitt & Lin, 2012). Though there are controversial studies identified where no specific uremic inhibitors were found(Eschbach, 19 1989).” Grammatical correction needed.

e) Page 5, Lines 12-13 “ESAs are also reported to cause death in cancer patients and promote malignancy(Bennett et al., 2009). “ Can the authors clarify the context this sentence was used?

f) Lines 22-25 Page 5 and Lines 1-3 Page 6. Unfortunately, case reports constitute poor support with regards to the strength of evidence regarding causality, especially with the extend of unmeasured confounding that is associated with single reports and the selection bias associated. Another aspect of this is that the authors document the stroke mechanism as a hypoxia / hypoperfusion when in reality several mechanisms including hypercoagulability, thrombocytosis/platelet dysfunction along with hypoxia have been proposed to contribute to the stroke presentations in this population.

e) Page 6, lines 20-21 “Atherosclerosis of intracranial and cervical arteries contributes to stroke resulting in sudden death.” Can the authors clarify this statement of atherosclerosis and sudden death or provide suitable references to this?

f) Page 7, lines 9-10 “ The prevalence of AF in men is generally higher than women in all age groups. (Kerr & Humphries, 2005).” Relevance of this in the current review context?

g) “The use of oral anticoagulants has been recommended in AF patients as prophylaxis for stroke, but its use is not well promoted due to the risk of increased bleeding(Qamar & Bhatt, 2016)” The authors need to clarify if this is in the setting of “advanced” renal dysfunction specifically considering that use of oral anticoagulation is recommended and encouraged in the setting of atrial fibrillation and in mild to moderate CKD who are not dialysis dependedent.

Aursulesei V, Costache II. Anticoagulation in chronic kidney disease: from guidelines to clinical practice. Clin Cardiol. 2019;42(8):774-782. doi:10.1002/clc.23196

h) Page 7, line s18-20 “Novel oral anticoagulants (NOACs) like apixaban, dabigatran, rivaroxaban are proved to be more effective and safer in treating stroke with AF” Grammatical corrections

i) Page 8, Lines 7-8 - A study has reported higher platelet count and reactivity in women(Ranucci et al., 2019). Relevance of this in the current review context?

j) Page 9, lines 12-13 “Uremic toxins (UTs) are the agents accumulating as a consequence of declining kidney function(Lisowska-Myjak, 2014).” “UTs plays a significant role in the establishment of” - Grammatical corrections needed.

k) Page 10 Lines 6-9 “Increased ADMA levels found in kidney diseases may be mainly attributed to two reasons, first, primarily its decreased excretion or second, deficiency of Dimethyl aminohydrolase 1 and 2 (DDAH) enzyme which are involved in the of ADMA breakdown into L-citrulline and dimethylamine(McCarty, 2004).” Grammar and sentence structuring.

l) Page 11, lines 14-15: The reference provided Gajjala et al. also has extensive information on cardiovascular disease but extremely limited information on cerebrovascular disease per se. The one by Kalim et al. has better information on this and should be appropriately referenced.

m) Page 11, ines 15-17 “Many studies report the prevalence of carbamylated protein homocitrulline in disorders like myocardial infarction, stroke, peripheral artery disease, etc” – Please provide appropriate references for this statement.

n) Page 12 lines 24-28 “ Plasma concentrations of Hcy are generally found to be higher in males than females. It is found to be dependent on genotype , diet, smoking, etc (Cohen et al., 2019).” Relevance of this in the review context?

o) Page 16, Lines 9-11 “Cerebral Microbleed (CMB) is a manifestation of cerebral small vessel disease, potentially representing its association with cerebrovascular events like stroke(Akoudad et al.,2015).” Can the authors clafify what they intend to convey with this sentence?

p) Page 16 lines 15-16 “Rotterdam study significantly states the first stroke outcome and its recurrence in patients exhibiting cerebral microbleeds(Akoudad et al., 2015).” Grammatical corrections needed.

q) Page 15 - The authors describe small vessel disease as one of the mechanisms by which renal dysfunction causes strokes, but, of note, small vessel disease is one of the stroke etiological subtypes and is an effect of inflammation, atherosclerosis, endothelial dysfunction, BBB dysruption etc, that are secondary to the renal dysfunction among other causes. Considering this as a direct renaly dysfunction related mechanism might need to be reconsidered.

r) Page 17, line 23 – The appropriate reference is noted below.
Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies [published correction appears in Lancet. 2003 Mar 22;361(9362):1060]. Lancet. 2002;360(9349):1903-1913. doi:10.1016/s0140-6736(02)11911-8

s) Page 19, lines 17-19
“It is majorly predicted to affect small perforating arteries like afferent arteries similarly in the brain also, microalbuminuria is shown to develop vascular damage resulting in microbleeds (Sandsmark et al., 2015).” Grammatical modifications needed.

t) Page 20 lines 16-17: “It is reported that statins have pleiotropic effects on intracranial vasculature and inflammatory modulation, promoting neuroprotection(Lewis & Segal, 2010).” Relevance of this in the review context?

u) Page 20 lines 3-15, “It is also reported that there is decreased cerebral blood flow(CBF) due to atherogenesis of aortocranial vessels in healthy patients for 2 or 3 years before the onset of stroke(Meyer et al., 1984)” Would this be better served in the arteriosclerosis section?

v) Page 21, line 8: “Palumbo et al., reported that transient ischemic attacks were 3 times more likely in patients with diabetes than in those without diabetes, and the risk of stroke was almost twice as great in patients with diabetes(Zsuga et al., 2012)” The Palumbo et al. paper has not been cited. Also, can the authors clarify the rationale of this statement in the setting of cerebro-renal interactions?

4) Treatment:

a) Page 22,lines 6-7 “Anticoagulation therapy for treating ischemic stroke accompanied by renal disease is not much preferred owing to bleeding concerns.” Please provide references to justify this statement and please refer to point 3 “g” since this statement is not completely accurate.

b) Page 22, lines 7-9 “A cohort study regarding the use of warfarin showed a reduction in stroke risk and but there was no significant reduction in non-end CKD patients.” Reference for this study.
c) Page 22, lines 9-10 “Furthermore, a study from Sweden (SWEDHEART) showed no bleeding risk along with low stroke risk in both types of the population(Olesen et al., 2012).”
This is inaccurate and excerpt from the original publication is as below -
Warfarin treatment was associated with a decreased risk of stroke or systemic thromboembolism among patients with chronic kidney disease, whereas warfarin and aspirin were associated with an increased risk of bleeding.
J.B. Olesen, G.Y. Lip, A.L. Kamper, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease N. Engl. J. Med., 367 (2012), pp. 625-635
d) Lines 16-19, Page 22: “A recent study involving 16,787 participants proved the superiority of the use of NOAC rather than vitamin k antagonists in case of stroke, hemorrhage, or all-cause death. The patients included had creatinine clearance > 25 ml/min, but there was no significant difference in bleeding risk among the patients in comparison to warfarin use.” Please provide reference for the study.

e) Page 23, Lines 1-3 “Interventions: Intravenous thrombolysis and intraarterial interventions like mechanical thrombectomy might also be considered as an option. Antihypertensive agents, SGLT-2 inhibitors or antihyperlipidemic drugs like statins might also be considered for use in treatment.” This is abrupt and mixes both acute reperfusion therapeutic options along with medications that are considered for secondary stroke management. A proper way to align this in the therapy is recommended. One way could be to stratify treatments as acute therapies versus stroke prevention strategies.

f) Page 25, lines 6-7 “ The prevalence of renal dysfunction and chronic kidney disease is rising as a significant risk factor for stroke.” Can the authors clarify the differentiation of “renal dysfunction” and chronic kidney disease?

g) Page 25, lines 11-12: “Studies reported that warfarin was used for decreasing the risk of stroke in CKD condition but was associated with an increased risk of bleeding(Olesen et al., 2012).” This is contradictory to the same reference information you provided in page 22, lines 9-10.

h) Page 25, lines 19-22: “Advanced cranial vascular imaging techniques like computed
tomography angiography (CTA), Magnetic resonance imaging angiography (MRA), and TCD ultrasonography are cost-effective and non-invasive methods to assess carotid plaque and arterial stenosis and the morphology of intracranial arteries(Chung et al., 2016).” Can the authors provide context/utility to this specifically in the setting of the cerebro-renal interaction and stroke? This was of note provided for TCD in the sentence following this.

5) Duplication of references. Page 27. Please check and revise.

Overall:
The authors present a review on the topic of Cerebro-renal Interaction and Stroke. As noted above, there are several areas that can be improved as delineated in my comments and suggestions. It would also better serve the manuscript if the authors choose to incorporate brevity and precision in their discussions. Prior to re-submission, I would recommend utilization of software to evaluate the similarity index with prior articles published on similar topics and use of English editing services considering the extensive grammatical issues throughout the manuscript - a few examples of which have been elucidated above.