Coagulation studies were performed in 16 children with steroid responsive minimal change nephrotic syndrome in order to elucidate the incidence of thromboembolic complications. Fibrinogen and alpha 2-macroglobulin concentrations were inversely correlated with serum albumin concentrations, antithrombin III correlated positively (p less than 0.001). Factor VIII:R:AG concentration was elevated. Coagulation disturbances in children are not less severe than in adults with nephrotic syndrome. Combined scintigraphic pulmonary ventilation and perfusion studies were employed in 26 children to detect noninvasively events of pulmonary embolism, respectively their residual changes. The lung scintigraphic investigation demonstrated a pattern consistent with pulmonary embolism in 7 patients (27.9%), residual changes in 10 (38.5%) and normal findings in 9 (34.9%). The incidence of thromboembolic complications in children with severe nephrotic syndrome is as high as reported for adults. Pulmonary symptoms may well be due to pulmonary embolism.

Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity. The disease is highly variable in its clinical expression, because of various mutations in the TNSALP gene. In approximately 14% of the patients tested in our laboratory, only one TNSALP gene mutation was found, despite exhaustive sequencing of the gene, suggesting that missing mutations are harbored in intron or regulatory sequences or that the disease is dominantly transmitted. The distinction between these two situations is of importance, especially in terms of genetic counseling, but dominance is sometimes difficult to conclusively determine by using familial analysis since expression of the disease may be highly variable, with parents of even severely affected children showing no or extremely mild symptoms of the disease. We report here the study of eight point mutations (G46 V, A99T, S164L, R167 W, R206 W, G232 V, N461I, I473F) found in patients with no other detectable mutation. Three of these mutations, G46 V, S164L, and I473F, have not previously been described. Pedigree and/or serum alkaline phosphatase data suggested possible dominant transmission in families with A99T, R167 W, and G232 V. By means of site-directed mutagenesis, transfections in COS-1 cells, and three-dimensional (3D) modeling, we evaluated the possible dominant effect of these eight mutations. The results showed that four of these mutations (G46 V, A99T, R167 W, and N461I) exhibited a negative dominant effect by inhibiting the enzymatic activity of the heterodimer, whereas the four others did not show such inhibition. Strong inhibition resulted in severe hypophosphatasia, whereas partial inhibition resulted in milder forms of the disease. Analysis of the 3D model of the enzyme showed that mutations exhibiting a dominant effect were clustered in two regions, viz., the active site and an area probably interacting with a region having a particular biological function such as dimerization, tetramerization, or membrane anchoring.

The renal handling of uric acid during cyclosporin A (CyA) treatment was investigated by clearance studies using 24-h urine collections in 28 paediatric renal transplant recipients (CyA group), and the results were compared with those of 19 renal transplanted children treated with azathioprine and prednisolone (AZA group), 35 children with chronic renal failure (CRF) and 10 children with normal renal function (N group). Serum uric acid levels were significantly higher in the CyA group (567 +/- 156 mumol/l) compared with the AZA group (378 +/- 98), the CRF group (415 +/- 119) and the N group (290 +/- 68). Mean uric acid clearances in each group measured 3.9 +/- 2.8 ml/min per 1.73 m2 (CyA), 5.6 +/- 3.4 (AZA), 4.0 +/- 2.2 (CRF) and 8.4 +/- 3.7 (N). Calculation of the net tubular uric acid reabsorption per millilitre glomerular filtration rate revealed a significantly increased value of 0.53 +/- 0.15 mumol/ml in the CyA group (P less than 0.01) compared with 0.34 +/- 0.08, 0.29 +/- 0.15 and 0.27 +/- 0.07 mumol/l for the AZA, CRF and N groups respectively. We therefore conclude that CyA treatment is associated with an increased net tubular reabsorption of uric acid, which may lead to hyperuricaemia.

The clinical data of 18 patients with X linked hypophosphataemia were analysed retrospectively. The height data were expressed as SD scores. There was no difference in the final height of patients treated with vitamin D (or 1,25-dihydroxyvitamin D) and phosphate for at least two years (n= 12) and that of 16 hypophosphataemic family members who had never been treated. The mean final SD score (-2.07) of treated patients, however, was significantly higher than the value before treatment (-2.79), which indicated an average absolute height gain of 4-4.5 cm compared with the expected height values. Six of the treated patients developed ultrasonographicaily detectable nephrocalcinosis with normal renal function. The daily phosphate intake and excretion of patients with nephrocalcinosis was significantly higher than that of patients with normal renal morphology. There was no difference in the doses of vitamin D between the two groups. The average urinary calcium:creatinine ratio of the two groups was similar to and below the hypercalciuric 0-6 mmol:mmol limit. The group with nephrocalcinosis, however, had a higher incidence of hypercalciuric episodes than the group without nephrocalcinosis (12 in 130 observations compared with six in 334 observations, respectively). The benefits and risks of treatment of patients with X linked hypophosphataemia must be further evaluated. The high dose of phosphate seems to be an important factor in the development of nephrocalcinosis in this group of patients. The aim of the present study was to analyse the effects of the combined treatment with vitamin D and phosphate on the growth of patients with X linked hypophosphataemia, to find out the incidence of ultrasonographic renal calcification,'8 and to elucidate the role of the treatment in renal calcification.Patients and methods Between 1974 and 1989, 18 patients with X linked hypophosphataemia were treated with combined vitamin D (or 1,25-DHVD) and oral phosphate in our clinic.22 Sixteen adult hypophosphataemic relatives who had not been treated during the growth period served as controls.All treated patients were diagnosed by the presence of rachitic bone changes, the persistence of hypophosphataemia, relative hyperphosphaturia, normocalcaemia, high alkaline phosphatase activity, and normal serum concentrations of parathyroid hormone.5 22 X linked dominant inheritance was confirmed by analysis of the pedigrees.All patients visited our outpatient clinic at regular intervals: infants and young children every three weeks to two months and adolescents and young adults every three to six months depending on the intensity of treatment. Urinary excretion of calcium and phosphate, serum calcium and phosphate concentrations, and creatinine clearance were measured routinely. Calcium, phosphate, and creatinine were estimated by routine laboratory methods.Hypercalcaemia

Minimal change nephrotic syndrome (MCNS) is the most frequent type of nephrotic syndrome (NS) in childhood. During the last decade only little progress has been made in the understanding of the etiology and pathogenesis of MCNS. However, treatment has been improved pragmatically by controlled cooperative studies, which have lead to an unexpected degree of standardization in pediatric nephrology. The Arbeitsgemeinschaft für Pädiatrische Nephrologie (APN) is conducting its own cooperative studies in close contact with the International Study of Kidney Diseases in Children (ISKDC). In Steroid Study II of APN two regimens of initial prednisone treatment are compared: standard initial versus short initial prednisone therapy. Preliminary results reveal that a complete remission of NS can be obtained with less than half of the prednisone dose usually applied by the standard regimen. The relapse rate after initial treatment, however, seems to be the same in both groups. In the Cytotoxic Drug Study I of APN the effectiveness of chlorambucil (0.15 mg/kg for 8 weeks) or cyclophosphamide (2 mg/kg for 8 weeks) in the treatment of steroid toxic frequent relapsers without steroid dependency (FRNS) and with steroid dependency (SDNS) are compared. In FRNS the treatment is followed by long lasting remissions in most cases, while in SDNS relapses occur very soon again. The latter group, therefore, does not profit from cytotoxic drugs in the dosage used. In a new trial, therefore, it is asked whether patients with SDNS will profit more from prolongation of cyclophosphamide treatment for 12 weeks.