The development of acute kidney injury (AKI) is a frequent complication in hospitalized patients that causes high morbidity and mortality.1,2 Beyond the immediate prognostic impact of renal function impairment, its importance extends to the medium and long term with complications such as cardiovascular events (CVD), development of chronic kidney disease (CKD) and mortality.3,4 Furthermore, considering AKI as a complex syndrome, other complications such as infections, neurological and cognitive alterations have been demonstrated.5

The association between renal and cardiac dysfunction is encompassed under the term cardiorenal syndrome.6 In both acute kidney injury and CKD, there is an increased incidence of CVD, which is due to numerous factors that are intricately related and include the activation of neurohumoral mechanisms (such as the renin-angiotensin-aldosterone system [RAAS], the sympathetic nervous system, and vasopressin secretion) capable of generating structural and functional changes at the cardiac level.7,8 In addition, certain factors such as arterial hypertension, water overload, acid-base balance, mineral metabolism disorders, inflammation or uremic toxins coexist in both pathologies, enhancing the deleterious effects on the renal and cardiac systems9–11 This means that many patients with renal dysfunction present structural and functional cardiac alterations that worsens their prognosis and whose early detection would allow their risk to be stratified.12,13

In the field of AKI, the usefulness of echocardiographic parameters and their prognostic impact have been less studied. For this reason, we present this study aimed at determining the association between cardiac ultrastructure and function and the incidence of cardiovascular events in patients who develop AKI.

We designed a single-center observational retrospective cohort study, which included all patients admitted with the diagnosis of AKI in 2013 and 2014. The aim was to analyze CVD after hospitalization and its relationship with cardiac ultrastructure and function. Patients with errors in the coding of AKI, those without data on renal function prior to admission, or those with a renal transplant were excluded. Likewise, those who died during admission, those who required renal replacement therapy at discharge or those who were lost to follow-up were excluded from the final analysis.

At baseline, we collected from electronic medical records epidemiological data (sex, age) and comorbidities (hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease, heart failure, atrial fibrillation, peripheral vascular disease, stroke, and previous neoplasia). The presence of cognitive impairment was established and the functional dependence index was calculated using a modified Barthel scale (out of a total of 40 points, the higher the score the greater the independence).14 Regading the renal function, we recorded the presence of CKD and the estimated glomerular filtration rate (eGFR) (by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at baseline, the minimum value during the episode of AKI and the final value (which was established seven days after the maximum deterioration of renal function).15 The severity of the AKI episode was determined according to the Acute Kidney Injury Network (AKIN) scale.16 This scale uses an analytical criterion based on serum creatinine and urine flow to define the stage, such that the higher the stage, the greater the severity:

Stage 1: increase of 1.5–1.9 times the baseline creatinine value or increase greater than 0.3 mg/dL or presence of urinary flow less than 0.5 mL/kg/hr for more than 6 h.

Stage 2: increase of 2–2.9 times the basal creatinine value or the presence of a urinary flow of less than 0.5 mL/kg/h for more than 12 h.

Stage 3: increase greater than three times the baseline creatinine value, creatinine value greater than 4 mg/dL or the need for renal replacement therapy; or urinary flow less than 0.3 mL/kg/h in 24 h or anuria for 12 h.

Of the usual treatments, those patients that were prescribed diuretics and/or RAAS blockers were collected.

En los pacientes en los que estaba disponible un ecocardiograma en los seis meses previos, se registraron los siguientes parámetros17:

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  Systolic dysfunction: defined as left ventricular ejection fraction (LVEF) less than 45%.

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  Diastolic dysfunction: defined as a ratio greater than 14 between E and e' waves, left atrial volume greater than 34 mL/m2, septal e' velocity less than 7 cm/s or lateral e' velocity less than 10 cm/s and tricuspid regurgitation velocity greater than 2.8 m/2 (three or more parameters must be met).18

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  Pulmonary hypertension: defined as pulmonary artery pressure greater than 30 mmHg.

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  Left ventricular hypertrophy: defined as a left ventricular mass index greater than 130 g/m2 (men) or 105 g/m2 (women).

According to LVEF, three categories were established: severely depressed (below 40%), moderately depressed (40–49%), normal (above 50%).19

During follow-up of 49 ± 28 months, cardiovascular events (fatal or non-fatal) were recorded, defined as heart failure, ischemic heart disease, peripheral vascular disease, stroke or severe arrhythmias. Factors associated with cardiovascular events were analyzed, including the impact of echocardiographic parameters.

The study complied with current data protection regulations as well as ethical principles and was approved by the Ethics Committee of the Hospital Universitario de La Princesa (reference 3447, 11/2018).

Our study demonstrates that cardiac abnormalities, and specifically diastolic dysfunction, independently predict the development of CVD after an episode of AKI. Moreover, in patients in whom they were available, echocardiographic parameters are a useful tool for stratifying the risk of developing CVD.

The clinical consequences of AKI include cardiovascular complications.20 Prospective studies, such as the recently published ASSESS-AKI, have shown that the simple fact of presenting an episode of AKI may increase the risk of presenting subsequent episodes of heart failure by up to 68%, establishing a cause-effect phenomenon. Despite the clinical evidence, the pathogenic explanation is not without controversy in the current literature. In a recent experimental study, based on a murine model, the authors demonstrate that an episode of AKI leads to the development of persistent diastolic dysfunction that could be considered as the triggering mechanism that conditions subsequent cardiovascular complications.21

Diastolic dysfunction is a pathology with a growing incidence and it is caused predominant by arterial hypertension, diabetes, and ischemic heart disease, most of which also produce renal alterations in an intricate mechanism that feeds back, enhancing the negative effects on the cardiorenal axis.22 In fact, our data confirm that age and diabetes worsen the cardiovascular prognosis of patients, both factors promoting increased myocardial stiffness and driving diastolic dysfunction itself.22

The description of diastolic dysfunction in patients with nephropathy has increased exponentially in recent years. In those with CKD, the prevalence of diastolic dysfunction increases with the deterioration of renal function and is even considered by some authors to be virtually universal in those requiring hemodialysis.13,23 Furthermore, the recently published population-based Atherosclerosis Risk in Communities Study establishes an independent association between numerous echocardiographic abnormalities and the incidence of CKD, suggesting the need to establish close monitoring of the functionality of both organs.24

In addition, the relationship between diastolic dysfunction and AKI presents little evidence at the present time. Cross-sectional clinical studies have been able to demonstrate that this cardiac alteration is associated with an increased risk of AKI during hospitalization, a situation that has been studied in specific populations such as cirrhosis, patients undergoing a contrast study, septic shock or elderly patients with hip fracture.25–28 The novelty of our study, beyond confirming that diastolic dysfunction is associated with greater severity of the episode of AKI (patients with diastolic dysfunction have a lower eGFR after the episode), is the demonstration of its impact on CVD-free survival after hospital discharge and in the long term.Undoubtedly, in the absence of confirmation of these data in prospective studies, the challenge is to establish closer monitoring of patients with diastolic dysfunction after AKI, but above all to determine specific therapeutic strategies to improve prognosis.

Impaired myocardial relaxation has also been shown to be an independent predictor of cardiovascular events in populations without AKI, which, due to its increasingly early detection and high prevalence, makes it necessary to establish specific measures to mitigate its consequences.29,30 To date, the only measures recommended have been based on the control of classic cardiovascular risk factors (diabetes, arterial hypertension, dyslipidemia, obesity) and non-classic risk factors (inflammation, uremia, hyperuricemia, among others).31 However, the publication of the EMPEROR-Preserved study opened the door to the first treatment with a potential prognostic improvement, empagliflozin.32 Although the results of this clinical trial are based on patients different from those presented in our study, it can be hypothesized its possible beneficial effect in patients with a higher cardiovascular risk after an episode of AKI.

Furthermore, as show in our study, the different echocardiographic abnormalities (systolic dysfunction, diastolic dysfunction, left ventricular hypertrophy [LVH] and/or pulmonary hypertension) are good markers for stratifying the risk of CVD in patients with AKI and could therefore be tools for establishing closer follow-up of certain subgroups of patients.

Our study is not without limitations. Firstly, it is a retrospective study, which entails the typical biases of this type of analysis. Despite the loss of data and the fact that, on occasions, these may not be completely homogeneous, the sample size we provided is sufficiently large to assess our objectives, and we were able to adjust the models for numerous variables. In this sense, we have applied the term AKI to define acute deterioration of renal function, although additional classifications are currently proposed that discriminate between AKI (renal damage up to seven days) and acute kidney disease (damage between seven days and three months).33 Secondly, as this was a real-life study, only 54% of the patients had an echocardiogram in the six months prior to the episode of AKI and these did not always describe all the alterations that we intend to study. To prevent certain alterations from going unnoticed, we decided to limit the validity of the echocardiograms to this time range, assuming that a greater number of patients would not have data on structure and renal function, but achieving greater accuracy as they were closer to the episode of AKI. Finally, the lack of an echocardiogram after AKI does not allow us to establish the effect of acute renal dysfunction on cardiac ultrastructure and function, so our data could be underestimated. However, in order to study this last limitation in depth, a prospective study with temporal homogeneity in the follow-up, at least in the performance of the control echocardiogram, would be required. In any case, we consider that the data provided by this study are sufficiently significant to be able to establish hypotheses that can be confirmed in studies with a more powerful design.

As a conclusion of the study, we can establish that diastolic dysfunction predicts the incidence of CVD after an episode of AKI. Furthermore, the risk of CVD can be stratified with the baseline parameters provided by echocardiographic studies, which would allow us to establish specific and close management of patients with structural or functional cardiac alterations.

This work has not received any type of funding.

The authors declare that they have no conflicts of interest.