Mutations in CYP24A1 and idiopathic infantile hypercalcemia.

BACKGROUND: Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS: We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS: Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS: The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.

Multi-center randomized controlled trial of cognitive treatment, placebo, oxybutynin, bladder training, and pelvic floor training in children with functional urinary incontinence.

OBJECTIVE: Functional urinary incontinence causes considerable morbidity in 8.4% of school-age children, mainly girls. To compare oxybutynin, placebo, and bladder training in overactive bladder (OAB), and cognitive treatment and pelvic floor training in dysfunctional voiding (DV), a multi-center controlled trial was designed, the European Bladder Dysfunction Study. METHODS: Seventy girls and 27 boys with clinically diagnosed OAB and urge incontinence were randomly allocated to placebo, oxybutynin, or bladder training (branch I), and 89 girls and 16 boys with clinically diagnosed DV to either cognitive treatment or pelvic floor training (branch II). All children received standardized cognitive treatment, to which these interventions were added. The main outcome variable was daytime incontinence with/without urinary tract infections. Urodynamic studies were performed before and after treatment. RESULTS: In branch I, the 15% full response evolved to cure rates of 39% for placebo, 43% for oxybutynin, and 44% for bladder training. In branch II, the 25% full response evolved to cure rates of 52% for controls and 49% for pelvic floor training. Before treatment, detrusor overactivity (OAB) or pelvic floor overactivity (DV) did not correlate with the clinical diagnosis. After treatment these urodynamic patterns occurred de novo in at least 20%. CONCLUSION: The mismatch between urodynamic patterns and clinical symptoms explains why cognitive treatment was the key to success, not the added interventions. Unpredictable changes in urodynamic patterns over time, the response to cognitive treatment, and the gender-specific prevalence suggest social stress might be a cause for the symptoms, mediated by corticotropin-releasing factor signaling pathways.

Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Disease-associated mutations have been described in the genes encoding the complement regulators complement factor H, membrane cofactor protein, factor B, and factor I. In this study, we show in two independent cohorts of aHUS patients that deletion of two closely related genes, complement factor H-related 1 (CFHR1) and complement factor H-related 3 (CFHR3), increases the risk of aHUS. Amplification analysis and sequencing of genomic DNA of three affected individuals revealed a chromosomal deletion of approximately 84 kb in the RCA gene cluster, resulting in loss of the genes coding for CFHR1 and CFHR3, but leaving the genomic structure of factor H intact. The CFHR1 and CFHR3 genes are flanked by long homologous repeats with long interspersed nuclear elements (retrotransposons) and we suggest that nonallelic homologous recombination between these repeats results in the loss of the two genes. Impaired protection of erythrocytes from complement activation is observed in the serum of aHUS patients deficient in CFHR1 and CFHR3, thus suggesting a regulatory role for CFHR1 and CFHR3 in complement activation. The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes.

Estimated one-yr glomerular filtration rate is an excellent predictor of long-term graft survival in pediatric first kidney transplants.

Acute rejection episodes following pediatric renal transplantation have been progressively reduced by recent immunosuppressive regimens. Nevertheless, grafts continue to fail over time and surrogate parameters for long-term RGS are lacking. We investigated post-transplant renal function within the first yr as an independent predictor of long-term RGS in 104 pediatric first kidney transplant recipients (mean age 11.1 +/- 3.9 yr; mean follow-up 8.3 +/- 3.5 yr) transplanted between January 1989 and December 2000. GFR was assessed by use of the Schwartz formula at 30 days and six and 12 months after transplantation, respectively. Patients were further stratified at all times according to GFR: (i) GFR<45 mL/min/1.73 m(2), (ii) GFR 45-80 mL/min/1.73 m(2), and (iii) GFR>80 mL/min/1.73 m(2). Cox regression analysis including factors potentially influencing long-term RGS, e.g., age, gender, transplant yr, HLA-mismatch, underlying renal disease, clinical acute rejection, absolute GFR as well as the change in GFR within the first yr was performed. Graft failure occurred in 24 out of 104 patients (23%) 6.2 yr (mean) after transplantation corresponding to a cumulative five-yr graft survival of 87.5%. GFRs at 30 days and six and 12 months were significantly associated with long-term RGS in the univariate cox regression analysis (GFR at 30 days, p = 0.045; GFR at six months, p = 0.004; GFR at 12 months, p < 0.001). None of the other variables were significant parameters of correlation. Multivariate cox analysis revealed a GFR below 45 mL/min/1.73 m(2) at 12 months after transplantation as the only independent predictor of long-term RGS (hazard ratio 55.9, 95% CI 5.29-591, p = 0.001). GFR at 12 months post-transplant is an excellent surrogate parameter for long-term RGS in children. This parameter might be useful as a primary end-point in short-term pediatric clinical trials.

Angiotensin receptor blocker reduces proteinuria independently of blood pressure in children already treated with Angiotensin-converting enzyme inhibitors.

BACKGROUND/AIMS: Dual blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) has higher antiproteinuric effects than single blockade in adults. In children, little is known on dual blockade of the renin-angiotensin system. The study investigates whether adding an ARB to proteinuric children already on ACEI reduces proteinuria. METHODS: A total of 10 children (median age 13.3 years) with chronic kidney disease and persistent proteinuria despite maximal dose of ACEI were included. Losartan was given at an initial dose 0.8 mg/kg/day. Proteinuria, blood pressure (BP) and renal function (glomerular filtration rate) were measured. RESULTS: Mean proteinuria decreased from 484 +/- 290 mg/mmol creatinine to 223 +/- 197 after 1-3 months of losartan treatment and remained stable at 234 +/- 153, 224 +/- 177 and 195 +/- 133 after 3-6, 6-12 months and at the last follow-up check (median 1.9 years, p < 0.05 for all visits vs. before treatment). The median percentage decrease in proteinuria was 66, 56, 44 and 66% during the study periods. No significant change in BP, glomerular filtration rate or serum potassium was observed. One child complained of rash, which led to discontinuation of losartan. CONCLUSION: Adding an ARB to current ACEI treatment can further reduce proteinuria in children with chronic kidney disease without affecting BP.

The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome.

Mutations in the gene encoding complement factor H (CFH) that alter the C3b/polyanions-binding site in the C-terminal region impair the capacity of factor H to protect host cells. These mutations are also strongly associated with atypical hemolytic uremic syndrome (aHUS). Although most of the aHUS-associated CFH mutations seem "unique" to an individual patient or family, the R1210C mutation has been reported in several unrelated aHUS patients from distinct geographic origins. Five aHUS pedigrees and 7 individual aHUS patients were analyzed to identify potential correlations between the R1210C mutation and clinical phenotype and to characterize the origins of this mutation. The clinical phenotype of aHUS patients carrying the R1210C mutation was heterogeneous. Interestingly, 12 of the 13 affected patients carried at least one additional known genetic risk factor for aHUS. These data are in accord with the 30% penetrance of aHUS in R1210C mutation carriers, as it seems that the presence of other genetic or environmental risk factors significantly contribute to the manifestation and severity of aHUS in these subjects. Genotype analysis of CFH and CFHR3 polymorphisms in the 12 unrelated carriers suggested that the R1210C mutation has a single origin. In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations.

Gram-negative peritonitis in children undergoing long-term peritoneal dialysis.

BACKGROUND: The proportion of gram-negative causative organisms in peritoneal dialysis-associated peritonitis is increasing. Little published information for this complication exists in children. The objective of this study is to evaluate the clinical presentation, early and late response to treatment, and identification of factors influencing the outcome of gram-negative peritonitis (GNP) in children. STUDY DESIGN: Case series. SETTING AND PARTICIPANTS: 104 children (aged 7.9 +/- 5.9 years) with 121 GNP episodes reported to the International Pediatric Peritonitis Registry from October 2001 through December 2004. PREDICTORS: Patient, clinical, bacteriological, and treatment features. OUTCOMES: Initial response to empirical treatment was assessed after approximately 72 hours of therapy. Final outcome was judged according to the occurrence of death, technique failure, relapse, need for catheter exchange, and a composite end point defining full functional recovery. RESULTS: 44% of episodes of GNP occurred in children younger than 5 years. Causative organisms included Pseudomonas species, 21%; Klebsiella species, 18%; Escherichia coli, 17%; and Acinetobacter species, 12%. Thirty-two percent of organisms classified as gram-negative were not identified further. Clinical manifestations were severe and uniform for all causative gram-negative agents. A substantial proportion (20%) of organisms were resistant to ceftazidime, with resulting suboptimal response to empirical therapy. By day 3 of initial empiric treatment, 85% of children with GNP had improved clinically (39%, complete resolution; 46%, improvement in symptoms), 10% showed poor response, and 5% had worsening of symptoms. Multivariate analysis identified severe abdominal pain, use of a single-cuff catheter, and intermittent (versus continuous) intraperitoneal ceftazidime administration as independent predictors of worse initial response to treatment. Full functional recovery was achieved in 86% of episodes. Nineteen patients (16%) required catheter removal, 11 (9%) experienced a relapse, 7 (6%) discontinued peritoneal dialysis therapy permanently, and 3 died. Lack of clinical improvement after 72 hours of therapy (odds ratio, 5.39; P < 0.01) and the presence of an exit-site infection (odds ratio, 7.69; P = 0.01) independently increased the risk of an incomplete functional recovery. LIMITATIONS: The study was not designed to assess absolute incidence figures or risk factors for the development of GNP in children. CONCLUSIONS: GNP is a significant complication of long-term peritoneal dialysis therapy in children, and a substantial proportion of affected children are at risk of permanent sequelae. Because results of empiric treatment with ceftazidime are suboptimal in the setting of this infection, alternative antimicrobial agents should be reconsidered.

Searching biomarker candidates in serum using multidimensional native chromatography. II Method evaluation with Alport syndrome and severe inflammation.

Biomarker search using multidimensional native liquid fractionation of serum in microplates was evaluated. From different donors, homologous sample fractions with UV absorbance depending on state of illness were selected, and their constituents were identified and quantitated by MS. Analysis of sera of patients with Alport syndrome and severe inflammation proved the reliability of the method by confirming characteristic alterations. Moreover, 23 new marker candidates were detected for Alport syndrome, some of them being involved in matrix degradation and repair, and 33 new candidates for severe inflammation, among them alpha1B-glycoprotein cysteine-rich secretory protein and an apparently low molecular-weight albumin variant.

Ambulatory blood pressure, proteinuria and uric acid in children with IgA nephropathy and their correlation with histopathological findings.

BACKGROUND/AIMS: In adults, nighttime hypertension and hyperuricemia are new risk factors for progression of IgA nephropathy (IgAN). In children, nighttime blood pressure (BP) and serum uric acid have never been investigated. The aim of the study was to investigate nighttime BP and uric acid in children with IgAN. METHODS: Data on children with IgAN from two pediatric nephrology centers were retrospectively reviewed (renal biopsy - subclasses according Hass I-V, ambulatory blood pressure monitoring ABPM, serum uric acid, proteinuria). RESULTS: Twenty-eight untreated children with IgAN were included. Hypertension was diagnosed on the basis of ABPM in 54% of children, 50% were nondippers and 25% have isolated nighttime hypertension. The mean ambulatory BP was higher at nighttime than during daytime (systolic nighttime BP 1.11 +/- 0.79 SDS vs. daytime 0.59 +/- 0.79, diastolic nighttime BP 1.16 +/- 0.95 vs. daytime 0.52 +/- 1.10, p < 0.01 for systolic and p = 0.01 for diastolic). Children with severe histological subclasses (III-IV) tended to have higher prevalence of hypertension than children with mild subclasses (I-II), 67% vs. 38%, p = 0.13. Hyperuricemia was diagnosed in 14% of children. A significant correlation was found between proteinuria and histopathological subclasses (r = 0.44, p < 0.05). CONCLUSION: Children with IgAN have often nighttime hypertension. Hypertension and proteinuria are associated with severe histopathological findings. Hyperuricemia is a rare finding in children.

Five-year outcome in pediatric patients with mycophenolate mofetil-based renal transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) based immunosuppression after renal transplantation has proven to be safe and beneficial for children and adolescents. However, long-term analysis, in particular of pediatric patients, is scarce. PATIENTS: Data of 140 patients receiving MMF versus azathioprine (AZA) in combination with cyclosporine A (CsA) and prednisone without induction were analyzed with a main focus on survival and renal function in long-term follow-up. RESULTS: After 5 years of follow-up, 44 MMF and 20 AZA patients were still on study. Graft survival of intent to treat (ITT) groups was 90.7% for MMF and 68.5% for AZA patients (P<0.001). Cumulative rejection free survival was 51.2% in MMF versus 37.0% in AZA patients (P<0.05). In association with early acute rejections (ARE), projected half-life was 14.4/4.5 years in patients with and 18.7/14.5 years without rejection in the MMF/AZA group, respectively. CONCLUSIONS: MMF based protocols improved long-term graft survival without an increase in side effects. Early ARE were associated with worse half-life of the graft, although more stressed in the AZA group. Thus, to improve quality of life in children for very long-term outcome, ARE should be further decreased and renal function should be better preserved.

Successful withdrawal of steroids in pediatric renal transplant recipients receiving cyclosporine A and mycophenolate mofetil treatment: results after four years.

BACKGROUND: Despite their numerous systemic side effects, glucocorticoids (steroids) still form a cornerstone in immunosuppressive regimens in pediatric renal transplant recipients. The addition of mycophenolate mofetil (MMF) to a cyclosporine A (CsA)-based immunosuppressive regimen after renal transplantation may allow steroid withdrawal and amelioration or avoidance of steroid-specific side effects. METHODS: In a retrospective case-control study, covering a mean follow-up period of 46 +/- 2.3 months and 40 patients aged 11.4 +/- 4.9 years, we analyzed the safety and efficacy of steroid withdrawal in pediatric renal transplant recipients receiving CsA micoroemulsion, MMF, and low-dose prednisone treatment. RESULTS: : Steroid withdrawal in all 20 pediatric renal transplant recipients receiving CsA and MMF was successful and not associated with an acute rejection episode; graft function remained stable. At baseline, the degree of growth retardation was comparable between the groups (mean height standard deviation scores [SDSs] -1.60 +/- 0.30 [withdrawal group] and -1.32 +/- 0.39 [case-control group]). After steroid withdrawal, prepubertal patients exhibited a significant catch-up growth with a mean height gain of 1.47 +/- 0.32 SDS, whereas height SDS did not improve in patients receiving steroids. Growth was also improved in pubertal patients who stopped taking steroids. Standardized body mass index in patients who stopped taking steroids decreased significantly by 49% from 0.87 +/- 0.31 SDS to 0.45 +/- 0.30 SDS. After steroid withdrawal, mean arterial blood pressure SDS decreased significantly by 45%. Moreover, the need for antihypertensive medication declined significantly in patients who stopped taking steroids. The white blood cell counts and hemoglobin levels were comparable between the groups. CONCLUSIONS: : This study suggests that steroids can be safely and successfully withdrawn in selected pediatric renal transplant recipients receiving immunosuppressive maintenance therapy consisting of CsA and MMF.

Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years.

BACKGROUND: Mycophenolate mofetil (MMF)-based immunosuppression has reduced the acute rejection rate in adults and in children in the early posttransplantation period. Three-year posttransplantation results have been reported for adults but not for children thus far. In the present open-labeled study, patients 18 years old and younger were evaluated prospectively for up to 3 years after renal transplantation (RTX). METHODS: Eighty-six patients receiving MMF in combination with cyclosporine and prednisone without induction were evaluated for patient survival, transplant survival, renal function, arterial blood pressure, adverse events, and opportunistic infections. These patients were compared with a historic control group (n=54) receiving azathioprine (AZA) instead of MMF. RESULTS: Patient survival after 3 years was 98.8% in the MMF group and 94.4% in the AZA group (NS). Intent-to-treat analysis of graft survival demonstrated superiority for MMF (98% vs. 80%; P<0.001). Cumulative acute rejection episodes occurred in 47% of patients in the MMF group versus 61% in the AZA group (P<0.05). Renal function was not significantly different, neither after 3 years nor in the long-term calculation. Antihypertensive medication was administered to 73% to 84% of patients, similar in both groups. Opportunistic infections were recorded only for MMF. Infection rates were comparable to those reported in adults. CONCLUSIONS: These results suggest that MMF is safe and beneficial as a longer term maintenance immunosuppressive drug in children and adolescents.

Cluster of hemolytic-uremic syndrome caused by Shiga toxin-producing Escherichia coli O26:H11.

BACKGROUND: The epidemiology and clinical characteristics of the hemolytic-uremic syndrome (HUS) caused by Escherichia coli O157:H7 are well-known, but HUS attributable to non-O157:H7 Shiga toxin (Stx)-producing E. coli (STEC) are less thoroughly described. Here we report a cluster of HUS cases caused by STEC O26:H11 the most common non-O157:H7 STEC isolated from sporadic cases of HUS in Europe. METHODS: Three children between 13 and 17 months of age, living in the same small town, developed HUS within an interval of 5 days. We present clinical and microbiologic data on the patients and their infecting isolates. RESULTS: The clinical course ranged from mild uncomplicated HUS to severe HUS complicated by multiorgan involvement. Microbiologic investigation demonstrated STEC of serotype O26:H11 in stools of all the patients. The phenotypic and molecular characterization of the STEC O26:H11 isolates demonstrated that these strains were identical and, unusual for STEC O26, they harbored the stx2 but not the stx1 gene. None of the patients had evidence of STEC O157:H7 infection either by culture or by E. coli O157 serology. The source of the STEC O26:H11 infection was undetermined. CONCLUSIONS: Our results demonstrate that diagnostic procedures based on the detection of stx genes and/or Stx production and subsequent subtyping of the isolates using molecular methods are necessary to identify such outbreaks caused by non-O157:H7 STEC.

Ambulatory blood pressure correlates with renal volume and number of renal cysts in children with autosomal dominant polycystic kidney disease.

OBJECTIVE: In adult patients with autosomal dominant polycystic kidney disease (ADPKD) renal volume was found to be significantly greater in hypertensive compared to normotensive patients. The purpose of this study was to find out if blood pressure (BP) is related to renal size also in children with ADPKD, for example, in an early stage of the disease. METHOD AND RESULTS: Sixty-two children with ADPKD and normal renal function (mean age 12.3+/-4.3 years) were examined by renal ultrasound and ambulatory BP monitoring (ABPM). Twenty-two children were hypertensive and 40 normotensive. Mean renal volume was significantly greater in hypertensive than in normotensive children (2.7+/-2.3 SDS versus 1.2+/-2.5 SDS, P<0.01) despite similar anthropometric data and renal function. Similarly the mean number of cysts was significantly higher in hypertensive patients than in normotensive (35+/-15 cysts versus 23+/-14 cysts, P<0.01). Renal volume correlated with daytime as well as with night-time systolic and diastolic BP (r=0.41-0.47, P<0.01). Correlations with renal length and the number of renal cysts were somewhat less (r=0.29-0.43, P<0.05 and 0.01, respectively). CONCLUSIONS: This study revealed a significant relationship between renal volume, renal length and number of renal cysts and BP. It is suggested that children with ADPKD should regularly be checked for BP changes by ABPM, especially those who show increased renal size or a high number of renal cysts on ultrasound. All these children are at high risk for development of hypertension.

BIOKID: randomized controlled trial comparing bicarbonate and lactate buffer in biocompatible peritoneal dialysis solutions in children [ISRCTN81137991].

BACKGROUND: Peritoneal dialysis (PD) is the preferred dialysis modality in children. Its major drawback is the limited technique survival due to infections and progressive ultrafiltration failure. Conventional PD solutions exert marked acute and chronic toxicity to local tissues. Prolonged exposure is associated with severe histopathological alterations including vasculopathy, neoangiogenesis, submesothelial fibrosis and a gradual loss of the mesothelial cell layer. Recently, more biocompatible PD solutions containing reduced amounts of toxic glucose degradation products (GDPs) and buffered at neutral pH have been introduced into clinical practice. These solutions contain lactate, bicarbonate or a combination of both as buffer substance. Increasing evidence from clinical trials in adults and children suggests that the new PD fluids may allow for better long-term preservation of peritoneal morphology and function. However, the relative importance of the buffer in neutral-pH, low-GDP fluids is still unclear. In vitro, lactate is cytotoxic and vasoactive at the concentrations used in PD fluids. The BIOKID trial is designed to clarify the clinical significance of the buffer choice in biocompatible PD fluids. METHODS/DESIGN: The objective of the study is to test the hypothesis that bicarbonate based PD solutions may allow for a better preservation of peritoneal transport characteristics in children than solutions containing lactate buffer. Secondary objectives are to assess any impact of the buffer system on acid-base status, peritoneal tissue integrity and the incidence and severity of peritonitis. After a run-in period of 2 months during which a targeted cohort of 60 patients is treated with a conventional, lactate buffered, acidic, GDP containing PD fluid, patients will be stratified according to residual renal function and type of phosphate binding medication and randomized to receive either the lactate-containing Balance solution or the bicarbonate-buffered Bicavera solution for a period of 10 months. Patients will be monitored by monthly physical and laboratory examinations. Peritoneal equilibration tests, 24-h dialysate and urine collections will be performed 4 times. Peritoneal biopsies will be obtained on occasion of intraabdominal surgery. Changes in small solute transport rates, markers of peritoneal tissue turnover in the effluent, acid-base status and peritonitis rates and severity will be analyzed.

Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids.

BACKGROUND: Basiliximab, a monoclonal CD25 antibody has proofed effective in reducing acute rejection episodes in adults in various immunosuppressive regimens. The effect of basiliximab in the pediatric population is controversial. METHODS: In a 12-month, double-blind, placebo-controlled trial, renal transplant patients aged 1 to 18 years were randomized to basiliximab or placebo with cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids. The intent-to-treat population comprised 192 patients (100 basiliximab and 92 placebo). RESULTS: The primary efficacy endpoint, time to first biopsy-proven acute rejection episode, or treatment failure by month 6, occurred in 16.7% of basiliximab-treated patients and 21.7% of placebo-treated patients (Kaplan-Meier estimates; hazard ratio 0.72, two-sided 90% confidence interval 0.416-1.26, n.s.). The rate and severity of subclinical rejections in protocol biopsies performed at 6 months posttransplant was higher in the basiliximab group (25.0%) than in the placebo group (11.7%). Patient and death-censored graft survival at 12 months was 97% and 99%, respectively, in the basiliximab cohort, and 100% and 99% among placebo-treated patients (n.s.). Renal function was similar in both treatment groups, and there were no significant between-treatment differences in the incidence of adverse events or infections. CONCLUSIONS: Addition of basiliximab induction to a regimen of cyclosporine microemulsion, mycophenolate mofetil, and steroids resulted in a numerically lower but not significant incidence of biopsy-proven acute rejection versus placebo and excellent graft and patient survival at 1 year in pediatric renal transplant recipients. Whether this numerical difference is a true therapeutic benefit in view of the higher rate and severity of subclinical rejections in the basiliximab group in the protocol biopsy will be investigated in a long-term follow-up study.

Reduced systemic advanced glycation end products in children receiving peritoneal dialysis with low glucose degradation product content.

BACKGROUND: Glucose degradation products (GDP) in peritoneal dialysis (PD) solutions are toxic to the peritoneal membrane and promote the formation of advanced glycation end products (AGE), which contribute to accelerated atherosclerosis and amyloidosis. Double chamber PD solutions have a markedly reduced GDP content. METHODS: We analysed GDP and AGE kinetics in 21 children (7 months to 18 years) on automated PD in a prospective multicentre trial with randomized administration of single chamber, high-GDP and double-chamber, low-GDP dialysis solution for 12 weeks each. Total AGE fluorescence, carboxymethyllysine (CML, ELISA) and 3-deoxyglucosone (3-DG, HPLC) were measured in plasma and PD effluent during a 4 h peritoneal equilibration test. Plasma AGE profiles were assessed by size selective gel permeation chromatography and compared with 23 healthy controls. RESULTS: Initial effluent 3-DG concentrations were 140+/-55 and 25+/-4 micromol/l with high- and low-GDP PD fluid, respectively and declined to 53+/-32 and 7+/-2 micromol/l within 4 h dwell time (P<0.001). The ex vivo AGE generating capacity was three times higher with the high-GDP solution and decreased significantly with dwell time. Plasma AGE levels were 1.8-7.4-fold above those of healthy controls; the elevation was most marked for the small molecular fraction (<2 kDa). Plasma AGE and CML levels were significantly higher after 12 weeks exposure to high-GDP solution (20991+/-4145 AU and 1505+/-617 ng/ml) than following treatment with low-GDP fluid (17518+/-4676 AU and 1151+/-438 ng/ml; both P<0.05). Four hour AGE clearance was higher with low-GDP solution (0.74+/-0.3 vs 0.44+/-0.15 ml/min*1.73 m2, P<0.01). CONCLUSION: GDP are rapidly absorbed from the peritoneal cavity. Administration of PD solutions with low-GDP content reduces plasma AGE levels and may thus improve the cardiovascular risk profile of dialysed children.

Successful renal transplantation in a patient with heterozygous prothrombin gene, factor V Leiden mutation and heparin-induced thrombocytopenia using r-hirudin as anticoagulant.

Vascular complications remain the most common cause of early renal allograft loss in patients with end-stage renal failure. Underlying thrombophilic disorders increase the risk of early graft thrombosis. A male adolescent with high-risk thrombophilia because of combined heterozygous factor V Leiden (G1691A) and prothrombin gene (G20210A) mutation developed HIT II. Hemodialysis and subsequent renal transplantation were undertaken using recombinant hirudin, a direct and selective thrombin inhibitor, as an anticoagulant. Primary function in the transplanted kidney was excellent. No thrombotic or hemorrhagic events have occurred and follow-up showed excellent long-term graft survival. Patients on HD have an increased risk for the development of HIT, and therefore, they need repetitive screening for the development of acquired thrombotic risk factors (e.g. HIT II or lupus anticoagulant). R-hirudin is efficacious and safe on both HD and following renal transplantation.

The role of defective complement control in hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (HUS) is a severe disease that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent evidence has shown that defective complement activation and defective complement control is a cause of HUS. So far, mutations in single genes coding for the cofactor and complement regulator factor H, the membrane cofactor protein (MCP/CD46), the serine protease factor I, and autoantibodies to factor H have been linked to HUS. All of these proteins affect the same enzyme the alternative pathway convertase C3bBb. This article explains how alternative pathway activation proceeds and how defective control increases activation, which ultimately leads to endothelial cell damage.

Blood pressure, renal function, and proteinuria in children with unilateral renal agenesis.

BACKGROUND/AIM: Unilateral renal agenesis (URA) is a model for a reduced nephron number that is believed to be a risk factor for blood pressure (BP) elevation and reduced renal function. The aim of the study was to investigate BP and renal function in children with URA. METHODS: Data on children with URA from two pediatric nephrology centers were firstly retrospectively reviewed (renal ultrasound and scintigraphy, clinical BP, creatinine clearance, urinalysis). Children with normal renal ultrasound and scintigraphy were thereafter investigated using ambulatory BP monitoring. RESULTS: Twenty-nine children with URA were investigated--14 children with an abnormal kidney (mostly scarring) and 15 children with healthy kidneys. Hypertension was diagnosed on the basis of clinical BP in 57% of the children with abnormal kidneys and on the basis of ambulatory BP monitoring in 1 child (7%) with healthy kidneys. The mean ambulatory BP in children with normal kidneys was not significantly different from that in controls. Forty-three percent of the children with abnormal kidneys had a reduced renal function, but none of children with normal kidneys. CONCLUSIONS: Children with abnormalities of a solitary kidney have often hypertension, proteinuria, or a reduced renal function. In contrast, children with healthy solitary kidneys have BP and renal function similar to those of healthy children.