George S. Reusz

Reference Values of Pulse Wave Velocity in Healthy Children and Teenagers

Carotid-femoral pulse wave velocity is an established method for characterizing aortic stiffness, an individual predictor of cardiovascular mortality in adults. Normal pulse wave velocity values for the pediatric population derived from a large data collection have yet to be available. The aim of this study was to create a reference database and to characterize the factors determining pulse wave velocity in children and teenagers. Carotid-femoral pulse wave velocity was measured by applanation tonometry. Reference tables from pulse wave velocities obtained in 1008 healthy subjects (aged between 6 and 20 years; 495 males) were generated using a maximum-likelihood curve-fitting technique for calculating SD scores in accordance with the skewed distribution of the raw data. Effects of sex, age, height, weight, blood pressure, and heart rate on pulse wave velocity were assessed. Sex-specific reference tables and curves for age and height are presented. Pulse wave velocity correlated positively (P<0.001) with age, height, weight, and blood pressure while correlating negatively with heart rate. After multiple regression analysis, age, height, and blood pressure remained major predictors of pulse wave velocity. This study, involving >1000 children, is the first to provide reference values for pulse wave velocity in children and teenagers, thereby constituting a suitable tool for longitudinal clinical studies assessing subgroups of children who are at long-term risk of cardiovascular disease.

Genotype/Phenotype Correlation in Nephrotic Syndrome Caused by WT1 Mutations

BACKGROUND AND OBJECTIVES The risk of developing Wilms tumor (WT) can be present or absent in patients with nephrotic syndrome (NS) caused by WT1 mutations. Here, the genotype/phenotype correlation regarding the outcome and risk for WT in 52 patients from 51 families with NS due to WT1 mutations is described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study followed 19 patients with mutations in intron 9 splice donor site (KTS mutations), 27 patients with missense mutations, 4 patients with nonsense mutations, 1 patient with a splice site mutation in intron 8, and 1 patient with a deletion. RESULTS Twenty-four different WT1 mutations were detected. Sixteen of the 19 patients with KTS mutations were females. These patients had isolated NS if karyotype was 46,XX and Frasier syndrome if karyotype was 46,XY. Patients with KTS mutations presented at a significantly older age and with a slower progression toward chronic kidney disease (CKD) stage 5, compared with missense mutations. Patients with nonsense mutations presented initially with WT. Six patients with missense mutations developed WT after the diagnosis of NS (interval-range from NS onset to WT of 0.1 to 1.4 years). CONCLUSIONS (1) KTS mutations cause isolated NS with absence of WT in 46,XX females. (2) KTS mutations cause Frasier syndrome with gonadoblastoma risk in 46,XY phenotypic females. (3) KTS mutations cause NS with a slower progression when compared with missense mutations. (4) Missense mutations can occur with and without WT. (5) WT1 analysis is important in young patients with NS for early detection and tumor prophylaxis.

Cardiovascular risk assessment in children with chronic kidney disease.

Chronic kidney disease (CKD) is a major factor contributing to cardiovascular (CV) morbidity and mortality with the highest risk in patients on dialysis. An estimation of CV risk is important not only to identify potential modifiable risk factors but also to evaluate the effect of treatments aimed to reduce the risk. Non-invasive methods of measuring vascular changes and circulating biomarkers are available to assess the presence and severity of cardiovascular damage. These include measures of structural (carotid intima-media thickness and coronary artery calcification score) and functional (aortic pulse wave velocity, 24-h ambulatory blood pressure monitoring, ambulatory arterial stiffness index, heart rate variability and flow-mediated dilatation) changes in the vessel wall. In addition, a number of circulating biomarkers of vascular damage and its progression have been studied. Many of these tests are well validated as surrogate markers of future cardiovascular events and death in adult CKD patients, but need technical adaptation, standardization and validation for use in children. With our current state of knowledge, these are best reserved for research studies and scarce clinical resources may be better utilized for preventative strategies to reduce the modifiable risk factors for calcification from early CKD stages.

Cardiovascular risk assessment in children following kidney transplantation

Dégi A, Kerti A, Kis É, Cseprekál O, Tory K, Szabó AJ, Reusz GS. Cardiovascular risk assessment in children following kidney transplantation.

Ambulatory arterial stiffness index in children after kidney transplantation

Given the increase in CV morbidity after RTx and the scarcity of CV events in pediatrics, surrogate markers should be assessed to characterize CV damage in this population. AASI is a marker of arterial stiffness in adults, predicting cardio‐ and cerebrovascular morbidity. Our aim was to assess the determinants of AASI in RTx children (n = 54, 15.5 ± 3.5 yr) and to examine its relationship to central PWV. AASI was calculated from 24 h ABPM. PWV was determined by applanation tonometry, body composition by multifrequency bioimpedance measurement. The dipping state, volume overload, and time on dialysis were the main predictors of AASI (p < 0.05). Children with established HT (n = 34) had increased AASI, extracellular body water, and BNP (p < 0.05). In contrast to AASI, PWV did not differ between HT and normotensive RTx patient groups. There was no correlation between AASI and PWV. PWV was increased in children who spent more than one yr on dialysis prior to RTx. In conclusion, increased AASI in HT RTx children better characterizes the actual volume‐ and pressure‐dependent arterial rigidity rather than long‐term morphological changes in large arteries as reflected by PWV.

Role of birth weight and postnatal growth on pulse wave velocity in teenagers

PURPOSE Low birth weight and accelerated postnatal growth appear to play a significant role in the pathogenesis of hypertension and cardiovascular disease in adulthood. The aim of the present study was to characterize the factors determining pulse wave velocity (PWV) in teenagers and, in particular, to verify the relationship with birth weight, postnatal growth, timing of adiposity rebound, lifestyle, and hemodynamic parameters. METHODS Carotid-femoral and carotid-radial pulse wave velocities of 558 healthy teenagers (age range: 16.2-19.9 years) were determined by means of a PulsePen tonometer. Birth weight and gestational age were obtained from obstetrical records, and data regarding postnatal growth were obtained from pediatric clinical records. RESULTS No change in aortic PWV was found in association with birth weight, postnatal growth, and timing of adiposity rebound. However, the study showed a strong association between accelerated growth from 0 to 12 months and carotid-radial PWV (trend: p = .02). Subjects with birth weight values <2,500 g showed higher values of upper limb PWV (p < .05) and higher values of diastolic and mean arterial pressure (p < .05). Stepwise regression analysis revealed that mean arterial pressure, age, and height were the main independent factors determining aortic PWV in this young population. CONCLUSIONS These results suggest that there is no linear correlation between birth weight and hemodynamic parameters in teenagers; however, subjects characterized by very low birth weight and accelerated postnatal weight gain appear to demonstrate increased upper limb PWV and diastolic and mean arterial pressure values.

Reference values of aortic pulse wave velocity in a large healthy population aged between 3 and 18 years.

G rowing evidence has shown the inferiority in efficacy and outcomes of beta-blockers compared with other agents for the management of hypertension [1–3]. Consequently, when overtreatment of hypertension is suspected, tapering beta-blockers appears plausible. Dynamic left ventricular outflow tract obstruction (LVOTO) resulting from the systolic anterior motion (SAM) of the mitral valve over a thickened septal wall has been described in conditions with an abnormal left ventricle (LV) geometry and is alleviated with beta-blocker therapy. Dynamic LVOT is seen in various conditions, including hypertrophic obstructive cardiomyopathy (HOCM), acute coronary syndrome of the left anterior descending (LAD) coronary artery, Takotsubo syndrome, positive inotropic use, mitral valve apparatus abnormalities and postaortic valve surgery [3–6]. However, the pathogenesis of left ventricular hypertrophy (LVH) [7], which presents with LVOTO, remains unclear. Is this is a distinct diagnosis from classical HOCM or a combination of HOCM and LVH? We present a case of a patient with resistant hypertension and hypertrophied septal wall who developed LVOTO after beta-blocker cessation resulting in an acute coronary event. A 54-year-old man with a history of resistant hypertension presented to the hospital after collapsing and losing consciousness while walking. This event was preceded by an episode of dizziness without chest discomfort, shortness of breath or palpitations. He was on multiple antihypertensive agents, including losartan, hydrochlorothiazide, metoprolol succinate and amlodipine. The preceding week, his primary care physician discontinued the metoprolol because of a gradually developing hypotension on the aforementioned regimen. An echocardiogram done 5 years ago was reported to be normal. He had no family history of sudden death or structural heart disease. On initial physical examination, he was asymptomatic with a heart rate of 98 beats/minute, and his blood pressure was 124/82 mmHg without orthostatic hypotension. Cardiovascular examination revealed an apically displaced apex with a grade 3/6 systolic murmur, without signs of heart failure. Electrocardiogram demonstrated septal and lateral wall T wave inversion. The initial cardiac enzymes were mildly elevated. His initial echocardiogram showed decreased LV ejection fraction (25%), mid and apical severe hypokinesis, asymmetric septal hypertrophy (2 cm septal width) and a SAM of the mitral valve with mitral-septal contact. There was a resting LVOTO gradient of 60–80 and 100 mmHg with Valsalva manoeuver (Fig. 1). An urgent cardiac catheterization showed subtotal occlusion of the

Subclinical cardiovascular changes in pediatric solid organ transplant recipients

It is already a commonplace conclusion drawn from many adult and pediatric registries and clinical studies that patients with end-stage renal disease (ESRD) are at high risk of cardiovascular disease (CVD). Renal transplantation (RTX) decreases that risk; however, it still remains much higher than that of the general population (1–3). Following transplantation, there are numerous early events and complications that influence outcome, including graft and patient survival (4). In the case of kidney transplantation, early bacterial and viral infections, acute rejection, delayed graft function, and some surgical technical issues are salient and serious complications requiring particular attention and care. In the case of other solid organ transplants, these initial events may be complicated by the occurrence of acute kidney injury (5, 6). This critical early post-transplant phase is generally followed by a “honeymoon” period, with stable graft function and improving quality of life. This may falsely reassure the medical team and patient and family that all is well and may limit attention to meticulous monitoring and control of graft function, blood pressure, and therapeutic drug monitoring.

Are kidney transplantation outcomes improved in children weighting 15 kilograms or less in the last decades

As perinatal and postnatal care of neonates with impaired kidney function is constantly improving, the number of infants needing renal replacement therapy is increasing. Consequently, the general attitude of clinicians to offer renal replacement therapy (RRT) during the first year of life is changing gradually. The ideal renal replacement modality for children and adolescents is renal transplantation (RTX), as both the short-term and long-term medical complications of hemo- and peritoneal dialysis confer inferior survival rates compared to RTX to this patent group. This article is protected by copyright. All rights reserved.

Comprehensive genetic testing in children with a clinical diagnosis of ARPKD identifies phenocopies

BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is genetically one of the least heterogeneous ciliopathies, resulting primarily from mutations of PKHD1. Nevertheless, 13–20% of patients diagnosed with ARPKD are found not to carry PKHD1 mutations by sequencing. Here, we assess whether PKHD1 copy number variations or second locus mutations explain these cases.MethodsThirty-six unrelated patients with the clinical diagnosis of ARPKD were screened for PKHD1 point mutations and copy number variations. Patients without biallelic mutations were re-evaluated and screened for second locus mutations targeted by the phenotype, followed, if negative, by clinical exome sequencing.ResultsTwenty-eight patients (78%) carried PKHD1 point mutations, three of whom on only one allele. Two of the three patients harbored in trans either a duplication of exons 33–35 or a large deletion involving exons 1–55. All eight patients without PKHD1 mutations (22%) harbored mutations in other genes (PKD1 (n = 2), HNF1B (n = 3), NPHP1, TMEM67, PKD1/TSC2). Perinatal respiratory failure, a kidney length > +4SD and early-onset hypertension increase the likelihood of PKHD1-associated ARPKD. A patient compound heterozygous for a second and a last exon truncating PKHD1 mutation (p.Gly4013Alafs*25) presented with a moderate phenotype, indicating that fibrocystin is partially functional in the absence of its C-terminal 62 amino acids.ConclusionsWe found all ARPKD cases without PKHD1 point mutations to be phenocopies, and none to be explained by biallelic PKHD1 copy number variations. Screening for copy number variations is recommended in patients with a heterozygous point mutation.