MCP1 2518 A/G polymorphism affects progression of childhood focal segmental glomerulosclerosis.

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.

Prevalence of hypertension and decreased glomerular filtration rate in obese children: results of a population-based field study.

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.

DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN.

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.

Role of CXCR1 (CKR-1) in inflammation of experimental mesangioproliferative glomerulonephritis.

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.

Genetic basis of cystinosis in Turkish patients: a single-center experience.

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.

Disruption of PTPRO causes childhood-onset nephrotic syndrome.

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_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.

COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.

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.

The distribution of juvenile idiopathic arthritis in the eastern Mediterranean: results from the registry of the Turkish Paediatric Rheumatology Association.

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.

Anti-neutrophil cytoplasmic antibodies (ANCA) in serum and bronchoalveolar lavage fluids of cystic fibrosis patients and patients with idiopathic bronchiectasis.

We investigated the presence of anti-neutrophil cytoplasmic antibodies (ANCA) in the serum and bronchoalveolar lavage fluid (BALF) of 21 cystic fibrosis (CF), 7 idiopathic bronchiectasis (IBR), and 11 control children and the relation between ANCA and any bacteria grown in BALF. Six of the CFs, but none of the IBRs or controls had positive serum cytoplasmic or perinuclear-ANCA (c-ANCA, p-ANCA). Serum autoantibodies against bactericidal/permeability increasing protein (BPI-ANCA) were positive in 2 CFs, 1 IBR and 1 control. While none of the CFs, IBRs or controls had positive BALF (c- or p-ANCA), 1 CF, 1 IBR and none of the controls had positive BALF BPI-ANCA. Pseudomonas aeruginosa was not grown in the specimens of any of the subjects. As the number of the patients in our study was very limited, further longitudinal and well-designed studies are necessary to show whether or not the presence of ANCA in serum or BALF relates to the presence of P. aeruginosa infection in the airways of CF and IBR patients.

Clinical course of primary focal segmental glomerulosclerosis (FSGS) in Turkish children: a report from the Turkish Pediatric Nephrology FSGS Study Group.

The clinical course of focal segmental glomerulosclerosis (FSGS) is heterogeneous in children. To evaluate the clinical course and the predictors of outcome in Turkish children with primary FSGS, a retrospective study was conducted by the Turkish Pediatric Nephrology Study Group in 14 pediatric nephrology centers. Two hundred twenty-two patients (92 boys, 130 girls, aged 1-16 years) with biopsy-proven primary FSGS were included. One hundred forty-eight patients were followed-up for a median of 51 months (range: 0.26-270). The clinical course was characterized by complete remission in 50 (33.8%), persistent proteinuria in 50 (33.8%) and progression to renal failure in 48 (32.4%) patients. Progression to end-stage renal disease (ESRD) was significantly higher in patients who did not attain remission. Complete remission, partial remission and progress to renal failure were recorded in 37%, 32% and 28%, respectively, of the patients (n = 73) treated with prednisone combined cyclophosphamide/cyclosporine A. However, in patients (n = 33) treated with pulse methyl prednisolone plus oral prednisone (up to 20 months) combined with cyclophosphamide, complete remission in 51.5% and partial remission in 27.3% of the patients were noted. Progression to renal failure was observed in 9.1% of this group of patients. Multivariate analysis showed that only plasma creatinine at presentation was an independent predictive value for outcome. Patients with serum creatinine level higher than 1.5 mg/dl had 6.6 times increased rate of progression to renal failure. Failure to achieve remission is a predictor of renal failure in children with primary FSGS. The use of immunosuppressive treatment in conjunction with prolonged steroid seems beneficial in primary FSGS in children.

The Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study: objectives, design, and methodology.

BACKGROUND AND OBJECTIVES: Children and adolescents with chronic kidney disease (CKD) are at high risk for cardiovascular morbidity and mortality. A systemic arteriopathy and cardiomyopathy has been characterized in pediatric dialysis patients by the presence of morphologic and functional abnormalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Comorbidity in Children with CKD (4C) Study is a multicenter, prospective, observational study aiming to recruit more than 600 children, aged 6 to 17 years, with initial GFR of 10 to 45 ml/min per 1.73 m(2). The prevalence, degree, and progression of cardiovascular comorbidity as well as its association with CKD progression will be explored through longitudinal follow-up. The morphology and function of the heart and large arteries will be monitored by sensitive noninvasive methods and compared with aged-matched healthy controls. Multiple clinical, anthropometric, biochemical, and pharmacologic risk factors will be monitored prospectively and related to the cardiovascular status. A whole-genome association study will be performed to identify common genetic variants associated with progression of cardiovascular alterations and/or renal failure. Monitoring will be continued as patients reach end-stage renal disease and undergo different renal replacement therapies. RESULTS: While cardiovascular morbidity in adults is related to older age and additional risk factor load (e.g., diabetes), the role of CKD-specific factors in the initiation and progression of cardiac and vascular disease are likely to be characterized with greater sensitivity in the pediatric age group. CONCLUSIONS: The 4C study is expected to provide innovative insight into cardiovascular and renal disease progression in CKD.

Etiology and outcome of acute kidney injury in children.

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.

EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria.

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

Toll-like receptors 2 and 4 cell surface expression reflects endotoxin tolerance in Henoch-Schönlein purpura.

We aimed to analyze the Toll-like receptor (TLR)2 and TLR4 expressions, which are known to be involved in the recognition of pathogens by the innate immune system, in patients with Henoch-Schönlein purpura. Twenty-three patients (10 males, 13 females, aged 4-16 years) with a clinical diagnosis of Henoch-Schönlein purpura were enrolled. Twenty healthy age-matched children (10 males, 10 females) served as controls. TLR2 and TLR4 expression levels on peripheral blood mononuclear cells (PBMCs) were determined by flow cytometric analysis. PBMCs were cultured with heat shock protein (HSP) 60 (1 microg/ml) as an endogenous ligand for TLR. Levels of TLR2 and TLR4 expression on PBMC were significantly lower in the Henoch- Schönlein purpura patients compared to healthy controls when stimulated with HSP60 and with lipopolysaccharide (LPS) (p < 0.05 for both). There was no significant difference between the stimulated and unstimulated samples from the patients. The lower TLR response to these ligands among these patients may reflect a tolerance to bacterial antigens. Further studies will clarify whether tolerance to microbial antigens may have a role in the pathogenesis and course of Henoch-Schönlein purpura.

Predictors of left ventricular hypertrophy in children on chronic peritoneal dialysis.

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.

Decrease in the rate of secondary amyloidosis in Turkish children with FMF: are we doing better?

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.

Risk factors in community-acquired urinary tract infections caused by ESBL-producing bacteria in children.

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.

Preventing tuberculosis in children receiving anti-TNF treatment.

Anti-tumor necrosis factor (TNF) treatment has been a breakthrough in the management of juvenile idiopathic arthritis (JIA). However, they are associated with a significant risk of tuberculosis. We evaluated JIA patients who received etanercept treatment from an eastern Mediterranean country with moderate tuberculosis frequency. JIA patients under anti-TNF treatment, etanercept, were enrolled to the study. Chest X-rays, Tuberculin Skin Test (TST), clinical histories, family screening, and physical examinations were reviewed retrospectively. If TST was above 10 mm in a patient with one Bacillus Calmette-Guerin, cultures and, if needed, thorax computerized tomography were obtained. These patients received 1-2 months of isoniazid (INH) treatment which was followed by an INH prophylaxis for a period of 9 months while etanercept treatment was started. All were re-evaluated within 3 months intervals. A total of 36 patients under etanercept treatment were enrolled to the study. Mean age of the patients was 14.00 years (range 4-22 years). Median duration of disease was 36.00 months (range 4-216 months). Median duration of etanercept therapy was 11.5 months (3-48 months) at final evaluation. Seven patients had an initial TST score above 10 mm. All received INH treatment as outlined above. They had normal examinations and X-rays during followup. With proper initial evaluation, anti-TNF treatment is safe even in countries where tuberculosis is moderately frequent. An initial 1-2 months of INH treatment followed by chemoprophylaxis for 9 months is suggested for children with a TST of >10 mm.

Neuroendocrine immune system in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder and is characterized by self-limited attacks of inflammation. Although mutations in the gene coding for pyrin are responsible for the inflammation seen in attacks, the question of whether the failure to mount an appropriate cortisol response to inflammation has any additive effects allowed us to plan this study. The aim was to determine the interactions between the neuroendocrine and immune system in patients with FMF and investigate the role of the neuroendocrine system in the acute inflammation process. Demographic characteristics, disease activity, mutation analysis, and duration of the disease were defined in 15 FMF patients (7 female, 8 male; mean age +/- SD: 9.1 +/- 4.2 years). The diagnosis was based on Tel-Hashomer criteria. Ten healthy volunteers and 21 active juvenile idiopathic arthritis (JIA) patients formed the control groups. Furthermore, 10 of these 15 patients with FMF were also studied during the attack-free period. Erythrocyte sedimentation rate (ESR) C-reactive protein (CRP), fibrinogen, adrenocorticotropic hormone (ACTH), cortisol, insulin-like growth factor-1 (IGF)-1, IGF binding protein (BP)-3, urinary cortisol levels, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-a were evaluated in FMF patients with attack and during the attack-free period. Although the median levels of ACTH (12.7 pg/ml) and cortisol (12 ug/dl) at 08:00 a.m. were lower in FMF patients during attack than in the attack-free period, these differences did not reach statistical significance. On the other hand, the median levels of ACTH were significantly lower during attack than in the healthy control group (p < 0.05). Median levels of IGF-1 (118.5 ng/ml) were significantly lower during FMF attack than in the attack-free period (p < 0.05). There was a negative correlation between IGF-1 and CRP (r = -0.47). The median level of IL-6 was 18.1 pg/dl during FMF attack and was significantly higher than in the attack-free period and in the healthy control group (p < 0.05). There was a negative correlation between cortisol level at 08:00 am and IL-6 (r = -0.45). When we compared JIA with FMF patients during attack, inappropriately low secretion of adrenal cortisol and ACTH and low urine cortisol levels were more pronounced in JIA than FMF Although it is more prominent in chronic inflammation, the neuroendocrine immune system seems to be impaired in relation to acute inflammation in FMF.

The use of low-dose cyclophosphamide followed by AZA/MMF treatment in childhood lupus nephritis.

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.