Publications by authors named "Ludmila Podracka"

38 Publications

Oxidative status in plasma, urine and saliva of girls with anorexia nervosa and healthy controls: a cross-sectional study.

J Eat Disord 2021 Apr 21;9(1):54. Epub 2021 Apr 21.

Department of Paediatrics, The National Institute of Children's Diseases and Faculty of Medicine, Comenius University, Limbová 1, 83340, Bratislava, Slovakia.

Background: Anorexia nervosa (AN) is a serious psychosomatic disorder with unclear pathomechanisms. Metabolic dysregulation is associated with disruption of redox homeostasis that might play a pivotal role in the development of AN. The aim of our study was to assess oxidative status and carbonyl stress in plasma, urine and saliva of patients with AN and healthy controls.

Methods: Plasma, spot urine, and saliva were collected from 111 girls with AN (aged from 10 to 18 years) and from 29 age-matched controls. Markers of oxidative stress and antioxidant status were measured using spectrophotometric and fluorometric methods.

Results: Plasma advanced oxidation protein products (AOPP) and advanced glycation end products (AGEs) were significantly higher in patients with AN than in healthy controls (by 96, and 82%, respectively). Accordingly, urinary concentrations of AOPP and fructosamines and salivary concentrations of AGEs were higher in girls with AN compared with controls (by 250, and 41% in urine; by 92% in saliva, respectively). Concentrations of thiobarbituric acid reactive substances (TBARS) in saliva were 3-times higher in the patients with AN than in the controls. Overall antioxidants were lower in plasma of girls with AN compared to the controls, as shown by total antioxidant capacity and ratio of reduced and oxidized glutathione (by 43, and 31%, respectively).

Conclusions: This is the first study assessing wide range of markers of oxidative status in plasma, urine and saliva of the patients with AN. We showed that both, higher levels of markers of oxidative stress and lower antioxidants play a role in redox disruption. Restoration of redox homeostasis might be of the clinical relevance.
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http://dx.doi.org/10.1186/s40337-021-00408-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059320PMC
April 2021

Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis.

Pediatr Nephrol 2021 Feb 26. Epub 2021 Feb 26.

Advicenne, Nîmes, France.

Background: A new prolonged-release formulation of potassium citrate and potassium bicarbonate, ADV7103, has been shown to improve metabolic control, palatability, and gastrointestinal safety in patients with distal renal tubular acidosis (dRTA) when compared to standard of care (SoC) treatments. The present work evaluates safety and efficacy of ADV7103 during 24 months.

Methods: Thirty pediatric and adult patients were included in an open-label extension study after a phase II/III trial. Safety and tolerability were assessed. Plasma bicarbonate and potassium levels, as well as urine parameters, were evaluated over time. Acceptability, adherence, and quality of life were also assessed. The evolution of clinical consequences of dRTA in the cohort was explored.

Results: There were 104 adverse events (AEs) reported, but only 9 gastrointestinal events observed in five patients (17%) were considered to be related to ADV7103 treatment. There were no AEs leading to treatment discontinuation. Plasma bicarbonate and potassium levels were in the normal ranges at the different visits, respectively, in 69-86% and 83-93% of patients. Overall adherence rates were ≥ 75% throughout the whole study in 79% patients. An average improvement of quality of life of 89% was reported at 24 months of study.

Conclusions: Common AEs concerned metabolism and gastrointestinal disorders; the former being related to the disease. Less than half of the gastrointestinal AEs were related to ADV7103 treatment and they were mostly mild in severity. Metabolic parameters were maintained in the normal ranges in most patients. Patient satisfaction was high and adherence to treatment was good and remained stable.

Trial Registration Number: Registered as EudraCT 2013-003828-36 on the 3rd of September 2013.
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http://dx.doi.org/10.1007/s00467-020-04873-0DOI Listing
February 2021

Dynamics of salivary markers of kidney functions in acute and chronic kidney diseases.

Sci Rep 2020 12 4;10(1):21260. Epub 2020 Dec 4.

Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08, Bratislava, Slovakia.

Saliva can be used as an alternative diagnostic fluid enabling easy and non-invasive disease monitoring. Urea and creatinine can be measured in saliva and both were shown to be increased in renal failure. However, the dynamics of these markers during the development of kidney diseases is unknown. We aimed to describe the dynamics of salivary urea and creatinine in various animal models of acute kidney injury (AKI) and chronic kidney disease (CKD) and in patients with different stages AKI or CKD. Ninety Wistar rats underwent bilateral nephrectomy (BNX), ischemia-reperfusion injury (IRI) or glycerol-induced kidney injury to model AKI. CKD was modelled using 5/6 nephrectomy. In the clinical part 57 children aged 12.6 ± 4.9 years with AKI (n = 11) or CKD (n = 46) and 29 healthy controls (aged 10.2 ± 3.7 years) were enrolled. Saliva and blood samples were collected in both, animal experiments and the human study. In animal models of AKI, plasma urea and creatinine were higher than in controls. An increase of salivary urea and creatinine (twofold) was observed in BNX and IRI, but only after 12 h and 24 h, respectively. In glycerol nephropathy and 5/6 nephrectomy, salivary urea increased (by 100% and by 50%), while salivary creatinine did not change during the observation period. Salivary urea and creatinine were significantly higher in all patients compared to controls (threefold) and in both, AKI and CKD they were associated with the severity of renal failure. Plasma and salivary concentrations correlated only in children with renal failure (R = 0.72 for urea; R = 0.93 for creatinine), but not in controls (R = -0.007 for urea; R = 0.02 for creatinine). Our study indicates that during the development of renal impairment saliva could be used for non-invasive monitoring in higher stages of AKI or CKD, rather than for screening of early stages of kidney diseases.
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http://dx.doi.org/10.1038/s41598-020-78209-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719178PMC
December 2020

Hypertensive crisis in an 11-year-old girl with kidney and inferior vena cava abnormalities and leg thrombosis: Questions.

Pediatr Nephrol 2020 Nov 20. Epub 2020 Nov 20.

Department of Pediatrics, Medical Faculty, Comenius University and National Institute of Children's Diseases, Limbova 1, 833 40, Bratislava, Slovakia.

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http://dx.doi.org/10.1007/s00467-020-04825-8DOI Listing
November 2020

Hypertensive crisis in an 11-year-old girl with kidney and inferior vena cava abnormalities and leg thrombosis: Answers.

Pediatr Nephrol 2020 Nov 20. Epub 2020 Nov 20.

Department of Pediatrics, Medical Faculty, Comenius University and National Institute of Children's Diseases, Limbova 1, 833 40, Bratislava, Slovakia.

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http://dx.doi.org/10.1007/s00467-020-04830-xDOI Listing
November 2020

Asymptomatic Hyperuricemia Associates with Cardiometabolic Risk Indicators in Overweight/Obese but Not in Lean Adolescents.

Diabetes Metab Syndr Obes 2020 27;13:3977-3992. Epub 2020 Oct 27.

Department of Pediatrics, Faculty of Medicine, Comenius University, Bratislava, Slovakia.

Purpose: In overweight/obese adolescents, asymptomatic hyperuricemia is associated with increased prevalence of metabolic syndrome, its components, and a higher cardiometabolic risk. Whether similar associations exist in lean hyperuricemic adolescents is unknown.

Subjects And Methods: In 2424 adolescents (51.9% females) aged 16-19 years, anthropometric variables, blood pressure, uric acid, glucose, insulin, lipid profile, inflammatory markers, and renal function were determined. Continuous cardiometabolic score was calculated. Normouricemic vs hyperuricemic subjects were compared among lean and overweight/obese individuals of both sexes.

Results: Females (5.4%) and males (13.3%) presented with hyperuricemia; among them 63% of females and 53% of males were lean. In both sexes, hyperuricemic lean and hyperuricemic overweight/obese adolescents displayed similar uric acid concentrations (eg, males: 455±30 vs 461±32 µmol/L, respectively, =0.933). Lean normouricemic adolescents manifested significantly lower uric acid levels than their overweight/obese peers (eg, males: 333±46 vs 357±41 µmol/L, respectively, <0.001). Lean normouricemic and hyperuricemic subjects presented similar cardiometabolic score (eg, males: 2.60±0.67 vs 2.64±0.60, respectively, =0.998); among overweight/obese adolescents those with hyperuricemia displayed higher scores compared with their normouricemic counterparts (eg, males: 3.36±1.04 vs 4.21±1.65, respectively, <0.001). A decision-tree model revealed phenotypes associated with higher uricemia, however, distribution of individuals with hyperuricemia among phenotypes was random.

Conclusion: In lean adolescents, hyperuricemia is not associated with cardiometabolic profile indicating an increased risk. Existence of this rather prevalent phenotype remains undetected unless lean and overweight/obese subjects are analyzed separately. Longitudinal studies are needed to elucidate the potential clinical consequences of asymptomatic hyperuricemia in lean subjects in later life.
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http://dx.doi.org/10.2147/DMSO.S267123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603647PMC
October 2020

A very early diagnosis of Alstrӧm syndrome by next generation sequencing.

BMC Med Genet 2020 09 1;21(1):173. Epub 2020 Sep 1.

MAGI's Lab, Genetic Testing Laboratory, Via Delle Maioliche 57/D, 38068, Rovereto, TN, Italy.

Background: Alström syndrome is a rare recessively inherited disorder caused by variants in the ALMS1 gene. It is characterized by multiple organ dysfunction, including cone-rod retinal dystrophy, dilated cardiomyopathy, hearing loss, obesity, insulin resistance, hyperinsulinemia, type 2 diabetes mellitus and systemic fibrosis. Heterogeneity and age-dependent development of clinical manifestations make it difficult to obtain a clear diagnosis, especially in pediatric patients.

Case Presentation: Here we report the case of a girl with Alström syndrome. Genetic examination was proposed at age 22 months when suspected macular degeneration was the only major finding. Next generation sequencing of a panel of genes linked to eye-related pathologies revealed two compound heterozygous variants in the ALMS1 gene. Frameshift variants c.1196_1202del, p.(Thr399Lysfs*11), rs761292021 and c.11310_11313del, (p.Glu3771Trpfs*18), rs747272625 were detected in exons 5 and 16, respectively. Both variants cause frameshifts and generation of a premature stop-codon that probably leads to mRNA nonsense-mediated decay. Validation and segregation of ALMS1 variants were confirmed by Sanger sequencing.

Conclusions: Genetic testing makes it possible, even in childhood, to increase the number of correct diagnoses of patients who have ambiguous phenotypes caused by rare genetic variants. The development of high-throughput sequencing technologies offers an exceptionally valuable screening tool for clear genetic diagnoses and ensures early multidisciplinary management and treatment of the emerging symptoms.
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http://dx.doi.org/10.1186/s12881-020-01110-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460749PMC
September 2020

Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments.

Pediatr Nephrol 2021 01 26;36(1):83-91. Epub 2020 Jul 26.

Advicenne, Nîmes, France.

Background: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme.

Methods: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety.

Results: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103.

Conclusions: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA.

Trial Registration: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04693-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701073PMC
January 2021

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

Kidney Int 2020 08 26;98(2):464-475. Epub 2020 Apr 26.

Department of Paediatrics, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.

One of the main objectives of the European health policy framework is to ensure equitable access to high-quality health services across Europe. Here we examined country-specific kidney transplantation and graft failure rates in children and explore their country- and patient-level determinants. Patients under 20 years of age initiating kidney replacement therapy from January 2007 through December 2015 in 37 European countries participating in the ESPN/ERA-EDTA Registry were included in the analyses. Countries were categorized as low-, middle-, and high-income based on gross domestic product. At five years of follow-up, 4326 of 6909 children on kidney replacement therapy received their first kidney transplant. Overall median time from kidney replacement therapy start to first kidney transplantation was 1.4 (inter quartile range 0.3-4.3) years. The five-year kidney transplantation probability was 48.8% (95% confidence interval: 45.9-51.7%) in low-income, 76.3% (72.8-79.5%) in middle-income and 92.3% (91.0-93.4%) in high-income countries and was strongly associated with macro-economic factors. Gross domestic product alone explained 67% of the international variation in transplantation rates. Compared with high-income countries, kidney transplantation was 76% less likely to be performed in low-income and 58% less likely in middle-income countries. Overall five-year graft survival in Europe was 88% and showed little variation across countries. Thus, despite large disparities transplantation access across Europe, graft failure rates were relatively similar. Hence, graft survival in low-risk transplant recipients from lower-income countries seems as good as graft survival among all (low-, medium-, and high-risk) graft recipients from high-income countries.
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http://dx.doi.org/10.1016/j.kint.2020.03.029DOI Listing
August 2020

Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis.

Clin Kidney J 2020 Apr 21;13(2):225-234. Epub 2019 Jun 21.

FMC Center of Dialysis, Miskolc, Hungary.

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.
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http://dx.doi.org/10.1093/ckj/sfz073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147314PMC
April 2020

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

Eur J Pediatr 2020 Sep 20;179(9):1481-1486. Epub 2020 Mar 20.

Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200, Aarhus N, Denmark.

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.
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http://dx.doi.org/10.1007/s00431-020-03634-3DOI Listing
September 2020

Myhre Syndrome Associated With Dunbar Syndrome and Urinary Tract Abnormalities: A Case Report.

Front Pediatr 2020 27;8:72. Epub 2020 Feb 27.

Department of Paediatrics, Medical School, Comenius University and National Institute of Children's Diseases, Bratislava, Slovakia.

Myhre syndrome is a rare condition caused by a mutation in the gene, which leads to a defective TGF-β/BMP signaling, resulting in the proliferation of abnormal fibrous tissues. Clinically, patients with Myhre syndrome manifest with defects of connective tissue (skin, muscles, joints), and cardiovascular and neurological impairment. In our report, we present a case of a 16-year-old female with skeletal abnormalities, reduced articular mobility, skin, and muscular hypertrophy and cardiovascular defects characteristic of Myhre syndrome. Long-term pulmonary hypertension and arterial hypertension were persistent in spite of antihypertensive treatment. Our patient was also diagnosed with chronic kidney disease and Dunbar syndrome, which is an external compression of the coeliac trunk or coeliac artery by the surrounding tissues. Until now, only a few cases of renal complications in Myhre syndrome have been published. We describe for the first time a female patient with genetically confirmed Myhre syndrome caused by the p.Ile500Val mutation presenting with an unusual occurrence of congenital vesicoureteral reflux, proteinuria with a decreased renal function, and a condition recognized as Dunbar syndrome.
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http://dx.doi.org/10.3389/fped.2020.00072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057230PMC
February 2020

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy.

Orphanet J Rare Dis 2019 11 8;14(1):247. Epub 2019 Nov 8.

FMC Center of Dialysis, Miskolc, Hungary.

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.
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http://dx.doi.org/10.1186/s13023-019-1237-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839100PMC
November 2019

Urea and creatinine levels in saliva of patients with and without periodontitis.

Eur J Oral Sci 2019 10 27;127(5):417-424. Epub 2019 Jun 27.

Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.

Despite the fact that saliva contains measurable concentrations of urea and creatinine, it is not widely used in clinical nephrology. One of the reasons is the high inter- and intra-individual variability in the salivary markers of kidney function. We hypothesized that gingival bleeding in patients with periodontitis could contribute to this variability by increasing the concentration of salivary urea or creatinine. Samples were collected from 25 patients with periodontitis and 29 healthy controls. In addition, saliva samples from five healthy volunteers were artificially contaminated with blood. The concentration of urea, but not that of creatinine, was more than twice as high in patients with periodontitis than in controls. Artificial contamination of saliva with blood did not affect the salivary concentration of creatinine. Salivary urea increased only with very high levels of contamination (≥2.5% blood in saliva), but that did not occur in patients. In conclusion, periodontitis increases the concentration of salivary urea, but this is not likely to be a result of contamination with blood. Future studies should investigate the composition of the oral microbiome, specifically regarding how it affects the concentration of salivary urea. Salivary creatinine seems to be a more robust non-invasive marker of renal functions than salivary urea.
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http://dx.doi.org/10.1111/eos.12642DOI Listing
October 2019

Salivary creatinine and urea are higher in an experimental model of acute but not chronic renal disease.

PLoS One 2018 6;13(7):e0200391. Epub 2018 Jul 6.

Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.

Plasma creatinine and urea are commonly used markers of kidney function in both acute and chronic renal failure. The needed repeated blood collection is associated with pain, stress and might lead to infections. Saliva has the potential to be a non-invasive alternative diagnostic fluid. The use of saliva in clinical practice is limited, since many factors affect the concentration of salivary biomarkers. The aim of our study was to analyze salivary creatinine and urea in the animal models of acute and chronic renal disease. Bilateral nephrectomy and adenine nephropathy were induced in adult male mice. Both, plasma creatinine and urea were higher in animals with renal failure compared to controls. Salivary creatinine was higher by 81% and salivary urea by 43% in comparison to the control group, but only in animals with bilateral nephrectomy and not in adenine nephropathy. Our results indicate that the increase of salivary creatinine and urea depends on the experimental model of renal failure and its severity. Further studies are needed to monitor the dynamics of salivary markers of renal function and to reveal determinants of their variability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200391PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034877PMC
January 2019

Prevalence of overweight/obesity among 7-year-old children-WHO Childhood Obesity Surveillance Initiative in Slovakia, trends and differences between selected European countries.

Eur J Pediatr 2018 Jun 17;177(6):945-953. Epub 2018 Apr 17.

National Institute of Children's Diseases and Faculty of Medicine of Comenius University, Limbová 1, 833 40, Bratislava, Slovakia.

The objectives of this study were (1) to assess the prevalence and time trends of overweight/obesity in Slovak children by applying WHO, IOTF, and the national criteria; (2) to compare the prevalence between selected European countries; and (3) to evaluate the central obesity by the waist-to-height ratio. The survey was performed within the WHO European Childhood Obesity Surveillance Initiative. The weight, height, waist, and hip were measured in 2795 children at the age of 7-7.99 years (50.1% boys; 55.5% in rural areas). The prevalence of overweight/obesity was determined using the LMS Growth. In boys, the prevalence of overweight/obesity was 17.1/14.9% according to WHO, 13.8/8.8% according to IOTF, and 9.9/8.8% according to the national criteria. Among girls, the prevalence reached 15.1/11.1%, 12.6/8.1%, and 7.5/9.5%, respectively. These rates corresponded to the average of the European countries. Central obesity was identified in 76.9% of overweight/obese, but also in 5.9% normal-weight subjects.

Conclusion: While overweight has increased by 3% the prevalence of obesity has doubled since 2001. The rise culminated approximately 6 years ago and has not increased since then. The body constitution differences should be considered when comparing the prevalence of overweight/obesity between populations and/or individuals. What is Known: • Knowledge of the prevalence of overweight/obesity is seminal for effective implementation of programs focusing on the reduction of incidence and prevalence of obesity in early childhood. What is New: • The most numerous and representative study on the prevalence of overweight/obesity in 7-year-old children involving 2795 (5%) of peers living in Slovakia. • The prevalence of obesity in Slovakia falls within the range of average rate of the European countries. Central obesity was identified in almost 20% subjects.
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http://dx.doi.org/10.1007/s00431-018-3137-7DOI Listing
June 2018

Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.

Clin J Am Soc Nephrol 2018 01 10;13(1):53-62. Epub 2017 Nov 10.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.

Design, Setting, Participants, & Measurements: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.

Results: In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. , , , and were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.

Conclusions: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.
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http://dx.doi.org/10.2215/CJN.04120417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753307PMC
January 2018

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

Pediatr Nephrol 2018 Jan 17;33(1):125-137. Epub 2017 Aug 17.

Amgen Inc., Thousand Oaks, CA, USA.

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.
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http://dx.doi.org/10.1007/s00467-017-3758-5DOI Listing
January 2018

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2017 Jun 30;161(2):152-157. Epub 2017 Mar 30.

Department of Paediatrics, Faculty of Medicine, PJ Safarik University in Kosice and Children's University Hospital, Kosice, Slovak Republic.

Background: Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is the most common orofacial birth defect with an aetiology involving both genetic and environmental factors. Genome-wide association studies (GWAS) have identified several genomic susceptibility regions for nsCL/P. In the present study, the three well established single nucleotide polymorphisms (SNPs) identified by GWAS (rs987525 at 8q24, rs7078160 at 10q25, and rs227731 at 17q22 loci) and one SNP identified by candidate gene study (rs642961 in IRF6 gene at 1q32 locus) were analysed for an association with nsCL/P in Slovak population.

Methods: Nucleotide variants were genotyped in 165 nsCL/P patients and 326 unaffected controls. All variants of interest were genotyped using high-resolution melting analysis after real-time PCR.

Results: We found significant differences between patient and control groups with respect to the allele and genotype frequencies for the SNPs at the 1q32, 8q24, and 17q22 loci. SNP at the 10q25 locus showed a trend toward association with nsCL/P risk.

Conclusions: The results suggest that SNPs at the 1q32, 8q24 and 17q22 loci may contribute to the nsCL/P risk in Slovak population.
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http://dx.doi.org/10.5507/bp.2017.009DOI Listing
June 2017

[Utilisation of salivary markers in nephrology].

Vnitr Lek 2016 ;62 Suppl 6:62-65

Saliva has a broad diagnostic potential which can be used for detection many pathological conditions including renal dysfunction. In saliva can be measured concentration of urea and creatinine as well as the other uremic markers. Saliva urea nitrogen and creatinine and blood urea and creatinine highly correlated therefore might be used for screening in patients with CKD. Saliva collection is truly non-invasive and is especially suitable for small children and elderly patients. Recently, semiquantitative saliva urea test strip is available. Saliva might become promising dia-gnostic biofluid in nephrological practice.Key words: chronic kidney disease - renal failure - salivary dipstick - salivary markers.
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November 2018

Salivary markers of kidney function - Potentials and limitations.

Clin Chim Acta 2016 Jan 26;453:28-37. Epub 2015 Nov 26.

Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Institute of Pathology & Department of Nephrology, RWTH Aachen University, Aachen, Germany.

Saliva can be collected non-invasively, repeatedly and without trained personnel. It is a promising diagnostic body fluid with clinical use in endocrinology and dentistry. For decades, it is known that saliva contains also urea, creatinine and other markers of renal function. Clinical studies have shown that the salivary concentrations of these markers could be useful for the assessment of kidney function without the need of blood collection. This article summarizes the clinical and experimental data on the use of saliva as a diagnostic fluid in nephrology and points out the advantages, pitfalls, technical requirements and future perspective for the use of saliva as a novel potential diagnostic biofluid.
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http://dx.doi.org/10.1016/j.cca.2015.11.028DOI Listing
January 2016

Anemia in children following renal transplantation-results from the ESPN/ERA-EDTA Registry.

Pediatr Nephrol 2016 Feb 18;31(2):325-33. Epub 2015 Sep 18.

University of Heidelberg Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany.

Background: Our aim was to determine the prevalence of sub-target hemoglobin (Hb) levels in children with a renal allograft and to identify potential determinants associated with these Hb levels.

Methods: Data from 3669 children with a functioning renal allograft, aged <18 years between 1 January 2000 and 31 December 2012, from 20 European countries were retrieved from the ESPN/ERA-EDTA Registry, providing 16,170 Hb measurements.

Results: According to the NKF/KDOQI classification and the UK-NICE guidelines, 49.8 and 7.8% of the patients, respectively, were anemic. Hb levels were strongly associated with graft function, with Hb levels of 12.6 g/dl in children with chronic kidney disease (CKD) stage 1, declining to 10.7 g/dl in children with CKD stage 5 (P < 0.001). Higher Hb levels were associated with the use of tacrolimus compared to ciclosporin (0.14 g/dl; 95% confidence interval 0.02-0.27; P = 0.002). Low Hb levels were associated with an increased risk of graft failure (P = 0.01) or combined graft failure and death (P < 0.01), but not with death alone (not significant).

Conclusions: Anemia is present in a significant proportion of European pediatric kidney transplant recipients and is associated with renal allograft dysfunction and type of immunosuppressants used. In our patient cohort, higher Hb levels were associated with better graft and patient survival and less hypertension.
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http://dx.doi.org/10.1007/s00467-015-3201-8DOI Listing
February 2016

KANK deficiency leads to podocyte dysfunction and nephrotic syndrome.

J Clin Invest 2015 Jun 11;125(6):2375-84. Epub 2015 May 11.

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalized with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTP-bound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling.
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http://dx.doi.org/10.1172/JCI79504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497755PMC
June 2015

Mineral metabolism in European children living with a renal transplant: a European society for paediatric nephrology/european renal association-European dialysis and transplant association registry study.

Clin J Am Soc Nephrol 2015 May 20;10(5):767-75. Epub 2015 Feb 20.

Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.

Background And Objectives: Data on mineral metabolism in pediatric renal transplant recipients largely arise from small single-center studies. In adult patients, abnormal mineral levels are related to a higher risk of graft failure. This study used data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry to study the prevalence and potential determinants of mineral abnormalities, as well as the predictive value of a disturbed mineral level on graft survival in a large cohort of European pediatric renal transplant recipients.

Design, Setting, Participants, & Measurements: This study included 1237 children (0-17 years) from 10 European countries, who had serum calcium, phosphorus, and parathyroid hormone measurements from 2000 onward. Abnormalities of mineral metabolism were defined according to European guidelines on prevention and treatment of renal osteodystrophy in children on chronic renal failure.

Results: Abnormal serum phosphorus levels were observed in 25% (14% hypophosphatemia and 11% hyperphosphatemia), altered serum calcium in 30% (19% hypocalcemia, 11% hypercalcemia), and hyperparathyroidism in 41% of the patients. A longer time since transplantation was associated with a lower risk of having mineral levels above target range. Serum phosphorus levels were inversely associated with eGFR, and levels above the recommended targets were associated with a higher risk of graft failure independently of eGFR.

Conclusions: Abnormalities in mineral metabolism are common after pediatric renal transplantation in Europe and are associated with graft dysfunction.
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http://dx.doi.org/10.2215/CJN.06200614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422235PMC
May 2015

MDR1 polymorphisms and idiopathic nephrotic syndrome in Slovak children: preliminary results.

Med Sci Monit 2015 Jan 6;21:59-68. Epub 2015 Jan 6.

Department of Pharmacology, P.J. Safarik University, Faculty of Medicine, Kosice, Slovakia.

Background: The role of the multidrug resistance-1 (MDR1 or ABCB1) gene polymorphisms 1236T>C, 2677T>G, and 3435T>C was studied in relation to susceptibility, demographics, and pathological characteristics, as well as their role in the therapeutic response (TR) to prednisone treatment in children with idiopathic nephrotic syndrome (INS).

Material/methods: The polymorphisms were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method in 46 children with INS and in 100 healthy controls. Different genetic models (codominant, dominant, recessive, and overdominant) were used for testing of associations between polymorphisms and phenotypes.

Results: Statistical analysis showed a significantly increased chance of TR in children carrying 3435TC genotype (OR=5.13, 95% CI=1.18-22.25; overdominant model). Moreover, INS patients under 6 years of age had significantly decreased frequencies of MDR1 1236CC (7.7% vs. 35%, p=0.029) or 2677GG (3.8% vs. 30.0%, p=0.033) genotypes. We also observed that patients with minimal change in disease and patients under 6 years of age at the onset of INS were initial responders more frequently when compared with children with focal segmental glomerulosclerosis and patients ≥6 years old at the onset (p=0.0001, p=0.027, respectively).

Conclusions: These data suggest that prednisone TR may be influenced by histology, age at the onset of INS, and MDR1 3435T>C polymorphism. The MDR1 1236T>C and 2677T>G polymorphisms were significantly associated with age at onset. Larger multicenter studies and studies across other ethnic groups are needed to elucidate the contradictory implications of MDR1 polymorphisms with INS in children.
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http://dx.doi.org/10.12659/MSM.891366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294597PMC
January 2015

Kidney diseases in Roma and non-Roma children from eastern Slovakia: are Roma children more at risk?

Int J Public Health 2014 Dec 1;59(6):1023-6. Epub 2014 Oct 1.

Paediatric Department, Faculty of Medicine, Safarik University, Tr. SNP 1, 040 11, Kosice, Slovak Republic,

Objectives: To compare the occurence of primary renal diseases (PRD) in Roma and non-Roma children.

Methods: Data on all outpatients (n = 921) from a tertiary pediatric nephrology centre (<19 years) in eastern Slovakia were collected. We assessed early signs and symptoms and PRD for Roma and non-Roma children.

Results: The proportion of Roma among patients was relatively small regarding early signs like proteinuria but large regarding PRD with gross clinically apparent symptoms (e.g. Alport syndrome, p < 0.01 and systemic lupus erythematosus, p < 0.05).

Conclusions: The overall proportion of Roma children in outpatients with kidney problems is smaller than the estimated proportion of Roma in all children in Slovakia, in particular for early signs, but not for major renal diseases.
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http://dx.doi.org/10.1007/s00038-014-0609-zDOI Listing
December 2014

Solitary functioning kidney in children--a follow-up study.

Kidney Blood Press Res 2014 9;39(4):272-8. Epub 2014 Aug 9.

Paediatric Department, Faculty of Medicine, Safarik University, Kosice, Slovak Republic.

Background/aims: This study aims to assess the cumulative incidence of elevated albuminuria, hypertension and decreased estimated glomerular filtration rate (eGFR) to identify possible renal injury in children with SFK.

Methods: Forty-two children with SFK (23 boys; 27 congenital) were included in a prospective follow-up study. Blood pressure, albuminuria and eGFR were assessed repeatedly and the cumulative incidence rate of various forms of renal injury, overall and by type of etiology, were evaluated. Finally, renal injury-free survival was analyzed.

Results: Mean follow-up was until age 11.3 years (SD 6.3 years). During follow-up, 16 (38.1%) patients met the criteria for renal injury, defined as hypertension (10; 23.8%), severely increased albuminuria (3; 7.1%) and a significantly impaired eGFR (<60 ml/min/1.73 m2) (5; 11.9%) and/or use of antihypertensive or antiproteinuric medication (11; 26.2%). Children with CAKUT in SFK had a significantly higher incidence of renal injury. The median time to develop renal injury was 12.8 years.

Conclusion: A substantial proportion of children with SFK develop renal injury during childhood, especially those with CAKUT in the SFK. Therefore, close follow-up of albuminuria, blood pressure and eGFR are warranted to identify chronic kidney disease in its early stages.
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http://dx.doi.org/10.1159/000355804DOI Listing
June 2015

Dyslipidaemia in children on renal replacement therapy.

Nephrol Dial Transplant 2014 Mar 29;29(3):594-603. Epub 2013 Oct 29.

ESPN/ERA-EDTA Registry, Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Information on lipid abnormalities in end-stage renal disease (ESRD) mainly originates from adult patients and small paediatric studies. We describe the prevalence of dyslipidaemia, and potential determinants associated with lipid measures in a large cohort of paediatric ESRD patients.

Methods: In the ESPN/ERA-EDTA registry, lipid measurements were available for 976 patients aged 2-17 years from 19 different countries from the year 2000 onwards. Dyslipidaemia was defined as triglycerides >100 mg/dL (2-9 years) or >130 mg/dL (9-17 years), high-density lipoprotein (HDL) cholesterol <40 mg/dL or non-HDL cholesterol >145 mg/dL. Missing data were supplemented using multiple imputation.

Results: The prevalence of dyslipidaemia was 85.1% in peritoneal dialysis (PD) patients, 76.1% in haemodialysis (HD) patients and 55.5% among renal allograft recipients. Both low and high body mass index (BMI) were associated with a less favourable lipid profile. Younger age was associated with a worse lipid profile among PD patients. HDL levels significantly improved after transplantation, whereas no significant improvements were found for triglyceride and non-HDL levels. In transplant recipients, use of cyclosporin was associated with significantly higher non-HDL and HDL levels than tacrolimus usage (P < 0.01). In transplant patients with eGFR < 29 mL/min/1.73 m(2), the mean triglyceride level was 137 mg/dL (99% confidence interval (CI): 119-159) compared with 102 mg/dL among those with eGFR > 90 mL/min/1.73 m(2) (P < 0.0001).

Conclusions: Dyslipidaemia is common among paediatric ESRD patients in Europe. Young age and PD treatment are associated with worse lipid profiles. Although lipid levels generally improve after transplantation, dyslipidaemia may persist due to decreased graft function, high BMI or to the use of certain immunosuppressants.
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http://dx.doi.org/10.1093/ndt/gft429DOI Listing
March 2014

Prevalence and predictors of the sub-target Hb level in children on dialysis.

Nephrol Dial Transplant 2012 Oct 27;27(10):3950-7. Epub 2012 Jun 27.

Department of Medical Informatics, University of Amsterdam, Amsterdam, The Netherlands.

Background: Anaemia is a common and potentially treatable co-morbidity of end-stage renal disease. We aimed to determine the prevalence of the sub-target haemoglobin (Hb) level among European children on dialysis and to identify factors associated with a low Hb level.

Methods: From the European Society for Paediatric Nephrology (ESPN)/European Renal Association-European Dialysis Transplant Association (ERA-EDTA) registry, data were available on 2351 children between 1 month and 18 years of age, totalling 5546 measurements from 19 countries.

Results: The mean Hb level was 10.8 g/dL (5th-95th percentiles, 7.4-13.9). Among those above 2 years of age, the mean Hb level was 10.9 g/dL (11.4% below 8.5 g/dL), while it was 10.3 g/dL among those below 2 years (11.2% below 8.0 g/dL). A total of 91.2% of the patients were on an erythropoiesis-stimulating agent (ESA). Hb levels increased with age and were higher in peritoneal dialysis compared with haemodialysis patients. Patients with congenital anomalies of the kidney and urinary tract showed the highest Hb levels, and those with cystic kidney diseases or metabolic disorders the lowest ones. Ferritin levels between 25 and 50 ng/mL were associated with the highest Hb levels. We found a weak inverse association between parathyroid hormone (PTH) and Hb. Whereas standardized blood pressure (BP) was not elevated in patients with above-target Hb, elevated systolic BP z-score was noted in those with sub-target Hb levels.

Conclusions: Sub-target Hb levels remain common in children on dialysis, in spite of virtually all children being treated with ESA; although we cannot exclude under-dosing. Optimal ferritin levels seemed to be slightly lower in children (25-50 ng/mL) than those in adults. Other risk factors for sub-target Hb are dialysis modality and a high PTH level.
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http://dx.doi.org/10.1093/ndt/gfs178DOI Listing
October 2012