Ebru Yılmaz

Cardiovascular Phenotypes in Children with CKD: The 4C Study

BACKGROUND AND OBJECTIVES Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6-17 years old with initial GFR of 10-60 ml/min per 1.73 m2. The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers. RESULTS A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; n=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements >95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level. CONCLUSIONS The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD.

Is Daytime Systolic Load an Important Risk Factor for Target Organ Damage in Pediatric Hypertension

The aim of this study was to compare ambulatory blood pressure (BP) monitoring (ABPM) data and determine which hypertension type is a risk factor in target organ damage. A total of 82 children (47 boys) with suspected hypertension based on office BP measurements and considered hypertensive by ABPM were studied. Target organ damage included the following: 35.3% hypertensive retinopathy, 25.6% microalbuminuria, 15.8% increased left ventricular mass index, 29.2% increased carotid intima‐media thickness (cIMT), 24.3% high augmentation index (AIx), and 19.5% high pulse wave velocity (PWV). The association between BP load, PWV, and cIMT was statistically significant. There were significant correlations between daytime systolic BP load, PWV, AIx, and cIMT. A statistically significant difference was also detected between nighttime systolic BP load, PWV, and cIMT values and nighttime diastolic BP load levels and values of AIx and cIMT. There was also a statistically significant difference between the high level of nighttime diastolic BP load and cIMT. The authors found that target organ damage was seen more often in children with primary hypertension who had systolic loads.

Endothelial nitric oxide synthase (eNOS) gene polymorphism in early term chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) is a complex phenomenon caused by underlying kidney disease with superimposed enviromental and genetic factors. CAN development begins with progressive renal microvascular injury. Endothelial cells play key roles in the regulation of vascular tone, permeability, and remodeling. A reduction in basal nitric oxide (NO) release as a result of genetic variation in endothelial NO synthase (eNOS) function may predispose to hypertension, thrombosis, vasospasm, and atherosclerosis, all contributing to the development of CAN. We analyzed the G894T mutation at exon 7 of the eNOS gene in relationship to CAN among 81 children with renal transplantations. The 20 patients who developed CAN underwent renal biopsies for histological confirmation. Proteinuria and hypertension were observed in CAN. We selected 173 healthy reference subjects. The G894T polymorphism of the eNOS gene was determined by PCR-restriction fragment-length polymorphism analysis. The group included 33 male and 48 female subjects who received 32 living-related grafts and 49 from deceased donors (DD) donors. Donor age (y) was 32.7 +/- 13.7 and the HLA A,B,DR mismatch number of the cadaveric cases was 3.5 +/- 0.79. The distribution of the genotypes were ENOS GG/GT/TT 48%, 33%, 19%, respectively. G-alleles frequency was 64.8%; T-allele frequency was 35.2%. ENOS G894T gene polymorphism did not seem to influence long-term renal allograft outcome. Recipient ENOS G894T gene polymorphism did not alter the risk of chronic allograft failure. Even if NO synthesis and bioactivity are influenced by this polymorphism, many vasoactive factors may have roles to suppress the advantageous effects of NO.

Success of continuous veno-venous hemodiafiltration treatment in children monitored in the intensive care units

Abstract Introduction: As intensive care units (ICU) have improved, presence of multiple-organ dysfunctions in majority of patients with acute renal failure (ARF) has become clearer. To facilitate multi-organ support, continuous renal replacement therapy (CRRT) techniques have been developed. This study is the one that reports the experience on children including newborns receiving CRRT monitored in ICU. Materials and Methods: The study was performed retrospectively in children who had Continuous Veno- Venous Hemodiafiltration (CVVHDF) as a CRRT modality in ICU. Clinical data, primary cause, consultation time, duration and initiation time of CVVHDF were recorded. Patients were classified as cardiac and non-cardiac in respect to primary dysfunction. Stage of renal failure was evaluated according to pRIFLE criteria. Outcome was identified as primary and secondary. Primary outcome was accepted as the composite correction of uremia and metabolic parameters, and regression of fluid overload, while secondary outcomes were assessed as improvement of hemodynamic instability and survival. Results: A total of 36 patients’ files were scanned. There were 10 cases in cardiac group and 26 cases in non-cardiac group. There were statistically better differences between primary and secondary outcome rates of cardiac cases. Although there was no difference between cardiac and non-cardiac cases in terms of primary outcome, secondary outcome was statistically significant. Timing of consultation and CVVHDF was not found to have an effect on the outcome. Conclusion: Our results indicated that CVVHDF treatment was successful even in cardiac patients with high mortality and in patients at their later stage of ARF.

Genetic, Environmental, and Disease-Associated Correlates of Vitamin D Status in Children with CKD

BACKGROUND AND OBJECTIVES Vitamin D deficiency is endemic in children with CKD. We sought to investigate the association of genetic disposition, environmental factors, vitamin D supplementation, and renal function on vitamin D status in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Serum 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, and 24,25-dihydroxy-vitamin D concentrations were measured cross-sectionally in 500 children from 12 European countries with CKD stages 3-5. All patients were participants of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study, had CKD stage 3-5, and were age 6-18 years old. Patients were genotyped for single-nucleotide polymorphisms in the genes encoding 25-hydroxylase, vitamin D binding protein, 7-dehydrocholesterol reductase, and 24-hydroxylase. Associations of genetic status, season, local solar radiation, oral vitamin D supplementation, and disease-associated factors with vitamin D status were assessed. RESULTS Two thirds of patients were vitamin D deficient (25-hydroxy-vitamin D <16 ng/ml). 25-Hydroxy-vitamin D concentrations varied with season and were twofold higher in vitamin D-supplemented patients (21.6 [14.1] versus 10.4 [10.1] ng/ml; P<0.001). Glomerulopathy, albuminuria, and girls were associated with lower 25-hydroxy-vitamin D levels. 24,25-dihydroxy-vitamin D levels were closely correlated with 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D (r=0.87 and r=0.55; both P<0.001). 24,25-dihydroxy-vitamin D concentrations were higher with higher c-terminal fibroblast growth factor 23 and inversely correlated with intact parathyroid hormone. Whereas 25-hydroxy-vitamin D levels were independent of renal function, 24,25-dihydroxy-vitamin D levels were lower with lower eGFR. Vitamin D deficiency was more prevalent in Turkey than in other European regions independent of supplementation status and disease-related factors. Single-nucleotide polymorphisms in the vitamin D binding protein gene were independently associated with lower 25-hydroxy-vitamin D and higher 24,25-dihydroxy-vitamin D. CONCLUSIONS Disease-related factors and vitamin D supplementation are the main correlates of vitamin D status in children with CKD. Variants in the vitamin D binding protein showed weak associations with the vitamin D status.

Role of Apolipoprotein E in Febrile Convulsion

Apolipoprotein E is consistently associated with the progression of some common human neurodegenerative diseases, e.g., epilepsy. We hypothesized that genetic variations in the apolipoprotein E gene have implications for susceptibility to, and prognoses in, febrile convulsion, which plays an apparent role in the development of epilepsy. We used the polymerase chain reaction and restriction enzyme digestion to characterize variations of the apolipoprotein E gene. Sixty-nine patients with febrile convulsion (simple/complex) and a corresponding cohort of healthy patients (n = 75) were used. There was no significant difference in genotypic distribution and allelic frequencies of the apolipoprotein E gene between the febrile convulsion and control groups. Comparing subpopulations of the febrile convulsion group (patients with simple and complex febrile convulsion), we noted that no patients with the epsilon3/epsilon4 genotype had complex febrile convulsions. The apolipoprotein E epsilon3/epsilon4 genotype was more frequently seen in the simple febrile than in the complicated febrile convulsion group (9 versus 0 patients, respectively). The data indicate an association with the epsilon3/epsilon4 genotype of the apolipoprotein E gene with a milder phenotype. Although apolipoprotein E4 is not a vulnerability factor regarding febrile convulsions, it seems effective in regard to prognoses.

Urine Matrix Metalloproteinase-3 Level as a Biomarker for Monitoring in Familial Mediterranean Fever Attacks

Objective: Matrix metalloproteinase-3 (MMP-3) has been implicated in experimental and clinical models of human inflammatory conditions. Increased MMPs levels have been shown in serum and body fluids in inflammatory conditions. Familial Mediterranean Fever (FMF) is an inherited, auto inflammatory disease characterized by recurrent self-limited bouts of fever and localized inflammation. We aimed to investigate whether urine MMP-3 level can serve as a biomarker for monitoring attack in FMF patients in daily practice. Methods: We studied 50 patients diagnosed with FMF according to Tel Hashomer criteria and 32 age-matched healthy controls. We determined all subjects both in attack (FMF-AP) and attack free period (FMF-AFP) groups. Serum and urine samples were obtained within the first 6-24 h of the AP, and 10 days later after the attack (AFP). The serum samples were measured on the same day while urine samples were frozen immediately and stored at -80°C. Results: The mean age at onset was 57.26 ± 33.5 months. The most common symptoms seen during the attacks were: fever (80%) abdominal pain (72%), arthritis (40%). In genotype distribution, homozygous M694V mutation was seen mostly (28%). During AP, urine MMP-3 levels of patients were higher as well as during AFP and controls (2.32 ± 0.51, 0.89 ± 2.29 ng/mL and 1.24 ± 0.17 ng/mL, respectively, p=0.00). In AP, urinary MMP levels were higher in patients with arthritis than others (p<0.05). Urinary MMP-3 levels were also significantly higher in males (2.29 ± 0.45 versus 2.24 ± 0.57, p=0, 00). The patients with M694V allele (n=29) had statistically significant high urine MMP-3 levels than others (2.37 ± 0.56 versus 1.99 ± 0.31, p=0.04, respectively). Also, acute phase reactants were higher in patients with M694V allele without statistically significant difference (p=0.89, 0.75, 0.86, 0.85, 0.7, respectively). Conclusion: In this study we focused on presence of MMPs in urine and showed inflammation-specific MMP patterns may provide clinicians valuable information in FMF patients.

Kronik diyaliz tedavisi alan çocuklarda eritropoetin kullanımının ortalama trombosit hacmine etkisi

Objective: In this study, it was aimed to determine the relationship between erythropoietin (EPO) use and mean platelet volume (MPV) in the children undergoing dialysis. Methods: MPV values before and after EPO use in 36 patients (16 hemodialysis - HD, 20 peritoneal dialysis PD) were retrospectively evaluated. Patients were divided into two groups according to weekly EPO need as; given less than 150 U/kg defined as low EPO and more than 150 U/kg as high EPO groups. The age, weight, primary cause of chronic renal failure, dialysis methods and EPO dosages of patients were recorded. Blood samples were taken before and 4 weeks after EPO usage and MPV values were noted from complete blood counts. Results: While significant increase was seen in the MPV values after EPO in comparison to MPV values before EPO in the HD group (8.18±1.52 fL vs. 9.20±1.46 fL; p=0.046); near significant difference was found in the MPV levels after EPO (8.28±1.80 fL vs. 9.39±1.50 fL; p=0,051) in PD group. In HD patients when high dose of EPO was given, MPV levels were found to be significantly elevated (7.81 ± 1.04 vs 9.61 ± 1.05; p=0.06) after EPO. However, no difference was seen with the lowe dose EPO subgroup (8.64 ± 1.97 ve 8.67 ± 1.81; p>0,05). No effect of EPO dose was found on MPV values in PD patients (9.57 ± 1.58 ve 9.1 ± 1.42; p>0.05). Conclusion: It was observed that EPO influenced MPV values in children undergoing HD, while no effect of erythropoietin was found on MPV values of PD patients. Physicians should be careful while using high dose erythropoietin in children with high thrombosis risk. J Clin Exp Invest 2014; 5 (3): 415-419

PW01-017 – Urine MMP-3 level as a biomarker for in FMF attack

Matrix metalloproteinase-3 (MMP-3) has been implicated in experimental and clinical models of human inflammatory conditions. Increased levels of MMPs have been shown in serum and other body fluids such as synovial fluid in inflammatory conditions including ankylosing spondylitis, rheumatoid arthritis and juvenile idiopathic arthritis (JIA). Familial Mediterranean fever (FMF) is an autosomal recessive, inherited, autoinflammatory disease characterized by recurrent, self-limited bouts of fever and localized inflammation, usually involving the peritoneum, pleura, joints or skin.