Fotios Papachristou

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

BACKGROUND AND OBJECTIVES Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Serum osteoprotegerin, RANKL and fibroblast growth factor-23 in children with chronic kidney disease

Osteoprotegerin (OPG), receptor activator of the nuclear factor κB ligand (RANKL) and fibroblast growth factor-23 (FGF-23) play a central role in renal osteodystrophy. We evaluated OPG/RANKL and FGF-23 levels in 51 children with chronic kidney disease (CKD) [n = 26 stage 3 or 4 (CKD3–4) and n = 25 stage 5 (CKD5)] and 61 controls. Any possible association with intact parathyroid hormone (iPTH) and bone turnover markers was also investigated. The OPG levels were lower in the CKD3–4 group (p < 0.001) and higher in the CKD5 group (p < 0.01) than in the controls, while RANKL levels did not differ. The FGF-23 levels were higher in both patient groups (p < 0.0001), while the levels of phosphate and iPTH were higher only in the CKD5 group (p < 0.0001). There were independent positive correlations between OPG and RANKL (β = 0.297, p < 0.01) and FGF-23 (β = 0.352, p < 0.05) and a negative correlation with the bone resorption marker TRAP5b (β = −0.519, p < 0.001). OPG was positively correlated with iPTH (R = 0.391, p < 0.01). An independent positive correlation between FGF-23 and phosphate (β = 0.368, p < 0.05) or iPTH (β = 0.812, p < 0.0001) was noted. In conclusion, we found that higher OPG levels in patients with CKD stage 5 correlated with the levels of RANKL, FGF-23, iPTH, and TRAP5b. These findings may reflect a compensatory mechanism to the negative balance of bone turnover. High FGF-23 levels in early CKD stages may indicate the need for intervention to manage serum phosphate (Pi) levels.

Urinary and serum biomarkers in ureteropelvic junction obstruction: a systematic review

Abstract Context: Ureteropelvic junction obstruction (UPJO) constitutes a predominant cause of obstructive hydronephrosis. Fundamental questions regarding the assessment and treatment of infants and children with obstructive nephropathy remain unanswered. Objective: Several studies have investigated the usefulness of substances that could serve as potential diagnostic and prognostic biomarkers in children with UPJO. Aim of the present study is to systematically review the literature on biomarkers that have been studied to date in patients with UPJO. Methods: The main search was conducted in the electronic databases MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) from inception through March 2014 using various combinations of Medical Subject Headings (MeSH). Results: The 14 included studies reported data on 380 UPJO patients who underwent surgery, 174 who were treated conservatively and 213 controls. Conclusion: Some biomarkers offer promising results however more multicenter, prospective carefully designed studies are needed to evaluate their diagnostic and prognostic value.

Pandemic influenza A (H1N1) 2009-associated hemolytic uremic syndrome

Sirs, Influenza A virus-associated hemolytic uremic syndrome (HUS) has been very rarely recognized in children and only five patients have been reported [1]. Pandemic influenza A (H1N1) 2009 has been associated with nonpulmonary acute organ dysfunction of multiple organs; however, H1N1associated HUS has not been reported [2]. Since both H1N1 and Streptococcus pneumoniae share neuraminidase activity and S. pneumoniae has been related to HUS, H1N1 could induce HUS via the same pathway [3]. It has also been recognized that neuraminidase of influenza virus may cause erythrocyte fusion and hemolysis [4]. We describe a case of a child with pandemic influenza A (H1N1) 2009-associated HUS. In November 2009, a previously healthy 71⁄2-year-old Caucasian boy, presented to us with a 3-day history of fever, sore throat, malaise, cough, and three episodes of blood-tinged vomiting. Two days later he developed oliguria. On admission, physical examination demonstrated body temperature 38.5°C, pulse rate 120/min, respiratory rate 30/min, blood pressure 110/70 mmHg, and mild periorbital edema. A respiratory specimen for H1N1 was taken due to the severe malaise of the child associated with respiratory tract symptoms. The initial laboratory data revealed anemia [hemoglobin (Hb) 7.5 g/dl], with marked anisocytosis and schitocytosis, thrombocytopenia (platelets 30,000/μl), severe renal failure with blood urea nitrogen (BUN) of 223 mg/dl, creatinine of 3.4 mg/dl, and metabolic acidosis, findings consistent with hemolytic uremic syndrome (HUS). Fibrinogen levels, and prothrombin and partial thromboplastin times were normal. Direct and indirect Coombs’ tests were negative and chest X-ray revealed normal findings. During the first few hours after admission Hb declined to 6.2 g/dl and platelets to 12,000/μl. Packed red cells and platelets were transfused and a peritoneal (Tenkoff) catheter was inserted for initiation of peritoneal dialysis. Plasma therapy was initiated because of the atypical presentation of HUS. On day 3, polymerase chain reaction demonstrated H1N1 in respiratory specimens and oseltamivir was started in doses adjusted for renal failure. Immune investigation, including complement factors C3 and MCP (CD46), as well as von Willebrand factor-cleaving protease (ADAMTS-13), revealed normal findings. On day 5 the child continued to be febrile and suffered respiratory distress with pCO2 of 45, pO2 of 59, respiratory rate 40 breaths per minute, and oxygen saturation of 88% while he was breathing 4 l by nasal cannula. His chest X-ray showed diffuse bilateral infusions, findings consistent with viral pneumonitis. The respiratory distress worsened and the child was transferred to the Intensive Care Unit (ICU) where he received mechanical ventilation and treatment with vancomycin and ceftriaxone. Because of hypertension he also received nifedipine and captopril treatment. His course was further complicated by generalized convulsions, barely controlled by valproic sodium and phenytoin. Magnetic resonance imaging (MRI) revealed multiple lesions in the white matter that were hyperintense on T2-weighted images, situated in the temporo-parieto-occipital regions and fewer in N. Printza (*) :D. Zafeiriou :V. Hatzidimitriou : F. Papachristou 1st Department of Pediatrics, Aristotle University, Konstantinoupoleos 49, 546 42 Thessaloniki, Greece e-mail: nprintza@in.gr

Acute phase 99mTc-dimercaptosuccinic acid scan in infants with first episode of febrile urinary tract infection

Background99mTc-dimercaptosuccinic acid (DMSA) scan is the golden standard for the diagnosis of acute pyelonephritis and renal scaring. We investigated the use of acute phase DMSA scan in infants presented promptly to the hospital because of the first episode of their febrile urinary tract infection (UTI).MethodsNinety-eight infants with microbiologically confirmed first episode of febrile UTI were studied. DMSA scans were carried out within 7 days in these infants after admission. Infants with an abnormal acute DMSA scan underwent a second DMSA scan 6–12 months later.ResultsOverall, acute DMSA scan was abnormal in 16 (16.3%) of the 98 patients. There were no differences in sex, age, fever over 38.5°C, blood inflammation indices, or evidence of vesicoureteral reflux (VUR) between patients with normal and abnormal acute DMSA scan (P>0.05). However, infants with grade III to V VUR as well as those with delayed treatment presented significantly increased renal involvement by acute DMSA scan (P<0.05). The sensitivity and specificity of abnormal acute DMSA scan to predict grade III to V VUR were 50% and 88% respectively. Its positive and negative likelihood ratios were 4.16 and 0.57, respectively. Of 16 children with abnormal initial DMSA scan results, 14 underwent a second DMSA scan. Follow-up DMSA scans were normal in 12 of the 14 children.ConclusionsParenchymal damage found in a minority of infants with febrile UTI presented promptly to the hospital. Acute phase DMSA scan should be carried out only in selected patients. An abnormal acute DMSA scan is a moderate predictor for dilated VUR and its ability to exclude VUR is restricted.

Simultaneous changes in serum HMGB1 and IFN-α levels and in LAIR-1 expression on plasmatoid dendritic cells of patients with juvenile SLE.. New therapeutic options?

We investigated the simultaneous changes in serum levels of HMGB1 and IFN-α as well as in LAIR-1 expression on plasmatoid dendritic cells (pDCs) of juvenile systemic lupus erythematosus (jSLE) patients in order to explore their involvement in the disease pathogenesis and their correlation with disease activity and other characteristics. In total, 62 blood samples were studied from 26 jSLE patients (18 girls), aged 8–16 years. Twenty healthy subjects (16 girls) of comparable age were included as healthy controls (HCs). Concentrations of serum HMGB1 and IFN-α were assessed by ELISA and LAIR-1 expression on pDCs by five-color flow cytometry. The disease activity index was assessed by SLEDAI and ECLAM scores. It was found that mean serum levels both of HMGB1 and IFN-α were significantly increased in jSLE patients compared to HCs and in jSLE patients with active disease with or without active nephritis compared to those with inactive disease. Mean serum levels of HMGB1 were positively correlated with levels of IFN-α and both were positively correlated with the SLEDAI and ECLAM scores. The expression of LAIR -1 on pDCs of jSLE patients was significantly lower than that of HCs. In conclusion, our findings indicate that serum HMGB1 not only represents a potential marker of disease activity but together with the lack of LAIR-1 inhibitory function may contribute to the sustained inflammatory action of IFN-α in jSLE. In this regard, blocking the action of HMGB1 and its receptors or enhancing the expression/inhibitory function of LAIR-1 on pDCs should be included in future immune interventions for controlling jSLE.

Hypertension screening during healthcare pediatric visits.

Background: Guidelines in both Europe and the United States recommend screening for hypertension during child care pediatric visits in children above 3 years old. The aims of the study were to assess the frequency of blood pressure (BP) measurement during preventive or chronic care pediatric visits and determine the factors that may associate with screening. Method: We prospectively included in the study consecutive children hospitalized in our department. Anthropometric measurements were performed in all children. Office BP was measured in children above 5 years old and mothers and/or fathers. Personal and family history, and self-reported BP screening during pediatric visits were recorded. Results: Hypertension screening had been performed at least once in 45.3% of the children during pediatric visits. Fifty per cent of the children with elevated BP levels had never been screened for hypertension. Low birth weight, history of prematurity, or chronic disease was not associated with increased frequency of screening, whereas screening was more likely in children above 3 years old with positive personal history (odds ratio 2.35, 95% confidence interval 1.07–5.15, P < 0.05). Obesity tended to increase the frequency of hypertension screening in all ages (odds ratio 2.60, 95% confidence interval 0.93–7.28, P = 0.06). Moreover, 37.5% of children without positive personal history exhibited BP levels above the 90th percentile, and 13.5% of mothers and 31.1% of fathers were not aware of their own elevated BP levels. Conclusion: These findings suggest that hypertension screening does not occur during pediatric visits for a considerable percentage of children, although a significant number of children and adolescents without positive history of hypertension or chronic disease may have elevated office BP levels.

Pandemic influenza A 2009 (H1N1) vaccination in high risk children with chronic renal diseases: Acceptance and perceptions

We aimed to evaluate the acceptance of pandemic influenza A 2009 vaccination in our high risk children with chronic renal diseases. . A total of 64 children/parents of pediatric nephrology department were approached to fill in a standardised questionnaire on influenza immunization profile. The H1N1 vaccination rates were 57.1% for transplant recipients, 61.5% for patients on peritoneal dialysis (PD), 36.4% for patients with various stages of chronic renal disease (CRD) and 26.7% for patients with glomerulonephritis (GN) on immunosuppressive therapy. Children on renal transplantation or PD had a fourfold higher rate of being vaccinated than children with GN (p=0.04). Causes of denying vaccination included fear of adverse effects (48.9%), lack of sufficient data on the new vaccine (31.9%) and others (19.2%). Patients being vaccinated were all urged by their pediatric nephrologist (100%), while patients not vaccinated were negatively influenced by media (41.4%), friends (24.1%), pediatrician (20.7%) and others (13.8%). Regarding parents education, higher level was associated with increased rate of children vaccination (p=0.04). It seems that patients with severe renal disease had better compliance with vaccination. The pediatric nephrologists had the most significant positive influence in contrast to the media which had the most negative influence.

The characteristics and outcome of primary vesicoureteric reflux diagnosed in the first year of life.

A retrospective trial was performed to study presentation, evaluation, management, complications and outcome of 186 infants with vesicoureteral reflux (VUR).

Peritonitis attributable to Kocuria rosea in a pediatric peritoneal dialysis patient.

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