Alberto Canepa

Use of new peritoneal dialysis solutions in children

Standard peritoneal dialysis (PD) solutions with low pH and containing high concentrations of lactate and glucose have been demonstrated to negatively affect the peritoneal membrane, mesothelial cell viability, residential peritoneal cells, and also to inhibit phagocytic functions. An increasing body of experimental evidence supports the idea that the peritoneal hypervascularization and fibrosis observed in long-term PD are causally related to the acute and chronic toxicity of conventional PD solutions. A Physioneal (lactate/bicarbonate mixed buffer pH 7-7.4), Physioneal, Extraneal (7.5% icodextrin), Nutrineal (1.1% amino-acid-containing solution) regimen, for example, offers a significant reduction in carbohydrate load (approximately 40-50%), lower exposure to and absorption of glucose degradation products, reduced oxidative stress, and improved volume control when compared with a first-generation DDDD (4 x Dianeal) regimen. The positive aspects of each solution that we have observed in our patients allow a recommendation on the potential benefit of using these solutions in children treated with PD. In fact, data from the literature as well as the results of the studies reported in this paper show that in children the application of neutral pH bicarbonate/lactate-buffered solution for the standard nighttime APD prescription, icodextrin solution for a long daytime dwell, and AA-based solution in malnourished patients is safe and effective. Extended clinical trials should be encouraged to better define the PD schedules for the combined use of these solutions that may be associated with the best clinical efficacy and the highest level of biocompatibility.

Long-term effect of amino-acid dialysis solution in children on continuous ambulatory peritoneal dialysis

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.

Two cases of swine H1N1 influenza presenting with hematuria as prodrome

Sirs, The multiorgan distribution of human influenza A (H1N1) virus is unknown. Studies in mouse models suggest a more common multiple organ localization than previously believed, including the lung, heart, thymus, liver and spleen [1]. Renal localization has never been reported [2]. We describe here two children who presented with hematuria 48 h before the start of classical pulmonary signs of influenza. The first patient was a 7-year female child who developed hemorrhagic cystitis with fever and was admitted to our hospital for clinical tests and therapy. Urinalysis showed the presence of normally shaped red blood cells, and the renal sonography scan revealed no abnormalities. Renal function was normal. After 48 h of intravenous ceftriaxone, the fever peaked at 39°C, and the child developed a non-productive cough without any alterations visible on the chest X-ray. After 48 h, the hematuria disappeared; the fever remitted after 96 h, and clinical conditions slowly improved. The second patient was a 13-year-old male adolescent who was admitted for macroscopic hematuria and fever. At presentation, the urine sediment showed the presence of casts, mostly cellular and jalino-granulose (Fig. 1); immunological tests (antinuclear antibodies, anti-double-stranded DNA, anti-neutrophil cytoplasmic antibodies, complement, immunoglobulins) were negative, and renal function was normal. Renal sonography showed normal kidney and urinary tract morphology. Also in this case, the fever peaked after 48 h, with minimal signs of respiratory involvement, and slowly decreased. Micro-hematuria and cellular casts in the sediment were still present after 7 days. Real time PCR for H1N1 demonstrated in both cases the presence of H1N1 virus in respiratory specimens; blood and urine were negative for the presence of the virus. Macroscopic hematuria may be the first sign of an incoming H1N1 viral episode. In our two patients,

Hyperinsulinemia and Insulin Resistance, Early Cardiovascular Risk Factors in Children with Chronic Kidney Disease

Background/Aims: Pediatric chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease. Still, hyperinsulinemia and insulin resistance, common cardiovascular risk factors, are not extensively investigated in children with CKD. We hypothesize that insulin abnormalities are present also in pediatric mild to moderate CKD, and associated with inflammation and malnutrition. Methods: We enrolled 26 children with CKD, and 34 healthy controls for analyses of blood samples and body composition. Insulin resistance was assessed using the homeostasis model assessment for insulin resistance (HOMA-IR). Results: The patients had higher insulin levels and HOMA-IR compared to the controls (p < 0.01 and p < 0.005), and they correlated inversely with estimated glomerular filtration rate (rho = –0.52, p < 0.01; rho = –0.37, p = 0.08). No association was found with inflammation or malnutrition. Conclusion: High insulin levels and HOMA-IR appear to be common in pediatric CKD patients, already in mild to moderate renal failure. We hypothesize that hyperinsulinemia and insulin resistance alone might be important risk factors for cardiovascular disease in children with CKD.

Proteome profile of peritoneal effluents in children on glucose- or icodextrin-based peritoneal dialysis

BACKGROUND We compared the proteome profile of peritoneal effluents obtained with icodextrin (Ico) or glucose (Glu) in paediatric patients and defined the oxido-redox status of proteins. METHODS Sixteen patients underwent two 14-h daytime dwells performed on subsequent days with 7.5% Ico and 3.86% Glu solutions. Protein composition was analysed by two-dimensional electrophoresis and mass spectrometry; oxidized products were evaluated by cyanine labelling. RESULTS Peritoneal transport kinetics of β2-microglobulin and cystatin C was linear for both solutions, but was significantly higher with Ico than with Glu, suggesting a better efficiency for these molecules. There was a linear correlation between total protein removal during Ico and Glu dialysis in the same patient, suggesting that it is a function of peritoneal membrane characteristics. The ratio between proteins removed by Ico and by Glu solutions was higher at low removal rate. Image gel analysis revealed 1064 and 774 spots, respectively, in Ico and Glu solutions; 524 were common, and 314 were higher in Ico than Glu effluents. Analysis of protein oxido-redox status showed a greater amount of oxidized albumin in Ico dialysate that was correlated with lower serum levels. CONCLUSIONS Our results indicate a better efficiency of Ico in removing small proteins. Removal of big proteins and their oxidized isoforms reflects potentially opposite effects. The long-term clinical consequences of removing also potentially important molecules are to be defined.

Modulation of proteinuria and renal xanthine oxidase activity by dietary proteins in acute adriamycin nephrosis in rats : lack of correlation with intra- and extracellular amino acids

Protein restriction ameliorates proteinuria in acute adriamycin (ADR) nephrosis and decreases the renal levels of xanthine oxidase (XO), a putative mediator of ADR nephrotoxicity. Hypothetically, the effect of protein restriction on renal XO levels may be due to variations in plasma and tissue proteic amino acids (AA). To elucidate this point, the levels of AA in plasma and in renal homogenates were determined in rats with ADR nephrosis and fed diets with different protein contents: (a) high (35%) casein; (b) standard (21%) casein; (c) low (9%) casein; (d) low casein plus a synthetic mixture of Val, Leu and Ile. The protein content of the diet determined certain marked variations in plasma AA: high levels of Val, Leu and Ile were found in rats fed on a high protein diet, while the same AA were low, in rats on low protein regimen. Supplementation of the low protein diet with a synthetic mixture of branched-chain AA (Val, Leu and Ile) normalized the plasma levels of these AA. In spite of these changes, tissue AA were similar in all groups, regardless of the protein contents of the diets. Furthermore, the levels of renal XO and proteinuria were unrelated to variations in plasma AA, since both parameters were low in protein-restricted and protein-restricted AA-supplemented rats while high in rats fed a high or normoproteic diet. These data demonstrate that low protein diets induce marked alterations in plasma AA composition which are similar in may respects to those found in protein malnutrition.(ABSTRACT TRUNCATED AT 250 WORDS)

Proteolytic activity and free amino acid concentrations in polymorphonuclear leucocytes.

Polymorphonuclear granulocytes (PMN) are valuable tools for evaluating amino acid (AA) metabolism in nucleated cells, although variations of free amino acid concentrations due to the methods used for the separation of the cells and the procedures used for lysis have been reported. Furthermore, analytical variations in PMN AA concentration may be induced by protease activation during preparation, so that free AA detected in cells could originate from proteolysis other than from the physiological metabolic pathways and transport systems. To study this possibility we measured granulocyte protease activity and AA concentrations in cell suspensions processed with and without the addition of antiproteolytic agents. Granulocyte AA concentrations and protease activity in samples treated with antiproteolytics were 8–15 times lower than in samples processed without antiproteolytics. The use of protease inhibitors throughout the sample preparation is necessary for reliable estimation of free AA in granulocytes.

Efficacy and tolerability of long-term oral cefaclor therapy in the prevention of urinary tract infections in infants and children

Abstract The efficacy and tolerability of long-term therapy with oral cefaclor 25 mg/kg per day administered in the evening was assessed in 30 infants and children with recurrent urinary tract infections (UTIs) most of which were associated with structural and functional abnormalities of the urinary tract. After 8 days of therapy, all organisms were eradicated with cefaclor, and patients who were symptomatic improved. Seventeen patients concluded 6 months of treatment with cefaclor. Urinary concentrations of cefaclor in these patients remained higher than the minimum inhibitory concentration needed to eradicate 90% of the bacteria responsible for UTIs. Six of these 17 patients continued antibiotic therapy for an additional 6 months and completed this second period of cefaclor therapy with neither recurrences nor side effects. Of the 13 patients who did not complete the 6-month study, 3 suffered reinfections. Cefaclor was well tolerated, with none of the patients experiencing side effects. Similarly, no changes were noted in serum creatinine, ions, or blood analyses. Cefaclor may be a good alternative to the usual antibacterial agents used in the prevention and cure of UTIs in children.

Molecular and Cellular Mechanisms for Proteinuria in Minimal Change Disease

Minimal Change Disease (MCD) is a clinical condition characterized by acute nephrotic syndrome, no evident renal lesions at histology and good response to steroids. However, frequent recurrence of the disease requires additional therapies associated with steroids. Such multi-drug dependence and frequent relapses may cause disease evolution to focal and segmental glomerulosclerosis (FSGS) over time. The differences between the two conditions are not well defined, since molecular mechanisms may be shared by the two diseases. In some cases, genetic analysis can make it possible to distinguish MCD from FSGS; however, there are cases of overlap. Several hypotheses on mechanisms underlying MCD and potential molecular triggers have been proposed. Most studies were conducted on animal models of proteinuria that partially mimic MCD and may be useful to study glomerulosclerosis evolution; however, they do not demonstrate a clear-cut separation between MCD and FSGS. Puromycin Aminonucleoside and Adriamycin nephrosis are models of glomerular oxidative damage, characterized by loss of glomerular basement membrane polyanions resembling MCD at the onset and, at more advanced stages, by glomerulosclerosis resembling FSGS. Also Buffalo/Mna rats present initial lesions of MCD, subsequently evolving to FSGS; this mechanism of renal damage is clearer since this rat strain inherits the unique characteristic of overexpressing Th2 cytokines. In Lipopolysaccharide nephropathy, an immunological condition of renal toxicity linked to B7-1(CD80), mice develop transient proteinuria that lasts a few days. Overall, animal models are useful and necessary considering that they reproduce the evolution from MCD to FSGS that is, in part, due to persistence of proteinuria. The role of T/Treg/Bcells on human MCD has been discussed. Many cytokines, immunomodulatory mechanisms, and several molecules have been defined as a specific cause of proteinuria. However, the hypothesis of a single cell subset or molecule as cause of MCD is not supported by research and an interactive process seems more logical. The implication or interactive role of oxidants, Th2 cytokines, Th17, Tregs, B7-1(CD80), CD40/CD40L, c-Mip, TNF, uPA/suPAR, Angiopoietin-like 4 still awaits a definitive confirmation. Whole genome sequencing studies could help to define specific genetic features that justify a definition of MCD as a “clinical-pathology-genetic entity.”

Adverse events linked with the use of chimeric and humanized anti-CD20 antibodies in children with idiopathic nephrotic syndrome

Anti‐CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti‐CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions.