Giacomo D. Simonetti

Pregnancy Outcome Following Exposure to Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Antagonists: A Systematic Review

The objective was to analyze the outcome following prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor antagonists (ARBs). For this purpose, a systematic review of published case reports and case series dealing with intrauterine exposure to ACE-Is or to ARBs using Medline as the source of data was performed. The publications retained for analysis included patients who were described individually, revealing, at minimum, the gestational age, substance used, period of medication intake, and the outcome. In total, 72 reports were included; 37 articles (118 well-documented cases) described the prenatal exposure to ACE-Is; and 35 articles (68 cases) described the prenatal exposure to ARBs. Overall, 52% of the newborns exposed to ACE-Is and 13% of the newborns exposed to ARBs did not exhibit any complications (P<0.0001). Neonatal complications were more frequent following exposure to ARBs and included renal failure, oligohydramnios, death, arterial hypotension, intrauterine growth retardation, respiratory distress syndrome, pulmonary hypoplasia, hypocalvaria, limb defects, persistent patent ductus arteriosus, or cerebral complications. The long-term outcome is described as positive in only 50% of the exposed children. Fetopathy caused by exposure to ACE-Is or ARBs has relevant neonatal and long-term complications. The outcome is poorer following exposure to ARBs. We propose the term “fetal renin-angiotensin system blockade syndrome” to describe the related clinical findings. Thirty years after the first description of ACE-I fetopathy, relevant complications are, at present, regularly described, indicating that the awareness of the deleterious effect of prenatal exposure to drugs inhibiting the renin-angiotensin system should be improved.

Determinants of Blood Pressure in Preschool Children The Role of Parental Smoking

Background— Hypertension is the leading risk factor for cardiovascular disease. Although accumulating evidence suggests tracking of blood pressure from childhood into adult life, there is little information regarding the relative contributions of genetic, prenatal, biological, behavioral, environmental, and social determinants to childhood blood pressure. Methods and Results— Blood pressure and an array of potential anthropometric, prenatal, environmental, and familial risk factors for high blood pressure, including parental smoking habits, were determined as part of a screening project in 4236 preschool children (age 5.7±0.4 years). Smoking was reported by 28.5% of fathers and 20.7% of mothers, and by both parents 11.9%. In addition to classic risk factors such as body mass index, prematurity, low birth weight, and parental hypertension, both systolic (+1.0 [95% confidence interval, +0.5 to +1.5] mm Hg; P=0.0001) and diastolic blood pressure (+0.5 [+0.03 to +0.9] mm Hg; P=0.03) were higher in children of smoking parents. Parental smoking independently affected systolic blood pressure (P=0.001) even after correction for other risk factors, such as body mass index, parental hypertension, or birth weight, increasing the likelihood of having a systolic blood pressure in the top 15% of the population by 21% (2% to 44%; P=0.02). Conclusions— In healthy preschool children, parental smoking is an independent risk factor for higher blood pressure, adding to other familial and environmental risk factors. Implementing smoke-free environments at home and in public places may provide a long-term cardiovascular benefit even to young children.

Salt Sensitivity of Children With Low Birth Weight

Compromised intrauterine fetal growth leading to low birth weight (<2500 g) is associated with adulthood renal and cardiovascular disease. The aim of this study was to assess the effect of salt intake on blood pressure (salt sensitivity) in children with low birth weight. White children (n=50; mean age: 11.3±2.1 years) born with low (n=35) or normal (n=15) birth weight and being either small or appropriate for gestational age (n=25 in each group) were investigated. The glomerular filtration rate was calculated using the Schwartz formula, and renal size was measured by ultrasound. Salt sensitivity was assigned if mean 24-hour blood pressure increased by ≥3 mm Hg on a high-salt diet as compared with a controlled-salt diet. Baseline office blood pressure was higher and glomerular filtration rate lower in children born with low birth weight as compared with children born at term with appropriate weight (P<0.05). Salt sensitivity was present in 37% and 47% of all of the low birth weight and small for gestational age children, respectively, higher even than healthy young adults from the same region. Kidney length and volume (both P<0.0001) were reduced in low birth weight children. Salt sensitivity inversely correlated with kidney length (r2=0.31; P=0.005) but not with glomerular filtration rate. We conclude that a reduced renal mass in growth-restricted children poses a risk for a lower renal function and for increased salt sensitivity. Whether the changes in renal growth are causative or are the consequence of the same abnormal “fetal programming” awaits clarification.

Acute hemorrhagic edema of young children (cockade purpura and edema): A case series and systematic review

BACKGROUND Acute hemorrhagic edema is an uncommon leukocytoclastic small-vessel vasculitis of young children. OBJECTIVE To determine clinical features and outcome of acute hemorrhagic edema of young children. METHODS Seven new cases are reported. A search of the literature revealed 287 published cases. RESULTS The 294 children (boys, 67%) ranged in age between 2 and 60 months (median, 11 months) and were in good general condition. In 195 children the disease developed after a simple acute infection. The exanthemata included large, round, red to purpuric plaques predominantly over the cheeks, ears, and extremities and mostly tender edema of the distal extremities, ears, and face. Involvement of body systems other than skin was rare. The children recovered spontaneously without sequelae. LIMITATIONS Results of this review must be viewed with an understanding of the limitations of the analysis process, which incorporated data exclusively from single case reports or case series. CONCLUSIONS Acute hemorrhagic edema of young children is a very benign vasculitis. Physicians might rapidly develop the skills necessary to diagnose this condition.

Demographics of blood pressure and hypertension in children on renal replacement therapy in Europe

Hypertension is a well-known complication in children on renal replacement therapy and an important risk factor for cardiovascular disease in later life. In order to define the prevalence of and risk factors for hypertension among children, we enrolled 3337 pediatric patients from 15 countries in the ESPN/ERA-EDTA Registry of whom 464 were on hemodialysis, 851 on peritoneal dialysis, and 2023 had received a renal allograft. Hypertension was defined as either systolic or diastolic blood pressures in the 95th percentile or greater for age, height, and gender or use of antihypertensive medication. Analyses were adjusted for age, gender, duration, and modality of renal replacement therapy. In 10 countries in which information on the use of antihypertensive medication was available, hypertension was present in over two-thirds of hemodialysis, peritoneal dialysis, or transplant patients. Blood pressure values above the 95th percentile were significantly more prevalent in very young patients (under 3 years) compared to 13- to 17-year olds (odds ratio 2.47), during the first year compared to over 5 years of renal replacement therapy (odds ratio 1.80), and in patients on hemodialysis compared to transplant recipients or those on peritoneal dialysis (odds ratios of 2.48 and 1.59, respectively). Over time, mean blood pressures decreased in both hemodialysis and transplant patients, but not in peritoneal dialysis patients. Hence, our findings highlight the extent of the problem of hypertension in children with end-stage renal disease in Europe.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

Ambulatory arterial stiffness index is increased in hypertensive childhood disease

Arterial hypertension in adults is often associated with an increased arterial stiffness, which correlates with the ambulatory arterial stiffness index (AASI) as derived from ambulatory blood pressure (BP) measurements. The purpose of this study was to demonstrate whether children with diagnosed hypertension have an increased AASI as in hypertensive adults. AASI was calculated from 185 ambulatory BP measurements of 114 hypertensive and 71 normotensive, healthy children. Hypertensive children had higher AASI values compared with their normotensive healthy counterparts (0.370 ± 0.120 versus 0.204 ± 0.199, p < 0.0001). Children with longer duration of hypertension or a history of primary or secondary aortic coarctation displayed even more elevated AASI values. A receiver operator curve derived cut-off of AASI set at 0.301 distinguished (p < 0.0001) hypertensive from normotensive children with an odds ratio of 8.2, a sensitivity of 81%, and a specificity of 65%. Moreover, AASI correlated with pulse and systolic BP. In conclusion, AASI is elevated in hypertensive children and correlates with the duration and the origin of hypertension in childhood.

Nervous system dysfunction in Henoch–Schönlein syndrome: systematic review of the literature

OBJECTIVE CNS or peripheral nervous system dysfunction sometimes occurs in Henoch-Schönlein patients. METHODS We review all Henoch-Schönlein cases published after 1969 with CNS dysfunction without severe hypertension and neuroimaging studies (n = 35), cranial or peripheral neuropathy (n = 15), both CNS and peripheral nervous system dysfunction without severe hypertension (n = 2) or nervous system dysfunction with severe hypertension (n = 2). Forty-four of the 54 patients were <20 years of age. RESULTS In patients with CNS dysfunction without or with severe hypertension the following presentations were observed in decreasing order of frequency: altered level of consciousness, convulsions, focal neurological deficits, visual abnormalities and verbal disability. Imaging studies disclosed the following lesions: vascular lesions almost always involving two or more vessels, intracerebral haemorrhage, posterior subcortical oedema, diffuse brain oedema and thrombosis of the superior sagittal sinus. Following lesions were noted in the subjects with cranial or peripheral neuropathy without severe hypertension: peroneal neuropathy, peripheral facial palsy, Guillain-Barré syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex. Persisting signs of either CNS (n = 9) or peripheral (n = 1) nervous system dysfunction were sometimes reported. CONCLUSIONS In Henoch-Schönlein syndrome, signs of nervous system dysfunction are uncommon but clinically relevant. This review helps clinicians managing Henoch-Schönlein syndrome with nervous system dysfunction.

Effects of antihypertensive drugs on blood pressure and proteinuria in childhood.

Background Historically, there have been few drug trials for antihypertensive treatment in childhood and recommendations have been extrapolated from data obtained in adulthood. During the last decade an increased awareness of the risks of childhood hypertension stimulated clinical trials of antihypertensive agents in children. Objective The aim of this article is to systematically review the studies published between 1995 and 2006 that deal with the effect of antihypertensive drugs on childhood hypertension or proteinuria. Methods Medline, Current Contents, personal files and reference lists were used as data sources. Results Fifty-two out of 79 initially found reports were excluded. Consequently 27 articles were retained for the final analysis. The blood pressure reduction was similar with angiotensin-converting enzyme inhibitors (10.7/8.1 mmHg), angiotensin II receptor antagonists (10.5/6.9 mmHg) and calcium-channel blockers (9.3/7.2 mmHg). In addition angiotensin-converting enzyme inhibitors (by 49% ) and angiotensin II receptor antagonists (by 59%) significantly reduced pathological proteinuria. Conclusions The blood pressure reduction of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists and calcium-channel blockers is almost identical. In children with pathological proteinuria angiotensin-converting enzyme inhibitors or angiotensin II antagonists are superior to calcium-channel blockers.

Body fluids and salt metabolism - Part I.

There is a high frequency of diarrhea and vomiting in childhood. As a consequence the focus of the present review is to recognize the different body fluid compartments, to clinically assess the degree of dehydration, to know how the equilibrium between extracellular fluid and intracellular fluid is maintained, to calculate the effective blood osmolality and discuss both parenteral fluid requirments and repair.