The findings of the current study suggest that although CKD stage 3A (eGFR 45–59 ml/min/1.73 m2) was a predictor of incident HF among community-dwelling older adults, this association lacked independence. In contrast, a more advanced CKD stage ≥3B was a stronger predictor of incident HF, which also had a modest independent association. We also observed that both CKD stages were associated with increased mortality. To the best of our knowledge, this is the first report of the relationship between various baseline CKD stages and incident HF from a prospective cohort study of community-dwelling older adults. These findings are important as they suggest that although CKD is an important predictor of incident HF, it may not be a risk factor for incident HF until it reaches an advanced stage, and even when CKD is more advanced, it may be only a modest risk factor with a late effect.
The disappearance of the significant unadjusted association between CKD stage 3A and incident HF after risk adjustments using various methods including propensity score matching suggest that the association was likely not intrinsic in nature and was the result of confounding by imbalances in baseline risk factors. Although the baseline prevalence of hypertension was similar between those with CKD stage ≥3B (vs. those with no CKD), those with CKD stage ≥3B may have developed hypertension at a higher rate and hypertension in those individuals may have been more difficult to control, thus explaining the independent increased risk of HF. It is also possible that a more severe impairment of sodium and fluid balance in CKD stage ≥3B may have expedited the development of clinical HF in those patients. An activated renin-angiogensin-aldosterone system and sympathetic nervous system in advanced CKD may also have increased their risk for new-onset HF [32
]. Finally, oxidative stress, inflammation, hypercoagulablity, and endothelial dysfunction associated with advanced CKD may have played a role in increasing the risk of incident HF [34
Although findings from our sensitivity analysis suggest that the association of CKD stage ≥3B with incident HF may be sensitive to an unmeasured confounder, sensitivity analysis cannot determine whether such an unmeasured confounder actually exists or not. To be a confounder, an unmeasured covariate, in addition to being associated with CKD, would also need to have a near-perfect association with incident HF and not have a strong association with any of the 50 measured baseline covariates used in our study, a possibility which seems highly unlikely. Further, because the sign-score test used in the sensitivity analysis is based on ranks of the data rather than their actual values, it is considerably less powerful than the matched Cox survival analysis, which may also in part explain the non-significant sensitivity analysis. Therefore, while the association between CKD stage ≥3B and incident HF based on our matched Cox survival analysis results are statistically significant, the conclusions may not be robust, and need to be viewed as preliminary and replicated in future studies.
The association between serum creatinine and incident HF is well recognized [1
]. However, serum creatinine concentration is affected by factors other than GFR [11
]. Several other studies have also examined the association between CKD and incident HF [38
]. However, our study is distinguished by the use of CKD-EPI formula to estimate GFR, use of various CKD stages, central adjudication of HF, longer follow-up, and a host of other outcomes. Major HF guidelines either do not mention CKD as an etiologic risk factor or mention ‘end-stage renal failure’ as a risk factor for HF [40
]. Findings from our study confirm that CKD stage 3A is not an independent risk factor, stage ≥3B may be, and the risk of HF among those with CKD stage ≥3B was not immediate. These observations would suggest that there might be a window of opportunity to prevent HF in those with CKD. However, whether more aggressive management of risk factors would be more effective in reducing the risk of incident HF is currently unknown and will need to be determined in future prospective studies.
There were several limitations to our study. Because CHS participants are community-dwelling older adults and many had no CKD, we used CKD-EPI to estimate eGFR and define CKD. Unlike the commonly used Modification of Diet in Renal Disease formula to estimate GFR [11
], the CKD-EPI is more reliable in those with eGFR >60 ml/min/1.73 m2
. However, the CKD-EPI has not been validated in older adults and misclassification is possible. It is also possible that participants without CKD developed CKD during follow-up, and it is possible that the resultant regression dilution may in part explain the non-significant findings of our study.
In conclusion, among community-dwelling older adults, CKD is a predictor of incident HF regardless of stage and CKD stage ≥3B may have an independent modest association with incident HF.