Shinzaburo Hattori

The 1998 report of the Japanese National Registry data on pediatric end-stage renal disease patients

Abstract 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% respec-tively), 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.

Effective and safe treatment with cyclosporine in nephrotic children: A prospective, randomized multicenter trial

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.

Complete rescue of lethal albino c(14CoS) mice by null mutation of 4- hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway

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 deletionc 14CoS mice and mice with target-disruptedFah 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 orFah −/−). The double mutantFah −/− 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 ofFah −/− undergo rapid apoptosis, and acute death follows. Essentially the same phenomena were observed whenFah −/− 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.

Quantitative and Qualitative Changes of Apolipoprotein AI-Containing Lipoproteins in Patients on Continuous Ambulatory Peritoneal Dialysis

Using immunoaffinity chromatography, two species of apo-AI containing lipoproteins (AILp); lipoprotein containing apo-AI and apo-AII (Lp-AI/AII), and lipoprotein containing apo-AI, but no apo-AII (Lp-AI) were isolated from 13 female patients on continuous ambulatory peritoneal dialysis (CAPD), then characterized. The results were compared with findings obtained in agematched normolipidemic (control I) and mild hypertriglyceridemic (control II) female subjects. In comparison with control I: In AILp, the levels of total cholesterol (TC), cholesteryl ester (CE) and phospholipid (PL), and the levels of apoE were significantly lower in the CAPD patients while the levels of triglyceride (TG) and apo-CIII were significantly higher in these patients. The levels of apo-AI and apo-AII did not differ between the CAPD and control subjects. In Lp-AI/AII, changes of TC, CE, PL, TG, and apolipoproteins were similar to those of AILp, except for the ratio of apo-AI/apo-AII and the level of apo-CII, which was higher in the CAPD patients. In Lp-AI, changes of TC, CE, PL, and TG were also similar to those of AILp and Lp-AI/AII, but the apo-AI level was significantly lower in the CAPD patients. In comparison with control II: In AILp, the levels of PL, apo-AI, apo-AII, and apo-E were significantly lower in CAPD patients, but the apo-CIII levels were significantly higher. In Lp-AI/AII, the levels of PL and apo-E were significantly lower in CAPD patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental changes in carbonic anhydrase II in the rat kidney

Abstract. We examined the distribution and maturational changes of carbonic anhydrase I (CAI) and carbonic anhydrase II (CAII) in microdissected nephron segments of Sprague-Dawley rats. CAI and CAII proteins were measured by enzyme-linked immunosorbent assay. CAI was not detected in any nephron segment in 7-week-old rats. CAII was present in the collecting ducts, proximal tubules, and thick ascending limbs of loop of Henle in 7-week-old rats. CAII contents were significantly higher in the early proximal tubules (S1) than in second (S2) and late (S3) portions of the proximal tubules, while the contents in S1 were less than in cortical collecting ducts (CCD), outer stripe and inner stripes of the outer medullary collecting ducts (OMCDo and OMCDi). CAII content in each of S1, CCD, and OMCD of 1-week-old rats was only 14% or less of that of adults, but increased steeply during the 2nd and 3rd weeks of life, reaching almost 40% at 3 weeks of age and 97% at 7 weeks. Our results indicate that CAII is present throughout the entire nephron of the rat, and that CAII content in S1, CCD, and OMCD increases exponentially during the first 7 weeks of life. Our data suggest that the immature low levels of CAII may explain, at least in part, the limited capacity of urinary acidification during neonatal life. Further studies are necessary to establish the role of such changes in CAII content in acid-base homeostasis during neonatal life.

Mitochondrial cytopathy with lactic acidosis, carnitine deficiency and DeToni-Fanconi-Debré syndrome

We reported a 6-year-old girl with mitochondrial cytopathy with lactic acidosis. The patient developed hypotonia, hearing loss, mental retardation, short stature, cataracta, hypoparathyroidism, DeToni-Fanconi-Debré syndrome and carnitine deficiency. Histological examination disclosed ragged red fibers and moderate lipid storage in skeletal muscle tissue and several structural abnormalities of mitochondria both in muscle tissue and proximal renal tubules. Biochemical examination of muscle tissue revealed a partial deficiency of pyruvate dehydrogenase complex and normal activities of cytochrome c oxidase, succinate cytochrome c reductase and NADH cytochrome c reductase. This is the first report of mitochondrial cytopathy representing DeToni-Fanconi-Debré syndrome associated with partial deficiency of pyruvate dehydrogenase complex and normal cytochrome c oxidase activity.

Glomerular IgA1 and IgA2 Deposits in IgA Nephropathies

IgA1 and IgA2 deposits in the renal glomeruli were studied in 29 biopsy specimens from 17 children with IgA nephropathy and 12 children with anaphylactoid purpura nephritis. IgA1 and IgA2 were detected with the indirect immunofluorescence method, using various combinations of dilutions of sheep antihuman IgA subclass antisera and fluorescein isothiocyanate conjugated rabbit antisheep IgG antiserum. The glomeruli of all the 29 specimens studied were strongly positive for IgA1, while only twelve specimens were positive for IgA2. Ten specimens without IgM deposits were all negative for J chain. These results indicate that the glomerular IgA deposits consist mainly of monomeric IgA1, with a minor share for IgA2. The serum IgA in normal individuals consists of about 90% IgA1 and 10% IgA2. Therefore, it was assumed that the serum IgA is deposited irrespective of subclass in the glomeruli of the patients with IgA nephropathies.

Another autosomal recessive form of focal glomerulosclerosis with neurological findings

Abstract. We report four patients in a consanguineous family with focal segmental glomerulosclerosis (FSGS), early onset nephrotic syndrome, eventual end-stage renal failure, psychomotor retardation, seizures and microcephaly or brain atrophy without hiatus hernia. Other characteristic dysmorphic features were convergent strabismus and narrow forehead. One patient had enamel hypoplasia of the upper incisors and deviation of bilateral thumbs to palm side. We could not detect an NPHS2 mutation in this family. We propose that this may be another autosomal recessive syndrome with FSGS and neurological findings.

Childhood‐type myositis and linear scleroderma

A 5-year-old girl had linear scleroderma on the flexor surface of the right arm; muscle wasting included the shoulder girdle. IgM fluorescence on blood vessels and along dermal-epidermal junction was observed by direct immunofluorescence in biopsied skin. Biceps muscle underlying the plaque of the scleroderma showed atrophy of entire fascicles, perifascicular atrophy, and cellular infiltration around blood vessels that are quite similar to those found in childhood-type dermatomyositis. In addition, various abnormalities, including edema and thickening of basal lamina, were found on blood vessels in muscle tissue. The results suggested that the autoimmune collagen vascular disorder is responsible for this condition.

Tubulointerstitial Nephritis Antigen: Primary Structure, Expression and Role in Health and Disease

Tubulointerstitial nephritis (TIN) antigen was originally identified as a nephritogenic antigen involved in anti-tubular basement membrane (TBM) antibody-mediated interstitial nephritis in humans [1, 2]. Immunofluorescent staining using sera from patients with antiTBM nephritis or mono/polyclonal antibodies specific to TIN antigen revealed its localization in the basement membranes of the proximal and, to a lesser extent, distal tubules and Bowman’s capsule in the kidney, and also the basal membrane of the intestinal mucosa [3–5]. Isolation studies using enzymatic digestion and denaturing agents led to identification of 54–58 and 40–50 kD glycoprotein isoforms as TIN antigens recognized by anti-TBM antibodies [1, 6, 7]. Subsequent studies revealed the affinity of this molecule to type-IV collagen and laminin [8, 9], its developmentally specific expression in fetal kidneys [10, 11], and defects in hereditary tubulointerstitital disorders such as juvenile nephronophthisis [12]. Recently, cDNAs encoding rabbit TIN antigen and its human homologue have been cloned and sequenced [13, 14]. The human TIN antigen has been mapped to chromosome 6p11.2–12 [14]. TIN antigen is now recognized as a component of the basement membrane matrix. Target Antigen Involved in Anti-TBM Nephritis