Associations between corrected serum calcium and phosphorus levels and outcome in dialysis patients in the Kumamoto Prefecture.

INTRODUCTION: Mortality in hemodialysis patients is relatively high; thus, its risk stratification is very important. There are insufficient data describing the current status of the management of serum phosphate and calcium levels. METHODS: We conducted a multicenter, prospective, registry study throughout the Kumamoto Prefecture in Japan. We enrolled 1993 patients at 58 facilities with complete explanatory data, including serum phosphate, corrected calcium, and intact parathyroid hormone levels. We categorized subjects into nine categories according to low, normal, and high levels of phosphate and corrected calcium levels. The endpoint was all-cause mortality. RESULTS: Of the total number of subjects, 56.1% of the patients were in the normal phosphate and calcium category, and 72% and 77.1% had controlled serum phosphate and calcium levels, respectively. Two hundred twenty-six deaths occurred during the follow-up period. In the nine categories, the highest mortality rates were observed in the highest corrected calcium and lowest phosphate categories. Stepwise backward multivariate regression analyses identified the serum corrected calcium level (OR, 1.38; 95% CI, 1.06-1.79; P = 0.016) and the serum phosphate level (OR, 1.26; 95% CI, 1.08-1.48; P = 0.003) as significant and independent predictors of all-cause mortality. CONCLUSIONS: The corrected serum calcium and phosphate levels are associated with mortality in our dialysis population, with poorest survival in patients with high corrected serum calcium and low serum phosphorus.

Anti-cataract Effect of Resveratrol in High-Glucose-Treated Streptozotocin-Induced Diabetic Rats.

Resveratrol, which is a polyphenol found in grapes, peanuts, and other plants, has health benefits for various chronic diseases. The aim of the present study was to examine the effect of resveratrol on cataract formation in diabetic rats. Male Wistar rats (7-week-old) were treated with streptozotocin, and the streptozotocin-treated animals were administered 5% D-glucose in drinking water to promote the formation of cataracts by inducing severe hyperglycemia. Resveratrol supplementation (10 or 30 mg/kg/d) in drinking water was initiated immediately after induction of diabetes was confirmed. The full lens images of the horizontal plane were captured with the digital camera system which we developed. Cataract formation was assessed by an observer-based scoring method and by quantitative analysis of digital images of the lens. Cataracts at the peripheral region of the lens were detected 2 weeks after induction of hyperglycemia and progressed depending on the length of the diabetic period. The majority of them developed severe cataracts after 9 weeks of hyperglycemia. Resveratrol did not prevent the appearance of diabetic cataracts but significantly delayed the progression of cataracts compared with controls. The contents of sorbitol and protein carbonyls in lenses of diabetic rats were higher than those of control rats. Resveratrol suppressed the increase in protein carbonyls, but not of sorbitol, in diabetic lenses. These results suggest that resveratrol delays the progression of diabetic cataracts partially through attenuation of oxidative damage to lens proteins. Resveratrol may be beneficial in preventing the progression of diabetic cataracts.

Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina.

Endoplasmic reticulum stress has been reported to be involved in the pathogenesis of retinitis pigmentosa, macular degeneration and diabetic retinopathy. In the present study, we examined the effects of deferiprone, an iron chelator, on photoreceptor degeneration induced by tunicamycin (300 nmol/eye), an endoplasmic reticulum stress inducer, in the rat retina. Scotopic electroretinogram measurement and morphometric evaluation were done 7 d after the injection of tunicamycin. In the scotopic electroretinogram, intravitreal deferiprone (5 nmol/eye) injected simultaneously with tunicamycin significantly reduced the decreases in a- and b-wave amplitudes induced by tunicamycin. Morphometric evaluation showed that deferiprone significantly reduced thinning of the outer nuclear layer, the inner segment and the outer segment. These results suggest that iron chelation therapy may be a good candidate for the treatment of eye diseases related to endoplasmic reticulum stress.

Effect of long-term treatment of L-ornithine on visual function and retinal histology in the rats.

L-Ornithine is a non-proteinogenic amino acid, abundant in freshwater clams and commercially available as an oral nutritional supplement. L-Ornithine is metabolized by ornithine-δ-aminotransferase. Deficiency of this enzyme causes gyrate atrophy of the choroid and retina, an autosomal recessive hereditary disease characterized by the triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy, with hyperornithinemia. However, it is unknown whether long-term L-ornithine supplementation affects visual function and retinal histology. The aim of the present study is to determine the effect of long-term supplementation of excess amounts of L-ornithine on visual function and retinal histology in rats. Male Brown Norway rats at six weeks of age were allowed free access to chow containing 4% (w/w) L-ornithine (the high ornithine diet) or that containing 4% (w/w) casein (the control diet) for 49 weeks. The dose of L-ornithine calculated from the food intake was approximately 0.8 g/d/animal, which was 100 times higher than the recommended dose for healthy humans. The amplitude of the a-wave of the scotopic rod-cone electroretinogram and the number of cells in the ganglion cell layer in the L-ornithine-treated group were larger than those in the control group 49 weeks after initiating the test diet. No functional or histological damage to the retina was seen up to 49 weeks after the start of the high-ornithine diet. The present study demonstrated that long-term supplementation of very high doses of L-ornithine for at least 49 weeks did not induce retinal damage.

Histological protection by cilnidipine, a dual L/N-type Ca(2+) channel blocker, against neurotoxicity induced by ischemia-reperfusion in rat retina.

Although a blockade or lack of N-type Ca(2+) channels has been reported to suppress neuronal injury induced by ischemia-reperfusion in several animal models, information is still limited regarding the neuroprotective effects of a dual L/N-type Ca(2+) channel blocker, cilnidipine. We histologically examined the effects of cilnidipine on neuronal injury induced by ischemia-reperfusion, intravitreous N-methyl-D-aspartate (NMDA) (200nmol/eye) and intravitreous NOC12 (400nmol/eye), an nitric oxide donor, in the rat retina, and compared its effects with those of omega-conotoxin MV IIA, an N-type Ca(2+) channel blocker and amlodipine, an L-type Ca(2+) channel blocker. Morphometric evaluation at 7 days after ischemia-reperfusion showed that treatment with cilnidipine (100microg/kg, i.v. or 0.5pmol/eye, intravitreous injection) prior to ischemia dramatically reduced the retinal damage. Treatment with omega-conotoxin MV IIA before ischemia (0.1pmol/eye, intravitreous injection) significantly reduced the retinal damage. However, amlodipine (30-100microg/kg, i.v. or 0.1-1pmol/eye, intravitreous injection) did not show any protective effects. Treatment with cilnidipine (100microg/kg, i.v.) reduced the retinal damage induced by intravitreous NMDA, but not NOC12. These results suggest that cilnidipine reduces Ca(2+) influx via N-type Ca(2+) channels after NMDA receptors activation and then protects neurons against ischemia-reperfusion injury in the rat retina in vivo. Cilnidipine may be useful as a therapeutic drug against retinal diseases which cause neuronal cell death, such as glaucoma and central retinal vessel occlusion.

MaxiK channel-triggered negative feedback system is preserved in the urinary bladder smooth muscle from streptozotocin-induced diabetic rats.

MaxiK channel, the large-conductance Ca2+-sensitive K+ channel, facilitates a negative feedback mechanism to oppose excitation and contraction in various types of smooth muscles including urinary bladder smooth muscle (UBSM). In this study, we investigated how the contribution of MaxiK channel to the regulation of basal UBSM mechanical activity is altered in streptozotocin-induced diabetic rats. Although the urinary bladder preparations from both control and diabetic rats were almost quiescent in their basal mechanical activities, they generated spontaneous rhythmic contractions in response to a MaxiK channel blocker, iberiotoxin (IbTx). The effect of IbTx on the mechanical activity was significantly greater in diabetic rat than in control animal. Similarly, the basal mechanical activity was increased with apamin, an inhibitor for some types of small conductance Ca2+-sensitive K+ channels, and this effect was more pronounced for diabetic rat. However, in both control and diabetic animals, IbTx action was stronger than that of apamin. Diabetes also enhanced the responses to BayK 8644, an L-type Ca2+ channel agonist. The extent of this enhancement in diabetic bladder vs. control was, however, almost the same as that attained with IbTx. Expression levels for MaxiK channel as well as apamin-sensitive K+ channels and L-type Ca2+ channel were not altered by diabetes, when determined as their corresponding mRNA levels. These results indicate that diabetes can potentially increase the basal UBSM mechanical activity. However, in diabetic UBSM, the main negative-feedback system triggered by MaxiK channel is still preserved enough to counteract the possible enhancement of this smooth muscle mechanical activity.