We carried out a nationwide survey on patients less than 20 years of age with pediatric chronic end-stage renal disease (ESRD) in Japan for the year 1998. There were 582 patients who had started on renal replacement therapy before 1998, and 105 patients who had been newly introduced to renal replacement therapy in that year. The prevalence rate of the ESRD patients already on treatment was 22 per million population (aged 0-19 years) in 1998. Older patients had a higher prevalence rate than younger ones. There were 345 patients on dialysis as of 1 January 1998, and 237 patients with transplants. The major diseases causing ESRD were renal hypoplasia/dysplasia and focal segmental glomerulosclerosis. Of the 237 patients (46.9%) who had received renal transplants before 1 January 1998, 262 patients (96%) received their transplants from living kidney donors. The incidence rate for the new ESRD patients was 4 per million population (aged 0-19 years) in 1998. Older patients had a slightly higher incidence rate than younger ones. Peritoneal dialysis was used more frequently than hemodialysis under 15 years (85%-95% and 39% respectively), especially in very young patients. The major diseases causing ESRD were the same as in the patients already on treatment. The transplant rate for the year 1998 was 10 per 100 dialysis patient-years (patients aged 0-19 years) with 9 living kidney donors. The death rate was 15.6 per 1,000 dialysis patient-years (patients aged 0-19 years); the major causes of death being cardiovascular diseases and infections.

Progenitors that can transdifferentiate into cells with hepatic or pancreatic phenotypes can be isolated from experimentally injured salivary glands of rodents. In this study, we isolated progenitors from "uninjured" adult human salivary glands by fluorescence-activated cell sorting using anti-CD49f and anti-Thy-1 antibodies. The sorted cells that were contained in the CD49f+/Thy-1+ fraction showed good proliferation on type I collagen. Single purified progenitor cells in plate culture expressed intracellular laminin, CD49f, Thy-1, and NGF receptor p75 (p75(NGFR)). Immunohistological analysis revealed the expression of Thy-1 and p75(NGFR) in stromal cells in the periductal area of the salivary gland. Under overconfluent conditions in plate culture, cell clusters containing insulin and glucagon-positive cells were occasionally formed. In order to produce differentiated cell clusters with uniform quality, we used a spherical culture system. Autonomous differentiation of cells in clusters into insulin-positive cells was induced in the spherical culture system. We measured C-peptide to estimate the endogenously produced insulin content. The C-peptide content of the spheroid bodies was low (3.5 ng/mg of protein), and they simultaneously expressed the early islet differentiation factor Nkx6.1, proendocrine gene neurogenin3, and ductal cell marker cytokeratin19. The progenitors existing in the interstitium of the salivary gland were able to transdifferentiate into cells with a pancreatic endocrine phenotype.

A previous trial showed that treatment of children with severe IgA nephropathy (IgAN) using prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduced the severity of immunologic renal injury and prevented any increase in the percentage of sclerosed glomeruli. This study compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (combination) with those of prednisolone alone in 80 children with newly diagnosed IgAN that showed diffuse mesangial proliferation. Patients were randomly assigned to receive either the combination or prednisolone alone for 2 yr. The primary end point was the disappearance of proteinuria, defined as urinary protein excretion <0.1 g/m 2 per d, and the secondary end points were urinary protein excretion at the end of treatment, the change in the percentage of sclerosed glomeruli during the trial, and adverse effects. The two study groups were similar in terms of baseline characteristics. Thirty-nine of the 40 patients who received the combination and 39 of the 40 who received prednisolone completed the trial. Thirty-six (92.3%) of the 39 patients who received the combination and 29 (74.4%) of the 39 who received prednisolone reached the primary end point by the 2-yr follow-up point (P ‫؍‬ 0.007 log-rank). The percentage of sclerosed glomeruli was unchanged in the patients who received the combination but increased from 3.1 ؎ 4.8 to 14.6 ؎ 15.2% in the prednisolone group (P ‫؍‬ 0.0003). The frequency of adverse effects was similar in the two groups. It is concluded that combination treatment may be better for severe IgAN than treatment with prednisolone alone.

We conducted a prospective, multicenter trial to evaluate the efficacy and safety of a 12-month course of cyclosporine in children with steroid-resistant nephrotic syndrome (SRNS). Thirty-five patients were enrolled, of whom 28 had minimal change or diffuse mesangial proliferation (MC/DMP), and seven had focal segmental glomerulosclerosis (FSGS). All patients received cyclosporine and prednisolone; patients with FSGS additionally received methylprednisolone pulse therapy (MPT). The dose of cyclosporine was adjusted to maintain a trough level of 120-150 ng/ml during the initial 3 months of treatment, followed by 80-100 ng/ml during months 4-12. The primary end point was the remission rate at month 12. Remission was achieved in 23 of 28 (82.1%) patients in the MC/DMP group and in six of the seven (85.7%) patients in the FSGS group. Follow-up renal biopsies were performed in 26 patients (nine at month 12, 17 at month 24), and cyclosporine-related nephrotoxicity was detected in one (3.8%). Major adverse events comprised severe bacterial infections (two patients) and posterior reversible encephalopathy syndrome (one patient). In conclusion, a high remission rate was achieved in our patient cohort using a combined cyclosporine/ prednisolone treatment regimen in children with SRNS who had MC/DMP and a combined cyclosporine/prednisolone plus MPT regimen in children who had FSGS.

We conducted a prospective, open-label multicenter trial to evaluate the efficacy and safety of treating children with frequently relapsing nephrotic syndrome with cyclosporine. Patients were randomly divided into two groups with both initially receiving cyclosporine for 6 months to maintain a whole-blood trough level between 80 and 100 ng/ml. Over the next 18 months, the dose was adjusted to maintain a slightly lower (60-80 ng/ml) trough level in Group A, while Group B received a fixed dose of 2.5 mg/kg/day. The primary end point was the rate of sustained remission with analysis based on the intention-to-treat principle. After 2 years, the rate of sustained remission was significantly higher while the hazard ratio for relapse was significantly lower in Group A as compared with Group B. Mild arteriolar hyalinosis of the kidney was more frequently seen in Group A than in Group B, but no patient was diagnosed with striped interstitial fibrosis or tubular atrophy. We conclude that cyclosporine given to maintain targeted trough levels is an effective and relatively safe treatment for children with frequently relapsing nephrotic syndrome.

Although indirect, our data suggest the existence of a vascular isoform of podocin with a different molecular mass. We propose that examination of podocin expression may help differentiate MCD from FSGS.

Hereditary tyrosinemia 1 (HT1) is characterized by progressive liver damage, from infancy, and by a high risk for hepatocellular carcinoma. HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. Lethal albino deletion c 14CoS mice and mice with target-disrupted Fah are models for HT1, but they die in the perinatal period, albeit with a different phenotype from that seen in HT1 in humans. We first asked whether homozygous null mutation of the 4-hydroxyphenylpyruvate dioxygenase gene Hpd could rescue the homozygous c 14CoS mice (c 14CoS /c 14CoS or Fah ؊/؊ ). The double mutant Fah ؊/؊ Hpd ؊/؊ mice appeared normal, at least until age 18 months, and there was no evidence of liver disease, findings that facilitated examination of the effect of Fah ؊/؊ on mature and unmodified hepatocytes in vivo. The hepatocytes of Fah ؊/؊ undergo rapid apoptosis, and acute death follows. Essentially the same phenomena were observed when Fah ؊/؊ Hpd ؊/؊ mice were administered homogentisate intraperitoneally. These changes in liver pathology in Fah ؊/؊ Hpd ؊/؊ mice after the administration of homogentisate were associated with massive urinary excretion of succinylacetone. These results suggest that accumulation of fumarylacetoacetate, maleylacetoacetate, or succinylacetone seems to trigger the endogenous process of apoptosis in hepatocytes that lack fumarylacetoacetate hydrolase activity. This apoptosis may be related to the development of hepatocellular carcinomas seen in HT1 patients and pharmaceutically treated fumarylacetoacetate hydrolase-deficient mice.

No abstract