[Treatment of fluid overload and kidney failure with periotoneal dialysis after heart surgery]. / Trattamento del sovraccarico di circolo e dell'insufficienza renale mediante dialisi peritoneale nel postintervento cardio-chirurgico.

BACKGROUND: Infants undergoing cardiac surgery with prolonged cardio-pulmonary bypass are particularly exposed to the risk of acute renal failure for renal hypoxia due to low cardiac output. METHODS: To limit fluid overload deriving from oligo-anuria and low cardiac output we have recently adopted an early peritoneal dialysis protocol, positioning the peritoneal catheter during the intervention and performing early exchanges at first signs of inadequate diuretic response and/or "leaky capillary syndrome" with diffuse edema. From 1-1 to 31-12-1997 12 patients (8 males), of median age of 65.5 days (range 1-350 days) and median weight of 3463 g (range 2380-6550 g) were treated with peritoneal dialysis (automated exchanges of 10 ml/kg body weight of 1.5% glucose, dwell time 20 minutes). Cardiac pathologies included complex hearth malformations. Cardiopulmonary bypass lasted a mean of 202 minutes (range 102-372 minutes). The children were treated for a minimum of 1 to 42 peritoneal dialysis sessions. The infusional therapy included human albumin and fresh frozen plasma to substitute losses and furosemide at the dose of 4 mg/kg/day to reduce the "leaky capillary syndrome". RESULTS: The results were very satisfactory: only 3 children died in the first 30 days after surgery. Renal function was normal at the end of the observation in 8/12 cases, and 2 cases presented chronic renal failure. CONCLUSIONS: Since similar series report a mortality rate of 33-79%, it is suggested that early peritoneal dialysis may have positively influenced the final survival rate.

Neonatal end-stage renal failure associated with maternal ingestion of cyclo-oxygenase-type-1 selective inhibitor nimesulide as tocolytic.

Cyclo-oxygenase-type-2 (COX-2) enzyme is fundamental for nephrogenesis, upregulated on fetal membranes and myometrium at parturition. Fetal COX-2 inhibition, due to maternal nimesulide assumption, can be responsible for neonatal chronic renal failure.

Providing the right stuff: feeding children with chronic renal failure.

The progressive loss of renal function in children with chronic renal failure (CRF) has a negative influence on their nutritional status and statural growth. Supportive therapies with 1-25 dihydroxy-vitamin D3, recombinant erythropoietin and growth hormone have significantly improved the biochemical and clinical features but the success of these therapies is largely related to an appropriate diet, with adequate protein/caloric intakes. Children more than adults have minimal protein requirements to avoid malnutrition and growth impairment FAO/WHO and RDA recommendations save as guidelines for a correct diet in children with CRF. Following these allowances leads to a "normoproteic" diet, with a protein intake which is often half the unrestricted one in Western European countries, but which is still likely to be not enough to protect against renal deterioration. Indeed the European Study Group for Nutritional Treatment of CRF in children failed to show a significant effect of diet on the mean decline of glomerular filtration rate over two years.

Frequency of renal diseases and clinical indications for renal biopsy in children (report of the Italian National Registry of Renal Biopsies in Children). Group of Renal Immunopathology of the Italian Society of Pediatric Nephrology and Group of Renal Immunopathology of the Italian Society of Nephrology.

BACKGROUND: Children's renal biopsy data were gathered for 3 consecutive years (1992-1994) by the Group of Renal Immunopathology of the Italian Society of Pediatric Nephrology, which opened a paediatric section of the Italian Registry of Renal Biopsies. MATERIALS: The Registry recorded the histological diagnosis and the clinical data at renal biopsy of 432 children < or = 15 years old (mean age 8.96 +/- 3.7 years). RESULTS: The most common glomerulonephritis (GN) at renal biopsy was idiopathic IgAGN (18.8%) and the most frequent secondary GN was Henoch-Schönlein purpura (HSP) nephritis (11.6%). Minimal-change disease (MCD) accounted for 11.6%, focal and segmental sclerosis (FSG) 8.5%, mesangial proliferative GN (MPGN) 9.5%, membranoproliferative GN 5.5%, and thin-membrane disease 5%. Lupus nephritis was diagnosed in 5% and Alport's GN in 3.9% of the cases. The annual incidence of primary GN in Italian children was 11.1 cases per million children population (p.m.c.p.), IgAN accounting for 3.1 cases, MCD 2.3, and HSP nephritis 1.9 cases p.m.c.p. respectively. Italian children underwent renal biopsy because of isolated microscopic haematuria in 19.3% of the cases, non-nephrotic proteinuria with or without microscopic haematuria in 31.2%, and nephrotic-range proteinuria in 34.2%, less frequently (15.3%) because of acute or chronic renal failure. Children with persistent isolated microscopic haematuria had most frequently IgAN (34.9%) or thin-membrane disease (25.3%), while those with non-nephrotic proteinuria had IgAN (30.4%) and HSP nephritis (23%). In cases with nephrotic proteinuria renal biopsy showed MCD in 34.5% of the cases, FSG in 16.9%, and MPGN in 12.2%. When renal biopsy was performed in chronic renal failure, chronic interstitial renal disease was detected in 62.5% of the cases. CONCLUSIONS: This National Registry provides data on the indications for performing renal biopsy in Italian children and on the frequency and annual incidence of histological lesions detected. IgAN, primary or related to HSP, was the most common nephritis in Italian children undergoing renal biopsy.

Adriamycin-induced proteinuria in nude mice: an immune-system-mediated toxic effect.

BACKGROUND: The renal minimal lesion disease induced in rats by adriamycin (ADR) is generally thought to be consequent to a direct cytotoxic effect of this drug on glomerular epithelial cells. Only recently an altered synthesis of mediators, including reactive oxygen species and monocyte-macrophage cytokines, has been hypothesized. METHODS: A mouse strain (nude) bearing a congenital thymic aplasia is a suitable experimental animal to evaluate the role of immune reactions in the development of the ADR nephropathy, provided mouse susceptibility to its toxic effect. Therefore, experimental mice were divided into three groups (G) each receiving adriamycin 7.5 mg/kg b.w.: GA (15 heterozygous nu/O mice with normal immune system); GB (15 homozygous nu/nu athymic mice); GC (15 homozygous nu/nu mice which were also splenectomized, irradiated, and treated with anti-asialo Gm1 antibody to abolish NK and decrease macrophage activity). All animals were maintained under pathogen-free conditions. Urinary proteins, albumin and TNF-alpha excretion were measured. RESULTS: After 14 days the proteinuria was 43.8+/-1.7 microg/min in GA, 30.2+/-2.9 microg/min in GB (P<0.05) and 12.2+/-2.8 microg/min in GC (GA vs GC, P<0.0001; GB vs GC, P<0.05). Albuminuria gave a similar profile. TNG-alpha urinary excretion was significantly higher in GA (17.3+/-3.2 mU/min) than in GB (5+/-0.6 mU/min, P<0.001) and GC (3.2+/-0.9 mU/min, P<0.001). A significant correlation was found in GA between urinary TNF-alpha and protein losses (r2=0.63 P<0.0001). Kidney tissue homogenates failed to show in each experimental group any evidence of mRNA encoding for TNF-alpha, which was detectable in peripheral mononuclear cells from GA and GB, but undetectable in GC mice. Segmental effacements of glomerular epithelial cell foot process were observed by electron-microscopy in GA only, while they were minimal in GB and absent in GC. Iron colloidal staining for anionic sites on frozen sections always showed a normal pattern. CONCLUSIONS: Nude mice bearing cellular immunity deficiency are protected from proteinuria following ADR toxicity. An impaired synthesis and release of lymphomonocyte mediators including TNF-alpha could be envisaged.

A possible role for nitric oxide in modulating the functional cyclosporine toxicity by arginine.

The renal damage consequent to cyclosporine A (CsA) administration ranges from hemodynamic alterations to irreversible chronic lesions. The initial vasoconstriction depends upon the imbalance between the various modulators of the renal vascular tone, among which the most powerful are endothelins and nitric oxide (NO). CsA could play a crucial role by inhibiting the Ca++/calmodulin-mediated activation of the constitutive NO synthase (NOS) isoform, which converts L-arginine (L-Arg) into NO and citrulline, with a 1:1 stoichiometry. To investigate the possibility of modulating CsA nephrotoxicity with L-Arg we studied six groups (G) of Lewis rats treated with daily gavage up to eight weeks: G1, CsA 40 mg/kg; G2, G1 plus L-Arg 300 mg/kg; G3, G2 plus the competitive inhibitor of NOS, NG-nitro-L-Arg (L-NNA); G4, L-Arg alone; G5, L-NNA alone; and G6, controls receiving vehicle alone. After eight weeks L-Arg treated rats were protected against the toxic effects of CsA [creatinine (Cr) values, G2, 0.62 +/- 0.05 mg/dl vs. G1, 0.99 +/- 0.16 mg/dl, P < 0.001; proteinuria (P), G2, 7.2 +/- 1.02 mg/day vs. G1, 15.1 +/- 1.9 mg/day, P < 0.01]. The administration of L-NNA abolished the protective effect of L-Arg (G3, Cr 1.23 +/- 0.16 mg/dl; P 16.9 = 2.3; P < 0.02 and P < 0.005, respectively vs. G2). The levels of Cr in G2 rats were superimposable to control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Macromolecular IgA and abnormal IgA reactivity in sera from children with IgA nephropathy. Italian Collaborative Paediatric IgA Nephropathy Study.

This multicenter study investigated the characteristics of circulating IgA molecules in 77 children: 42 had primary IgA nephropathy (IgAN), 20 were non-IgA glomerulonephritides (CGN) and 15 had urological problems (U). Fifteen assays were employed including the detection of macromolecular IgA [IgA immune complexes (IgAIC) by the conglutinin (K) assay, heavy molecular weight IgA in 2.5% polyethylene glycol (PEG), mixed IgA/IgGIC (Jacalin assay), IgA-Fibronectin (IgA-F) aggregates]IgA antibodies to alimentary antigens (gliadin, glycgli, glutein, ovalbumin, bovine serum albumin) and IgA binding to mesangial antigens (fibronectin, laminin, type IV collagen) or polycations (poly-L-lysine). Total IgA and IgA reacting with jacalin, supposed to bear an altered galactosylation, were measured as well. Mean levels of each kind of macromolecular IgA were significantly increased in children with IgAN in comparison to U disease (K-IgAIC p < 0.05, PEG-IgAIC p < 0.01, IgA/IgGIC p < 0.004, IgA-F aggregates p < 0.0003). However, IgA-F were the only macromolecular IgA significantly higher in IgAN than in CGN (p < 0.0005). IgA-F aggregates did not correlate with any urinary sign of activity, while K-IgAIC data were significantly related with microscopic hematuria (p < 0.05) and past history of gross hematuria (p < 0.02). Children with IgAN had mean levels of IgA reacting with the lectinic fractions of gliadin significantly higher than CGN (p < 0.01) and U groups (p < 0.003). IgAN displayed an enhanced production of IgA reacting with mesangial matrix components vs CGN (p < 0.03) and U (p < 0.0003) groups and showed altered interactions with positively charged molecules (poly-L-Lysine, p < 0.01) and carbohydrate residues (jacalin p < 0.05). In IgAN there is an increased circulation of altered IgA favouring the formation of macromolecular IgA, including true IgAIC or IgA aggregated by carbohydrate interactions. The affinity for the mesangial matrix glycoproteins and for the mesangial area electrical charge might further enhance the trapping and deposition of the immune material containing IgA. IgA-F aggregates seem to be a marker of this event, while complement binding molecules in IgAIC correspond to the hematuric manifestation of the nephritogenic process.

[Optimization of the treatment of idiopathic nephrotic syndrome in children]. / Ottimizzazione del trattamento della sindrome nefrosica idiopatica in età pediatrica.

From 1981 to 1992, 81 children affected by idiopathic nephrotic syndrome were treated in our Division. The majority were males (74%), with mean age at diagnosis of 4.8 (0-14)) years. They had a mean follow-up of 5.7 (0.5-11) years. The renal function at diagnosis was normal in all cases, proteinuria was selective in 86.4% of the cases. 28 children with somehow atypical behaviour underwent renal biopsy. In this negatively selected group the more frequent histologic forms were focal segmental glomerular sclerosis (33.5%), minimal change disease (37.4%), IgM mesangial glomerulonephritis (16.6%), membranous nephropathy (12.5%). First choice drug was in all cases prednisone. In the last years the trend for steroid therapy was to adopt long protocols (16 weeks), with a total dose of 105-133 mg/kg per therapeutic cycle. About 90% of children had a favourable response to steroids, but half of them were frequent relapser. In these cases the long term stable remission was obtained with steroids alone in 10.8% of the cases, with the association of cyclophosphamide in 62%. In a minor fraction and in the steroid resistant (13.6% of the total cases) levamisol and cyclosporin were also adopted. 2.4% of the cases progressed to end stage chronic renal failure. Most of the steroid sensitive children were in remission after 3-4 years of disease, only 6% relapsed more than 5 years after diagnosis.

[IgA serology in idiopathic IgA deposit nephropathy in children]. / La sierologia IgA nelle nefriti idiopatiche a depositi IgA del bambino.

It is generally thought that in primary IgA nephropathy (IgAN) an altered immune response favours high levels of serum IgA directed against environmental or mesangial antigens (Ag) leading to circulating IgA containing immune complexes (IgAIC). The aim of this multicenter collaborative study was to evaluate some of the IgA immunologic abnormalities in children with IgAN. We investigated 42 children with biopsy-proved IgAN, 21 children with non-IgA glomerulonephritides (CD) and 15 with previous urologic disorders without any evidence of immunologic disease (U). The following methods were used: detection of macromolecular IgA (IgAIC by the conglutinin solid-phase assay, heavy MW IgA measured in 2.5% polyethylene glycol precipitate, IgA-fibronectin aggregates, mixed IgA-IgGIC); serum levels of IgA to alimentary Ags (gliadin, glyc-gli, ovalbumin, bovine serum albumin) and mesangial Ags (fibronectin, laminin, type IV collagen) and reactivity of IgA with the lectin jacalin. In children affected with IgAN serum levels of macromolecular IgA were significantly higher in comparison to U group (p < 0.05-p < 0.0005). IgA-fibronectin aggregates only were significantly higher also than CD group (p < 0.0005). Mean levels of antigliadin IgA were significantly higher in IgAN than in controls (CD p < 0.01 and U p < 0.03) and similar data were found for IgA to mesangial matrix (laminin and fibronectin), which were significantly greater in IgAN than in CD and U (p < 0.01-p < 0.0002). Serum IgA in children with IgAN showed a greater affinity for both polycations and glycosylated molecules. Children affected by IgAN present abnormalities in serum IgA similar to those observed in adults with the same disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional consequences of the binding of gliadin to cultured rat mesangial cells: bridging immunoglobulin A to cells and modulation of eicosanoid synthesis and altered cytokine production.

Oral immunization with gliadin (GLI) can induce immunoglobulin A mesangial deposits (IgA nephropathy [IgAN]) in mice. A role for GLI in human IgAN has been inferred from an association with celiac disease, increased serum anti-GLI IgA in patients with IgAN, and benefit from a gluten-free diet observed in some IgAN patients. These effects might be due to the antigenic or lectinic properties of GLI. The aim of our study was to investigate whether GLI binding to glycosylated residues (ie, lectinic activity) favors binding of GLI to cultured rat mesangial cells, bridging IgA macromolecules. We also sought to determine whether GLI binding alters mesangial cell function. Gliadin binds to rat mesangial cells in the third and fourth passages, as determined by immunofluorescence. Gliadin binding is inhibited by co-incubation with 1 mol/L N-acetyl-D-glucosamine and 1 mol/L alpha-D-mannose, sugars competitive for this lectinic bond. Quantification by biotinylated GLI revealed a significant dose-dependent binding of GLI (P < 0.001) inhibited by N-acetyl-D-glucosamine (P < 0.05). Some saccharolytic enzymes, like invertase, modify the cell surface to decrease GLI binding (P < 0.02). In addition, GLI promoted the binding of purified mouse polymeric IgA to mesangial cells. The binding of GLI to mesangial cells modulates arachidonic acid metabolism by cultured mesangial cells, significantly inhibiting prostaglandin E2 production (P < 0.02), increasing synthesis of thromboxane B2 (P < 0.01) and tumor necrosis factor (P < 0.001), but not interleukin-1 beta. These responses were abrogated by co-incubation with N-acetyl-D-glucosamine and/or pretreatment with invertase. Non-immune binding of an environmental alimentary lectin, GLI, to mesangial cells in culture might favor the binding of IgA and IgAIC to mesangial cells, enhancing both IgA mesangial trapping and in situ IgA deposit formation. This could occur via GLI-specific antibodies or by virtue of the binding of nonspecific IgA on a lectinic basis, or both. Moreover, related changes in eicosanoid synthesis might stimulate mesangial cell growth and mesangial matrix production, together with mesangial cell contraction, contributing to the pathogenesis of IgAN.

Glomerular permselectivity to macromolecules in reflux nephropathy: microalbuminuria during acute hyperfiltration due to aminoacid infusion.

Reflux nephropathy is an important cause of chronic renal failure in children. After the parenchymal scar, the progression is thought to be mediated by glomerular hypertension in remnant nephrons resulting in modifications in permselectivity to macromolecules. Proteinuria correlates with a progressive course. The glomerular permselectivity to macromolecules in basal conditions and after acute hemodynamic stress was investigated in 28 children whose bilateral vesico-ureteric reflux (VUR) had been previously surgically corrected (meanly 5.6 years before) and with normal creatinine clearance (CrCl). Bilateral renal scarring (0 to 8 scale for both kidneys) was 4.3 +/- 1.6. Albuminuria (UAE) was evaluated in basal conditions and under acute hyperfiltration induced by amino acid (Aa) infusion. After isotonic saline at 310 ml/hour/1.73 m2, 6 mg/kg/min of Aa were infused for 2 hrs. UAE was significantly higher than controls in basal conditions (p < 0.01), and further increased after Aa infusion (p < 0.02). Microalbuminuria was detectable in 53.5% of the children in basal conditions and in 64.3% after Aa. Also urinary beta 2 microglobulin significantly increased at the end of the test (p < 0.001). CrCl significantly increased at the first hour (p < 0.05). Children with severe renal parenchymal scarring had greater UAE (p < 0.01) and beta 2M (p < 0.02) values after provocative test than those with mild renal damage. In 8 children GFR and ERPF were measured by means of inulin and p-hippurate clearance respectively. The variations in UAE during Aa infusion were significantly correlated with GFR dynamics (p < 0.05) while they were not influenced by ERPF modifications.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokine mRNA expression by cultured rat mesangial cells after contact with environmental lectins.

We previously demonstrated that gliadin, a lectinic component of gluten, induces IgA mesangial deposits in orally immunized mice, binds in vitro polymeric IgA and cultured rat mesangial cells modulating their arachidonic acid metabolism. We investigated the effects of gliadin and other environmental lectins on some mesangial cell functions, including synthesis and release of cytokines and lipid mediators. Several lectins, particularly gliadin, affected the mRNA expression of c-myc and c-fos, two proto-oncogenes involved in the transcriptional enhancement of the gene cascade, which are markers of cell growth, differentiation and mitosis. Lectins modulated the ability of cultured rat mesangial cells to express mRNA for cytokines involved in the inflammation and in the regulation of the immune response. TNF-alpha and IL-6 mRNA transcription were enhanced by gliadin and other lectins, and TNF release was variably increased. Conversely, IL-1 production was less affected or slightly depressed. PAF production was not detectable while PGE2 was generally reduced and TXB2 enhanced. Gliadin was one of the lectins most active on the mesangial cells, and its effects were reversed by the addition of N-Acetylglucosamine, a sugar specific for some lectinic bindings, suggesting a carbohydrate interaction. The effects of the various lectins were distinct and only partially convergent, ruling out an aspecific mesangial cell activation. These data suggest that lectins might interfere with mesangial cell functions and modify the mesangial cell homeostasis.

[Acute renal failure. 3 years' activity of a pediatric dialysis unit]. / Insufficienza renale acuta. Tre anni di attività di un centro dialisi pediatrico.

Acute renal failure is a frequent and dramatic clinical syndrome, producing a wide variety of serious and potentially lethal disorders in infancy. Review of 30 cases of severe acute renal failure occurred from 1985 in our unit reveals that the major causes are: acute tubular necrosis (33%), hemolytic uremic syndrome (16%), post-streptococcal glomerulonephritis (16%). 16 patients aged from 7 days to 15 years weighing 2 to 59 kilos, underwent dialysis: 8 HD, 7 PD, 1 both. Functional recovery occurred in 13 patients (82%); 3 patients died for the condition that precipitated renal insufficiency.