Background:We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods:In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results:Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Conclusions:Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.

Inborn errors of metabolism (IEM) are a highly heterogeneous group of genetic conditions and represent a relevant cause of morbidity and mortality in the pediatric population. IEM, which are individually rare but collectively numerous, are well-recognized entities of the generic class of "rare" diseases. Since the first descriptions by Garrod at the beginning of the 20th century, several hundred new disorders have been defined, as new biochemical and molecular diagnostic tools became available. The clinical pictures of single diseases are extremely diverse, ranging from acute life-threatening manifestations to chronic late-onset forms, with single or multiorgan involvement. Mental retardation and progressive neurological impairment often characterize the clinical course. One of the principles to prevent high morbidity and mortality rates is early recognition followed by prompt therapeutic intervention. Therefore, a small number of treatable IEM is subject to neonatal mass screening. More recently, an innovative technique, based on tandem mass spectrometry, has expanded the range of neonatal screening to several additional disorders. Owing to the extreme heterogeneity, as well as to the increasing number of new disorders, exhaustive and updated epidemiological data on the overall occurrence of IEM are lacking. A national retrospective study was conducted to define the epidemiological profile of IEM in Italy and to estimate the costs related to the disease burden. Other relevant issues of our investigations focused on creating protocols of treatment for neonatal IEM, and on the development of new methods for the biochemical diagnosis.

Objectives We sought to investigate the effectiveness of glucocorticoid administration or continuous venovenous hemodiafiltration on endothelin and corticotropin-releasing factor release or clearance during prolonged fetal cardiac bypass and on the overall performance of fetuses. Methods Circulating endothelin 1, 2, and 3 and corticotropin-releasing factor levels were measured in fetal ewes during a 60-minute cardiac bypass period performed with an inline axial flow pump. Blood samples were collected before, during, and 90 minutes after cardiac bypass. Animals were divided into 4 groups. The betamethasone group (n = 6) received maternal treatment with 12 mg of betamethasone 1 and 2 days before the experiment. The methylprednisolone group (n = 5) received fetal treatment with 40 mg/kg intravenous methylprednisolone at the beginning of cardiac bypass. The continuous venovenous hemodiafiltration group (n = 4) underwent continuous venovenous hemodiafiltration with a 0.3-m2 polysulfone filter during cardiac bypass. The final group was the control group (n = 4). Results Maternal steroid pretreatment failed to decrease endothelin or corticotropin-releasing factor production when compared with levels in the control animals. Fetal treatment with methylprednisolone produced a significant decrease in endothelin 2 production during cardiac bypass (P < .02) and endothelin 1 production at the end of the experiment (P < .02). Continuous venovenous hemodiafiltration blocked completely the increase of endothelin and corticotropin-releasing factor levels during cardiac bypass (P < .02), which was maintained 90 minutes after cardiac bypass. Acid-base balance was preserved during cardiac bypass by the continuous venovenous hemodiafiltration but worsened after disconnection of the extracorporeal circuit, whereas animals treated with methylprednisolone had better pH, Paco2, and bicarbonate levels by the end of the experiment. The overall tolerance of the procedure was better in the continuous venovenous hemodiafiltration group during cardiac bypass and in the methylprednisolone group at the end of the experiment. Conclusions Continuous venovenous hemodiafiltration provides sustained stability of endothelin levels during fetal cardiac bypass. This technique might help, in association with fetal steroid treatment, to contain the inflammatory response leading to postbypass placental dysfunction.

. We investigated the prognostic indicators in ten hyperammonemic neonates: four treated by continuous arteriovenous hemodialysis (CAVHD), four with continuous venovenous hemodialysis (CVVHD), and two with hemodialysis (HD). Plasma ammonium levels decreased significantly within the first 24 h irrespective of dialysis modality (from 1419 to 114 µmol/l, median values; P <0.0001). CVVHD achieved the highest ammonium clearance. HD provided highest ammonium extraction but clearance was hampered by severe hemodynamic instability. Five patients had a good outcome (normal at follow-up of 9–59 months), five had poor outcome (four died and one has severe neurological damage). Total coma duration was shorter in patients who had a good outcome (47±11 vs 78±13 h; P =0.02). Remarkably, only coma duration before dialysis determined this difference (22.2±10.1 vs 48.8±11.2 h; P =0.02). In cases with good outcome, coma duration was <33 h, whereas the others exceeded this limit. The prognosis was not related to dialysis modality, rapidity in reducing ammonium levels or to the underlying metabolic defect. In conclusion, results showed CVVHD to be the optimal modality for extracorporeal ammonium detoxification. However, the most relevant indicator for prognosis was coma duration before the start of dialysis. Therefore, major efforts should be made to refer patients quickly to highly specialized centers.

The incidence of cancer is increased follow- ing kidney transplantation. Chronic myelogenous leukemia (CML) has been previously reported in ten adult patients and only one pediatric patient post kidney transplantation. We report one male patient aged 18.8 years, on chronic dialysis from the age of 2 years, who was transplanted from a cadaver donor at the age of 8 years. He was treated with recombinant human growth hormone (rhGH) before transplantation and with azathioprine after kidney transplantation. Eight years after transplantation, CML was diagnosed and he was successfully treated with hydroxyurea and α-interferon. The follow-up is 28 months. The possible role of the combined action of rhGH and azathioprine in CML genesis is discussed.

Purpose: The arteriovenous fistula (AVF) of Brescia-Cimino fulfills nearly all of the criteria for an optimal access for chronic hemodialysis, such as long-term patency rate, low complication rate, and respect of vascular morphologic features. Alternative dialytic methods (i.e., external shunts and vascular grafts) cannot easily be applied to pediatric patients, and in addition, these methods are responsible for higher complication rates. Methods: From January 1985 to December 1994, 112 Brescia-Cimino AVFs were performed in 90 children (average age, 5.5 years; range, 5 months to 18 years). The average weight of the children was 28 kg (range, 6.5 to 54 kg); 16% of AVFs were performed in children who were less than 5 years old, and 18% in children who were less than 15 kg in body weight. Results: Chronic renal failure was caused by a nephropathy in 53 cases (14 with a nephrotic syndrome), and 37 cases had a uropathy. In all cases a phlebography was performed before the microsurgical treatment. Since 1994 an inflatable tourniquet has been placed on the selected upper arm because of an optimal exsanguination of the operating field. The primary patency rate was obtained in all but six of the children; 35% of AVFs had either immediate or late complications. Thrombosis was the most frequent complication that we observed. In comparison with 79% of late thrombosis, 60% of early thrombosis was cured. Of the 80 AVFs, 63.5% with a 4-year follow-up are still patent. Conclusion: We emphasize the following two conclusions: first, microsurgery is essential to create AVFs with good results in children as well as in adult patients; and second, the results improved after the adoption of an upper-arm exsanguination and ischemia (pressure range, 400 mm Hg to 600 mm Hg) that avoided spasm of the vessels with a final 35% reduction in surgical time. (J Vasc Surg 1998;27:640-4.)

Growth retardation in children with chronic renal failure (CRF) despite normal or elevated GH levels indicates a peripheral insensitivity to the action of GH. One possible molecular mechanism is a reduced density of GH receptors in GH target organs. In humans, the circulating high affinity GH binding protein (GHBP) is thought to reflect GH receptor expression, because it is derived from the extracellular domain of the GH receptor by proteolytic cleavage. We, therefore, analyzed serum GHBP levels by ligand-mediated immunofunctional assay in 126 children with CRF compared to reference values obtained by analysis of 773 healthy children. In 77% of CRF patients, serum GHBP concentrations were below the mean for age- and gender-matched controls. The decrease in serum GHBP levels was related to the degree of renal dysfunction. In advanced CRF (glomerular filtration rate, <35 mL/min.1.73 m(2)), mean age- and gender-adjusted GHBP levels were -1.40 +/- 0.18 Sn score; 36% of patients had GHBP levels below the normal range (<-2 so score). Children with endstage renal disease (n = 26) had the lowest GHBP levels (-2.25 +/- 0.22 so score). Multiple linear regression analysis revealed that body mass index, rather than glomerular filtration rate, is the prevailing determinant of serum GHBP levels in CRF. GHBP levels correlated with both the spontaneous growth rate (r = 0.44; P < 0.0001) and the growth response to GH therapy (r = 0.48; P < 0.005), indicating decreased sensitivity to both endogenous and exogenous GH. Subcutaneous GH therapy did not consistently affect serum GHBP levels after 3 months of treatment. It is suggested that low GHBP levels in children with CRF represent a quantitative tissue GH receptor deficiency as one of the molecular mechanisms of GH insensitivity.