Takashi Shigematsu

Enhanced Expression of Osteopontin in Human Diabetic Artery and Analysis of Its Functional Role in Accelerated Atherogenesis

We have previously reported that high glucose stimulates osteopontin (OPN) expression through protein kinase C-dependent pathways as well as hexosamine pathways in cultured rat aortic smooth muscle cells. The finding prompted us to study in vivo expression of OPN in diabetes mellitus. In the present study, we found by immunohistochemistry that medial layers of the carotid arteries of streptozotocin-induced diabetic rats and the forearm arteries of diabetic patients stained positively for OPN antibodies, whereas the staining from arteries of control rats and nondiabetic patients was negative. We also found that OPN stimulated the migration and enhanced platelet-derived growth factor (PDGF)-mediated DNA synthesis of cultured rat aortic smooth muscle cells. OPN and PDGF synergistically activated focal adhesion kinase as well as extracellular signal-regulated kinase; this finding seems to explain the OPN-induced enhancement of PDGF-mediated DNA synthesis. Taken together, our present results raise a possibility that OPN plays a role in the development of diabetic vascular complications.

Lanthanum carbonate effectively controls serum phosphate without affecting serum calcium levels in patients undergoing hemodialysis.

Abstract:  Treating hyperphosphatemia without increasing the calcium load in chronic kidney disease patients on dialysis is important, as conventional treatment frequently results in ectopic calcification. Sevelamer, a monotherapy for hyperphosphatemia is frequently associated with gastrointestinal disorders, often resulting in discontinuation of treatment. Lanthanum carbonate is a novel non‐calcium‐based phosphate binder for the treatment of chronic kidney disease. Here, its clinical efficacy and safety were assessed in Japanese dialysis patients. A placebo‐controlled, randomized, double‐blind, parallel group, multicenter study was performed in Japanese dialysis patients. Patients were treated with various dosages of lanthanum carbonate or a placebo daily for six weeks. The primary efficacy endpoint was the change in serum phosphate level from the baseline. Secondary endpoints included achievement rates to target serum phosphate levels and changes in serum calcium levels. Safety was evaluated by the incidence of drug‐related and treatment‐emergent adverse events. A significant reduction in serum phosphate level was demonstrated for all dosages from Week 1. This dose‐dependent effect was also observed in the changes in serum calcium × phosphate product, yet there was no notable difference in serum calcium or serum intact parathyroid hormone levels. The incidence of drug‐related adverse events was dose‐dependent, with the most common being gastrointestinal symptoms. Lanthanum carbonate effectively controls serum phosphate levels and is generally tolerable to Japanese chronic kidney disease patients on dialysis, as reported for the Caucasian population. The optimal dosage in Japanese patients needs to be confirmed using a flexible‐dose titration schedule.

Multicenter prospective randomized, double-blind comparative study between lanthanum carbonate and calcium carbonate as phosphate binders in Japanese hemodialysis patients with hyperphosphatemia.

BACKGROUND The efficacy of lanthanum carbonate as a phosphate binder for the treatment of hyperphosphatemia has been reported, but not from a double-blind, comparator-controlled comparative study. METHODS The safety and efficacy of lanthanum carbonate and calcium carbonate on serum phosphate and calcium levels in Japanese hemodialysis patients were assessed by a randomized, double-blind, comparator-controlled, parallel group, multicenter study. This study is the first study using a randomized, double-blind method to compare lanthanum carbonate and calcium carbonate as phosphate binders. RESULTS In the double-blind phase, the changes in the serum phosphate level were similar in the lanthanum carbonate and calcium carbonate groups. The differences in the corrected serum calcium level or the calcium x phosphate products between the 2 groups were not statistically significant. However, the mean change in the corrected serum calcium level from baseline to the last outpatient visit was significantly lower in the lanthanum carbonate group than in the calcium carbonate group. The incidence of hypercalcemia in the lanthanum carbonate group was also significantly lower than in the calcium carbonate group. CONCLUSION Both compounds show similar efficacy on the serum phosphate level in patients undergoing hemodialysis when the dose is managed in a dose-variable and double-blind manner. However, lanthanum carbonate is superior in terms of lowering the incidence of hypercalcemia.

Regulation of Fibroblast Growth Factor 23 Production in Bone in Uremic Rats

Background: Fibroblast growth factor 23 (FGF23) regulates renal phosphate reabsorption and 1α,25-dihydroxyvitamin D [1,25(OH)2D3] metabolism. Patients with chronic kidney disease (CKD) have increased levels of circulating FGF23, but the direct regulation of this elevation of FGF23 is incompletely understood. Method:We measured plasma parameters in uremic rats fed a high-phosphorus diet and then performed parathyroidectomy (PTX) to determine its effect. We also investigated FGF23 mRNA expression in various tissues to identify the major source of circulating FGF23. Result: The uremic rats displayed dramatic changes in plasma FGF23 levels, consistent with increased expression of FGF23 in bone. Elevated FGF23 was associated with phosphate and parathyroid hormone (PTH). After PTX, the elevated FGF23 had decreased, consistent with decreased expression of FGF23 in bone. Significant decreases in plasma FGF23 were associated with PTH and 1,25(OH)2D3, but not phosphate. Conclusion: Elevated plasma FGF23 levels in uremic rats reflect the increased expression of FGF23 in bone. The expression of FGF23 in bone may be regulated by a PTH-1,25(OH)2D3 axis-dependent pathway and another PTH-dependent and 1,25(OH)2D3-independent pathway in uremic rats. The pathway may be decided by the degree of renal dysfunction.

Inhibitory effects of etidronate on the progression of vascular calcification in hemodialysis patients.

Abstract:  The present study was designed to determine if etidronate inhibits the development of aortic calcification in hemodialysis (HD) patients. Eighteen Japanese HD patients were divided randomly into etidronate‐treated or control groups. Etidronate was given orally at the dose of 200 mg just before sleep on the day of dialysis, which was performed three times per week. In the control group, the aortic calcification area (ACA) increased after 6 months. In the patients who received etidronate, however, when compared to the control group, increases in ACA were significantly suppressed. Serum Ca, P, and the Ca × P product did not change during etidronate treatment. These results suggest that etidronate inhibits the progression of vascular calcification without changes in serum Ca and P levels.

Long-Term Cinacalcet HCl Treatment Improved Bone Metabolism in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism

Background/Aims: Few clinical trials conducted with cinacalcet have thoroughly addressed its effects of on bone metabolism. We assessed the effects of cinacalcet on bone markers in Japanese hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). Methods: 200 Japanese HD patients with intact PTH (iPTH) levels ≥300 pg/ml were enrolled. The dose of cinacalcet was titrated from 25 up to 100 mg/day to achieve iPTH levels ≤250 pg/ml for 52 weeks. Results: At the end of the study visit, 57.8% of patients (115/199) had achieved iPTH levels ≤250 pg/ml. Serum Ca, phosphorus (P) and Ca × P levels decreased rapidly and were maintained throughout the study. At week 52, all bone metabolic markers levels had decreased significantly from baseline. Although bone resorption markers gradually decreased throughout the study period, bone alkaline phosphatase significantly increased during the first 4 weeks and then gradually decreased. Conclusions: The time courses of changes in bone markers after cinacalcet treatment resembled those observed after surgical parathyroidectomy (PTx), sometimes described as the hungry bone syndrome, indicating that cinacalcet treatment induces a rapid recovery in bone response to calcium. In addition, long-term efficacy and safety of cinacalcet were also observed in Japanese patients undertaking long-term hemodialysis (167.0 ± 81.4 months).

Efficacy of Combined Sevelamer and Calcium Carbonate Therapy for Hyperphosphatemia in Japanese Hemodialysis Patients

Abstract:  In Japan, calcimimetics and other phosphate binders such as lantanum carbonate are not available for patients on long‐term hemodialysis (HD), so we prospectively evaluated the clinical efficacy of the combination of sevelamer hydrochloride and calcium carbonate (CaCO3) for hyperphosphatemia. The study group comprised 65 HD patients who had been administered CaCO3 (≥1500 mg/day) for hyperphosphatemia [≥6.0 mg/dL (≥1.94 mmol/L)]. At the beginning of the study the dose of CaCO3 was reduced by 1500 mg/day and the patients divided into two groups according to the dose of additional sevelamer hydrochloride: group A 2250 mg/day; group B 3000 mg/day. Oral active vitamin D therapy was unchanged. Fourteen patients (21.5%) dropped out because of adverse effects and of the 51 remaining patients 35 (53.8%) suffered from gastrointestinal problems. Serum phosphate concentration decreased significantly [from 7.5 ± 0.8 mg/dL (2.42 ± 0.26 mmol/L) to 6.6 ± 1.3 mg/dL (2.13 ± 0.42 mmol/L), P < 0.01] in group B only after the 8 weeks of combination therapy. The calcium–phosphate product (Ca × Pi) also decreased in group B only [from 74.4 ± 13.4 mg2/dL2 (5.99 ± 1.07 mmol2/l2) to 63.7 ± 15.8 mg2/dL2 (5.13 ± 1.27 mmol2/l2), P < 0.001]. The combination of sevelamer hydrochloride and CaCO3 is a suitable regimen for hyperphosphatemia treatment in HD patients because it avoids both the hypercalcemia of CaCO3 and the adverse effects of sevelamer hydrochloride when each is used as single‐drug therapy. The ability of sevelamer hydrochloride to decrease the serum phosphate concentration is 2/3 (2250/1500 mg) that of CaCO3.

The Negative Ca2+ Balance Is Involved in the Stimulation of PTH Secretion

The low calcium (Ca2+) dialysate have been developed to diminish the risk of hypercalcemia with the administration of active vitamin D and Ca2+ carbonate as phosphate binder. Today, increasing numbers of hemodialysis (HD) patients have been on the low Ca2+ dialysate (Ca2+ = 2.5 mEq/l). However, the clinical consequences of a negative calcium net-balance which may be induced by the use of low Ca dialysate are not well evaluated. In the present study, we explored the effects of low Ca2+ dialysate on the calcium balance and the PTH secretion. Eighty one chronic HD patients (male/female: 47/34; mean age: 60.2 ± 1.5 years; mean HD periods: 11.1 ± 0.8 years) who had been dialyzed with 3.0 mEq/l Ca2+ dialysate were studied. All patients were transferred to the low Ca dialysate, which actually brought about a negative net-balance in Ca (mean: –94.5 mg) and an increase in serum intact PTH levels (mean: +23.7%: p = 0.03) during a single HD session. However, no changes in serum ionized Ca2+ were found in spite of negative Ca2+ balance. One month after change to the low Ca2+ dialysate (total 12 sessions in each case), serum intact PTH levels increased significantly (186.7 ± 19.5 vs. 216.2 ± 21.9 pg/ml: p = 0.01) in spite of the fact that no changes were found in serum ionized Ca2+, Pi and Mg. This result indicates that the negative Ca2+ balance during low-Ca2+ hemodialysis-stimulated PTH secretion, which offset the decrease of serum Ca2+; a trade-off phenomenon between negative Ca balance and PTH. This suggests that low Ca2+ dialysate may exaggerate the progression of secondary hyperparathyroidism.

Calcium oxalate crystal deposition in metabolic syndrome model rat kidneys.

Objective:  Although an epidemiological link between the metabolic syndrome and kidney stone formation has been reported, the mechanism by which metabolic syndrome promotes kidney stone formation has yet to be elucidated. We investigated calcium oxalate (CaOx) kidney stone formation in a rat metabolic syndrome model.

Most patients with coronary artery calcification have no coronary artery stenosis and hyperphosphatemia should be important in reevaluating the K/DOQI guidelines.

Address correspondence and reprints requests to Dr. Keitaro Yokoyama, Division of Nephrology and Hypertension, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8471, Japan. Email: keitaro@jikei.ne.jp Dear Editor, The incidence of cardiovascular complications is very high in end-stage renal disease (ESRD) patients, and life expectancy significantly depends on the complications resulting from coronary artery stenosis. According to the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease published in 2003 (1), hyperphosphatemia influences coronary artery calcification (CAC) in ESRD patients and the use of active vitamin D should be limited in patients with hyperphosphatemia. However, hyperphosphatemia is one of several factors, which effect CAC in ESRD patients. Thus we evaluated the relationship between hyperphosphatemia coronary artery stenosis as well as CAC using 16-slice multislice CT (MSCT) with CT angiography (CTA) in ESRD patients. We recruited 31 ESRD patients (18 male and 13 female, mean age 62 ± 12 years, mean duration of dialysis 6.6 ± 6.6 years) and calculated their coronary artery calcification score (CACS) according to the algorithm suggested by Agaston et al. With contrast enhancement, we evaluated their CTA based on the American Heart Association classification for coronary angiography (CAG). In the first, each coronary segment was classified as either interpretable or not interpretable according to the image quality. Second, when the patent lumen of each segment was 25% or less of the luminal diameter, it was screened for the presence of severe stenosis. As above, whether severe stenosis or occlusion was present or absent could be assessed. In 16 slice MSCT, calcified coronary lesions were found in 24 cases (80%), including 13 cases with a severe degree of calcification of CACS (more than 400). However, the serum phosphorus level was > 5.6 mg/dL in 39% of patients in this sample. With regards to the CT value of each coronary segment with contrast enhancement, severe stenosis or occlusion was found in 13% of patients. Univariate analysis suggested a relationship between serum Ca values and CACS. No statistically significant differences were seen with regard to age, dialysis duration, diabetes, serum phosphorus or serum intact-PTH. We could confirm that the calcified coronary lesions were found in 24 cases (80%), however, most of them did not have severe coronary artery stenosis or occlusion and hyperphosphatemia (serum phosphorus > 5.5 mg/dL). Hyperphosphatemia might merely be one of several factors which influence CAC in ESRD patients. Thus, we should clarify the pathophysiology of CAC in ESRD patients besides hyperphosphatemia to reevaluate the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease.