Non-Pharmacological Activation of the Renal Kallikrein–Kinin System: Dietary Potassium as a Novel Renoprotective Approach

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review written by Ardiles and Figueroa highlights the renoprotective effect of dietary potassium in pre-clinical models of chronic kidney disease (CKD). Compelling evidence suggests that potassium-rich diets stimulate the renal kallikrein-kinin system (KKS), which reverses hypertension and CKD progression by acting as a vasodilator, anti-inflammatory, and antifibrotic system in the distal nephron. The mechanism involves the up-regulation of kinin B₂ receptor expression, leading to reduced blood pressure, oxidative stress, apoptosis, inflammation, and fibrosis. In humans, higher potassium intake enhances kallikrein excretion and lowers cardiovascular and renal risk, independently of aldosterone, and low potassium intake has the potential to exacerbate CKD progression. Combined with sodium reduction, a potassium-rich diet represents a rational, low-cost renoprotective strategy that could mitigate CKD progression and improve cardiovascular health.

This is a well-written and comprehensive review with a potential clinical impact. Nevertheless,

a few major issues need to be adequately addressed:

1- Indicate in Abstract and Methods whether or not this is a narrative review, following scholarly standards for non-systematic literature syntheses (SANRA). How were performed the literature search and sources? Identify study selection and eligibility with explicit inclusion and exclusion criteria. Is this a selection of articles published in English only and limited or not to original research articles? What is the pre-defined time frame covered by this work?

2- The concept described herein that the stimulation of the KKS through potassium-rich diets brings cardiovascular and renal protective effects is not original per se since it has been described close to 40 years ago (refs 25, 27, 115, 118-123). Also, the renoprotective effects of the KKS and ACEi are well known. This review focuses mainly on historical studies while more recent studies should also be included and discussed. Hence, this review needs updating. I would suggest to complement with Tables to dissociate pre-clinical and clinical studies.

3- The role of the kinin B1 receptor in chronic kidney disease has been completely overlooked. Recent studies show the involvement of B1R in renal inflammation, oxidative stress and fibrosis. While the B2 receptor appears to exert protective effect, the B1 receptor is deleterious in several renal diseases.

Other specific points to address:

Juxtaglomerular cells as the site of renin synthesis and storage should be better identified in Figure 1 and in the text (line 88); this is part of the afferent arteriole.

Line 96: delete JE049 in reference to HOE140

Line 103, Figure 1 legend: the macula dense (MD). Should be macula densa (MD). The macula densa is found in the terminal portion of the distal straight tubule (thick ascending limb of the loop of Henle), after which the distal convoluted tubule begins. Make it clear! Also confirm whether kallikrein and kininogen are synthesised only by principal cells and not by intercallar cells in the renal tubule.

Line 110: …sodium and water absorption producing diuresis and natriuresis. Change «absorption» by «reabsorption»

Line 222: TGF-b1 should be replaced by TGF-β1

Lines 256-259: make clear that kinins activate eNOS via B2R and iNOS via B1R with appropriate references.

Line 271: … the pleiotropic effects of the KKS on the central nervous system [68]. Ref 68 is not relevant for this statement as this citation does not refer to CNS.

Figure 2 is confused: Confirm the type of cells (principal and/or intercallar) on which B2R and K+ act. Why GPCR structure on cells are activated by K+.

 

 

 

 

Author Response

It is in word archive

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript focuses on the concept that dietary potassium intake may confer renoprotective effects through the modulation of the renal kallikrein–kinin system (KKS). While the overall narrative is clearly structured, the manuscript exhibits several substantive methodological and translational limitations that warrant major revision before it can meet the standards of the journal. 
First, although the authors claim to integrate evidence from both experimental models and clinical studies, the manuscript does not provide any explicit description of the literature search strategy or inclusion and exclusion criteria, making it impossible for readers to assess the completeness or potential bias in study selection. 
Second, the manuscript relies heavily on animal data and on previously published work from the authors’ group, whereas human data are limited in scope and insufficiently differentiated between observational studies and interventional trials, resulting in an unclear hierarchy of evidence. 
In addition, the discussion of the purported benefits of high potassium intake and KKS activation is largely unidirectional; crucial clinical considerations, especially the risk of hyperkalemia, are insufficiently addressed. The manuscript does not stratify safety and applicability by CKD stage, comorbid conditions, or the concomitant use of RAAS inhibitors, MRAs, and other commonly prescribed therapies, leading to an overly optimistic interpretation of clinical feasibility. 
Moreover, although the KKS is biologically characterized by both protective and deleterious actions, its pro-inflammatory effects, nociceptive signaling, and potential oncogenic implications are only superficially mentioned, lacking the balanced, critical appraisal expected in a contemporary review. The manuscript also does not contextualize KKS-related mechanisms within the landscape of current renoprotective standards of care—such as SGLT2 inhibitors, non-steroidal MRAs, and GLP-1 receptor agonists, thereby rendering parts of the clinical discussion outdated. 
Structurally, experimental and human data are interwoven within the same sections, reducing clarity; reorganizing the content and incorporating summary tables would substantially improve transparency and comparability across studies. Although the abstract and introduction describe the work as a comprehensive review, the absence of methodological rigor makes it resemble a narrative review rather than an evidence-based synthesis. 
Furthermore, important recent literature is not included, the proportion of self-citations is relatively high, and real-world dietary potassium constraints in CKD populations are insufficiently discussed, all of which weaken the manuscript’s objectivity and completeness. 
The uniformly favorable portrayal of KKS activation also diminishes scientific rigor. The authors are encouraged to include a clearly defined section on research gaps and future directions, outlining the types of clinical trials needed, potential surrogate biomarkers, and strategies for identifying patient subgroups most likely to benefit from increased potassium intake. 
In summary, although the mechanistic synthesis of the renal KKS and experimental evidence is valuable, significant deficiencies remain in methodological transparency, evidence stratification, translational safety analysis, literature balance, and overall scholarly impartiality. Accordingly, I recommend major revision prior to further consideration.

Comments on the Quality of English Language

I leave my common in the report

Author Response

Answers in word file

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

In this manuscript, the authors describe "Non-Pharmacological Activation of the Renal Kallikrein–Kinin System: Dietary Potassium as a Novel Renoprotective Approach". While this manuscript is well written, it would be helpful if the authors address the issue below.

1) In lines 85 - 90, a key feature that describes the anatomical proximity of the human and rat kidneys regarding the connection between the tubule cells and the glomerular vascular pole and the figure (figure 1) that illustrate this close proximity should be on the same page. This is crucial in order to reduce unnecessary distraction to potential readers.

In short, this manuscript could be of benefit to its target readers if the above issue is addressed.

Author Response

Answers in Word file

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

Most of the text comprises the known physiology of the renal function, esp. the renal kallikrein-kinin system (KKS), its critical role in regulating blood pressure and other kinin functions and the mechanisms of ACE inhibitor drugs that increase kinin levels. Since renal fibrosis is centrally regulated by TGF-b it is hypothesized that inhibition of TGF-b by kinins modifies the various biochemical processes that lead to the renal dysfunction. Since potassium stimulates kallikrein synthesis and kinin BCR expression the mechanisms which trigger the protective effect of potassium are further evaluated partially supported by previous own experiments.

The conclusion is that a potassium-rich diet together with reduced sodium intake is a potential alternative to the pharmaceutical approach.

Although the hypothesis is plausible, the authors do not provide evidence that a potassium rich diet actually protects renal function in humans.

Since the manuscript is a review, not a research paper, it may be accepted for publication.

However, for final acceptance the authors should search for more human data, which indicate the protective effect of potassium supplementation and expand the section, which evaluates the plausibility of the hypothesis.

 

 

Author Response

Answer in Word file

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Authors have significantly improved their review and addressed favorably all points raised by this reviewer. Only a few minor mistakes need to be corrected prior the publication of this nice review:

P. 4, line 56: '' of date of publication'' and not ''data''

P. 6, line 102: write correctly ''juxtaglomerular cells''

P. 7, line 110: B1R is activated by BK metabolites. It should be des-Arg9-BK and Lys-des-Arg9-BK (instead of Lys-BK which is a B2R agonist)

Reference 109: the title is missing

 

Author Response

It is in the attached word file 

Author Response File: Author Response.docx