Diastolic function and ambulatory hypertension in children with chronic kidney disease

Abstract

Diastolic dysfunction is one of the earliest cardiac abnormalities in patients with chronic kidney disease (CKD). We analyzed echocardiographic markers of left ventricular function from 786 children and adolescents (1,658 person-visits) enrolled in the Chronic Kidney Disease in Children (CKiD) cohort, a large prospective observational study of children with CKD. Primary outcome was E/e’ ratio as a marker of left ventricular compliance. Abnormal diastolic function was defined as E/e’>8.0. Those with an abnormal E/e’ ratio were younger, had a lower estimated glomerular filtration rate and hemoglobin, and a higher prevalence of hypertension and left ventricular hypertrophy (LVH) compared to children with a normal E/e’. In adjusted analysis, a higher E/e’ ratio was independently associated with ambulatory (sustained) hypertension (1.66 [95%CI: 1.15–2.42]). Other significant independent predictors were higher LVMI z-score, increased BMI z-score, lower hemoglobin, higher phosphorus level, and younger age. Casual BP was not significantly associated with higher E/e’. These data indicate that ambulatory blood pressure might better identify children with CKD at risk for subclinical cardiac dysfunction than clinic blood pressure alone.

Introduction

Cardiovascular disease (CVD) develops early in the course of chronic kidney disease (CKD) in children. It is usually subclinical and manifests as left ventricular hypertrophy (LVH), increased carotid artery intima-medial thickness (cIMT), and increased vascular stiffness.¹

Abnormal markers of LV systolic and diastolic function have also been reported in children with CKD.^2–7 Diastolic dysfunction is one of the earliest manifestation of cardiac dysfunction and is associated with the development of heart failure in adults, including those with CKD.^8–10 Thus, understanding the factors contributing to the development of LV diastolic dysfunction in children and adolescents with CKD is important to reducing future cardiovascular risk. Some studies have suggested that elevated blood pressure (BP) and worse kidney function are independently associated with LV dysfunction³ while other studies showed no such relationships.^5,11 To better understand the relationships between diastolic function, hypertension, and severity of CKD, we analyzed echocardiographic markers of LV function from children and adolescents enrolled in the Chronic Kidney Disease in Children (CKiD) cohort, a large prospective observational study in children with mild to moderate CKD. The objective of this study was to determine the effect of BP control and kidney dysfunction on LV diastolic function.

Methods

The data that support the findings of this study are available from the CKiD data coordinating center that will be responsible for maintaining data availability upon reasonable request.

Study population and study design:

The Chronic Kidney Disease in Children (CKiD) study is a prospective observational cohort study that enrolled children aged 1 to 16 years with estimated GFR (eGFR) between 30 and 90 ml/min per 1.73 m² at 54 pediatric nephrology centers across North America. The study design, methods, and exclusion criteria have been previously described.¹² The study was approved by a monitoring board appointed by the National Institute of Diabetes and Digestive and Kidney Diseases and by the institutional review boards of each participating center. Informed consent was obtained from each participant’s parent or guardian and from participant when age appropriate.

Participants:

CKiD enrolled 1079 participants from January 2005 to January 2020. Participants underwent annual study visits at which height, weight, BP, and laboratory values were determined. For the present analysis, we included 1,658 person-visits from 786 children who had echocardiography data from one or more visits and complete data on BP, with a median follow-up of 3.35 years.

Blood pressure and hypertension:

Casual BP was measured by auscultation at annual study visits, and defined as normal, elevated, or stage 1 and stage 2 hypertension according to the 2017 Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents.¹³ Ambulatory blood pressure monitoring (ABPM) recorded BP every 20 minutes for a continuous 24-hour period, and it was collected one year after the first study visit and every two years thereafter at local clinical sites (i.e., even visits at year 2, year 4, etc.). Criteria for a successful ABPM study included at least one successful BP recording in ≥75% of wake hours and ≥75% of sleep hours, and at least 21 hours with no more than 3 hours of missing readings in a 24-hour period. Abnormal ABPM was defined as either a wake or sleep mean SBP/DBP ≥ gender-and-height-specific 95^th percentile.^14,15 Participants with casual elevated BP or hypertension (stage 1 and stage 2) and an abnormal ABPM were classified as having sustained hypertension; those with a normal casual BP but abnormal ABPM were classified as masked hypertensive; those with casual hypertension but a normal ABPM were considered as white coat hypertensive and those with both normal casual BP and normal ABPM as normotensive.

Echocardiographic assessment:

All participants underwent an echocardiogram evaluation every two years since the second year in the CKiD study (e.g., even visits at year 2, year 4 and etc., the same as ABPM). The specific procedure for echocardiographic determination of left ventricular mass (LVM) and function used in the CKiD study has been described.¹⁶ Briefly, M-mode and Doppler echocardiography were performed at participating centers, and reading and analyses of echocardiographic data were performed by the Cardiovascular Imaging Core Research Laboratory (CICRL) at Cincinnati Children’s Hospital Medical Center. Left ventricular mass was indexed (LVMI) to height (g/m^2.7) to account for body size.¹⁷ LVH was defined as LVMI ≥ the 95^th percentile for healthy children and adolescents.¹⁸ Because LVMI indexed to height does not fully account for changes due to growth, we also expressed LVMI as a z-score based on age and sex.¹⁸ Systolic function was ascertained by shortening fraction (SF). Values < 25% indicate abnormally low SF.¹⁹ Diastolic function was assessed via E/A ratio (early-to-atrial LV filling ratio) and e’/a’ ratio (early-to-late mitral annular peak velocity) as two markers of LV relaxation, and E/e’ ratio (estimate of LV filling pressure) as a marker of LV compliance.²⁰ Tissue Doppler imaging of the mitral annular inflow was recorded at the lateral and septal annulus with the average of e′ from the lateral and septal regions included in the E/e’ ratio for the primary analysis. We also performed a secondary analysis in which e’ was defined from the lateral region only. Abnormal diastolic function was defined as E/A < 1.0, e’/a’ < 1.0, and E/e’ > 8.0 (with E/e’>14.0 considered to be clinically significant).^21,22

Covariates included age, male sex, black race, body mass index (BMI) z-score, eGFR, urine protein to creatinine ratio (UPCR), systolic BP (SBP) and diastolic BP (DBP) z-scores, lab markers (serum calcium, phosphorous bicarbonate, hemoglobin) and antihypertensive medications. Obesity was categorized as normal (BMI <85^th percentile), overweight (BMI ≥85^th to 95^th percentile), and obese (≥95^th percentile). GFR was estimated using the bedside CKiD equation based on serum creatinine and height for those under 18 years²³, and the CKiD 2012 equation based on serum creatinine and cystatin c for those at or above 18 years for better assessments among young adults.²⁴ We used the average from the current visit with echocardiography (even visit) and the immediate visit prior to echocardiography (odd visit) for BP z-scores and lab markers. Antihypertensive medications included angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and any combinations of both, and the use of antihypertensive medications was further classified as: never use (not used at the prior or current visit), discontinued use (used at prior visit only), new use (use at current visit only), and continued use (use at both visits).

Statistical analysis:

Demographic and clinical characteristics are presented as counts with percentage for categorical variables and median with interquartile ranges [IQR] for continuous variables. Since the presence of an abnormal E/A ratio and e’/a’ ratio was rare with a prevalence <2%, the subsequent analyses focused on E/e’ ratio as a primary outcome. We applied repeated measures regression models and used age at current echocardiography visit as time metrics to analyze longitudinal data. Generalized estimating equations (GEE) were used to account for within-person correlation and estimate robust standard errors for 95% confidence intervals (95% CI).

We examined the association between log-transformed E/e’ ratio and hypertension status using univariate regression models. We added a set of pre-specified demographic and clinical variables as potential confounders to the model partially adjusted for hypertension status and LVMI z-score individually; and variables with a p-value <0.10 were included in the final multivariate model. Casual SBP and DBP z-scores were included in model 1; hypertensive status based on combination of casual and ambulatory BP (normal BP, masked hypertension and sustained hypertension) was included in model 2. Covariates included sex, race, BMI z-score/obesity, hypertensive medication use (never user as reference), eGFR and UPCR at current visit, and standardized average laboratory marker (i.e. serum calcium, phosphorus, bicarbonate, hemoglobin) from the current and previous visits. To compare strength of association across multiple laboratory markers and across different units, we standardized bicarbonate and hemoglobin per one standard deviation on original scale, calcium and phosphorus on log scale, and eGFR and UPCR on log 2 scale; the standard deviations were specific to this study population. We then repeated the analyses using E/e’ based on e’ from the lateral and septal regions only.

Results with two-sided p<0.05 were considered as statistically significant. All analyses were performed using SAS 9.4 for Windows (SAS Institute Inc., NC), and figures were generated using R 3.5.1 (Vienna, Austria).

Results

Baseline characteristics of the 786 children enrolled in the CKiD study and included in our analyses are presented in Table 1. About one-third of children had casual BP > 90^th percentile (elevated casual BP, Stage 1 and 2 casual hypertension), 15% had masked hypertension and 19% had sustained hypertension; 65% were using antihypertensive medications. There were few participants with E/A or e’/a’ ratios < 1.0. E/e’ ratio > 8.0 was found in 241 (14.5%) person-visits by 174 participants. Four participants had E/e’ ratio > 14 and, among them, all had e’/a’ > 1.0. Most children had normal systolic function; SF <25% was found in 2.8 %. The prevalence of LVH was 11%. There were 168 black participants. Compared to Non-blacks, Blacks had higher SBP/DBP z-scores, higher BMI, and a greater prevalence of LVH. No significant differences in E/e’ based on race was found (data are not shown).

Table 1.

Demographic and clinical characteristics.

Characteristics	Unique individuals at baseline N=786
Age at Echocardiography Visit, year	12 [8, 16]
Male Sex, n (%)	477 (60.7)
Blacks, n (%)	164 (20.9)
Hispanic Ethnicity, n (%)	109 (13.9)
Non-Glomerular Diagnosis, n (%)	573 (72.9)
BMI z-score	0.36 [−0.39, 1.21]
Normal (BMI <85th percentile)	588 (71.7)
Overweight (BMI ≥85th to 95th percentile)	93 (12.0)
Obese (BMI ≥95th percentile)	127 (16.3)
eGFR, ml/min/1.73m2	53 [37, 69]
UPCR	0.3 [0.1, 1]
Casual SBP, mmHg	107 [100, 117]
Casual DBP, mmHg	65 [59, 74]
Casual SBP z-score	0.20 [−0.47, 0.95]
Casual DBP z-score	0.28 [−0.33, 1.04]
Elevated Casual SBP/DBP, n (%)	64 (12.5)
Casual Hypertension (Stage 1 and 2), n (%)	109 (21.4)
Masked Hypertension, n (%)	74 (14.5)
Sustained Hypertension, n (%)	97 (19.0)
Antihypertensive Medication, n (%)	506 (64.4)
LVMI, g/m2.7	31 [26, 37]
LVMI z-score	0.15 [−0.67, 1.04]
LVH, n (%)	84 (10.8)
Shortening Fraction (SF), %	37 [34, 41]
SF < 25%, n (%)	22 (2.8)
E/A Ratio	1.8 [1.5, 2.3]
E/A <1.0, n (%)	3 (0.4)
e'/a' Ratio	2.2 [1.8, 2.7]
e'/a' <1.0, n (%)	6 (0.8)
E/e' Ratio	6.3 [5.4, 7.5]
E/e'>8.0, n (%)	122 (15.5)
Bicarbonate, mmol/L	23 [21, 25]
Hemoglobin, g/dL	12.8 [11.8, 13.8]
Anemia, n (%)	210 (27.4)
iPTH (pg/mL) a	45.4 [29.5, 70.4]
Phosphorus, mg/dL	4.5 [4, 5]
Calcium (mg/dL)	9.5 [9.2, 9.8]

Abbreviation: eGFR, estimated glomerular filtration rate; UPCR, urine protein to creatinine ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVMI, left ventricular mass index; LVH, left ventricular hypertrophy; iPTH, intact parathyroid hormone.

^aAll baseline iPTH is missing as iPTH is measured at Visit 1B, Visit 3, Visit 5 etc. We presented the iPTH level at previous annual visit (i.e., one year prior the echocardiographic visit), and the missingness is 152/786=19%.

Table 2 compares person-visits with normal (≤ 8) versus abnormal (> 8) E/e’ ratios. Those with abnormal E/e’ ratios were younger, had lower eGFR, hemoglobin, and bicarbonate levels, higher serum phosphorus, casual SBP z-scores, higher LVMI z-score, and a higher prevalence of casual hypertension, LVH, and abnormally low SF (< 25%) compared to children with a normal E/e’.

Table 2.

Characteristics by E/e’ status among 1658 person-visits by 786 participants

Characteristics	Abnormal E/e’ (> 8) n=241	Normal E/e’ (≤ 8) n=1417
Age at Echocardiography visit, year	12 [9, 15]	14 [10, 17]
Male Sex, n (%)	146 (60.6)	869 (61.3)
Blacks, n (%)	54 (22.4)	250 (17.6)
Hispanic ethnicity, n (%)	30 (12.5)	199 (14.0)
Non-glomerular Diagnosis, n (%)	199 (82.6)	1098 (77.5)
eGFR, ml/min/1.73m2	48 [31, 63]	49 [34, 65]
UPCR	0.32 [0.14, 1.07]	0.36 [0.13, 1.00]
Casual SBP z-score	0.60 [−0.20, 1.48]	0.15 [−0.50, 0.84]
Casual DBP z-score	0.44 [−0.41, 1.13]	0.25 [−0.33, 0.99]
Casual hypertension, n (%)	74 (44.3)	313 (28.1)
Antihypertensive medication, n (%)	159 (66.5)	914 (64.5)
LVMI, g/m2.7	32 [27, 39]	29 [24, 34]
LVMI z-score	0.47 [−0.33, 1.40]	0.00 [−0.84, 0.81]
LVH, n (%)	40 (17.0)	109 (7.8)
Shortening Fraction (SF)	0.39 [0.35, 0.42]	0.37 [0.33, 0.40]
SF < 25%	12 (5.0)	39 (2.8)
Phosphorus, mg/dL	4.6 [4.2, 5.1]	4.4 [3.9, 4.9]
Bicarbonate, mmol/L	23 [21, 25]	24 [21, 26]
Hemoglobin, g/dL	12.6 [11.4, 13.5]	12.9 [11.8, 13.9]
Anemia, n (%)	91 (38.4)	412 (29.9)
BMI z-score	0.68 [−0.11, 1.57]	0.27 [−0.49, 1.17]
Normal (BMI <85th percentile)	148 (64.4)	946 (72.3)
Overweight (BMI ≥85th to 95th percentile)	27 (11.7)	183 (14.0)
Obese (BMI ≥95th percentile)	55 (23.9)	179 (13.7)
iPTH (pg/mL) a	61.2 [39.0, 97.7]	48.2 [31.0, 74.1]
Calcium (mg/dL)	9.4 [9.2, 9.8]	9.5 [9.2, 9.8]

Abbreviation: eGFR, estimated glomerular filtration rate; UPCR, urine protein to creatinine ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; iPTH, intact parathyroid hormone.

^aAll iPTH is measured at odds visit (e.g., Visit 1B, Visit 3, Visit 5). We presented the iPTH level at previous annual visit (i.e., one year prior the echocardiographic visit), and missingness is 15% (44/285) and 12% (176/1417) in abnormal group and normal E/e’ group, respectively.

When we compared the frequency of E/e’>8, using a combination of casual and ambulatory BP, an abnormal E/e’ ratio was more frequent in person-visits with sustained systolic hypertension than in those with normal casual and ambulatory BP (21% vs. 12%), p=0.01), Figure 1.

Figure 1.

Prevalence of E/e’ ratio >8.0 by hypertension status.

The results of repeated measures regression to analyse longitudinal data of factors associated with an elevated E/e’ ratio are shown in Table 3. E/e’ ratio was independently associated with ambulatory (sustained) hypertension (p=0.007), LVMI z-score (p=0.028), increased BMI z-score (p=0.004), lower hemoglobin level (p=0.017), and increased phosphorus level (p=0.016). Casual SBP z-score was significantly associated with elevated E/e’ in univariate analysis, but it was no longer significant after adjustment for LVMI z-score. Similarly, eGFR, UPCR and bicarbonate levels were significantly associated with abnormal E/e’ ratio in univariate analysis, but the relationship was attenuated after adjustment for hypertension status and LVMI z-score.

Table 3.

Multivariate analysis of factors associated with E/e’ ratio.

GEE model	Univariate		Multivariate model 1		Multivariate model 2
	Estimate [95%CI]	P value	Estimate [95%CI]	P value	Estimate [95%CI]	P value
Average casual SBP z-score	1.03 [1.01, 1.05]	0.007	1.02 [0.99, 1.04]	0.253
Average casual DBP z-score	1.01 [0.98, 1.03]	0.513	1.00 [0.97, 1.03]	0.924
Hypertension status*		0.011				0.004
Normal blood pressure	1 [ref]				1 [ref]
Masked hypertension	1.01 [0.97, 1.06]	0.592			1.01 [0.96, 1.07]	0.719
Sustained hypertension	1.08 [1.03, 1.14]	0.002			1.07 [1.02, 1.13]	0.007
LVMI z-score	1.04 [1.03, 1.06]	<.0001	1.02 [1.00, 1.04]	0.039	1.02 [1.00, 1.04]	0.028
Black race	1.05 [1.00, 1.09]	0.032	1.05 [1.00, 1.11]	0.046	1.04 [0.99, 1.10]	0.121
BMI z-score	1.03 [1.02, 1.05]	<.0001	1.03 [1.01, 1.05]	0.002	1.03 [1.01, 1.05]	0.004
Average hemoglobin, per SD	0.96 [0.95, 0.98]	<.0001	0.97 [0.95, 1.00]	0.019	0.97 [0.95, 0.99]	0.017
Average calcium, per SD on log scale	0.97 [0.96, 0.99]	0.001	0.99 [0.97, 1.01]	0.266	0.98 [0.97, 1.00]	0.108
Average phosphorus, per SD on log scale	1.04 [1.02, 1.06]	<.001	1.03 [1.01, 1.06]	0.004	1.03 [1.01, 1.05]	0.016

Abbreviation: eGFR, estimated glomerular filtration rate; UPCR, urine protein to creatinine ratio; LVH, left ventricular hypertrophy; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Note: All models were adjusted for age at echocardiography visit. Covariates were added to the partial models adjusted for hypertension status and LVMI z-score individually, and those with p value <0.1 were included in the final multivariate model.

^*p-values were from type 3 tests that examined the significance of overall effect of hypertension status (i.e., masked hypertension and sustained hypertension together) and hypertensive medication use (i.e., use at prior visit only, use at current visit only, and use at both visits together).

A sensitivity analysis using E/e’ with e’ from lateral (Tables S1 and S2) or septal only regions (Table S3) showed similar results.

Discussion

The results of this large longitudinal observational cohort study of children and adolescents with mild to moderate CKD demonstrated that a significant number of participants had an abnormal marker of diastolic function as measured by E/e’ ratio. E/e’ ratio is an index of LV filling pressures that estimates LV myocardial compliance at end-diastole. It is considered to be a reproducible marker of diastolic function with values < 8.0 typically indicating normal LV filling pressure, and values >14 (4 children in our study) being a good indicator with high specificity of elevated filling pressures.²¹ These early diastolic changes are important because the presence of diastolic dysfunction, as reflected by an abnormal E/e’, is a known precursor to heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) in adults.²⁵

Hypertension is a well-known risk factor for HFpEF in adults.²⁶ In children, recent studies showed an association of elevated casual SBP with a higher E/e’ ratio. For example, data from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study demonstrated an independent association of worse E/e’ with higher SBP, and a better E/e’ z-score with RAS inhibition.³ The results from the Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth (SHIP-AHOY) showed a higher E/e’ in adolescents with SBP ≥ 90^th percentile versus those with lower SBP.²⁷ Unlike the above studies, casual BP was not significantly associated with the E/e’ ratio in our multivariable analysis, possibly because the majority of our patients (66%) had normal casual BP or well-controlled hypertension (BP < 90^th percentile). In contrast, sustained hypertension as determined by 24-hour ABPM was an independent predictor of elevated E/e’. These data indicate that ABPM might better identify children with CKD at risk for subclinical cardiac dysfunction than casual BP alone and justify a more aggressive therapeutic approach to BP control in these children. The importance of ABPM in adults with CKD was recently examined in the Chronic Renal Insufficiency Cohort (CRIC) study.²⁸ In that study, uncontrolled ambulatory hypertension was associated with higher mortality and worse cardiovascular and kidney outcomes independent of clinic BP.²⁸

While hypertension promotes the development of LVH, in our study both sustained hypertension and increased LVMI were independent predictors of an elevated E/e’ in multivariable analysis suggesting a synergistic effect on diastolic function. The relationship between LVH and diastolic dysfunction is well established. The increased myocardial stiffness associated with LVH lowers ventricular compliance and thus raises ventricular filling pressure.^29,30 Multiple mechanisms have been proposed as potential mechanisms by which hypertension, independent of LVH, could result in diastolic dysfunction, including an altered time course of relaxation, increased blood volume, and interactions between the left and right ventricles within the restraints of the pericardium.^30,31

While an E/e’ value > 8 is defined as abnormal, E/e’ between 8–14 in adults is considered as a gray zone with “indeterminate” filling pressure.²¹ To diagnose a patient with clinically significant diastolic dysfunction, the current algorithm in adults calls for meeting >2 criteria (average E/e’ >14, septal e’ velocity < 7 cm/s or lateral e’ velocity <10 cm/s, tricuspid regurgitation velocity > 2.8 m/s, and left atrial volume index > 34 ml/m²). A recent study showed that incorporation of peak left atrial longitudinal strain (PALS) helps to predict increased intra-cardiac pressure and clinically significant diastolic dysfunction in those with an E/e’ 8–14.³² The CKiD echocardiographic measurements do not include all the proposed measures, so we were unable to use the proposed algorithm or PALS. Thus, the clinical significance of E/e’ 8–14 in our cohort could not be fully assessed. The E/e’ ratio values in our study were similar to E/e’ values in the general pediatric population with hypertension. For example, using the same definition of E/e’ (e’ average of lateral and septal regions), the SHIP-AHOY study²⁷ showed an E/e’ of 6.5±1.5 in adolescents in the high risk group (BP >90^th percentile) vs. 6.4±1.7 in our cohort despite a much higher average BP in SHIP-AHOY participants (136/86 mmHg) than in the CKiD cohort (109/67 mmHg). Similarly, in a recent study by Gu et al³³ of children with primary hypertension, the E/e’ (also based on average lateral and septal e’) was 6.0±1.3 in those with LVMI in the first tertile and 6.5±1.2 in those whose LVMI was in the third tertile. These results are also consistent with older data which showed a mean E/e’ of 6.3±1.7 in children with primary hypertension.³⁴ Comparable levels of E/e’ in our cohort to children with primary hypertension, even among those with LVH³³, suggest that in addition to hypertension or LVH, other factors might contribute to abnormal diastolic function in children with CKD.

As other cardiac parameters, normative values of markers of diastolic function are age-dependent.³⁵ However, we decided to present the prevalence of an abnormal E/e’ ratio based on a value of 8.0 as a cut off since this value is used in clinical practice. To account for age-dependency, we performed multivariate analyses adjusted for age.

As in children without CKD or hypertension ³⁶, a higher BMI z-score (obesity) was another independent predictor of elevated E/e’ in our study. Potential mechanisms of obesity-induced diastolic dysfunction might include systemic inflammation, cardiac lipotoxicity and hemodynamic alterations.³⁷ A lower hemoglobin level was also associated with a higher E/e’. Similar associations were seen in a smaller study of children with CKD from Turkey.³⁸ In adults with and without CKD, anemia is a known contributing factor leading to diastolic dysfunction.^39,40 Our study also confirmed the results of an early smaller study of children with CKD showing a significant association of worse E/e’ with hyperphosphatemia², a well-known risk factor for CVD in the CKD population.¹⁰

While the majority participants in our study with an abnormal E/e’ had values that were in the 8–14 range, four children had an E/e’ ratio >14 suggesting significant diastolic dysfunction. Importantly, among them, all children had e’/a’ >1.0 which might indicate the later stages of diastolic dysfunction - the restrictive phase of the disease.

Perspective

The results of this study showing an association of sustained hypertension with elevated E/e’ ratio suggest that ambulatory BP might better identify children with CKD at risk for subclinical cardiac abnormalities than casual BP alone. Taking into account the fact that CVD is a leading co-morbidity and cause of death in childhood onset CKD, our results warrant regular assessment of cardiac structure and function in children with CKD, especially in those with elevated BP.

Novelty and Significance.

1. What Is New?

• Children with chronic kidney disease (CKD) have a high prevalence of subclinical markers of abnormal left ventricular (LV) diastolic function

• Ambulatory hypertension is associated with abnormal LV diastolic function. This association was independent of left ventricular hypertrophy (LVH)

2. What Is Relevant?

• The study examined the effect of BP control and kidney dysfunction on LV diastolic function and determined that ambulatory hypertension is an independent predictor of abnormal markers of diastolic function

3. Summary:

• Our study demonstrated that ambulatory BP might better identify children with CKD at risk for subclinical cardiac abnormalities than casual BP alone.

• These data warrant regular assessment of cardiac structure and function in children with CKD, especially in those with elevated