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Background: Childhood acute lymphoblastic leukemia (ALL) fortunately has high survival rates, and understanding longer term implications of therapy is critical. In this study, we aimed to investigate kidney health outcomes by assessing the prevalence of renal dysfunction and hypertension (HTN) in children with ALL at 1-5 years after ALL diagnosis., Methods: This was a single-center, cross-sectional study of children with ALL who were 1-5 years post diagnosis. Glomerular filtration rate (GFR) measurements were calculated, and urine samples were collected to assess for protein/creatinine and albumin/creatinine. Blood pressure (BP) was determined by standard oscillometric technique, and children ≥6 years of age were eligible for ambulatory blood pressure monitoring (ABPM)., Results: Forty-five patients enrolled in the study, and 21 completed ABPMs. Fifteen patients (33%, 95% CI: 20%-49%) developed acute kidney injury (AKI) at least once. Thirteen (29%, 95% CI: 16%-44%) had hyperfiltration, and 11 (24%) had abnormal proteinuria and/or albuminuria. Prevalence of HTN based on clinic measurements was 42%. In the 21 ABPM patients, 14 had abnormal results (67%, 95% CI: 43%-85%), with the majority (11/21) demonstrating abnormal nocturnal dipping pattern., Conclusions: Among children with ALL, there is a high prevalence of past AKI. The presence of hyperfiltration, proteinuria, and/or albuminuria at 1-5 years after ALL diagnosis suggests real risk of developing chronic kidney disease (CKD) over time. There is a high prevalence of HTN on casual BP readings and even higher prevalence of abnormal ABPM in this group. The high prevalence of impaired nocturnal dipping by ABPM indicates an increased risk for future cardiovascular or cerebral ischemic events., (© 2022 Wiley Periodicals LLC.)

Background: To define the incidence of acute kidney injury (AKI), chronic kidney disease (CKD), and hypertension (HTN) in pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) over a recent 9-year period., Methods: This study is a retrospective cohort study of all pediatric patients diagnosed with ALL at Nationwide Children's Hospital from January 1, 2008, to December 31, 2016. Patient demographic and clinical data including serum creatinine and blood pressure were collected at diagnosis up to 9 years post diagnosis., Results: A total of 222 patients were identified for this study. The overall incidence of AKI in our cohort was high, with 101 subjects (45.5%, CI 38.8-52.3%) developing AKI at least once. CKD status could only be determined in 214 patients due to limited later GFR data. The incidence of CKD was low with only 5 of 214 patients developing CKD (2.3%, CI: 0.8-5.4%). The overall incidence of HTN at diagnosis was 45.6% (95% CI: 59.1-72%), and at 1 month post diagnosis was 65.8% (95% CI: 59.1-72.0%). Chronic HTN could only be determined in 216 patients due to limited blood pressure data. Chronic HTN was noted in 34.3% of patients (74/216, 95% CI: 28-41%)., Conclusions: Among children with ALL, the incidence of AKI is relatively high at the time of diagnosis. However, development of CKD is relatively rare, suggesting good mid-term kidney prognosis. There is a high incidence of HTN at the time of diagnosis, 1 month post diagnosis, and chronic HTN that often goes untreated. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: In order to better understand the educational needs regarding appropriate recognition, diagnosis and management of pediatric hypertension (HTN), we asked practicing pediatricians questions regarding their educational needs and comfort level on this topic., Methods: We conducted 4 focus group sessions that included 27 participants representing pediatric residents, adolescent medicine physicians, clinic based pediatricians and office based pediatricians. Each focus group session lasted for approximately an hour and 90 pages of total transcriptions were produced verbatim from audio recordings., Results: Four reviewers read each transcript and themes were elucidated from these transcripts. Overall, 5 major themes related to educational needs and clinical concerns were found: utilization of resources to define blood pressure (BP), correct BP measurement method(s), co-morbidities, barriers to care, and experience level with HTN. Six minor themes were also identified: differences in BP measurement, accuracy of BP, recognition of HTN, practice pattern of care, education of families and patients, and differences in level of training. The focus group participants were also questioned on their preferences regarding educational methods (i.e. e-learning, small group sessions, self-study, large group presentations) and revealed varied teaching and learning preferences., Conclusions: There are multiple methods to approach education regarding pediatric HTN for primary care pediatricians based on provider preferences and multiple educational activities should be pursued to achieve best outcomes. Based on this data, the next direction will be to develop and deliver multiple educational methods and to evaluate the impact on practice patterns of care for children and adolescents with HTN.

A population pharmacokinetic study was conducted in 74 hypertensive children (mean age 10.4 +/- 4.4 years [mean +/- SD]) receiving amlodipine (mean dose 0.17 +/- 0.13 mg/kg/d) chronically. Multiple blood samples were obtained from each subject to characterize amlodipine pharmacokinetics. Plasma amlodipine concentrations were determined by liquid chromatography/mass spectrophotometry with multiple-reaction monitoring detection. Population pharmacokinetic analysis was performed using NONMEM. Amlodipine concentrations were similar in subjects dosed either once or twice daily. Amlodipine pharmacokinetics were well described by a 1-compartment model with first-order absorption and elimination. For a subject at the population median weight (45 kg), predicted apparent clearances (CL/F) were 23.7 L/h for males and 17.6 L/h for females, and the apparent volume of distribution (V/F) was 25.1 L/kg. Dosing frequency did not appear to affect amlodipine concentrations in children. Weight-adjusted CL/F and V/F of amlodipine in younger children were significantly greater than in older children, suggesting a need for higher doses when treating young children with amlodipine.

Background: Patient weight and family history are significant risk factors for the development of hypertension in children. Multiple genetic factors have been identified in primary (essential) hypertension in adults; however, the delineation of genetic factors in the separate populations of children with primary or secondary hypertension are not well understood. Heritability is the proportion of observed variation in a particular trait that can be attributed to an inherited genetic factor in contrast to environmental factors. In the consideration of hypertension, heritability can be assessed in terms of an underlying continuous gradient of the liability for developing hypertension. With this assumption it is possible to compute heritability using hypertension incidence among relatives and described by Falconer. Heritability values range from 0 (no genetic contribution) to 1 (complete genetic contribution). The aim of this study was to determine the genetic contribution to primary and secondary hypertension in a pediatric population through heritability analysis., Methods: This was a retrospective case-control analysis of medical records of children (n=276) followed in the Pediatric Nephrology Clinic over a 4-year period from 1999 to 2002. There were 192 children and adolescents with primary hypertension (124 male, 68 female, age 0 to 21 years) and 84 children and adolescents with secondary hypertension (46 male, 38 female, age 0 to 21 years). Each hypertensive group served as the control for the other. Estimates of heritability were made using Falconer's method 2. The model assumes independence between the environment and genetic factors and that the joint distribution of liabilities between parent and child are normally distributed. Problems can arise from computing heritability due to dominance within loci, correlations between nongenetic familial effects, or the presence of a major gene., Results: Of the children and adolescents with primary hypertension, 49% had parents with primary hypertension; and of the children and adolescents with secondary hypertension, 24% had parents with primary hypertension. Of the children and adolescents with primary hypertension, 10% had parents with secondary hypertension; and of the children and adolescents with secondary hypertension, 46% had parents with secondary hypertension. The estimated heritability for primary hypertension was 0.84 (SE=0.21). The estimated heritability for secondary hypertension was 1.14 (SE=0.21). As the value was >1, this indicates that the fit of the liability model is poor and that a few genes, or even one major gene, were significantly involved in the causes of secondary hypertension in the children and adolescents studied., Conclusions: The results suggest that primary and secondary hypertension do not share the same type of genetic profile. Primary hypertension in children and adolescents is likely due to a large number of additive contributions of genes, although a highly correlated environmental component can not be excluded. The continuous liability model is inappropriate for secondary hypertension because the estimate was substantially greater than one. This study supports the model that secondary hypertension in children and adolescents may be related to just a few genes.

Improved recognition of the relationship between childhood and adult blood pressures and identification of end-organ damage in children, adolescents, and young adults with hypertension has led to increased focus by pediatricians and general practitioners on the detection, evaluation, and treatment of hypertension. Notably, detection, evaluation, and treatment of pediatric hypertension has increased significantly since the first Task Force Report on High Blood Pressure in Children and Adolescents in 1977 with advances in both nonpharmacologic and pharmacologic treatments.Angiotensin-converting enzyme inhibitors (e.g. captopril, enalapril, lisinopril, ramipril) and calcium channel antagonists (e.g. nifedipine, amlodipine, felodipine, isradipine) are the most commonly prescribed antihypertensive medications in children due to their low adverse-effect profiles. Diuretics (e.g. thiazide diuretics, loop diuretics, and potassium-sparing diuretics) are usually reserved as adjunct therapy. Newer agents, such as angiotensin receptor antagonists (e.g. irbesartan), are currently being studied in children and adolescents. These agents may be an option in children with chronic cough secondary to angiotensin-converting enzyme inhibitors. beta-Adrenoreceptor antagonists (e.g. propranolol, atenolol, metoprolol, and labetalol), alpha-adrenoreceptor antagonists, alpha-adrenoreceptor agonists, direct vasodilators, peripheral adrenoreceptor neuron agonists, and combination products are less commonly used in pediatric patients because of adverse events but may be an option in children unresponsive to calcium channel blockers, angiotensin converting-enzyme inhibitors, or angiotensin receptor blockers.

The objectives of this study were (1) to determine the relationship of body mass index (BMI) to primary or secondary hypertension in children and adolescents and (2) to assess BMI at the age of onset of hypertension in children and adolescents. Patient demographics, BMI, family history, presentation of disease, etiology of hypertension, medication, laboratory data, and findings from other procedures were recorded for all patients with hypertension followed in the Pediatric Nephrology Clinic at Children's Hospital, Columbus, Ohio, over a 4-year period. In total, 314 patients were studied: 218 with primary hypertension and 96 with secondary hypertension. Our patient population (166 males, 148 females) was diverse in age (13+/-6.3 years) and ethnicity (237 Caucasians, 54 African-Americans, 23 other). BMI was greater in patients with primary (27.5+/-9.2 kg/m2) versus secondary (23.9+/-9.3 kg/m2) hypertension (P=0.002). Children with primary hypertension with an increased BMI presented at an earlier age than children with secondary hypertension and an increased BMI. The age of onset (10.5+/-2.6 years) in primary hypertension was related to increased BMI (r=0.12, P=0.001); however, there was no relationship between BMI and age of onset of secondary hypertension (P=0.21). Children whose family members had essential hypertension had increased BMI compared with children without a family history of essential hypertension. Based on the logistic regression model constructed from our data, the likelihood of primary versus secondary hypertension was influenced by the presence of family history of hypertension independent of presence of obesity in the child. In conclusion, increased BMI is more common in children with primary than secondary hypertension; earlier onset of primary hypertension in the pediatric population was associated with increased BMI; the assessment of BMI is important in the evaluation of secondary as well as primary hypertension; the role of obesity in the development of secondary as well as primary hypertension in children merits further study.

Essential hypertension in pediatric patients may require pharmacological treatment. There is a need for efficacious, safe, and well-tolerated antihypertensive agents with a once-a-day dosing regimen in children and adolescents. The aim of the trial was to evaluate the dose-response and tolerability of the dihydropyridine calcium channel blocker, felodipine extended-release tablets (felodipine ER), given once daily to pediatric patients with essential hypertension. A randomized double-blind, parallel-group, multi-center clinical study comparing felodipine ER (2.5, 5, or 10 mg once daily) and placebo was performed on pediatric patients with a baseline systolic (SBP) or diastolic blood pressure (DBP) above the 95th percentile for age, sex, and height. Of 133 randomized patients, 128 (96.2%) completed the 3 weeks of double-blind treatment. The study population included 50% children 6-12 years of age or Tanner stage

We designed a study to determine the efficacy and safety of amlodipine given once daily in the pediatric population. Twenty-one patients (mean age 13.1 years) with either essential (n=160) or renal (n=5) hypertension, and newly diagnosed (n=15) or poorly controlled or intolerant on existing antihypertensive therapy (n=6), were included. Patients received amlodipine once daily at a starting mean dose of 0.07+/-0.04 mg/kg per day. The total daily dose of amlodipine was increased 25%-50% every 5-7 days if the mean home blood pressure measurements (HBPM) were above the 95th percentile for age and gender. A baseline followed by a repeat 24-h ambulatory blood pressure monitor study (ABPM) was performed in 20 patients when the mean HBPM was below the 95th percentile goal. The mean titrated dose required to control BP was 0.29+/-0.11 mg/kg per day for those < 13 years, 0.16+/-0.11 mg/kg per day for those > or = 13 years, 0.23+/-0.14 mg/kg per day for essential, hypertension and 0.24+/-0.13 mg/kg per day for renal hypertension. The ABPM demonstrated that amlodipine provided effective BP control as primary therapy in 14 essential patients. Adverse effects included fatigue (n=6), headache (n=5), facial flushing (n=4), dizziness (n=3), edema (n=3), abdominal pain (n=3), chest pain (n=2), nausea (n=1), and vomiting (n=1). Quality of life appeared to improve during therapy. Amlodipine was an effective once daily antihypertensive agent with an acceptable safety profile. Higher doses of amlodipine were required for younger patients, and monotherapy was effective in patients with essential hypertension.

Signs or symptoms of renal disease in adolescents deserve prompt attention and appropriate evaluation. Adolescents are susceptible to a variety of urinary tract disorders. The key issue in the evaluation of hematuria or proteinuria in adolescents is the existence of concomitant signs of renal disease. For isolated hematuria or proteinuria, demonstration of persistence and a reasoned evaluation are in order. Hypertension in adolescents must be carefully documented and, when present, considered seriously. The fact that most teens with persistent elevated blood pressures have essential hypertension is still a great concern because for most of these adolescents the hypertension will be lifelong and, if left untreated, can be associated with significant morbidity and mortality in the adult years.

In the present study, we investigated the combined, nephrotoxic effects of cyclosporine (CsA) and hypertension in young, spontaneously hypertensive rats (SHR). After 4 weeks of CsA therapy, SHR, compared with oil-treated SHR, showed an acceleration in the development of hypertension, mild renal insufficiency, and the accumulation of periodic-acid-Schiff-positive (PAS [+]) material in periglomerular arterioles. By electron microscopy, PAS(+) material was composed of intracytoplasmic inclusion bodies consistent with the accumulation of renin granules. This finding was demonstrated in SHR after 4 weeks of CsA therapy but not after 8 weeks of therapy. By contrast, CsA had no significant effect on blood pressure in Wistar-Kyoto rats, a normo-tensive control. To investigate the effect of unilateral nephrectomy (UNx) on the development of renal histopathologic changes in this model, SHR were subjected to uninephrectomy and CsA or oil therapy. UNx accelerated the development of hypertension in all SHR groups. SHR subjected to UNx demonstrated no renal histopathologic changes after CsA or oil treatment. In conclusion, CsA accelerates the development of hypertension in SHR, and this effect is probably renin-mediated. The combination of UNx and CsA therapy in the SHR does not result in significant renal histologic damage.