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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.

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 r = 0.72, p r = 0.50, p p Conclusions Impaired kidney concentrating capacity is present in most children with ARPKD and is associated with decreased eGFR and hypertension. Graphical abstract

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.

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.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.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 (p0.0001), number of cysts increased at a rate of 0.8 cyst/kidney/year, and the prevalence of hypertension increased significantly from 20 to 38% (p0.015). The eGFR and absolute urinary protein excretion remained stable.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.

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. 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. 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). 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.

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 66% 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.

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.

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.

Arterial hypertension is a common complication in patients with autosomal recessive polycystic kidney disease (ARPKD), occurring in 33-75% of children when measured by office blood pressure (OBP). Ambulatory blood pressure monitoring (ABPM) is a superior tool for investigating blood pressure relative to OBP. The aim of our study was to investigate the prevalence and control of hypertension in children with ARPKD based on ABPM.This retrospective study evaluated 36 children with ARPKD and at least one ABPM performed in two our tertiary paediatric nephrology centres and 29 children with at least two ABPM. Ambulatory hypertension was defined as mean daytime or night-time BP at least 95th percentile or use of antihypertensives and controlled hypertension as normal ambulatory BP in children on antihypertensive drugs.The first ABPM study revealed ambulatory hypertension in 94% of children. Untreated or uncontrolled ambulatory hypertension was diagnosed in 67% and controlled hypertension in only 28%. Masked hypertension was found in 5.5% and white-coat hypertension in 14%. The last ABPM study revealed ambulatory hypertension in 86% (all 86% hypertensive children on drugs, i.e. no untreated hypertension), the prevalence of controlled hypertension increased to 59%. Masked hypertension was detected in 8.3% and white-coat hypertension in 10%. Ambulatory blood pressure correlated neither with kidney length nor with glomerular filtration rate. Echocardiography demonstrated left ventricular hypertrophy (LVH) in 27% of children at the time of their first ABPM.The prevalence of ambulatory hypertension is very high in children with ARPKD, while the control of hypertension improves over time.

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.

Background and Aims Tolvaptan (TOL) is a vasopressin V2 receptor antagonist that inhibits total kidney volume (TKV) growth and kidney function decline in adults with rapidly progressing ADPKD. The therapeutic potential of TOL in pediatric patients at risk of early disease progression has not been previously reported. We conducted a clinical trial of TOL in children and adolescents with early manifesting ADPKD to evaluate pharmacodynamic properties and preliminary efficacy and safety information in this age group. Method This was a Phase 3b, 2-part trial (EudraCT: 2016-000187-42; ClinicalTrials.gov: NCT02964273). Phase A (reported here) was a 1-year, randomized, double-blind, placebo (PBO)-controlled, multicenter trial; Phase B is an ongoing, 2-year, open-label extension. Subjects had to be diagnosed with ADPKD (presence of renal cysts with family history and/or genetic diagnosis), with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and body weight ≥20 kg. The target population was aged 12-17 years; subjects aged 4-11 years were also allowed to enter if eligibility criteria were met. Starting and maintenance TOL/PBO doses were based on body weight. The co-primary endpoints were changes from baseline in spot urine osmolality (Uosm) and specific gravity at Week 1; additional endpoints were the 12-month changes in TKV and eGFR. Safety and tolerability were monitored. In this exploratory trial, outcomes were summarized descriptively, with no statistical comparisons planned between groups. Results Of 91 subjects enrolled (66 aged 12–17 years and 25 aged 1.5 x baseline) occurred in 4 TOL subjects and no PBO subject. No subject had elevated transaminases or drug-induced liver injury. Serious adverse events were reported in 1 TOL subject (viral pericarditis) and 6 PBO, none considered related to treatment. One subject discontinued due to pollakiuria (TOL) and 1 due to dizziness (PBO). Conclusion TOL demonstrated activity indicative of effective V2 receptor antagonism in children and adolescents with ADPKD. In addition, our trial yielded preliminary results suggestive of efficacy in slowing TKV growth and eGFR decline with acceptable tolerability, warranting further investigation in pediatric patients with ADPKD. The 2-year, Phase B extension to this trial is ongoing. Sponsored by OPDC, Inc.

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 aim of our study was to investigate the prevalence of hypertension in children with RCAD syndrome due to HNF1B gene abnormalities and to search for possible risk factors for development of hypertension. 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). Hypertension was defined using the current ESH 2016 criteria 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. Hypertension was diagnosed using office BP in 22% of the children (n = 7) In the 7 performed ABPM 1 child (14%) was diagnosed with 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: Hypertension is rare in children with RCAD syndrome. The low prevalence of hypertension seems to be the hallmark of the disease.

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.

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.

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. German Society for Pediatric Nephrology (GPN); ESCAPE Network; European Society for Paediatric Nephrology (ESPN); German PKD foundation; Koeln Fortune program; GEROK program of the Medical Faculty of University of Cologne; Marga and Walter Boll-Foundation; German Federal Ministry of Research and Education (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1515, 01GM1903]; working group CAKUT of the ESPN; working group Inherited Kidney Diseases of the ESPN We thank the German Society for Pediatric Nephrology (GPN) and the ESCAPE Network for their support. We thank Mr Mathias Burgmaier (Aachen) and Mr Samuel Kilian (Heidelberg) for support in conducting statistical analysis. ML was supported by grants of the GPN, the European Society for Paediatric Nephrology (ESPN), the German PKD foundation, the Koeln Fortune program, the GEROK program of the Medical Faculty of University of Cologne, and the Marga and Walter Boll-Foundation. FS, CB, and ML are supported by the German Federal Ministry of Research and Education (BMBF grant 01GM1515 and 01GM1903). KB was supported by the Koeln Fortune program and the GEROK program of the Medical Faculty of University of Cologne, as well as the Marga and Walter Boll-Foundation. This work was generated within the European Reference Network for Rare Kidney Disorders (ERKNet). The work was supported by the working groups CAKUT and Inherited Kidney Diseases of the ESPN.

Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.

Each year, around 2% of the four million hectares of farmland in Czechia changes owners. However, after years of significant growth in prices, a slowdown in pace and demand is expected. Rising interest rates, a strengthening of the crown and legislative changes in 2018 have influenced the price of farmland. Yet the prices of farmland in Czechia are a third of those in the countries of Western Europe, and so it still represents an interesting opportunity for investors. Currently, land is bought primarily by the farmers who work it. In Czechia, 80% of farmers farm on hired land, and rent increases are starting to be an issue for many of them. The return on the investment in agricultural land is currently around 50 years for an owner and 25 years for a farmer working the land. As research has shown, the price of farmland is an important factor in the sustainable development of agriculture in Czechia, along with the greening of production and the fight against soil erosion and the effects of climate change.

Background: Factor H-related-5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement and follow-up data.Results: 120 patients with a histologically-proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger-sequencing, and selected mutants were studied as recombinant proteins in ELISA and SPR.Eight relevant CFHR5 variations in 14 patients (11.7%) were observed, 5 of them identified as pathogenic for C3G. The FHR-5G278S and FHR-5R356H mutations altered the interaction of FHR-5 with C3b, when compared to the FHR-5WT. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period, furthermore, it showed clear association with signs of hypocomplementemia and clinically meaningful clusters.Conclusions: Our observations support the hypothesis that FHR-5 protein and its genetic alterations play a role in the pathogenesis of IC-MPGN/C3G.

Hypertensive crisis is a relatively rare condition in children. However, if not treated, it might be life-threatening and lead to irreversible damage of vital organs. Clinical presentation of patients with hypertensive crisis can vary from very mild (hypertensive urgency) to severe symptoms (hypertensive emergency) despite similarly high blood pressure (BP). Individualized assessment of patients presenting with high BP with emphasis on the evaluation of end-organ damage rather than on the specific BP number is a key in guiding physician's initial management of a hypertensive crisis. The main aim of the treatment of hypertensive crisis is the prevention or treatment of life-threatening complications of hypertension-induced organ dysfunction, including neurologic, ophthalmologic, renal, and cardiac complications. While the treatment strategy must be directed toward the immediate reduction of BP to reduce the hypertensive damage to these organs, it should not be at a too fast rate to cause hypoperfusion of vital organs by an excessively rapid reduction of BP. Thus, intravenous continuous infusions rather than intravenous boluses of antihypertensive medications should be the preferable mode of initial treatment of children with hypertensive emergency.

Background Hypomagnesaemia is present in 40–50% of children with autosomal dominant renal cysts and diabetes syndrome (RCAD). On the contrary, the prevalence of hypomagnesaemia in children with autosomal dominant polycystic kidney disease (ADPKD) has never been examined. We aimed to investigate whether hypomagnesaemia is present in children with polycystic kidney diseases. Methods Children with cystic kidney diseases were investigated in a cross-sectional study. Serum concentrations of magnesium (S-Mg) and fractional excretion of magnesium (FE-Mg) were tested. Fifty-four children with ADPKD ( n = 26), autosomal recessive polycystic kidney disease (ARPKD) ( n = 16) and RCAD ( n = 12) with median age of 11.2 (0.6–18.6) years were investigated. Results Hypomagnesaemia (S-Mg Conclusions Hypomagnesaemia is absent in children with ADPKD or ARPKD and could serve as a marker for differential diagnostics between ADPKD, ARPKD and RCAD in children with cystic kidney diseases of unknown origin where molecular genetic testing is lacking. However, while hypomagnesaemia, in the absence of diuretics, appears to rule out ADPKD and ARPKD, normomagnesaemia does not rule out RCAD at least in those aged

Arterialni tuhost odraži vlastnosti cevni stěny. Studie u dospělých pacientů prokazaly, že arterialni tuhost je rizikovým faktorem morbidity a mortality z kardiovaskularnich přicin. V posledni době vzrůsta použivani neinvazivnich metod měřeni arterialni tuhosti, jako je rychlost pulsni vlny i v pediatricke populaci, a to jak ve výzkumu, tak v klinicke praxi. S rozsiřenim těchto neinvazivnich metod do dětskeho věku přibývaji rychle nase znalosti o faktorech a stavech, ktere jsou spojeny s vzestupem arterialni tuhosti. Mezi tyto faktory patři nejen tradicni kardiovaskularni rizikove faktory, ale take stavy, jakými jsou intrauterinni růstova retardace, metabolický syndrom, obezita, diabetes mellitus a chronicke onemocněni ledvin, vaskulitidy a vaskulopatie spojene s různými syndromy, kongenitalni srdecni vady a některe systemove choroby. Casne rozpoznani zvýsene tuhosti arterii v dětstvi by mohlo vest k casne lecebne intervenci. V tomto smyslu jsou ale nezbytne longitudinalni intervencni studie, ktere by potvrdily, že zlepseni tuhosti cev u normalni i rizikove pediatricke populace povede k sniženi kardiovaskularniho rizika v casne dospělosti.

Ozcakar, Zeynep/0000-0002-6376-9189; Memaran, Nima/0000-0002-9510-3154; DUZOVA, ALI/0000-0002-4365-2995; Sugianto, Rizky Indrameikha/0000-0002-7929-507X WOS: 000511956000006 PubMed: 31811541 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).

Background A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. Methods A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. Results High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2—which is not reliable because of the small number of cases—strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3–4 had worse renal survival than patients in Clusters 1–2. Conclusions Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

Every child with hypertension requires long-term follow-up. The long-term follow-up should be focused on achievement of target BP, assessment of adherence with antihypertensive therapy and non-pharmacological measures and reassessment of target organ damage. The intervals for follow-up checks should be individualized according to achieved BP, adherence and presence of target organ damage.

Background Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. Results One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. Conclusions In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10–15% of IC-MPGN/C3G patients.

The aim of our study was to investigate whether nocturnal blood pressure (BP) dip is associated with increased left ventricular mass index and hypertrophy in children with hypertension (HT). We retrospectively reviewed data from all children with confirmed ambulatory HT in our center and performed ambulatory blood pressure monitoring (ABPM) and echocardiography at the same time. Left ventricular hypertrophy (LVH) was defined as left ventricular mass index (LVMI) ≥95th centile. Non-dipping phenomenon was defined as nocturnal BP dip10 %. A total of 114 ABPM studies were included, the median age of children was 15.3 years (3.8-18.9), 80 children had renoparenchymal HT without end-stage renal failure, 34 had primary HT, and 27 studies were done on untreated children and 87 on treated children. Non-dipping phenomenon was present in 63 (55 %) studies (non-dippers). The LVMI adjusted for age was not significantly different between non-dippers and dippers (0.87 ± 0.03 vs. 0.81 ± 0.02, p = 0.13). Left ventricular hypertrophy was not significantly higher in non-dippers than in dippers (20 vs. 9 %, p = 0.12).Hypertensive children without end-stage renal failure with non-dipping phenomenon do not have increased prevalence of LVH or higher LVMI adjusted for age than hypertensive children with preserved nocturnal BP dip.• Adult and pediatric hypertensive patients with end-stage renal failure have often nocturnal blood pressure non-dipping phenomenon. • Non-dipping phenomenon is in patients with end-stage renal failure associated with increased prevalence of left ventricular hypertrophy. What is New: • Pediatric hypertensive patients without end-stage renal failure with blood pressure non-dipping phenomenon do not have increased prevalence of left ventricular hypertrophy.

BACKGROUND Proteinuria is a common complication in adults with autosomal dominant polycystic kidney disease (ADPKD) and serves as a risk factor for progression. However, proteinuria has rarely been examined in children with ADPKD and the type of proteinuria has not yet been investigated. The aim of the study was to assess the prevalence and to analyse the types of proteinuria in children with ADPKD. METHODS Children with ADPKD followed-up in our tertiary centres during the years 2012-2013 were investigated in a cross-sectional study. Morning urine was tested for total protein (PROT), albumin (ALB) and alpha-1-microglobulin (AMG). Renal function was assessed from serum creatinine as estimated glomerular filtration rate. RESULTS Thirty-seven children of median age 11.2 (2.0-18.0) years were investigated. Median (range) PROT, ALB and AMG (in mg/mmol creatinine) were 15.1 (6.2-64.8), 2.54 (0.54-37.25) and 3.22 (0.04-10.16), respectively. Pathological total proteinuria (>22) was found in 30% of children, albuminuria (>2.2) in 49% of children and alpha-1-microglobulinuria (>0.55) in 65% of children. No correlation was found between PROT, ALB or AMG and office blood pressure, kidney size or estimated glomerular filtration rate. CONCLUSIONS Proteinuria in children with ADPKD is a frequent finding, the most common type is tubular proteinuria. It should be measured in all ADPKD children.

BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease is the most common inheritable kidney disease, frequently thought to become symptomatic in adulthood. However, patients with autosomal dominant polycystic kidney disease may develop signs or symptoms during childhood, in particular hypertension. Although ambulatory BP monitoring is the preferred method to diagnose hypertension in pediatrics, data in children with autosomal dominant polycystic kidney disease are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our retrospective multicenter study was conducted to collect ambulatory BP monitoring recordings from patients with autosomal dominant polycystic kidney disease age 1 cm per kidney and daytime hypertension (odds ratio, 1.70; 95% confidence interval, 1.21 to 2.4; P=0.002), nighttime hypertension (odds ratio, 1.31; 95% confidence interval, 1.05 to 1.63; P=0.02), or 24-hour hypertension (odds ratio, 1.39; 95% confidence interval, 1.08 to 1.81; P=0.01). Kidney length, expressed as SD score, was also significantly associated with nighttime hypertension (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.42; P=0.10). CONCLUSIONS: These data indicate high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages. ispartof: CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY vol:13 issue:6 pages:874-883 ispartof: location:United States status: published

Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novelWe developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD