Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.

Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2.

Most patients with congenital anomalies of the kidney and urinary tract (CAKUT) remain genetically unexplained. In search of novel genes associated with CAKUT in humans, we applied whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies, and identified a rare heterozygous missense variant in the DACT1 (dishevelled binding antagonist of beta catenin 1) gene encoding a cytoplasmic WNT signaling mediator. Our patient's features overlapped Townes-Brocks syndrome 2 (TBS2) previously described in a family carrying a DACT1 nonsense variant as well as those of Dact1-deficient mice. Therefore, we assessed the role of DACT1 in CAKUT pathogenesis. Taken together, very rare (minor allele frequency ≤ 0.0005) non-silent DACT1 variants were detected in eight of 209 (3.8%) CAKUT families, significantly more frequently than in controls (1.7%). All seven different DACT1 missense variants, predominantly likely pathogenic and exclusively maternally inherited, were located in the interaction region with DVL2 (dishevelled segment polarity protein 2), and biochemical characterization revealed reduced binding of mutant DACT1 to DVL2. Patients carrying DACT1 variants presented with kidney agenesis, duplex or (multi)cystic (hypo)dysplastic kidneys with hydronephrosis and TBS2 features. During murine development, Dact1 was expressed in organs affected by anomalies in patients with DACT1 variants, including the kidney, anal canal, vertebrae, and brain. In a branching morphogenesis assay, tubule formation was impaired in CRISPR/Cas9-induced Dact1-/- murine inner medullary collecting duct cells. In summary, we provide evidence that heterozygous hypomorphic DACT1 variants cause CAKUT and other features of TBS2, including anomalies of the skeleton, brain, distal digestive and genital tract.

Masked Hypertension in Healthy Children and Adolescents: Who Should Be Screened?

PURPOSE OF REVIEW: The goal is to review masked hypertension (MH) as a relatively new phenomenon when patients have normal office BP but elevated out-of-office BP. Firstly, it was described in children in 2004. It has received increased attention in the past decade. RECENT FINDINGS: The prevalence of MH in different pediatric populations differs widely between 0 and 60% based on the population studied, definition of MH, or method of out-of-office BP measurement. The highest prevalence of MH has been demonstrated in children with chronic kidney disease (CKD), obesity, diabetes, and after heart transplantation. In healthy children but with risk factors for hypertension such as prematurity, overweight/obesity, diabetes, chronic kidney disease, or positive family history of hypertension, the prevalence of MH is 9%. In healthy children without risk factors for hypertension, the prevalence of MH is very low ranging 0-3%. In healthy children, only patients with the following clinical conditions should be screened for MH: high-normal/elevated office BP, positive family history of hypertension, and those referred for suspected hypertension who have normal office BP in the secondary/tertiary center.

Hypertension in pediatric kidney transplantation.

Arterial hypertension (HTN) in children after kidney transplantation is an important risk factor not only for graft loss but also for cardiovascular morbidity and mortality. The prevalence of posttransplant HTN ranges between 60% and 90%. The etiology of posttransplant HTN is multifactorial and includes residual chronic native kidney disease, immunosuppressive therapy, and chronic allograft dysfunction among other causes. Clinic blood pressure (BP) should be measured at each outpatient visit. However, ambulatory blood pressure monitoring (ABPM) is the gold standard method for BP evaluation in children after kidney transplantation, as it often reveals masked and nocturnal HTN; given this, it should be regularly performed in each transplanted child. All classes of antihypertensive drugs are used in the treatment of posttransplant HTN because it has never been proven that one class is better than another. However, in several retrospective studies, the use of calcium channel blockers is associated with better graft function. The optimal target BP for transplanted children is still a matter of debate; it is recommended to target the same BP as for healthy children, that is, <95th percentile. Control of HTN in transplanted children remains poor - only 20%-50% of treated children have normal BP. There is a great potential for improvement of antihypertensive treatment that could potentially result in improvement of both graft and patient survival in children after kidney transplantation.

Kidney concentrating capacity in children with autosomal recessive polycystic kidney disease is linked to glomerular filtration and hypertension.

BACKGROUND: Impaired kidney concentration capacity is present in half of the patients with autosomal dominant polycystic kidney disease (ADPKD). The kidney concentrating capacity was further impaired within the animal model of autosomal recessive polycystic kidney disease (ARPKD). To date, only one small study has investigated it in children having ARPKD. Therefore, we aimed to study the kidney concentrating ability in a larger cohort of children with ARPKD. METHODS: Eighteen children (median age 8.5 years, range 1.3-16.8) were retrospectively investigated. A standardized kidney concentrating capacity test was performed after the application of a nasal drop of desmopressin (urine osmolality > 900 mOsmol/kg). The glomerular filtration rate was estimated using the Schwartz formula (eGFR) and blood pressure (BP) was measured as office BP. RESULTS: Kidney concentrating capacity was decreased (urine osmolality < 900 mOsmol/kg) in 100% of children with ARPKD. The median urine osmolality after desmopressin application was 389 (range 235-601) mOsmol/kg. Sixteen patients (89%) were defined as hypertensive based on their actual BP level or their use of antihypertensive drugs. The maximum amounts of urinary concentration correlated significantly with eGFR (r = 0.72, p < 0.0001) and hypertensive scores (r = 0.50, p < 0.05), but not with kidney size. Twelve patients (67%) were defined as having CKD stages 2-4. The median concentrating capacity was significantly lower in children within this group, when compared to children with CKD stage 1 possessing a normal eGFR (544 mOsmol/kg, range 413-600 mOsmol/kg vs. 327 mOsmol/kg, range 235-417 mOsmol/l, p < 0.001). CONCLUSIONS: Impaired kidney concentrating capacity is present in most children with ARPKD and is associated with decreased eGFR and hypertension. A higher resolution version of the Graphical abstract is available as Supplementary information.

Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease.

PURPOSE: Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition characterized by massive kidney enlargement and developmental liver defects. Potential consequences during childhood include the need for kidney replacement therapy (KRT). We report the design of 2 ongoing clinical trials (Study 204, Study 307) to evaluate safety, tolerability, and efficacy of tolvaptan in children with ARPKD. METHODS: Both trials are of multinational, multicenter, open-label design. Age range at enrollment is 28 days to < 12 weeks in Study 204 and 28 days to < 18 years in Study 307. Subjects in both studies must have a clinical diagnosis of ARPKD, and those in Study 204 must additionally have signs indicative of risk of rapid progression to KRT, namely, all of: nephromegaly, multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and oligohydramnios or anhydramnios. Target enrollment is 20 subjects for Study 204 and ≥ 10 subjects for Study 307. RESULTS: Follow-up is 24 months in Study 204 (with optional additional treatment up to 36 months) and 18 months in Study 307. Outcomes include safety, tolerability, change in kidney function, and percentage of subjects requiring KRT relative to historical data. Regular safety assessments monitor for possible adverse effects of treatment on parameters such as liver function, kidney function, fluid balance, electrolyte levels, and growth trajectory, with increased frequency of monitoring following tolvaptan initiation or dose escalation. CONCLUSIONS: These trials will provide data on tolvaptan safety and efficacy in a population without disease-specific treatment options. TRIAL REGISTRATION: Study 204: EudraCT 2020-005991-36; Study 307: EudraCT 2020-005992-10.

Isolated nocturnal hypertension in pediatric kidney transplant recipients.

BACKGROUND: Isolated nocturnal hypertension (INH) is defined as nighttime hypertension in the setting of normal daytime blood pressure (BP), diagnosed by ambulatory BP monitoring (ABPM). METHODS AND RESULTS: Hypertension affects 60%-80% of pediatric kidney transplant recipients, and INH is the most common type of ambulatory hypertension. INH is associated with an increased prevalence of hypertension-mediated target organ damage such as left ventricular hypertrophy in adults and in pediatric kidney transplant recipients. CONCLUSION: Ambulatory BP monitoring should be performed annually in all pediatric kidney transplant recipients to diagnose hypertension phenotypes that are not detectable by office BP such as masked hypertension, white-coat hypertension, or INH. Isolated nocturnal hypertension in pediatric transplant patients requires study as a treatment target.

Hypertension in obese children is associated with vitamin D deficiency and serotonin dysregulation.

BACKGROUND: Obesity and hypertension represent serious health issues affecting the pediatric population with increasing prevalence. Hypovitaminosis D has been suggested to be associated with arterial hypertension. Serotonin by modulating nitric oxide synthase affect blood pressure regulation. The biological mechanism by which vitamin D specifically regulates serotonin synthesis was recently described. The aim of this paper is to determine the associations between vitamin D, serotonin, and blood pressure in obese children. METHODS: One hundred and seventy-one children were enrolled in the prospective cross-sectional study. Two groups of children divided according to body mass index status to obese (BMI ≥95th percentile; n = 120) and non-obese (n = 51) were set. All children underwent office and ambulatory blood pressure monitoring and biochemical analysis of vitamin D and serotonin. Data on fasting glucose, insulin, HOMA, uric acid, and complete lipid profile were obtained in obese children. RESULTS: Hypertension was found only in the group of obese children. Compared to the control group, obese children had lower vitamin D and serotonin, especially in winter. The vitamin D seasonality and BMI-SDS were shown as the most significant predictors of systolic blood pressure changes, while diastolic blood pressure was predicted mostly by insulin and serotonin. The presence of hypertension and high-normal blood pressure in obese children was most significantly affected by vitamin D deficiency and increased BMI-SDS. CONCLUSIONS: Dysregulation of vitamin D and serotonin can pose a risk of the onset and development of hypertension in obese children; therefore, their optimization together with reducing body weight may improve the long-term cardiovascular health of these children.

Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.

Clinical practice recommendations for recurrence of focal and segmental glomerulosclerosis/steroid-resistant nephrotic syndrome.

Recurrence of primary disease is one of the major risks for allograft loss after pediatric RTx. The risk of recurrence of FSGS/SRNS after pediatric RTx in particular can be up to 86% in idiopathic cases. There is a need for consensus recommendations on its prevention and treatment. The CERTAIN study group has therefore performed a thorough literature search based on the PICO model of clinical questions to formulate educated statements to guide the clinician in the process of decision-making. A set of educated statements on prevention and treatment of FSGS/SRNS after pediatric RTx has been generated after careful evaluation of available evidence and thorough panel discussion. We do not recommend routine nephrectomy prior to transplantation; neither do we recommend abstaining from living donation. Special attendance needs to be given to those patients who had already experienced graft loss due to FSGS/SRNS recurrence. Early PE or IA with or without high-dose CsA and/or rituximab seems to be most promising to induce remission. The educated statements presented here acknowledge that FSGS/SRNS recurrence after pediatric RTx remains a major concern and is associated with shorter graft survival or even graft loss. The value of any recommendation needs to take into account that evidence is based on cohorts that differ in ethnicity, pre-transplant history, immunosuppressive regimen, definition of recurrence (eg, clinical and/or histological diagnosis) and treatment modalities of recurrence.

Should ACE inhibitors or calcium channel blockers be used for post-transplant hypertension?

Arterial hypertension in renal transplant recipients warrants antihypertensive treatment. The preferable choice of antihypertensives that should be used in patients after kidney transplantation remains a matter of debate; however, calcium channel blockers (CCB) and angiotensin-converting enzyme inhibitors (ACEI) are currently the most commonly used antihypertensives. This educational review summarizes the current evidence about the effects of these two classes of medications in transplant recipients. Several studies have demonstrated that both classes of drugs can reduce blood pressure (BP) to similar extents. Meta-analyses of adult randomized controlled trials have shown that graft survival is improved in patients treated with ACEIs and CCBs, and that CCBs increase, yet ACEIs decrease, graft function. Proteinuria is usually decreased by ACEIs but remains unchanged with CCBs. In children, no randomized controlled study has ever been performed to compare BP or graft survival between CCBs and ACEIs. Post-transplant proteinuria could be reduced in children along with BP by ACEIs. The results of the most current meta-analyses recommend that due to their positive effects on graft function and survival, along with their lack of negative effects on serum potassium, CCBs could be the preferred first-line antihypertensive agent in renal transplant recipients. However, antihypertensive therapy should be individually tailored based on other factors, such as time after transplantation, presence of proteinuria/albuminuria, or hyperkalemia. Furthermore, due to the difficulty in controlling hypertension, combination therapy containing both CCBs and ACEIs could be a reasonable first-step therapy in treating children with severe post-transplantation hypertension.

Isolated nocturnal hypertension is associated with increased left ventricular mass index in children.

BACKGROUND: Isolated nocturnal hypertension (INH) is associated with increased prevalence of left ventricular hypertrophy (LVH) and cardiovascular morbidity and mortality in adult patients. Unlike in adults, data illustrating the possible association between INH and cardiac target organ damage is lacking in children. This study aimed to investigate whether INH is associated with increased left ventricular mass index (LVMI) and LVH in children. METHODS: Retrospective data from all untreated children with confirmed ambulatory hypertension (HT) in our center was reviewed. Ambulatory blood pressure monitoring (ABPM) and echocardiography were performed concurrently. Ambulatory normotensive children served as controls. LVH was defined as LVMI ≥ 95th percentile. RESULTS: There were 102 ABPM studies; of these, 79 children had renal HT, and 23 had primary HT. Median age of children was 13.2 years (3.8-18.9). Nineteen children had INH, 9 children had isolated daytime HT, 54 had daytime and nighttime HT, and 20 were normotensive. The LVMI adjusted for age (patient's LVMI/95th percentile of the LVMI) was significantly higher in children with INH than in normotensive children (0.83 ± 0.03 vs. 0.74 ± 0.03, p = 0.03). Left ventricular hypertrophy was present in 11% of children with INH; this was not significantly higher than in normotensive children (0%, p = 0.23). CONCLUSIONS: This study investigated the association between INH and cardiac structure in children with primary and renal HT and showed children with INH had higher LVMI adjusted for age than normotensive children and children with INH had similar LVMI adjusted for age to children with isolated daytime HT.

Increasing prevalence of hypertension during long-term follow-up in children with autosomal dominant polycystic kidney disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Kidney cysts form over the course of the disease and kidney function slowly declines, usually leading to kidney failure in middle to late adulthood. However, some symptoms, such as hypertension or proteinuria, can be present at an earlier age. In this study, we aimed to quantify early complications in children over time. METHODS: All 69 children with ADPKD from our pediatric nephrology center who met inclusion criteria (follow-up ≥ 1 year and ≥ 2 recorded visits) were studied. Analysis of changes in kidney size, cyst count, estimated glomerular filtration rate (eGFR), urinary protein excretion, and blood pressure was performed. RESULTS: The median time of follow-up was 6.3 years (range 8.4-14.8). Over the follow-up, kidneys grew from 109 to 115% of expected length (p < 0.0001), number of cysts increased at a rate of 0.8 cyst/kidney/year, and the prevalence of hypertension increased significantly from 20 to 38% (p < 0.015). The eGFR and absolute urinary protein excretion remained stable. CONCLUSIONS: This study shows that children with ADPKD suffer from increasing prevalence of hypertension during the course of the disease parallel to the increasing number of kidney cysts and size despite normal and stable kidney function and proteinuria. A higher resolution version of the Graphical abstract is available as Supplementary information.

Blood pressure in children with renal cysts and diabetes syndrome.

Cystic kidney diseases such as autosomal recessive or dominant polycystic kidney disease (ARPKD and ADPKD) are associated with high prevalence of arterial hypertension. On the contrary, studies on hypertension in children with renal cysts and diabetes (RCAD) syndrome caused by abnormalities in the HNF1B gene are rare. Therefore, the primary aim of our study was to investigate the prevalence of high blood pressure in children with RCAD syndrome due to HNF1B gene abnormalities and secondary to search for possible risk factors for development of high blood pressure. Data on all children with genetically proven RCAD syndrome from three pediatric nephrology tertiary centers were retrospectively reviewed (office blood pressure (BP), ambulatory blood pressure monitoring (ABPM), creatinine clearance, renal ultrasound, echocardiography, albuminuria/proteinuria). High blood pressure was defined as BP ≥ 95th percentile of the current ESH 2016 guidelines and/or by the use of antihypertensive drugs. Thirty-two children with RCAD syndrome were investigated. Three children received ACE inhibitors for hypertension and/or proteinuria. High blood pressure was diagnosed using office BP in 22% of the children (n = 7). In the 7 performed ABPM, 1 child (14%) was diagnosed with hypertension and one child with white-coat hypertension. Creatinine clearance, proteinuria, albuminuria, body mass index, enlargement, or hypodysplasia of the kidneys and prevalence of HNF1B-gene deletion or mutation were not significantly different between hypertensive and normotensive children.Conclusion: High blood pressure is present in 22% of children with RCAD syndrome. What is Known: • Arterial hypertension is a common complication in children with polycystic kidney diseases. What is New: • High office blood pressure is present in 22% and ambulatory hypertension in 14% of children with renal cyst and diabetes (RCAD) syndrome.

Unattended automated office blood pressure measurement in children.

PURPOSE: We studied the performance of unattended automated office blood pressure (uAOBP) measurement in children, in relation to oscillometric office BP (OBP) and ambulatory blood pressure monitoring (ABPM). MATERIALS AND METHODS: One hundred and eleven stable treated and untreated outpatients investigated for hypertension underwent uAOBP measurements (seated unattended in a quiet room separate from the renal clinic room, six times after a 5 min rest with the BpTRU device), and immediately before using the oscillometric device. Ambulatory 24 h blood pressure monitoring (ABPM) was performed on the same day in a subgroup of 42 children. RESULTS: UAOBP measurements were successful in 106 children (95%), 5 pre-school children did not tolerate to be alone in the room. The mean ± SD systolic/diastolic uAOBP, OBP and daytime ABP were 109.1 ± 14.0/70.8 ± 10.7 mmHg, 121.6 ± 16.5/77.6 ± 10.5 mmHg and 123.5 ± 11.3/73.7 ± 6.8 mmHg, respectively. Systolic/diastolic uAOBP was significantly lower than OBP by 13.6/7.6 mmHg (p < 0.0001) and lower than daytime ABP by 14.4 ± 0.5/2.9 ± 0.3 mmHg (p < 0.0001). The heart rate was not significantly different during uAOBP than during OBP measurements. On Bland Altman analysis the uAOBP underestimated OBP by a mean of 15.6 mmHg for systolic BP and by 8.6 mmHg for diastolic BP. In all 9 children with white-coat systolic hypertension uAOBP was within the normal range (<95th pc for OBP), in six of nine children with white-coat diastolic hypertension uAOBP was within the normal range however, in three of them it was elevated despite normal ABP. CONCLUSION: uAOBP measurement is feasible in school-aged children, its values are considerably lower than OBP as well as daytime ABP and it could help with detection of white-coat systolic hypertension. The clinical applicability of uAOBP in children should be confirmed in further studies.

Results in the ESPN/ERA-EDTA Registry suggest disparities in access to kidney transplantation but little variation in graft survival of children across Europe.

One of the main objectives of the European health policy framework is to ensure equitable access to high-quality health services across Europe. Here we examined country-specific kidney transplantation and graft failure rates in children and explore their country- and patient-level determinants. Patients under 20 years of age initiating kidney replacement therapy from January 2007 through December 2015 in 37 European countries participating in the ESPN/ERA-EDTA Registry were included in the analyses. Countries were categorized as low-, middle-, and high-income based on gross domestic product. At five years of follow-up, 4326 of 6909 children on kidney replacement therapy received their first kidney transplant. Overall median time from kidney replacement therapy start to first kidney transplantation was 1.4 (inter quartile range 0.3-4.3) years. The five-year kidney transplantation probability was 48.8% (95% confidence interval: 45.9-51.7%) in low-income, 76.3% (72.8-79.5%) in middle-income and 92.3% (91.0-93.4%) in high-income countries and was strongly associated with macro-economic factors. Gross domestic product alone explained 67% of the international variation in transplantation rates. Compared with high-income countries, kidney transplantation was 76% less likely to be performed in low-income and 58% less likely in middle-income countries. Overall five-year graft survival in Europe was 88% and showed little variation across countries. Thus, despite large disparities transplantation access across Europe, graft failure rates were relatively similar. Hence, graft survival in low-risk transplant recipients from lower-income countries seems as good as graft survival among all (low-, medium-, and high-risk) graft recipients from high-income countries.

Sex and age as determinants for high blood pressure in pediatric renal transplant recipients: a longitudinal analysis of the CERTAIN Registry.

BACKGROUND: High prevalence of arterial hypertension is known in pediatric renal transplant patients, but how blood pressure (BP) distribution and control differ between age groups and whether sex and age interact and potentially impact BP after transplantation have not been investigated. METHODS: This retrospective analysis included 336 pediatric renal transplant recipients (62% males) from the Cooperative European Pediatric Renal Transplant Initiative Registry (CERTAIN) with complete BP measurement at discharge and 1, 2 and 3 years post-transplant. RESULTS: At discharge and 3 years post-transplant, arterial hypertension was highly prevalent (84% and 77%); antihypertensive drugs were used in 73% and 68% of the patients. 27% suffered from uncontrolled and 9% from untreated hypertension at 3 years post-transplant. Children transplanted at age < 5 years showed sustained high systolic BP z-score and received consistently less antihypertensive treatment over time. Younger age, shorter time since transplantation, male sex, higher body mass index (BMI), high cyclosporine A (CSA) trough levels, and a primary renal disease other than congenital anomalies of the kidney and urinary tract (CAKUT) were significantly associated with higher systolic BP z-score. Sex-stratified analysis revealed a significant association between high CSA and higher systolic BP in older girls that likely had started puberty already. An association between BP and estimated glomerular filtration rate was not detected. CONCLUSIONS: BP control during the first 3 years was poor in this large European cohort. The description of age- and sex-specific risk profiles identified certain recipient groups that may benefit from more frequent BP monitoring (i.e. young children) or different choices of immunosuppression (i.e. older girls).

Molecular basis and outcomes of atypical haemolytic uraemic syndrome in Czech children.

Atypical haemolytic uraemic syndrome is an ultra-rare, life-threatening disease. Causative variants in genes that encode complement factors can be identified in 40-70% of cases. We performed genetic analysis of 21 Czech children with atypical haemolytic uraemic syndrome. Genetic or acquired predisposition to the disease was identified in the majority of our patients: CFHR1 and CFHR3 deletions in 14/21 (67%; 13 of them were positive for anti-complement factor H antibodies), variants in complement genes or DGKE in 13/21 (62%). Multiple genetic findings were identified in eight patients (38%). The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population was estimated to be 0.092 (CI 0.053-0.131) cases per million inhabitants and 0.92 (CI 0.53-1.32) cases per 100,000 births for the entire reporting period. Ten patients were initially treated with plasma exchange and eight with eculizumab or with a combination of eculizumab and plasma exchange. At the last follow-up, 20 patients were alive and one patient had end-stage renal disease.Conclusion: The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population corresponds to the reported incidence in Europe. We detected the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies in Czech paediatric patients. Treatment by eculizumab led to superior outcomes and prevention of the disease relapses compared with plasma exchange therapy. Our results may help to understand the polygenic nature of atypical haemolytic uraemic syndrome as a disease that results from a combination of various risk factors. What is Known: • Atypical haemolytic uraemic syndrome (aHUS) is considered a polygenic and multifactorial disease. Genetic predisposition to aHUS is identified in 40-70% of children. • Anti-complement factor H antibodies are usually found in 6-25% of affected children. What is New: • Potentially causative genetic or acquired factors were confirmed in the majority of patients. The prevailing finding was the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies (62% of patients). • The incidence of aHUS in Czech children is 0.092 (CI 0.053-0.131) cases per million inhabitants and 0.92 (CI 0.53-1.32) cases per 100,000 births for the entire reporting period.

Human leukocyte antigen association with familial steroid-sensitive nephrotic syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood. Cases with the familial occurrence of SSNS suggest that genetics may play a role in the disease. Human leucocyte antigen (HLA) alleles have been associated with SSNS. We present genetic findings in nine families (44 participants), each with at least two affected siblings. A total of 19 patients were affected with familial SSNS. Six of nine families showed linkage to markers on chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. Interestingly, we also found linkage of disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score Z = 3.02.Conclusion: Our findings confirm the linkage of HLA markers on chromosome 6, which strengthens the association of HLA alleles in SSNS. What is Known: • Human leukocyte antigen (HLA) alleles have been associated with idiopathic steroid-sensitive nephrotic syndrome (SSNS). Only few studies have investigated the association between HLA alleles and familial SSNS. What is New: • We present evidence of linkage of familial SSNS to chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. We also found linkage of the disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score of Z = 3.02 following autosomal recessive inheritance pattern.

Effects of the strict control of blood pressure in pediatric renal transplant recipients-ESCORT trial.

OBJECTIVES: Strict BP control can retard progression of CKD in children. This prospective 3-year randomized controlled trial is aimed to investigate whether strict BP control can retard progression of chronic allograft dysfunction. METHODS: Twenty-three pediatric patients were randomly selected to the standard BP group (STAND, target 24-hour MAP 50-95th percentile, n = 11) or the intensified BP group (INTENS, target 24-hour MAP <50th percentile, n = 12). The primary endpoint was an annual reduction in eGFR (Schwartz formula, mL/min/1.73 m2 /y), secondary graft survival, BP, proteinuria, and safety. RESULTS: A total of 21 children (age at entry 11.2 (range 6.2-16.8) years) completed the study, with 73% of children in INTENS and 70% of children in STAND group reached their goal BP. Ambulatory indexed 24-hour MAP decreased significantly in INTENS group (from 0.94 (range 0.86-1.17) to 0.85 (range 0.79-1.01, P < 0.01)) but not in STAND group (from 0.93 (range 0.85-1.07) to 0.90 (range 0.84-1.01)). Proteinuria did not change significantly in either group (22.1 mg/mmol creatinine to 15.3 in STAND group vs 25.7 to 11.8 in INTENS group). The annual reduction in eGFR did not differ between the INTENS and STAND groups (-1.9 mL/min/1.73 m2 /y (range +6.4 to -14.3) vs -0.9 (range +4.0 to -8.5)). CONCLUSION: This first randomized controlled trial on strict BP control has demonstrated that strict BP control is feasible in 73% of children but the strict BP control does not lead to retardation of graft function decline in comparison with standard BP control. However, the results need to be interpreted with caution keeping the major limitation of the study, that is, small sample size in mind.