Nephropathic cystinosis, a lysosomal storage disease caused by mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin, is characterized by generalized proximal tubule (PT) dysfunction that progresses, if untreated, to end-stage renal disease. The pathogenesis of defective PT cellular transport in nephropathic cystinosis remains unclear. We characterized a recently generated line of C57BL/6 Ctns mice and analyzed endocytic uptake, lysosome function, and dedifferentiation and proliferation markers using primary cultures of PT epithelial cells derived from Ctns(-/-) and Ctns(+/+) littermates. Metabolic studies revealed that Ctns(-/-) mice show a progressive PT dysfunction characterized by low-molecular-weight (LMW) proteinuria, glucosuria and phosphaturia, before structural damage and in the absence of renal failure. These changes are related to decreased expression of the multi-ligand receptors megalin and cubilin and to increased dedifferentiation (ZONAB transcription factor) and proliferation (PCNA and Cyclin D1) rates. Studies on PT cells derived from Ctns(-/-) kidneys confirmed cystine overload, with accumulation of enlarged, dysfunctional lysosomes and reduced expression of endocytic receptors reflected by decreased uptake of specific ligands. These changes were related to a loss of integrity of tight junctions with a nuclear translocation of ZONAB and increased proliferation, as observed in Ctns(-/-) kidneys. These data reveal that the absence of cystinosin in PT cells triggers aberrations of the endolysosomal compartment, transport defects and an abnormal transcription program in the early stage of nephropathic cystinosis. Insights into the early manifestations of cystinosis may offer new targets for intervention, before irreversible renal damage.

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Methylmalonic acidemia (MMA) is an inborn error of organic acid metabolism. Patients with severe disease develop many complications despite treatment; often, the disease progresses to severe damage of the central nervous system or to end-stage renal disease (ESRD). When medical treatment is ineffective, liver, kidney, or combined liver and kidney transplantation is advocated. At present, there are no definite guidelines as for the organ to be transplanted, and results are inconsistent. We report on a 27-year-old woman with MMA MUT0. The clinical symptoms developed at age 4 months. She progressed to ESRD and received a kidney transplant in November 1996 at age 17 years. One hundred and twenty months after transplant, renal function is normal; although urinary levels of methylmalonic acid are above normal limits, no episodes of metabolic decompensation have been observed after transplantation. Although liver is the major site of methylmalonyl-CoA mutase activity, this case and similar ones in the literature suggest that the smaller mutase activity present in the transplanted kidney may be sufficient to ensure partial correction of the metabolism of organic acids sufficient to prevent the onset of episodes of metabolic decompensation. It is worth investigating whether kidney transplant can be a safer and more satisfactory alternative to liver transplantation in cases of MMA unresponsive to medical treatment although urine MMA excretion remains significantly elevated.

It is as yet unclear whether blood pressure load (BPL) can affect renal function in pre-hypertensive children. We have studied 250 children, with a mean age of 9.12 +/- 3.28 years, with the aim of assessing if pre-hypertension in children can indeed affect renal function. The study cohort consisted of 146 children with pre-hypertension (group P) and a control group of 104 children with normal blood pressure (group C). All children were tested for orthostatic proteinuria, an exclusion criterion, glomerular filtration rate (GFR), and proteinuria, and ambulatory blood pressure monitoring was performed. Based on the BPL, group P was further subdivided into group P1 (BPL 40%, high BPL). We found that GFR was reduced in pre-hypertensive children (90.74 +/- 48.69 vs. 110.32 +/- 20.30 ml/min per 1.73 m(2), p < 0.0001) and that proteinuria was increased (145.36 +/- 110.91 vs. 66.84 +/- 42.94 mg/m(2) per 24 h; p < 0.0001). However, mean values were still within normal limits. A comparison of the group with high BPL and that with low BPL revealed that the former had relatively reduced GFR (79.15 +/- 42.04 vs. 96.78 +/- 51.20 ml/min per 1.73 m(2); p < 0.006) and increased proteinuria (198.29 +/- 142.17 vs. 118.31 +/- 80.07 mg/m(2) per 24 h; p < 0.036). In comparison to the reference values of the normal population, the GFR was reduced and proteinuria was increased in the group with high BPL. Based on our results, pre-hypertension in children with high BPL seems to be associated with reduced GFR and increased proteinuria. A reasonable doubt remains that the patients with higher proteinuria and larger reduction of GFR may harbor an as yet unknown subclinical renal condition responsible for the onset of pre-hypertension. Therefore, children with even mildly elevated BP are at risk of developing renal damage and should change their lifestyle to prevent further increases in BP.

Neuroblastoma (NB) is the most common pediatric neuroendocrine tumor, and it is characterized by a quite variable clinical course. We previously found a great variability in the expression of somatostatin receptor type 2 (sst2) in several human NB cell lines and primary tumors. In this report we investigated whether expression of sst2 is somehow related to clinical outcome. We performed a retrospective study on 54 patients with a maximum follow-up of 100 months. The concentration of specific messenger ribonucleic acid (mRNA) for sst2 was measured by competitive RT-PCR and validated, in a small subset of samples, by quantitative imaging of gene (in situ hybridization) and protein (immunohistochemistry) expression. We found that sst2 mRNA was variably expressed in all NB tumors (range, 2.5 x 10(5) to 8 x 10(9) molecules/microg RNA) with a relevant reduction in the more advanced stage (P < 0.01). Analysis of Kaplan-Meier curves indicated that sst2 expression is positively related to the overall (P < 0.0001) and event-free (P < 0.0001) survival. Expression of sst2 was negatively related to tumor stage (P < 0.02) and MYCN amplification (P < 0.001), a poor prognostic factor. However, the prognostic information derived from sst2 is apparently independent from MYCN amplification, as assessed by stratifying sst2 values according to MYCN. In addition, the expression of sst2 was the only significant prognostic factor (P < 0.02) when it was included in a multivariate model containing other well known prognostic factors such as age, stage, and MYCN amplification. Hence, we propose that sst2 expression represents a new prognostic marker for NB. The main clinical value of a quantitative measure of sst2 lies in its ability to detect patients at low risk, independently from other prognostic factor, including MYCN amplification.

Somatostatin analogs are effective in inhibiting growth of human breast cancer cell lines. These antiproliferative effects are mediated by specific receptors located on cell membranes. The somatostatin receptor subtype 2 (sst2) is the principal mediator of somatostatin effects in normal and cancer cells, and its presence has already been demonstrated in breast cancer. The purpose of our study was to evaluate the clinical relevance of the expression of sst2 by quantifying its mRNA in a large group of infiltrating breast cancers and their corresponding normal tissues.The expression of sst2 mRNA was measured with quantitative real time RT-PCR in 169 breast cancers and in their corresponding unaffected tissues. We evaluated the association of sst2 expression with the commonest clinical-pathologic features of breast cancer. The correlation with a marker of cell proliferation (Ki-67) and with receptor concentration was also evaluated.In cancer tissues, we found that the absolute concentrations of sst2 mRNA were significantly higher in estrogen receptor (ER)-positive samples ðP ¼ 0:002Þ as well as in lymph-node-negative cancers ðP ¼ 0:04Þ (Student's t-test or one-way ANOVA). In addition, sst2 mRNA was significantly higher in breast cancers than in corresponding unaffected tissues ðP ¼ 0:0002Þ. However, when the clinicalpathologic parameters were considered, this gradient maintained its statistical significance only in tumors expressing positive prognostic markers, such as the presence of ER ðP ¼ 0:0005Þ and progesterone receptors (PgR) ðP ¼ 0005Þ, and the lack of lymph-node involvement ðP ¼ 0:0003Þ. The same difference was also significant in postmenopausal women ðP ¼ 0:001Þ and in T1 patients ðP ¼ 0:001Þ. In addition, sst2 mRNA expression was significantly higher ðP ¼ 0:008Þ in lowproliferating breast cancers. Finally, we found that the quantitative expression of sst2 mRNA was directly related to the PgR concentration in breast cancer tissues ðP < 0:001Þ.Our data seem to indicate that an upregulation of sst2 gene expression is a common feature of breast cancers which, on the basis of conventional predictive parameters, are expected to have a better prognosis. Featuring a possible role of somatostatin analogs in combined endocrine therapies for breast cancer, our results seem to confirm that the sst2 status of the tumor should be previously investigated.

In the short term, the combination of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists for children with proteinuria of renal origin reduced proteinuria significantly, compared with baseline or either drug alone. Furthermore, echocardiographic studies gave evidence of reduction of left ventricular hypertrophy. Additional studies are needed to evaluate long-term results.

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