Belatacept and Eculizumab for Treatment of Calcineurin Inhibitor-induced Thrombotic Microangiopathy After Kidney Transplantation: Case Report.

Thrombotic microangiopathy (TMA) after kidney transplantation is an uncommon and challenging cause of graft dysfunction and is associated with early graft loss. An idiosyncratic endothelial reaction to calcineurin inhibitors (CNIs) has been implicated as a frequent cause of TMA. This reaction is marked by uncontrolled activation of complement and subsequent cellular destruction. Usual therapy consists of withdrawal of the inciting drug and plasmapheresis to minimize levels of circulating complement. Recently, eculizumab, a monoclonal antibody to complement component C5, has been used for the treatment of atypical hemolytic uremic syndrome. Belatacept, an inhibitor of T cell costimulatory protein CTLA-4 has been used in immunosuppression strategies aimed at minimization of CNI. Here we report the first case of treatment of CNI-associated TMA/hemolytic uremic syndrome with withdrawal of tacrolimus and initiation of both belatacept and eculizumab. The case describes a favorable clinical course for both graft and patient, and is accompanied by a review of the literature.

The impact of peripartum factors on the onset and duration of lactation.

Knowledge of peripartum indicators of those mother-infant pairs that are at increased risk of early failure of lactation may improve specific support of breastfeeding. Mode of delivery, labor complications, hyperbilirubinemia, milk intake and weight development were evaluated in healthy term infants in a hospital (n = 338). Delayed onset of lactation was observed in primiparae and in study participants with peripartum complications. The quantitative intake of human milk, assessed by test weighing 0-24 h and 24-48 h after the onset of lactation, was not significantly different between these groups. In addition, volume intake, weight gain and lactation success were tracked in 77 infants. Partial feeding of infant formula or an intake of <150 g of human milk per day 24-48 h after the onset of lactation was linked to weaning within 4 weeks. Ninety-one percent of the infants were exclusively breastfed at discharge; this value had declined to 49, 35 and 20% at 4, 12 and 20 weeks, respectively. Peripartum factors may contribute to early lactation failure; the long-term success of breastfeeding was predominantly determined outside the hospital.

Fanconi-Bickel syndrome--a congenital defect of facilitative glucose transport.

Fanconi-Bickel syndrome (FBS, OMIM 227810) is a rare type of glycogen storage disease (GSD). It is caused by homozygous or compound heterozygous mutations within GLUT2, the gene encoding the most important facilitative glucose transporter in hepatocytes, pancreatic beta-cells, enterocytes, and renal tubular cells. To date, 112 patients have been reported in the literature. Most patients have the typical combination of clinical symptoms: hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, a characteristic tubular nephropathy, and severely stunted growth. In 63 patients, mutation analysis has revealed a total of 34 different GLUT2 mutations with none of them being particularly frequent. No specific therapy is available for FBS patients. Symptomatic treatment is directed towards a stabilization of glucose homeostasis and compensation for renal losses of various solutes. In addition to the clinical and molecular genetic aspects of FBS, this review discusses the pathophysiology of the disease and compares it to recent findings in GLUT2 deficient transgenic animals. An overview is also provided on recently discovered members of the rapidly growing family of facilitative glucose transporters, which are novel candidates for congenital disorders of carbohydrate metabolism.

Molybdenum in infancy: balance studies in patients with intestinal stomata.

UNLABELLED: This study investigated the supply of the essential trace element molybdenum (Mo) in infants with preternatural anus. It was divided into two separate investigations: (A) the complete fecal excretion of nine patients was collected in fractions over 24 h; and (B) 72 h balance studies and parallel plasma analysis were conducted in five infants and complemented by the longitudinal comparison of one of these patients with his (otherwise healthy) premature sister. Atomic absorption spectroscopy (balance studies) and high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS, plasma) were used for analysis. The following results were obtained. (A) The fecal Mo concentration ranged from 1.98 to 42.02 nmol Mo g(-1) dry fecal weight. (B) The daily intake in the balance studies was 43.2 (11.33-100.5) nmol Mo kg(-1) and the median retention was -2.91 (-32.45 to 48.6) nmol Mo kg(-1). In the premature twins the boy with an intestinal stoma had a negative balance and lost -3.32 micromol within 32 d, while his sister retained +0.45 micromol Mo in the same period. Plasma Mo ranged between 9.4 and 46.7 nmol l(-1). CONCLUSION: The negative Mo balance results may indicate an increased risk of Mo deficiency in infants requiring a long-term preternatural anus.

Molybdenum supply of very low-birth-weight premature infants during the first months of life.

This explorative study was performed to assess basic data on the Mo metabolism of premature infants. Premature (n = 18, gestational age < or = 32 wk, birth weight < or = 1,500 g) and healthy formula-fed term infants (n = 14) were nourished and corrected for gestational age, identically. Plasma was collected at 3, 16, and 52 wk and 72 h balances were performed at 3 wk of age. In the premature infants, these investigations were preceded by two balance studies and an initial plasma collection. Increased Mo intake and low relative urinary excretion resulted in a retention of 4.4 (0.99-7.77) microg Mo/kg initially in premature infants (median, range). Parallel plasma concentrations were 5.5 (2.5-7.3) microg Mo/L, declining to 2.36 (0.73-3.87) microg Mo/L at 4 wk. Term infants rendered 1.49 (0.29-1.7) microg Mo/L (p < 0.05), with no significant differences later. It was concluded that the supplementation of formulas for premature infants with Mo should be recinded until there is evidence for its necessity. Index Entries: Mo; premature infants; trace elements; formula; nutrition.

Plasma selenium in preterm and term infants during the first 12 months of life.

The goal of the present study was to prospectively assess the plasma selenium (Se) concentrations of term and preterm infants during the first year of life in relation to gestational age and nutrition. Blood specimens were collected from orally formula-fed preterm infants (gestational age < 32 weeks, birth weight < 1500 g): 1.) in hospital and 2.) corrected for gestational age parallel to healthy term breast and formula-fed infants at the ages of 1, 4 and 12 months. All infants were fed according to a standardized nutritional concept, solids and follow-up formula were introduced at the age of 4 months. Plasma selenium in preterm infants in hospital was 11.7 (6.5-20.8) microg/l and 11.6 (8.8-16.7) microg/l at 4 weeks corrected for gestational age. At the age of 4 months plasma selenium was still significantly lower than in the other groups: Preterm infants: 17.1 (10.4-30.5) microg/l; formula-fed term infants: 31.3 (24.3-47.5) microg/l; breast-fed term infants: 45.6 (27.1-65.1) microg/l). The levels of breast-fed infants were significantly higher than those of both formula-fed groups up until the introduction of solids. Preterm infants had significantly low plasma selenium levels up until a postnatal age of at least 6 months. The levels were lower than those of term infants fed an identical unsupplemented infant formula during the first 4 months of life. These data support routine monitoring in hospital and selenium supplementation of preterm infants, preferably in hospital before discharge.

Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands.

Glycogen storage disease type IIIA (GSD IIIA) is caused by mutations of the amyloglucosidase gene (AGL). For most populations, none of the AGL mutations described to date is particularly frequent. In this paper, we report that six children with GSD IIIA from the Faroe Islands were found to be homozygous for the novel nonsense mutation c.1222C>T (R408X) of the AGL gene. This mutation is easily detected by restriction enzyme digest with NsiI after mismatch PCR. Investigating five intragenic polymorphisms, we could show that this mutation was always associated with the same haplotype. The c.1222C>T mutation could be detected on two chromosomes of another 50 unselected GSD IIIA patients of other European or North American origin which means that this mutation plays a minor role worldwide. From the fact that we are currently aware of a total of 14 GSD IIIA cases in the Faroese population of 45 000, the observed prevalence is 1 : 3100. While the novel AGL mutation c.1222C>T was not detectable among 198 German newborns, nine out of 272 children from the Faroese neonatal screening program were found to be heterozygous for this mutation. Thus, the calculated prevalence is 1 : 3600 (95% CI 1:700-1:6400). We conclude that due to a founder effect, the Faroe Islands have the highest prevalence of GSD IIIA world-wide. The detection of the molecular defect has facilitated the diagnosis and has offered the opportunity for prenatal diagnosis in this patient group.

Molybdenum balance studies in premature male infants.

UNLABELLED: Despite the fact that the trace element molybdenum (Mo) is essential, there is insufficient knowledge about the demands in infancy. Mo balances were therefore assessed under consideration of formula Mo concentrations ranging from 0.125 to 2.704 micromol/l. Sixteen premature male infants participated in the investigation. Their birth weights were between 1,500 and 1,990 g, the median (range) gestational age was 34 (32-36) weeks and the post-conceptual age at the time of study 37.4 (34.1-40.6) weeks. Twenty-four balance studies were performed and the materials analysed by atomic absorption spectroscopy. Infants with a "low" Mo intake received 0.024 (0.020-0.035) micromol/ kg per day, had a urinary excretion of 0.02 (0.008-0.045) and a retention of 0.0006 (-0.03 to 0.008) micromol/kg per day. Infants with a "high" intake received 0.284 (0.227-0.487) micromol/kg per day, had a urinary excretion of 0.243 (0.118-0.378) and a retention of 0.022 (-71.1 to 141.44) micromol/kg per day. Since the median urinary excretion exceeded 60% of the Mo intake at low and high intakes, sufficient resorption but minimal retention was assessed at low intakes of Mo. CONCLUSION: In view of the limited knowledge of long-term exposure to an elevated molybdenum intake and the substantial retention observed at higher intakes, upper limits should be set for molybdenum concentrations in preterm infant formulas.

Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome.

The hyperinsulinism-hyperammonemia syndrome (HHS) has been shown to result from 'gain-of-function' mutations of the glutamate dehydrogenase (GlDH) gene, GLUD1. In the original report, all mutations were found in a narrow range of 27 base pairs within exons 11 and 12 which predicted an effect on the presumed allosteric domain of the enzyme and all these mutations were associated by a diminished inhibitory effect of guanosine triphosphate (GTP) on GlDH activity. We have investigated 14 patients from seven European families with mild hyperinsulinism. In four families, more than one member was affected. In eight cases hyperammonemia was documented, and eight cases had signs of significant leucine sensitivity. In one of the families, a novel heterozygous missense mutation in exon 6 [c.833C>T (R221C)] was detected, and in all other cases from six unrelated families the novel heterozygous missense mutation c.978G>A (R269H) was found in exon 7. When GIDH activity was measured in lymphocytes isolated from affected patients, both mutations were shown to result in a normal basal activity but a diminished sensitivity to GTP. It is the first time that this effect is reported for mutations located in the presumed catalytic site and outside the GTP allosteric domain of the enzyme. The observation of the high prevalence of the exon 7 mutation both in familial and sporadic cases of HHS suggests a mutation hot spot and justifies a mutation screening for this novel mutation by mismatch PCR-based restriction enzyme digestion in patients with hyperinsulinism.

Molybdenum in infancy: methodical investigation of urinary excretion.

PROJECT: The clinical evaluation of trace element metabolism in infancy is based on optimal pre-analytical procedures. Urinary molybdenum excretion, the major determinant of its retention, was investigated to deduce criteria for representative specimen collection. PROCEDURES: 1.) Molybdenum concentration was analyzed in 24-hour urinary specimens (n = 193) to evaluate the range in pediatric patients. 2.) In 20 children aged 0.4 to 9.3 (mean 2.3) years admitted for a micturition cystourethrogram, three urinary collection methods (catheter, spontaneous midstream samples, urinary collection bags) were compared. 3.) Diurnal variations of molybdenum concentration were assessed by fractional urinary colLection in preterm infants fed infant formula or human milk (n = 10). Analysis was performed using atomic absorption spectroscopy. RESULTS: 1.) The molybdenum concentration in 24hour specimens was 4.0 (0-123) microg Mo/l. 2.) Urine gained by catheter collection (n = 20) rendered 7.0 (0.5-60.1) microg Mo/l, midstream samples and the use of urinary collection bags showed a concentration of 21.25 (0-91) microg Mo/l (p > 0.05). 3.) Fractional collection over 72 hours rendered a significant increase in only one participant. Diurnal differences of the urinary molybdenum concentration were significant between 3-6 p.m. and 6-9 p.m.. The molybdenum/creatinine quotient differed between the time intervals 3-6 p.m. and 9-12 p.m., as well as 9-12 a.m. and 6-9 a.m. (p < 0.05). CONCLUSION: Pediatric routine procedures are suitable for the assessment of urinary molybdenum excretion. The diurnal variations assessed are of minor clinical relevance, but should be considered by respective definition of collecting times and reference values.

Molybdenum metabolism: stable isotope studies in infancy.

The essential trace element molybdenum (Mo) is bound to and required for the function of molybdoenzymes, e.g. sulfite and xanthine oxidase. Dietary recommendations for early infancy are based on limited knowledge about its metabolism. 100Mo was used as an extrinsic tag to study the absorption and kinetics of excretion in infancy. 10 infants with a gestational age of 35 (30-39) weeks, a birth weight of 2.0 (0.9-2.3) kg and a post-natal age of 20 (10-54) days were studied. They received 25 microg 100Mo/kg with a feed of human milk or formula. Fractional urinary and fecal collections were conducted preceding the 100Mo intake and for 48-72 hours afterwards. The materials were analyzed by atomic absorption spectroscopy and inductively coupled plasma mass spectrometry. The median absorption of 100Mo intake was 97.5 (96.3 to 99.1) %. The retention of nutritive Mo intake and 100Mo in the study period was 11.2 (3.8-15.7) microg Mo/kg, equivalent to 35.7 (12.7-55.6) %. The Mo concentration increased to a peak value in urine within 8 (6-13) hours and in feces within 24 (7-48.5) hours. In addition, increases of copper in feces and urine were observed in 8 of 9 infants studied. Mo given orally is well resorbed in premature infants, and predominantly excreted in the urine. Dietary recommendations should prevent excessive intakes in infancy.

Molecular analysis in glycogen storage disease 1 non-A: DHPLC detection of the highly prevalent exon 8 mutations of the G6PT1 gene in German patients.

We investigated the molecular basis of glycogen storage disease type 1 non-A (GSD1 non-A) in 21patients. In addition to 8 novel mutations within the G6PT1 gene (c.250T>A, c.580G>A, c.627C>T, c.653-4delAG, c. 844C>A, c.1071A>C, c.1268G>A, c.1348G>A), we found a remarkably high prevalence of exon 8 mutations in German patients. The c.1211-2delCT mutation and the c.1184G>T mutation accounted for 32% and 29% of mutant chromosomes, respectively, supporting the hypothesis of a Middle European origin of these two mutations. Together with less common mutations, 79% of German GSD1 non-A patients were either homozygous or heterozygous for an exon 8 mutation. In addition to direct sequencing, these exon8 mutations could be detected by mutation-specific methods such as the detection of heteroduplex formation on polyacrylamide gel electrophoresis or by the amplification of DNA segments by allele-specific oligonucleotides. Furthermore, the use of denaturating high performance liquid chromatography (DHPLC) allowed a 100% detection and discrimination of all exon 8 mutations. In conclusion from these results, we recommend the use of either conventional or DHPLC screening as the initial non-invasive and efficient diagnostic procedure in patients with GSD1 non-A from populations with a similar distribution of mutations. Hum Mutat 16:177, 2000.

Molybdenum supplementation in phenylketonuria diets: adequate in early infancy?

BACKGROUND: Molybdenum concentrations in formulas exceed those in human milk by far. Infants with phenylketonuria require semisynthetic phenylalanine-restricted diets. Because these diets are presently supplemented with molybdenum, a study was conducted to determine whether retention and plasma concentration in the recipients are equivalent to those of healthy breast-fed infants. METHODS: Balance and plasma studies were conducted in healthy breast-fed infants (n = 17) and in patients with phenylketonuria (n = 4) at the age of 4 weeks, and the plasma investigations were repeated at the ages of 4 and 12 months. The samples were analyzed by atomic absorption spectroscopy (balance studies) and high-resolution inductively coupled plasma mass spectrometry (plasma). RESULTS: Molybdenum intake and retention in all infants with phenylketonuria were more than 18 times those of breast-fed infants. The plasma concentrations reflected these differences. A median of 0.04 microg/l was assessed in breast-fed infants at 4 weeks and less than 0.02 microg/l at 4 months of age. Comparative results of infants with phenylketonuria were 2.9 microg/l and 2.5 microg/l, respectively. There were no significant differences between the groups at 12 months of age. CONCLUSIONS: The phenylketonuria diets investigated showed excessive retention and plasma concentrations of the essential trace element molybdenum in early infancy. In view of these findings, the present practice of molybdenum fortification should be revised.

Magnesium balance studies in premature and term infants.

BACKGROUND: The knowledge of magnesium requirements of premature infants is still very limited, although it is essential for the optimal composition of suitable formulas. AIM OF THE STUDY: The study concept was 1) to assess physiological magnesium balance data of healthy term infants and longitudinal results from formula-fed premature infants and 2) to deduce conclusions on the magnesium content of the formulas. METHODS: Premature infants (n = 14, birth weight < or = 1500 g, gestational age < or = 32 weeks) were studied in conventional balance trials with 1) a semi-elemental diet (A), 2) preterm infant formula (B), and 3) infant formula (C). In addition, healthy term formula-fed (n = 11, D) and breast-fed (n = 14, E) infants were investigated. Analysis was performed by flame atomic absorption spectroscopy. RESULTS: The median magnesium intake ranged between 4.84 mg/kg x d-1 (breast-fed infants) and 16.33 mg/kg x d-1 (premature infants). The term breast-fed infants retained nearly as much magnesium as term formula-fed infants (3.37 vs. 3.97 mg/kg x d-1), due to a low percental fecal and urinary excretion. A higher magnesium retention was observed in the premature group: A: 7.97 mg/kg x d-1, B: 5.3 mg/kg x d-1, 3.) C: 5.54 mg/kg x d-1. CONCLUSION: In view of the high percental magnesium retention in formula-fed premature infants, excessive supply should be avoided. The long-term effects of lower intakes have to be monitored.