Mapping renal impairment and cardiac structure and function: a comprehensive analysis of prospective cohort study, Mendelian randomization and shared genetic etiology

  1. Haozhang Huang
  2. Jin Liu
  3. Xiaozhao Lu
  4. Shiqun Chen
  5. Yang Zhou
  6. Jiyan Chen
  7. Ning Tan
  8. Wei Jiang
  9. Yong Liu

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Background

The elevated risk of heart failure in kidney dysfunction is well-identified. However, the influence of early alteration of renal impairment on cardiac structure and function, as well as their shared genetic susceptibility associations have not been well reported.

Aim

To investigate the associations between renal function and cardiac parameters using cardiac magnetic resonance images (CMR).

Methods

Of 29,546 European subjects underwent CMR test were recruited from UK Biobank study. Multivariable generalized linear regression was used to analyze the association of different kidney function indexes with CMR-traits. Genetic correlation between early renal impairment and CMR-traits were evaluated by linkage disequilibrium score regression and Mendelian randomization.

Design

A comprehensive analysis of prospective cohort study, Mendelian randomization and shared genetic etiology.

Results

Observational and genetic correlation analyses consistently reveal that a mild reduction in estimated glomerular filtration rate (eGFR) is independently associated with lower biventricular volume parameters and left ventricular cardiac output (LVCO), respectively. Through a rigorous application of Heritability Estimation from and Summary Statistics (ρ-HESS) and cross-trait meta-analysis, we identified 20 novel shared loci (e.g. rs2472297, located at CYP1A1 ) between eGFR based on cystatin C decline and reduced right ventricular end systolic volume (RVESV), and 2 loci (rs4371638, located at SHROOM3 ; rs34591452, located at STRA6 ) showed strong evidence of colocalization (probability for H4>0.95). Pathway enrichment analysis revealed that pathways of eGFR decline and reduced RVESV associated with enzyme inhibitor activity, endopeptidase regulator activity, and cysteine−type endopeptidase inhibitor activity.

Conclusions

Our study indicates significant observational and genetic correlations between early renal impairment and lower biventricular volume parameters and LVCO.

Article activity feed

  1. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/16990655.

    This study investigates the genetic links between renal impairment and cardiac structural and functional changes. The rationale for the analysis is well explained and the analysis is solid. Please find below some suggestions for further improvement. 

    1. The abstract is well-structured but could benefit from a brief mention of the study's limitations to provide a balanced overview. Please add a sentence about the study's limitations, such as its cross-sectional design and focus on a European population. 2. The introduction provides a clear rationale for the study and highlights the gap in existing research. It could include more details on the biological plausibility of the genetic links between kidney function and cardiac structure. Please expand on the known pathophysiological mechanisms that might underpin the observed associations. 3. Some complex methodologies, such as Mendelian randomization and ρ-HESS, may not be fully accessible to all readers. Please provide a brief, non-technical explanation or supplementary figure explaining these methods for clarity. 4. The use of LDSC and ρ-HESS is appropriate, but the rationale for choosing these specific methods over others could be more explicitly stated. 5. Please include a statement on the treatment of missing data (e.g., imputation methods) in the methods section. 6. The discussion could address the potential impact of confounding variables in more detail. For example, please discuss how potential confounders (e.g., lifestyle factors, comorbidities) were controlled for or could have influenced the results. 7. The broader implications for clinical practice and future research are briefly mentioned. You may elaborate on how these findings might influence clinical screening practices or the development of interventions targeting both renal and cardiac health.

    Competing interests

    The author declares that they have no competing interests.

  2. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/16990676.

    Does the introduction explain the objective of the research presented in the preprint? Yes The introduction clearly outlines the objective of the research, which is to investigate the associations between renal function and cardiac parameters through cardiac magnetic resonance imaging and to explore shared genetic susceptibility.
    Are the methods well-suited for this research? Highly appropriate The methodologies employed, including multivariable generalized linear regression, Mendelian randomization, and genetic correlation analyses, are well-suited to address the research questions posed.
    Are the conclusions supported by the data? Highly supported The conclusion could be enhanced by providing more specific recommendations for future research, such as the applicability of these findings in diverse populations or the need for long-term monitoring of cardiac health in patients with renal impairment.
    Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear The data presentations, including tables and figures, effectively illustrate the results and make it easy for readers to understand the findings.
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly The authors provide a thorough discussion of their findings, adequately explain the implications, and propose reasonable next steps for future research in this area.
    Is the preprint likely to advance academic knowledge? Highly likely This preprint presents novel findings that significantly contribute to the understanding of the kidney-heart connection and may inform future research and clinical practices.
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, it's of high quality
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes In employing generalized linear models, it is advisable for the authors to consider socioeconomic status and physical activity as confounding factors for adjustment, as these variables could potentially influence the relationship between renal and cardiac health. The authors reference multiple studies in the discussion; however, a more in-depth comparison that highlights the similarities and differences with previous research would strengthen this section. Additionally, an expanded discussion regarding the potential clinical significance of the identified shared genetic loci could offer valuable insights for future research directions.

    Competing interests

    The author declares that they have no competing interests.

  3. Version published to 10.1101/2025.08.24.25333620 on medRxiv