Ismail Dursun

The relationship between circulating endothelial microparticles and arterial stiffness and atherosclerosis in children with chronic kidney disease

BACKGROUND Endothelial dysfunction is an important factor in the pathogenesis of atherosclerosis, and endothelial microparticles (EMPs) are considered as markers of endothelial dysfunction. In this study, we aimed to examine the relationship between EMPs and arterial stiffness and atherosclerosis in children with chronic kidney disease (CKD). METHODS This cross-sectional study included 37 dialysis patients (12 haemodialysis, 25 peritoneal dialysis), 33 pre-dialysis patients and 18 healthy controls. Both in vivo and in vitro (HUVECs) evaluations were used for the study. Circulating EMPs were measured by flow cytometry. The carotid artery intima-media thickness (cIMT) and pulse wave velocity (PWV) were measured by using high-resolution ultrasound. Study groups were compared for circulating EMP, cIMT and PWV. The relationship between EMPs and arterial stiffness and atherosclerosis was evaluated. RESULTS The levels of PWV, cIMT, CD144 + EMP and CD146 + EMP in the dialysis group were significantly higher than those in the pre-dialysis and control groups (P < 0.05). Additionally, the levels of cIMT, CD144 + EMP and CD146 + EMP in the pre-dialysis group were significantly higher than those in the control group (P < 0.05). In all CKD patients, the CD144 + EMP was significantly positively associated with blood pressures, age, known duration of disease, CRP and PTH, and was significantly negatively associated with haemoglobin, GFR and albumin. The CD146 + EMP was significantly positively associated with blood pressures, age and CRP. In a multiple linear regression analysis, in the CKD group, cIMT was independently related to mean blood pressure and dialysis duration. PWV was independently related to the CD144 + EMP and mean blood pressure. CONCLUSION Our results suggest that endothelial damage starts in the early stage of CKD, that the endothelial dysfunction becomes overt with the increase of cardiovascular risk factors and that EMPs may be a reliable marker of the subclinical atherosclerosis and arterial stiffness.

Genotype–phenotype correlation in children with familial Mediterranean fever in a Turkish population

Background: The aim of the present study was not only to review clinical and demographic features of child‐onset familial Mediterranean fever (FMF) patients but also to investigate whether there is a phenotype–genotype correlation in the same patient population.

Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome

Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

Increased endothelial microparticles in obese and overweight children.

Abstract Background: Obesity in children increases the risk of atherosclerosis. Endothelial dysfunction is an important factor in the pathogenesis of atherosclerosis, and endothelial microparticles (EMPs) are considered as markers of endothelial dysfunction. In this study, we aimed to evaluate circulating EMPs in obese and overweight children and to disclose the measure of obesity with the strongest relation with circulating microparticles and carotid atherosclerosis. Methods: This prospective study included 55 obese and overweight children and 23 healthy controls. Insulin resistance was studied. Both in vivo and in vitro human umbilical vein endothelial cell evaluations were used for the study. Circulating EMPs (CD144 and CD146) were measured by flow cytometry. The carotid artery intima-media thickness (cIMT) and left ventricular mass index (LVMI) were measured using ultrasound and echocardiography, respectively. Study groups were compared for anthropometric measurement, insulin resistance, circulating EMP, cIMT, and LVMI. The relationship among overweight, obesity, and circulating EMPs were investigated. Results: Blood pressure, CD144+EMP levels, and LVMI were statistically higher in the patients group than in the control group. The multiple logistic regression analysis and the backward elimination method showed that CD144+EMP and systolic blood pressure had a linear relationship with overweight and obesity. Conclusion: Our results suggest that endothelial damage starts in the early stage of childhood obesity and that obese and overweight children have increased circulating CD144+EMPs, showing that endothelial dysfunction and increased CD144+EMPs may be related to obesity.

Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database

Enzymatic loss in alkaptonuria (AKU), an autosomal recessive disorder, is caused by mutations in the homogentisate 1,2 dioxygenase (HGD) gene, which decrease or completely inactivate the function of the HGD protein to metabolize homogentisic acid (HGA). AKU shows a very low prevalence (1:100,000-250,000) in most ethnic groups, but there are countries with much higher incidence, such as Slovakia and the Dominican Republic. In this work, we report 11 novel HGD mutations identified during analysis of 36 AKU patients and 41 family members from 27 families originating from 9 different countries, mainly from Slovakia and France. In Slovak patients, we identified two additional mutations, thus a total number of HGD mutations identified in this small country is 12. In order to record AKU-causing mutations and variants of the HGD gene, we have created a HGD mutation database that is open for future submissions and is available online ( http://hgddatabase.cvtisr.sk/ ). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from the original AKU database ( http://www.alkaptonuria.cib.csic.es ) and also all so far reported variants and AKU patients. Where available, HGD-haplotypes associated with the mutations are also presented. Currently, this database contains 148 unique variants, of which 115 are reported pathogenic mutations. It provides a valuable tool for information exchange in AKU research and care fields and certainly presents a useful data source for genotype-phenotype correlations and also for future clinical trials.

Urinary uric acid : creatinine ratios in healthy Turkish children.

Background:  Determining uric acid : creatinine ratios in random urine samples may be useful to assess the excretion of uric acid in children. Because it was shown that urinary uric acid excretion varies with age and geographic area, it is important to have accurate reference values of uric acid excretion. The aim of the present study was therefore to obtain regional reference values for urinary uric acid : creatinine ratios in healthy Turkish children.

Distal vaginal atresia resulting in obstructive uropathy accompanied by acute renal failure

Children with hydrometrocolpos due to distal vaginal atresia may present with severe obstructive uropathy. Here we report a 27-day-old infant with a hydrometrocolpos causing life-threatening renal failure. Percutaneous drainage of the hydrometrocolpos resulted in dramatically improved clinical and laboratory findings in the patient.

Role of sodium during formation of edema in children with nephrotic syndrome

Background:  The pathogenesis of edema in nephrotic syndrome is not entirely understood. The aim of this study was to contribute to the discussion on edema pathogenesis in nephrotic syndrome by following changes in volume and sodium retention for the course of the disease in children with steroid‐sensitive nephrotic syndrome (SSNS).

Comparison of the efficacy of once- and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever – a randomized controlled noninferiority trial

BackgroundIn this study, we examined the efficacy and safety of a once-daily dosage schema of colchicine compared with a twice-daily dosage schema in pediatric patients with familial Mediterranean fever (FMF).MethodsIn this 24-week, multicenter, randomized controlled noninferiority trial, pediatric patients newly diagnosed with FMF carrying a homozygous or compound heterozygous mutation and not receiving any treatment were included. Patients were randomly assigned using a block randomization method to receive treatment with a once- or twice-daily dosage. Clinical and laboratory characteristics and medication side effects were recorded and compared between groups. The study was carried out in compliance with Good Clinical Practice and the Consolidated Standards for Reporting of Trials (CONSORT) statement.ResultsA total of 92 patients were selected, and 79 patients completed the study. There were 42 patients in the once-daily dosage group and 37 in the twice-daily dosage group. The results indicated that the once-daily dosage was not inferior to the twice-daily dosage regarding decrease in attack frequency and duration as well as improvement in clinical findings and Mor severity scores. Alterations in laboratory findings indicating inflammation, such as erythrocyte sedimentation rate, C-reactive protein, and serum amyloid A, were similar in both groups. The rates of drug side effects were similar between the once- and twice-daily dosage groups, implying comparable safety of colchicine, with the exception of diarrhea, which was slightly higher in the once-daily dosage group.ConclusionsUsing colchicine with either a once- or twice-daily dosage provides similar clinical and laboratory improvements. Considering both efficacy and safety, colchicine can be prescribed with a once-daily dosage.Trial Registration IDClinicalTrials.gov identifier NCT02602028. Registered 5 November 2015.

Dynamics of circulating microparticles in chronic kidney disease and transplantation: Is it really reliable marker?

The deterioration of endothelial structure plays a very important role in the development of vascular diseases. It is believed that endothelial dysfunction starts in the early stage of kidney disease and is a risk factor of an unfavorable cardiovascular prognosis. Because a direct assessment of biological states in endothelial cells is not applicable, the measurement of endothelial microparticles (EMPs) detached from endothelium during activation or apoptosis is thought to be a marker of early vascular disease and endothelial dysfunction in children with chronic kidney disease (CKD). Few studies have shown increased circulating EMPs and its relationship with cardiovascular risk factors in patients with CKD. MPs contain membrane proteins and cytosolic material derived from the cell from which they originate. EMPs having CD144, CD 146, CD31(+)/CD41(-), CD51 and CD105 may be used to evaluate the vascular endothelial cell damage and determine asymptomatic patients who might be at higher risk of developing cardiovascular disease in CKD and renal transplant.