Fibroblast growth factor 23 production in bone is directly regulated by 1{alpha},25-dihydroxyvitamin D, but not PTH.

Fibroblast growth factor 23 (FGF23), which is primarily produced by osteocytes in bone, regulates renal phosphate excretion and 1α,25-dihydroxyvitamin D [1,25(OH)(2)D(3)] metabolism. Patients with chronic kidney disease (CKD) have increased levels of circulating serum FGF23, but the direct effect on circulating FGF23 levels in renal insufficiency is still unclear. To identify the major regulator of FGF23 synthesis in renal insufficiency, we compared the effect of parathyroid hormone (PTH) and 1,25(OH)(2)D(3) on FGF23 synthesis in the calvariae of normal rats with that of uremic rats in vitro. 1,25(OH)(2)D(3) treatment significantly increased the FGF23 concentration in the medium from both groups, but the degree of increase in the uremic group was markedly higher than in the control group. A significant increase in FGF23 mRNA expression occurred as early as 4 h after treatment and reached the maximum within 8 h in the uremic group, whereas in the normal group a significant increase in FGF23 mRNA expression was observed only at 8 h. In addition, the expression of vitamin D receptor (VDR) mRNA in the calvariae of uremic rats was markedly higher than in normal rats. However, in neither group did PTH treatment affect the medium FGF23 concentration or the FGF23 mRNA levels. These results suggest that FGF23 synthesis in bone is regulated by 1,25(OH)(2)D(3) directly, not by PTH, and that increased VDR mRNA expression induced the relatively swift and strong response in the uremic group.

[Secondary osteoporosis UPDATE. Therapy for bone-mineral disease in CKD-5D patients].

Recently, much of the attention given to bone-mineral disorder as the prognostic factor for mortality has focused on their links to chronic kidney disease (CKD-MBD; chronic kidney disease-mineral bone disease), especially in dialysis patients. Bone disease in dialysis patients showed heterogeneity caused by multiple factors other than postmenopausal osteoporosis. Evaluation of the bone mineral density with DEXA and the bone metabolic markers becomes useless for the assessment of bone fragility in dialysis patients. Prevalence of bone fracture in end-stage renal disease patients is 3-4 times higher than that in general population. The skeletal fracture in ESRD patients is suggested to be related with malnutrition. Guidelines of the therapy for bone-mineral disorder in dialysis patients is centered on the prevention of cardio-vascular disease and the mortality. Physicians should carefully understand these effects in the daily clinical practices.

[Phosphate binder up to date].

It has become clear that hyperphosphatemia is the major risk factor on the patients' survival undergoing regular renal replacement therapy. One of the mechanism of this impact on survival is ectopic calcification like vascular calcification. The standard therapy for hyperphosphatemia is phosphate removal by renal replacement therapy. However, since the amount of phosphate removal with today's hemodialysis procedure is not enough, the phosphate binder as depressant of phosphate absorption is still essential. Aluminum compound had been prohibited from 1992 due to serious adverse effect like aluminum encephalopathy and osteomalacia.Calcium carbonate and sevelamer hydrochloride are common phosphate binder. The combination therapy of both phosphate binders is recommended to avoid involvement in adverse effects of the both drugs. Lanthanum carbonate is developing compound as a new and powerful phosphate binder. It is expected as a new non-calcium and non-aluminum phosphate binder with powerful phosphate binding effect. However, the adverse effect of the Lanthanum carbonate is still obscure. Further investigation is acquired.

Symptomatic bradycardia probably due to tizanidine hydrochloride in a chronic hemodialysis patient.

A 71-year-old woman was admitted to the Wakayama Medical University Hospital with dizziness and loss of body balance. She had started hemodialysis at the age of 70. During the 33 days before admission, she received oral tizanidine hydrochloride at 3 mg/day for leg cramps. An admission electrocardiogram (ECG) demonstrated sinus bradycardia of 47 bpm. A 24-h ECG showed a total number of heartbeats of 68,779 and an average heart rate of 48 bpm. The maximum RR interval was 3720 msec. The electrophysiology test demonstrated slight sinus node dysfunction. There was no major organic heart disease. We suspected that tizanidine was the cause of bradycardia and stopped administration of this drug. After discontinuation symptoms gradually disappeared. The serum concentration of the tizanidine showed a higher trough of 1.78 ng/mL. In conclusion, because there was a disappearance of symptoms and a lightening of bradycardia due to the discontinuation of this medication, tizanidine was strongly suspected as the cause of severe bradycardia.

[Enhanced expression of EGFR, TGF-alpha, EGF in hyperplastic parathyroid glands in established stage of renal failure in rats].

It was reported that the parathyroid gland hyperplasia correlated with enhanced co-expression of TGF-alpha and its receptor EGFR at early stages of renal failure. This time, we investigated the time course for EGFR and its ligands, TGF-alpha, and EFG expression, and the influence of high-phosphorus (P) diet to EGFR and EGF expression, and the effect of EGFR-tyrosine kinase inhibitor (Gefitinib, [IRESSA; AstraZeneca]; TKI) in rat PTGs with established stage of renal failure. The levels of EGFR, EGF, TGF-alpha mRNA in rat PTGs were increased for the time periods. The serum intact PTH levels, and EGFR, EGFmRNA in rat PTGs were suppressed in normal-P diet group. Nuclei positive cells for PCNA in TKI group were suppressed. The levels of p21mRNA were increased in TKI group. These results suggested that the enhanced expression of EGFR, TGF-alpha and EGF participate in the cell proliferation of hyperplastic PTGs in established stage of renal failure.

[Outlines of K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease].

Recently "K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease" was published. It consists of sixteen precise guidelines which cover the wide range of this field. It is expected that these guidelines contribute ESRD treatment in Japan in spite of some differences in medical practice for dialysis therapy between Japan and the United States. This article briefly summarizes the outlines of these guidelines.

Effect of beta(2)-microglobulin adsorption column on dialysis-related amyloidosis.

BACKGROUND: beta2-microglobulin (beta2-m) is considered a major pathogenic factor in dialysis-related amyloidosis (DRA), often seen in long-term dialysis patients. No effective therapy for this severely debilitating disease is currently available. Lixelle, an adsorption column, has been developed for the elimination of beta2-m; the efficacy of this column has been evaluated in this study. METHODS: Seventeen hemodialysis patients with DRA were first treated with high-flux dialysis for a minimum of 1 year. This was followed by 1-year treatment with Lixelle column connected in series to the high-flux dialyzer. Treatments were used three times a week for both phases of this study. During the study period, beta2-m, pinch strength, motor terminal latency, and activities of daily living were evaluated. RESULTS: After 1-year treatment with high-flux dialysis the beta2-m level remained unchanged; however, after 1-year treatment with the addition of the Lixelle column, beta2-m level decreased significantly from 34.5 +/- 8.4 mg/L to 28.8 +/- 7.3 mg/L (P < 0.05). After 1 year of Lixelle column use, the pinch strength increased from 6.8 +/- 4.7 pounds to 9.1 +/- 5.5 pounds (P < 0.01), and the median motor terminal latency was significantly reduced from 5.1 +/- 1.0 mseconds to 4.5 +/- 1.1 mseconds. A significant improvement was also observed in the activities of daily living score of the upper extremities. CONCLUSION: These results suggest that the addition of Lixelle to the high-flux dialyzer is associated with a significant clinical improvement in DRA patients.

[The new trend on the treatment of secondary hyperparathyroidism].

Recently various treatments for secondary hyperparathyroidism were developed. Those include a cation polymer as phosphate binder, active metabolite of vitamin D and its analogue, and various kinds of calcimimetics as Ca-sensing receptor agonist. For the secondary hyperparathyroidism refractory to those medication, direct injection of ethanol or vitamin D and its analogue is considered. All those treatments may contribute prevention and control of secondary hyperparathyroidism.