Cardiac and Vascular Adaptation in Pediatric Patients with Chronic Kidney Disease: Role of Calcium-Phosphorus Metabolism

Patients

Forty-four children and adolescents with CRI (CKD stages 2 to 4), 16 on maintenance dialysis and 35 healthy individuals of comparable age and gender, were recruited between 2002 and 2004 to participate in the study. Inclusion criteria were (1) age 6 to 21 yr; (2) measured GFR between 15 and 89 ml/min per 1.73 m² for patients with CRI; (3) at least 6 wk of maintenance dialysis for dialysis patients; (4) absence of congenital, structural, or primary myocardial disease; and (5) good quality ultrasonic and echocardiographic images. The Institutional Review Board of Cincinnati Children’s Hospital Medical Center approved the study, and informed consent was obtained from each patient.

Healthy children were recruited from the families of personnel at Cincinnati Children’s Hospital. They were selected to be similar to the patient group by age and gender. Patients’ medical records were reviewed for age; gender; race; dialysis modality; cause of CKD; duration of CKD (since diagnosis); duration of dialysis; and pertinent medications, including antihypertensives, calcium-based phosphate binders (P-binders), and calcitriol. All patients had a history and a physical examination. Each patient had serum creatinine, calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), hemoglobin, and fasting lipid profile determined at time of echocardiography and carotid artery ultrasound for patients with CRI and during a routine monthly visit preceding research visit for dialysis patients. Dyslipidemia was defined on the basis of the Kidney Disease Outcomes Quality Initiative guidelines (8).

Body mass index (BMI) was calculated as weight (kg)/height (m)². BP was measured during a research visit at the time of echocardiography by auscultation using an appropriate-size cuff, with a mercury manometer, and with the patient in the sitting position. BP were indexed to the age-, gender-, and height-specific 95th percentile for each patient (measured systolic [SBP] or diastolic BP [DBP] was divided by the age-, gender-, and height-specific 95th percentiles). Hypertension was defined as indexed SBP or DBP ≥1.0.

The GFR for patients with CRI was determined by a single intravenous injection of Ioversol 74% (Optiray 350; Mallinckrodt Inc., St. Louis, MO) (9). Iodine was measured in timed blood samples by x-ray fluorescence analysis (Renalyzer PRX90; Diatron AB Inc., Lund, Sweden), and GFR was calculated from the slope of the iodine disappearance curve. Patients on hemodialysis were dialyzed three times per week for 3 to 4.5 h at each session. Change in body weight during the dialysis preceding the carotid artery and echocardiographic evaluations was calculated. “Dry weight” was defined as the body weight below which hypotension or muscle cramps occurred. Children on peritoneal dialysis had daily treatment using the continuous cycling peritoneal dialysis modality. The dialysis adequacy was estimated by most recent double-pool Kt/V values.

Echocardiography to evaluate cardiac structure and function was performed by two experienced research sonographers blinded to the patient’s status as described elsewhere (6,7). Left ventricular mass (LVM) was measured by two-dimensional directed M-mode echocardiography at rest according to the American Society of Echocardiography criteria (10). LVM index (LVMI; mass divided by height raised to a power of 2.7 [g/m^2.7]) was used as a measure of LVH that accounted for body size (11). LVH was defined as LVMI >95th percentile for normal children and adolescents (12). Relative wall thickness (RWT) was measured to assess the LV geometry. Patients with increased LVMI (≥95th percentile) and elevated RWT (≥0.41) had concentric LVH; those with increased LVMI and normal RWT (<0.41) had eccentric LVH. Concentric remodeling was defined as elevated RWT but with normal LVMI. Diastolic function was estimated by both Doppler echocardiography and tissue Doppler imaging. Specifically, the mitral Doppler inflow velocities (E, A) and the mitral annular velocities (Em) were obtained. The index of LV compliance, E/Em, was calculated.

Carotid artery ultrasound was performed using a GE Vivid 7 Horton Norway, M12L, 5.0- to 11.0-MHz probe immediately after echocardiography by the same research sonographers who were blinded to the disease status of the patient. The method has been described elsewhere (5). An ultrasound imager distal to the carotid artery bifurcation on a segment of posterior wall with the length of at least 1 cm was used for the study. Measurements were performed for at least three consecutive heartbeats. Video images were selected and stored in digital form off-line; mean cIMT and the internal diameter of the right common carotid artery during systole and diastole then were calculated. Indices of arterial function were calculated (13). Distensibility (DC) = 2(ΔD/D)/(SBP − DBP), where D is carotid artery diastolic diameter and ΔD is change in artery diameter during systole. The stiffness parameter (β) = (ln[SBP/DBP])/(ΔD/D). The incremental modulus of elasticity (Einc), the marker of intrinsic properties of the arterial wall, was calculated from the ratio of the lumen cross-sectional area (LCSA) and wall cross-sectional area (WCSA): LCSA = πD²/4; WCSA = π(D/2 + cIMT)² − π(D²/2)²; Einc = 3(1 + [LCSA/WCSA])/DC.

Statistical Analyses

Values are presented as the mean value ± SD. A two-sample t test or Mann-Whitney rank sum test was used to compare continuous variables. The general linear model (GLM) procedure was used to compare means ± SD among all three groups in an ANOVA. Categorical variables were compared using the χ² test or Fisher exact test. The associations between variables were assessed by Spearman correlation analysis. Stepwise multiple regression analysis was performed to assess independent predictors of abnormal cIMT or arterial compliance. Variables with P < 0.15 from univariate analyses were entered in the regression analysis. The SAS 9.1 statistical package was used in the analysis. P ≤ 0.05 was considered statistically significant.

Patient Characteristics

There were no significant differences in age and BMI among control, CRI, and dialysis groups (Table 1). Children who had CRI and were on dialysis were shorter and had higher SBP and DBP than healthy control subjects. The mean GFR for children with CRI was 46.3 ± 21.8 ml/min per 1.73 m²; 13 (29%) of the patients had CKD stage 2, 17 (39%) had stage 3, and 14 (32%) had stage 4. Among children with CRI, 15 (34%) were taking BP medications. Eight of these were taking an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as an antiproteinuric agent. Among dialysis patients, 8 (50%) were taking BP medications. All dialyzed children received calcium-based P-binders and calcitriol, whereas only three patients with CRI were taking P-binders and 14 (32%) were taking calcitriol (Table 2).

The average time on dialysis was 1.2 ± 1.3 yr (range 0.3 to 3.7 yr). Among dialyzed patients, 10 were on hemodialysis (two patients with arteriovenous graft, one patient with fistula, and seven patients with permanent right atrial catheter) and six were on chronic continuous peritoneal dialysis. The mean Kt/V for the 10 hemodialysis patients was 1.7 ± 0.7 (range 1.1 to 2.3) and for six peritoneal dialysis patients was 3.7 ± 0.8 (range 1.8 to 4.6). The mean intradialytic body weight change for hemodialyzed children was 3.2% (range 0.2 to 6.7%). Children who were on maintenance dialysis had a significantly higher blood urea nitrogen, serum P, Ca × P product, iPTH, and cumulative intake of P-binders and calcitriol compared with children with CRI (Table 2). There was a significant correlation between time on dialysis and serum P level (r = 0.60, P = 0.04), Ca × P product (r = 0.50, P = 0.04), and cumulative intake of P-binders (r = 0.48. P = 0.05).

Cardiac Structure and Function

Both children with CRI and those on dialysis had elevated LVMI compared with control subjects (P < 0.0001; Table 3). Dialyzed children had significantly higher LVMI (P < 0.001) and higher prevalence of LVH (63 versus 29%; P < 0.05) when compared with children with CRI. LVMI in renal patients (children with CRI and those on dialysis, n = 60) was correlated with hemoglobin (r = −0.48, P < 0.0001), iPTH (r = 0.39, P = 0.003), P (r = 0.27, P = 0.04), and Ca × P product (r = 0.25, P = 0.06); BP was not significantly correlated with LVMI. Stepwise multivariate analysis demonstrated that higher iPTH level (β = 0.01, P = 0.04) and lower hemoglobin level, (β = −2.5, P = 0.04) were independent predictors of increased LVMI.

Both children with CRI and those on dialysis had diastolic dysfunction, evidenced by significantly lower Em (P < 0.001) and significantly higher E/Em ratio than control subjects (P < 0.001; Table 3). Dialysis patients had significantly lower Em (P < 0.001) than children with CRI. Multivariate analysis showed that in renal patients (n = 60), Em was inversely related to iPTH level (β = −0.0004, P < 0.001) and LVMI (β = −0.07, P = 0.017). Direct associations were observed for the relationship between E/Em and iPTH (β = 0.002, P < 0.02) as well as the relationship between E/Em and LVMI (β = 0.05, P = 0.03).

Carotid Artery Structure and Function

Children with CRI and those on dialysis had increased cIMT compared with the control group. Children on dialysis had significantly higher stiffness parameter (β) and Einc and significantly lower DC when compared with both CRI patients and control subjects. Arterial compliance was similar in patients with CRI and control subjects (Table 4).

In children with CRI, cIMT was associated with serum P (r = 0.36, P = 0.04), Ca × P product (r = 0.36, P = 0.04), and LVMI (r = 0.27, P = 0.07). No significant correlation was found between cIMT and BP, lipid levels, renal function, or other variables. In the dialysis group, cIMT was significantly higher in children on dialysis for >6 mo (0.52 ± 0.06 versus 0.43 ± 0.08 mm; P < 0.0001) and in children who were taking more than one BP medication (0.53 ± 0.10 versus 0.45 ± 0.08; P = 0.04). Children with residual kidney function had significantly lower cIMT than children without residual kidney function (0.41 ± 0.07 versus 0.49 ± 0.10; P = 0.05). In the dialysis group, cIMT was correlated directly with cumulative dose of P-binders (r = 0.64, P < 0.001). DC in this group was inversely related to pulse pressure (PP; r = −0.65, P < 0.01), iPTH (r = −0.53, P < 0.05), cumulative dose of calcitriol (r = −0.55, P = 0.02) and P-binders (r = −0.56, P = 0.01), and RWT (r = −0.56, P = 0.03). Arterial stiffness (β) was associated directly with PP (r = 0.50, P < 0.05), iPTH level (r = 0.60, P < 0.01), cumulative dose of calcitriol (r = 0.60, P = 0.01) and P-binders (r = 0.57, P = 0.01), and RWT (r = 0.52, P = 0.05). Einc was correlated with PP (r = 0.58, P = 0.01), iPTH (r = 0.53, P = 0.03), and RWT (r = 0.57, P = 0.03).

The results of multiple regression analyses for all patients with renal disease (CRI and dialysis) are shown in Table 5. After adjustment for interrelations among variables, serum Ca × P product was the only significant independent predictor of increased cIMT; PP and P level were significant independent predictors of increased stiffness parameter; PP and iPTH predicted Einc. However, when cIMT was entered into the multivariate analysis, the P level was no longer a significant predictor of stiffness parameter. In this model, cIMT (β = 1.53, P = 0.002) and PP (β = 0.05, P < 0.0001) predicted carotid artery stiffness parameter (model R² = 0.39); no changes in the model occurred for Einc. PP was the only independent predictor of decreased arterial DC. P-binders were not included in the models, because only three patients in the CRI group were taking this medication. To investigate the role of P-binders and calcitriol on cIMT and arterial stiffness, we performed analyses for the dialysis patients separately (Table 6). Cumulative dose of P-binders predicted cIMT. PP, iPTH, and cumulative dose of P-binders predicted DC. Cumulative dose of calcitriol and PP predicted stiffness parameter and Einc.