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.

Calcinosis in juvenile dermatomyositis: a possible role for the vitamin K-dependent protein matrix Gla protein.

OBJECTIVES: The aims of the present study were to investigate whether the calcification inhibitor matrix Gla protein (MGP) is expressed in muscle biopsies of patients with juvenile dermatomyositis (JDM), and whether different forms of MGP are differentially expressed in JDM patients with and without subcutaneous calcifications. METHODS: Muscle tissue from six JDM patients (three without calcinosis, two with calcinosis and one recently diagnosed patient), four patients with muscular dystrophy, three patients with IBM and five normal histological control subjects was used for immunohistochemistry staining using novel antibodies to different conformations of MGP. RESULTS: In the JDM patients, all forms of MGP [non-carboxylated MGP (ucMGP), carboxylated MGP (cMGP), non-phosphorylated MGP (serMGP) and phosphorylated MGP (pserMGP)] were more intensely stained in the perifascicular compared with the central muscle fibres. In addition, these MGP species were demonstrated in the pathological muscle fibres of IBM and dystrophy patients, but hardly in normal histological muscle tissue. In JDM patients with calcifications, only pserMGP was increased compared with those without calcifications. All forms of MGP were also found in various staining intensities in the microvasculature and macrophages of normal histological and disease biopsies. CONCLUSIONS: MGP was expressed at the site of muscle damage in JDM patients as well as in patients with muscular dystrophy and IBM. The difference in staining intensity of pserMGP appeared to distinguish between JDM patients with and without calcifications, whereas cMGP, the other functional form, was equally expressed.

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.

Renal Fanconi syndrome with ultrastructural defects in lysinuric protein intolerance.

Renal Fanconi syndrome developed rapidly in a 3-year-old Moroccan girl with established lysinuric protein intolerance. She was hospitalized because of lowered consciousness, uncoordinated movements and hepatosplenomegaly after a febrile period. Laboratory investigations revealed plasma ammonia 270 micromol/L (normal <70 micromol/L), ferritin 159 micromol/L (normal 2-59 micromol/L), LDH 1180 U/L (normal 26-534 U/L). LPI was diagnosed based on the findings of reduced plasma ornithine, arginine and lysine, and an increased level of glutamine. Urinary orotic acid (645 micromol/mmol creatinine; normal <3.6) was strongly increased. A defect in the SLC7A7 amino acid transporter was established (homozygous c.726G > A mutation). Detailed renal function tests including an acid challenge test, bicarbonate loading, and tubular maximal reabsorption of glucose showed complex tubular dysfunction. No evidence of respiratory chain defects was found in muscle or kidney tissue. No morphological abnormalities were demonstrated in the mitochondria. Ultrastructural analysis of proximal tubular cells showed vacuolization and sloughing of the apical brush border (Fig. 1). Renal involvement in LPI has only been described in a few reports; however, no detailed studies of the renal acidification mechanism were performed. Our patient had evidence of a full-blown Fanconi syndrome. Surprisingly, a metabolic acidosis was found with a moderately increased serum anion gap combined with repeatedly normal plasma organic acid values. This finding is in contrast with the diagnosis of renal tubular acidosis. Patients with hyperlysinaemia have a similar heavy load on the renal tubules; they never develop a renal Fanconi syndrome. Therefore, we consider the intratubular accumulation of lysine an unlikely candidate for the development of the renal Fanconi syndrome.

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.

Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency.

Several prospective trials have shown that recombinant human growth hormone (GH) accelerates growth significantly during the first years of therapy, but the effects of long-term GH therapy with regard to long-term growth response and safety have not yet been established. Forty-five Dutch prepubertal children [28 boys, 17 girls, mean (SD) age 7.8 (3.4) years] with chronic renal insufficiency (CRI) and severe growth retardation started GH therapy between 1988 and 1991 within one of the randomized Dutch trials. Long-term GH therapy, in this study a maximum of 8 years, resulted in a sustained and significant improvement of height standard deviation score (SDS) compared with baseline values (P<0.001). The mean height SDS reached the lower end (-2 SDS) of the normal growth chart after 3 years of GH therapy. During the following years the mean height SDS gradually increased, thereby approaching the mean target height SDS after 6 years of GH therapy. Three factors were significantly associated with the height SDS after 4 years of GH therapy: height SDS at the start (+) of therapy, age at the start of therapy (-), and the duration of dialysis treatment (-). Bone maturation did not accelerate during long-term GH therapy. Children on a conservative regimen at the start of GH therapy had no accelerated deterioration of renal function during 6 years of GH therapy. The average daily GH dose administered over the years had no significant influence on the glomerular filtration rate after 4 years. GH therapy had no adverse effects or significant effect on parathyroid hormone concentration, nor were there any radiological signs of renal osteodystrophy. Puberty started at a median age, within the normal range, of 12.4 years in boys and 12.0 years in girls, respectively. Long-term GH therapy leads to a sustained improvement in height SDS in children with growth retardation secondary to CRI, resulting in a normalization of height in accordance with their target height SDS, without evidence of deleterious effects on renal function or bone maturation. A GH dosage of 4 IU/m2 per day appears efficient and safe. Our long-term data show that final height will be within the normal target height range when GH therapy is continued for many years.

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.

Hyperhomocyst(e)inaemia in children with chronic renal failure.

BACKGROUND: Hyperhomocyst(e)inaemia has been identified as a significant risk factor for the occurrence of atherosclerosis in adults with chronic renal failure. Because of its presumed direct toxic effect on the vascular wall, long-standing hyperhomocyst(e)inaemia in children with chronic renal failure might have an important influence on their risk of future development of atherosclerosis. Hitherto no data on hyperhomocyst(e)inaemia in children with renal failure have been published. METHODS: We investigated 16 children with chronic renal failure on conservative management, 12 children on haemodialysis and 17 children with a renal transplant. Age-matched controls were used for comparison. Plasma homocyst(e)ine levels after an overnight fast were determined by HPLC. Glomerular filtration rate was estimated by the Schwartz formula. RESULTS: Mean plasma homocyst(e)ine levels were 12.6 +/- 5.2 micromol/l in the conservatively managed group, 22.2 +/- 13.5 micromol/l in the haemodialysed group, 14.2 +/- 2.1 micromol/l in transplanted children with an estimated GFR > 60 ml/min/1.73 m2 and 17.5 +/- 5.1 micromol/l in transplanted children with a lower estimated GFR. In all groups homocyst(e)ine levels were significantly elevated as compared to controls. Homocyst(e)ine levels were significantly correlated with age and negatively correlated with estimated GFR and serum folate levels. CONCLUSIONS: Hyperhomocyst(e)inaemia is a feature of chronic renal failure in children as well as in adults. Elevated homocyst(e)ine levels can already be demonstrated in children with renal failure before end-stage renal disease has developed and persist after renal transplantation. Whether treatment of hyperhomocyst(e)inaemia in children with renal failure decreases the risk for future atherosclerosis remains to be proven.

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.

Leukemic cell colony formation in soft agar by bone marrow cells and peripheral blood cells from untreated acute leukemia patients.

An in vitro culture technique for colony formation of marrow cells and peripheral blood cells from untreated acute leukemia patients and from patients in relapse is described. The colonies from bone marrow cells of an untreated acute myelogenous leukemia (AML) patient were demonstrated to be of leukemic origin by cytogenetic analysis. Cells obtained from colonies of leukemic origin contained the human malignancy-associated nucleolar antigen (HMNA) as detected by indirect immunofluorescence. This nucleolar antigen was not present in marrow or peripheral blood cells or cells from colonies of marrow from hematologically normal individuals. Colonies could be grown from over 70% of the marrow and peripheral blood samples from untreated acute leukemia patients. The median number of colonies obtained was 75 per 10(5) marrow cells from patients with AML. In 1/3 of the cases an increased number of colonies could be grown from marrow cell suspensions kept in liquid culture for 5 days. This is indicative of the proliferative capacity of the colony forming cell population. This assay may be useful for detection of residual clonogenic leukemic cells in marrow and peripheral blood cell suspensions.