Tapeto-retinal degeneration is frequent in patients with nephronophthisis. Association of the most severe forms of tapeto-retinal dystrophy with NPH identifies a syndrome described first by Senior et al and Loken et al. This syndrome is distinct on molecular grounds from pure renal nephronophthisis (NPH1), which has its gene locus mapped on chromosome 2q13. We describe three families with large homozygous deletion of the NPH1 locus in which mild to moderate ocular lesions due to tapeto-retinal degeneration coexisted and were correlated to renal defects. This new association of NPH1 with retinal dystrophy is characterized by focal lesions of retina and is pauci-symptomatic in clinical presentation. For this reason it may remain unrecognized in most NPH1 patients.

Adult↗

PubMed1998

[Critical evaluation of growth hormone treatment in children with chronic renal insufficiency].

Growth failure remains a major complication of chronic renal insufficiency in children, which greatly affects their quality of life. Based upon the data published in the literature it appears that growth hormone therapy improves growth in these children, with little secondary effects. However, some uncertainties persist concerning the safety and efficacy of this therapy, so that careful evaluations must continue.

Child↗

PubMed1998

Chronic renal replacement therapy in children: which index is best for adequacy?

BACKGROUND: The dialysis dose, Kt/V, and Solute Removal Index (SRI) have been proposed as tools to measure and compare adequacy of different renal replacement therapies in adults. The aim of our study was to elucidate whether the Kt/V and SRI could be appropriate parameters to compare different treatments and define adequacy targets in children. METHODS: Twenty-two pediatric chronic dialysis patients (2 to 17 years) were prospectively studied. Six patients were on continuous ambulatory peritoneal dialysis (CAPD), 7 patients were on automatic nightly peritoneal dialysis (ANPD), and 9 were on hemodialysis (HD). Patients had no peritonitis and were not hospitalized during the previous two months and, as proved by growth and subjective well being, were in steady state condition at the initiation of the protocol. As a consequence, the treatment delivered was assumed to be adequate and the prospective analysis was carried out within one month. Urea levels in dialysate, plasma and urine were measured to determine urea kinetics and measure adequacy parameters. RESULTS: Instantaneous urea clearance was much higher when hemodialysis was used (124.67 +/- 32.04 ml/min) compared to CAPD (2.79 +/- 0.29 ml/min) and ANPD (6.60 +/- 1.42 ml/min), as expected. The Urea dialytic clearance per week was greater in HD (67320 +/- 17299 ml) than in CAPD(28144 +/- 2895 ml) and ANPD (29910 +/- 4234 ml). Residual renal function contributed to the overall weekly clearance by 47% in CAPD, while it was only by 19% in HD and 26% in ANPD. The overall weekly clearance was therefore 79,842 ml/week in HD, 53,340 ml/week in CAPD and 41,012 ml/week in ANPD. Weekly dialytic Kt/V results were much higher in HD (3.75) than in CAPD (1.78) and ANPD (2.37). To these values, the renal Kt/V was added, reaching the values of overall (dialytic + renal) weekly Kt/V of 4.53 in HD, 3.41 in CAPD and 3.41 in ANPD. Although higher Kt/V values were observed in HD, when the SRI % was considered, HD appeared to be less efficient compared with the other two techniques. Since postdialytic rebound in HD patients averaged 22.5%, we may speculate that hemodialysis in children is less efficient than continuous or daily peritoneal dialysis because of a remarkable cardipulmonary recirculation and solute sequestration. CONCLUSION: In the global evaluation, dialysis SRI% appears to be more reliable as an index of adequacy compared to Kt/V in children. At least an integration between the two indices is strongly recommended.

Adolescent↗

PubMed1998

Autosomal dominant medullary cystic disease: a disorder with variable clinical pictures and exclusion of linkage with the NPH1 locus.

BACKGROUND: The nephronophthisis-medullary cystic disease (NPH/MCD) complex represents a heterogeneous group of hereditary tubulointerstitial nephritis. The most common variant is juvenile recessive NPH, for which a gene locus (NPH1) has been mapped on chromosome 2q13. MCD is a less common dominant condition usually recognized later in life, which resembles NPH in many aspects, still presenting remarkable clinical differences. Nothing is known about the chromosome locus of MCD. METHODS: Five MCD families were studied. Diagnosis was made by inference from family history, type of inheritance, clinical signs and histology. Multipoint linkage analysis was performed by markers D2S293, D2S340 and D2S160 spanning the entire NPH1 locus. RESULTS: Diagnosis of MCD was made in 28 affected members (16 males; 12 females), belonging to five families. Histological diagnosis was available in 10 patients; clinical diagnosis in 11; seven deceased relatives had diagnosis of chronic nephritis. The age at diagnosis ranged from 8 to 65 years. Renal medullary cysts were found in a minority of patients. In family 1, the disease was associated with hyperuricaemia and gouty arthritis. Progression of renal disease presented intra- and extra-family variability with members of the same family showing mild elevation of creatinine or terminal renal failure. The NPH1 locus associated to recessive NPH was excluded from linkage to the dominant MCD. CONCLUSIONS: MCD might be more common than previously assumed. Variability in clinical presentation and absence of histopathological hallmarks contribute to make the diagnosis uncommon. The most remarkable clinical difference with NPH is the age of onset in some kindreds and a delayed progression towards renal failure. The exclusion of linkage to the NPH1 locus suggests the existence of an MCD responsible locus, still to be mapped.

Adolescent↗

PubMed1998

Differences in tumor necrosis factor-alpha soluble receptor serum concentrations between patients with Henoch-Schönlein purpura and pediatric systemic lupus erythematosus: pathogenetic implications.

OBJECTIVE: Animal models of immune complex mediated tissue injury have shown different patterns of proinflammatory cytokine production according to the subtype of immunoglobulin involved. The IgA immune complex model differs from the IgG model by the lack of involvement of tumor necrosis factor (TNF) in the pathogenesis of tissue damage. We investigated in age matched patients the possible difference in TNF involvement in a predominantly IgA mediated disease, Henoch-Schönlein purpura (HSP), in comparison with systemic lupus erythematosus (SLE), in which vascular injury is mostly associated with local deposition of IgG immune complexes. METHODS: Serum concentrations of TNF-alpha and its soluble receptors (sTNF-R) p55 and p75 were studied in 20 patients with pediatric SLE at various degrees of disease activity, in 16 patients with highly active HSP, and in 15 healthy controls by enzyme amplified sensitivity immunoassay. SLE disease activity was evaluated using 2 scores, the European Consensus Group Study for SLE Disease Activity Criteria and the SLE Disease Activity Index. RESULTS: Serum concentrations of TNF-alpha fell within the normal range in patients with both SLE and HSP irrespective of disease activity. Conversely, patients with SLE displayed increased serum levels of sTNF-R that correlated positively with the degree of disease activity (r = 0.60, p < 0.001; r = 0.71, p < 0.001, for p55 and p75, respectively). In contrast, no difference in the serum levels of sTNF-R was found between patients with highly active HSP and controls. CONCLUSION: Our study provides the first circumstantial evidence that pediatric SLE and HSP are characterized by differential involvement of TNF in the pathogenesis of tissue damage.

Adolescent↗

PubMed1997

Micro-injection of recombinant lysyl oxidase blocks oncogenic p21-Ha-Ras and progesterone effects on Xenopus laevis oocyte maturation.

Previous evidence suggested an anti-oncogenic role for lysyl oxidase, mainly in ras-transformed cells. Here we prove that recombinant lysyl oxidase is actually able to antagonize p21-Ha-Ras-induced Xenopus laevis oocyte maturation. Lysyl oxidase was also effective on progesterone-dependent maturation, indicating a block lying downstream of Ras. Maturation induced by activated 'maturation promoting factor', normally triggered by progesterone, was also inhibited by lysyl oxidase. Finally, lysyl oxidase did not abolish p42Erk2 phosphorylation upon maturation triggering, suggesting a block downstream of Erk2. Further investigation showed that lysyl oxidase action depends on protein synthesis and is therefore probably mediated by a newly synthesized protein.

Aminopropionitrile↗

PubMed1997

alpha 1-Antitrypsin (AAT) deficiency and ANCA-positive systemic vasculitis: genetic and clinical implications.

A high incidence of alpha 1-antitrypsin (AAT) deficiency has been reported in patients with C-ANCA systemic vasculitis in association with antibodies against proteinase-3 (PR3). To clarify the role of AAT deficiency in the acute vasculitic process as well as in progression of the disease, we studied 84 patients with either C-ANCA or P-ANCA vasculitis with special reference to: (a) the AAT gene, (b) the phenotypic (Pi) variants and (c) the serum levels during both acute illness and remission. The PiZ gene was found in six patients (8% vs. 1.5% controls) irrespective of the type of autoantibodies (C-ANCA vs. P-ANCA). All PiZ patients displayed the ability to raise their AAT serum levels up to the normal range during acute illness. In contrast, 24 patients with the PiM phenotype presented low AAT serum levels during acute illness. In all these patients, the AAT levels returned to normal values during the remission. Low AAT levels were associated with low levels of C-reactive protein (PCR) (P < 0.001), with a less severe renal involvement or a minor risk of death, and, in one tested patient, with a novel point mutation (TCGA-->TCAA) at the enhancer-promoter region of the AAT gene. Low AAT serum levels did not correlate with either type/titre of autoantibody or distribution/severity of the vasculitis process. In the case-control study, high AAT levels emerged as a major determinant of progression towards end-stage renal failure [odds ratio 3 (95% CI 1.1-8.4)]. These results indicate: (a) a high incidence of the PiZ gene of AAT in systemic vasculitis irrespective of the type of autoantibodies; (b) a novel form of AAT deficiency associated with the normal PiM phenotype becoming manifest only during acute illness; (c) dysregulation of the acute-phase response affecting selectively AAT or both AAT and PCR; (d) correlation between low plasma levels of AAT and less severe renal involvement or risk of death.

Adult↗

PubMed1997

Lysyl oxidase expression and collagen cross-linking during chronic adriamycin nephropathy.

Collagen cross-linking induced by lysyl oxidase has been implicated in liver and lung fibrosis. To define the role of this process in kidney fibrosis, we investigated the renal expression of lysyl oxidase and the content in collagen cross-links at various stages of chronic Adriamycin nephropathy in Sprague-Dawley rats. Lysyl oxidase expression was determined by RT-PCR; collagen pyridinium residues, indicating lysyl oxidase induced cross-links, were evaluated by HPLC. These parameters followed a synergic albeit asynchronous outcome: (a) lysyl oxidase mRNA levels in total kidney, glomeruli and medulla from Adriamycin-treated rats increased up to 3 times compared to controls between week 8 and 12, then returning within the normal range; (b) the pyridinium residue content did not show any significant difference between Adriamycin-treated and control rats, until diffuse interstitial fibrosis developed (16 weeks), showing at this time a 2- to 3-fold increment. Lysyl oxidase was expressed by several renal cell lines and in tubular-epithelial cells it was up-regulated in vitro by TGF beta-1, a recognized fibrogenetic factor in Adriamycin nephropathy. Our observations demonstrated that an increased expression of lysyl oxidase in the kidney precedes the development of diffuse fibrotic lesions and that, at this stage, collagenic structures contain highly cross-linked components, the final product of lysyl oxidase activity. The evidence of lysyl oxidase up-regulation in tubular epithelial cells by the same factor implicated in Adriamycin toxicity in the kidney suggests a common pathogenetic mechanism. Collagen cross-link formation by lysyl oxidase may be implicated in the pathogenesis of irreversible, fibrotic renal lesions.

Animals↗

PubMed1996

HLA matching in pediatric recipients of a first kidney graft. A single center analysis.

We retrospectively examined the effect of HLA-A, -B, and -DR serological matching on graft survival in 88 pediatric end-stage renal disease patients who underwent primary renal transplantation. Actuarial graft survivals (GS) at 2 and 6 years in patients with zero DR mismatches (MM) (12 patients) or 1 DR MM (58 patients) were significantly higher than those in patients with 2 DR MM (18 patients) (2-year GS: 100% vs. 90% vs. 59%; 6-year GS: 100% vs. 79% vs. 59%, respectively). Because of the low number of patients in the zero DR MM group, only the GS difference between 1 DR MM and 2 DR MM had a significant result at 1 year (92% vs. 68%). No clear HLA matching effect was obtained in the HLA-A and -B loci. When DR were combined with A or B antigens (0-2 MM vs. 3-4 MM), significantly higher GS at 1, 2, and 6 years persisted for patients with 0-2 MM only in the A, DR group (96%, 94%, and 85% vs. 68%, 63%, and 56%, respectively). It is suggested that avoidance of mismatching for DR alleles at the serological level, in the selection of pediatric recipients of first cadaveric renal transplantation, leads to an improvement of both short- and longterm graft outcome.

Adolescent↗

PubMed1996

X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene.

The COL4A5 gene encodes the alpha5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the alpha5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients.

Adult↗

PubMed1996

Nutritional status in children receiving chronic peritoneal dialysis.

Chronic peritoneal dialysis (CPD), widely used in uremic children, may have contrasting effects on the nutritional status of patients. Metabolic and nutritional abnormalities due to the combined effects of uremia per se, glucose absorption from the dialysate and catabolic factors, such as protein and amino acid losses into dialysate, poor appetite, and recurrent episodes of peritonitis are the most important. Although CPD allows for fewer dietary restrictions and supplies an extra amount of calories by glucose absorbed with the peritoneal fluid, when protein and energy intakes are assessed the protein intake was almost sufficient or more than that prescribed, whereas the energy intake was low. In CPD children the standard deviation score for weight, height, triceps skinfold thickness, and midarm circumference has been reported as more severely impaired in children less than ten years old. Anthropometric parameters did not worsen during CPD treatment. Plasma proteins and albumin are reported as being low in CPD children. The dietary intake and protein losses have been considered to be the most important determinants of the albumin level in CPD patients. The reported average dialysate losses of free amino acids (AA) during CPD in children vary from 0.02 to 0.03 g/kg/day in different studies. The patterns of plasma AA in CPD is represented by reduced levels of branched chain AA and of other essential amino acids and increased concentrations of some nonessential AA. Several factors may influence plasma AA profile: uremia per se, hormonal alterations, protein and AA losses, and dietary intake. A more specific uremic AA pattern is found in muscle, the largest pool of free AA in the body. Studies on muscle AA in adults on CPD are conflicting: some authors have reported several muscle AA alterations, but others have shown an almost normal pattern. Low valine and leucine muscle levels have been reported in children on CPD.

Adolescent↗

PubMed1996

Comparison of patient hospitalization in chronic peritoneal dialysis and hemodialysis: a pediatric multicenter study.

Patient hospitalization was compared in 207 pediatric patients (age < or = 15 years at the start of dialysis) on chronic peritoneal dialysis (CPD) (127 patients) or center hemodialysis (HD) (80 patients), treated in 17 dialysis centers during the period 1989 to 1994, and followed up for at least three months. The hospitalization rate was expressed as hospital days per patient-month, and was calculated on the overall period of treatment and separately for the first and second year. Since the age at start of dialysis markedly differed between CPD (8.2 +/- 4.7 years) and HD (11.2 +/- 2.9 years) patients (with no HD patient younger than five years), results are separately presented in three patient groups: CPD patients aged < 5 years (A); CPD patients aged five to 15 years (B); HD patients (C). The duration of hospitalization was subdivided according to the following different causes: routine (monitoring of dialysis adequacy), complications of the modality, patient primary renal disease, and other causes. The results are presented in Table 1. A statistically significant difference in total days hospitalized was found between each of the two groups of CPD patients and the HD patients; the results for hospitalization for dialysis-related complications were higher in the group of younger children on CPD, while the difference between the two age-matched groups of patients on CPD and HD was not significant.

Adolescent↗

PubMed1996

Protracted levamisole in children with frequent-relapse nephrotic syndrome.

Explore the source record for details and available documents.

Adjuvants, Immunologic↗