Summary
Background
Cardiovascular disease is the primary cause of mortality and morbidity among patients with chronic kidney disease.
Aims
To investigate whether echocardiography can predict the occurrence of major cardiovascular events in patients with severe chronic kidney disease.
Patients
Patients with stable stage 4 chronic kidney disease (estimated glomerular filtration rate 15–29 mL/min/1.73 m 2 ) and followed in the nephrology department were included. Clinical, biological, electrocardiographic and echocardiographic data were recorded. Endpoint was defined as fatal or non-fatal cardiovascular event (acute coronary syndrome, acute heart failure, stroke, sustained ventricular arrhythmias, arterial thrombotic events and death).
Results
We included 71 patients (46 men); mean age 72 ± 14 years. Mean glomerular filtration rate was 21.9 ± 4.8 mL/min/1.73 m 2 . Over a mean follow-up of 258 ± 30 days, 18 (25%) patients reached endpoint (death in 7/18). Male sex, blood urea, atrial fibrillation, Sokolow index, left atrial size, pulmonary arterial pressure, indexed left ventricular mass and protodiastolic peak velocity of transmitral Doppler flow were significantly higher whereas left ventricular ejection fraction was significantly lower in these patients. By multivariable analysis, blood urea and left ventricular ejection fraction remained predictive of major cardiovascular event with odds ratios of 1.10 (95% confidence interval 1.02–1.18) and 0.93 (95% confidence interval 0.89–0.97), respectively. The negative predictive value was 95% when left ventricular ejection fraction was > 50% with blood urea < 15 mmol/L.
Conclusion
Patients with stage 4 chronic kidney disease are at high risk of major cardiovascular events and death. Echocardiographic evaluation is effective in identifying patients at highest risk of adverse cardiac events.
Résumé
Contexte
Les maladies cardiovasculaires sont la première cause de morbimortalité en cas d’insuffisance rénale chronique.
Objectif
Déterminer si l’échographie pouvait prédire la survenue d’événements indésirables cardiovasculaires majeurs en cas d’insuffisance rénale chronique sévère.
Patients
Les patients avec insuffisance rénale chronique sévère (stade 4, débit de filtration glomérulaire entre 15 et 29 mL/min/1,73 m 2 ) stable suivis en néphrologie ont été inclus. Les données cliniques, biologiques, électrocardiographiques et échographiques ont été enregistrées. Le critère d’évaluation a été défini par la survenue d’événements cardiovasculaires mortels ou non (syndrome coronarien aigu, insuffisance cardiaque aiguë, accident vasculaire cérébral, arythmie ventriculaire soutenue, événements thrombotiques artériels et décès).
Résultats
Nous avons inclus 71 patients (46 hommes), d’âge moyen 72 ± 14 ans. Le débit de filtration glomérulaire moyen était de 21,9 ± 4,8 mL/min/1,73 m 2 . Au cours d’un suivi moyen de 258 ± 30 jours, 18 patients (25 %) ont atteint le critère d’évaluation (dont sept décès). Le sexe masculin, l’urémie, la fibrillation atriale, l’indice de Sokolow, la taille de l’oreillette gauche, la pression artérielle pulmonaire, la masse ventriculaire gauche indexée et le pic protodiastolique du flux doppler transmitral étaient significativement plus élevés alors que la fraction d’éjection ventriculaire gauche significativement plus faible chez ces patients. En analyse multivariée, l’urémie et la fraction d’éjection ventriculaire gauche restaient prédictives d’évènement (OR 1,10 (IC 95 % [1,02, 1,18]) et 0,93 IC 95 % [0,89, 0,97], respectivement). La valeur prédictive négative était de 95 % lorsque la fraction d’éjection ventriculaire gauche était supérieure à 50 % avec une urémie inférieure à 15 mmol/L.
Conclusion
La morbimortalité cardiovasculaire est élevée en cas d’insuffisance rénale chronique sévère. L’évaluation échocardiographique est efficace pour identifier les patients à haut risque.
Background
A strong association exists between chronic kidney disease (CKD) and cardiovascular disease (CVD), with an increase in CVD observed with declining glomerular filtration rate . Indeed, CVD is the main cause of morbidity and mortality in CKD patients. In a study conducted by Go et al. , with more than one million patients classified into subgroups according to CKD stage, annual mortality and cardiovascular morbidity were 11.4% and 21.8%, respectively, in stage 4 patients. Cardiovascular risk is, however, difficult to assess in patients with stage 4 or stage 5 CKD, and risk scores, such as those derived from the Framingham study, are not accurate in the CKD population .
In patients undergoing dialysis, the value of echocardiography to predict cardiovascular events and death has been reported . However, data are lacking from patients with stage 4 CKD to help identify those at higher risk of cardiovascular morbidity . Using the modification of diet in renal disease (MDRD) formula , 0.5% of the adult participants in the NHANES 1999–2006 cohort had an estimated glomerular filtration rate < 30 mL/min/1.73 m 2 . Few studies have been conducted in these patients – mainly evaluations of subgroups. In addition, randomized clinical trials usually exclude patients with severe CKD . Unlike patients undergoing dialysis, stage 4 CKD patients are not generally considered as a specific population in the cardiology setting and no specific echocardiographic data from these patients have been reported . However, earlier detection of patients at high risk of cardiovascular complications could help physicians to adapt therapy and follow-up accordingly, thereby potentially delaying the occurrence of adverse cardiac events or the initiation of renal replacement therapy.
The aim of this prospective cohort study was to identify echocardiographic variables that may predict cardiac and vascular complications in patients with stage 4 CKD and to describe cardiovascular status, echocardiographic data and occurrence of cardiac and vascular adverse events.
Patients
Inclusion criteria and study population
In our centre, patients with stable stage 4 CKD are seen in consultation every 3 months for regular follow-up. All prospective patients attending these consultations over a period of 5 months with stable stage 4 CKD and an estimated glomerular filtration rate between 15 and 30 mL/min/1.73 m 2 according to the MDRD formula were considered eligible for inclusion. Patients were included during their consultation if they gave informed consent. Data were collected during standard care. Exclusion criteria were as follows: acute renal failure with serum creatinine increase of 50% from baseline level in the 3 previous months; CKD diagnosed < 3 months previously; and history of transplantation.
Data collection
Cardiovascular history, traditional risk factors for CVD (hypertension, diabetes mellitus, current smoking, hyperlipidaemia, being overweight and family history of vascular disease), the cause of nephropathy and body surface area were recorded. In all patients, heart rate and arterial blood pressure were measured and a 12-lead electrocardiogram was performed at inclusion.
Transthoracic echocardiography was performed in all participants, using ACUSON SEQUOIA C256 equipment (Siemens, Munich, Germany) with data obtained in digital format and stored for off-line analysis. Two independent operators interpreted the echocardiography blind with respect to clinical data, according to the American Society of Echocardiography recommendations , with an average of at least three successive measurements (five if atrial fibrillation [AF] was present). Left ventricular ejection fraction (LVEF) (Simpson’s biplane method), left ventricular mass (cubes method according to American Society of Echocardiography convention ), left atrium surface area (four-chamber planimetry) and pulmonary arterial pressures (derived from tricuspid and/or pulmonary regurgitation flow) were measured. Right atrial pressure was estimated by inferior vena cava diameter and the presence of inspiratory collapse. Inferior vena cava diameter < 2 cm with collapse > 50% during inspiration and > 2 cm with collapse < 50% suggested right atrial pressures of 5 and 15 mmHg, respectively; intermediate cases suggested a right atrial pressure of 10 mmHg. Left ventricular filling pattern was also collected with transmitral Doppler flow analysis and the measurements of E mitral protodiastolic peak velocity, E mitral deceleration time, A mitral end-diastolic peak velocity, A mitral duration, isovolumetric relaxation time and Doppler tissue imaging on the lateral side of mitral annulus (early peak velocity). Valvular diseases were quantified using the reference methods. Left ventricular mass and aortic valve area were indexed to body surface area.
LVEF < 50%, indexed left ventricular mass > 95 g/m 2 for women and > 115 g/m 2 for men, left atrial surface area > 20 cm 2 and systolic pulmonary artery pressure > 40 mmHg were considered abnormal. Biological variables were also recorded (serum creatinine, blood urea, calcium, phosphate, protein, albumin, haemoglobin, intact parathyroid hormone, glycated haemoglobin, C-reactive protein and 24-hour proteinuria).
During the follow-up period, all-cause death and cardiovascular death were recorded. A composite endpoint of major acute cardiac and vascular events (MACE) was defined as cardiovascular death, non-fatal cardiovascular events, acute coronary syndromes (with or without ST-segment elevation), ischaemic stroke, acute arterial ischaemia, acute heart failure or sustained ventricular arrhythmias. In addition, cardiovascular and all-cause admissions, need for dialysis, kidney transplant and death were recorded.
The study was designed to follow patients up to 1 year after inclusion.
Statistical analysis
Quantitative data are presented as mean ± standard deviation and qualitative data as number and percentage. Event-free survival analysis was performed using Kaplan-Meier survival analysis and compared using the log-rank test. Variables that differed significantly between groups by univariate analysis were included in the multivariable analysis, using an ascending stepwise Cox proportional hazards model. We planned to perform the analysis in two stages, due to the small number of expected events. Firstly, echocardiographic and non-echocardiographic variables would be analysed separately and the independent variables would subsequently be included in the final multivariable analysis combining both echocardiographic and non-echocardiographic variables. A post hoc analysis of the predictive value of the combination of independent predictors using established cut-off values was also performed (50% for LVEF and 2 × upper limit of normal [ULN] for urea). A Kaplan-Meier curve was drawn to visualize the prognostic value of independent variables significantly associated with MACE occurrence and of their combination. All analyses were performed using SPSS 19 software (IBM, SPSS Inc. Chicago, IL, USA) and for all tests a P value < 0.05 was considered significant.
Results
Study population and MACE
We prospectively screened 78 patients, of whom 71 were included (46 men and 25 women). Six patients did not give consent to participate and one was excluded after echocardiography, because of severe aortic valve stenosis requiring surgery. All but one of the 71 included patients were white, mean age was 72 ± 14 years (range 27–95) and 10 patients had an arteriovenous fistula.
The baseline characteristics of the study population are displayed in Table 1 . Only four patients had no risk factors, while 15, 22, 15 and 15 patients had one, two, three and four or more risk factors, respectively. Thirty-one patients had previous atheromatous disease with a history of at least one of the following: acute coronary syndrome ( n = 15), stroke ( n = 9), peripheral arteriopathy ( n = 16) and renal artery stenosis ( n = 3). The primary causes of CKD were nephrosclerosis (41%), diabetic nephropathy (31%), tubulointerstitial nephritis (10%), chronic glomerulonephritis (8%) and other causes (10%). Renal biopsy was performed in 14 patients to confirm the type of nephropathy. Permanent AF was present in 10 patients (14%).
| All ( n = 71) | Event-free ( n = 53) | Event ( n = 18) | P | |
|---|---|---|---|---|
| Men | 46 (65) | 30 (57) | 16 (89) | 0.01 |
| Age (years) | 72 ± 14 | 70.7 ± 14.5 | 76 ± 11.5 | 0.17 |
| Cardiovascular history | ||||
| Acute heart failure | 14 (20) | 7 (13) | 7 (39) | 0.02 |
| Atheromatous disease | 31 (44) | 20 (38) | 11 (61) | 0.06 |
| Cardiovascular risk factors | ||||
| Hypertension | 58 (82) | 41 (77) | 17 (94) | 0.12 |
| Diabetes mellitus | 25 (35) | 18 (34) | 7 (39) | 0.79 |
| Dyslipidaemia | 30 (42) | 24 (45) | 6 (33) | 0.71 |
| BMI > 25 kg/m 2 | 40 (56) | 31 (58) | 9 (50) | 0.44 |
| Smoking (current/stopped < 3 years) | 10 (14) | 8 (15) | 2 (11) | 0.29 |
| Family history of early vascular disease | 6 (9) | 4 (8) | 2 (11) | 0.49 |
| Haemodynamic variables | ||||
| Systolic blood pressure (mmHg) | 139 ± 19 | 140 ± 17 | 137 ± 22 | 0.24 |
| Diastolic blood pressure (mmHg) | 74 ± 9 | 74 ± 10 | 72 ± 7 | 0.28 |
| Heart rate (beat/min) | 69 ± 12 | 70 ± 12 | 68 ± 10 | 0.81 |
| Medical therapy | ||||
| ACEI or ARB | 55 (78) | 40 (76) | 15 (83) | 0.44 |
| Antiplatelet agent | 29 (41) | 18 (34) | 11 (61) | 0.11 |
| Statins | 17 (24) | 11 (21) | 6 (33) | 0.54 |
| Diuretic | 50 (70) | 34 (64) | 16 (89) | 0.002 |
| Beta-blocker | 29 (41) | 17 (32) | 11 (61) | 0.049 |
| Biological variables | ||||
| Creatinine (μmol/L) | 281 ± 122 | 276 ± 127 | 295 ± 107 | 0.58 |
| eGFR (MDRD mL/min/1.73 m 2 ) | 21.9 ± 4.8 | 22.4 ± 4.5 | 20.5 ± 5.2 | 0.38 |
| Blood urea (mmol/L) | 18.7 ± 7.0 | 16.9 ± 6.1 | 23.4 ± 7.2 | 0.001 |
| Blood urea/creatinine | 69 ± 19 | 65 ± 18 | 81 ± 18 | 0.001 |
| Proteinuria (g/24 h) | 1.2 ± 1.6 | 1.1 ± 1.4 | 1.4 ± 2.1 | 0.37 |
| Albumin (g/L) | 40 ± 5 | 40 ± 24 | 38 ± 4 | 0.13 |
| Calcium (mmol/L) | 2.31 ± 0.16 | 2.33 ± 0.15 | 2.27 ± 0.17 | 0.21 |
| Phosphate (mmol/L) | 1.34 ± 0.31 | 1.32 ± 0.30 | 1.40 ± 0.32 | 0.33 |
| iPTH (pg/mL) | 200 ± 236 | 181 ± 171 | 234 ± 326 | 0.53 |
| HbA1c (%) | 6.5 ± 1.5 | 6.20 ± 1.52 | 6.65 ± 1.20 | 0.40 |
| Haemoglobin (g/L) | 120 ±12 | 121 ± 12 | 118 ± 14 | 0.48 |
| CRP > 3 mg/L | 34 (48) | 17 (32) | 6 (33) | 0.25 |
| Atrial fibrillation | 10 (14) | 2 (4) | 8 (44) | < 0.001 |
| Sokolow index (mm) | 20 ± 7 | 19 ± 7 | 25 ± 9 | 0.009 |
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