Cardiovascular Phenotypes in Children with CKD: The 4C Study

Abstract

Background and objectives: Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD.

Design, setting, participants, & measurements: The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6-17 years old with initial GFR of 10-60 ml/min per 1.73 m². The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers.

Results: A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; n=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements >95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level.

Conclusions: The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD.

Keywords: Biomarkers; Blood Pressure Monitoring, Ambulatory; Body Mass Index; Carotid Intima-Media Thickness; Child; Comorbidity; Europe; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Phenotype; Phosphorus; Phosphorus, Dietary; Prevalence; Prospective Studies; Pulse Wave Analysis; Renal Insufficiency, Chronic; arteriosclerosis; blood pressure; glomerular filtration rate; hypertension; left ventricular hypertrophy; pulse wave velocity; vesico-ureteral reflux.

Figure 1.

24-hour blood pressure and eGFR in patients with or without antihypertensive treatment. The 24-hour mean arterial pressure SD scores (SDSs) in children with underlying glomerular (red squares) and nonglomerular nephropathies (blue circles) with (colored symbols) or without antihypertensive medication (outlined symbols) according to eGFR. Lines represent 5th, 50th, and 95th reference percentiles of 24-hour mean arterial pressure. AHT, Antihypertensive Treatment.

Figure 2.

24-hour blood pressure and left ventricular mass index in patients with or without antihypertensive treatment. The 24-hour mean arterial pressure SD scores (SDSs) and left ventricular (LV) mass index in children with underlying glomerular (red squares) and nonglomerular nephropathies (blue circles) with (colored symbols) or without antihypertensive medication (outlined symbols). Vertical and horizontal lines represent 95th reference percentiles of 24-hour mean arterial pressure and LV mass index, respectively. The dashed line represents the linear regression line. AHT, Antihypertensive Treatment.

Figure 3.

Surrogate marker measurements. Distribution of carotid intima-media thickness (IMT; left panel) and pulse wave velocity (PWV; right panel). Curves represent 5th, 10th, 25th, 50th, 75th, 90th, and 95th reference percentiles.

Figure 4.

Intermediate end points by CKD stage. Percentages of patients presenting with zero, one, two, or three intermediate cardiovascular end points by CKD stage. Intermediate end points are left ventricular mass index, carotid intima-media thickness, or central pulse wave velocity exceeding the 95th percentile for height.