Combined podocyte, fibrotic and echocardiographic correlates of an operationally defined subclinical cardiorenal phenotype in chronic kidney disease: an exploratory study

Figures

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  Figure 1.. Pathophysiological cascade of an operationally defined early cardiorenal phenotype in CKD. The parallel mechanistic pathways that are activated by upstream renal drivers (hypertension, diabetes, glomerulonephritis) converge on tissue-level remodeling in the kidney (tubulointerstitial fibrosis, urinary nephrin and type IV collagen) and the myocardium (interstitial fibrosis, serum galectin-3; wall stress, serum NT-proBNP). The integrated downstream phenotype is subclinical cardiac remodeling with preserved ejection fraction, enlarged left atrium and increasing E/e′.

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  Figure 2.. Inter-relationships among renal, fibrotic, cardiac and echocardiographic markers. The thickness of the line is proportional to the absolute value of the Spearman correlation coefficient that is reported in the cohort. Renal markers (urinary nephrin, type IV collagen) are associated with cardiac fibrosis (galectin-3) and cardiac wall-stress (NT-proBNP) markers, both of which converge on the diastolic-function index E/e′ that combines anatomical and haemodynamic remodeling. The highest correlations are between urinary nephrin and E/e′ and between cystatin C and E/e′, supporting the concept of podocyte injury and dual-compartment filtration markers as upstream markers of subclinical cardiorenal involvement.

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  Figure 3.. Receiver-operating-characteristic curves for E/e′. Resting E/e′ (red curve) has an AUC of 0.69 (95% CI 0.61–0.74) for the exploratory discriminative association with the operationally defined subclinical cardiorenal phenotype in CKD patients without overt heart failure. The AUC is numerically higher at 0.81 (0.75–0.83) (green curve) by adding a six-minute walk test as a physiological stressor and re-imaging immediately afterwards. The diagonal dashed line is the non-informative reference.

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  Figure 4.. Conceptual framework for future investigation of an early cardiorenal phenotype in CKD (exploratory and hypothesis-generating; not a validated screening algorithm and not recommended for clinical implementation without prospective external validation). A six-step conceptual framework comprising identification of at-risk research participants (step 1), first-line renal characterization (step 2), the podocyte–fibrotic biomarker panel examined as a candidate biomarker signature (step 3), resting and post-exercise echocardiography (step 4), exploratory research stratification based on the combined biomarker–echocardiographic profile (step 5) and candidate strategies for future investigation requiring prospective validation (step 6). The framework is offered as hypothesis-generating only; it is not a clinical decision-support tool or a recommended management pathway and each component needs to be prospectively validated before use in the clinic.