Hirotaka Komaba

Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients.

Fibroblast growth factor 23 (FGF23) exerts its effect by binding to its cognate FGF receptor 1 (FGFR1) in the presence of its co-receptor Klotho. Parathyroid glands express both FGFR1 and Klotho, and FGF23 decreases parathyroid hormone gene expression and hormone secretion directly. In uremic patients with secondary hyperparathyroidism (SHPT), however, parathyroid hormone secretion remains elevated despite extremely high FGF23 levels. To determine the mechanism of this resistance, we measured the expression of Klotho, FGFR1, and the proliferative marker Ki67 in 7 normal and 80 hyperplastic parathyroid glands from uremic patients by immunohistochemistry. All uremic patients had severe SHPT along with markedly high FGF23 levels. Quantitative real-time reverse transcription PCR showed that the mRNA levels for Klotho and FGFR1correlated significantly with their semi-quantitative immunohistochemical intensity. Compared with normal tissue, the immunohistochemical expression of Klotho and FGFR1 decreased, but Ki67 expression increased significantly in hyperplastic parathyroid glands, particularly in glands with nodular hyperplasia. These results suggest that the depressed expression of the Klotho-FGFR1 complex in hyperplastic glands underlies the pathogenesis of SHPT and its resistance to extremely high FGF23 levels in uremic patients.

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

FGF23–parathyroid interaction: implications in chronic kidney disease

Over the past few years there have been considerable advances in our understanding of the physiological regulation of mineral homeostasis. One of the most important breakthroughs is the identification of fibroblastic growth factor 23 (FGF23) and its role as a key regulator of phosphate and 1,25-dihydroxyvitamin D metabolism. FGF23 exerts its biological functions by binding to its cognate receptor in the presence of Klotho as a cofactor. FGF23 principally acts on the kidney to induce urinary phosphate excretion and suppresses 1,25-dihydroxyvitamin D synthesis, thereby indirectly modulating parathyroid hormone secretion. FGF23 also acts directly on the parathyroid to decrease parathyroid hormone synthesis and secretion. In patients with chronic kidney disease, FGF23 levels increase progressively to compensate for phosphate retention, but these elevated FGF23 levels fail to suppress the secretion of parathyroid hormone, particularly in the setting of uremia. Recent data suggest that this parathyroid resistance to FGF23 may be caused by decreased expression of Klotho-FGFR1 complex in hyperplastic parathyroid glands. This review summarizes recent insights into the role of FGF23 in mineral homeostasis and discusses the involvement of its direct and indirect interaction with the parathyroid gland, particularly focusing on the pathophysiology of secondary hyperparathyroidism in chronic kidney disease.

Cinacalcet Effectively Reduces Parathyroid Hormone Secretion and Gland Volume Regardless of Pretreatment Gland Size in Patients with Secondary Hyperparathyroidism

BACKGROUND AND OBJECTIVES Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls. RESULTS Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm(3) (group S) and 25 had at least one enlarged gland larger than 500 mm(3) (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n = 87) where parathyroid gland volume progressively increased with traditional therapy alone. CONCLUSIONS Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

The role of FGF23 in CKD—with or without Klotho

During the past few years, fibroblast growth factor 23 (FGF23) has emerged as a central player of disordered mineral metabolism in patients with chronic kidney disease (CKD). The physiological actions of FGF23 are to promote phosphaturia, decrease production of 1,25-dihydroxyvitamin D and suppress secretion of parathyroid hormone mediated through FGF receptors and the co-receptor Klotho. Recent epidemiological studies demonstrate strong associations between elevated FGF23 levels in patients with CKD and poor clinical outcomes. In patients with end-stage renal disease, markedly increased levels of FGF23 fail to exert Klotho-dependent effects owing to the absence of a functioning kidney and downregulation of the parathyroid complex of Klotho and FGF receptor 1. In this setting, FGF23 may exert a toxic effect on the cardiovascular system in a Klotho-independent manner. Future research should examine whether treatment to attenuate the pathogenic action of FGF23 provides survival benefits in patients with CKD.

Effect of Intravenous Saccharated Ferric Oxide on Serum FGF23 and Mineral Metabolism in Hemodialysis Patients

Background/Aims: Fibroblast growth factor-23 (FGF23) plays a central role in the development of hypophosphatemia and inappropriately low 1,25-dihydroxyvitamin D induced by iron therapy for iron-deficiency anemia. The aim of this study was to examine the effect of intravenous saccharated ferric oxide on serum FGF23 levels and mineral metabolism in hemodialysis patients. Methods: This prospective study enrolled 27 hemodialysis patients who had iron-deficiency anemia defined by a hemoglobin concentration <10.5 g/dl and serum ferritin <100 ng/ml. Intravenous saccharated ferric oxide at a dose of 40 mg was administered three times weekly over 3 weeks. The dose of active vitamin D and phosphate binders was kept unchanged. Serum FGF23, intact parathyroid hormone (PTH) and other parameters were prospectively monitored for 5 weeks. Results: Serum FGF23 levels were markedly elevated [3,453 (338–6,383) pg/ml] at baseline. After 3 weeks of intravenous saccharated ferric oxide treatment, serum FGF23 further increased to 4,701 (1,251–14,396) pg/ml, and returned to the baseline values after 2 weeks of observation. There was also a significant decrease in intact PTH but no changes in serum calcium and phosphorus. Conclusions: Intravenous saccharated ferric oxide induces further increase in elevated FGF23 levels in hemodialysis patients. This increase does not induce hypophosphatemia and inappropriately low 1,25-dihydroxyvitamin D in the absence of functioning kidney, but may result in transient PTH suppression – possibly by directly acting on the parathyroid.

Oxidative and Nitrosative Stress and Progression of Diabetic Nephropathy in Type 2 Diabetes

Background: The role of nitric oxide (NO) is controversial in diabetes nephropathy progression and the mechanisms remain unknown, especially in non-obese type 2 diabetes. To examine mechanisms of nephropathy progression in non-obese type 2 diabetes, we used spontaneously diabetic Torii (SDT) rats, a newly established model of non-obese type 2 diabetes. Methods: Fourteen male Sprague-Dawley rats were used as a control (20 weeks, n = 6; 30 weeks, n = 8), and 20-week-old male SDT rats were divided into 2 groups: diabetic (DM, n = 8) and DM + insulin (n = 8) groups. Twenty- and 36-week-old rats were sacrificed, and blood, urine, and histomorphometric analyses, mRNA expression analysis of endothelial NO synthase (eNOS) and NADPH oxidase, and blood pressure measurement were performed. Results: At 36 weeks, NO metabolites, and 8-hydroxydeoxyguanosine (8-OHdG) were significantly higher in the diabetic group than in the other 2 groups. Further renal studies showed increased glomerular volume and mesangial area, and intensified eNOS, 8-OHdG, and nitrotyrosine immunostaining in the diabetic group. Oxidative and nitrosative stress were positively associated with increased glomerular volume and mesangial area, which were mostly recovered by insulin therapy. Conclusions: NO and oxidative stress increased in SDT rats, suggesting that these play key roles in nephropathy progression in non-obese type 2 diabetes.

Increased Serum High-Molecular-Weight Complex of Adiponectin in Type 2 Diabetic Patients with Impaired Renal Function

Background/Aim: Adiponectin, an adipocyte-derived protein, has been shown to exert antidiabetic, anti-inflammatory, and antiatherosclerotic effects. Although recent reports show an increase in the total adiponectin levels in chronic kidney disease patients and in patients with end-stage renal disease, the nature of biodegradation and renal involvement of adiponectin is largely unknown. We aimed at determining whether the high-molecular-weight (HMW) complex of adiponectin is associated with renal insufficiency in type 2 diabetic patients. Methods: A total of 179 type 2 diabetic patients were selected from among outpatients and divided into four groups according to their albumin-to-creatinine ratio: patients with normoalbuminuria (n = 86), patients with microalbuminuria (n = 44), patients with macroalbuminuria (n = 23), and patients on hemodialysis (n = 26). The serum HMW adiponectin was specifically assayed with a commercially available enzyme-linked immunosorbent assay kit. Results: The HMW adiponectin levels were higher in patients on hemodialysis (17.1 ± 8.2 µg/ml) and in those with macroalbuminuria (14.3 ± 8.7 µg/ml) than in patients with normoalbuminuria (7.2 ± 5.6 µg/ml) and microalbuminuria (10.8 ± 7.0 µg/ml). Univariate linear regression analysis showed that the HMW adiponectin concentrations correlated negatively with the estimated glomerular filtration rate in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria (r = –0.42, p < 0.001). Multiple stepwise regression analysis disclosed that estimated glomerular filtration rate, pioglitazone therapy, gender differences, and systolic blood pressure were independently associated with HMW adiponectin levels (r = 0.56). Conclusions: The serum HMW adiponectin concentrations are higher in type 2 diabetic patients with nephropathy, and these levels are also associated with renal insufficiency.

Parathyroid Function in Chronic Kidney Disease: Role of FGF23-Klotho Axis

The parathyroid gland plays a central role in the regulation of mineral metabolism. In patients with chronic kidney disease (CKD), circulating levels of parathyroid hormone (PTH) are progressively increased as kidney function declines, as a result of phosphate retention, hypocalcemia, decreased production of 1,25-dihydroxyvitamin D [1,25(OH)2D], endogenous changes within the parathyroid gland, and skeletal resistance to the actions of PTH. In addition, the identification of fibroblast growth factor 23 (FGF23) and its cofactor Klotho offers important implications for the deeper understanding of disordered mineral metabolism in CKD. In early CKD, increased FGF23 to maintain neutral phosphate balance results in suppression of renal 1,25(OH)2D production and thereby triggers the early development of secondary hyperparathyroidism. FGF23 also acts directly on the parathyroid to decrease PTH synthesis and secretion, but this effect is blunted in advanced stages of CKD, due to decreased expression of the Klotho-FGF receptor 1 complex and increased concentrations of C-terminal FGF23 that competes with full-length FGF23 for binding to the receptor complex. Recent clinical studies also reported that high levels of FGF23 are associated with morbidity and mortality as well as treatment resistance to active vitamin D, suggesting the potential of FGF23 as a novel biomarker to guide treatment of disordered phosphate metabolism in CKD. This review will discuss the pathogenesis of secondary hyperparathyroidism, particularly focusing on the emerging role of the FGF23-Klotho axis in patients with CKD.

Adiponectin is associated with brain natriuretic peptide and left ventricular hypertrophy in hemodialysis patients with type 2 diabetes mellitus.

Background: Adiponectin, an adipocyte-derived hormone, has been shown to prevent the progression of left ventricular hypertrophy (LVH). However, recent studies have demonstrated increased levels of adiponectin according to the severity of chronic heart failure. We therefore investigated the relationships between adiponectin, brain natriuretic peptide (BNP), and LVH in type 2 diabetic patients on hemodialysis. Methods: The study population comprised 41 type 2 diabetic patients on hemodialysis. Left ventricular mass index (LVMI) and criteria for LVH were determined on the basis of echocardiographic findings. Serum adiponectin and plasma BNP levels were assayed with a commercially available kit. Results: Serum adiponectin levels significantly correlated with BMI (r = –0.49, p < 0.01), HDL-C (r = 0.36, p < 0.05) and TG (r = –0.49, p < 0.01). In addition, serum adiponectin levels correlated significantly and positively with plasma BNP levels (r = 0.36, p < 0.05). This relationship remained significant after adjustment for age, gender, and BMI (r = 0.34, p < 0.05). Serum adiponectin levels as well as plasma BNP levels were significantly higher than in patients without LVH (p < 0.05; p < 0.01, respectively), accompanied by a positive correlation between these levels and LVMI (r = 0.42, p < 0.01; r = 0.32, p < 0.05, respectively). Conclusion: Increased levels of adiponectin were associated with elevated BNP levels and LVH in hemodialysis patients with type 2 diabetes mellitus. It is speculated that adiponectin levels may be modulated by chronic hypervolemic state in this population.