Tomáš Seeman

Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension

Hypertension in children and adolescents has gained ground in cardiovascular medicine, thanks to the progress made in several areas of pathophysiological and clinical research. These guidelines represent a consensus among specialists involved in the detection and control of high blood pressure in children and adolescents. The guidelines synthesize a considerable amount of scientific data and clinical experience and represent best clinical wisdom upon which physicians, nurses and families should base their decisions. They call attention to the burden of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers, to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents.

2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents

Increasing prevalence of hypertension (HTN) in children and adolescents has become a significant public health issue driving a considerable amount of research. Aspects discussed in this document include advances in the definition of HTN in 16 year or older, clinical significance of isolated systolic HTN in youth, the importance of out of office and central blood pressure measurement, new risk factors for HTN, methods to assess vascular phenotypes, clustering of cardiovascular risk factors and treatment strategies among others. The recommendations of the present document synthesize a considerable amount of scientific data and clinical experience and represent the best clinical wisdom upon which physicians, nurses and families should base their decisions. In addition, as they call attention to the burden of HTN in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents.

CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder caused by CLDN16 mutations. CLDN16 encodes the renal tight junction protein claudin-16, which is important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle’s loop. That FHHNC is frequently associated with progressive renal failure suggests additional roles for claudin-16 in the maintenance of tight junction integrity. An investigation of 32 patients with FHHNC and 17 different mutations was previously reported; here, the analysis is expanded to 39 additional patients and 12 new mutations. Expression studies revealed that five of the12 new mutations led to partial loss of claudin-16 function and the remaining seven led to complete loss of function. The 23 patients who had mutations resulting in complete loss of function of both alleles were significantly younger at the onset of symptoms than the 46 patients who had at least one mutant allele providing partial function (2.2 versus 5.6 years; P _ 0.01). In addition, those with complete loss of function had a more rapid decline in GFR (7.3 versus 2.9 ml/min per 1.72 m2/y; P _ 0.01), leading to 54% requiring renal replacement therapy by age 15 compared with 20% of those with residual function (P _0.05). These data suggest that residual function of claudin-16 may delay the progression of renal failure in FHHN

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.

Screening for NPHS2 Mutations May Help Predict FSGS Recurrence after Transplantation

Steroid-resistant focal segmental glomerulosclerosis (FSGS) often recurs after renal transplantation. In this international survey, we sought to identify genotype-phenotype correlations of recurrent FSGS. We surveyed 83 patients with childhood-onset primary FSGS who received at least one renal allograft and analyzed 53 of these patients for NPHS2 mutations. The mean age at diagnosis was 6.7 years, and the mean age at first renal transplantation was 13 years. FSGS recurred in 30 patients (36%) after a median of 13 days (range, 1.5 to 152 days). Twenty-three patients received a second kidney transplant, and FSGS recurred in 11 (48%) after a median of 16 days (range, 2.7 to 66 days). None of the 11 patients with homozygous or compound heterozygous NPHS2 mutations developed recurrent FSGS compared with 45% of patients without mutations. These data suggest that genetic testing for pathogenic mutations may be important for prognosis and treatment of FSGS both before and after transplantation.

Control of hypertension in children after renal transplantation

Abstract: The aim of this cross‐sectional single‐center study was to investigate the efficacy of hypertension control in children who underwent transplantation using ambulatory blood pressure (BP) monitoring, and to determine the risk factors associated with poor control of hypertension. Thirty‐six children fulfilled the inclusion criteria. The mean age was 13.9±4.4 yr; the mean time after renal transplantation was 2.7±2.4 yr (0.5–10.1). Hypertension was defined as a mean ambulatory BP ≥95th centile for healthy children and/or requiring antihypertensive drugs. Hypertension was regarded as controlled if the mean ambulatory BP was <95th centile in children already on antihypertensive drugs, or uncontrolled if the mean ambulatory BP was ≥95th centile in treated children. Hypertension was present in 89% of children. Seventeen children (47%) had controlled hypertension, and 14 (39%) had uncontrolled hypertension. One child (3%) had untreated hypertension, and only four children (11%) showed normal BP without antihypertensive drugs. The efficacy of hypertensive control was 55% (17 of 31 children on antihypertensive drugs had a BP<95th centile), i.e. 45% of treated children still had hypertension. Children with uncontrolled hypertension had significantly higher cyclosporine doses (6.1 vs. 4.3 mg/kg/day, p=0.01) and tacrolimus levels (9.2 vs. 6.1 μg/L, p<0.05), and there was a tendency toward use of lower number of antihypertensive drugs (2.0 vs. 1.5 drugs/patient, p=0.06) and lower use of angiotensin‐converting enzyme (ACE) inhibitors (7 vs. 35%, p=0.09) and diuretics (29 vs. 59%, p=0.14) than in children with controlled hypertension. In conclusion, nearly 90% of our children after renal transplantation are hypertensive and the control of hypertension is unsatisfactorily low. The control of hypertension could be improved by increasing the number of prescribed antihypertensive drugs, especially ACE inhibitors, and diuretics, or by using higher doses of currently used antihypertensives.

Blood Pressure, Renal Function, and Proteinuria in Children with Unilateral Renal Agenesis

Background/Aim: Unilateral renal agenesis (URA) is a model for a reduced nephron number that is believed to be a risk factor for blood pressure (BP) elevation and reduced renal function. The aim of the study was to investigate BP and renal function in children with URA. Methods: Data on children with URA from two pediatric nephrology centers were firstly retrospectively reviewed (renal ultrasound and scintigraphy, clinical BP, creatinine clearance, urinalysis). Children with normal renal ultrasound and scintigraphy were thereafter investigated using ambulatory BP monitoring. Results: Twenty-nine children with URA were investigated – 14 children with an abnormal kidney (mostly scarring) and 15 children with healthy kidneys. Hypertension was diagnosed on the basis of clinical BP in 57% of the children with abnormal kidneys and on the basis of ambulatory BP monitoring in 1 child (7%) with healthy kidneys. The mean ambulatory BP in children with normal kidneys was not significantly different from that in controls. Forty-three percent of the children with abnormal kidneys had a reduced renal function, but none of children with normal kidneys. Conclusions: Children with abnormalities of a solitary kidney have often hypertension, proteinuria, or a reduced renal function. In contrast, children with healthy solitary kidneys have BP and renal function similar to those of healthy children.

Hypertension after renal transplantation

Hypertension is a common and serious complication after renal transplantation. It is an important risk factor for graft loss and morbidity and mortality of transplanted children. The etiology of posttransplant hypertension is multifactorial: native kidneys, immunosuppressive therapy, renal-graft artery stenosis, and chronic allograft nephropathy are the most common causes. Blood pressure (BP) in transplanted children should be measured not only by casual BP (CBP) measurement but also regularly by ambulatory BP monitoring (ABPM). The prevalence of posttransplant hypertension ranges between 60% and 90% depending on the method of BP measurement and definition. Left ventricular hypertrophy is a frequent type of end-organ damage in hypertensive children after transplantation (50–80%). All classes of antihypertensive drugs can be used in the treatment of posttransplant hypertension. Hypertension control in transplanted children is poor; only 20–50% of treated children reach normal BP. The reason for this poor control seems to be inadequate antihypertensive therapy, which can be improved by increasing the number of antihypertensive drugs. Improved hypertension control leads to improved long-term graft and patient survival in adults. In children, there is a great potential for antihypertensive treatment that could also result in improved graft and patient survival.

Ambulatory blood pressure monitoring in children with unilateral multicystic dysplastic kidney

Abstract Multicystic dysplastic kidney (MCDK) is one of the most common congenital renal anomalies. Arterial hypertension is a potential complication of MCDK. Blood pressure (BP) has so far been measured only casually and the frequency of hypertension has been estimated to be between 0%–8%. Ambulatory blood pressure monitoring (ABPM) provides more precise information on BP than the casual BP measurement. The aim of this study was to investigate the BP profile in children with MCDK using ABPM. A group of 25 children (16 girls), with a mean age of 7.8 years (range 3.8–17.7 years) were investigated. ABPM was performed using the oscillometric SpaceLabs 90207 device. Hypertension was defined as mean systolic and/or diastolic BP during the day and/or in the night exceeding 95th percentile for ABPM. Five (20%) children showed hypertension, two of them had combined daytime and night-time hypertension and three had isolated nocturnal hypertension, although daytime BP was between the 90th–95th percentile in two of them. Children with ultrasonographical and/or laboratory signs of contralateral kidney abnormalities showed a higher incidence of hypertension than those without abnormalities (two of four versus 3 of 21). The mean night-time systolic and diastolic BP of children with MCDK was significantly higher than in healthy children (+0.50 and +0.54 SDS, respectively, P=0.012 and 0.03, respectively). Three of the hypertensive children were already nephrectomised. All five hypertensive children showed ultrasonographical and/or laboratory signs of contralateral kidney abnormalities. Hypertensive children had significantly higher microalbuminuria than normotensive children (6.9 ± 3.2 mg/mmol creatinine versus 1.8 ± 0.7, P=0.03). The nocturnal BP fall (dip) was attenuated in five children, only one of whom was hypertensive. Conclusion Arterial hypertension in children with multicystic dysplastic kidney is seen more often if based on ambulatory blood pressure monitoring than on casual blood pressure recordings. The main risk factor for developing hypertension is contralateral kidney damage. Ambulatory blood pressure monitoring should be performed in children with multicystic dysplastic kidney, especially in those with contralateral kidney abnormalities.

Genotype-phenotype associations in WT1 glomerulopathy.

WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.