Biomedical subjects

T Miki

Publications and source records attributed to T Miki.

At least 199 records · Page 11Linked to original sources

PubMed1999

Angiopoietin-3, a novel member of the angiopoietin family.

A cDNA clone encoding angiopoietin-3 protein (Ang3), a novel member of the angiopoietin family, was identified. Ang3 cDNA was cloned from a human aorta cDNA library. Ang3 is a 503 amino acid protein having 45.1% and 44.7% identity with human angiopoietin-1 and human angiopoietin-2, respectively. Ang3 mRNA is expressed in lung and cultured human umbilical vein endothelial cells (HUVECs). Ang3 mRNA expression in HUVECs was slightly decreased by vascular endothelial cell growth factor treatment, suggesting that the regulation of Ang3 mRNA expression is different from that of Ang2.

Amino Acid Sequence↗

PubMed1999

Heparan sulfate proteoglycan modulates keratinocyte growth factor signaling through interaction with both ligand and receptor.

Keratinocyte growth factor (KGF) is an unusual fibroblast growth factor (FGF) family member in that its activity is largely restricted to epithelial cells, and added heparin/heparan sulfate inhibits its activity in most cell types. The effects of heparan sulfate proteoglycan (HSPG) on binding and signaling by acidic FGF (aFGF) and KGF via the KGFR were studied using surface-bound and soluble receptor isoforms expressed in wild type and mutant Chinese hamster ovary (CHO) cells lacking HSPG. Low concentrations of added heparin (1 microgram/mL) enhanced the affinity of ligand binding to surface-bound KGFR in CHO mutants, as well as ligand-stimulated MAP kinase activation and c-fos induction, but had little effect on binding or signaling in wild type CHO cells. Higher heparin concentrations inhibited KGF, but not aFGF, binding and signaling. In addition to the known interaction between HSPG and KGF, we found that the KGFR also bound heparin. The biphasic effect of heparin on KGF, but not aFGF, binding and signaling suggests that occupancy of the HSPG binding site on the KGFR may specifically inhibit KGF signaling. In contrast to events on the cell surface, added heparin was not required for high-affinity soluble KGF-KGFR interaction. These results suggest that high-affinity ligand binding is an intrinsic property of the receptor, and that the difference between the HSPG-dependent ligand binding to receptor on cell surfaces and the HSPG-independent binding to soluble receptor may be due to other molecule(s) present on cell surfaces.

Animals↗

PubMed1999

Abnormal distribution of hippocampal mossy fibers in rats exposed to X-irradiation in utero.

The effects of prenatal X-irradiation (0.3, 0.6, 1.2 or 1.8 Gy) on the hippocampal development were examined at six weeks of age in rats. The laminar structure of the hippocampus was deranged in the rats exposed to 0.6 Gy or more. Pyramidal cells in the CA-3 region were more susceptible than those in the CA-1 region. Aberrant mossy fiber terminals were observed in the stratum oriens of the CA-3 region (infrapyramidal mossy fibers) in rats exposed to 0.3 Gy or more.

Animals↗

PubMed1999

Relation of left ventricular hypertrophy and geometry to asymptomatic cerebrovascular damage in essential hypertension.

Increased left ventricular (LV) mass and abnormal geometry have a powerful prognostic value for cardiovascular morbidity and mortality including stroke. However, there have been no studies on the association between LV hypertrophy and preclinical brain damage in essential hypertensive patients. In the present study, we investigated the relation between LV hypertrophy and asymptomatic cerebrovascular damage identified by magnetic resonance imaging in 150 essential hypertensive patients, with an emphasis on LV geometry. Patients were divided into the following 4 groups according to their LV mass index and relative wall thickness; normal ventricular geometry (n = 50), concentric remodeling (n = 22), eccentric hypertrophy (n = 44), and concentric LV hypertrophy (n = 34). Lacunar lesions and leukoaraiosis were evaluated. The prevalence of lacunae was significantly higher in patients with LV remodeling than in patients with normal LV (chi-square 19.6, p = 0.0002). The number of lacunae was significantly higher in patients with LV hypertrophy than in patients with normal LV or concentric remodeling (F [3,146] = 8.03, p<0.0001). The severity of leukoaraiosis was also significantly greater in patients with LV hypertrophy than in patients with a normal left ventricle (chi-square 14.5, p = 0.02). Stepwise regression analysis confirmed that LV mass index and relative wall thickness, in addition to age and systolic blood pressure, were independent predictors for asymptomatic cerebrovascular damage, even in the absence of neurologic abnormalities. In hypertensive patients, LV hypertrophy, and especially concentric LV hypertrophy, provides important prognostic information on the presence of pre-clinical brain damage.

Blood Pressure↗

PubMed1999

The proto-oncogene Bc16 inhibits apoptotic cell death in differentiation-induced mouse myogenic cells.

The Bc16 gene is located at chromosomal band 3q27, a breakpoint for translocation that frequently occurs in B cell lymphomas. Bc16 has been found to be preferentially expressed in germinal center B cells, and expression of this gene has been shown to be essential for germinal center formation in vivo. The physiological function of Bc16 and its role in lymphomagenesis, however, are not yet known. Since significant expression of Bc16 has been demonstrated in skeletal muscle, we have utilized a differentiation-inducible mouse myogenic cell line, C2C12, to elucidate the function of the Bc16 gene product. Expression of Bc16 mRNA was very low in growing myocytes, but was increased in differentiating myocytes cultured in serum-starved medium. Incubation of these cells with cytokines or chemicals that are known to block differentiation suppressed this increased Bc16 message abundance, indicating that Bc16 induction is related to the process of terminal differentiation in muscle cells. While a fraction of myocytes is known to undergo apoptosis after serum-starvation to induce differentiation, adenovirus-mediated overexpression of Bc16 enhanced the viability of the differentiating cells by preventing the apoptosis. High levels of Bc16 antisense mRNA expression induced substantial apoptosis during the differentiation of C2C12 cells, but this was effectively prevented by infection with adenovirus that expressed Bc16 sense mRNA. These results indicate that Bc16 acts to prevent apoptotic cell death in differentiating myocytes. The deregulation of expression of this antiapoptotic gene may also contribute to the development of B cell lymphomas.

Animals↗

PubMed1999

Selective occlusion of choroidal neovascularization by photodynamic therapy with a water-soluble photosensitizer, ATX-S10.

BACKGROUND AND OBJECTIVE: To determine the optimal treatment parameters for selective occlusion of choroidal neovascularization (CNV) by photodynamic therapy (PDT) by using the photosensitizer ATX-S10 and a diode laser (wavelength = 670 nm). MATERIALS AND METHODS: Experimental CNV was induced in rat fundi by argon laser photocoagulation. The distribution of ATX-S10 in the chorioretina was analyzed by fluorescence microscopy, and the optimal treatment parameters for selective occlusion of CNV were investigated by changing the dosage and timing of laser irradiation. CNV closure and resulting damage of the surrounding tissue were documented by fluorescein angiography and light and electron microscopies. RESULTS: Fluorescence of ATX-S10 was observed to be localized in the vascular lumen of the retina and choroid within 5 min after dye injection and increased in intensity in CNV up to 2-6 h and decreased rapidly in normal tissue. Laser irradiation with radiant exposures of 7.4 J/cm2 applied immediately after dye injection or with 22.0 J/cm2 at 2-4 h later effectively occluded the induced CNV without causing significant damage to normal retinal capillaries and large choroidal vessels. CONCLUSIONS: PDT using ATX-S10 can selectively occlude CNV. ATX-S10 is a potentially useful photosensitizer for the treatment of CNV.

Animals↗

PubMed1999

Second window of protection against infarction in conscious rabbits: real or artifactual.

To date, most studies of the second window of protection against infarction (SWOP) have evaluated infarct size by staining with triphenyltetrazolium chloride (TTC) soon after reperfusion. However, early TTC staining has been found to be an unreliable indicator of the ultimate infarct size following some interventions. Therefore, we tested whether SWOP could induce a sustained limitation of infarct size. Instrumented, conscious rabbits underwent 30 min of coronary occlusion. Infarct size was determined by either TTC staining after 3 h of reperfusion or conventional histology after 72 h of reperfusion. In the TTC study, 43.5+/-3.1% of the risk zone infarcted in the control group. Four cycles of 5 min ischemia/10 min reperfusion 24 h prior to 30 min ischemia significantly reduced infarct size measured by TTC to 32.5+/-2.3% (P<0.05 v control). In the histological study 57.8+/-3.6% of the risk zone infarcted in the control group. However, ischemic preconditioning 24 h prior to the 30 min ischemia did not protect the heart (59.3+/-4.4% infarction). Thus the infarct-limiting effect of SWOP evaluated with early TTC staining could not be demonstrated when infarction was assessed by histology after 3 days of reperfusion. These data suggest that SWOP may not have a sustained anti-infarct effect, but rather may simply delay the progression to infarction.

Animals↗

PubMed1999

Rathke's cleft cyst with pituitary apoplexy: case report.

We report a Rathke's cleft cyst which presented as pituitary apoplexy, a rare presentation. A 46-year-old woman suffered sudden headache and visual loss. T1-weighted MRI 3 weeks after this apoplectic episode demonstrated a cystic lesion between the anterior and posterior lobes of the pituitary, with some high-signal material layering in it. The mass showed spontaneous regression on an image 3 weeks later. Trans-sphenoidal surgery confirmed the diagnosis of a Rathke's cleft cyst with a haematoma within it.

Blindness↗

PubMed1999

Heterogeneity of multiorgan metastases of human lung cancer cells genetically engineered to produce cytokines and reversal using chimeric monoclonal antibodies in natural killer cell-depleted severe combined immunodeficient mice.

Lung cancer is a major cause of cancer deaths, most of which can be attributed to distant multiorgan metastases. To examine the cellular and molecular mechanisms of lung cancer metastasis to distant organs, we have established novel models of human lung cancer (small cell and non-small cell lung cancer) metastasis in natural killer cell-depleted severe combined immunodeficient (SCID) mice. We investigated whether local production of the cytokines responsible for regulation of macrophage function at tumor growth sites affects the pattern of lung cancer metastasis in distant organs. Several lung cancer cell lines were genetically engineered to produce human macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1), and their metastatic potentials were assessed. Interestingly, M-CSF gene transduction had an antimetastatic effect for the liver and lymph nodes, but not the kidneys. In contrast, MCP-1 gene-modified lung cancer cells and their parent cells had identical metastatic potentials. These findings indicate a possible role for cytokines and suggest that lung cancer has metastatic heterogeneity. Examining ways of controlling human lung cancer metastases, we investigated the antimetastatic effect of chimeric monoclonal antibodies (MAbs) against P-glycoprotein and ganglioside GM2 (MH162 and KM966, respectively). Both MAbs, when given on days 2 and 7, inhibited the development of distant metastases of lung cancer in a dose-dependent fashion. Combined use of anti-P-glycoprotein MAb with M-CSF or MCP-1 gene transduction caused complete inhibition of metastasis of H69/VP cells. The antimetastatic effect of these MAbs in vivo was mainly due to an antibody-dependent cell-mediated cytotoxicity reaction mediated by mouse macrophages. These findings suggest that the mouse-human chimeric MAb in combination with cytokine gene transduction may be useful for the eradication of lung cancer metastases in humans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Failure of N-2-mercaptopropionyl glycine to reduce myocardial infarction after 3 days of reperfusion in rabbits.

Recent studies have reported that prolonged infusion of N-2-mercaptopropionyl glycine (MPG), a diffusible antioxidant, could limit infarct size in dogs. However, there are no comparable studies testing this agent in other species. We examined the efficacy of MPG in a rabbit model of infarction. Rabbit hearts were subjected to a 30-min coronary artery occlusion. Infarct size expressed as a percentage of risk zone was determined by either triphenyltetrazolium chloride (TTC) staining after 3h of reperfusion (study 1) or by histology after 72 h of reperfusion (study 2). In study 1, 37 +/- 2.6% of the risk zone infarcted in the control group. Intravenous MPG at a rate of 100 mg/kg/h starting 15 min after the onset of ischemia and continuing until 1 h after reperfusion had no effect on infarct size (35.4 +/- 3.4% infarction). However, infusion of MPG until the end of reperfusion significantly reduced infarct size as measured with TTC to 17.2 +/- 2.5% (p < 0.01 vs. control group). In study 2, 48.6 +/- 4.0% of the risk zone infarcted in the control group. In the treatment group MPG was started as above and was continued for 4 h of reperfusion followed by an intramuscular injection at the termination of the intravenous infusion. No protection was seen after 72 h of reperfusion (43.8 +/- 2.1% infarction). These findings reveal that MPG at a dose and schedule that appeared to protect the dog heart could not effect sustained protection in the rabbit heart. TTC staining revealed that MPG appeared to have preserved viability for up to 3 h of reperfusion suggesting that failure may have been due to early withdrawal of the drug. Alternatively, early TTC staining may yield spurious results under conditions in which protection is dependent upon antioxidant or free radical scavenger treatment as has previously been suggested. It is concluded that MPG as administered in the previous canine studies does not limit infarct size in all species, thus raising a concern about MPG's potential efficacy in man.

Animals↗

PubMed1999

The role of Bcl6 in mature cardiac myocytes.

OBJECTIVE: The Bcl6 gene encodes a sequence-specific transcriptional repressor and is ubiquitously expressed in adult murine tissues including heart muscle. The objective of this study was to examine the role of Bcl6 in cardiac myocytes. METHOD: We developed Bcl6-deficient (Bcl6-/-) mice and histologically examined hearts from these mice. RESULTS: Massive myocarditis with eosinophilic infiltration occurred in Bcl6-/- mice after 4-6 weeks of age. Since expression of the Bcl6 gene was induced in normal cardiac myocytes after 2 weeks of age and thereafter detected through adulthood, loss of Bcl6 in mature cardiac myocytes may be related to the induction of eosinophilic myocarditis. To examine the effects of eosinophils from Bcl6-/- mice on normal hearts, bone marrow cells from Bcl6-/- mice were adoptively transferred into sublethally irradiated RAG1-deficient mice. Although massive eosinophilic infiltration was detected in conjunctivas and spleens from the chimeric mice, myocarditis was never observed. Electron microscopic analysis of cardiac myocytes from Bcl6-/- mice revealed a spectrum of degenerative changes prior to eosinophilic infiltration. CONCLUSION: Bcl6 maynot be essential for the maturation of cardiac myocytes but may play a role in protecting mature cardiac myocytes from eosinophilic inflammation.

Adoptive Transfer↗

PubMed1999

Adriamycin-mediated potentiation of cytotoxicity against freshly isolated bladder cancer cells by autologous non-activated peripheral blood lymphocytes and tumor infiltrating lymphocytes.

PURPOSE: Previous studies indicated that cancer patients lack functional anti-tumor cytotoxic lymphocytes. However, anti-tumor cytotoxic lymphocytes may coexist with immunoresistant tumor cells. We reasoned that anti-tumor cytotoxic activity of lymphocytes may be revealed if the tumor cells are sensitized to killing. It has been reported that adriamycin (ADR) exhibits various immunomodulating activities. In the present study, we investigate the effect of ADR on the susceptibility of freshly isolated bladder cancer cells to lysis by autologous non-activated peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL). MATERIALS AND METHODS: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. RESULTS: Treatment of ADR-resistant fresh bladder cancer cells with ADR at 0.1 microg./ml. or more for 3 hours or more enhanced their susceptibility to lysis by autologous PBL. This ADR-induced enhancement of susceptibility of fresh bladder cancer cells to lysis by PBL was also observed when lymphokine activated killer cells, purified natural killer cells and T lymphocytes were used as effector cells. Furthermore, while cytotoxicity of freshly derived TIL against autologous bladder cancer cells was minimal, significant cytotoxicity was observed with ADR-treated bladder cancer cells. The ADR analogs, epirubicin and pirarubicin, also enhanced the susceptibility of bladder cancer cells to lysis by autologous PBL. Treatment of bladder cancer cells with ADR had no effect on the expression of MHC class I on the cancer cells or the frequency of bladder cancer target cell conjugates to autologous PBL. Treatment of bladder cancer cells with ADR augmented their sensitivity to anti-Fas monoclonal antibody and tumor necrosis factor-a. Pretreatment of effector cells with ADR had no effect on their cytotoxic function. CONCLUSIONS: These findings demonstrate that PBL and TIL in patients with bladder cancer exhibit anti-tumor cytotoxic function, but their function is not manifested due to development or acquisition of tumor cell resistance to killing. However, the resistance of bladder cancer cells to killing by cytotoxic lymphocytes is overcome if cancer cells are sensitized by subtoxic concentrations of ADR. These findings suggest that treatment of bladder cancer patients with low doses of ADR may sensitize the cancer cells to killing by autologous circulating and tumor infiltrating lymphocytes and may be a novel immunotherapeutic modality for the treatment of drug-resistant and/or immune-resistant bladder cancer.

Aged↗

PubMed1999

Age-related scattered hypofluorescent spots on late-phase indocyanine green angiograms.

PURPOSE: Scattered hypofluorescent spots may be seen on indocyanine green (ICG) angiograms of regions that do not show abnormalities when viewed with an ophthalmoscope. Hypofluorescent spots are found in several pathologic conditions, typically in inflammatory diseases. In this report, we describe hypofluorescent spots in normal fundi and show that such spots can be age-related. METHODS: Video-fundus camera ICG angiograms of 115 eyes of 109 patients aged 12 to 85 years with normal fundi or with only age-related maculopathy were reviewed. The relation between age and scattered hypofluorescent spots, and between age-related maculopathy and spots was examined utilising regression analysis. RESULTS: Scattered hypofluorescent spots were seen throughout the posterior pole in 24 eyes of 23 patients and in a portion of the posterior pole in 30 eyes of 29 patients. The hypofluorescent spots were noted between 26 and 37 minutes after dye injection. Patient age ranged from 51 to 80 years, and regression analysis showed that the frequency of hypofluorescent spots increased significantly with aging (p < 0.05). However, age-related maculopathy did not show a significant relation to the spots. CONCLUSION: Scattered hypofluorescent spots seen in the posterior pole during the late-phase of ICG angiograms can apparently be due to aging of the fundus.

Adolescent↗

PubMed1999

Role of UW solution and sodium nitroprusside in reperfusion of liver xenografts from guinea-pig to rat.

Guinea-pig livers are poorly reperfused when transplanted into rats. We have observed that, in contrast to that of the rat, the guinea-pig intrahepatic portal vein (PV) has a thick layer of smooth muscle. It is possible that, after perfusion of the liver with ice-cold saline, this could go into spasm, resulting in poor reperfusion. To test this hypothesis, guinea-pig livers were perfused with different solutions stored at varying temperatures and transplanted into LEW rats. To prevent xenograft hyperacute rejection, all xenograft recipients were treated with 80 U/kg cobra venom factor (CVF) i.v. on days -1 and 0. In addition to the percentage reperfusion, PV resistance and recipient survival were also monitored. In group I, liver xenografts perfused with ice-cold saline (4 degrees C) reperfused poorly (20-30%), resulting in the development of portal hypertension (16.5 cmH2O vs. 12 cmH2O in naive LEW rats) and shortened mean survival time (11.7 +/- 4.2 h). In contrast, group II livers perfused with saline at room temperature (23 degrees C) underwent homogeneous reperfusion (98-100%) with no increase in portal vein resistance, indicating that low temperature was the main trigger for the spasm of the PV. Moreover, recipient survival in this group was significantly prolonged to a mean of 22 + 2.6 h (P < 0.01). Although UW solution (group III) and the vasodilator sodium nitroprusside (NP) (group IV) when used alone improved the degree of hepatic reperfusion, it was still not optimal. The supplementation, however, of UW solution with NP in group V animals resulted in homogeneous reperfusion (98%) with no portal hypertension and consistent prolonged graft survival of 21.0 +/- 1.7 h. Therefore, this study has determined that the riddle of the abnormal reperfusion of guinea-pig liver xenografts by rat blood is nonimmune mediated and is due to the spasm of the strong smooth muscle in the PV tree produced by cold perfusates.

Adenosine↗

PubMed1999

Effect of recombinant human granulocyte colony stimulating factor (lenograstim) on chemotherapy induced neutropenia in patients with urothelial cancer.

BACKGROUND: A multicenter cooperative study to evaluate clinical usefulness of recombinant human granulocyte colony stimulating factor (rG-CSF; lenograstim) in the treatment of neutropenia associated with cancer chemotherapy was conducted in patients with urothelial cancer. METHODS: Therapeutic responses were compared within each patient between the observation and study treatment phases. RESULTS: Treatment with rG-CSF raised the nadir of the neutrophil count (343 to 3015/mm3), reduced the duration of neutropenia (6.2 to 0.4 days) and hastened recovery from the neutropenic state (23.5 to 5.5 days). Febrile neutropenia was encountered in 12 patients during the observation phase alone and in only one patient during the study treatment phase alone. The mean duration of febrile neutropenia was also shortened (0.39 to 0.12 days). In addition, the duration of antibiotic therapy was significantly reduced during treatment. The percentage of patients completing the chemotherapeutic regimens of combination M-VAC therapy was markedly increased to 81.0% as a result of rG-CSF therapy compared with 44.8% in the observation phase. Adverse reactions were observed in four patients and abnormal laboratory values were found in nine patients. None of these adverse events was of a serious nature. CONCLUSIONS: These results indicate that rG-CSF is a useful drug for the treatment of neutropenia associated with chemotherapy in urothelial cancer.

Adjuvants, Immunologic↗

PubMed1999

The effect of the timing of ethanol exposure during early postnatal life on total number of Purkinje cells in rat cerebellum.

We have previously shown that exposing rats to a high dose of ethanol on postnatal d 5 can affect Purkinje cell numbers in the cerebellum whilst similar exposure on d 10 had no such effect. The question arose whether a longer period of ethanol exposure after d 10 could produce loss of Purkinje cells. We have examined this question by exposing young rats to a relatively high dose (approximately 420-430 mg/dl) of ethanol for 6 d periods between the ages of either 4 and 9 d or 10 and 15 d of age. Exposure was carried out by placing the rats in an ethanol vapour chamber for 3 h per day during the exposure period. Groups of ethanol-treated (ET), separation controls (SC) and mother-reared controls (MRC) were anaesthetised and killed when aged 30 d by perfusion with buffered 2.5% glutaraldehyde. Stereological methods were used to determine the numbers of Purkinje cells in the cerebellum of each rat. MRC, SC and rats treated with ethanol between 10-15 d of age each had, on average, about 254-258 thousand cerebellar Purkinje cells; the differences between these various groups were not statistically significant. However, the rats treated with ethanol vapour between 4-9 d of age had an average of only about 128000+/-20000 Purkinje cells per cerebellum. This value was significantly different from both the MRC and group-matched SC animals. It is concluded that the period between 4 and 9 d of age is an extremely vulnerable period during which the rat cerebellar Purkinje cells are particularly susceptible to the effects of a high dose of ethanol. However, a similar level and duration of ethanol exposure commencing after 10 d of age has no significant effect on Purkinje cell numbers.

Animals↗

PubMed1999

A proline- and glutamine-rich protein promotes apoptosis in neuronal cells.

During development, excess neurons are eliminated by programmed cell death. Similarly, conditionally immortalized (SV40-Tts) rat hippocampal and septal cells undergo cell death following differentiation with several factors such as fibroblast growth factor, constitutively activated Raf-1, or phorbol esters. The mechanism by which cell death occurs has not been identified. Using RNA differential display, we have identified and characterized a novel immediate early gene (denoted PQR for proline- and glutamine-rich) induced during differentiation of both rat hippocampal and septal cell lines. The 44-kDa PQR protein, rich in PQ, PH, and QQ repeats, is homologous to a murine protein (TDAG51) required for Fas-mediated apoptosis in T cells. To determine whether PQR acts as a mediator of apoptosis in neuronal cells, the hippocampal H19-7 cells were microinjected with either a plasmid expressing PQR cDNA or an antibody against PQR. Microinjection of differentiating H19-7 cells with a neutralizing antibody against PQR increased the number of surviving cells by 50%. Transient expression of PQR in both differentiating and nondifferentiating H19-7 cells decreased the number of surviving cells by 35-50%; this reduction was reversed by microinjection of PQR antibody. Finally, levels of Fas transcripts are not increased in the neuronal cells, indicating that the mechanism of action differs from that in T cells. These results demonstrate that PQR can be induced by growth factors and differentiating agents and can itself induce apoptosis in hippocampal H19-7 cells. Furthermore, these data suggest that PQR can function more generally as a mediator of apoptosis and provide a possible mechanism for induction of programmed cell death during neuronal development.

Animals↗

PubMed1999

Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure.

BACKGROUND: In patients with chronic renal failure (CRF), abnormalities in vitamin D metabolism are known to be present, and several factors could contribute to the abnormalities. METHODS: We measured serum levels of three vitamin D metabolites, 1,25(OH)2D, 24, 25(OH)2D and 25(OH)D, and analyzed factors affecting their levels in 76 nondialyzed patients with CRF (serum creatinine> 1.6 and < 9.0 mg/dl), 37 of whom had diabetes mellitus (DM-CRF) and 39 of whom were nondiabetic (nonDM-CRF). RESULTS: Serum levels of 1,25(OH)2D were positively correlated with estimated creatinine clearance (CCr; r = 0.429; P < 0.0001), and levels of 24,25(OH)2D were weakly correlated with CCr (r = 0.252, P < 0.05); no correlation was noted for 25(OH)D. Serum levels of all three vitamin D metabolites were significantly and positively correlated with serum albumin. Although there were no significant differences in age, sex, estimated CCr, calcium and phosphate between DM-CRF and nonDM-CRF, all three vitamin D metabolites were significantly lower in DM-CRF than in nonDM-CRF. To analyze factors influencing vitamin D metabolite levels, we performed multiple regression analyses. Serum 25(OH)D levels were significantly and independently associated with serum albumin, presence of DM and serum phosphate (R2 = 0.599; P < 0.0001). 24,25(OH)2D levels were significantly and strongly associated with 25(OH)D (beta = 0.772; R2 = 0.446; P < 0.0001). Serum 1,25(OH)2D levels were significantly associated only with estimated CCr (R2 = 0. 409; P < 0.0001). CONCLUSIONS: These results suggest that hypoalbuminemia and the presence of DM independently affect serum 25(OH)D levels, probably via diabetic nephropathy and poor nutritional status associated with diabetes, and that 25(OH)D is actively catalyzed to 24,25(OH)2D in CRF, probably largely via extrarenal 24-hydroxylase. Serum levels of 1,25(OH)2D were significantly affected by the degree of renal failure. Thus, this study indicates that patients with CRF, particularly those with DM, should receive supplements containing the active form of vitamin D prior to dialysis.

24,25-Dihydroxyvitamin D 3↗