Hideaki Okabe

SERUM URIC ACID AND RENAL PROGNOSIS IN PATIENTS WITH IGA NEPHROPATHY

Background/Aims: This study was designed to elucidate the clinical significance of serum uric acid (SUA) and the relationship between hyperuricemia and renal prognosis in IgA nepropathy. Methods: The correlation between SUA and other clinical parameters were examined in 748 IgA nephropathy patients (432 males and 316 females). Among these patients, 226 (144 males and 82 females) who were followed for more than 5 years were examined for the relationship between hyperuricemia and renal prognosis. Results: In IgA nephropathy, SUA correlated negatively with creatinine clearance (Ccr), and positively with urinary protein and tubulointerstitial damage. SUA was higher in patients with hypertension or diffuse proliferative glomerulonephritis. Hyperuricemia was a risk factor for renal prognosis, both in terms of serum creatinine (p = 0.0025) and Ccr (p = 0.0057). In 56 patients with normal Ccr at renal biopsy, the change of Ccr after more than 8 years was –22.3 ± 20.8% in 13 patients with hyperuricemia, compared with +2.6 ± 39.4% in 43 patients without hyperuricemia (p = 0.0238). Hyperuricemia was related independently to deterioration of Ccr (p = 0.0461). Conclusion: Hyperuricemia in IgA nephropathy is derived from both glomerular and tubulointerstitial damage, and correlated with hypertension. Hyperuricemia is a risk factor for renal prognosis in IgA nephropathy.

Newly Discovered Familial Juvenile Gouty Nephropathy in a Japanese Family

Our attention was initially called to 2 young Japanese sisters with gout and renal insufficiency, which led to an investigation of members of their family with similar conditions. One sister, a 26-year-old woman who had suffered from polyuria since infancy, suffered from gout and renal insufficiency. Her younger sister also had a history of polyuria, hyperuricemia, and moderately reduced renal function. Their urinary uric acid levels were reduced but purine enzyme activities in the erythrocytes were normal. A renal biopsy specimen from the younger sister showed severe interstitial fibrosis with tubular atrophy. An investigation of the family revealed an autosomal dominant transmission pattern. We believe these are new familial cases of juvenile gouty nephropathy found in a Japanese family.

Familial Juvenile Gouty Nephropathy: Exclusion of 16p12 from the Candidate Locus

Background/Aims: Familial juvenile gouty nephropathy (FJGN, MIM 162000) is an autosomal-dominant renal disease characterized by underexcretion-type hyperuricemia, gouty arthritis, and progressive renal disease at younger ages. We analyzed the localization of the responsible gene for FJGN concerning the chromosomal region of 16p12 using parametric linkage analysis in our FJGN. Methods: The affected members of this family were accompanied with polyuria due to nephrogenic diabetes insipidus and without hypertension. Fifteen samples were collected from 9 affected and 6 nonaffected members of the family. By using microsatellite markers mainly focused on the short arm of chromosome 16, two point and multipoint linkage analyses were carried out. Results: All of the 2-point logarithm of odds (LOD) scores were typically negative and all of the multipoint LOD scores were less than –3.0 in our FJGN family. Conclusion: The results suggested that the localization of the responsible gene to 16p12 can be excluded in our FJGN family. This finding means that the responsible gene for FJGN is not common.

Analysis of urolithiasis in patients with gout and hyperuricemia using ultrasonography

The number of patients with gout and hyperuricemia is increasing in Japan. Urolithiasis is one of the important complications in this disease and early diagnosis of urolithiasis is necessary in disease management. Therefore, we expected to find an exact incidence of urolithiasis in Japanese gouty and hyperuricemic patients in our study. We examined 208 patients using ultrasonography (US) of the abdomen at our hospital (171 primary gout and 37 asymptomatic hyperuricemia). We examined the incidence of urolithiasis in US of the abdomen, past history and urine occult blood reaction in gouty and hyperuricemic patients. We also examined the duration of the current illness. The total number of ‘positive findings’ in US of the abdomen was 64 among 208 cases (30.8%). For these 64 with ‘positive findings’, 51.6% had ‘calcification’ or ‘stone formation’ in bilateral kidneys and 48.4% showed ‘positive findings’ before the onset of gouty arthritis. Among the 208 cases, 16.3% had a history of urolithiasis. Of the 59 cases with ‘stone formation’ among the 64 with ‘positive findings’ in US of the abdomen, 10.2% showed a positive urine occult blood reaction. The frequency of detecting a ‘positive findings’ was evidently proportional to the detection of this illness. In conclusion, the incidence of urolithiasis in gouty and hyperuricemic patients was examined by US of the abdomen. The value of this diagnostic modality was highly appreciated in this instance. The following were suggested as important approaches for the management of gouty or hyperuricemic patients: correction of the serum uric acid levels, early diagnoses of urolithiasis by US of the abdomen, proper alkalization of urine and sufficient diuresis.

Mutations in Xanthine Dehydrogenase Gene in Subjects with Hereditary Xanthinuria

Xanthine dehydrogenase is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and uric acid from xanthine during the final stage of purine metabolism. Xanthine dehydrogenase exists as a dimer and each subunit has a molecular weight of 145000. Human xanthine dehydrogenase cDNA consists of 4002 nucleotides (1) and the gene is mapped to chromosome 2p23 (2). Mapping of the functions on xanthine dehydrogenase was performed for 3 peptide domains generated by the protein cleavage (1). The N-terminal 20 kD domain includes a 2Fe/2S non-heme iron binding site while the adjacent 40 kD and the C-terminal 85 kD domains include flavin binding and molybdenum cofactor binding domains, respectively (1). Most of xanthine dehydrogenase usually exist as the dehydrogenase form and the enzyme is converted to the oxidase form, xanthine oxidase, by the proteolytic cleavage and the oxidation of cystein residues under certain conditions (3). Xanthine dehydrogenase has recently been attracting attention for its possible involvement in triggering tissue damage by producing free radicals. It is exhibited in many studies that xanthine oxidase injured the tissues on the conditions, such as post-ischemic reperfusion tissue injury, adult respiratory distress syndrome and lung injury resulting from influenza virus infection (4–8).

An epidemiologic study on pathogenesis of uric acid urolithiasis

Recently, the number of patients with gout and hyperuricemia has increased in Japan; therefore, we expected to find an increase in the number of uric acid stones in our study. We examined the frequency of uric acid stones and its relationship with the number of patients with gout and hyperuricemia or their nutritional state. We reviewed the records of 5477 patients with urolithiasis who visited our hospital between 1975 and 1993. During this period, the incidence of calcium-containing stones remained at 86%. The percentage incidence of uric acid and urate stones during the same period showed a steady increase to 7.2%. This increase was computed to be 3-fold that of 1975. The male gender dominates among the patients with uric acid and urate stones. We believe that the increases in the incidence of gout and hyperuricemia and alcohol consumption are responsible for this trend.