Autoantibodies Targeting Nephrin in Podocytopathies.

BACKGROUND: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear. METHODS: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin. RESULTS: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice. CONCLUSIONS: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.).

Post-transplant recurrence of focal segmental glomerular sclerosis: consensus statements.

Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.

Trends and socioeconomic inequality of the burden of congenital abnormalities of the kidney and urinary tract among children and adolescents.

BACKGROUND: Although congenital abnormalities of the kidney and urinary tract (CAKUT) is the leading cause of childhood onset chronic kidney disease (CKD) and kidney failure, comprehensive information on the disease burden among children and adolescents globally is lacking. We aim to report the trends and socioeconomic inequality of CAKUT burden for people aged 0-24 years from 1990 to 2019·. METHODS: We reported the prevalence, mortality and disability-adjusted life-years (DALYs) for CAKUT based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, quantified the association of disease burden and socio-demographic index (SDI), calculated the slope index of inequality (SII) the relative index of inequality (RII) and concentration index. RESULTS: In 2019, the global prevalence, mortality, and DALYs of CAKUT among individuals aged 0-24 years were 167.11 (95%Confident Interval 166.97, 167.25), 0.30 (0.29, 0.30), and 32.22 (32.16, 32.29) per 100 000 population. The greatest prevalence, mortality and DALYs were recorded in the 0-4 year age group. The greatest mortality and DALYs were recorded in low SDI countries and territories. During 1990 to 2019, the prevalence, mortality and DALYs decreased globally, while in low and low-middle countries and territories the reduction was much less slower. India, Nigeria and Pakistan had the highest DALYs. Saudi Arabia and China exhibited a markedly decrease of CAKUT burden. Globally for every 0.1 increase in SDI, there was a 20.53% reduction in mortality, a 16.31% decrease in DALYs, but a 0.38% rise in prevalence. CONCLUSIONS: Inequality for disease burden of varying SDI was increasing globally. Thus, specific preventive and health service measures are needed to reduce the global burden from CAKUT.

Factors influencing circuit lifetime in paediatric continuous kidney replacement therapies - results from the EurAKId registry.

BACKGROUND: Continuous kidney replacement therapy (CKRT) has recently become the preferred kidney replacement modality for children with acute kidney injury (AKI). We hypothesise that CKRT technical parameters and treatment settings in addition to the clinical characteristics of patients may influence the circuit lifetime in children. METHODS: The study involved children included in the EurAKId registry (NCT02960867), who underwent CKRT treatment. We analysed patient characteristics and CKRT parameters. The primary end point was mean circuit lifetime (MCL). Secondary end points were number of elective circuit changes and occurrence of dialysis-related complications. RESULTS: The analysis was composed of 247 children who underwent 37,562 h of CKRT (median 78, IQR 37-165 h per patient). A total of 1357 circuits were utilised (3, IQR 2-6 per patient). MCL was longer in regional citrate anticoagulation (RCA), compared to heparin (HA) and no anticoagulation (NA) (42, IQR 32-58 h; 24, IQR 14-34 h; 18, IQR 12-24 h, respectively, p < 0.001). RCA was associated with longer MCL regardless of the patient's age or dialyser surface. In multivariate analysis, MCL correlated with dialyser surface area (beta = 0.14, p = 0.016), left internal jugular vein vascular access site (beta = -0.37, p = 0.027), and the use of HA (beta = -0.14, p = 0.038) or NA (beta = -0.37, p < 0.001) vs. RCA. RCA was associated with the highest ratio of elective circuit changes and the lowest incidence of complications. CONCLUSION: Anticoagulation modality, dialyser surface, and vascular access site influence MCL. RCA should be considered when choosing first-line anticoagulation for CKRT in children. Further efforts should focus on developing guidelines and clinical practice recommendations for paediatric CKRT.

Dyslipidemia in children with chronic kidney disease-findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study.

BACKGROUND: Dyslipidemia is an important and modifiable risk factor for CVD in children with CKD. METHODS: In a cross-sectional study of baseline serum lipid levels in a large prospective cohort study of children with stage 3-5 (predialysis) CKD, frequencies of abnormal lipid levels and types of dyslipidemia were analyzed in the entire cohort and in subpopulations defined by fasting status or by the presence of nephrotic range proteinuria. Associated clinical and laboratory characteristics were determined by multivariable linear regression analysis. RESULTS: A total of 681 patients aged 12.2 ± 3.3 years with a mean eGFR of 26.9 ± 11.6 ml/min/1.73 m2 were included. Kidney diagnosis was classified as CAKUT in 69%, glomerulopathy in 8.4%, and other disorders in 22.6% of patients. Nephrotic range proteinuria (defined by a urinary albumin/creatinine ratio > 1.1 g/g) was present in 26.9%. Dyslipidemia was found in 71.8%, and high triglyceride (TG) levels were the most common abnormality (54.7%). Fasting status (38.9%) had no effect on dyslipidemia status. Except for a significant increase in TG in more advanced CKD, lipid levels and frequencies of dyslipidemia were not significantly different between CKD stages. Hypertriglyceridemia was associated with younger age, lower eGFR, shorter duration of CKD, higher body mass index (BMI-SDS), lower serum albumin, and higher diastolic blood pressure. CONCLUSIONS: Dyslipidemia involving all lipid fractions, but mainly TG, is present in the majority of patients with CKD irrespective of CKD stage or fasting status and is significantly associated with other cardiovascular risk factors.

Characterization of patients with aHUS and associated triggers or clinical conditions: A Global aHUS Registry analysis.

INTRODUCTION: Atypical haemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) associated with complement dysregulation; aHUS may be associated with other 'triggers' or 'clinical conditions'. This study aimed to characterize this patient population using data from the Global aHUS Registry, the largest collection of real-world data on patients with aHUS. METHODS: Patients enrolled in the Global aHUS Registry between April 2012 and June 2021 and with recorded aHUS-associated triggers or clinical conditions prior/up to aHUS onset were analysed. aHUS was diagnosed by the treating physician. Data were classified by age at onset of aHUS (< or ≥18 years) and additionally by the presence/absence of identified pathogenic complement genetic variant(s) and/or anti-complement factor H (CFH) antibodies. Genetically/immunologically untested patients were excluded. RESULTS: 1947 patients were enrolled in the Global aHUS Registry by June 2021, and 349 (17.9%) met inclusion criteria. 307/349 patients (88.0%) had a single associated trigger or clinical condition and were included in the primary analysis. Malignancy was most common (58/307, 18.9%), followed by pregnancy and acute infections (both 53/307, 17.3%). Patients with an associated trigger or clinical condition were generally more likely to be adults at aHUS onset. CONCLUSION: Our analysis suggests that aHUS-associated triggers or clinical conditions may be organized into clinically relevant categories, and their presence does not exclude the concurrent presence of pathogenic complement genetic variants and/or anti-CFH antibodies. Considering a diagnosis of aHUS with associated triggers or clinical conditions in patients presenting with TMA may allow faster and more appropriate treatment.

The creation of an adaptable informed consent form for research purposes to overcome national and institutional bottlenecks in ethics review: experience from rare disease registries.

Background: The lack of harmonization of evaluation criteria by Ethics Committees in the European Union (EU) has led to inconsistent ethics reviews received by research sites participating in multicenter non-interventional studies. The European General Data Protection Regulation (GDPR) appears to be implemented at national level with a substantial degree of variance in interpretation. The European Reference Networks (ERNs) were struggling in setting an Informed Consent Form (ICF) for registries, allowing reuse of data for research purposes. The aim of this work is to develop an adaptable ICF for research purposes to be used in ERN registries. Methods: To work on this challenge, a team was established within the European Joint Programme on Rare Diseases (EJP RD) to develop a patients' registry ICF template allowing easy adaptation to ERNs, country, and site-level specificities. ERN and patients' representatives validated the choice of developing a GDPR-compliant template for research purposes. The feedback received from 34 Ethics Committees on the Clinical Patient Management System ICF, including the submission of patients' data to the ERN registries and the EU consent regulatory framework were analyzed along with existing ontologies for data access and reuse. An adaptable ICF was developed following iterative cycles of consultation and review by clinicians, research experts, ethics and regulatory advisors, and patients' representatives. The development of pediatric material for minor participants was also undertaken. Results and Conclusion: Research oriented ICF templates for adults and for parents/legal representatives of patients were released in 26 national languages. This adaptable ICF aims to foster, according to patients' preferences, the reuse of registries data for research purposes in compliance with the applicable laws and standards. Pediatric material is being finalized to collect minors' assent. ICF machine-readability is also progressing to enhance data discovery and facilitate its access and reuse conditions.

Investigating the use of finerenone in children with chronic kidney disease and proteinuria: design of the FIONA and open-label extension studies.

INTRODUCTION: Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria. OBJECTIVE: FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria. DESIGN: FIONA (NCT05196035; Eudra-CT: 2021-002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months' duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m2 if ≥ 1 to < 18 years or a serum creatinine level ≤ 0.40 mg/dL for infants 6 months to < 1 year) with significant proteinuria despite ACEi or ARB usage. The primary objective is to demonstrate that finerenone, added to an ACEi or ARB, is superior to placebo in reducing urinary protein excretion. FIONA OLE (NCT05457283; Eudra-CT: 2021-002905-89) is a single-arm, open-label study, enrolling participants who have completed FIONA. The primary objective of FIONA OLE is to provide long-term safety data. FIONA has two primary endpoints: urinary protein-to-creatinine ratio (UPCR) reduction of ≥ 30% from baseline to day 180 and percent change in UPCR from baseline to day 180. A sample size of 198 participants (aged 2 to < 18 years) in FIONA will provide at least 80% power to reject the null hypothesis of either of the two primary endpoints. CONCLUSION: FIONA is evaluating the use of finerenone in children with CKD and proteinuria. Should safety, tolerability, and efficacy be demonstrated, finerenone could become a useful additional therapeutic agent in managing proteinuria and improving kidney outcomes in children with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05196035. Registered on 19 January 2022.

Prospective Study of Modifiable Risk Factors of Arterial Hypertension and Left Ventricular Hypertrophy in Pediatric Patients on Hemodialysis.

Introduction: Fluid and salt overload in patients on dialysis result in high blood pressure (BP), left ventricular hypertrophy (LVH) and hemodynamic instability, resulting in cardiovascular morbidity. Methods: Analysis of 910 pediatric patients on maintenance hemodialysis/hemodiafiltration (HD/HDF), prospectively followed-up with 2758 observations recorded every 6-months in the International Pediatric Hemodialysis Network (IPHN). Results: Uncontrolled hypertension was present in 55% of observations, with 27% of patients exhibiting persistently elevated predialysis BP. Systolic and diastolic age- and height-standardized BP (BP-SDS) were independently associated with the number of antihypertensive medications (odds ratio [OR] = 1.47, 95% confidence interval 1.39-1.56, 1.36 [1.23-1.36]) and interdialytic weight gain (IDWG; 1.19 [1.14-1.22], 1.09 [1.06-1.11]; all P < 0.0001). IDWG was related to urine output (OR = 0.27 [0.23-0.32]) and dialysate sodium (dNa; 1.06 [1.01-1.10]; all P < 0.0001). The prevalence of masked hypertension was 24%, and HD versus HDF use was an independent risk factor of elevated age- and height-standardized mean arterial pressure (MAP-SDS) (OR = 2.28 [1.18-4.41], P = 0.01). Of the 1135 echocardiograms, 51% demonstrated LVH. Modifiable risk factors included predialysis systolic BP-SDS (OR = 1.06 [1.04-1.09], P < 0.0001), blood hemoglobin (0.97 [0.95-0.99], P = 0.004), HD versus HDF modality (1.09 [1.02-1.18], P = 0.01), and IDWG (1.02 [1.02-1.03], P = 0.04). In addition, HD modality increased the risk of LVH progression (OR = 1.23 [1.03-1.48], P = 0.02). Intradialytic hypotension (IDH) was prevalent in patients progressing to LVH and independently associated with predialysis BP-SDS below 25th percentile, lower number of antihypertensives, HD versus HDF modality, ultrafiltration (UF) rate, and urine output, but not with dNa. Conclusion: Uncontrolled hypertension and LVH are common in pediatric HD, despite intense pharmacologic therapy. The outcome may improve with use of HDF, and superior anemia and IDWG control; the latter via lowering dNa, without increasing the risk of IDH.

Changes in the cardiovascular risk profile in children approaching kidney replacement therapy.

Background: Despite significant cardiovascular (CV) morbidity in children on dialysis and after kidney transplantation, data on the evolution of CV damage in children with chronic kidney disease (CKD) approaching kidney replacement therapy (KRT) is unknown. Methods: The burden, progression, and predictors of CV damage before KRT onset were explored in two prospective multicenter cohorts from Europe and Canada: Cardiovascular Comorbidity in Children with CKD (4C) and Haemodiafiltration, Heart and Height (3H) studies, conducted from 2009-19 and 2013-16, respectively. CV damage and risk factors were evaluated (i) cross sectionally at KRT-start (n = 248), and (ii) longitudinally over the 2-years preceding KRT start (n = 157; 331 patient-visits). Longitudinal analyses with mixed-effects models estimated associations of modifiable CV risk factors with change in carotid intima-media thickness (cIMT) standard deviation score (SDS), pulse wave velocity (PWV-SDS), left ventricular (LV) mass and systolic dysfunction. Findings: 248 patients, age 14.3 (12.2, 16.2) years were evaluated at median 35 (28-114) days before KRT start. Elevated cIMT-SDS and PWV-SDS were present in 43% and 25%, and LV hypertrophy and systolic dysfunction in 49% and 33%. Aortic stiffness and LV hypertrophy significantly increased, especially in the year before KRT start (adjusted odds ratio, OR 0.33, P = 0.002 and OR 0.54, P = 0.01, respectively). 79% of children had >3 modifiable CV risk factors at KRT onset. Diastolic BP and BMI were strongly associated with a linear increase in all CV measures. After controlling for CV risk factors, the time to KRT onset no longer predicted the burden of CV damage. Interpretation: This comprehensive CV evaluation shows the progressive accrual of modifiable risk factors and a high burden of CV damage in the years preceding KRT onset. CV damage in the pre-KRT period is preventable. Funding: Supported by EU4Health Programme (101085068) and Kidney Research UK (RP39/2013).

Long-term Effects of Kidney Transplantation Compared With Dialysis on Intima-media Thickness in Children-Results From the 4C-T Study.

BACKGROUND: Children requiring kidney replacement therapy experience high burden of cardiovascular (CV) disease leading to increased mortality. Intima-media thickness (IMT) indicating atherosclerosis is a validated surrogate marker for future CV events. METHODS: We investigated the effect of different treatment modalities (dialysis, preemptive kidney transplantation (KTx), late KTx after dialysis) on IMT by multivariable linear mixed-effect modeling. Patients were enrolled in a prospective cohort study. RESULTS: A total of 261 analyzed children had a mean follow-up of 3 y. Children after preemptive and late KTx had lower levels of IMT when compared with dialysis. Using an interaction term, a significant progression of IMT over time was seen during dialysis (ß = 0.0053 mm/y, P   =  0.004). IMT before the start of therapy was the most influential determinant in all models. Low IMT was associated with maintenance steroid treatment after preemptive KTx. High IMT on dialysis was associated with higher systolic blood pressure, lower body mass index, lower serum albumin, and lower bicarbonate. CONCLUSIONS: IMT remained rather stable in children several years after KTx. In contrast, children on dialysis had higher IMT values, which increased over time. In these children, blood pressure control, calorie and protein intake, and acid-base homeostasis seem important. Taken together, children might profit from early transplantation to limit accumulation of CV risk.

Steroid-Resistant Nephrotic Syndrome due to NPHS2 Variants Is Not Associated With Posttransplant Recurrence.

Introduction: Unlike idiopathic nephrotic syndrome (NS), hereditary podocytopathies are not expected to recur after kidney transplantation. However, some reports of posttransplant recurrence of NS in patients carrying variants in the NPHS2 gene have been described, notably with the p.Arg138Gln variant, which is more prevalent in Europe. The objective of this study was to assess the risk of recurrence after kidney transplantation in a large cohort of patients with biallelic NPHS2 pathogenic variants. Methods: Since January 2010, 61 patients identified at Necker-Enfants Malades Hospital and 56 enrolled in the PodoNet Registry with biallelic variants in the NPHS2 gene were transplanted and were compared with 44 transplanted children with steroid-resistant NS (SRNS) without any identified pathogenic variant. Results: Of the 117 patients, 23 carried the p.Arg138Gln variant in the homozygous state and 16 in the compound heterozygous state. The other 78 patients carried different variants in the homozygous (n = 44) or compound heterozygous state. Only 1 patient with NPHS2-related SRNS experienced posttransplant recurrence (median follow-up of cohort 8.5 years [2.5-15]). Conversely, 7 of 44 patients (16%) without any identified pathogenic variant recurred within a maximum of 7 days after transplantation (median follow-up 8.9 years [0.6-13.9]). Conclusion: In this large cohort, the risk of patients with causative variants in the NPHS2 gene to develop NS recurrence after kidney transplantation was extremely low. This is coherent with the pathophysiology of intrinsic slit-diaphragm disease. These data are reassuring and should be considered when counselling patients, making living kidney donation, whether related or not, a safe choice.

Clinical practice recommendations for kidney involvement in tuberous sclerosis complex: a consensus statement by the ERKNet Working Group for Autosomal Dominant Structural Kidney Disorders and the ERA Genes & Kidney Working Group.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the presence of proliferative lesions throughout the body. Management of TSC is challenging because patients have a multifaceted systemic illness with prominent neurological and developmental impact as well as potentially severe kidney, heart and lung phenotypes; however, every organ system can be involved. Adequate care for patients with TSC requires a coordinated effort involving a multidisciplinary team of clinicians and support staff. This clinical practice recommendation was developed by nephrologists, urologists, paediatric radiologists, interventional radiologists, geneticists, pathologists, and patient and family group representatives, with a focus on TSC-associated kidney manifestations. Careful monitoring of kidney function and assessment of kidney structural lesions by imaging enable early interventions that can preserve kidney function through targeted approaches. Here, we summarize the current evidence and present recommendations for the multidisciplinary management of kidney involvement in TSC.

Best Practice of Peritoneal Dialysis-Associated Gram-Negative Peritonitis in Children: Insights From the International Pediatric Peritoneal Dialysis Network Registry.

Introduction: Gram-negative peritonitis (GNP) is associated with significant morbidity in children receiving long-term peritoneal dialysis (PD) and current treatment recommendations are based on limited data. Methods: Analysis of 379 GNP episodes in 308 children (median age 6.9 years, interquartile range [IQR]: 3.0-13.6) from 45 centers in 28 countries reported to the International Pediatric Peritoneal Dialysis Network registry between 2011 and 2023. Results: Overall, 74% of episodes responded well to empiric therapy and full functional recovery (FFR) was achieved in 82% of cases. In vitro bacterial susceptibility to empiric antibiotics and lack of severe abdominal pain at onset were associated with a good initial response. Risk factors for failure to achieve FFR included severe abdominal pain at onset and at 60 to 72 hours from treatment initiation (odds ratio [OR]: 3.81, 95% confidence interval [CI]: 2.01-7.2 and OR: 3.94, 95% CI: 1.06-14.67, respectively), Pseudomonas spp. etiology (OR: 1.73, 95% CI: 1.71-4.21]) and in vitro bacterial resistance to empiric antibiotics (OR: 2.40, 95% CI: 1.21-4.79); the risk was lower with the use of monotherapy as definitive treatment (OR: 0.40, 95% CI: 0.21-0.77). Multivariate analysis showed no benefit of dual antibiotic therapy for treatment of Pseudomonas peritonitis after adjustment for age, presenting symptomatology, 60 to 72-hour treatment response, and treatment duration. Monotherapy with cefazolin in susceptible Enterobacterales peritonitis resulted in a similar FFR rate (91% vs. 93%) as treatment with ceftazidime or cefepime monotherapy. Conclusion: Detailed microbiological assessment, consisting of patient-specific and center-specific antimicrobial susceptibility data, should guide empiric treatment. Treatment "deescalation" with the use of monotherapy and narrow spectrum antibiotics according to susceptibility data is not associated with inferior outcomes and should be advocated in the context of emerging bacterial resistance.

Renal and Extrarenal Phenotypes in Patients With HNF1B Variants and Chromosome 17q12 Microdeletions.

Introduction: Hepatocyte nuclear factor 1-beta (HNF1B) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease. Methods: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype (HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia. Results: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19-0.44, P < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POUh) DNA-binding and transactivation domains rather than the POU-specific domain (POUs) DNA-binding domain (HR: 0.15 [95% CI: 0.06-0.37), P < 0.001 and HR: 0.25 (95% CI: 0.11-0.57), P = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia. Conclusion: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POUs DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling.

Cardiovascular rhythmicity in overweight and obese children / Ritmicidade cardiovascular em crianças com sobrepeso e obesidade

Abstract Introduction: Obesity is thought to play a role in the disruption of cardiac rhythmicity in obese children, but this is mostly an unexplored field of investigation. We aimed to evaluate the impact of overweight and obesity on circadian and ultradian cardiovascular rhythmicity of prepubertal children, in comparison with normal weight counterparts. Methods: We performed a cross sectional study of 316 children, followed in the birth cohort Generation XXI (Portugal). Anthropometrics and 24-hour ambulatory blood pressure were measured and profiles were examined with Fourier analysis for circadian and ultradian blood pressure (BP) and heart rate (HR) rhythms. Results: Overweight/obese children presented more frequently a non-dipping BP pattern than normal weight counterparts (31.5% vs. 21.6%, p = 0.047). The prevalence of 24-hour mean arterial pressure (MAP) and 8-hour HR rhythmicity was significantly lower in obese children (79.3% vs. 88.0%, p = 0.038 and 33.3% vs. 45.2%, p = 0.031, respectively). The prevalence of the remaining MAP and HR rhythmicity was similar in both groups. No differences were found in the median values of amplitudes and acrophases of MAP and HR rhythms. Discussion: The alterations found in rhythmicity suggest that circadian and ultradian rhythmicity analysis might be sensitive in detecting early cardiovascular dysregulations, but future studies are needed to reinforce our findings and to better understand their long-term implications.

Resumo Introdução: Acredita-se que a obesidade desempenhe um papel na desregulação da ritmicidade cardíaca em crianças obesas, mas esse é um campo de investigação ainda pouco explorado. O objetivo deste trabalho foi avaliar o impacto do sobrepeso e da obesidade na ritmicidade cardiovascular circadiana e ultradiana de crianças pré-púberes, em comparação com crianças com peso normal. Métodos: Realizamos um estudo transversal com 316 crianças, acompanhadas na coorte de nascimentos Geração XXI (Portugal). Foram medidos dados antropométricos e a pressão arterial ambulatorial de 24 horas, e os perfis foram examinados com uma análise de Fourier para ritmos circadianos e ultradianos de pressão arterial (PA) e frequência cardíaca (FC). Resultados: Crianças com sobrepeso/obesidade apresentaram mais frequentemente um padrão de PA não-dipper em comparação com crianças com peso normal (31,5% vs. 21,6%; p = 0,047). A prevalência da pressão arterial média (PAM) de 24 horas e da ritmicidade da FC de 8 horas foi significativamente menor em crianças obesas (79,3% vs. 88,0%; p = 0,038 e 33,3% vs. 45,2%; p = 0,031, respectivamente). A prevalência das restantes ritmicidades da PAM e da FC foi semelhante em ambos os grupos. Não foram encontradas diferenças nos valores medianos das amplitudes e acrofases dos ritmos de PAM e FC. Discussão: As alterações encontradas na ritmicidade sugerem que a análise da ritmicidade circadiana e ultradiana pode ser sensível na detecção de desregulações cardiovasculares precoces, mas são necessários novos estudos para reforçar nossos achados e entender melhor suas implicações a longo prazo.

Persistence of behavioral abnormalities following corticosteroid therapy in children with initial episode of idiopathic nephrotic syndrome: a prospective longitudinal observation / Persistência de anormalidades comportamentais após corticoterapia em crianças com episódio inicial de síndrome nefrótica idiopática: uma observação longitudinal prospectiva

Abstract Introduction: Treatment of nephrotic syndrome with corticosteroid can cause several side- effects including behavioral abnormalities. The objectives of the study were to observe the proportion of non-relapsers having persistence of behavioral abnormalities after completion of treatment of initial episode and compare the abnormalities with relapsers, and to determine risk factors for persistence. Methods: Seventy-five children with a first episode of idiopathic nephrotic syndrome and 60 normal children were rated by parents for behavioral problems using the Child Behavior Checklist. The Parenting Stress Index was also evaluated. The children were rated before treatment and 12 and 36 weeks after. Results: Both relapsers and non-relapsers showed abnormalities in internalizing and externalizing domains at 12 weeks of steroid therapy. Non-relapsers had abnormal scores in the internalizing domain in 63.5 % and externalizing domain in 48.1% of cases at 36 weeks. Relapsers had abnormal scores in all the three behavior domains, but a significantly higher proportion of relapsers had abnormal scores regarding total behavior (65.2% vs 28.8%, p<0.01) and child domains (100% vs 57.7%, p<0.001) of Parenting Stress Index in comparison to non-relapsers at 36 weeks. Occurrence of relapse increased the risk (odds ratio 5.76, 95% CI 1.35-10.76, p< 0.001) for persistence of abnormal total behavior at 36 weeks follow-up. Conclusion: Persistence of abnormalities was observed not only in relapsers but also in non-relapsers. Relapse was found to be a significant risk factor for persistence of abnormal behaviors in these patients.

Resumo Introdução: O tratamento da síndrome nefrótica com corticosteroide pode causar vários efeitos colaterais, incluindo anormalidades comportamentais. Os objetivos do estudo foram observar a proporção de não-recidivos com persistência de anormalidades comportamentais após conclusão do tratamento do episódio inicial, comparar as anormalidades com os recidivos, e determinar fatores de risco para persistência. Métodos: 75 crianças com primeiro episódio de síndrome nefrótica idiopática e 60 crianças normais foram avaliadas pelos pais por problemas comportamentais usando o Checklist de Comportamento Infantil. O Índice de Estresse Parental também foi avaliado. As crianças foram avaliadas antes do tratamento, 12 e 36 semanas após. Resultados: Tanto recidivos quanto não recidivos mostraram anormalidades nos domínios de internalização e externalização às 12 semanas de terapia com esteroides. Não-recidivos apresentaram pontuações anormais no domínio de internalização em 63,5%, e no domínio de externalização, em 48,1% dos casos em 36 semanas. Recidivos tiveram pontuações anormais em todos os três domínios de comportamento, mas uma proporção significativamente maior de recidivos apresentou pontuações anormais em relação ao comportamento total (65,2% vs 28,8%, p<0,01) e domínios infantis (100% vs 57,7%, p<0,001) do Índice de Estresse Parental em comparação com não recidivos às 36 semanas. A ocorrência de recidiva aumentou o risco (odds ratio 5,76, 95% IC 1,35-10,76, p< 0,001) de persistência de comportamento total anormal em 36 semanas de acompanhamento. Conclusão: A persistência de anormalidades foi observada não apenas em recidivos, mas também em não recidivos. A recidiva foi um fator de risco significativo para a persistência de comportamentos anormais nesses pacientes.

Evitando o legado da doença renal - Foco na infância / Averting the legacy of kidney disease-focus on childhood

Resumo O Dia Mundial do Rim de 2016 estará focado na doença renal na infância e os antecedentes da doença renal no adulto ,que pode começar na mais tenra infância. A doença renal crônica (DRC) na infância é diferente daquela dos adultos, como o maior grupo de diagnóstico entre as crianças inclui anomalias congênitas e doenças hereditárias, com glomerulopatias e doença renal com diabetes sendo relativamente incomum. Além disso, muitas crianças com lesão renal aguda acabarão por desenvolver sequelas que podem levar à hipertensão e doença renal crônica mais tarde na infância ou na idade adulta. As crianças nascidas precoces ou aquelas que nascem pequenas para a idade gestacional têm relativamente maior risco de desenvolver DRC mais tarde na vida. As pessoas com parto de alto risco e história no início da infância devem ser acompanhadas de perto, a fim de se detectar sinais precoces da doença renal em tempo hábil, para submetê-las à prevenção ou tratamento eficaz. O tratamento pode ser bem-sucedido para DRC avançada na infância; há evidência de que as crianças se saem bem melhor do que os adultos, se receberem terapia de substituição renal, incluindo diálise e transplante, enquanto que apenas uma minoria das crianças podem necessitar desse último. Uma vez que existem disparidades no acesso aos cuidados de saúde, é necessário um esforço de modo a que as crianças com doença renal, onde quer que morem, possam ser tratadas de forma eficaz, independentemente das suas circunstâncias geográficas ou econômicas. Nossa esperança é que o Dia Mundial do Rim, leve informação ao público em geral, aos formuladores de políticas públicas e cuidadores sobre as necessidades e possibilidades que cercam a doença renal na infância.

Abstract World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early or who are small-for date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, while only a minority of children may require this ultimate intervention Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy makers and caregivers about the needs and possibilities surrounding kidney disease in childhood.

Día mundial del riñón 2016, evitando el legado de la enfermedad renal, con enfoque en la niñez / World kidney day 2016, "adverting the legacy of kidney disease, focus on childhood

El Día Mundial del Riñón 2016 se enfoca en las enfermedades renales durante la infancia y en los antecedentes de la enfermedad renal del adulto que puede iniciar en la edad temprana. La Enfermedad Renal Crónica (ERC) en la infancia difiere de la de los adultos en que predominan las causas derivadas de anomalías congénitas y trastornos hereditarios, siendo poco frecuentes las glomerulopatías y la enfermedad renal asociada a diabetes. Adicionalmente, muchos niños con Injuria Renal Aguda pueden eventualmente desarrollar secuelas que lleven a hipertensión y ERC durante la adolescencia o la vida adulta. Los niños nacidos prematuros o pequeños para la edad gestacional tienen un incremento del riesgo para desarrollar ERC durante su vida. Personas con alto riesgo al nacer o en la primera infancia, deberán ser monitorizadas estrechamente para ayudar a detectar a tiempo signos tempranos de enfermedad renal a fin de proporcionar una prevención o tratamiento efectivos. Una terapia exitosa es factible para niños con ERC avanzada; existe evidencia que demuestra que los niños evolucionan mejor que los adultos cuando reciben terapia de reemplazo renal, incluyendo diálisis y trasplante, aunque solo una minoría de los niños puede requerir este tratamiento. Debido a las inequidades en el acceso a la atención médica, es necesario hacer un esfuerzo para que los niños con enfermedad renal, donde sea que vivan, puedan ser tratados de manera eficaz, independientemente de su ubicación geográfica y situación y económica. Nuestra esperanza es que el Día Mundial del Riñón pueda informar al público en general, a los tomadores de decisiones y a los profesionales de la salud, sobre las necesidades y las posibilidades que existen alrededor de la enfermedad renal en la infancia

World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the lar- gest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early or who are small-for date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, while only a minority of children may require this ultimate intervention Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy makers and caregivers about the needs and possibilities surrounding kidney disease in childhood