Keitaro Yokoyama

Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder

Masafumi Fukagawa, Keitaro Yokoyama, Fumihiko Koiwa, Masatomo Taniguchi, Tetsuo Shoji, Junichiro James Kazama, Hirotaka Komaba, Ryoichi Ando, Takatoshi Kakuta, Hideki Fujii, Msasaaki Nakayama, Yugo Shibagaki, Seiji Fukumoto, Naohiko Fujii, Motoshi Hattori, Akira Ashida, Kunitoshi Iseki, Takashi Shigematsu, Yusuke Tsukamoto, Yoshiharu Tsubakihara, Tadashi Tomo, Hideki Hirakata, and Tadao Akizawa for CKD-MBD Guideline Working Group, Japanese Society for Dialysis Therapy

A nonclassical vitamin D receptor pathway suppresses renal fibrosis

The TGF-β superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-β-SMAD signal transduction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D3-bound [1,25(OH)2D3-bound] vitamin D receptor (VDR) specifically inhibits TGF-β-SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25(OH)2D3 treatment prevented renal fibrosis through the suppression of TGF-β-SMAD signal transduction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligands. These ligands selectively inhibited TGF-β-SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)2D3-dependent suppression of TGF-β-SMAD signal transduction is independent of VDR-mediated transcriptional activity. In addition, these ligands did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. Thus, our study provides a new strategy for generating chemical compounds that specifically inhibit TGF-β-SMAD signal transduction. Since TGF-β-SMAD signal transduction is reportedly involved in several disorders, our results will aid in the development of new drugs that do not cause detectable adverse effects, such as hypercalcemia.

Effects of Serum Calcium, Phosphorous, and Intact Parathyroid Hormone Levels on Survival in Chronic Hemodialysis Patients in Japan

Abstract:  Disturbances in bone mineral metabolism are common in chronic hemodialysis (HD) patients and often underlie morbid conditions and mortality; however, no large epidemiological study for Asian dialysis patients has been performed. We analyzed the database of the Japanese Society for Dialysis Therapy registry. In this study, data from patients who were on HD at the end of 2000 was compiled. The Coxs proportional hazard analysis was carried out to evaluate the significance of the impact of variables related to bone mineral metabolism on survival after adjusting for possible confounding variables. The study period was three years, and a cohort of 27 404 HD patients was studied. The hazard ratios were 1.098 (P = 0.0129) for serum calcium levels ranging 10.0–10.9 mg/dL, and 1.243 (P = 0.0001) for serum calcium levels >11.0 mg/dL when the reference serum calcium level range was 9.0–9.9 mg/dL. Similarly, the hazard ratios were significantly higher in a serum phosphorous level of 5.0 mg/dL than for the reference serum phosphorous level range of 4.0–4.9 mg/dL. For intact parathyroid hormone (iPTH), the hazard ratios were significantly small (<119 pg/mL) when the reference iPTH level range was 180–359 pg/mL. However, the hazard ratio did not increase when the iPTH level increased to >360 pg/mL. Results showed that disturbances in bone mineral metabolism, such as those involving serum calcium, phosphorous, and iPTH, have a significant impact on survival in Japanese dialysis patients.

Ferric Citrate Hydrate for the Treatment of Hyperphosphatemia in Nondialysis-Dependent CKD

BACKGROUND AND OBJECTIVES Ferric citrate hydrate is a novel iron-based phosphate binder being developed for hyperphosphatemia in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A phase 3, multicenter, randomized, double blind, placebo-controlled study investigated the efficacy and safety of ferric citrate hydrate in nondialysis-dependent patients with CKD. Starting in April of 2011, 90 CKD patients (eGFR=9.21±5.72 ml/min per 1.73 m(2)) with a serum phosphate≥5.0 mg/dl were randomized 2:1 to ferric citrate hydrate or placebo for 12 weeks. The primary end point was change in serum phosphate from baseline to the end of treatment. Secondary end points included the percentage of patients achieving target serum phosphate levels (2.5-4.5 mg/dl) and change in fibroblast growth factor-23 at the end of treatment. RESULTS The mean change in serum phosphate was -1.29 mg/dl (95% confidence interval, -1.63 to -0.96 mg/dl) in the ferric citrate hydrate group and 0.06 mg/dl (95% confidence interval, -0.20 to 0.31 mg/dl) in the placebo group (P<0.001 for difference between groups). The percentage of patients achieving target serum phosphate levels was 64.9% in the ferric citrate hydrate group and 6.9% in the placebo group (P<0.001). Fibroblast growth factor-23 concentrations were significantly lower in patients treated with ferric citrate hydrate versus placebo (change from baseline [median], -142.0 versus 67.0 pg/ml; P<0.001). Ferric citrate hydrate significantly increased serum iron, ferritin, and transferrin saturation compared with placebo (P=0.001 or P<0.001). Five patients discontinued active treatment because of treatment-emergent adverse events with ferric citrate hydrate treatment versus one patient with placebo. Overall, adverse drug reactions were similar in patients receiving ferric citrate hydrate or placebo, with gastrointestinal disorders occurring in 30.0% of ferric citrate hydrate patients and 26.7% of patients receiving placebo. CONCLUSION In patients with nondialysis-dependent CKD, 12-week treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and fibroblast growth factor-23 while simultaneously increasing serum iron parameters.

Serum phosphate and calcium should be primarily and consistently controlled in prevalent hemodialysis patients.

Mineral metabolism affects mortality in hemodialysis patients and is identified by imbalances in serum phosphate (P), calcium (Ca), and parathyroid hormone (PTH). We examined associations between annual mineral values (P, Ca, PTH) and mortality in a 3‐year cohort (Dec 2006–2009) of 128 125 hemodialysis patients using three models, that is, baseline, time‐dependent and time‐average Cox models. We also examined associations between achieved Japanese guideline targets (P: 3.5−6.0 mg/dL, corrected Ca 8.4−10.0 mg/dL, intact PTH 60−180 mg/dL) and all‐cause survival to elucidate which parameter should be controlled as a priority. High and low serum P (>6.0 or ≤3.5 mg/dL), high Ca (>9.5 mg/dL), higher PTH (>300 pg/mL) and lower PTH (≤60 pg/mL) were significantly associated with high mortality in all three models (P < 0.01). When we examined the association between combination of mineral targets and mortality, patients who achieved all targets simultaneously (20% of subjects, reference) showed lowest mortality. Those who achieved both P and Ca targets showed the same mortality as the reference group. Those who only met P target had a lower risk of death (hazard ratio = 1.17) compared to those that achieved Ca or PTH target (1.41, 1.47, respectively). As time of achieving P and Ca targets increased, all‐cause mortalities diminished incrementally, significantly. Mineral metabolism disorder would lead to high mortality in prevalent hemodialysis patients. Among mineral values, P would be the strongest predictor for high mortality. Consistent achievement of P and Ca targets would lead to good survival.

A randomized trial of JTT-751 versus sevelamer hydrochloride in patients on hemodialysis

BACKGROUND JTT-751 is a novel phosphate binder containing ferric citrate as the active ingredient. METHODS In this Phase 3, multicenter, randomized, open-label, parallel-group study, we compared the efficacy and safety of JTT-751 and sevelamer hydrochloride in patients undergoing hemodialysis. A total of 230 patients with a serum phosphate ≥1.97 and <3.23 mmol/L were randomized to JTT-751 (dose adjusted between 1.5 and 6.0 g/day) or sevelamer hydrochloride (dose adjusted between 3.0 and 9.0 g/day) for 12 weeks. The primary outcome was change in serum phosphate from baseline to end of treatment. Secondary outcomes included the changes in corrected serum calcium and intact parathyroid hormone (PTH). The changes in ferritin, transferrin saturation and erythropoiesis-stimulating agent dose were additional outcomes. RESULTS Changes in serum phosphate at the end of treatment were -0.82 mmol/L in the JTT-751 group and -0.78 mmol/L in the sevelamer group, establishing non-inferiority of JTT-751 compared with sevelamer (least squares mean, -0.03 mmol/L; 95% confidence interval, -0.13 to 0.07 mmol/L). Corrected serum calcium increased and PTH decreased from baseline within both groups; changes between groups were similar. Gastrointestinal disorders were the most common adverse events in both groups; the incidence of diarrhea was higher in the JTT-751 group, while constipation occurred frequently in the sevelamer group. Treatment with JTT-751 resulted in significant relative increases in serum ferritin and transferrin saturation. CONCLUSIONS Efficacy and safety of JTT-751 was comparable to sevelamer in patients on hemodialysis with hyperphosphatemia. Differential adverse effects were observed; biochemical markers of iron status increased in patients treated with JTT-751. TRIAL REGISTRATION NUMBER CTI-111433 (The Japan Pharmaceutical Information Center at: http//www.clinicaltrials.jp). Date of registration: 7 March 2011.

Effect of Oral JTT-751 (Ferric Citrate) on Hyperphosphatemia in Hemodialysis Patients: Results of a Randomized, Double-Blind, Placebo-Controlled Trial

Background/Aims: JTT-751 (ferric citrate hydrate) is a novel oral, iron-based phosphate binder being developed for the treatment of hyperphosphatemia among chronic kidney disease patients who are on dialysis. This study investigated the dose-response and safety of JTT-751 among Japanese hemodialysis patients. Methods: This was a multicenter, randomized, placebo-controlled, double-blind, parallel-group, comparative study. A total of 192 subjects with serum phosphorus (P) levels between 6.1 and 10.0 mg/dl were randomized to JTT-751 (1.5, 3 or 6 g/day) or to placebo treatment for 28 days. Changes in serum P level from baseline were examined. Results: In the full analysis set, the mean change in serum P level at week 4 was 0.04, –1.28, –2.16 and –4.10 mg/dl in the placebo, 1.5-grams, 3-grams and 6-grams/day groups, respectively, demonstrating a dose-response relationship up to 6 g/day. Overall, a reduction in serum P levels to ≤5.5 mg/dl was achieved in 2.5, 16.7, 50.0 and 92.6% of subjects, in the placebo, 1.5-grams, 3-grams and 6-grams/day groups, respectively. The most common adverse events (AEs) were gastrointestinal disorders. Most AEs were mild. In 25 patients, treatment was discontinued due to increased transferrin saturation ≥50%; however, this was not considered to be a safety issue. Conclusions: When hemodialysis subjects received JTT-751 at doses between 1.5 and 6 g/day for 28 days, serum P levels were significantly reduced in a dose-dependent manner (p < 0.001). JTT-751 was found to be efficacious and safe, with the majority of subjects in the 6-grams/day group achieving a serum P level of ≤5.5 mg/dl.

Experimental IgA Nephropathy Induced by a Low-Dose Environmental Mycotoxin, Nivalenol

Based on the hypothesis that IgA nephropathy (IgAN) is triggered by some exogenous antigen(s) which induces dysregulation of the mucosal immune system, we developed an experimental model of orally induced IgAN by an environmental mycotoxin, nivalenol (NIV), which often contaminates agricultural products in Southeast Asia and Japan. In the present study, low doses of oral NIV reproducibly induced significant IgA deposits in the glomerular mesangium and elevated serum IgA levels in mice irrespective of the strain; the degree of immunopathological changes analogous to human IgAN was associated with the dose and duration of NIV treatment. Furthermore, a competitive enzyme-linked immunosorbent assay with an NIV analogue-protein conjugate disclosed that the IgA antibody in the sera from the NIV model mice had a higher affinity to the mycotoxin. Conclusively, these findings suggest that NIV induces some pathological changes in mice which resemble those in human IgAN, and that this mycotoxin is associated with pathogenesis in some types of glomerulonephritis.

A higher serum alkaline phosphatase is associated with the incidence of hip fracture and mortality among patients receiving hemodialysis in Japan

BACKGROUND Monitoring of serum alkaline phosphatase (ALP) is recommended in the management of chronic kidney disease-mineral and bone disorder (CKD-MBD). However, unlike calcium, phosphate or parathyroid hormone, the relationship between serum ALP and patient outcome receiving hemodialysis (HD) in Japan is unknown. METHODS Baseline data of 185 277 HD patients with duration >90 days (66 ± 12 years, males 61.9%, and median HD duration of 5.8 years) were extracted from a nationwide dialysis registry at the end of 2009 in Japan. Outcomes were then evaluated using the registry at the end of 2010 using a multivariate logistic regression analysis. RESULTS During 1-year follow-up, 14 230 (7.9%) patients died of all causes, including 6396 (3.6%) cardiovascular deaths. In addition, 1586 patients (1.0%) were newly diagnosed as hip fractures. All-cause and cardiovascular mortality and the incidence of hip fracture were higher in line with the increase in baseline serum ALP. On multivariate analysis, patients with the highest ALP quartile had higher all-cause and cardiovascular mortalities and a higher incidence of hip fracture than those with the lowest quartile [odds ratio (OR) 1.46, 95% confidence interval (CI) 1.33-1.60; OR 1.25, 95% CI 1.10-1.42; and OR 1.71, 95% CI 1.33-2.18, respectively]. CONCLUSIONS In this large cohort study, higher serum ALP levels were independently associated not only with mortality but also with the incidence of hip fracture in Japanese HD patients. Further study is needed to test whether serum ALP measurements could improve the patient outcomes.

Serum soluble α-klotho in hemodialysis patients.

BACKGROUND The extracellular domain of klotho is cleaved and released into various extracellular fluids, such as blood, urine, and cerebrospinal fluid, as soluble α-klotho (sαKl). METHODS We measured sαKl in 53 hemodialysis patients and 20 healthy controls to examine its role in mineral metabolism. RESULTS The sαKl level of the hemodialysis patients was 430 pg/ml (386 - 540 pg/ml, which was lower than that of healthy controls 740 pg/ml (550 - 913 pg/ml, p < 0.01). The serum sαKl level showed a positive correlation with serum phosphorus (P) (σ = 0.33, p = 0.014), while serum corrected Ca tended to be negatively correlated with sαKl (σ = -0.26, p = 0.06). Both parameters showed the same trends in healthy subjects. However, there was no significant association between serum sαKl and age (σ= 0.21, p = 0.14), intact PTH (σ = -0.08, p= 0.55), whole PTH (σ = -0.08, p = 0.59), or FGF23 (σ = -0.07, p = 0.62). Multiple regression analysis showed that P was independently associated with the serum sαKl levels (total adjusted R2 = 0.18, p = 0.02). CONCLUSIONS The sαKl level was lower in hemodialysis patients than in healthy persons. Serum P level was independently associated with the serum sαKl level.