Methylation cycle, arginine-creatine pathway and asymmetric dimethylarginine in paediatric renal transplant.

BACKGROUND: Hyperhomocysteinaemia represents an important cause of morbidity in recipients of renal transplants, but few investigations have been carried out to evaluate the status of the methylation cycle and its relation with levels of new cardiovascular biomarkers, such as asymmetric dimethylarginine (ADMA). METHODS: Twenty-six children and adolescents aged 7-18 years (17 male, 9 female) with stable renal transplants were recruited for the study. None had received treatment with folate, vitamin B(12) or statins. Levels of ADMA in plasma and of components of the methylation cycle and arginine (Arg)-creatine pathway in plasma and urine were analysed by specific analytical methods. Results were compared to those obtained by us with identical methods in healthy children of similar age. RESULTS: Concentrations of homocysteine (Hcys), S-adenosylhomocysteine (SAH) and ADMA were significantly higher, while S-adenosylmethionine (SAM)/SAH and Arg/ADMA ratios were significantly lower than controls. Arg/ADMA ratio correlated with plasma guanidinoacetate. The components of the methylation cycle, Hcys and SAH correlated with renal function. CONCLUSIONS: Children with renal transplant showed low methylation power (SAM/SAH) mainly due to increased levels of SAH which acts as a cardiovascular biomarker. Elevated values of ADMA and low Arg/ADMA coefficients also represent a novel finding because it inhibits nitric oxide synthesis contributing to endothelial dysfunction and cardiovascular risk in such patients.

Persistence of essential fatty acid deficiency in cystic fibrosis despite nutritional therapy.

To study the evolution of plasma fatty acid composition of patients with cystic fibrosis (CF) in relation to nutritional status, pancreatic function, and development of CF-related liver disease (CFRLD) and diabetes mellitus, 24 CF pediatric patients with stable pulmonary disease were studied before and after an approximate period of 8 y. Nutritional status, pulmonary function, pancreatic function, and presence of CFRLD or diabetes mellitus were recorded. Results were compared with data obtained in 83 healthy children. Patients with CF have significantly lower linoleic acid (LA), docosahexaenoic acid (DHA), lignoceric acid, and LA x DHA product and higher oleic acid, mead acid, dihomo-gamma-linoleic acid, and docosapentaenoic acid (DPA). Comparison of samples taken at first and second studies revealed a significant decrease in LA levels and lignoceric acid associated with a significant increase in dihomo-gamma-linoleic acid levels. Patients with CFRLD showed significantly higher mead acid/arachidonic acid ratio and lower total omega6 polyunsaturated fatty acids content. There was no relation of plasma fatty acids composition with pancreatic function, pulmonary function, or diabetes mellitus. Follow-up of patients with CF shows that essential fatty acids deficiency, particularly in LA and DHA content, persisted unmodified along time despite an adequate nutritional therapy. Future studies after supplementation with omega3 polyunsaturated fatty acids should be undertaken.

Fatty acid deficiency profile in children with food allergy managed with elimination diets.

AIM: To evaluate plasma fatty acid (FA) composition of children with food allergy undergoing elimination diets that avoided the offending antigens. METHODS: Twenty-five children (14 male, 11 female) aged 3.8 +/- 1.6 years (range 2-7 years) affected of multiple food allergy and managed with elimination diets participated in a cross-sectional study. Results of plasma fatty acids were compared with data obtained in 61 healthy children. RESULTS: The patients had significantly lower values for plasma content in total polyunsaturated fatty acids, omega3 polyunsaturated fatty acids and long-chain omega3 polyunsaturated fatty acids (p < 0.001) and particularly, in eicosapentaenoic acid (EPA) (20:5omega3) and docosahexaenoic acid (DHA) (22:6omega3) (p < 0.001). Moreover, all established indices (essential fatty acid [EFA] index ((omega3 +omega6)/(omega7 +omega9)) (p < 0.001) and sufficiency of docosahexaenoic acid index (C22:6omega3/C22:5omega6) (p < 0.001)) confirmed the presence of EFA deficiency. CONCLUSION: Children with food allergy managed with restricted intake of foods such as milk, egg, fish and vegetables are at risk of developing a deficiency in EFA and particularly in omega3 long-chain polyunsaturated fatty acids, which are especially necessary for adequate growth, neurological development and cardiovascular health.

The arginine-creatine pathway is disturbed in children and adolescents with renal transplants.

Cardiovascular disease is an important cause of morbidity in recipients of renal transplants. The aim of the present study was to analyze the status of the arginine-creatine pathway in such patients, given the relationship between the arginine metabolism and both renal function and the methionine-homocysteine cycle. Twenty-nine children and adolescents (median age 13, range 6-18 years), who had received a renal allograft 14.5-82.0 months before, were recruited for the study. On immunosuppressive therapy, all patients evidenced an adequate level of renal function. Plasma concentrations of homocysteine and glycine were significantly higher, whereas urinary excretions of guanidinoacetate and creatine were significantly lower than controls. Urinary excretions of guanidinoacetate and creatine correlated positively with creatinine clearance. Urinary excretion of creatine was negatively correlated with plasma concentration of homocysteine. The demonstration of disturbances in the arginine-creatine pathway in patients with well-functioning renal transplants and in absence of chronic renal failure represents a novel finding. We speculate that the low urinary excretion of guanidinoacetate and creatine is probably related to the nephrotoxic effect of immunosuppressive therapy and to defective methylation associated with the presence of hyperhomocysteinemia.

Arachidonic acid content in adipose tissue is associated with insulin resistance in healthy children.

BACKGROUND: The fatty acid composition of membrane structural lipids, which is partly dependent on dietary intake, is associated with insulin action. AIM: To examine the association between fatty acid composition of adipose tissue and skeletal muscle phospholipids with insulin resistance markers in a healthy pediatric population. METHODS: Using a cross-sectional design, we studied 83 healthy children divided into 3 groups, ages 2 to 5, 6 to 10 and more than 10 years. MEASUREMENTS: Fatty acid composition of adipose tissue triacylglycerols and skeletal muscle phospholipids, plasma lipid profile and fasting plasma levels of glucose and insulin were measured. RESULTS: There was a linear increase of insulinemia, glycemia and homeostasis adipose tissue model assessment (HOMA) index throughout the pediatric age range. Linoleic acid proportion in skeletal muscle and arachidonic acid proportion in adipose tissue also increased significantly with age. An age-independent positive correlation between insulinemia or HOMA index and arachidonic acid content in adipose tissue triacylglycerols (r = 0.47, P < 0.001) was found. An age-dependent negative correlation was present between insulinemia or HOMA index and oleic acid content in skeletal muscle phospholipids (r = -0.30, P = 0.03 and r = -0.28, P < 0.04, respectively). Trans fatty acids content did not correlate with any marker of insulin resistance. CONCLUSION: Healthy children present a prepubertal increase of insulin resistance, which is significantly correlated with arachidonic acid content in adipose tissue.

Essential fatty acid deficiency profile in patients with nephrotic-range proteinuria.

Plasma free fatty acids are bound to albumin, filtered through the glomeruli, and reabsorbed at the proximal nephron. The aim of the present investigation was to determine if urinary loss of fatty acids results in essential fatty acid (EFA) deficiency in patients with nephrotic-range proteinuria. We studied 12 patients aged 9 months to 23 years (eight male, four female) four suffering from congenital nephrotic syndrome (NS) and eight from different renal diseases. Six patients were studied postrenal transplantation. Proteinuria ranged between 41 and 829 mg/m2/h. Results were compared with data obtained in 83 healthy children. The patients had significantly lower values for plasma arachidonic acid content and EFA index (omega3 + omega6/omega7 + omega9). Deficiency in polyunsaturated fatty acids (PUFA) was especially manifest in infants with congenital NS. Plasma content of arachidonic and docosahexaenoic acids related negatively with the degree of proteinuria. In the lineal regression model, the degree of proteinuria explained 60% of the variability of plasma values of those fatty acids. We conclude that plasma fatty acid status should be regularly monitored in patients with nephrotic-range proteinuria, especially in young infants with congenital NS, who represent a population at special risk with regard to neurological development.

Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement.

Claudins are major components of tight junctions and contribute to the epithelial-barrier function by restricting free diffusion of solutes through the paracellular pathway. We have mapped a new locus for recessive renal magnesium loss on chromosome 1p34.2 and have identified mutations in CLDN19, a member of the claudin multigene family, in patients affected by hypomagnesemia, renal failure, and severe ocular abnormalities. CLDN19 encodes the tight-junction protein claudin-19, and we demonstrate high expression of CLDN19 in renal tubules and the retina. The identified mutations interfere severely with either cell-membrane trafficking or the assembly of the claudin-19 protein. The identification of CLDN19 mutations in patients with chronic renal failure and severe visual impairment supports the fundamental role of claudin-19 for normal renal tubular function and undisturbed organization and development of the retina.

Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults.

Autosomal dominant pseudohypoaldosteronism type 1 (adPHA1) is a rare condition that is characterized by renal resistance to aldosterone, with salt wasting, hyperkalemia, and metabolic acidosis. It is thought of as a mild disorder; affected children's symptoms respond promptly to salt therapy, and treatment is not required after childhood. Mutations in the mineralocorticoid receptor gene (MR) cause adPHA1, but the long-term consequences of MR deficiency in humans are not known. Herein are described six novel adPHA1-causing MR mutations (four de novo) and evidence that haploinsufficiency of MR is sufficient to cause adPHA1. Furthermore, genotype-phenotype correlation is reported in a large adPHA1 kindred. A number of cases of neonatal mortality in infants who were at risk for adPHA1 were identified; coupled with the frequent identification of de novo mutations in affected individuals, this suggests that the seemingly benign adPHA1 may have been a fatal neonatal disorder in previous eras, preventing propagation of disease alleles. In contrast, it is shown that adult patients with adPHA1 are clinically indistinguishable from their wild-type relatives except for presumably lifelong elevation of renin, angiotensin II, and aldosterone levels. These data highlight the critical role of MR in the maintenance of salt homeostasis early in life and illuminate the sodium dependence of pathologic effects of renin and angiotensin II. They furthermore argue that nongenomic effects of aldosterone play no significant role in the long-term development of cardiovascular disease.

Osteogenesis imperfecta: anthropometric, skeletal and mineral metabolic effects of long-term intravenous pamidronate therapy.

BACKGROUND: Administration of bisphosphonates represents a beneficial therapy in children and adolescents with severe osteogenesis imperfecta (OI) because it significantly reduces the annual rate of bone fractures. AIM: To evaluate the anthropometric, skeletal and mineral metabolic effects of long-term intravenous pamidronate therapy in OI. METHODS: Ten patients, aged 5 mo to 25 y, with OI received cyclical intravenous pamidronate. The yearly dose of pamidronate was approximately 9 mg/kg/d at all ages. Duration of treatment varied from a minimum of 2 y to a maximum of 5 y. Growth, bone mass and mineral metabolic parameters were studied at baseline and repeated every year thereafter. Bone mass was assessed by calculation of bone mineral apparent density (L2-L4 BMAD). This represents the first study on the changes in size-adjusted measures of bone mass observed with such therapy. RESULTS: While on therapy, all children and adolescents grew normally but did not experience any manifest catch-up growth. A significant decrease in the incidence of bone fractures was observed. In seven patients with severe forms, L2-L4 BMAD increased by 80% after the first 2 y of therapy but tended to stabilize or even decrease over the following years despite maintenance of therapy. A significant inverse correlation could be established between urinary Ca excretion and L2-L4 BMAD (r = -0.30, p < 0.05). CONCLUSION: Our results confirm that cyclical pamidronate infusions reduce the incidence of bone fractures and allow normal growth. The improvement in bone mass initially observed after the first 2 y of therapy is not always sustained over the following years despite maintenance of therapy.

Fatty acid composition of skeletal muscle and adipose tissue in Spanish infants and children.

There is a relationship between the fatty acid profile in skeletal muscle phospholipids and peripheral resistance to insulin in adults, but similar data have not been reported in infancy and childhood. The objective of this study was to investigate the fatty acid composition of skeletal muscle and adipose tissue across the paediatric age range. The fatty acid profile of skeletal muscle phospholipids and adipose tissue triacylglycerols was analysed in ninety-three healthy Spanish infants and children distributed into four groups: group 1 (0 to <2 years, n 10); group 2 (2 to <5 years, n 41); group 3 (5 to <10 years, n 24); group 4 (10 to 15 years, n 18). In skeletal muscle phospholipids, oleic acid (18: 1n-9cis) content decreased significantly whereas that of linoleic (18: 2n-6) acid increased significantly with age (P for trend <0.01). In adipose tissue, the contents of triacylglycerol and linoleic acid increased significantly across the paediatric age range (P for trend <0.01), whereas dihomo-gamma-linolenic (20: 3n-6) and arachidonic (20: 4n-6) showed significant differences between groups. The variations in fatty acid composition observed with age indicated an imbalance in dietary n-3/n-6 long-chain PUFA.

An analysis of renal tubular acidosis by the Stewart method.

Renal tubular acidosis (RTA) comprises a group of disorders characterized by a low capacity for net acid excretion and persistent hyperchloremic, metabolic acidosis. To investigate the role of chloride, we performed hypotonic (0.45%) saline-loading experiments in 12 children with alkali-treated distal RTA (dRTA) and compared the results with data obtained from 17 healthy control subjects. In patients, but not in controls, saline loading induced both hyperchloremia and metabolic acidosis. Hyperchloremia was associated with high total and high distal fractional reabsorption of chloride [C(H20)/(C(H20)+C(Cl))]. The increase in plasma chloride varied inversely with the fractional excretion of chloride (C(Cl)) and correlated with the decrease in blood pH. However, the urinary excretion of bicarbonate did not correlate with either changes in blood pH or plasma bicarbonate concentration. Our findings suggest that the mechanism of hyperchloremia was enhanced Cl(-)/HCO(3) (-) exchange by the distal tubule. The resulting metabolic acidosis is better explained by changes in the strong ion difference (the Stewart theory) than by changes in the urine bicarbonate excretion (the traditional theory).

Inherited renal tubulopathies associated with metabolic alkalosis: effects on blood pressure.

Inherited tubular disorders associated with metabolic alkalosis are caused by several gene mutations encoding different tubular transporters responsible for NaCl renal handling. Body volume and renin-angiotensin-aldosterone system status are determined by NaCl reabsorption in the distal nephron. Two common hallmarks in affected individuals: hypokalemia and normal / high blood pressure, support the differential diagnosis. Bartter's syndrome, characterized by hypokalemia and normal blood pressure, is a heterogenic disease caused by the loss of function of SLC12A1 (type 1), KCNJ1 (type 2), CLCNKB (type 3), or BSND genes (type 4). As a result, patients present with renal salt wasting and hypercalciuria. Gitelman's syndrome is caused by the loss of funcion of the SLC12A3 gene and may resemble Bartter's syndrome, though is associated with the very low urinary calcium. Liddle's syndrome, also with similar phenotype but with hypertension, is produced by the gain of function of the SNCC1B or SNCC1G genes, and must be distinguished from other entities of inherited hypertension such as Apparently Mineralocorticoid Excess, of glucocorticoid remediable hypertension.

Abnormalities in plasma fatty acid composition in human immunodeficiency virus-infected children treated with protease inhibitors.

AIM: To study plasma fatty acid composition in human immunodeficiency virus-infected children treated with protease inhibitors and its relation with other components of the metabolic syndrome observed after this therapy. DESIGN: Cross-sectional study from collected clinical database. SUBJECTS: 17 children with HIV infection treated with protease inhibitors. Nine patients received ritonavir (20-30 mg/kg/d) and the remaining eight received nelfinavir (60-90 mg/kg/d). Duration of protease inhibitors treatment was 711+/-208 d. As controls, we used 112 matched blood samples from apparently healthy children admitted for minor surgical procedures. METHODS: Plasma fatty acids were determined using a Hewlett Packard GC 5890 gas chromatograph. RESULTS: Plasma levels of cholesterol and triglycerides and insulin-like growth factor 1 (IGF-1) tended to be high in protease inhibitor-treated patients. Plasma content of omega6 long-chain polyunsaturated fatty acids and, in particular, of the highly unsaturated 22ratio4omega6 and 22ratio5omega6, was significantly increased. Also, infected children had increased Delta6 and Delta4 desaturase activities and decreased Delta5 desaturase activity. Significant correlations were present between plasma IGF-1 level and plasma triglycerides, plasminogen activator inhibitor-1 activity and Delta6 desaturase activity. CONCLUSION: HIV-infected, protease inhibitor-treated children exhibit a metabolic syndrome which is associated with significant changes in plasma fatty acid composition. These changes are similar to those observed in situations of insulin resistance and are linked to variations in plasma IGF-1 concentration.

Bone mineral density and bone turnover in patients with Bartter syndrome.

The aim of this investigation was to evaluate bone mineral density (BMD), by use of DXA, and bone turnover, in patients with Bartter syndrome (BS). Ten patients (2 with BS type II and 8 with BS type III) were included in the procedure. Age at study varied between 2 and 30 years. During the studies usual treatment with indomethacin, spironolactone, and potassium chloride was maintained. Results were compared with those obtained in the 20 asymptomatic parents. Height of the patients at the time of the study did not differ from reference values (Z-score -1.2 to +0.8). Three patients (1 with BS type II and 2 with BS type III) presented reduced lumbar spine BMD or overt osteopenia (BMD Z-scores: -2.3, -1.3, and -1.1). BMD did not correlate significantly with age. Paternal and maternal femoral neck BMD values correlated significantly with lumbar spine BMD of the patients (r=0.65, P<0.05, and r=0.80, P<0.01). Lumbar spine BMD Z-scores correlated negatively with urinary Ca excretion when values both from patients and parents were jointly analyzed (r=-0.43, P<0.05). Plasma calcium concentration was significantly higher (P<0.001) and plasma phosphate Z-score was significantly lower (P<0.05) in the patients than in the parents. However, no significant differences were observed in values for intact PTH, 1,25 (OH)(2)D(3) and 25 (OH)D(3). Intact PTH values correlated positively with BMD Z-scores at lumbar spine (r=0.45, P<0.05) and at femoral neck (r=0.63, P<0.01). Age-corrected biochemical markers of bone formation (plasma alkaline phosphatase and osteocalcin concentrations) were normal whereas age-corrected markers of bone reabsorption (urinary PYD and DPD excretion) were significantly higher than parental values (P<0.01 and <0.05, respectively). We conclude that: (1) reduced BMD is not an exclusive feature of neonatal BS and it can be also observed in classic BS; (2) the loss of bone mineral is not progressive, probably because of the hypocalciuric effect of indomethacin therapy; and (3) this study did not determine whether loss of bone mass is the cause or the consequence of hypercalciuria although the beneficial effect of indomethacin therapy implies the latter.

A founder mutation in the CLCNKB gene causes Bartter syndrome type III in Spain.

The term "Bartter syndrome" encompasses a group of closely related inherited tubulopathies characterized by markedly reduced NaCl transport by the distal nephron. At present, five different genetic variants have been demonstrated. The majority of patients with so-called classic Bartter syndrome carry inactivating mutations of the CLCNKB gene encoding the basolateral ClC-Kb chloride channel (Bartter syndrome type III). The purpose of this study was to investigate the underlying mutation in cases of classic Bartter syndrome followed at our center. Ten patients, including two sisters, with clinical and biochemical features of classic Bartter syndrome were included in the mutational analysis. They originated from different regions of Spain with either Basque or Spanish ancestry. There was no history of consanguineous marriage in any of the kindreds. The parents and siblings of each patient, as well as a population of 300 healthy control adult subjects, were also analyzed. All ten patients were found to be homozygous for an identical missense mutation in the CLCNKB gene, substituting a threonine for an alanine at codon 204 (A204T) in the putative fifth transmembrane domain of the protein. None of the 300 control subjects were homozygous for the A204T allele. Overall, the A204T mutation was detected on 2/600 control chromosomes. Despite sharing a common mutation, the clinical manifestations of the syndrome in the patients varied from lack of symptoms to severe growth retardation. Demonstration of a point mutation within the CLCNKB gene as the apparently unique cause of Bartter syndrome type III in Spain is highly suggestive of a founder effect. Our results also support the lack of correlation between genotype and phenotype in this disease.

Long-term renal follow-up of extremely low birth weight infants.

There is evidence that low birth weight caused by intrauterine growth retardation adversely affects normal renal development. Very little information on this issue is available on children born very prematurely. This investigation examined clinical and functional renal parameters in 40 children (23 boys, 17 girls) ranging in age between 6.1 and 12.4 years and weighing less than 1000 g at birth. Results were compared to those obtained in 43 healthy children of similar age and gender. Study subjects were significantly smaller and thinner than control subjects (mean height SDS: -0.36 vs. +0.70; and mean BMI SDS: -0.56 vs. +1.18). Systolic, diastolic, and mean blood pressures did not differ from those of controls. Renal sonography revealed no abnormality, and mean percentiles for renal length and volume appeared normal. In comparison with controls, plasma creatinine concentration (0.62+/-0.1 vs. 0.53+/-0.1 mg/dl) and estimated creatinine clearance (117+/-17 vs. 131+/-17 ml min(-1) 1.73 m(-2)) differed significantly. No significant differences were observed in microalbuminuria values, but five study subjects (12.5%) presented values above the upper limit of normality. A defect in tubular phosphate transport was also evident: TmP/GFR (3.6+/-0.4 vs. 4.2+/-0.8 mg/dl) and TRP (83+/-5% vs. 90+/-4%) were significantly lower, and urinary P excretion, estimated by the ratio UP/UCr, was significantly higher (1.2+/-0.4 vs. 0.9+/-0.4 mg/mg) than controls. Urinary calcium excretion, estimated by the UCa/UCr ratio, was also significantly higher (0.15+/-0.07 vs. 0.12+/-0.09 mg/mg). These data clearly demonstrate that both GFR and tubular phosphate transport are significantly diminished in school-age children born with extreme prematurity, probably as a consequence of impaired postnatal nephrogenesis.

Acidosis increases magnesiuria in children with distal renal tubular acidosis.

In experimental animals, metabolic acidosis increases renal magnesium (Mg) excretion, whereas metabolic alkalosis reduces it. The objective of this study was to examine renal magnesium handling (U(Mg)) in children with primary distal renal tubular acidosis (DRTA). We measured U(Mg) in 11 children (3 females, 8 males, aged 6.9+/-4.9 years) with primary DRTA. They were studied either during spontaneous acidosis post treatment removal (3 patients) or after ammonium chloride (100 mmol/m2) induced acidosis (8 patients), and then following oral sodium bicarbonate load (4 g/1.73 m2). During acidosis (plasma pH 7.28+/-0.09, bicarbonate 13.2+/-4.3 mEq/l), U(Mg) was elevated (U(Mg/Cr) 0.18+/-0.06 mg/mg, normal values 0.1+/-0.06, P=0.003) although plasma Mg (P(Mg)) was in the normal range (1.93+/-0.31 mg/dl, controls 1.77+/-0.19, P=NS). After acute correction of metabolic acidosis (plasma pH 7.44+/-0.05, bicarbonate 25.6+/-1.6 mEq/l, P<0.001; urine pH 7.52+/-0.28, bicarbonate 86.9+/-39.1 mEq/l), U(Mg) decreased significantly (P=0.003), returning to control values after about 2 h (U(Mg/Cr) 0.09+/-0.06 mg/mg). Bicarbonate load resulted not only in reduction in U(Mg) but also in a decrease in urinary calcium excretion (U(Ca/Cr)) from 0.46+/-0.17 mg/mg to 0.14+/-0.12 mg/mg (P<0.001). We conclude that in children with primary DRTA, urinary Mg excretion is markedly increased and that this defect, like the hypercalciuric defect, is correctable by sodium bicarbonate administration.

Influence of diet on atherogenic risk in children with renal transplants.

Cardiovascular disease is one of the main causes of morbidity and mortality in recipients of renal transplants. Although the risk for cardiovascular disease is in part genetically determined, it may also be influenced by diet. The aim of the present study was to analyze the cross-sectional association of dietary intake of nutrients with biochemical markers of atherogenic risk. The influence of diet on the plasma profile of fatty acids was specifically investigated. Twenty-nine children and adolescents (mean age 14 years, range 6-18 years) with stable renal transplants and on a normal diet recorded their food intake for a period of 3 days. The mean calorie intake was 40.6 kcal/kg per day (protein provided 16% of total calories, carbohydrates 45%, and fat 39%). Plasma levels of total cholesterol and low-density lipoprotein-cholesterol were significantly and positively related to intake of monounsaturated fatty acids ( r=0.66, P =0.007 and r =0.62, P =0.02, respectively) and to plasma levels of elaidic acid, a trans fatty acid ( r=0.43, P =0.02 and r =0.54, P =0.01, respectively). Insulin resistance, estimated from values of plasma glucose ( r=0.70, P =0.03), plasma insulin ( r=0.59, P =0.02), and HOMA index ( r=0.62, P =0.01), was also directly related to the intake of monounsaturated fatty acids. Plasma plasminogen activator inhibitor-1 activity correlated positively with total fat intake ( r=0.59, P =0.04). Plasma levels of homocysteine were negatively related to the intake of carbohydrates ( r=-0.62, P =0.02). We conclude that reasonable dietary recommendations to minimize the atherogenic risk in children with stable renal transplants should include a protein intake adjusted to the requirements for age, a large intake of carbohydrates leading to a low glycemic load, and a fat intake of less than 30% of the total calorie intake. The amount of monounsaturated and trans fatty acids in the diet should be especially limited. A sufficient intake of polyunsaturated fatty acids, with an adequate ratio between omega 6 and omega 3 components, should also be provided.

Neonatal hypercalcemia.

The causes of hypercalcemia during the neonatal period are varied. Diagnosis is based on the plasma levels of parathyroid hormone (PTH). (a) PTH in plasma is diminished; exogenous o r endogenous calcium overloading is suspected. (b) PTH in plasma is increased; hyperparathyroidism caused by homozygous or heterozygousloss-of-function mutations in the CaR gene is suspected. (c) PTH i n plasma is normal; low or normal urinary calcium excretion (i.e.relative hypocalciuria) and normal PTH plasma levelsare relevant findings of familial hypocalciuric hypercalcemia (FHH) syndrome.

Branchio-oto-renal syndrome.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by the association of branchial cysts or fistulae, external ear malformation and/or preauricular pits, hearing loss and renal anomalies. Mutations in the EYA1 gene, a human homologue of the drosophila "eyes absent" gene, are identified as the cause of BOR syndrome.