Our study demonstrated that in the cohort of patients studied, CKD was highly prevalent in stages B and C of CHF, and significantly associated with a greater occurrence of death and hospitalization due to cardiac causes. The unfavorable impact of concomitant occurrence of CKD and CHF was observed in stages B and C of cardiac disease. These findings complement previous observations in patients with more severe forms of CHF (NYHA class IV), that CKD is a frequent complication with an unfavorable impact in the course of the disease [9, 11, 15, 17, 19, 23, 28, 29].
Estimation of the GFR used to define glomerular filtration rate (GFR) and CKD stages according to the criteria of the US National Kidney Foundation is considered the new standard of evaluation and severity of renal diseases [12, 27]. So far, the utility of this system of staging based on the GFR as a risk factor for prediction of adverse outcome has not been extensively evaluated in patients in less advanced stages of CHF [16, 28]. The cohort studied, after adjustment of other important risk factors for unfavorable CV outcomes presented at the baseline period, demonstrated that the occurrence of CKD independently determined a greater occurrence of mortality and hospitalization, an observation still little explored in outpatients with CHF.
The greater occurrence of CV outcomes in patients with CHF and CKD can be explained by the overlap of risk factors common in both diseases separately [30–32]. Previous studies, limited to analyses of databases and stratification of patients into levels of renal function based on dichotomous divisions or tertiles, have demonstrated an association between increased mortality and renal function in patients with CHF . Our findings of CKD as an independent risk factor for CV outcomes is in accordance with other large cohort studies based on communities and other populations with cardiovascular diseases [6, 8, 12, 13, 15, 16, 18, 34, 35].
The natural course of CHF in its initial stages associated with CKD is still unknown, since, thus far, most studies have evaluated primarily hospitalized patients with severe form of the disease (NYHA class IV), mainly in cross-sectional analyses, and improperly using serum creatinine as a diagnosis of CKD and sometimes excluding patients with CKD from the analysis .
In our study, it was observed that CKD (GFR <60 mL/min/1.73 m2) present in stages B and C of CHF was associated with 100% and 64.7% of the CV outcomes, respectively. These results provide new information regarding the "natural" course of systolic CHF in its early stages, and if confirmed in studies with greater number of patients, they can define renal function staging as a major tool to identify risk factors for adverse outcomes in patients with less severe CHF.
The unfavorable impact of CKD in the evolution of CHF stages B and C imposes a better understanding of the reasons for such an adverse association. In CHF, low cardiac output, neurohumoral stimulation, aggressive use of diuretics, treatment with renin-angiotensin-aldosterone system blockers, anemia, and comorbidities, such as hypertension and diabetes mellitus, can contribute to the reduction of GFR, and the observed functional deficit merely reflects the severity of CHF in the baseline period [34–37]. However, it is important to highlight that our study only included outpatients already on optimized treatment for CHF. Furthermore, we did not observe statistical differences in the frequency of diabetes and hemoglobin levels in patients with CHF, with and without CKD, which eliminates the possibility of these parameters as determinants of adverse outcomes. These findings reinforce our proposal that CKD per se, due to its own risk factors (pro-inflammatory markers, vascular rigidity, dyslipidemia, hyper-homocysteinemia, proteinuria, hypervolemia, and metabolic alterations of calcium and phosphorus), is an important determinant of the observed increase in CV outcomes . In an attempt to better evaluate the unfavorable impact of CKD in the evolution of CHF, we utilized a multivariate analysis to test the hypothesis that renal dysfunction is an independent determinant of poor prognoses, or merely a complication of CHF. We adjusted for other covariables, such as CKD in the baseline period, stage C of CHF, ejection fraction, elevated LDL-cholesterol levels, sedentarism, and serum sodium; and despite these adjustments, the concomitance of CKD increased 3.6 times the occurrence of CV events. This finding reinforces our hypothesis that CKD, independently of the presence of other known risk factors, contributes to the higher occurrence of death and hospitalization for cardiac causes in the early stages of CHF.
It is important to recognize the limitations of our study. Renal function was evaluated by the GRF estimated from creatinine, and not by the use of methods considered to be the gold standard, such as inulin clearance . In addition, we chose to exclusively utilize the functional component of the definition of CKD, in other words, GFR <60 mL/min/1.73 m2; however, previous studies have demonstrated that it is below this level of renal function that the risk of mortality increases for all causes of CHF [12, 34]. Albuminuria, the main marker of structural renal injury, another component of the definition of CKD, is fundamental in patients with GF >60 ml/min/1, 73 m2, and was not determined in this study since its occurrence could be mitigated by the use of optimized angiotensin-converting enzyme inhibitors, AT1 blockers, and aldosterone antagonists, thereby inducing false negative diagnoses . Additionally, our patients were selected from an outpatient clinic attended mainly by hypertensive, diabetic, and obese patients, and thus, the cohort did not entirely reflect the different etiologies of CHF, but, of course, the most prevalent.
CKD, a recognizable common risk factor for adverse outcomes in more severe forms of CHF, is also frequent in patients in the early stages of the disease. Our results corroborate with the proposal for using GFR, mainly when it is <60 mL/min/1.73 m2, as a strong prognostic risk factor for adverse CV outcomes in CHF, also in patients with less advanced heart failure. These findings suggest that clinical physicians, particularly cardiologists, should incorporate the serial estimation of GFR in order to optimize the results of treatment in CHF. Future studies could elucidate the determinants of the decrease in GFR in CHF stages B and C, and whether or not preservation of renal function will associate with an improved outcome of the cardiac disease.