Puberty is associated with increased deterioration of renal function in patients with CKD: data from the ItalKid Project.

OBJECTIVE: To analyse the timing of end stage renal disease in children with chronic kidney disease (CKD). DESIGN: A population-based cohort study. SETTING: A nationwide registry (ItalKid Project) collecting information on all patients with CKD aged <20 years. PATIENTS: 935 children with CKD secondary to renal hypodysplasia with or without urologic malformation. In a subgroup of patients (n=40) detailed pubertal staging was analysed in relation to CKD progression. MAIN OUTCOME MEASURES: Kidney survival (KS) was estimated using renal replacement therapy (RRT) as the end-point. Puberty was staged by identifying the pubertal growth spurt. RESULTS: A non-linear decline in the probability of KS was observed, with a steep decrease during puberty: the probability of RRT was estimated to be 9.4% and 51.8% during the first and second decades of life, respectively. A break-point in the KS curve was identified at 11.6 and 10.9 years of age in male and female patients, respectively. CONCLUSIONS: The present analysis suggests that puberty is associated with increased deterioration of renal function in CKD. The mechanism(s) underlying this unique and specific (to children) pattern of progression have not yet been identified, but it may be that sex hormones play a role in this puberty-related progression of CKD.

Soluble adhesion molecules and cytokines in children affected by recurrent infections of the upper respiratory tract.

The objective of this study was to compare plasma levels of soluble adhesion molecules and Th1-Th2 type cytokines in 44 children with frequently recurrent respiratory infections (FRRI) of upper airways, defined as having nine or more episodes per year, and in 34 children without recurrence; all subjects were followed-up for 12 mo. The viral etiology was determined by cultures from nasal, pharyngeal, and ear secretions, using PCR and immunofluorescence. Plasma levels of five soluble adhesion molecules (E-selectin, P-selectin, L-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) and interferon (IFN)-gamma, IL-12, IL-4, and IL-10 were measured in patients and in 15 healthy controls using sandwich ELISA. During acute phase, all patients showed significant increase in plasma levels of soluble adhesion molecules; during the follow-up, the levels were greater in children with FRRI. A difference of cytokine profile was demonstrated between the patients with and without FRRI: an increased IL-4 and IL-10 release with decreased levels of IFN-gamma and IL-12 suggested a skewing into Th2-type response, in patients with FRRI. This pattern persisted during the follow-up. In patients without recurrence, an increased IFN-gamma and IL-12 release, together with decreased levels of IL-4 and IL-10, showed a skewing into Th1-type responses; in the follow-up these cytokines reached normal values. In conclusion, the abnormal levels of all examined parameters in children with FRRI may reflect the persistence of an inflammatory microenvironment in the airways and an activation of the immune system that may contribute to the frequently recurrence of the respiratory disease.

Beta-thalassemia is a modifying factor of the clinical expression of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a codominant disorder due to a variety of mutations of the low-density lipoprotein (LDL) receptor gene that result in an elevation of plasma LDL-cholesterol (LDL-C). Plasma levels of LDL-C show large interindividual variation even in subjects carrying the same mutation of the LDL receptor gene. This variability may be due to genetic factors (modifier genes). Several surveys indicate that the overall contribution of common polymorphisms of modifier genes (such as the genes encoding apolipoproteins E and B) to this variability is less than 10%. In contrast, beta-thalassemia has a profound LDL-lowering effect. This was documented in FH patients identified on the island of Sardinia, in Italy, where 12% of the inhabitants are carriers of beta-thalassemia due to a single mutation (Q39X) of the beta-globin gene that abolishes the synthesis of beta-globin chain of hemoglobin (beta(o)-thalassemia). Plasma LDL-C in FH heterozygotes carrying the beta(o)-thalassemia trait is 25% lower than in noncarriers, regardless of the LDL receptor gene mutation. It is likely that this effect is due to two main mechanisms: (1) increased uptake of LDL by the bone marrow to provide cholesterol for the increased proliferation of erythroid progenitor cells and (2) increased production of inflammatory cytokines that reduce the hepatic secretion and increase the catabolism of LDL. In view of its LDL-C-lowering effect, beta-thalassemia trait may protect FH heterozygotes against premature coronary atherosclerosis.

Risk factors for poor renal prognosis in children with hemolytic uremic syndrome.

Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D(-)STEC(- )recovered normal renal function compared with 65%-76% of D(+)STEC(+), D(+)STEC(-) and D(-)STEC(+ )patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D(-) but STEC(+) patients have a significantly better prognosis.

Elevated incidence of hypospadias in two sicilian towns where exposure to industrial and agricultural pollutants is high.

We found significant elevated incidence of hypospadias in two towns in Southeastern Sicily selected on the basis of the presence of intense industrial (Augusta) and agricultural (Vittoria) activities. Cases and controls were chosen in records collected from a surveillance system on abnormal live births in the same area and in a large city (Catania) located in an area at low risk of exposure to environmental pollutants. From 1991 to 1998, 16 cases of isolated hypospadias were recorded among male live births in Augusta (12.1 per 1000 male live births) and 24 cases in Vittoria (7.4 per 1000 male live births) with an incidence significantly higher than that expected (3.2 per 1000 in Southeastern Sicily). Relative risks in Augusta and Vittoria were 3.8 (95% confidence interval: 2.16-6.14) and 2.3 (95% confidence interval: 1.48-3.43; P=0.00003 and 0.04, respectively). In Augusta, the incidence of hypospadias was higher than in Vittoria. Significant log odds ratios were found for occupational exposure in fathers both in Augusta and Vittoria (P=0.0478 and 0.026, respectively). However, daily contact with pollutants in Augusta may not be sufficient by itself to determine hypospadias and other factors might be involved. Similar factors may act also in Vittoria. Thus, contact with large amounts of pesticides is, by itself, a risk factor for hypospadias, though genetic and other environmental factors might be involved.

Molecular analysis of the SGLT2 gene in patients with renal glucosuria.

The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutations were detected. Most of them were private; only a splice mutation was found in 5 families of different ethnic backgrounds, and a 12-bp deletion was found in two German families. Fourteen individuals (including the original patient with 'renal glucosuria type 0') were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.6 to 202 g/1.73 m(2)/d (81 - 1120 mmol/1.73 m(2)/d). Some, but not all, of their heterozygous family members had an increased glucose excretion of up to 4.4 g/1.73 m(2)/d (24 mmol/1.73 m(2)/d). Likewise, in index cases with glucosuria below 10 g/1.73 m(2)/d (55 mmol/1.73 m(2)/d) an SGLT2 mutation, if present, was always detected in the heterozygous state. We conclude that SGLT2 plays an important role in renal tubular glucose reabsorption. Inheritance of renal glucosuria shows characteristics of a codominant trait with variable penetrance.

Non-allelic heterogeneity in familial unilateral renal adysplasia.

We report three families with dominant unilateral renal adysplasia without vesico-ureteral reflux. No dysmorphia or anomalies were evident in the reproductive system. Ophthalmological examination excluded the presence of optic nerve coloboma or other ocular anomalies. No mutations were detected in the EMX(2) and in PAX(2) genes of affected members. Other homeobox genes could be responsible for this anomaly in these three families.

Optic disc drusen, angioid streaks, and mottled fundus in various combinations in a Sicilian family.

BACKGROUND: We describe a Sicilian family in which optic disc drusen, angioid streaks, and mottled fundus--without dermatological signs of pseudoxanthoma elasticum (PXE)--are present in various combinations and segregate as an autosomal dominant trait. Since these ocular manifestations can be part of the clinical signs of PXE, we examined the possible involvement of a mutation in the ABCC6 gene, which is known to be responsible for PXE. METHODS: Linkage analysis was performed with both intragenic and flanking markers. We used marker D16B9722 and a single-nucleotide polymorphism located in exon 15 of the ABCC6 gene. LOD score values were calculated on the assumption of a gene frequency of 0.0001 and both complete penetrance and reduced penetrance (90%), with theta values between 0.0 and 0.4. RESULTS: LOD score values excluded the involvement of the ABCC6 gene. CONCLUSIONS: The dominant transmission of optic disc drusen, mottled fundus, and angioid streaks in this family is not due to alterations in the ABCC6 gene.