Elisabeth A.M. Cornelissen

Jeune syndrome: description of 13 cases and a proposal for follow-up protocol

Jeune syndrome (asphyxiating thoracic dystrophy, ATD) is a rare autosomal recessive skeletal dysplasia characterized by a small, narrow chest and variable limb shortness with a considerable neonatal mortality as a result of respiratory distress. Renal, hepatic, pancreatic and ocular complications may occur later in life. We describe 13 cases with ages ranging from 9xa0months to 22xa0years. Most patients experienced respiratory problems in the first years of their life, three died, one experienced renal complications, and one had hepatic problems. With age, the thoracic malformation tends to become less pronounced and the respiratory problems decrease. The prognosis of ATD seems better than described in literature and in our opinion this justifies long term intensive treatment in the first years. We also propose a follow-up protocol for patients with ATD.

Incidence of late vitamin K deficiency bleeding in newborns in the Netherlands in 2005: evaluation of the current guideline

Vitamin K prophylaxis is recommended to prevent the hazard of haemorrhage caused by vitamin K deficiency in newborns. The present Dutch guideline recommends 1xa0mg of vitamin K1 orally at birth, followed by a daily dose of 25xa0μg of vitamin K1 from 1 to 13xa0weeks of age for breastfed infants. Since the introduction of this prophylaxis, the incidence of vitamin K deficiency bleeding (VKDB) has decreased; however, late VKDB is still reported. From 1 January to 31 December 2005, a nationwide active surveillance was performed by the Netherlands Paediatric Surveillance Unit (NSCK) to study the current incidence and aetiology of late VKDB in infants. Six cases could be validated as late VKDB: all were breastfed, one fatal idiopathic intracranial haemorrhage at the age of 5xa0weeks and five bleedings secondary to an underlying cholestatic liver disease between the age of 3 and 7xa0weeks. The total incidence of late VKDB and idiopathic late VKDB was calculated to be 3.2 (95% CI: 1.2–6.9) and 0.5 (95% CI: 0–2.9) per 100,000 live births, respectively. With the current Dutch guideline, idiopathic late VKDB is rare but late VKDB secondary to cholestasis still occurs in breastfed infants. Doubling the daily dose of vitamin K1 to 50 μg, as is comparable to formula-feeding, may possibly prevent VKDB in this group. Further research, however, is needed to prove this hypothesis.

Fungal peritonitis in children on peritoneal dialysis

Fungal peritonitis is a rare but serious complication in children on peritoneal dialysis (PD). In this study, risk factors were evaluated, and therapeutic measures were reviewed. A retrospective, multi-centre study was performed in 159 Dutch paediatric PD patients, between 1980 and 2005 (3,573 months). All peritonitis episodes were reviewed. Fungal peritonitis episodes were evaluated based on possible risk factors and treatment strategy. A total of 321 episodes of peritonitis occurred, with 9 cases of fungal peritonitis (2.9%). Candida peritonitis occurred most frequently (78%). Seven patients (78%) had used antibiotics in the prior month. Fungal peritonitis patients had a higher previous bacterial peritonitis rate compared to the total study population (0.13 versus 0.09 episodes/patient*month), with twice as many gram negative organisms. In all fungal peritonitis patients, the PD catheter was removed. In four patients restart on PD was possible. Fungal peritonitis is a rare complication of PD in children, but is associated with high technique failure. The most important risk factors are a high bacterial peritonitis rate, prior use of antibiotics, and previous bacterial peritonitis with gram negative organisms. The PD catheter should be removed early, but in children, peritoneal lavage with fluconazole before removal may be useful to prevent technique failure.

Tubular reabsorption and local production of urine hepcidin-25

BackgroundHepcidin is a central regulator of iron metabolism. Serum hepcidin levels are increased in patients with renal insufficiency, which may contribute to anemia. Urine hepcidin was found to be increased in some patients after cardiac surgery, and these patients were less likely to develop acute kidney injury. It has been suggested that urine hepcidin may protect by attenuating heme-mediated injury, but processes involved in urine hepcidin excretion are unknown.MethodsTo assess the role of tubular reabsorption we compared fractional excretion (FE) of hepcidin-25 with FE of β2-microglobulin (β2m) in 30 patients with various degrees of tubular impairment due to chronic renal disease. To prove that hepcidin is reabsorbed by the tubules in a megalin-dependent manner, we measured urine hepcidin-1 in wild-type and kidney specific megalin-deficient mice. Lastly, we evaluated FE of hepcidin-25 and β2m in 19 patients who underwent cardiopulmonary bypass surgery. Hepcidin was measured by a mass spectrometry assay (MS), whereas β2m was measured by ELISA.ResultsIn patients with chronic renal disease, FE of hepcidin-25 was strongly correlated with FE of β2m (ru2009=u20090.93, P <0.01). In megalin-deficient mice, urine hepcidin-1 was 7-fold increased compared to wild-type mice (pu2009<u20090.01) indicating that proximal tubular reabsorption occurs in a megalin- dependent manner. Following cardiac surgery, FE of hepcidin-25 increased despite a decline in FE of β2m, potentially indicating local production at 12–24xa0hours.ConclusionsHepcidin-25 is reabsorbed by the renal tubules and increased urine hepcidin-25 levels may reflect a reduction in tubular uptake. Uncoupling of FE of hepcidin-25 and β2m in cardiac surgery patients suggests local production.

Lower urinary tract symptoms after renal transplantation in children.

PURPOSEnWe investigated the prevalence and nature of LUTS after renal Tx in children. The focus of the study was the presence of LUTS in children without a history of urological symptoms. We also studied the relationship between the characteristics of these patients and the occurrence of LUTS.nnnMATERIALS AND METHODSnData were gathered using a written questionnaire, frequency volume chart, free uroflowmetry, transabdominal ultrasonography and medical records. The study group (30 patients) consisted of 9 children (30%) undergoing renal transplantation with an underlying urological disease and 21 (70%) with an underlying nephrological disease.nnnRESULTSnIn the nephrological group the incidence of high capacity bladder was 75%, residual urine 50%, UTI 43%, hesitancy 38%, intermittent flow 33%, bladder pain 33%, nighttime incontinence 29%, nocturia 24%, feeling of incomplete emptying 15%, daytime incontinence 14%, straining 14%, urgency 10%, burning sensation 10% and intermittency 5%. No substantial difference in the occurrence of LUTS, UTI or high bladder capacity after Tx was found between children with an underlying urological disease and those with an underlying nephrological disease. On average, patients in both groups suffered from 3 different LUTS.nnnCONCLUSIONSnAfter renal Tx children with a nephrological disease demonstrated a high incidence of LUTS. The occurrence of LUTS combined with UTI and increased bladder capacity indicates that these children are at risk for development of myogenic failure. This finding emphasizes the importance of close urological followup after Tx in children with urological and nephrological disease.

Early Development of Hyperparathyroidism Due to Loss of PTH Transcriptional Repression in Patients With HNF1β Mutations

CONTEXTnHeterozygous mutations or deletions of the transcription factor hepatocyte nuclear factor 1β (HNF1β) result in a heterogeneous syndrome characterized by renal cysts and diabetes, together with a variety of other extrarenal and renal manifestations. Interestingly, in several patients with HNF1β abnormalities, we observed early hyperparathyroidism and PTH levels that we judged inappropriately high compared with the degree of renal function decline.nnnOBJECTIVEnBased on the above clinical observations, we tested the hypothesis of a direct role of HNF1β in the transcriptional regulation of the human PTH gene in the parathyroid gland.nnnDESIGN, SETTING, AND PATIENTSnImmunostaining of human parathyroid sections, RT-PCR, chromatin immunoprecipitation (ChIP), and luciferase reporter assays in human embryonic kidney cells (HEK293) were performed. We eventually report clinical data from all 11 HNF1β patients known at our institute, 9 with heterozygous HNF1β whole-gene deletions and 2 with heterozygous HNF1β mutations.nnnRESULTSnPTH levels were high in 8 patients. In 2 of these patients, the hyperparathyroidism was clearly appropriate for the level of kidney function, whereas PTH might be discrepant in the others. We demonstrated HNF1β expression in PTH-positive cells of human parathyroid gland. Chromatin immunoprecipitation analysis showed that HNF1β directly binds responsive elements within the human PTH promoter. Cotransfection of a PTH promoter- luciferase construct with a wild-type HNF1β construct resulted in a maximal reduction of 30% of PTH promoter activity. Importantly, HNF1β mutants lacked this inhibitory property. Serial deletions in the PTH promoter construct revealed that the inhibitory effect of HNF1β resides between -200 and -70 bp from the transcription initiation site.nnnCONCLUSIONSnOur data demonstrate that HNF1β is a novel repressor of human PTH gene transcription, which could contribute to the development of hyperparathyroidism in patients with HNF1β mutations or deletions.

Halitosis in cystinosis patients after administration of immediate-release cysteamine bitartrate compared to delayed-release cysteamine bitartrate

Halitosis due to dimethylsulfide (DMS) generation is a major side effect of cysteamine in the treatment of cystinosis. Recently, an enteric coated formulation of cysteamine bitartrate (RP103) administered twice daily was demonstrated to be non-inferior for lowering WBC cystine levels compared to the non-enteric coated formulation (Cystagon®), administered 4 times per day. Since both formulations had different pharmacokinetic profiles, we compared DMS breath levels after administration of either RP103 or Cystagon® in four cystinosis patients. Although cysteamine areas under the curve (AUCs) were comparable, AUC of DMS was lower after the administration of RP103 compared to Cystagon®. This observation is of importance in cystinosis patients, since halitosis hampers compliance with cysteamine therapy.

Unexplained hypothermia and bradycardia in two pediatric patients with Wegener’s granulomatosis

Sirs,We report remarkable symptoms of Wegener’s granuloma-tosis (WG), which might occur more often than reported sofar. Two patients (13 and 16 years old) with acute renalfailure due to WG developed simultaneous hypothermia(<36.5˚C) and bradycardia (<60 bpm) duringthefirst weeksof treatment with intravenous pulse methylprednisolone(IPM), cyclophosphamide (CYC), hemodialysis (HD), andtherapeutic plasma exchange (TPE). In both patients, rapidlyprogressivepauci-immuneglomerulonephritiswasconfirmedby renal biopsy, and antineutrophil cytoplasmic antibody(ANCA)-serology was positive. They received 3-day IPMtherapy(1g/1.73m