Echocardiographic parameters and renal outcomes in patients with preserved renal function, and mild- moderate CKD

Chronic kidney disease (CKD) is highly prevalent among patients with congestive heart failure (CHF) and is associated with higher mortality rates [1]. In the CHARM trials, for example, an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m² was an independent predictor of cardiovascular death or admission for decompensated heart failure [2].

Echocardiography can identify abnormalities in heart function or structure that are associated with kidney dysfunction [3]. Abnormal left ventricular (LV) geometry, lower mid-wall fractional shortening, and higher LV mass index have been described among patients with CKD compared with patients with preserved renal function in a cohort of participants with heart failure with preserved ejection fraction [3]. In other studies, echocardiographic parameters predicted cardiovascular events among CKD patients, although there was no net reclassification improvement when these parameters were added to a model including clinical and laboratory variables [4].

Although these data are intriguing, the echocardiographic characteristics of patients across the spectrum of cardiac function – with both preserved or reduced LV ejection fraction and with or without CHF – have not been adequately described across different eGFR stages, especially in patients with mildly decreased eGFR. It is also uncertain whether echocardiographic parameters predict CKD progression. The objective of this study was to describe the echocardiographic characteristics of patients with preserved renal function and mild or moderate CKD referred for echocardiography, and to assess associations of echocardiographic parameters with changes in renal function.

We assessed echocardiographic characteristics of patients with preserved renal function and mild or moderate CKD in a cohort of individuals referred for echocardiography. We found that patients with CKD have a higher prevalence of structural and functional LV and RV abnormalities, which are already apparent in early CKD (eGFR 60–89 ml/min/1.73m²). We also identified that RV systolic function or dilation and pulmonary artery pressure are independently associated with a composite renal outcome of serum creatinine doubling, dialysis, or transplantation. Both RV and LV echocardiographic features were associated with mortality.

Park et al. analyzed the CRIC population and found that decreasing renal function was associated with LV hypertrophy, abnormal LV geometry, diastolic dysfunction, but not with systolic dysfunction [5]. Gori et al. described cardiac structure and function in 217 individuals with heart failure with preserved ejection fraction from the PARAMOUNT trial [3]. They found that renal impairment was associated with abnormal LV geometry, higher LV mass or LV mass index, and lower mid-wall fractional shortening [3]. Creatinine clearance was also identified as an independent predictor of heart failure with preserved ejection fraction in a retrospective study of patients with hypertension and preserved ejection fraction [6]. In a cohort of post-myocardial infarction patients from the VALIANT trial, worse renal function was associated with smaller LV, larger left atrial volume, and higher LV mass index [7]. In contrast, in hypertensive patients with asymptomatic diastolic dysfunction from the VALIDD and EXCEED trials, eGFR group was not associated with echocardiographic measures of LV structure and function [8].

Our findings confirm most of these observations in a much larger population including patients with and without CHF. We also report a significant association of worse renal function with LV systolic impairment, and we expand the previous findings by looking at RV parameters and their association with CKD.

We found that only pulmonary artery pressure and parameters related to the RV are associated with CKD progression. The AASK study addressed this issue in African-American patients with pre-existing non-diabetic hypertensive CKD and showed that LV mass index was not associated with a combined outcome of doubling of creatinine or end-stage renal disease [9]. On the contrary, a retrospective analysis of the Jackson Heart Study, also in an African-American population, showed a significant association of LV mass, but not LV ejection fraction or pulmonary artery pressure, with a composite outcome of eGFR decline > 30% or progression to end-stage renal disease [10]. A small cohort study in stage 3–5 CKD patients demonstrated that concentric LV hypertrophy was associated with progression to dialysis, whereas LV ejection fraction and increased left atrium diameter were associated with CKD progression, defined as eGFR decline > 3 ml/min/1.73m² annually [11, 12]. In addition, a study in 300 elderly patients showed that LV hypertrophy was independently associated with eGFR decline > 5 ml/min/1.73m² per year [13]. In the ESCAPE trial, a significant correlation was identified between baseline creatinine levels and right atrial pressure levels in patients admitted with heart failure [14]. Park et al., using magnetic resonance imaging, demonstrated that LV mass and concentricity, a measurement of abnormal cardiac size, were associated with eGFR decline and incident CKD [15].

Discrepancies with our findings may reflect differences in baseline renal and heart function, demographic characteristics and the use of a clinical cohort in our study compared to highly selected prospective research or trial cohorts in the prior studies. Furthermore, renal outcomes were not defined in the same way. Lack of association between LV mass index and renal outcomes or mortality in our study may be due to values below hypertrophic levels for the majority of individuals. LV mass could be more reliably assessed with more advanced techniques, such as magnetic resonance imaging. Similarly, lack of association between pulmonary artery pressure and renal outcomes in the Jackson Heart Study may be due to relatively normal pulmonary artery pressure values among study participants.

Our findings extend these findings by demonstrating a significant, independent association between RV diameter or function and CKD progression in a population that primarily did not have CHF. Worsening RV function and elevated pulmonary artery pressures may be associated with higher renal vein pressures, a purported mechanism underlying the cardiorenal syndrome [16, 17]. Similarly, salt and water retention in the setting of decreasing eGFR may contribute to volume overload and increased renal vein pressures that may impair renal perfusion and cause ischemia-mediated sclerotic changes. On the contrary, LV dysfunction may not significantly impact renal function provided that renal perfusion pressure remains in an acceptable range. However, these findings are only hypothesis generating and need to be prospectively confirmed. Finally, we also report a significant association between mortality and abnormal RV structure or function. No prior data exist on the association between right heart parameters and mortality in patients with CKD, to our knowledge.

Our study has several limitations. It is a retrospective study of patients referred for echocardiography and may not reflect the complete spectrum of patients with preserved renal function or mild eGFR impairment since sicker patients are more likely to be referred for echocardiography and those with more advanced cardiopulmonary disease are more likely to have RV dysfunction. Furthermore, no information was available on the indication for the echocardiogram. Echocardiograms were ordered to answer specific clinical questions rather than to provide systemic assessment of cardiac structure and they were interpreted by multiple clinicians rather than by a core lab, raising the possibility of confounding introduced by wide inter-reader variability between sonographers. In particular, RV assessment is fraught with potential errors of judgment and high degree of inter-observer variability. Additionally, tissue Doppler imaging results, diastolic function, and valve structure and function were not extractable for most patients.

Index echocardiograms might have been conducted in the setting of decompensated CHF and may not reflect baseline cardiac status or could have been followed by acute changes in kidney function. However, our findings were qualitatively similar in a subgroup analysis including only outpatient echocardiograms in which these issues would be less likely. We similarly cannot rule out the possibility that addition of renin-angiotensin-system agents in individuals with more severe echocardiographic changes partly accounted for associations with CKD progression, although our results were adjusted for use of these agents at baseline. Furthermore, the clinical indication of the echocardiogram may have already caused changes in eGFR. Capture of medication changes during follow-up is not readily available to us at this time. Finally, there were no BP or proteinuria values available for most patients in this dataset, and no information was available on the cause of death. Nevertheless, a sample size several times larger than all prior cohorts, assessment of multiple echocardiographic parameters, and most importantly a sufficient number of outcomes to be powered to examine associations with CKD progression and mortality represent unique strengths of our analysis.

More studies are needed to prospectively confirm the identified associations and carefully evaluate the right heart with comprehensive assessment of the RV including lateral tricuspid annular systolic velocity and acceleration, fractional area and long-axis change, tricuspid annular systolic excursion, myocardial performance index, and lateral free wall peak systolic strain, as well as inferior vena cava diameter and distensibility [18, 19]. These results also merit analysis in the setting of advanced CKD (eGFR < 30 ml/min/1.73m²).

In conclusion, structural and functional abnormalities of the right and left ventricle are more common in individuals with mild or moderate renal impairment and associated with mortality while RV function and structure are independently associated with CKD progression even in early stage CKD. Prospective studies with quantitative assessment of the RV are needed to validate our observations and better understand the underlying mechanisms.