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Biomedical subjects

M Fukagawa

Publications and source records attributed to M Fukagawa.

At least 55 records · Page 3Linked to original sources
PubMed1998

Pirfenidone improves renal function and fibrosis in the post-obstructed kidney.

BACKGROUND: Pirfenidone (PFD) is a novel anti-fibrotic agent that can prevent and even reverse extracellular matrix accumulation in several organs, as shown by experimental and clinical studies. Unilateral ureteral obstruction (UUO) is a well-characterized model of experimental renal disease culminating in tubulointerstitial fibrosis. METHODS: UUO or sham-operated rats were administered PFD (500 mg/kg/day) in their food for 21 days to examine the effect on collagen production. The renal function was measured in the kidney after release of obstruction which had been maintained for one week to examine the effects of PFD on restoration after renal dysfunction. RESULTS: The collagen content detected by hydroxyproline progressively increased in kidney with UUO for 21 days. These increases were significantly suppressed by administration of PFD. PFD had no effect on collagen production in sham-operated rats. Expression of mRNA for type IV and I collagen and matrix metalloproteinase-2 in the cortex increased with UUO, but was inhibited by PFD treatment. The levels of cortical transforming growth factor-beta (TGF-beta) mRNA progressively rose with UUO for 21 days, but this increase also could be suppressed by PFD. Inulin clearance of the obstructed kidney was markedly depressed and remained low at five weeks after release. A progressive increase in hydroxyproline content was also observed in the post-obstructed kidney despite the release of obstruction. Administration of PFD following the release not only attenuated collagen accumulation, but also induced recovery of the impaired renal function. CONCLUSIONS: These results demonstrate that PFD can attenuate both renal fibrosis and renal damage in this model, and suggest that PFD can be clinically useful for preventing progressive, irreversible renal failure.

Administration, Oral↗
PubMed1997

Imaging of the parathyroid in chronic renal failure: diagnostic and therapeutic aspects.

On the basis of recent advances in our understanding of the pathogenesis of chronic renal failure, imaging of parathyroid hyperplasia in chronic dialysis patients has become a highly useful tool not only for identification, but also for evaluation of the nature of abnormal glands and for various intervention strategies. Rational imaging approaches, different from those used for primary hyperparathyroidism, should be established for secondary hyperparathyroidism.

Humans↗
PubMed1997

Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partial nephrectomy.

Pirfenidone (PFD) is a new compound that prevents and even reverses the extracellular matrix accumulation in several organs as shown by experimental and clinical studies. In the present study, we examined the effect of PFD (500 mg/kg daily in the food) on the progression of chronic renal failure (CRF) in the 5/6 nephrectomy rat model. Proteinuria progressively increased in rats with renal ablation (C) at 12 weeks. Urinary protein excretion in PFD-treated rats (P) was numerically lower than C, but the difference did not reach statistical significance. In contrast, in the chronic phase, PFD improved renal function and reduced collagen accumulation detected by hydroxyproline content (OH-Pro) in the cortex of the remnant kidney. Although creatinine clearance decreased with time in C, the values in P were significantly better at 10 and 12 weeks. The OH-Pro in C at 12 weeks was significantly higher than that of no-ablation, sham-operated rats, whereas OH-Pro in CRF was lower in (P). Expression of mRNA for type IV and I collagen in the cortex also increased in C, but it was inhibited in (P). To study the role that TGF-beta plays in the regulatory process following CRF, we examined the expression of TGF-beta mRNA in this model. Levels of cortical TGF-beta mRNA in C were significantly elevated at 12 weeks. The increase was suppressed by PFD. These results demonstrate that PFD attenuates the development of CRF by preventing collagen accumulation in this model, and suggest that PFD can be clinically useful for treating CRF.

Animals↗
PubMed1996

Ultrasonographic intervention of parathyroid hyperplasia in chronic dialysis patients: a theoretical approach.

Calcitriol pulse therapy has markedly changed the management of secondary hyperparathyroidism in chronic dialysis patients. However, there are still many patients even resistant to this therapy. Our observation of parathyroid size by ultrasonography revealed that these patients usually have enlarged parathyroid glands larger than 0.5 cm3. Such large parathyroid glands are composed of nodular hyperplasia with monoclonal cell proliferation, whose calcitriol receptor density is lower than that of diffuse hyperplasia, thus more resistant to calcitriol. Based on such a pathophysiological model, we have shown that destruction of the largest parathyroid gland was sufficient to restore the responsiveness to calcitriol therapy in these refractory patients. By using colour Doppler ultrasonography, we could also optimize the site and volume of ethanol injection and could detect the recurrence of parathyroid cell growth easily, with lower risk of complications. This selective route of drug delivery to parathyroid glands can be also used for direct injections of calcitriol solution as we have reported. Thus, evaluation of parathyroid size by sensitive ultrasonography is an essential marker for the management of parathyroid hyperfunction in chronic dialysis patients. It is also suggested that ultrasonographic intervention of parathyroid hyperplasia may not only be a useful and safe adjunct to calcitriol pulse therapy, but may also serve as a new therapeutic modality for parathyroid diseases in future.

Calcitriol↗
PubMed1995

Molecular basis for the management of secondary hyperparathyroidism in chronic renal failure.

Recent clinical and experimental data suggest that the resistance of parathyroid cells to the physiological concentration of calcitriol plays an important role in the pathogenesis and the progression of secondary hyperparathyroidism in chronic renal failure. This resistance is due to the decreased density of the calcitriol receptor in parathyroid cells, which may result from impaired upregulation of calcitriol receptor. Since patients with larger parathyroid glands were more resistance to calcitriol pulse therapy than those with smaller glands and calcitriol receptor density inversely correlated with gland weight, the size of the parathyroid gland may serve as a marker for the degree of resistance to calcitriol. Furthermore, the possible role of phosphorus in the control of parathyroid function has been suggested recently. Thus, it is most important to prevent the progression of parathyroid hyperplasia in chronic renal failure by the early use of active vitamin D, calcitriol pulse therapy, and dietary phosphorus restriction.

Animals↗
PubMed1995

Prevention of enhanced parathyroid hormone secretion, synthesis and hyperplasia by mild dietary phosphorus restriction in early chronic renal failure in rats: possible direct role of phosphorus.

In order to evaluate the effect of dietary phosphorus (P) restriction on the pathogenesis of secondary hyperparathyroidism (2 degrees HPT) in chronic renal failure (CRF), we studied parathyroid function and parathyroid cell proliferation in 5/6 nephrectomized rats (CRF rats) fed with three different dietary P contents (0.6, 0.3 and 0.1%). Four weeks after 5/6 nephrectomy, serum immunoreactive parathyroid hormone (PTH) concentration, PTH mRNA level in parathyroid glands and the size of parathyroid glands were increased in CRF rats compared to those of sham-operated rats when both groups of rats were fed with normal P (0.6%) diet. These changes were not accompanied by any detectable changes of serum concentrations of calcium (Ca), inorganic phosphate (Pi) or calcitriol. In contrast, such evidence of 2 degrees HPT was obliterated in CRF rats fed with 0.3 or 0.1% P diet. In rats fed with 0.3% P diet, serum concentrations of Ca, Pi, and calcitriol were not different from those of sham-operated rats or from CRF rats fed with normal P diet. In contrast, serum Ca and calcitriol concentrations increased and serum Pi decreased in CRF rats fed with 0.1% P diet. These data suggest that 2 degrees HPT can be completely prevented at the levels of PTH secretion, synthesis and parathyroid cell proliferation by mild dietary P restriction (0.3%) alone, and that such effects may not depend upon the changes in serum concentrations of Ca, Pi or calcitriol, but may depend on reduced dietary P content per se. Thus, mild dietary P restriction from the early stage of CRF may be clinically effective for the prevention of 2 degrees HPT.

Animals↗
PubMed1994

Embryonic expression of mouse bone morphogenetic protein-1 (BMP-1), which is related to the Drosophila dorsoventral gene tolloid and encodes a putative astacin metalloendopeptidase.

cDNAs encoding a mouse gene closely related to human bone morphogenetic protein-1 (BMP-1) have been isolated from an 8.5-day p.c. embryo cDNA library. Analysis of the predicted amino acid sequence shows that the protein contains a putative zinc-binding astacin metalloendopeptidase domain, five Clr/s domains, and two potential Ca(2+)-binding EGF-like repeats. In overall domain organization it more closely resembles the Drosophila tolloid gene product than human BMP-1. By RNase protection, transcripts can be detected in the embryo at 6.5 days p.c. and persist at least until 16.5 days p.c. By in situ hybridization, transcripts are seen at high levels in the maternal deciduum and in the late-gastrulation stage embryo at low levels throughout the mesoderm. This low level of mesodermal expression continues through development but somewhat higher levels are seen in developing membranous and endochondral bone, in the submucosa of the intestine, the dermis of the skin, and the mesenchyme of the spleen and lung. High levels of BMP-1 transcripts are also seen from 9.5 days p.c. in the floorplate region of the developing neural tube. Potential therefore exists for the interaction of BMP-1 protein with products of TGF-beta-related genes expressed during embryogenesis.

Amino Acid Sequence↗
PubMed1994

Reduction of functioning parathyroid cell mass by ethanol injection in chronic dialysis patients.

Recent data suggest that the larger parathyroid glands are more resistant to calcitriol therapy than the smaller glands due to more severe reduction of calcitriol receptor number. To control severe secondary hyperparathyroidism resistant to calcitriol pulse therapy in chronic dialysis patients, we introduced repeatable and quantitative ethanol injection(s) into the largest parathyroid gland under ultrasonographic guidance with a specifically modified needle. Efficacy of each injection and the recurrence of hyperparathyroidism were confirmed by color Doppler ultrasonography and could undergo additional ethanol injection(s) into the optimal site. When the ethanol injection(s) into the largest gland was not sufficient to control PTH hypersecretion, we injected ethanol into the next largest gland. We performed 32 injections into 16 parathyroid glands in nine dialysis patients. PTH decreased to less than 200 pg/ml after the final injection in seven patients and they remained controlled either by the following conventional oral active vitamin D or calcitriol pulse therapy. The other two patients, whose PTH decreased but not to less than 200 pg/ml, also became controllable with the following calcitriol pulse therapy. Recurrent nerve palsy was encountered in 2 out of 32 injections, but only transiently. Our data suggest that the measurement of the size of parathyroid glands is an important factor in the management strategy of secondary hyperparathyroidism in chronic dialysis patients, and that ethanol injection(s) into the largest parathyroid gland(s) could be an effective and safe strategy to restore the responsiveness to calcitriol therapy, by reducing the functioning parathyroid cell mass most resistant to calcitriol.

Adult↗
PubMed1994

Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long-term prognosis of calcitriol pulse therapy in chronic dialysis patients.

To clarify whether the changes of parathyroid size have any correlations with the long-term prognosis of calcitriol pulse therapy, we examined the time course of serum levels of parathyroid hormone (PTH) and size of parathyroid glands in 14 chronic dialysis patients during and after the oral calcitriol pulse therapy. In 5 patients without any detectable glands, secondary hyperparathyroidism was easily controlled by calcitriol pulse therapy and then by conventional oral active vitamin D therapy. In 2 patients with detectable gland(s) in whom size of all parathyroid glands as well as PTH hypersecretion regressed to normal by calcitriol pulse therapy, secondary hyperparathyroidism could then remain controlled at least for 12 months after switching to conventional oral active vitamin D therapy. In contrast, in 7 patients in whom size of all parathyroid glands did not regress to normal by calcitriol pulse therapy, secondary hyperparathyroidism relapsed after switching to the conventional therapy, even if PTH hypersecretion could be controlled temporarily. Our findings suggest that the time course of parathyroid hyperplasia detected by ultrasonography is an important determinant of the efficacy and the prognosis of calcitriol pulse therapy. Thus, the change of parathyroid gland size as well as PTH hypersecretion should be taken into account for the management of secondary hyperparathyroidism.

Administration, Oral↗
PubMed1993

Recent progress in management of secondary hyperparathyroidism of chronic renal failure.

Recent progress in cellular and molecular biology has had a great impact on our understanding of parathyroid hormone-vitamin D physiology and of the pathogenesis of secondary hyperparathyroidism in chronic renal failure and made possible the development of new therapeutic approaches for management of bone disease in dialysis patients. Management of parathyroid hyperplasia by calcitriol pulse therapy is one example. Suppression of parathyroid hyperfunction by other vitamin D analogues was also proposed, and some of these analogues are now under clinical trial. Further, percutaneous ethanol injection into hyperplastic parathyroid glands under ultrasonographic guidance has become the choice practical procedure under certain clinical settings and can be an effective alternate to surgical parathyroidectomy. In this article, we review selected and pertinent progress in the pathogenesis and management of secondary hyperparathyroidism and parathyroid hyperplasia, major causes of morbidity in chronic dialysis patients, emphasizing the important contributions made by laboratory research and critical clinical observations.

Animals↗
PubMed1993

Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.

The resistance of parathyroid cells to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in uremic hyperparathyroidism is thought to be caused, in part, by a 1,25(OH)2D3 receptor (VDR) deficiency in the parathyroids. However, results of biochemical studies addressing VDR numbers in the parathyroids are controversial. Several studies have found VDR content to be decreased in the parathyroids of uremic patients and animals, while others have found no such decrease in the parathyroids of uremic animals. To clarify the role of VDR, we investigated VDR distribution in surgically-excised parathyroids obtained from chronic dialysis patients by immunohistochemistry. We classified the parathyroids as exhibiting nodular or diffuse hyperplasia. Our studies demonstrated a lower density of VDR in the parathyroids showing nodular hyperplasia than in those showing diffuse hyperplasia. Even in the parathyroids showing diffuse hyperplasia, nodule-forming areas were present; these areas were virtually negative for VDR staining. A significant negative correlation was found between VDR density and the weight of the parathyroids. These findings indicate that the conflicting results of biochemical studies may be caused by the heterogeneous distribution of VDR; the decreased VDR density in parathyroids may contribute to the progression of secondary hyperparathyroidism and to the proliferation of parathyroid cells that is seen in uremia.

Chronic Disease↗
PubMed1993

Shunt nephritis: efficacy of an antibiotic trial for clinical diagnosis.

Coagulase negative staphylococcus, a normal skin flora, is especially nosopoietic under shunt management, because coagulase negative staphylococcus sometimes forms a biofilm around itself at catheter tips in vivo, which shields the organism from the effects of antibiotics. But it is difficult to distinguish this pathogen from a possible confounding contamination of a blood culture. In this article, we report a case, and discuss how a patient with suspected shunt nephritis should be examined and treated. In addition, to further histological and prognostic interpretation, we review the previously reported cases of shunt nephritis in Japanese adults.

Adult↗
PubMed1992

Renal osteodystrophy and vitamin D derivatives: cellular mechanisms of hyperparathyroidism in uremia.

In the early phase of chronic renal failure, physiological concentrations of 1,25(OH)2D in circulation may become insufficient to regulate parathyroid cell function normally. As a result, the set-point of PTH secretion to plasma Ca ion concentration shifts to the right, PTH synthesis becomes enhanced at transcriptional level, and parathyroid cells begin to proliferate. This resistance of the parathyroid cells to the physiological concentration of 1,25(OH)2D may be in part due to the reduction of 1,25(OH)2D receptor density in parathyroid cells. However, the mechanism by which the number of 1,25(OH)2D receptors decreases in parathyroid cells in early renal failure remains to be elucidated.

Calcitriol↗