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We describe a child presenting with oligoclonal plasma IgM (1.2 g%) and nephrotic syndrome with focal segmental glomerulosclerosis. Oligoclonality was demonstrated by the analysis of the complementary determining region 3 (CDR 3) on immunoglobulin heavy chains and by two dimensional electrophoresis and Western blot analysis that showed the bulk of isoforms having a cationic muU chain compared with the normal homologue (pI 7.5 vs 6.5). Urinary light chains were absent, and bone marrow aspirate was normal. Usual therapies for nephrotic syndrome with steroids and cyclosporin were useless. At the age of 9 years the patient was treated with plasmapheresis plus cyclophosphamide (2 mg/kg per day for 60 days), which temporarily reduced plasma IgM, and proteinuria was normal for 3 years. After this period, due to new recurrence of nephrotic syndrome, the patient received a cycle with anti-CD20 antibodies (500 mg/m(2) every week for a month) associated with a cycle of plasmapheresis that normalized proteinuria again, and, after 3 years, the proteinuria is still in remission. This is the first case of nephrotic syndrome associated with oligoclonal plasma IgM and mesangial IgM deposits. Both cyclophosphamide and anti-CD20 antibodies associated with plasmapheresis induced, at different stages, stable and protracted remission of proteinuria without evident side effects. Long term efficacy and safety of the association are still to be determined.

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac ( n=103) or CyA microemulsion ( n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baseline characteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA therapy (59.1%) ( P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group ( P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62+/-20 ml/min per 1.73 m(2), n=84) than in the CyA group (56+/-21 ml/min per 1.73 m(2), n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences ( P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable.

Side effects such as cutaneous vasculitis, which occur during prolonged levamisole treatment, may discourage the utilization of the drug in relapsing nephrotic syndrome. We describe a child who developed disseminated vasculitis during prolonged treatment with levamisole. The acute phase was characterized by hepatosplenomegaly, hemolytic anemia, IgM anticardiolipin and p-antineutrophil cytoplasmic antibodies. One month after withdrawal of therapy all symptoms had disappeared and tests normalized. This case report, together with other reports on cutaneous vasculitis, suggest caution and close monitoring during prolonged levamisole therapy.

Early tubular alterations were studied in 53 children with insulin-dependent diabetes mellitus (IDDM), 32 of whom were followed at regular 6-monthly intervals for 3 years. The urinary levels of retinol-binding protein (RBP), beta 2-microglobulin and brush border antigens (BBA) (determined by monoclonal enzyme immunoassay) were taken as indices of functional and cellular tubular alterations; urinary albumin was considered an early marker of glomerular alterations. All indices of tubular alterations were higher in IDDM children than in 368 normal children, while albuminuria was unchanged. Urinary levels of BBA, however, varied widely during follow-up, with 25 of the 32 IDDM patients who were followed at regular intervals having pathological values for BBA on at least one occasion, followed by normalization. Metabolic alteration was found to be the main cause of this variability, since a high statistical correlation was found between urinary BBA and fructosamine (P < 0.001) and between RBP and the stable fraction of glycosylated haemoglobin (P < 0.001). The data confirm that transient tubular proteinuria occurs in diabetic children before any other marker of renal involvement such as microalbuminuria. The maintenance of good metabolic control is essential to normalize this early abnormality that can be considered a reversible sign of functional renal involvement.

This study was designed to evaluate the occurrence and the type of proteinuria in 82 children with vesico-ureteric reflux (VUR) with or without renal scars. The urinary excretion of the high molecular weight protein albumin was taken as an index of glomerular alterations and the excretion of retinol-binding protein (RBP), beta 2-microglobulin and brush border antigens (BBA) (measured by monoclonal antibody-based enzyme-linked immunosorbent assay) was taken as an index of tubular alterations. All such markers were increased in children with VUR and were related to the degree of renal function. Patients showing reduced creatinine clearance had very high levels of albuminuria, microproteinuria and BBA, with all these variables reciprocally correlated. In children with normal renal function however, only microproteins (not albumin or BBA) were slightly increased, thus indicating an isolated tubular defect without involvement of the proximal segment of the tubule. However, microprotein excretion did not correlate with the grade of scarring (99mtechnetium-dimercaptosuccinic acid scan), both RBP and beta 2-microglobulin excretion being normal in 75% of children with radioisotopic signs of renal lesions but increased in 17% of children without scars. Therefore, tubular proteinuria identifies different groups of children with VUR but is not related to renal scarring. Prospective studies will define the usefulness of proteinuria as a reliable indicator of renal outcome.

Normal pubertal progression is associated with quantitative and qualitative changes in gonadotrophin release. Uraemic children show a delayed or disturbed puberty. We have therefore examined nocturnal gonadotrophin and sex steroid secretion in seven males and three females [age 11-15 years, pubertal stage (PS) 1-3] with chronic renal failure on conservative treatment. In addition to immunoreactive luteinizing hormone (i-LH) we have measured the biological activity of LH (b-LH). Nine children aged 12-17 years with PS 1-3 and normal renal function served as a control group. In two uraemic children, i-LH, b-LH, follicle stimulating hormone and sex steroids were evaluated before and 7 days after pulsatile LH-releasing hormone (LHRH) administration (150 ng/kg body weight subcutaneously every 120 min). Mean i-LH levels were higher in uraemic children than in controls. An increase in i-LH during sleep was found in all controls and in eight of ten uraemic subjects. Mean b-LH levels were lower during sleep and the b/i LH ratio was reduced in uraemic children with PS 2-3 whether asleep or awake compared with controls. Pulsatile administration of LHRH provoked a rise of i-LH and b-LH levels with an increased b/i LH ratio, suggesting an intact pituitary responsiveness. These preliminary data indicate that the gonadotrophin control of LH is abnormal in uraemic children, and that biopotency of LH secretion might be improved after short-term pulsatile LHRH administration.

A study was undertaken to clarify the usefulness of two cationic dyes, alcian blue (AB) and ruthenium red (RR) in demonstrating the defect in cellular membranes noted in minimal change nephropathy (MCN). The binding of both dyes to RBC membranes purified from normal and nephrotic children was evaluated by electrophoretic titration curves. When examined separately, AB was found to precipitate spontaneously, producing macro-aggregates with no electrophoretic mobility at pH 5. This was presumed to be the result of hydrophobic interaction of the dye with itself. The same phenomenon was observed when this dye was incubated at 37 degrees C with RBC ghost's from normal children, when AB presented a sigmoidal curve with a net positive charge for pHs higher than 5.5 and lower than 5 and no electrophoretic mobility at pH 5. However, incubation of AB with RBC ghosts from children with MCN resulted in an improvement of the solubility of the dye which then migrated with a net positive charge along the whole gradient of pH from 3.5 to 9. The presence of zwitterionic neutral detergents such as CHAPS, but not of a charged substance such as protamine sulphate, inhibited precipitation at pH 5 when incubated with membranes from normal children, supporting the hydrophobic nature of the phenomenon. When RR was used instead of AB, it was fully protonated (i.e. did not precipitate) when analysed alone, but when incubated with normal RBC ghosts, it also revealed no electrophoretic mobility at pH 5.(ABSTRACT TRUNCATED AT 250 WORDS)

The study involved eight metabolically stable children, with chronic renal failure on continuous ambulatory peritoneal dialysis (CAPD) whom we followed for 12-18 months. For the first 6 months CAPD was performed with dextrose; for the subsequent 6-12 months the morning exchange was substituted with a 1% amino-acid (AA) solution. The following parameters did not change during the study: serum creatinine, uric acid, inorganic phosphate, serum bicarbonate, potassium, cholesterol, triglycerides, total protein, albumin and transferrin. The only parameter that changed was blood urea nitrogen, which increased moderately. The anthropometric parameters did not show significant variation before and after AA dialysis. The plasma AA profile, which under basal conditions showed lower levels of several essential AAs, improved during the treatment period, with a partial correction of the imbalance. It is possible that this correction of plasma AAs may positively influence the metabolism of some organs such as the brain, muscle and those of the hepatosplanchnic region. The intracellular pool of free AAs, measured in polymorphonuclear leucocytes, was severely altered before the treatment and after 6 and 12 months showed only minor variations. It is possible that some modifications in the proportion of the different AAs in the dialysis solution or an improvement in the concentration or in the number of exchanges per day are necessary in order to change the nutritional status and to modify the intracellular AA pool.

The structural composition of erythrocyte ghosts was analysed in children affected by steroid-responsive (SRNS) and unresponsive nephrotic syndrome (SUNS). No variation of either intrinsic or extrinsic ghost proteins was found by discontinuous SDS-electrophoresis associated with a very sensitive double staining technique. By contrast, the composition of inner-layer phospholipids--phosphatidyl ethanolamine (PE) and phosphatidyl serine (PS)--was altered in SRNS with minor changes also involving phosphatidic acid, phosphatidyl inositol and lysophosphatidyl choline. Signs of peroxidative damage were present in both SRNS and SUNS ghosts and inside the cells; these included high levels of fluorescent amino-iminopropene derivates of PE and PS, increased intraerythrocytic amounts of malonyldialdehyde and decreased levels of reduced glutathione. Taken together these results support the concept that in SRNS and SUNS erythrocytes are target cells for peroxidative damage. In SRNS peroxidation of membrane lipids results in a marked alteration of the phospholipid composition of erythrocyte ghosts.