In the present study, we investigated whether high BNP concentrations are associated with CV events and mortality, independent of cardiac structure and function, in patients with CKD. Independent associations of log BNP with cardiac parameters (LAD, LVMI, and LVEF) were identified using multiple linear regression analysis, and even if these parameters were included in multivariable Cox analyses, high BNP concentration was identified as an independent risk factor for adverse outcomes (fatal or nonfatal CV events, and the composite event of fatal or nonfatal CV events, or non-CV death). Furthermore, subgroup analyses showed that baseline covariates such as prior CV diseases, eGFR, LVEF, LAD, and LVMI did not significantly affect the associations between BNP and the two outcomes.
In the heart–kidney hemodynamic model, the kidneys control the extracellular fluid volume by regulating sodium excretion and reabsorption, and the heart controls systemic hemodynamics. When one of these organs fails, a vicious circle develops in which the RAAS, the nitric oxide-reactive oxygen species balance, the sympathetic nervous system, and inflammation interact and synergize, thereby leading to an increase in morbidity and mortality 24,25. Cardiorenal syndrome (CRS) is defined as a pathophysiologic disorder of the heart and kidneys, whereby acute or chronic dysfunction in one organ induces acute or chronic dysfunction in the other. Five subtypes of this syndrome have also been defined: type 1, acute cardio-renal; type 2, chronic cardio-renal; type 3, acute reno-cardiac; type 4, chronic reno-cardiac; and type 5, secondary CRS. In CRS type 2, chronic cardiac abnormalities result in kidney injury or dysfunction. In contrast, in CRS type 4, CKD contributes to a decrease in cardiac function, cardiac hypertrophy, and/or an increase in the risk of adverse CV events 26,27. To date, several studies have demonstrated that poor kidney function or a decline in function are associated with higher risks of CVD and mortality 28,29,30. Cardiac biomarkers, such as BNP and NT-proBNP, have shown prognostic value in patients at various stages of kidney dysfunction, and therefore have potential applications in patients with CRS types 2 or 4 26.
Several previous studies have documented associations of BNP/NT-proBNP with kidney function or cardiac alterations. A previous study demonstrated that BNP concentrations are less affected than those of NT-proBNP by kidney dysfunction 31. Vickery et al. reported that LVMI is independently associated with both BNP and NT-proBNP, whereas eGFR had an independent effect on the BNP, and especially on the NT-proBNP, concentrations in patients with CKD 23. BNP concentration has also been reported to be independently associated with left ventricular overload, but not with kidney function 13. Furthermore, Tagore et al. reported that there is an independent inverse correlation between eGFR and NT-proBNP, but not BNP, in patients with stages 3 or 4 CKD 22. In the present study, simple linear regression analysis revealed a significant inverse association between log BNP and eGFR, but multiple linear regression analysis did not. In addition, in multiple analysis, independent associations between log BNP and cardiac parameters were identified, as in previous studies 23. These findings suggest that in patients with CKD, BNP concentration may be influenced by abnormalities in cardiac structure and function, rather than kidney dysfunction. However, the previous studies that characterized the associations of BNP with CV outcomes and mortality in patients with CKD did not include cardiac parameters as covariates 12,13,14; therefore, the fact that significant associations of BNP concentrations with adverse outcomes identified in the present study were independent of indices of cardiac structure and function provides valuable additional information.
Volume overload is not uncommon in patients with CKD and is associated with both traditional and nontraditional CV risk factors 32. A previous study demonstrated that volume overload, assessed using bioelectric impedance spectroscopy, is an independent risk factor for CV morbidity and all-cause mortality in patients with advanced CKD stages 33. In the present study, the volume status of the participants was not assessed using a body composition monitor, but their LADs were assessed using echocardiography, and log BNP was found to be independently and positively associated with LAD. It has previously been reported that LAD has a significant positive correlation with estimated plasma volume 34, and BNP has been reported to be a biomarker of volume status in patients with CKD 35. Therefore, in the present cohort, participants with high BNP concentrations may have had more severe volume overload, and the implied association between high BNP and volume overload might explain the link between high BNP concentration and adverse outcomes.
BNP concentration may increase in response to myocardial ischemia, even if this is not accompanied by heart failure 36,37. Therefore, it may have value for the identification of subclinical cardiac disease in patients who do not have clinical heart failure 38. Subclinical myocardial injury has also been reported to be associated with higher risks of CVD and all-cause mortality in individuals who do not have CVD 39. Given these findings, we can speculate that high BNP-related subclinical myocardial injury might be attributable to the association between BNP and adverse outcomes.
The present study had several limitations. First, all the participants were recruited at a single regional hospital; therefore, the sample was fairly homogeneous and subject to selection bias. Second, we recruited consecutive patients who were admitted to the hospital; they were relatively old, were all Japanese, and the number of male participants was approximately 1.8-times higher than that of female participants. Finally, we only used a single BNP measurement, which may not be a highly accurate predictor of adverse outcomes. In optimally treated patients with chronic heart failure, the use of a BNP-guided strategy has been reported to be associated with a lower risk of chronic heart failure-related death or hospitalization because of chronic heart failure than the use of a conventional strategy based on clinical expertise 40. In addition, a recent study demonstrated that BNP monitoring is associated with a lower risk of a requirement for kidney replacement therapy in patients with CKD who are not on dialysis 41. Therefore, further studies are warranted to determine whether longitudinal BNP monitoring lower the risks of CV events and mortality in patients with CKD.
In conclusion, in patients with CKD, high BNP concentrations are associated with adverse outcomes, such as CV events and mortality, independent of confounding variables such as cardiac parameters. These findings suggest that BNP is a useful biomarker of the risk associated with adverse outcomes in patients with CKD.