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Monocyte chemoattractant protein-1 (MCP-1) is a highly specific chemokine for monocytes and plays roles in pathogenesis of various renal diseases. The aim of this study is to investigate the effect of MCP1 2518 A/G polymorphism on the incidence and clinical course of focal segmental glomerulosclerosis (FSGS) in children. MCP1 2518 A/G genotype was identified by PCR-RFLP in 60 biopsy-proven FSGS patients, 76 steroid sensitive nephrotic syndrome (SSNS) patients, and 96 healthy children. MCP-1 levels in urine and serum were measured by ELISA in all patients and the correlations of genotype with MCP-1 levels and clinical outcome were evaluated. The genotype frequencies for MCP1 were similar in all groups. The percentage of patients who develop chronic renal failure was higher in patients with AA allele compared to GA or GG alleles (46% vs. 35% respectively, p < 0.01, Odds ratio: 1.59). Serum MCP-1 levels were similar in all groups, whereas urinary MCP-1 levels of the patients with FSGS (1680 pg/mg creatinine) were significantly higher than that of patients with SSNS (365 pg/mg creatinine, p < 0.05) and healthy controls (348 pg/mg creatinine; p < 0.05). Urinary MCP-1 levels were correlated with the degree of proteinuria in FSGS group (r = 0.529, p = 0.016). Our results suggest that the AA genotype might be a risk factor for the progression of renal disease in FSGS and MCP1 genotyping may help the physicians to predict prognosis in these patients.

Background: Obesity has risen considerably in the Western world and the trend is increasing in non-Western, developing countries, as well. Several school screening studies showed the relation between body mass index and hypertension. In adults, obesity is associated with an increased risk of development and progression of kidney disease. However, data at the epidemiological level are limited, both for children and adults. The aim of this study was to determine the prevalence of obesity and evaluate its association with hypertension and glomerular filtration rate (GFR) among children in Turkey., Methods: A population-based field study in which individuals were accessed by house visits throughout Turkey has been conducted. The study sample (3622 children; 5-18 years; 49.6% female, mean age 11.88 ± 3.40 years) was selected to represent the Turkish population regarding geographical region, gender and age (5-18 years). Obesity was defined as the body mass index ≥95th percentile for age and gender. The Schwartz formula was used to estimate GFR. Blood pressure (BP) percentile was determined according to age, gender and length., Results: The prevalence of overweight, obesity and hypertension were 9.3, 8.9 and 6.1%, respectively. Logistic regression analysis revealed urban area (OR 1.50; 95% CI 1.15-1.96; P = 0.003) as an independent risk for obesity and age decreased (OR 0.921; 95% CI 0.890-0.924; P < 0.001) risk for obesity. Obese children had the highest rate of hypertension (11.4 versus 5.6%; P < 0.001; OR 2.17, 95% CI 1.49-3.17; P < 0.001) and stage II hypertension (3.8 versus 0.7%; OR 6.01, 95% CI 2.93-12.33; P < 0.001). Systolic and diastolic BP z-scores were significantly higher in obese children. The mean estimated (eGFR) was lower in obese children (122.7 ± 21.6 versus 129.4 ± 23.1, P < 0.001). The rates of children with eGFR < 90 and <75 mL/min/1.73 m(2) were higher in obese patients, but did not reach statistical significance., Conclusions: Our nation-wide population-based field study among children showed that the prevalence of obesity is increasing in Turkey. The prevalence of hypertension and stage II hypertension, BP z-scores and eGFR were associated with obesity. We suggest that obese children are future candidates for chronic kidney disease. Longitudinal research is necessary to better understand these associations. Strategies for the prevention and management of obesity are also important for emerging countries and for children.

Renal microangiopathies and membranoproliferative GN (MPGN) can manifest similar clinical presentations and histology, suggesting the possibility of a common underlying mechanism in some cases. Here, we performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy. Furthermore, we identified two additional DGKE variants in a cohort of 142 unrelated patients diagnosed with membranoproliferative GN. This gene encodes the diacylglycerol kinase DGKε, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgkε colocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGKε variants affect the intracellular concentration of diacylglycerol. Taken together, these results not only identify a genetic cause of a glomerular microangiopathy but also suggest that the phosphatidylinositol cycle, which requires DGKE, is critical to the normal function of podocytes.

CXCR1 (CKR-1), a receptor of IL-8, is expressed in various cells including neutrophils and monocytes, both of which play a major role in proliferating glomerular diseases. We investigated time-dependent expression of CXCR1 and the effect of single-dose cyclosporine A (CsA) treatment on this expression in experimental mesangioproliferative glomerulonephritis induced by anti-thymocyte serum (ATS). Wistar rats were divided into three groups. Group 1 (control, n = 24) received non-immune serum. Group 2 (nephritis, n = 24) received ATS. Group 3 (nephritis + CsA, n = 24) received ATS and CsA concomitantly. Kidneys from six rats in each group were removed at sixth hour, 3 days, 5 days, and 7 days. ATS induced proteinuria compared to controls (p < 0.001) and CsA precluded the development of proteinuria. Glomerular inflammation and mesangial proliferation were significantly higher in ATS group than control and CsA-treated rats (p < 0.001). ATS injection caused marked interstitial inflammation that was precluded by CsA (p < 0.001). CXCR1 was not expressed in control kidneys. However, ATS induced expression of CXCR1 in both glomeruli and tubulointerstitium. CsA treatment precluded CXCR1 expression in both glomeruli and tubulointerstitium only in the first 6 h. CXCR1 may contribute to inflammation in experimental mesangioproliferative glomerulonephritis. CsA may be beneficial by inhibiting CXCR1 expression and corresponding inflammation.

We report the molecular findings for the CTNS gene in 12 Turkish cystinosis patients aged 7-29 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. Cystinosis was diagnosed at age 1 month to 9 years. Seven patients reached end-stage renal failure at ages ranging from 6.5 to 15 years. Whereas three of the remaining five have renal Fanconi syndrome with proteinuria, two have had kidney failure of varying degrees. Molecular analyses involved an initial multiplex polymerase chain reaction (PCR) to determine the presence or absence of the 57-kb northern European founder deletion in CTNS, followed by sequencing of the ten coding exons of CTNS. Comprehensive mutation analysis verified that none of the 12 patients carried the common 57-kb deletion. We identified four previously reported nucleotide variations associated with cystinosis and five new variants: a 10-kb deletion, three missense variants, and a nucleotide substitution in a potential branch point site of intron 4. This study is the first molecular analysis of Turkish cystinosis patients and provides guidance for the molecular diagnosis of cystinosis in this population.

Idiopathic nephrotic syndrome (INS) is a genetically heterogeneous group of disorders characterized by proteinuria, hypoalbuminemia, and edema. Because it typically results in end-stage kidney disease, the steroid-resistant subtype (SRNS) of INS is especially important when it occurs in children. The present study included 29 affected and 22 normal individuals from 17 SRNS families; genome-wide analysis was performed with Affymetrix 250K SNP arrays followed by homozygosity mapping. A large homozygous stretch on chromosomal region 12p12 was identified in one consanguineous family with two affected siblings. Direct sequencing of protein tyrosine phosphatase receptor type O (PTPRO; also known as glomerular epithelial protein-1 [GLEPP1]) showed homozygous c.2627+1G>T donor splice-site mutation. This mutation causes skipping of the evolutionarily conserved exon 16 (p.Glu854&#95;Trp876del) at the RNA level. Immunohistochemistry with GLEPP1 antibody showed a similar staining pattern in the podocytes of the diseased and control kidney tissues. We used a highly polymorphic intragenic DNA marker-D12S1303-to search for homozygosity in 120 Turkish and 13 non-Turkish individuals in the PodoNet registry. This analysis yielded 17 candidate families, and a distinct homozygous c.2745+1G>A donor splice-site mutation in PTPRO was further identified via DNA sequencing in a second Turkish family. This mutation causes skipping of exon 19, and this introduces a premature stop codon at the very beginning of exon 20 (p.Asn888Lysfs*3) and causes degradation of mRNA via nonsense-mediated decay. Immunohistochemical analysis showed complete absence of immunoreactive PTPRO. Ultrastructural alterations, such as diffuse foot process fusion and extensive microvillus transformation of podocytes, were observed via electron microscopy in both families. The present study introduces mutations in PTPRO as another cause of autosomal-recessive nephrotic syndrome., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal failure. Identification of single-gene causes of SRNS has generated some insights into its pathogenesis; however, additional genes and disease mechanisms remain obscure, and SRNS continues to be treatment refractory. Here we have identified 6 different mutations in coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset SRNS with sensorineural deafness. The deleterious effects of these human COQ6 mutations were validated by their lack of complementation in coq6-deficient yeast. Furthermore, knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q10 treatment. In rats, COQ6 was located within cell processes and the Golgi apparatus of renal glomerular podocytes and in stria vascularis cells of the inner ear, consistent with an oto-renal disease phenotype. These data suggest that coenzyme Q10-related forms of SRNS and hearing loss can be molecularly identified and potentially treated.

Background: Nephronophthisis (NPHP) is the most common genetic cause of end-stage renal disease (ESRD) in the first 3 decades of life. Treatment of patients with NPHP is symptomatic; kidney transplantation is the treatment of choice when ESRD is established. We report herein our center's experience with kidney transplantation for children with juvenile NPHP., Patients: We retrospectively analyzed medical records of 9 renal transplant recipients with a primary diagnosis of juvenile NPHP confirmed by genetic analysis and/or renal biopsy findings in a single center from 1996 to 2010., Results: Of the 9 patients, 6 received a living related and 3 a cadaveric donor transplantation. Preemptive renal transplantation was performed in 7 patients. The median age of the patients was 13.38 ± 4.6 years; the median follow-up period was 17 months. Posttransplantation immusuppression comprised corticosteroids, a calcineurin inhibitor, and mycophenolate mofetil or azathioprine. One patient lost his renal graft owing to renal graft thrombosis, and grade II chronic allograft nephropathy was diagnosed by renal biopsy on the 62th day after renal transplantation in another patient. The median glomerular filtration rates after transplantation at 1, 3, and 5 years were 85, 75.2, and 83.2 mL/min/1.73 m(2), respectively., Conclusion: We observed preserved graft functions for long periods among renal transplant recipients with juvenile NPHP. Chronic allograft nephropathy developed rarely on long follow-up., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: To analyse the demographics, main clinical and laboratory features and subtype distribution of juvenile idiopathic arthritis (JIA) in an eastern Mediterranean country, based on a multicentre registry., Methods: Between March 2008 and February 2009 with this cross-sectional study, consecutive patients seen with JIA in selected centres were registered through a web-based registry. All patients were classified according to the International League of Associations for Rheumatology (ILAR) criteria., Results: There were 634 patients with a mean age of 11.84 ± 4.66 years and the female/male ratio was 1.2. The distributions of JIA patients according to onset of disease were as follows: systemic 92 (14.5%), oligoarticular extended 26 (4.1%), oligoarticular persistent 234 (36.9%), rheumatoid factor (RF) positive polyarthritis 20 (3.2%), RF negative polyarthritis 129 (20.3%), enthesitis-related 120 (18.9%), psoriatic 13(2.1%). The frequency of uveitis was 15.7% among all of the oligoarthritis patients. Anti-nuclear antibody (ANA) was positive mainly among the oligoarticular onset patients. Twenty-one patients also had Familial Mediterranean fever (FMF). Among systemic JIA patients, the frequency of macrophage activation syndrome (MAS) was 15.2% (n=14). At the end of the mean follow-up of 7.6 ± 4.4 years, 305 (48.1%) patients were defined to have inactive disease on medication, and 106 (16.7%) were completely free of any disease symptoms without medication., Conclusions: Enthesitis related arthritis had a high frequency whereas psoriatic arthritis was very rare compared to other series. We suggest that there are certain differences in the characteristics of JIA in our eastern Mediterranean population. Thus, genetic studies need to be assessed in these populations separately and findings of genome wide association studies need to be confirmed in different populations.

IIH is a syndrome of increased intracranial pressure characterized by headache, visual disturbance, papilledema with normal cranial neuroimaging. It is associated with many factors in childhood. From the renal perspective renal insufficiency, chronic dialysis, steroid treatment, and recombinant human growth hormone have been associated with IIH. It has also been described in pediatric recipients several months to years following kidney transplantation. In this study, we present a pediatric kidney transplant recipient receiving CyA, prednisone, and mycophenolate mofetil who was discovered to have pseudopapilledema during routine ophthalmological examination. He had no additional signs of increased intracranial pressure. Awareness of possible side effects in the follow-up of these patients may improve management of these children., (© 2009 John Wiley & Sons A/S.)

The aim of this prospective, multicenter study was to define the etiology and clinical features of acute kidney injury (AKI) in a pediatric patient cohort and to determine prognostic factors. Pediatric-modified RIFLE (pRIFLE) criteria were used to classify AKI. The patient cohort comprised 472 pediatric patients (264 males, 208 females), of whom 32.6% were newborns (median age 3 days, range 1-24 days), and 67.4% were children aged >1 month (median 2.99 years, range 1 month-18 years). The most common medical conditions were prematurity (42.2%) and congenital heart disease (CHD, 11.7%) in newborns, and malignancy (12.9%) and CHD (12.3%) in children aged >1 month. Hypoxic/ischemic injury and sepsis were the leading causes of AKI in both age groups. Dialysis was performed in 30.3% of newborns and 33.6% of children aged >1 month. Mortality was higher in the newborns (42.6 vs. 27.9%; p < 0.005). Stepwise multiple regression analysis revealed the major independent risk factors to be mechanical ventilation [relative risk (RR) 17.31, 95% confidence interval (95% CI) 4.88-61.42], hypervolemia (RR 12.90, 95% CI 1.97-84.37), CHD (RR 9.85, 95% CI 2.08-46.60), and metabolic acidosis (RR 7.64, 95% CI 2.90-20.15) in newborns and mechanical ventilation (RR 8.73, 95% CI 3.95-19.29), hypoxia (RR 5.35, 95% CI 2.26-12.67), and intrinsic AKI (RR 4.91, 95% CI 2.04-11.78) in children aged >1 month.

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease in the world. The most serious complication of FMF is the development of secondary amyloidosis. Besides genetic factors, environment has been implicated in the development of this complication. The main objective of this study is to analyze whether there has been a substantial decrease of secondary amyloidosis in Turkey and possible effective factors. For this purpose, clinical features of the patients diagnosed with secondary amyloidosis between the years 1978 and 1990 were compared with those diagnosed between 2000 and 2009. Severity scores were determined by the use of a scoring system modified for children. Median ages of the group diagnosed between 1978 and 1990 (n = 115; 12.1% among a total of 947 renal biopsies) and diagnosed after 2000 (n = 19; 2% among a total of 974 renal biopsies) were 12 and 13 years, respectively. There were no significant differences between the two patient groups according to gender, age, age of onset, disease duration, and disease severity. There was, however, a clear decrease in the percentage of biopsies with secondary amyloidosis from 12.1% (1978-1990) to 2% (after 2000; p < 0.001). Our results have shown that there has been a significant decrease in the rate of secondary amyloidosis in Turkey. The main reason for this decrease is better medical care with increased awareness and treatment of the disease. However, we suggest that the improvement of infectious milieu may possibly have had a positive effect on the course of this monogenic disease, since inflammatory pathways related to innate immunity are deregulated.

Conflicting results have been reported in small non-homogenous groups of children with chronic renal failure in terms of casual blood pressure and ambulatory blood pressure monitoring (ABPM) parameters and left ventricular hypertrophy (LVH). The aim of our study was to assess the value of ABPM and hematological and biochemical parameters in predicting LVH in children on chronic peritoneal dialysis (CPD). Echocardiography and 24-h ABPM were performed in addition to routine biochemical and hematological evaluations in 47 children on CPD (26 male, 21 female; mean age 14.74 +/- 3.52 years). Mean daytime systolic blood pressure (SBP) and mean daytime diastolic blood pressure (DBP) values were found to be higher than the mean casual SBP and DBP (p = 0.001) values. Thirty-three (70.2%) children had LVH. The correlations between the left ventricular mass index and ABPM variables were good. Stepwise multiple regression analysis revealed daytime SBP load (beta = 0.652; p < 0.01) and hematocrit (beta = -0.282; p < 0.01) to be independent predictors of LVH. The sensitivity, specificity, positive predictive value, and negative predictive values for the combination of the SBP load >15% and hematocrit value <31% for predicting LVH were 95 [95% confidence interval (CI) 76-99], 78 (95%CI 45-94), 91 (95%CI 73-98), and 88% (95%CI 69-96%), respectively. We conclude that: (1) LVH is prevalent in children on CPD, and (2) a target hematocrit level >31% and daytime SBP load <15% may be preventive for the progression of LVH in the follow-up of children on CPD.

Objectives: To validate the previously proposed classification criteria for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA)., Methods: Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis

In this study, risk factors were investigated in children with community-acquired urinary tract infections (UTI) caused by extended-spectrum beta-lactamases (ESBL)-producing E. coli or Klebsiella spp. One hundred and fifty-five patients were diagnosed with ESBL-positive UTI (case group) in the outpatient clinics of Hacettepe University Children's Hospital between 1 January 2004 and 31 December 2006. A control group, 155 out of 4,105 children, was matched by age and sex among children with ESBL-negative UTI. A total of 310 patients' files were evaluated retrospectively. As regards the symptoms of UTI, no statistical differences were seen between the two groups. Although the most frequently isolated microorganism was E. coli in both groups, Klebsiella spp. was found to be more frequent in those diagnosed with ESBL(+) UTI (p < 0.001). Having an underlying disease and hospitalization, infections, and use of antibiotics within the last 3 months were found to be potential risk factors (p < 0.001). With conditional logistic regression analysis, having an underlying disease and hospitalization within the last 3 months were identified as independent risk factors for ESBL(+) UTI. In conclusion, the recognition of risk factors for UTI, caused by ESBL(+) bacteria in children, may aid in the identification of high-risk cases and may enable proper management of these patients.

Behçet disease is the only primary vasculitis that affects both arteries and veins of any size. We present our treatment protocol in disease with vascular involvement in seven pediatric patients. All seven patients met the international criteria for the disease before the age of 16 years. Only one was a girl. The vascular involvement was as follows: Two patients had superficial vein thrombosis, two patients had atrial or ventricular thrombosis, one had arterial involvement with pulmonary aneurysms, and two had thrombosis of the venous sinuses in the central nervous system. The median duration of vascular involvement was 4 months (range 3-24 months) after the diagnosis of BD and was concomitant with diagnosis in three patients. All received colchicine and steroids. The ones with thrombosis in the venous system received additional azathioprine, whereas those with pulmonary arterial or cardiac involvement initially received cyclophosphamide for 150-180 mg/kg total dose (IV or oral) and then were switched to azathioprine for a further 6 months. All except the patient with pulmonary arterial involvement received a course of anticoagulation treatment as well. These patients have been followed up for a period of at least 18 months and so far are free of vascular relapses. One has developed a severe uveitis necessitating further therapy. In conclusion, features of vascular involvement should be carefully sought for in patients with Behçet disease. Effective management has enabled disease-free survival in the presented patients.

The aim of our study was to evaluate the neuroendocrine system in patients with juvenile idiopathic arthritis (JIA) regarding the activity of disease. Twenty-one JIA patients (mean age +/- standard deviation 10.5 +/- 4.1 years) were included. None of the patients was taking steroids or antitumor necrosis factor-alpha therapy during this study. Ten healthy volunteers and ten volunteers with upper respiratory tract infection composed the control groups. Furthermore, ten of the 21 JIA patients were also evaluated during the remission period. Erythrocyte sedimentation rate, C-reactive protein, adrenocorticotropic hormone (ACTH), cortisol, prolactin, insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein 3, free T3, free T4, thyroid-stimulating hormone, interleukin-6 (IL-6) levels, and 24-h urinary cortisol were evaluated both during the active period and remission. The median levels of ACTH and cortisol at 08:00 a.m. were significantly lower in patients with active JIA than patients in remission period and the control groups (p < 0.05). Furthermore, the median level of urine cortisol in active JIA patients was significantly lower than remission period and control groups (p < 0.05). The median level of IGF-1 was significantly lower in active patients than that of remission (p < 0.05). The median level of IL-6 in active JIA patients was significantly higher than those in remission and control groups (p < 0.05). Our preliminary study suggested that impaired secretion of adenohypophyseal hormones and distorted bilateral interactions between the immune and endocrine systems in JIA. Further studies are needed to clarify the consequences of the impaired hormone secretion in JIA.

Cyclophosphamide (CYC) has been the landmark in the treatment of lupus nephritis. However, long-term treatment with CYC is associated with significant side effects. We aimed to evaluate the efficacy of short-term intravenous (IV) CYC treatment as a remission induction treatment followed by azathioprine (AZA) or mycophenolate mofetil (MMF) as a maintenance treatment. Twenty patients (18 girls) with biopsy-proven class III (5) and IV (15) lupus nephritis were included in to the study. Detailed clinical and laboratory data and patient outcomes were evaluated. All patients received three methylprednisolone (MP) IV pulses, followed by oral prednisone 0.5-1 mg/kg per day and one IV pulse of CYC per month for 6 months. Azathioprine was started as a remission-maintaining treatment. In ten of 20 patients, treatment was switched to MMF. The mean age at the time of diagnosis was 16.11 +/- 3.49 years, and the mean duration of follow-up was 49.6 +/- 27 months. Fourteen patients (70%) had complete remission, three (15%) had partial remission, one (5%) continued to have active disease, and two (10%) progressed to end-stage renal disease. Nine of the patients (45%) with complete remission had received AZA, and switching to MMF increased complete remission rate (additional five patients; 25%). In conclusion, short-term (6-month) IV bolus CYC treatment followed by AZA is a safe and effective treatment in children with severe lupus nephritis, and using MMF increases remission rate in resistant cases.

Human congenital anomalies of the kidney and urinary tract (CAKUT) represent the major causes of chronic renal failure (CRF) in children. This set of disorders comprises renal agenesis, hypoplasia, dysplastic or double kidneys, and/or malformations of the ureter. It has recently been shown that mutations in several genes, among them BMP4, are associated with hereditary renal developmental diseases. In BMP4, we formerly identified three missense mutations (S91C, T116S, N150K) in five pediatric CAKUT patients. These BMP4 mutations were subsequently studied in a cellular expression system, and here we present functional data demonstrating a lower level of messenger RNA (mRNA) abundance in Bmp4 mutants that indicates a possible negative feedback of the mutants on their own mRNA expression and/or stability. Furthermore, we describe the formation of alternative protein complexes induced by the S91C-BMP4 mutation, which results in perinuclear endoplasmic reticulum (ER) accumulation and enhanced lysosomal degradation of Bmp4. This work further supports the role of mutations in BMP4 for abnormalities of human kidney development.

Objective: Juvenile idiopathic arthritis (JIA) is a childhood rheumatic disease of unknown etiology. Two subgroups of JIA, i.e., oligoarticular and polyarticular, are thought to have an autoimmune component, and show a higher female:male ratio. Skewed X chromosome inactivation (XCI) has previously been shown to be associated with scleroderma and autoimmune thyroiditis, 2 autoimmune disorders occurring predominantly in females. This study was undertaken to extend the analysis to the pediatric age group and to determine the XCI profiles of patients with JIA., Methods: A polymorphic repeat in the androgen receptor gene was genotyped to determine XCI status in 81 female patients with JIA (21 with polyarticular disease and 60 with oligoarticular disease) and 211 healthy female controls. DNA obtained from venous blood samples was used for this analysis., Results: Informative data were obtained on 62 JIA patients and 155 controls. Skewed XCI was observed in 14 patients (22.6%) and 11 controls (7.1%) (P = 0.0036), and extreme skewing was apparent in 8 patients (12.9%) and 2 controls (1.3%) (P = 0.0008)., Conclusion: Our findings in the present study indicate that skewed XCI may be a risk factor for the occurrence of autoimmune disorders, including JIA.

Background: Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor., Methods: After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion., Results: A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease., Conclusions: Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.), (2009 Massachusetts Medical Society)

Although more commonly presenting in adulthood, approximately 15-20% of systemic lupus erythematosus (SLE) cases occur before age 16 years. Unfortunately, SLE is usually more severe when presenting in childhood, and frequently involves vital organs such as the kidney. Over the past several decades, mortality rates have dropped, largely due to earlier diagnosis, improved management of the SLE and improved general medical care to reduce infection. Treatment strategies for nephritis in children is largely adopted from experience in adults, and the recent advances in therapeutic options for adults have brought new treatment to children. However, determining efficacy is difficult due to the absence of clinical trial data. Furthermore, determination of safety in a developing child or adolescent cannot be extrapolated from adult studies. As survival has improved, numerous secondary complications have emerged, including early atherosclerosis. As for adults with SLE, it is generally accepted that atherogenesis in SLE results from both disease- and treatment-related factors. Most surprising is that persons with childhood-onset SLE can develop myocardial ischaemia as early as 20-30 years of age. Better understanding of the pathogenesis and development of preventative strategies is needed to ensure that these young people do not succumb to atherosclerosis instead of to SLE.

Objectives: Several sets of criteria mainly for adults have been proposed for the diagnosis of FMF. The aim of the present study is to validate the most widely used diagnostic 'Tel Hashomer' criteria in children and to establish a new set of criteria for use in childhood., Methods: The study group consisted of 170 recently diagnosed FMF patients who had mutations at both alleles. They were interviewed about the presence of 35 features and manifestations of FMF at the time of diagnosis. Controls were consecutive patients without FMF (n = 141) who had episodes of fever and clinical features mimicking that of FMF. The diagnostic performance of the candidate features was assessed by multiple logistic regression analysis., Results: The sensitivity and specificity of Tel Hashomer criteria in our study group were 98.8 and 54.6%, respectively. The multiple logistic regression analysis showed that 5 (fever, abdominal pain, chest pain, arthritis and family history of FMF) of the 35 candidate criteria discriminate FMF from controls with a sensitivity and specificity of 88.8 and 92.2%, respectively. The presence of two or more of these five criteria diagnosed FMF with a sensitivity of 86.5% and a specificity of 93.6%., Conclusion: It was demonstrated that although the Tel Hashomer criteria were successful in diagnosing the FMF patients in childhood, its specificity was definitely low in children. The new set of criteria has a high sensitivity and specificity for the diagnosis of FMF and is practical to use on an everyday basis.

Background: Worldwide, familial Mediterranean fever (FMF) is the most common autoinflammatory disease. It has been suggested that environmental factors affect the phenotype as some patients do not develop the complication of secondary amyloidosis., Objective: To analyse whether disease severity in Turkish children with FMF, living in Turkey and Germany is different., Patients and Methods: A total of 55 Turkish children living in Turkey were compared with 45 Turkish children born and raised in Germany. Mean age among the group from Turkey and Germany was 42.2 and 44.29 months, respectively. M694V was the leading mutation in both groups. The severity scores were compared with two scoring systems, modified according to published paediatric data for dosage., Results: There was no significant difference between the mean C-reactive protein and erythrocyte sedimentation rate levels of the two groups. According to the modified Sheba Center score, 78.2% of patients from the group living in Turkey had a severe course compared with 34.1% from the group living in Germany. The modified score of Pras et al also showed more severe disease in the patients from Turkey. The difference between the two groups for both scoring systems were significant (both p<0.05)., Conclusions: We believe the modified scores that we introduce can be widely used for children. Our results suggest that the environment affects the phenotype of a monogenic disease of the innate inflammatory pathway.

Objective: To demonstrate the role of sonography in depicting periarticular changes in juvenile systemic lupus erythematosus (SLE) and to find out whether certain tendons in juvenile SLE patients were different from those of healthy controls., Methods: Thirty juvenile SLE patients (27 female, 3 male) were recruited for this study. Sonographic evaluations were performed in the knee, ankle, elbow, wrist, and metacarpophalangeal (MCP) joints on the nondominant sides of the individuals. For comparison, 32 healthy volunteers were included as a control group., Results: Knee effusion was observed more frequently in the juvenile SLE group compared with the control group (P = 0.00). When tendon thickness measurements were compared between the groups, flexor and extensor tendons of the third finger (at MCP joint level) of juvenile SLE patients were found to be thinner (P = 0.04 and P = 0.03, respectively). Tendon thickness values did not correlate with disease duration or SLE disease activity index scores (P > 0.05)., Conclusion: The main findings of our study were relevant with 1) increased involvement of the knee, ankle, hand extensor tendons, wrist, elbow, and hand flexor tendons (in decreasing order of frequencies) in juvenile SLE, and 2) decreased extensor/flexor tendon thicknesses in the hands of juvenile SLE patients. Physicians should be aware of the potentially disabling scenario of tendon pathologies. Defining the extent of joint and tendon pathologies in juvenile SLE may guide us in the management of the disease.

Background/aim: The aim of this retrospective study was to evaluate the presentation, clinical and pathological manifestations and outcome of the Henoch-Schönlein purpura (HSP) nephritis in children., Methods: Clinical and laboratory data of 443 children with HSP nephritis aged between 3 and 16 years from 16 pediatric nephrology reference centers were analyzed retrospectively. The biopsy findings were graded according to the classification developed by the International Study of Kidney Disease in Children (ISKDC)., Results: Renal biopsy was performed in 179 of the patients with HSP nephritis. The most common presenting clinical finding in patients who were biopsied was nephrotic range proteinuria (25%) which was followed by nephritic-nephrotic syndrome (23.5%). The biopsy findings according to the ISKDC were as follows: class I: 8.3%; II: 44.1%; III: 36.3%; IV: 6.7%; V: 3.3%; VI: 1.1%. All of the patients who developed end-stage renal disease had nephritic-nephrotic syndrome at presentation. Of 443 patients, 87.2% had a favorable outcome and 12.8% had an unfavorable outcome. The overall percentage of children who developed end-stage renal disease at follow-up was 1.1%. Logistic regression analysis did not show any association of initial symptoms and histology with outcome., Conclusion: In the presented cohort, the presence of crescents in the first biopsy or presenting clinical findings did not seem to predict the outcome of HSP nephritis in children. We conclude that children with HSP nephritis even with isolated microscopic hematuria and/or mild proteinuria should be followed closely., (Copyright 2009 S. Karger AG, Basel.)

The aim of the present study was to determine whether intima-media thickness (IMT) of the common (CCA) and internal carotid arteries (ICA) was increased due to chronic inflammation occurring in familial Mediterranean fever (FMF) patients compared to healthy controls. Erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), serum amyloid A protein (SAA), lipid profile and homocysteine levels were examined in 70 FMF patients [median age 14 years (range 4-24)] in an attack free period and in 50 healthy controls [median age 14 years (range 4-18)]. All the patients were homozygous or compound heterozygous for MEFV mutations. IMT of both CCA and ICA was evaluated with a high resolution B-mode ultrasonography. ESR, CRP, fibrinogen and SAA levels were significantly higher in FMF patients as compared to healthy controls (P < 0.05). Intima media thickness of the common carotid artery was found to be significantly higher in FMF patients when compared to those in healthy controls [0.37 mm (0.26-0.61) vs. 0.28 mm (0.21-0.35), P < 0.001]. The median ICA-IMT was significantly increased in the patients when compared to those in the controls [0.25 mm (0.18-0.44) vs. 0.22 mm (0.10-0.26), P < 0.001]. A positive correlation between CCA-IMT and SAA levels (r = 0.24, P = 0.04) was found while ICA-IMT positively correlated with ESR (r = 0.31, P = 0.008) and fibrinogen levels (r = 0.30, P = 0.012). Intima media thickness, an early predictor of atherosclerosis, may be associated with subclinical inflammation in children with FMF. Further studies will enlighten whether these patients will be predisposed more to coronary artery disease.

Henoch-Schonlein purpura (HSP) is the most common systemic vasculitis in children. Although long-term outcome is generally good, serious complications may occur. Thrombosis has been reported only as an extremely rare complication of HSP. Here, we describe a 15-year-old-boy with features of HSP, who developed left main iliac, external iliac and femoral vein thrombosis. Factor VIII (FVIII) and homocystein levels were found to be high. This suggests that HSP itself may lead to a prothrombotic state and increase the risk of developing thrombosis in patients who have any risk factors.

Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.

Nephrotic syndrome represents a form of acquired thrombophilia thereby causing increased risk of thrombosis. In patients with nephrotic syndrome both venous and arterial thrombosis can occur; however, intracardiac thrombus is among the rarest reported in the literature. In this case report, we present a 10.5-yr-old boy with right atrial thrombosis and an acute rejection episode after renal transplantation due to end stage renal disease caused by focal segmental glomerulosclerosis manifested by nephrotic syndrome. The clinical course was successfully managed with surgical removal of thrombus, institution of anticoagulant as well as antirejection therapy. This report draws attention to the risks that could be associated with thrombosis in renal recipients with congenital or acquired thrombophilias and emphasizes the importance of identifying risk factors for thrombosis in these patients.

Distinct eye abnormalities have been described in children with nephrotic syndrome, particularly in diffuse mesangial sclerosis (i.e. Pierson syndrome). The aim of the study was to investigate whether there were any associated ocular anomalies in children with steroid-resistant nephrotic syndrome (SRNS), all of whom had revealed primary focal segmental glomerulosclerosis in biopsy. Thirty-three SRNS patients (16 male, 17 female) with a median age of 10.5 years (range 3-25 years) were enrolled in the study. Twenty steroid-sensitive nephrotic syndrome (SSNS) patients (ten male, ten female) with a median age of 8 years (range 3-15 years) served as controls. All SRNS patients were examined by mutational analysis for mutations in the NPHS2, WT1, and LAMB2 genes. Nine out of 33 SRNS patients (27.2%) showed various eye abnormalities. However, no abnormal ocular findings were detected in any of the SSNS patients. Abnormal eye findings detected in SRNS patients were anisometropic amblyopia (n = 4), Mittendorf's dots (n = 4), myopic astigmatism (n = 3) and exotropia (n = 1). Macular pigment changes (n = 1), posterior subcapsular opacities (n = 1) and cataract (n = 1) were considered as steroid-induced side effects. In four patients, more than one eye abnormality was found. Mutational analysis for the NPHS2, WT1 and LAMB2 genes revealed disease-causing mutations in 24.2% of patients. Homozygous NPHS2 mutations were detected in five patients (15.1%), all of whom had parental consanguinity. In three patients (9%) from non-consanguineous parents, heterozygous de novo WT1 mutations were detected as disease-causing mutations. No LAMB2 mutation was detected in any patient. While four out of five (80%) patients with homozygous NPHS2 mutations showed at least one abnormal ocular finding (i.e. Mittendorf's dot or anisometric amblyopia), none of the patients with a WT1 mutation had ocular involvement. In conclusion, ocular involvement may accompany SRNS caused by primary focal segmental glomerulosclerosis (FSGS). Ophthalmologic evaluation at the time of diagnosis might be beneficial to characterize further the spectrum of this possible association.

Introduction: Renal transplantation in patients with lower urinary tract dysfunction (LUTD) of various origins is a challenging issue in the field of pediatric transplantation. We report our single-center experience to evaluate patient and graft survivals as well as the risks of the surgery and immunosuppressive therapy., Patients and Methods: Among 70 pediatric transplant patients, 11 displayed severe LUTD. Videourodynamic tests were performed on all patients preoperatively as well as postoperatively if required. The cause of urologic disorders were neurogenic bladder (n = 5) and urethral valves (n = 6). Clean intermittent catheterization (CIC) was needed in six patients to empty the bladder. To achieve a low-pressure reservoir with adequate capacity pretransplantation augmentation ileocystoplasty was created in four patients and gastrocystoplasty in one patient. Three of the patients received kidneys from cadaveric and eight from living donors. All patients were treated with calcineurin-based immunosuppressive therapy., Results: The mean age at transplantation was 15 +/- 4.7 years. The median follow-up after transplantation was 36 months (6 to 62 months). At their last visit the median creatinine level was 0.95 mg/dL (0.8 to 2.4 mg/dL). Three patients had recurrent symptomatic urinary tract infections who had augmented bladder on CIC. One patient with ileocystoplasty who developed urinary leak and ureteral stricture in the early postoperative period was treated by an antegrade J stent., Conclusion: Severe LUTD carried high risks for the grafted kidney. However, our data suggested that renal transplantation is a safe and effective treatment modality, if the underlying urologic diseases properly managed during the transplantation course. Since surgery and follow-up is more complicated, patient compliance and experience of transplantation team have significant impacts on outcomes.

Central nervous system (CNS) manifestations are not rare in pediatric rheumatic diseases. They may be a relatively common feature of the disease, as in systemic lupus erythematosus (SLE) and Behçet's disease. Direct CNS involvement of a systemic rheumatic disease, primary CNS vasculitis, indirect involvement secondary to hypertension, hypoxia and metabolic changes, and drug associated adverse events may all result in CNS involvement. We have reviewed the CNS manifestations of SLE, Behçet's disease, Henoch-Schönlein purpura, polyarteritis nodosa, juvenile idiopathic arthritis, juvenile ankylosing spondylitis, familial Mediterranean fever, scleroderma, sarcoidosis, Wegener's granulomatosis, Takayasu's arteritis, CINCA syndrome, Kawasaki disease, and primary CNS vasculitis; and adverse CNS effects of anti-rheumatic drugs in pediatric patients. The manifestations are diverse; ranging from headache, seizures, chorea, changes in personality, depression, memory and concentration problems, cognitive impairment, cerebrovascular accidents to coma, and death. The value of cerebrospinal fluid (CSF) examination (pleocytosis, high level of protein), auto-antibodies in serum and CSF, electroencephalography, neuroimaging with computerized tomography, magnetic resonance imaging, SPECT, PET, and angiography depends on the disease. Brain biopsy is gold standard for the diagnosis of CNS vasculitis, however it may be inconclusive in 25% of cases. A thorough knowledge of the rheumatic diseases and therapy-related adverse events is mandatory for the management of a patient with rheumatic disease and CNS involvement. Severe CNS involvement is associated with poor prognosis, and high mortality rate. High dose steroid and cyclophosphamide (oral or intravenous) are first choice drugs in the treatment; plasmapheresis, IVIG, thalidomide, and intratechal treatment may be valuable in treatment-resistant, and serious cases.

Introduction: The recurrence of primary disease in transplantation is a well-known problem. We report our single-center experience to assess the frequency of the recurrence of primary glomerulonephritis in children after renal transplantation., Patients and Methods: Medical reports of 14 children with primary glomerular disease were evaluated. Among the 14 grafts were 10 from living related and four from cadaveric donors. Ten were diagnosed as focal segmental glomerulosclerosis (FSGS), two membranoproliferative glomerulonephritis (MPGN), and two polyarteritis nodosa (PAN). The original diagnosis was biopsy-proven in every case. All patients were treated with calcineurin-based immunosuppressive therapy., Results: The mean age was 15.5 +/- 5.4 years. The median transplantation duration was 47 months; however, one of the FSGS patient had hyperacute rejection. Five years later she received a second graft with a serum creatinine of 0.7 mg/dL at 7 years after transplantation. Posttransplant recurrence of FSGS was confirmed in two patients (20%), who were treated with plasmapheresis with no improvement of proteinuria, two FSGS patients had thromboses after transplantation. One had a cardiac thrombosis with heterozygote MTHFR mutation and one, a renal artery thrombosis and loss of graft with prothrombin 20210A mutation. They all have functioning grafts except these two. We did not observe recurrence of PAN or MPGN in patients., Conclusion: Although the number of patients is quite small, our recurrence rate was compatible with the previous reports. Additionally, we strongly recommend evaluation of all risk factors for thrombosis and give appropriate anticoagulation.

Objectives: Digital subtract angiography is the gold standard for anatomic assessment of renal vasculature for living renal donors. However, multidetector-row computerized tomography (MDCT) is less invasive than digital subtract angiography and provides information of kidney stones and other intra-abdominal organs. In this study, preoperative MDCT angiography results were compared with the peroperative findings to evaluate the accuracy of MDCT for the evaluation of renal anatomy., Methods: From December 2002 to May 2007, all 60 consecutive living kidney donors were evaluated with MDCT angiography preoperatively. We reported the number and origin of renal arteries, presence of early branching arteries, and any intrinsic renal artery disease. Renal venous anatomy was evaluated for the presence of accessory, retroaortic, and circumaortic veins using venous phase axial images. The calyces and ureters were assessed with delayed topograms. The results of the MDCT angiography were compared with the peroperative findings., Results: A total of 67 renal arteries were seen peroperatively in 60 renal units. Preoperative MDCT angiography detected 64 of them. The two arteries not detected by MDCT had diameters less than 3 mm. Anatomic variations were present in nine veins, five of which were detected by CT angiography. Sensitivity of MDCT angiography for arteries and veins was 95% and 93%, respectively. Positive predictive values were 100% for both arteries and veins., Conclusion: MDCT angiography offers a less invasive, rapid, and accurate preoperative investigation modality for vascular anatomy in living kidney donors. It also provides sufficient information about extrarenal anatomy important for donor surgery.

Aim: In this single-center cohort, we retrospectively analyzed the efficacy and safety of tacrolimus in pediatric renal transplantation., Methods: We examined the medical records of 22 consecutive renal transplantation recipients (12 boys, 10 girls) receiving tacrolimus, to evaluate occurrence of acute rejection (AR) episodes, glomerular filtration rates (GFR), and side effects., Results: The mean recipient age was 15.07 +/- 3.96 years. Seven grafts came from cadaveric, and 15 from living related donors. The patients were placed on immunosuppression with prednisolone and tacrolimus plus azathioprine (n = 8) or mycophenolate mofetil (MMF) (n = 12) or enteric-coated mycophenolate sodium (n = 2). Eighteen patients received basiliximab on days 0 and 4. There were three AR episodes at 5, 9, and 12 months. Mean GFR at the end of 1 and 2 years were 97.1 +/- 24.0 mL/min/1.73 m(2) and 116.9 +/- 42.2 mL/min/1.73 m(2), respectively. There was no graft loss. Hypertension, hyperlipidemia, and hyperglycemia were present in 14 (63.6%), 3 (13.6%), and 3 (13.6%) patients, respectively, without gingival hyperplasia, tremor, or hypertrichosis. Supraventricular tachycardia was noticed in five patients (22.7%), three of whom needed antiarrhythmic drugs (13.6%)., Conclusion: Our single-center experience with tacrolimus, steroid plus azathioprine or MMF or enteric-coated mycophenolate sodium regimen in pediatric kidney recipients showed a low rate of AR with excellent graft survival and function at 1 and 2 year posttransplantation. The increased rate of supraventricular tachycardia in this regimen had not been previously reported; this association merits further studies.

Cardiovascular diseases are the main causes of morbidity and mortality following renal transplantation. Atherosclerotic structural changes, which can be detected by high-resolution B-mode ultrasonography, begin before clinical findings. However, little is known about the extent of these abnormalities in children after renal transplantation. We aimed to determine early structural changes of large arteries in renal transplant recipients without cardiovascular disease and to evaluate the role of clinical and laboratory features on IMT of carotid arteries. IMT and hemoglobin, serum levels of creatinine, acute phase proteins, lipid profile, and homocysteine were examined in 24 asymptomatic renal transplant recipients (median age 16.5 yr; range 8-25), and 20 healthy controls (median age 16 yr; range 9-24). CCA and ICA were evaluated in patients and controls with a high-resolution B-mode ultrasonography in multiple projections to optimize detection of carotid IMT. Measurement of IMT of both CCA [0.36 mm (range 0.16-0.48) vs. 0.28 mm (range 0.21-0.35), p < 0.001] and ICA [0.27 mm (range 0.16-0.48) vs. 0.22 mm (range 0.1-0.26), p < 0.001] were significantly higher in renal recipients than in healthy controls. Among several parameters assessed, only significant correlations were found between duration of CRF, duration of dialysis prior to transplantation and ICA-IMT (p = 0.06 and p = 0.02, respectively) and between mean past serum calcium-phosphorus ion product and CCA-IMT (p = 0.002). In conclusion, our observations indicate that vascular changes begin early in the course of CRF and are directly related to time on CRF and dialysis. These changes can be detected by measuring CCA/ICA-IMT ultrasonographically. We suggest that early renal transplantation can potentially avoid long-term cardiovascular events in children with end stage kidney disease.

Objectives: Patients who receive tumour necrosis factor-alpha (TNF-alpha) blockers are mostly immunosuppressed. A study was performed to investigate whether an interferon-gamma (IFN-gamma) assay could represent an alternative approach to the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI) in these patients., Design: We prospectively enrolled 106 individuals into the study in two groups. Group 1 consisted of 38 healthy individuals and Group 2 included 68 patients with chronic inflammatory diseases evaluated for LTBI before the use of TNF-alpha blockers., Results: Of all participants, nine had indeterminate IFN-gamma test results. Agreement between the two tests was poor in both groups (kappa values respectively -0.54 and 0.18). In a total of 97 subjects, 10 (10.3%) were positive by the IFN-gamma test and 49 (50.5%) by TST., Conclusion: We found poor agreement between TST and the IFN-gamma test in our study. Our limited preliminary data should be accepted as a basis for designing future studies that will be helpful for physicians to decide whether the IFN-gamma test is more sensitive than the TST test in detecting LTBI before the use of TNF-alpha blockers.

Objective: To assess a possible relationship between prematurity and casual blood pressure (BP) by means of 24-hour ambulatory BP monitoring (ABPM)., Study Design: ABPM was performed in 41 children aged 5 to 17 years who were born prematurely with (n = 11) or without intrauterine growth restriction, and in 27 matched children who were born at term with a birth weight appropriate for gestational age., Results: Although BP did not differ between the preterm group and control subjects during the daytime, nocturnal standardized systolic BP was elevated (P < .05) and a lack of nocturnal decrease was more prevalent in the preterm children compared with the control subjects (73% versus 41%, P = .01). The difference was caused by a marked increase of nighttime systolic BP in the light-for-date children (1.17 +/- 0.61 standard deviation scores; P < .01), although preterm children with appropriate weight (0.33 +/- 1.00) were not different from control subjects (0.09 +/- 0.73). Nighttime BP standard deviation scores were closely correlated with standardized heart rate, compatible with a role of sympathetic hyperactivation., Conclusion: Subtle abnormalities of BP regulation, indicated by a selective increase of nocturnal systolic BP, are present during childhood in subjects born prematurely, and are prominent in those with intrauterine growth restriction.

Renovascular disease accounts for 8-10% of all cases of paediatric hypertension, whereas, in adults, its incidence is approximately 1%. The Turkish Paediatric Hypertension Group aimed to create the first registry database for childhood renovascular hypertension in Turkey. Twenty of the 28 paediatric nephrology centres in Turkey responded to the survey and reported 45 patients (27 girls, 18 boys) with renovascular hypertension between 1990 and 2005. The age at presentation ranged from 20 days to 17 years. The mean blood pressure at the diagnosis was 169/110 mmHg. Chief complaints of symptomatic patients were headache (38%), seizure (18%), epistaxis (4%), growth retardation (4%), cognitive dysfunction (4%), polyuria (2%), palpitation (2%), and hemiplegia (2%). Renovascular hypertension was found incidentally in 11 children. The diagnosis of renovascular hypertension was established with conventional angiography in 39 patients, MR angiography in three, CT angiography in two, and captopril diethylene triamine penta-acetic acid (DTPA) scintigraphy in one patient. Twenty-one children had bilateral renal artery stenosis and 24 had unilateral renal artery stenosis. Of these, 14 (31%) had fibromuscular dysplasia; 12 (27%) Takayasu's arteritis; six (13%) neurofibromatosis; two (5%) Williams syndrome; one (2%) Kawasaki disease; one (2%) mid-aortic syndrome; one (2%) extrinsic compression to the renal artery, and eight (18%) unspecified bilateral renal artery stenosis. Hypertension was controlled with antihypertensive drugs in 17 patients. Percutaneous transluminal angioplasty (PTRA) or surgery had to be performed in 28 patients: PTRA in 16 patients, PTRA + surgery in one patient and surgery in 11 patients (four nephrectomies). The importance of vasculitic disease, especially Takayasu's arteritis, should not be underestimated in children with renovascular hypertension.

Background: Henoch-Schönlein purpura (HSP) is a systemic, small vessel vasculitis, which is very common among pediatric population. Findings of previous reports addressing the preventive effect of corticosteroid treatment in HSP nephritis have been inconsistent. The aim of this study was to determine whether corticosteroid therapy was effective in preventing Henoch-Schönlein nephritis., Methods: The medical records of 216 children with HSP, seen in 2 tertiary care pediatric nephrology centers, were reviewed retrospectively. The effect of corticosteroid therapy on preventing nephritis was assessed in 157 patients who had no evidence of nephritis at the initial urinalysis. The treatment group (n=61) had received oral corticosteroids for gastrointestinal symptoms and/or arthritis. The dosage of prednisone was 1 mg/kg per day for 1-2 weeks, with weaning over a week. We compared the rate of renal involvement during follow-up between the groups who were treated with corticosteroids and not., Results: Nephritis developed in 17 of the 61 (27.8%) corticosteroid-treated patients and 18 of the 96 (18.7%) untreated patients during follow-up., Conclusion: There was no evidence that corticosteroids reduced the risk of renal involvement in HSP, and these results do not support the use of corticosteroids in early HSP to prevent renal injury.

The most important complication of FMF is the development of amyloidosis. It is more common in the eastern Mediterranean compared to the US. The individual response to endotoxin may have a significant effect on the development of amyloidosis in FMF patients. To investigate the association between CD14 promotor C-159T polymorphism and development of amyloidosis, one hundred and forty-six patients who had FMF and had not developed amyloidosis; 26 with FMF and secondary amyloidosis and 92 controls were genotyped at the CD14-C159T locus. There was no difference between the genotype distribution of FMF patients (CC 30.0%, CT 50.0%, TT 20.0%) and controls (CC 29.2%, CT 45.8%, TT 25%); or between FMF patients with amyloidosis (CC 30.8%, CT 53.8%, TT 15.4%) or without amyloidosis (CC 29.2%, CT 45.8%, TT 25%). Our study shows that the CD14-C159T polymorphism is not associated with FMF or development of amyloidosis in the population studied. The effect of the genetic variations in the endotoxin signaling pathway under different environmental conditions such as high and low endotoxin exposure remain to be determined.

Aim: The aims of this study were to evaluate the characteristics of childhood vasculitides and to establish the first registry in Turkey, an eastern Mediterranean country with a white population., Patients and Methods: A questionnaire was distributed to the main referral centers asking for the registration of the Henoch-Schönlein purpura (HSP) patients in the last calendar year only and 5 years for other vasculitides. Demographic, clinical, and laboratory data were assessed., Results: Vasculitic diseases were registered from 15 pediatric centers. These centers had a fair representation throughout the country. In the last calendar year, incidences were as follows: HSP 81.6%, Kawasaki disease (KD) 9.0%, childhood polyarteritis nodosa (C-PAN) 5.6%, Takayasu arteritis (TA) 1.5%, Wegener's granulomatosis 0.4%, and Behçet disease 1.9%. There was no clear gender dominance. The mean age was 11.05+/-4.89 years. Acute phase reactants were elevated in almost all, highest figures being in C-PAN. Renal involvement was present in 28.6% of HSP and 53% of the C-PAN patients. Abdominal aorta was involved in all TA patients. Among the C-PAN patients, 25% had microscopic PAN with necrotizing glomerulonephritis; antineutrophil cytoplasmic antibody was positive in those who were studied. Among the patients, 12.5% and 15% had classic PAN and cutaneous PAN, respectively. The remaining majority were classified as systemic C-PAN diagnosed with biopsies and/or angiograms demonstrating small to midsize artery involvement. The overall prognosis was better than reported in adult series., Conclusion: This is the largest multicenter study defining the demographic data for childhood vasculitides. The distribution of childhood vasculitides was different in our population where KD is much less frequent, whereas HSP constitutes an overwhelming majority. C-PAN was more frequent as well.

Objective: To review the results of our treatment protocol in the last 7 years., Study Design: Six patients (4 girls, 2 boys) with an age range of 12 to 17 years were diagnosed with Takayasu arteritis (TA) during this period. Patients were allocated to receive (1) oral steroids and methotrexate (MTX) (12.5 mg/m(2)/week) if they had disease limited to one side of the diaphragm only without pulmonary disease involvement (two patients); and (2) oral steroids and oral cyclophosphamide (CYC) (maximum total dose 150 mg/kg) followed by oral MTX for maintenance as above if the disease was more widespread (four patients)., Results: One patient died of pulmonary vasculitis during the first month of therapy. The remaining three patients with involvement of both the thoracic and abdominal aorta and branches received the second protocol for 12 to 18 months. All entered remission. Aortic bypass, aortorenal bypass, balloon dilatation, and unilateral nephrectomy were performed in these patients., Conclusions: The presented single-center experience suggests that CYC induction and corticosteroids followed by MTX is an effective and safe treatment for childhood TA.

Objective: Familial Mediterranean fever (FMF) is an autoinflammatory disease common in eastern Mediterranean populations. The most severe complication is the development of secondary amyloidosis. Toll-like receptor (TLR-2) plays a critical role in linking the recognition of microbes to immune activation. We investigated whether the Arg753Gln TLR2 polymorphism affected the development of secondary amyloidosis in patients with FMF., Methods: We studied 75 patients with FMF, 40 patients with FMF who developed secondary amyloidosis, and 116 healthy controls. TLR2 gene Arg753Gln mutations were analyzed with a polymerase chain reaction-restriction fragment length polymorphism method., Results: The frequency of the Arg753Gln TLR2 polymorphism among the Turkish population was 6%, whereas it was 25.2% among patients with FMF (p < 0.01). The difference of the frequency of the polymorphism between FMF patients with and without amyloidosis was significant: 15/40 (37.5%) and 14/75 (18.6%), respectively (p = 0.02)., Conclusion: The Arg753Gln polymorphism may affect the severity of this monogenic disease by influencing the innate immune response to pathogens. The presence of the polymorphism may influence the phenotype of FMF in geographic areas where bacterial insult is more common.

Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.

Objective: We aimed to compare whether carriers for the MEFV mutations display an increase or decrease in certain features. We compared the frequency of a number of inflammatory symptoms and diseases in carriers and a control population., Methods: A questionnaire was designed to be applied to parents of children with FMF and a control group of parents. Clinical features and some diseases including the frequency of febrile episodes, abdominal pain, arthralgia, prophylaxis with penicillin, acute rheumatic fever, rheumatoid arthritis, vasculitis, spondyloarthropathy, urinary tract infection, asthma, allergy, irritable bowel disease, appendectomy and tonsillectomy were inquired. 676 parents of 440 children with FMF were surveyed in this study. Controls (n: 774) were selected as parents of healthy children., Results: The presence of febrile episodes more than four per year, arthralgia, past diagnosis for acute rheumatic fever, rheumatoid arthritis and prophylaxis of penicillin, acute rheumatic fever, and rheumatoid arthritis were significantly higher in asymptomatic parents for the MEFV mutations compared to controls. The frequency of allergy was found to be significantly lower in the asymptomatic parents as compared to controls. There was no significant difference at the frequency of urinary tract infection and tonsillectomy between the parents of the patents and controls., Conclusions: We suggest that one MEFV mutation may indeed be conferring a heightened inflammation as suggested by the increased frequency in inflammatory symptoms. The carrier status for MEFV mutations seem to be unique, in that they cause an alteration in the state of "health".

Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By homozygosity mapping in a consanguineous family with isolated congenital nephrotic syndrome, we identified a potential candidate region on chromosome 3p. The LAMB2 gene, which was recently reported as mutated in Pierson syndrome (microcoria-congenital nephrosis syndrome; OMIM #609049), was located in the linkage interval. Sequencing of all coding exons of LAMB2 revealed a novel homozygous missense mutation (R246Q) in both affected children. A different mutation at this codon (R246W), which is highly conserved through evolution, has recently been reported as causing Pierson syndrome. Subsequent LAMB2 mutational screening in six additional families with congenital nephrotic syndrome revealed compound heterozygosity for two novel missense mutations in one family with additional nonspecific ocular anomalies. These findings demonstrate that the spectrum of LAMB2-associated disorders is broader than previously anticipated and includes congenital nephrotic syndrome without eye anomalies or with minor ocular changes different from those observed in Pierson syndrome. This phenotypic variability likely reflects specific genotypes. We conclude that mutational analysis in LAMB2 should be considered in congenital nephrotic syndrome, if no mutations are found in NPHS1, NPHS2, or WT1.

Background: Renal hypodysplasia, characterized by a decrease in nephron number, small overall kidney size, and maldeveloped renal tissue, is a leading cause of chronic renal failure in young children. Familial clustering and renal hypodysplasia phenotypes observed in transgenic animal models suggest a genetic contribution. Uroplakin IIIa (encoded by UPIIIA) is an integral membrane protein present in urothelial plaques, and the murine UPIIIa knockout is associated with urothelial anomalies and vesicoureteral reflux. De novo UPIIIA mutations recently were identified in 4 of 17 patients with severe bilateral renal adysplasia., Methods: To evaluate the overall role of UPIIIA in human renal hypodysplasia pathogenesis, we performed UPIIIA mutation analysis in a cohort of 170 pediatric patients affected by severe unilateral or bilateral renal hypodysplasia. Eighty-one patients were affected by bilateral nonobstructive renal hypodysplasia; of these, 61 were without vesicoureteral reflux. Eighty-four patients presented with unilateral nonobstructive renal hypodysplasia, including 24 patients with unilateral multicystic dysplastic kidneys. Family history was positive in 11%., Results: Mutation analysis showed 2 heterozygous mutations not observed in 200 race-matched control chromosomes. In only 1 family was distribution of the UPIIIA mutation consistent with a disease-causing effect. This de novo missense mutation (Gly202Asp) was identified in a patient with unilateral multicystic dysplastic kidneys. The second (intronically located) mutation appeared unlikely to be disease causing because it did not segregate with an obvious disease phenotype in the affected family., Conclusion: Our results indicate that de novo mutations in UPIIIA can be involved in defective early kidney development, but probably constitute only a rare cause of human renal hypodysplasia in a minor subset of individuals.