Nikoleta Printza

The bone and mineral disorder of children undergoing chronic peritoneal dialysis

The mineral and bone disorder of chronic kidney disease remains a challenging complication in pediatric end-stage renal disease. Here, we assessed symptoms, risk factors and management of this disorder in 890 children and adolescents from 24 countries reported to the International Pediatric Peritoneal Dialysis Network Registry. Signs of this disease were most common in North American patients. The prevalence of hyperphosphatemia increased with age from 6% in young infants to 81% in adolescents. Serum parathyroid hormone (PTH) was outside the guideline targets in the majority of patients and associated with low calcium, high phosphorus, acidosis, dialysis vintage and female gender. Serum calcium was associated with dialytic calcium exposure, serum phosphorus with low residual renal function and pubertal status. PTH levels were highest in Latin America and lowest in Europe. Vitamin D and its active analogs were most frequently administered in Europe; calcium-free phosphate binders and cinacalcet in North America. Clinical and radiological symptoms markedly increased when PTH exceeded 300 pg/ml, the risk of hypercalcemia increased with levels below 100 pg/ml, and time-averaged PTH concentrations above 500 pg/ml were associated with impaired longitudinal growth. Hence, the symptoms and management of the mineral and bone disorder of chronic kidney disease in children on peritoneal dialysis showed substantial regional variation. Our findings support a PTH target range of 100-300 pg/ml in the pediatric age group.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

Management of Anemia in Children Receiving Chronic Peritoneal Dialysis

Little information exists regarding the efficacy, modifiers, and outcomes of anemia management in children with CKD or ESRD. We assessed practices, effectors, and outcomes of anemia management in 1394 pediatric patients undergoing peritoneal dialysis (PD) who were prospectively followed in 30 countries. We noted that 25% of patients had hemoglobin levels below target (<10 g/dl or <9.5 g/dl in children older or younger than 2 years, respectively), with significant regional variation; levels were highest in North America and Europe and lowest in Asia and Turkey. Low hemoglobin levels were associated with low urine output, low serum albumin, high parathyroid hormone, high ferritin, and the use of bioincompatible PD fluid. Erythropoiesis-stimulating agents (ESAs) were prescribed to 92% of patients, and neither the type of ESA nor the dosing interval appeared to affect efficacy. The weekly ESA dose inversely correlated with age when scaled to weight but did not correlate with age when normalized to body surface area. ESA sensitivity was positively associated with residual diuresis and serum albumin and inversely associated with serum parathyroid hormone and ferritin. The prevalence of hypertension and left ventricular hypertrophy increased with the degree of anemia. Patient survival was positively associated with achieved hemoglobin and serum albumin and was inversely associated with ESA dose. In conclusion, control of anemia in children receiving long-term PD varies by region. ESA requirements are independent of age when dose is scaled to body surface area, and ESA resistance is associated with inflammation, fluid retention, and hyperparathyroidism. Anemia and high ESA dose requirements independently predict mortality.

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.

Underweight, overweight and obesity in paediatric dialysis and renal transplant patients

BACKGROUND The prevalence of childhood overweight is rising worldwide, but in children on renal replacement therapy (RRT) a poor nutritional status is still the primary concern. We aimed to study the prevalence of, and factors associated with, underweight and overweight/obesity in the European paediatric RRT population. Moreover, we assessed the evolution of body mass index (BMI) after the start of RRT. METHODS We included 4474 patients younger than 16 years from 25 countries of whom BMI data, obtained between 1995 and 2010, were available within the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry. Prevalence estimates for under- and overweight/obesity were calculated using age and sex-specific criteria of the World Health Organization (WHO, 0-1 year olds) and the International Obesity Task Force cut-offs (2-15 year olds). RESULTS The prevalence of underweight was 3.5%, whereas 20.8% of the patients were overweight and 12.5% obese. Factors associated with being underweight were receiving dialysis treatment and infant age. Among transplanted recipients, a very short stature (OR: 1.64, 95% CI: 1.40-1.92) and glucocorticoid treatment (OR: 1.23, 95% CI: 1.03-1.47) were associated with a higher risk of being overweight/obese. BMI increased post-transplant, and a lower BMI and a higher age at the start of RRT were associated with greater BMI changes during RRT treatment. CONCLUSIONS Overweight and obesity, rather than underweight, are highly prevalent in European children on RRT. Short stature among graft recipients had a strong association with overweight, while underweight appears to be only a problem in infants. Our findings suggest that nutritional management in children receiving RRT should focus as much on the prevention and treatment of overweight as on preventing malnutrition.

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.

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.

Prevalence and predictors of the sub-target Hb level in children on dialysis

BACKGROUND Anaemia is a common and potentially treatable co-morbidity of end-stage renal disease. We aimed to determine the prevalence of the sub-target haemoglobin (Hb) level among European children on dialysis and to identify factors associated with a low Hb level. METHODS From the European Society for Paediatric Nephrology (ESPN)/European Renal Association-European Dialysis Transplant Association (ERA-EDTA) registry, data were available on 2351 children between 1 month and 18 years of age, totalling 5546 measurements from 19 countries. RESULTS The mean Hb level was 10.8 g/dL (5th-95th percentiles, 7.4-13.9). Among those above 2 years of age, the mean Hb level was 10.9 g/dL (11.4% below 8.5 g/dL), while it was 10.3 g/dL among those below 2 years (11.2% below 8.0 g/dL). A total of 91.2% of the patients were on an erythropoiesis-stimulating agent (ESA). Hb levels increased with age and were higher in peritoneal dialysis compared with haemodialysis patients. Patients with congenital anomalies of the kidney and urinary tract showed the highest Hb levels, and those with cystic kidney diseases or metabolic disorders the lowest ones. Ferritin levels between 25 and 50 ng/mL were associated with the highest Hb levels. We found a weak inverse association between parathyroid hormone (PTH) and Hb. Whereas standardized blood pressure (BP) was not elevated in patients with above-target Hb, elevated systolic BP z-score was noted in those with sub-target Hb levels. CONCLUSIONS Sub-target Hb levels remain common in children on dialysis, in spite of virtually all children being treated with ESA; although we cannot exclude under-dosing. Optimal ferritin levels seemed to be slightly lower in children (25-50 ng/mL) than those in adults. Other risk factors for sub-target Hb are dialysis modality and a high PTH level.