Urine soluble TLR4 levels may contribute to predict urinary tract infection in children: the UTILISE Study.

BACKGROUND: One of the most common bacterial infections in childhood is urinary tract infection (UTI). Toll-like receptors (TLRs) contribute to immune response against UTI recognizing specific pathogenic agents. Our aim was to determine whether soluble TLR4 (sTLR4), soluble TLR5 (sTLR5) and interleukin 8 (IL-8) can be used as biomarkers to diagnose UTI. We also aimed to reveal the relationship between urine Heat Shock Protein 70 (uHSP70) and those biomarkers investigated in this study. METHODS: A total of 802 children from 37 centers participated in the study. The participants (n = 282) who did not meet the inclusion criteria were excluded from the study. The remaining 520 children, including 191 patients with UTI, 178 patients with non-UTI infections, 50 children with contaminated urine samples, 26 participants with asymptomatic bacteriuria and 75 healthy controls were included in the study. Urine and serum levels of sTLR4, sTLR5 and IL-8 were measured at presentation in all patients and after antibiotic treatment in patients with UTI. RESULTS: Urine sTLR4 was higher in the UTI group than in the other groups. UTI may be predicted using 1.28 ng/mL as cut-off for urine sTLR4 with 68% sensitivity and 65% specificity (AUC = 0.682). In the UTI group, urine sTLR4 levels were significantly higher in pyelonephritis than in cystitis (p < 0.0001). Post-treatment urine sTLR4 levels in the UTI group were significantly lower than pre-treatment values (p < 0.0001). CONCLUSIONS: Urine sTLR4 may be used as a useful biomarker in predicting UTI and subsequent pyelonephritis in children with UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Overt Hypothyroidism and Severe Growth Retardation in a Preschool Girl with Poorly Controlled Nephrotic Syndrome: Case Report and Literature Review.

Background: Nephrotic children may develop thyroid hormone dysfunction due to urinary excretion of thyroid hormones. In contrast to the subclinical hypothyroidism that affects around 30% of children with nephrotic syndrome (NS), the patient in this case had overt hypothyroidism and severe growth retardation. Clinical case: A 5 years and 8 months old girl with steroid-dependent NS was referred from another center due to persistent edema and decreased diuresis, being treated with mycophenolate mofetil (MMF) 250 mg once a day and L-thyroxine 50 mcg daily since 4 months of NS onset because of hypothyroidism. Her albumin was 12.64 g/l, cholesterol 25.64 mmol/l and proteinuria 5 g/l. Severe growth retardation was observed: patient's height was 93.5 cm (-13 cm <3 percentile), weighted 17.2 kg (15-25 percentile). Her disease vintage was over 3 years. Girl's growth velocity has slowed down from 3.5 months. The patient received a high cumulative dose of prednisolone (approx. 7800 mg in 1 year and 8 months). Thyroid-stimulating hormone was higher (18.04 mU/L) with reduced FT4 11.43 pmol/l and IGF-1 < 15 µg/L. Kidney biopsy revealed minimal change disease, and genetic testing was negative. Intensive NS treatment with methylprednisolone pulse therapy, enlarged doses of MMF and albumin infusion were started and L-thyroxine dose was increased to 75 mcg. TPOAb was in normal range (12.65 IU/ml). After 3 weeks she was discharged with no edema and after stopping methylprednisolone treatment thyroid function normalized and L-thyroxin was discontinued. Two weeks later standard growth hormone stimulation test with clonidine showed partially insufficient growth hormone secretion. During NS remission with normalization of thyroid function (TSH 6.680 mU/l, FT4 13.85 pmol/l) and normalization of IGF-1 level (132 mcg/l) partial catch-up growth was observed (height velocity increased from 3.5 cm/year to 7.3 cm/year, based on 4-month calculation period). Conclusions: Clinicians should be aware of a risk of developing hypothyroidism and consider thyroid function testing during the treatment of children with NS, as well as actively treat hypothyroidism and evaluate growth.

Case Report: SARS-CoV-2 Associated Acute Interstitial Nephritis in an Adolescent.

Acute interstitial nephritis (AIN) has been recently recognized as one of the infrequent kidney involvement phenotypes among adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although SARS-CoV-2 associated intrinsic kidney disease has been scarcely reported in children, only one case of AIN temporally associated with the infection has been described in the pediatric population so far. We presented a case of a 12-year old boy who presented with fatigue, anorexia, and polydipsia following an RT-PCR that confirmed SARS-CoV-2 infection seven weeks prior to admission. Initial workup revealed increased serum creatinine (235 µmol/L), glucosuria, low-molecular-weight proteinuria, mild leukocyturia, and microhematuria with hyaline and granular casts on microscopy. Antibodies against the SARS-CoV-2 S protein receptor-binding domain confirmed prior infection with high titers. Kidney biopsy showed diffuse active interstitial nephritis with negative immunofluorescence and positive immunohistochemistry for SARS-CoV-2 in the inflammatory cells within the interstitium. Electron microscopy revealed several SARS-CoV-2-like particles. Kidney function continued to deteriorate despite several days of supportive therapy only (peak serum creatinine 272 µmol/L); thus, treatment with methylprednisolone pulse-dose therapy was initiated and was followed by oral prednisolone with gradual tapering. Kidney function completely recovered after 3 weeks post-discharge and remained normal after 11 weeks of follow-up (last estimated glomerular filtration rate 106 ml/min/1.73 m2) with only residual microhematuria. Our case adds to the emerging evidence of SARS-CoV-2 as a potential etiological agent of AIN in children and also suggests that interstitial kidney injury may result from secondary inflammatory damage. Epidemiological history, serologic testing, and SARS-CoV-2 detection in biopsy should be considered in the work-up of children with AIN of unknown etiology.

Identification of 27 Novel Variants in Genes COL4A3, COL4A4, and COL4A5 in Lithuanian Families With Alport Syndrome.

Introduction: Alport syndrome (AS) is an inherited disorder characterized by hematuria, proteinuria, and kidney function impairment, and frequently associated with extrarenal manifestations. Pathogenic variants in COL4A5 usually cause X-linked Alport syndrome (XLAS), whereas those in the COL4A3 or COL4A4 genes are associated with autosomal dominant (AD) or recessive (AR) inheritance. To date, more than 3000 different disease-causing variants in COL4A5, COL4A3, and COL4A4 have been identified. The aim of this study was to evaluate the clinical and genetic spectrum of individuals with novel, pathogenic or likely pathogenic variants in the COL4A3-A5 genes in a previously unstudied cohort. Methods: In this study molecular analysis by next generation sequencing (NGS) was performed on individuals from a Lithuanian cohort, with suspected AS. The presence of AS was assessed by reviewing clinical evidence of hematuria, proteinuria, chronic kidney disease (CKD), kidney failure (KF), a family history of AS or persistent hematuria, and specific histological lesions in the kidney biopsy such as thinning or lamellation of the glomerular basement membrane (GBM). Clinical, genetic, laboratory, and pathology data were reviewed. The novelty of the COL4A3-A5 variants was confirmed in the genetic variant databases (Centogene, Franklin, ClinVar, Varsome, InterVar). Only undescribed variants were included in this study. Results: Molecular testing of 171 suspected individuals led to the detection of 99 individuals with 44 disease causing variants including 27, previously undescribed changes, with the frequency of 9/27 (33,3%) in genes COL4A5, COL4A3 and COL4A4 equally. Three individuals were determined as having digenic AS causing variants: one in COL4A3 and COL4A4, two in COL4A4 and COL4A5. The most prevalent alterations in genes COL4A3-5 were missense variants (n = 19), while splice site, frameshift, unknown variant and stop codon changes were detected more in genes COL4A4 and COL4A5 and accounted for 3, 3, 1 and 1 of all novel variants, respectively. Conclusion: Genotype-phenotype correlation analysis suggested that some variants demonstrated intra-familial phenotypic variability. These novel variants represented more than half of all the variants found in a cohort of 171 individuals from 109 unrelated families who underwent testing. Our study expands the knowledge of the genetic and phenotypic spectrum for AS.

Obesity and Eating Disorders in Children and Adolescents: The Bidirectional Link.

Obesity, eating disorders and unhealthy dieting practices among children and adolescents are alarming health concerns due to their high prevalence and adverse effects on physical and psychosocial health. We present the evidence that eating disorders and obesity can be managed or prevented using the same interventions in the pediatric age. In the presence of obesity in the pediatric age, disordered eating behaviors are highly prevalent, increasing the risk of developing eating disorders. The most frequently observed in subjects with obesity are bulimia nervosa and binge-eating disorders, both of which are characterized by abnormal eating or weight-control behaviors. Various are the mechanisms overlying the interaction including environmental and individual ones, and different are the approaches to reduce the consequences. Evidence-based treatments for obesity and eating disorders in childhood include as first line approaches weight loss with nutritional management and lifestyle modification via behavioral psychotherapy, as well as treatment of psychiatric comorbidities if those are not a consequence of the eating disorder. Drugs and bariatric surgery need to be used in extreme cases. Future research is necessary for early detection of risk factors for prevention, more precise elucidation of the mechanisms that underpin these problems and, finally, in the cases requiring therapeutic intervention, to provide tailored and timely treatment. Collective efforts between the fields are crucial for reducing the factors of health disparity and improving public health.

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD.

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

The European Rare Kidney Disease Registry (ERKReg): objectives, design and initial results.

BACKGROUND: The European Rare Kidney Disease Reference Network (ERKNet) recently established ERKReg, a Web-based registry for all patients with rare kidney diseases. The main objectives of this core registry are to generate epidemiological information, identify current patient cohort for clinical research, explore diagnostic and therapeutic management practices, and monitor treatment performance and patient's outcomes. The registry has a modular design that allows to integrate comprehensive disease-specific registries as extensions to the core database. The diagnosis (Orphacode) and diagnostic information (clinical, imaging, histopathological, biochemical, immunological and genetic) are recorded. Anthropometric, kidney function, and disease-specific management and outcome items informing a set of 61 key performance indicators (KPIs) are obtained annually. Data quality is ensured by automated plausibility checks upon data entry and regular offline database checks prompting queries. Centre KPI statistics and benchmarking are calculated automatically. RESULTS: Within the first 24 months since its launch, 7607 patients were enrolled to the registry at 45 pediatric and 12 specialized adult nephrology units from 21 countries. A kidney disease diagnosis had been established in 97.1% of these patients at time of enrolment. While 199 individual disease entities were reported by Orphacode, 50% of the cohort could be classified with 11, 80% with 43 and 95% with 92 codes. Two kidney diagnoses were assigned in 6.5% of patients; 5.9% suffered from syndromic disease. Whereas glomerulopathies (54.8%) and ciliopathies including autosomal dominant polycystic kidney disease (ADPKD) (31.5%) were the predominant disease groups among adults, the pediatric disease spectrum encompassed congenital anomalies of the kidney and urinary tract (CAKUT) (33.7%), glomerulopathies (30.7%), ciliopathies (14.0%), tubulopathies (9.2%), thrombotic microangiopathies (5.6%), and metabolic nephropathies (4.1%). Genetically confirmed diagnoses were reported in 24% of all pediatric and 12% adult patients, whereas glomerulopathies had been confirmed by kidney biopsy in 80.4% adult versus 38.5% pediatric glomerulopathy cases. CONCLUSIONS: ERKReg is a rapidly growing source of epidemiological information and patient cohorts for clinical research, and an innovative tool to monitor management quality and patient outcomes.

Reverse Phenotyping Maternal Cystic Kidney Disease by Diagnosis in a Newborn: Case Report and Literature Review on Neonatal Cystic Kidney Diseases.

Kidney cysts are the most common kidney lesion, while congenital kidney cysts are mostly found in pediatric population. Neonatal kidney cysts can develop due to fetal malformations, rare genetic disorders or can be acquired which is very rare. Kidney cysts may be the only isolated finding or be part of the overall phenotype. They can be asymptomatic, found by ultrasound accidentally or can manifest from mild to life-threatening symptoms. Therefore, early diagnosis is very important. Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the most common causes of kidney cysts in the neonatal population. This review highlights the most common kidney cystic diseases during the neonatal period and a rare clinical case of HNF1B-associated disease.

Phenotypes and Baseline Risk Factors of Acute Kidney Injury in Children After Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Acute kidney injury (AKI) is a frequent and widely recognized complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite relatively high prevalence, AKI after allo-HSCT and its risk factors in children remain obscure. The aim of this study was to describe the prevalence and course of AKI during the first 100 days after allo-HSCT in children and to investigate its associations with baseline characteristics. Methods: Retrospective single-center chart review of all patients under 18 who underwent allo-HSCT during 2011-2017 was performed. AKI was defined using the pediatric RIFLE criteria and only the patients with pRIFLE stage I (eGFR decrease by 50% or more) or higher were considered for the analysis. Recurrent AKI and acute kidney disease (AKD) were defined according to the Acute Disease Quality Initiative consensus. Demographic, clinical, and procedure-related characteristics were recorded at the day of HSCT. Results: Fifty-one patients (68.6% boys) with a median age of 9 years (range: 0.25-17) were included. During a median follow-up of 82 (IQR, 60-98) days, 27 (52.9%) patients experienced a total of 39 AKI episodes, translating into one AKI episode per 100 patient days. Multiple AKIs occurred in 11 (21.6%) patients and 18 (35.3%) progressed to AKD. Four patients died, all with ongoing or previous AKI. Patients with AKD were, on average, older (10 vs. 6 years; p = 0.03) and had higher baseline body mass index (BMI) [standard deviation score (SDS) 0.83 vs. 0.04, p = 0.05], whereas patients with recurrent AKI had higher baseline estimated glomerular filtration rate (eGFR) (244.1 vs. 193.9 ml/min/1.73 m2, p = 0.02). In the adjusted Cox models (HR; 95% CI), older age (1.10; 1.01-1.20) was associated with higher risk of overall AKI and higher eGFR (1.02; 1.01-1.04) was associated with higher risk of recurrent AKI, while older age (1.17; 1.04-1.31), higher eGFR (HR 1.01; 1.0-1.02), and higher BMI SDS (1.66; 1.01-2.72) were associated with higher risk of AKD. Conclusions: AKI is a frequent early complication of allo-HSCT in children, and approximately one fifth experience AKI recurrence and one third develop AKD. Older age, higher BMI, and higher eGFR at the day of transplant may have an effect on the risk of AKI development and its course.

Acute dialysis in children: results of a European survey.

The number of children with acute kidney injury (AKI) requiring dialysis is increasing. To date, systematic analysis has been largely limited to critically ill children treated with continuous renal replacement therapy (CRRT). We conducted a survey among 35 European Pediatric Nephrology Centers to investigate dialysis practices in European children with AKI. Altogether, the centers perform dialysis in more than 900 pediatric patients with AKI per year. PD and CRRT are the most frequently used dialysis modalities, accounting for 39.4% and 38.2% of treatments, followed by intermittent HD (22.4%). In units treating more than 25 cases per year and in those with cardiothoracic surgery programs, PD is the most commonly chosen dialysis modality. Also, nearly one quarter of centers, in countries with a gross domestic product below $35,000/year, do not utilize CRRT at all. Dialysis nurses are exclusively in charge of CRRT management in 45% of the cases and pediatric intensive care nurses in 25%, while shared management is practiced in 30%. In conclusion, this survey indicates that the choice of treatment modalities for dialysis in children with AKI in Europe is affected by the underlying ethiology of the disease, organization/set-up of centers and socioeconomic conditions. PD is utilized as often as CRRT, and also intermittent HD is a commonly applied treatment option. A prospective European AKI registry is planned to provide further insights on the epidemiology, management and outcomes of dialysis in pediatric AKI.

Iron deficiency anemia-related gut microbiota dysbiosis in infants and young children: A pilot study.

Nutritional iron deficiency (ID) causes not only anemia but also malfunction of the entire human organism. Recently, a role of the gut microbiota has been hypothesized, but limited data are available especially in infants. Here, we performed a pilot study to explore the gut microbiota in 10 patients with iron deficiency anemia (IDA) and 10 healthy controls aged 6-34 months. Fresh stool samples were collected from diapers, and the fecal microbiota was profiled by next-generation sequencing of the V3-V4 hypervariable region of the 16S rRNA gene. Except for diet diversity, the breastfeeding status at the enrollment, the exclusive breastfeeding duration, and the introduction of complementary foods did not differ between groups. Distinct microbial signatures were found in IDA patients, with increased relative abundance of Enterobacteriaceae (mean relative abundance, patients vs. controls, 4.4% vs. 3.0%) and Veillonellaceae (13.7% vs. 3.6%), and reduced abundance of Coriobacteriaceae (3.5% vs. 8.8%) compared to healthy controls. A decreased Bifidobacteriaceae/Enterobacteriaceae ratio was observed in IDA patients. Notwithstanding the low sample size, our data highlight microbiota dysbalance in IDA worth for further investigations, aimed at unraveling the ID impact on the microbiome trajectory in early life, and the possible long-term consequences.

Renal Replacement Therapy in Children in Lithuania: Challenges, Trends, and Outcomes.

Background and Objectives: Pediatric renal replacement therapy (RRT) in Lithuania resumed in 1994 after a 12-year pause in renal transplantation. Management of end stage renal disease (ESRD) has changed, and outcomes have improved over decades. Our aim was to evaluate the dynamics of RRT in Lithuania in the period 1994⁻2015, describe its distinctive features, and compare our results with other countries. Materials and Methods: Data between 1994 and 2015 were collected from patients under the age of 18 years with ESRD receiving RRT. The data included: Hemodialysis (HD), peritoneal dialysis (PD), transplantation incidence and prevalence, transplant waiting time, dialysis modalities before transplantation, causes of ESRD and gender distribution in transplanted patients, and patient and graft survival. Results: RRT incidence and prevalence maintained an increase up until 2009. Sixty-four transplantations were performed. Juvenile nephronophthisis (25.9%) was the primary cause of ESRD in transplanted children. The transplant waiting time median was 8.0 months. The male to female ratio post-transplantation was 1.02. Patient survival after transplantation at 10 years was 90.0%, while graft survival for living (related) was 77.0% and 51.1% for deceased. Twelve patients died while on RRT. Conclusions: RRT numbers are increasing in Lithuania. HD is the primary treatment of choice before transplantation, with continued low numbers of preemptive transplantation. Patient survival post-transplantation is favorable, though graft survival is less satisfactory.

Assessment of Risk Factors for Iron Deficiency Anemia in Infants and Young Children: A Case-Control Study.

INTRODUCTION: Iron deficiency anemia (IDA) is common in children aged 0-35 months in Lithuania. Nevertheless, there are no studies investigating IDA in this age group. We aimed to identify the major risk factors for disease development focusing on medical history and dietary habits. METHODS: A prospective case-control study was conducted in a university hospital. The enrolled cohort was divided into three groups: IDA infants (IDA-In; n = 36, aged 3-11 months), IDA children (IDA-Ch; n = 23, aged 12-32 months), and healthy controls (HCs; n = 32, aged 6-34 months). RESULTS: There was a higher number of premature, low birth weight (LBW), and faster gaining weight infants in the IDA-In group. Their diet diversity was lower than IDA-Ch and HC. In contrast, the IDA-Ch group had no signs of impaired iron stores at birth or higher iron need for fast growth; their diet diversity was similar to that of HC, but meat was introduced later as compared with those in the IDA-In and HC groups. Consumption of cow's milk was rather low among all study participants, but consumption of sugar-added products was found to be a new emerging problem. Exclusive breastfeeding did not differ in duration and prevalence; the age for introduction of complementary foods was similar in all groups. CONCLUSIONS: Low compliance with World Health Organization (WHO) recommendations on breastfeeding and complementary feeding suggests an urgent need for nutritional counseling in early childhood, especially in premature, LBW, and fast gaining weight infants.

Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease.

OBJECTIVE: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. STUDY DESIGN: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life. RESULTS: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys. CONCLUSIONS: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD.

Prevalence of Hypertension in Children with Early-Stage ADPKD.

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 <18 years old. Basic anthropometric parameters as well as data on kidney function, BP treatment, and kidney ultrasound were also collected. RESULTS: Data from 310 children with autosomal dominant polycystic kidney disease with a mean age of 11.5±4.1 years old were collected at 22 European centers. At the time when ambulatory BP monitoring was performed, 95% of children had normal kidney function. Reference data for ambulatory BP monitoring were available for 292 patients. The prevalence rates of children with hypertension and/or those who were treated with antihypertensive drugs were 31%, 42%, and 35% during daytime, nighttime, or the entire 24-hour cycle, respectively. In addition, 52% of participants lacked a physiologic nocturnal BP dipping, and 18% had isolated nocturnal hypertension. Logistic regression analysis showed a significant association between a categorical cyst score that was calculated on the basis of the number of cysts >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.

De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease.

BACKGROUND: Darbepoetin alfa is a commonly prescribed erythropoiesis-stimulating agent (ESA) for correcting anemia in pediatric chronic kidney disease (CKD) patients. However, little information exists on its use in ESA-naïve patients. This study evaluated the efficacy and safety of darbepoetin alfa in pediatric patients initiating ESA therapy. METHODS: One-hundred sixteen pediatric ESA-naïve subjects (aged 1-18 years) with CKD stages 3-5D and hemoglobin (Hb) <10 g/dl from 43 centers in the US, Europe, and Mexico were randomized by age (three groups) and dialysis status (yes vs. no) to receive darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) subcutaneously (not on dialysis and peritoneal dialysis subjects) and intravenously (hemodialysis subjects). The drug was titrated to achieve Hb levels of 10.0-12.0 g/dl over 25 weeks. Patient- and parent-reported health-related outcomes were measured by the Pediatric Quality of Life Inventory (PedsQL™) in children ≥2 years. RESULTS: In both groups, mean Hb concentrations increased to ≥11.0 g/dl over the first 3 months of treatment and remained stable within the 10.0-12.0 g/dl target range. The median time to achieve hemoglobin ≥10 g/dl was slightly longer for subjects <12 years (QW and Q2W, both 28 days) vs. those ≥12 years (23 and 22 days, respectively). Adverse event profiles were similar between groups, with QW, four (7%) and Q2W, five (9%). PedsQL™ scores showed modest increases. CONCLUSIONS: Darbepoetin alfa can be safely administered either QW or Q2W to ESA-naïve pediatric patients with CKD-related anemia to achieve Hb targets of 10.0-12.0 g/dl.

Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children.

Importance: Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C-derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults. Objective: To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD. Design, Setting, and Participants: Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016. Exposures: Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73 m2, or initiation of renal replacement therapy. Main Outcomes and Measures: The primary end point in this study was renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73 m2. Results: Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73 m2. The 5-year end point-free renal survival was 64.5% (95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9% (95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P = .007). Conclusions and Relevance: Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD.

The impact of IgM deposits on the outcome of Nephrotic syndrome in children.

BACKGROUND: The significance of IgM deposits in glomerular mesangium has been controversial since they were first described due to the variations in the both the definitions used and described impact on clinical outcome. The aim of our study was to evaluate the significance of the IgM deposits in the glomerular mesangium for outcomes of nephrotic syndrome (NS) in children. METHODS: Forty-five children with NS who underwent renal biopsy at tertiary pediatric hospital from January 1st, 2000 to December 31st, 2015 and the pathology diagnosis of minimal change disease, focal segmental glomerulosclerosis and mesangial hypercellularity (MH) were retrospectively analyzed. IgM positivity was defined as ≥1+ imunofluorescence with predominantly mesangial distribution. The patients were stratified into IgM-positive (n = 18) and IgM-negative (n = 27). RESULTS: At the end of the median follow-up 4.5 years (range 0.17-13.14), the IgM-positive group was represented by 11 patients (61.1%) in remission, 3 patients (16.7%) with active disease and normal kidney function, 2 (11.1%) patients with active disease and impaired kidney function, 2 (11.1%) patients on renal replacement therapy. Accordingly, the IgM-negative group included 13 patients (48.1%) in remission, 12 (44.4%) with active disease and normal kidney function, 1 (3.7%) with active disease and impaired kidney function, 1 (3.7%) on renal replacement therapy, with no statistical significance between groups (p = 0.186). CONCLUSIONS: This study did not reveal significant differences of the disease outcomes between IgM-positive and IgM-negative groups.

Metabolic acidosis is common and associates with disease progression in children with chronic kidney disease.

Recent studies in adult chronic kidney disease (CKD) suggest that metabolic acidosis is associated with faster decline in estimated glomerular filtration rate (eGFR). Alkali therapies improve the course of kidney disease. Here we investigated the prevalence and determinants of abnormal serum bicarbonate values and whether metabolic acidosis may be deleterious to children with CKD. Associations between follow-up serum bicarbonate levels categorized as under 18, 18 to under 22, and 22 or more mmol/l and CKD outcomes in 704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of pediatric patients with CKD stages 3-5, were studied. The eGFR and serum bicarbonate were measured every six months. At baseline, the median eGFR was 27 ml/min/1.73m2 and median serum bicarbonate level 21 mmol/l. During a median follow-up of 3.3 years, the prevalence of metabolic acidosis (serum bicarbonate under 22 mmol/l) was 43%, 60%, and 45% in CKD stages 3, 4, and 5, respectively. In multivariable analysis, the presence of metabolic acidosis as a time-varying covariate was significantly associated with log serum parathyroid hormone through the entire follow-up, but no association with longitudinal growth was found. A total of 211 patients reached the composite endpoint (ESRD or 50% decline in eGFR). In a multivariable Cox model, children with time-varying serum bicarbonate under 18 mmol/l had a significantly higher risk of CKD progression compared to those with a serum bicarbonate of 22 or more mmol/l (adjusted hazard ratio 2.44; 95% confidence interval 1.43-4.15). Thus, metabolic acidosis is a common complication in pediatric patients with CKD and may be a risk factor for secondary hyperparathyroidism and kidney disease progression.