Duygu Övünç Hacıhamdioğlu

ADCK4 mutations promote steroid-Resistant nephrotic syndrome through CoQ10 biosynthesis disruption

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

22q11 deletion syndrome: current perspective

Chromosome 22q11 is characterized by the presence of chromosome-specific low-copy repeats or segmental duplications. This region of the chromosome is very unstable and susceptible to mutations. The misalignment of low-copy repeats during nonallelic homologous recombination leads to the deletion of the 22q11.2 region, which results in 22q11 deletion syndrome (22q11DS). The 22q11.2 deletion is associated with a wide variety of phenotypes. The term 22q11DS is an umbrella term that is used to encompass all 22q11.2 deletion-associated phenotypes. The haploinsufficiency of genes located at 22q11.2 affects the early morphogenesis of the pharyngeal arches, heart, skeleton, and brain. TBX1 is the most important gene for 22q11DS. This syndrome can ultimately affect many organs or systems; therefore, it has a very wide phenotypic spectrum. An increasing amount of information is available related to the pathogenesis, clinical phenotypes, and management of this syndrome in recent years. This review summarizes the current clinical and genetic status related to 22q11DS.

The Association between Serum 25-Hydroxy Vitamin D Level and Urine Cathelicidin in Children with a Urinary Tract Infection.

Objective: Cathelicidin is an important antimicrobial peptide in the urinary tract. Cathelicidin expression is strongly stimulated by 1,25-dihydroxy vitamin D in epithelial cells, macrophages/monocytes, and neutrophils. Vitamin D and cathelicidin status in children with urinary tract infection (UTI) caused by Escherichia coli is unknown. To establish the relationship between serum vitamin D and urine cathelicidin levels in children with a UTI caused by Escherichia coli. Methods: Serum 25-hydroxy vitamin D and urine cathelicidin levels were measured in 36 patients with UTI (mean age 6.8±3.6 years, range: 0.25-12.6 years) and 38 controls (mean age 6.3±2.8 years, range: 0.42-13 years). Results: There were no significant differences in urine cathelicidin levels between the study and control groups (p>0.05). Eight (22.2%) patients in the study group and 21 (58.3%) children in the control group were found to have sufficient vitamin D (≥20 ng/mL). Patients with sufficient vitamin D had higher urine cathelicidin levels than the controls with sufficient vitamin D (respectively 262.5±41.1 vs. 168±31.6 ng/mL, p=0.001). There were no significant differences between the patients and controls with insufficient vitamin D (p>0.05). Conclusion: The children with vitamin D insufficiency may not be able to increase their urine cathelicidin level during UTI caused by Escherichia coli. There is a need of prospective studies in order to prove a beneficial effect of vitamin D supplementation for the restoration of cathelicidin stimulation and consequently for prevention of UTI recurrence.

Cerebral vein thrombosis in a four year old with Behçet's disease.

Behçets disease (BD) is a multisystem disorder. The main pathology in BD is vasculitis that involves arteries and veins of all calibers. Central nervous system involvement occurs in 5-10% of patients. Increased morbidity and mortality is rarely observed in children. The mean age at onset in pediatric BD is approximately 7 years. Neurologic involvement in BD is usually observed after 3-6 years. We report the case of a four-year-old Turkish boy with BD with sagittal sinus thrombosis treated with infliximab. The patient presented papilledema without neurologic signs. Although long-term efficacy evaluations are needed in this case, infliximab therapy may be a good option in childhood BD with refractory sinus thrombosis. This is the youngest case of BD with sagittal sinus thrombosis reported so far.

Long-term results of children diagnosed with idiopathic nephrotic syndrome; single center experience

AIM The aim of this study was to determine the long-term results of children followed up with a diagnosis of nephrotic syndrome in a single center. MATERIALS AND METHOD The medical data of 33 patients aged between 6 months and 10 years who were diagnosed with idiopathic nephrotic syndrome in our center between January 2000 and December 2012 and followed up for a period of 2-12 years were reviewed (Gulhane Military Medical Academy Ethics committee, 07.11.2012/10). RESULTS The mean age of disease onset was 3.2±2.04 years (range: 0.5-10 years) and the mean follow-up period was 6±3.4 years (range: 2-12 years). Thirteen (39.4%) of the study group (or the patients) were female and 20 (60.6%) were male. Twenty seven (1.8%) of the patients were sensitive to steroid and 6 (18.1%) were resistant to steroid. Four (12.1%) of the steroid-resistant patients had steroid-dependent nephrotic syndrome, 5 (15.2%) had frequently relapsing nephrotic syndrome and 18 (54.5%) had rarely relapsing nephrotic syndrome. Histopathological diagnoses of six patients who underwent biopsy because of resistance to steroid were as follows: focal segmental glomerulosclerosis (n=3), C1q nephropathy (n=1), diffuse mesangial proliferation (n=1) and membraneous nephropathy (n=1). Fifteen (45.5%) patients entered into full remission and 2 (6%) patients developed chronic renal failure. Treatment complications including decreased bone mineral density in three patients (9%), short stature in 2 patients (6%) and cataract in 2 patients (6%) developed. CONCLUSIONS Children with nephrotic syndrome carry a risk in terms of short stature, osteoporosis, cataract and renal failure in the long-term follow-up. It was observed that our rates of response to steroid were similar to the literature and the most common histopathological diagnosis was focal segmental glomerulosclerosis in our patients who underwent biopsy because of resistance to steroid. It was thought that multi-center studies should be conducted to demonstrate regional or national differences related with long-term results of childhood nephrotic syndrome.

İdrar interlökin-13, CD80, CD28, matriks metaloproteinaz-2 ve granzim B‘nin çocukluk çağı minimal değişim nefrotik sendrom patogenezindeki rolleri

Objective: Minimal change disease (MCD) is the most common cause of nephrotic syndrome in childhood but its pathogenesis remains poorly understood. A T-cell-derived factor or factors were initially alleged as contributing to the disease pathogenesis. However, podocyte CD80 expression is now a commonly discussed theory. The aim of this study was to investigate the pathogenesis of MCD by determining urine interleukin-13, CD80, CD28, matrix metalloproteinase-2 (MMP-2), and granzyme B levels. Methods: Thirty patients and thirty healthy children were evaluated in this study. Six patients had biopsy proven MCD. The remaining patients were considered to have MCD because of their age at time of diagnosis; response to steroid treatment, absence of gross hematuria, hypocomplementemia or renal failure; and normal blood pressures in the active stage. The nephrotic-phase urine interleukin-13, CD80, CD28, MMP-2, and granzyme B levels of all patients were compared with the remission-stage urine levels of the same patients and control subjects. The urine samples were collected immediately before the application of immunosuppressive drugs or other treatment modalities. Results: Significantly higher interleukin-13, CD80, CD28, and MMP-2 levels were observed in the relapse period compared with both the remission period and control subjects. There was a significant positive correlation between the active-stage urine interleukin-13 and CD80 levels (r=0.619, p<0.001). Conclusion: Interleukin-13, CD80, CD28, and MMP-2 seem to have roles in the pathogenesis of MCD and using inhibitors of these molecules in treatment of steroid and immunosuppressive-resistant MCD cases can be thought. J Clin Exp Invest 2014; 5 (3): 354-361

Evaluation of lipid peroxidation and antioxidant system in healthy iron-replete infants receiving iron prophylaxis.

OBJECTIVE Iron supplementation is commonly recommended for infants; however, there are some reports that it causes oxidative damage. The aim of this study was to investigate the potential effects of iron supplementation at 4 mo of age, for a period of 2 mo, on lipid peroxidation and free radical scavenging enzymes. METHODS Twenty-seven healthy 4-mo-old infants chosen randomly and given iron supplementation (ferrous sulfate, 10 mg of elemental iron per day) constituted the study group and 26 healthy 4-mo-old infants who were chosen randomly and not given iron supplementation constituted the control group. Weight, height, head circumference, complete blood cell count, serum ferritin level and intraerythrocytic zinc, iron, copper, malondialdehyde, catalase, superoxide dismutase, and glutathione peroxidase levels were measured in the two groups at 4 and 6 mo of life. RESULTS Compared with controls at 6 mo of age, no significant differences were observed for intraerythrocytic zinc (0.5 ± 0.1 versus 0.6 ± 0.2 μg/mL, P > 0.05), copper (0.2 ± 0.1 versus 0.2 ± 0.2 μg/mL, P > 0.05), iron (130.8 ± 10.9 versus 127.4 ± 11.1 μg/mL, P > 0.05), malondialdehyde (21.4 ± 3.5 versus 22.4 ± 2.3 nmol/g of hemoglobin, P > 0.05), catalase (135.4 ± 23.9 versus 135.1 ± 23.3 MU/g of hemoglobin, P > 0.05), superoxide dismutase (1736.4 ± 141.1 versus 1701.3 ± 103.9 U/g of hemoglobin, P > 0.05), and glutathione peroxidase (8.9 ± 1.6 versus 8.4 ± 1.6 U/g of hemoglobin, P > 0.05) levels. CONCLUSION Our study indicates that the supplemental use of elemental iron 10 mg/d for a period of 2 mo in healthy iron-replete infants did not cause lipid peroxidation or an impairment of antioxidant status.

The Clinical and Mutational Spectrum of Turkish Patients with Cystinosis

BACKGROUND AND OBJECTIVES Infantile nephropathic cystinosis is a severe disease that occurs due to mutations in the cystinosis gene, and it is characterized by progressive dysfunction of multiple organs; >100 cystinosis gene mutations have been identified in multiple populations. Our study aimed to identify the clinical characteristics and spectrum of cystinosis gene mutations in Turkish pediatric patients with cystinosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We identified the clinical characteristics and spectrum of cystinosis gene mutations in Turkish patients with cystinosis in a multicenter registry that was established for data collection. The data were extracted from this registry and analyzed. RESULTS In total, 136 patients (75 men and 61 women) were enrolled in the study. The most common clinical findings were growth retardation, polyuria, and loss of appetite. None of the patients had the 57-kb deletion, but seven novel mutations were identified. The most common mutations identified were c.681G>A (p.Glu227Glu; 31%), c.1015G>A (p.Gly339Arg; 22%), and c.18_21 del (p.Thr7Phefs*7; 14%). These mutations were associated with earlier age of disease onset than the other mutations. To understand the effects of these allelic variants on clinical progression, the mutations were categorized into two major groups (missense versus deletion/duplication/splice site). Although patients with missense mutations had a better eGFR at the last follow-up visit, the difference was not significant. Patients in whom treatment began at age <2 years old had later onset of ESRD (P=0.02). Time to ESRD did not differ between the patients with group 1 and group 2 mutations. CONCLUSIONS The most common cystinosis gene mutations identified in Turkey were c.681G>A (p.Glu227Glu), c.1015G>A (p.Gly339Arg), and c.18_21 del (p.Thr7Phefs*7). Patients with less severe cystinosis gene mutations tend to have better kidney outcome.

Elevated Urinary T Helper 1 Chemokine Levels in Newly Diagnosed Hypertensive Obese Children.

Objective: Increasing evidence suggests that T helper (Th) cells play a significant role in the pathogenesis of hypertension. The aim of this study was to evaluate the effect of obesity and anti-hypertensive treatment on urinary Th1 chemokines. Methods: The study groups consisted of three types of patients: hypertensive obese, healthy, and non-hypertensive obese. Pre-treatment and post-treatment samples of the hypertensive obese group and one sample from the other two groups were evaluated for urinary chemokine: regulated on activation, normal T cell expressed and secreted (RANTES), interferon-gamma-inducible protein 10 (IP10), and monokine induced by interferon-gamma (MIG). In the hypertensive obese group, urine microalbumin: creatinine ratio was examined before and after treatment. We recommended lifestyle changes to all patients. Captopril was started in those who could not be controlled with lifestyle changes and those who had stage 2 hypertension. Results: Twenty-four hypertensive obese (mean age 13.1), 27 healthy (mean age 11.2) and 22 non-hypertensive obese (mean age 11.5) children were investigated. The pre-treatment urine albumin: creatinine ratio was positively correlated with pre-treatment MIG levels (r=0.41, p<0.05). RANTES was significantly higher in the pre-treatment hypertensive and non-hypertensive obese group than in the controls. The urinary IP10 and MIG levels were higher in the pre-treatment hypertensive obese group than in the non-hypertensive obese. Comparison of the pre- and post-treatment values indicated significant decreases in RANTES, IP10, and MIG levels in the hypertensive obese group (p<0.05). Conclusion: Th1 cells could be activated in obese hypertensive children before the onset of clinical indicators of target organ damage. Urinary RANTES seemed to be affected by both hypertension and obesity, and urinary IP10 and MIG seemed to be affected predominantly by hypertension.