Neurocognitive functioning in school-aged cystinosis patients.

INTRODUCTION: Cystinosis is an autosomal recessive disorder leading to intralysosomal cystine accumulation in various tissues. It causes renal Fanconi syndrome and end stage renal failure around the age of 10 years if not treated with cysteamine. Children with cystinosis seem to have a normal intelligence but frequently show learning difficulties. These problems may be due to specific neurocognitive deficits rather than impaired renal function. Whether cysteamine treatment can improve cognitive functioning of cystinosis patients is thus far unknown. We aim to analyze neurocognitive functioning of school-aged cystinosis patients treated with cysteamine in order to identify specific deficits that can lead to learning difficulties. PATIENTS AND METHODS: Fourteen Dutch and Belgian school-aged cystinosis patients were included. Glomerular filtration rate was estimated using the Schwartz formula. Children were tested for general intelligence, visual-motor integration, inhibition, interference, sustained attention, accuracy, planning, visual memory, processing speed, motor planning, fluency and speed, and behavioural and emotional functioning using standardized methods. RESULTS: Glomerular filtration rate ranged from 22 to 120 ml min(-1) 1.73 m(-2). Median full-scale intelligence was below the average of a normal population (87, range 60-132), with a discrepancy between verbal (median 95, range 60-125) and performance (median 87, range 65-130) intelligence. Over 50% of the patients scored poorly on visual-motor integration, sustained attention, visual memory, planning, or motor speed. The other tested areas showed no differences between patients' and normal values. CONCLUSION: Neurocognitive diagnostics are indicated in cystinosis patients. Early recognition of specific deficits and supervision from special education services might reduce learning difficulties and improve school careers.

Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation.

Focal segmental glomerulosclerosis (FSGS) is a histologic diagnosis in several kidney diseases characterized by proteinuria and a severe decrease in kidney function. Mutations in several genes were found in patients with primary FSGS, one of which is a CD2-associated protein CD2AP (originally referred to as CMS). This gene encodes an adaptor protein that plays a role in endocytosis, cell motility, and cell survival. Mice deficient in Cd2ap (the mouse homolog) die due to kidney failure, while heterozygous mice develop lesions similar to those of FSGS patients. In the kidney, CD2AP regulates the actin cytoskeleton. The only previously described patient with CD2AP mutation had a severely truncated protein. In this study, we describe a patient with a novel mutation resulting in a premature stop codon yielding a protein truncated by only 4%. This shortened CD2AP protein displays a significantly decreased F-actin binding efficiency in vitro with no expression of the mutated allele in the patient's lymphocytes. Heterozygous expression of the CD2AP mutation in both parents did not lead to any kidney pathology, as both have normal glomerular filtration rates and no proteinuria.

Is biopsy required prior to cyclophosphamide in steroid-sensitive nephrotic syndrome?

AIM: The present studywas designed to retrospectively evaluate the use of renal biopsies prior to cyclophosphamide therapy. The aim of the study was to determine in how many cases histological outcome of the biopsies had subsequently changed the decision to treat or refrain from treatment. PATIENTS AND METHODS: Between January 1980 and September 2001, 85 children with steroid-sensitive nephrotic syndrome (SSNS) underwent a renal biopsy in the University Hospitals of Utrecht and Nijmegen before the start of an 8-week cyclophosphamide treatment. MCNS was suspected in all children because of the following criteria: edema, proteinuria, hypoalbuminemia, absence of macroscopic hematuria and in rare cases microscopic hematuria, no permanent hypertension, normal C3 serum level, a normal glomerular filtration rate as determined by creatinine clearance and age > 1 year. Cyclophosphamide therapy was indicated because of a frequently relapsing (FR) course of illness in 8 children, because of steroid dependence (SD) in 22 children and because of combined FR and SD in 55 children. Steroid-resistant children were excluded from this study. RESULTS: Histology confirmed the diagnosis MCNS in 84 out of 85 children. In addition to MCNS, IgA deposits were observed in renal specimens of 2 children. In 1 SD child, the initial diagnosis MCNS was changed 3 years later when a repeated biopsy showed progression into focal segmental glomerulosclerosis (FSGS). CONCLUSION: In summary, no renal biopsy is required prior to cytotoxic therapy in children with uncomplicated steroid-sensitive nephrotic syndrome.

Oral L-carnitine does not decrease erythropoietin requirement in pediatric dialysis.

The use of recombinant human erythropoietin (rhEPO) has greatly facilitated the treatment of anemia in children with chronic renal failure, but is expensive. Several reports on adult patients have shown that supplementation with L-carnitine can decrease the requirement for rhEPO. The objective of this study was to investigate the effect of oral supplementation with L-carnitine on the rhEPO requirement in children on dialysis. We investigated 16 children on dialysis (11 hemodialysis, 5 peritoneal dialysis) with a median age of 10.2 years. All children were stable on rhEPO treatment at least 3 months before study entrance. After obtaining baseline data, all children were supplemented with L-carnitine 20 mg/kg/day. Data were collected for 26 weeks. Follow-up was completed for 12 patients (8 hemodialysis, 4 peritoneal dialysis). At baseline free carnitine (32+/-18 micromol/l) and total carnitine levels (54+/-37 micromol/l) were normal. At the end of the study free carnitine levels had increased to 97+/-56 micromol/l (P<0.05) and total carnitine levels to 163+/-90 micromol/l (P<0.05). There was no significant change in rhEPO requirement. Hemoglobin level or hematocrit did not change significantly during the study. In conclusion we could not demonstrate a beneficial effect of supplementation with L-carnitine on rhEPO requirement in children on dialysis.

Comparing a urea kinetic monitor with Daugirdas formula and dietary records in children.

The use of the online urea monitor has not been validated in children on hemodialysis. We compared online measured Kt/V(urea) and protein catabolic rate (PCR) with single- and double-pool Daugirdas formula (DF and eDF) based Kt/V(urea) and with protein intake derived from dietary records (DPI). In 8 children aged 8-18 years, 26 measurements were performed with the online urea monitor (UM 1000) with double-needle access. In 7 children, aged 4-14 years, 12 additional measurements were performed using single-needle dialysis. Pre-dialysis serum urea was determined by the monitor in equilibrated ultrafiltrate, obtained with ultrafiltration rates (UF) of 0.5 or 1.0 l/h, in 10 and 23 experiments respectively, and compared with the laboratory results. Urea determination in ultrafiltrate correlated well with blood sample urea: r=0.945 and 0.88 for UF rates of 0.5 l/h and 1.0 l/h, respectively. The correlation of online Kt/V with DF and eDF was 0.79 for double-needle and 0.21 for single-needle access. Bland-Altmann analysis showed a mean bias of 0.02 and 0.001, but levels of agreement of +0.3 and -0.3 for double-needle and +0.77 and -0.77 for single-needle dialysis respectively with DF. Maximum percentage error for double-needle access was 18% and 59% for single-needle access. The correlation of DPI with PCR was 0.5. A Bland-Altmann plot showed a mean bias of =0.22 with upper and lower limits of agreement of +0.55 and -0.1, respectively. Online urea kinetic modelling is feasible in children with double-needle hemodialysis only. Even with small dialyzers, an accurate serum urea measurement is obtained. PCR underestimates dietary protein intake.

Bone density and body composition in chronic renal failure: effects of growth hormone treatment.

Metabolic bone disease and growth retardation are common complications of chronic renal failure (CRF). We evaluated bone mineral density (BMD), bone metabolism, body composition and growth in children with CRF, and the effect of growth hormone treatment (GHRx) on these variables. Thirty-three prepubertal patients with CRF were enrolled including 18 children with growth retardation, who were treated with growth hormone for 2 years. Every 6 months, BMD of lumbar spine and total body, and body composition were measured by dual-energy X-ray absorptiometry. Biochemical parameters of bone turnover were assessed. Mean BMD of children with CRF did not differ from normal. During GHRx, BMD and bone mineral apparent density of lumbar spine and height SDS increased, whereas BMD of total body did not change. Lean body mass increased in the GH group. Alkaline phosphatase increased significantly in the GH group only. The other biochemical parameters of bone turnover increased in both groups, none of them correlated with the changes in BMD. No serious adverse effects of GHRx were reported. In conclusion, BMD of children with CRF did not differ from healthy children. Adequate treatment with alpha-calcidiol or the short duration of renal failure may have attributed to the absence of osteopenia in our patients. BMD of the axial skeleton and growth improved with GHRx.

Misstaging in nephroblastoma. Causes and consequences. A report of the Sixth Nephroblastoma Trial and Study of the International Society of Paediatric Oncology.

In the Wilms tumour trials and studies of the International Society of Paediatric Oncology (SIOP), the postoperative treatment is based on the extension (stage) and the histological type. Incorrect staging results in under- or overtreatment. The authors studied the causes and consequences of misstaging in SIOP 6. In this study, the final stage was defined by a central panel of pathologists after review of the surgical and histopathological forms and study of representative microscopical sections. In 46 out of 509 trial patients there was a discrepancy between the final stage and the stage determined at the participating centres: 33 patients were understaged of whom 27 survived more than 5 years (18% died) and 13 patients were overstaged of whom 11 survived more than 5 years (15.3% died). All children with tumour extension into the renal pelvis and treated as stage I instead of stage II survived without evidence of disease. Therefore, it was decided to treat these children in the next study as a stage I. In 17 cases the treatment was based on the surgical stage before the pathological stage was known or the treatment was given according to the stage determined by the local pathologist without waiting for the panel review. The numbers are too small to conclude on the consequences of overtreatment on late effects. For all clinicians the main and most important conclusion of this study is: wait for the final pathology report before initiating postoperative therapy.

Bone mineral density, bone metabolism and body composition of children with chronic renal failure, with and without growth hormone treatment.

OBJECTIVE: Osteopenia has been reported in adult patients with chronic renal failure (CRF). Only a few studies have been performed in children. The objective of this study was to evaluate bone mineral density (BMD), bone turnover, body composition in children with CRF and to study the effect of GH on these variables. DESIGN: Two groups were identified: patients with growth retardation who received GH (GH-group) and patients most of whom were not growth retarded who did not receive GH (no-GH-group). After an observation period of 6 months, the patients in the GH-group started GH treatment. Patients were studied every 6 months during 18 months. PATIENTS: Thirty-six prepubertal patients (27 boys and 9 girls), mean age 7.9 years, with CRF participated in the study. The GH-group consisted of 17 patients of whom 14 completed one year treatment. The no-GH-group consisted of 19 patients, of whom 16 were followed for 6 months, 14 for 12 months and 13 for 18 months. MEASUREMENTS: Lumbar spine BMD, total body BMD and body composition were assessed by dual energy X-ray absorptiometry, compared to age-and sex-matched reference values of the same population and expressed as standard deviation scores (SDS). BMD of appendicular bone was measured by quantitative microdensitometry (QMD). Blood samples were obtained to assess bone metabolism and growth factors. RESULTS: Baseline mean lumbar spine and total body BMD SDS of all patients were not significantly different from normal. Mean lumbar spine and total body BMD SDS did not change significantly in the GH-group during GH treatment. The change of QMD at the midshaft during the first 6 months of GH treatment was significantly smaller than during the observation period (P < 0.01). Height SDS and biochemical markers of both bone formation and bone resorption increased significantly during GH treatment; 1,25-dihydroxyvitamin D remained stable. Lean tissue mass increased (P < 0.001) and percentage body fat decreased (P < 0.01) during GH treatment. BMD, the biochemical markers of bone turnover which are independent of renal function, and body composition remained stable in the no-GH-group. CONCLUSIONS: Mean lumbar spine and total body BMD of children with chronic renal failure did not differ from healthy controls. The lack of a GH-induced increase in 1,25-dihydroxyvitamin D levels, probably due to treatment with alpha-calcidol, might be linked to the absence of a response in BMD during GH treatment in children with chronic renal failure.

[Henoch-Schoenlein purpura-nephritis followed by IgA-nephritis in 3 children]. / Henoch-Schönlein-purpura-nefritis gevolgd door IgA-nefropathie bij drie kinderen.

In three patients, two boys of 7 and 10 and a girl of 9 years old, a kidney disease was diagnosed which evolved from Schönlein-Henoch nephritis to IgA nephropathy or Berger's disease. These two kidney diseases show striking similarities in pathological and immunological respects. Several patients have been described in the literature who suffered from both clinical pictures consecutively and of families in which different members showed either one or the other disease. A remarkable finding was the persistence of an elevated IgA serum level in all three children after the Schönlein-Henoch nephritis had subsided. These cases show the importance of long-term follow up of patients who had Schönlein-Henoch nephritis, in order to diagnose late renal complications at an early stage. They also give more evidence in favour of the assumption that Schönlein-Henoch nephritis and IgA nephropathy have a common aetiology.