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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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.

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.