Vascular Damage in Children With Chronic Kidney Disease

See related article, pp 863–869

Children with chronic kidney disease (CKD) have an increased mortality risk during childhood and as a young adult. Precisely, the lifespan of a pediatric patient on dialysis is shortened by 50 years compared with that of control individuals, matched for age and ethnicity.¹ Children with end-stage renal disease have a 10-year survival rate of ≈80% and an age-specific mortality rate of ≈30× that seen in children without end-stage renal disease.² In spite of a lower exposure to classical risk factors (diabetes mellitus, smoking, and hyperlipidemia), the most common cause of death in these children is cardiovascular disease. Hypertension, alterations in mineral metabolism, anemia, or chronic inflammation may explain part of this increased cardiovascular risk. In adults with CKD, increased aortic stiffness may lead to left ventricular hypertrophy and left ventricular dysfunction and is an important independent predictor of future cardiovascular events and mortality.

In children with moderate to severe CKD, there are fewer reports showing that arterial stiffness may contribute to cardiovascular morbidity or mortality. In addition, carotid-femoral pulse wave velocity (cfPWV) assessed by applanation tonometry—the most commonly used measure of arterial stiffness—may be challenging to measure, especially in younger children, because it is time-consuming and require patient collaboration.³ Finally, even if the patient is cooperative, it can be more difficult to maintain a sufficiently strong signal from the smaller arteries of younger children. It also requires a trained operator and access to the femoral artery in the inguinal area—a potentially disturbing maneuver, particularly in adolescents. Oscillometric assessment of pulse wave velocity (PWV) using a pressure cuff has the advantages of being quick, convenient, and operator independent.³

In the last 10 years, several important papers describing arterial stiffness in pediatric population with CKD have been published; importantly, these studies were mostly focused on end-stage renal disease (see Table). In children with end-stage renal disease, on dialysis, cfPWV and augmentation index are increased compared with those in healthy subjects.^4,7 A direct correlation between the time spent on dialysis and deterioration of vascular function was described; this decline was also associated with abnormal levels of calcium, phosphorus, and parathyroid hormone, as well as with dyslipidemia and increased blood pressure (BP).^4,10 There are some reports suggesting improvements in arterial abnormalities post-transplant. However, subclinical arteriopathy is still present in young transplant recipients. Transplanted patients have a significantly higher PWV compared with controls; PWV is correlated with systolic BP and age.^6,10

In children with predialysis CKD, available data are scarce. In the last year, 2 important papers were published, the last one in this issue of Hypertension.¹² In the first one, Sinha et al¹¹ measured common carotid artery mechanical properties, cfPWV, carotid, and peripheral BP in children with CKD from the Evelina London Children’s Hospital (n=188; 11.9±3.7 years; 26%, 25%, 30%, 16%, and 3% in CKD stages 1, 2, 3, 4 and 5, respectively) and in healthy controls (n=38; 11.5±3.3 years).¹¹ The authors found that (1) cfPWV values did not differ between children with CKD and healthy controls (5.3±0.9 versus 5.3±0.8 m/s, respectively) and were not significantly related to glomerular filtration rate (GFR); (2) when children with CKD and suboptimal BP control (values ≥75th percentile) are compared with normotensive controls, there are significant differences in functional elastic properties of the carotid artery (distensibility: 92±31 versus 114±33 kPa⁻¹ ×10⁻³, P=0.03; compliance: 2.1±0.7 versus 2.6±0.7 m² kPa⁻¹ ×10⁻⁶, P=0.02; Young elastic modulus: 0.151±0.068 versus 0.109±0.049 kPa ×10³, P=0.02; and wall stress: 83.6±23.5 versus 68.7±14.9 kPa, P=0.02); but not in cfPWV.

Savant et al,¹² in this issue of Hypertension, compared cfPWV, assessed via applanation tonometry in children enrolled in the CKiD (Chronic Kidney Disease in Children) cohort to normative data from healthy children and examined risk factors associated with elevated cfPWV.¹¹ Of the 95 participants with measured cfPWV, 60% were male, 19% were black, mean age was 15.1 years, average mean arterial pressure was 80 mm Hg, and median GFR was 63 mL/min per 1.73 m²; 91 participants had an iohexol-measured GFR, and for the remaining 4 participants, the authors used an estimated GFR. The main findings are as follows: (1) cfPWV increased significantly with age and mean arterial pressure, but not with GFR; (2) arterial stiffness was comparable to that of normal children. Importantly, the normative cfPWV data in healthy children was assessed using the PulsePen device, while cfPWV in CKD children was measured using the SphygmoCor device; a previous paper showed that data obtained by the 2 devices are in accordance with each other, the mean difference between cfPWV measured by SphygmoCor and PulsePen being 0.12 ±0.77 m/s.¹³ However, the limits of agreement between SphygmoCor and PulsePen cfPWV were −1.5 to 1.5 m/s. As the current mean cfPWV was 5.0 m/s in the CKiD study cohort, it is important to note that a limit of agreement of 3 m/s represents an error of 60%.

The authors also found that black race, which was significantly associated with elevated cfPWV in univariable analysis, retained significance after controlling for other factors in the multivariable analysis. The increased arterial stiffness for the black race compared with whites was also described in other cohort (adolescents and young adults with type 2 diabetes mellitus and also in adults with CKD). The number of black patients included in this study was small; thus, the interaction between race and the progression of arterial stiffness and cardiovascular damage in CKD will be interesting to follow in future research.

Although important, this study has several important limitations: (1) this is only a cross-sectional analysis; the prospective design of the CKiD study will allow longitudinal assessments of cfPWV, which could help reveal cfPWV changes as kidney function declines; (2) the presence of multiple operators at different clinical sites could have biased the results; (3) participants enrolled in the CKiD study–North American multicenter pediatric cohort may differ from the general population of children with CKD; (4) the relatively preserved kidney function, supported by a median GFR of 63 mL/min per 1.73 m². In addition, this cohort had a relatively large proportion of children with shorter disease duration and, hence, less exposure to reduced GFR, elevated BP, and other factors that may contribute to increase PWV.

These 2 trials are important contributions toward defining knowledge: in both, the authors found that arterial stiffness did not differ between CKD and healthy controls and were not significantly related to eGFR. In contrast, structural and functional alterations, including increased arterial wall thickness and stiffness in children on dialysis compared with healthy controls, have been described. The relatively preserved kidney function (median GFR of 54 mL/min, respectively, 63 mL/min per 1.73 m²) could be a possible explanation for such contradictory findings.

A comparable value of cfPWV in children with or without CKD does not exclude the existence of early significant subclinical vascular damage. Epidemiological and clinical studies have provided ample evidence that functional and structural damage begins early in the course of renal failure and progress markedly after dialysis start.

The best evidence supporting this disconnection between available measures of vascular functional damage and molecular significant abnormalities was provided by Shroff et al⁵ in an elegant study combining ex vivo vessels investigations with artery intima–media thickness and cfPWV in the same subjects. The authors found that all predialysis and 25% of dialysis vessels have normal carotid artery intima–media thickness, despite significant calcium accumulation in the vessel wall. Moreover, vessel stiffness, as measured by PWV, and coronary calcification on a computed tomography scan were seen in only 2 children with the highest vessel calcium loads.

In this context, current data suggests that our clinical investigation tools are not sensitive enough to detect early stages of calcification and arteriosclerosis in children with CKD and underlying vessel damage. We still consider that in children with CKD, we should include the assessment of vascular function (arterial stiffness, intima–media thickness) in the initial evaluation of these patients. Based on recent data, more attention should be given to patients with suboptimal BP control or from black descent.

• © 2017 American Heart Association, Inc.