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Osteoprotegerin (OPG) is a soluble glycoprotein which inhibits osteoclastic formation and activity. Circulating OPG levels are elevated in uremia. The role of elevated circulating OPG levels in uremia remains unknown. Blood samples were obtained from 22 non-diabetic dialysis patients who underwent iliac bone biopsy examination. The serum OPG concentration was assayed by ELISA. The circulating OPG levels showed a negative correlation with the ratio of eroded surface/bone surface (ES/BS) in biopsied iliac bone samples among 15 of those with plasma intact PTH levels less than 300 pg/mL (P0.05, r(2) = 0.270). Patients with serum OPG levels less than 2.0 ng/mL showed significantly greater ES/BS values than those with levelsor =3.0 ng/mL, while the intact PTH levels were comparable among those groups. These tendencies disappeared when seven patients with plasma intact PTH levels more than 300 pg/mL were included into the analysis. In conclusion, circulating OPG levels showed a significant negative correlation with a bone resorption parameters in dialysis patients with mild secondary hyperparathyroidism. Circulating OPG might have a suppressive effect on osteoclastic bone resorption in dialysis patients.

Fibroblast growth factor 23 (FGF23) is a recently characterized peptide hormone produced mainly in the bone. It is secreted in response to dietary phosphorus load, and its main function is the promotion of urinary phosphate excretion and the suppression of active vitamin D (1,25D) production in the kidney. As such, FGF23 plays an important role in the maintenance of systemic phosphate homeostasis. In the advanced stages of chronic kidney disease (CKD), the kidney cannot excrete a phosphate load even in the presence of high levels of FGF23. This results in both hyperphosphatemia and a low level of 1,25D that stimulates the secretion of parathyroid hormone (PTH), leading to the development of secondary hyperparathyroidism. In chronic dialysis patients without residual renal function, FGF23 levels become extremely high due to stimulation by vitamin D therapy as well as by high levels of serum phosphate and PTH. Recent investigations have demonstrated that serum FGF23 level can be a useful marker for the prediction of the future development of refractory hyperparathyroidism and the response to vitamin D therapy in dialysis patients. In addition, putative protective roles of FGF23 against calcification have also been speculated on. Further elucidation of the mechanisms of FGF23 action will be needed to understand the various roles of FGF23 in CKD-Mineral and Bone Disorder (CKD-MBD).

Abeta-2M-amyloidosis is a type of systemic amyloidosis that is specifically seen in patients with chronic kidney diseases. The precursor protein of Abeta-2M-amyloid fibril is beta2-microglobulin, and its elevated serum level is the main cause of Abeta-2M-amyloidosis in patients with kidney failure. However, the precise mechanism of Abeta-2M-amyloidogenesis remains unclear. In vitro analyses of Abeta-2M amyloidogenesis are still being actively conducted. Osteolytic lesions are often found around synovial membrane with Abeta-2M-amyloid deposition. Both evident osteoclastogenesis and active osteoclastic bone resorption are found, while osteoblastic bone formation is absent in the lesion most likely associated with the inflammation caused by infiltrating macrophages/monocytes into Abeta-2M-amyloid deposition. The precise cell biological mechanism of this inflammatory change is unknown. Further studies are needed to establish specific treatments against this as yet unsolved problem with long-term dialysis therapy.

Fibroblast growth factor 23 (FGF23) is a member of the fibroblast growth factor superfamily which displays a strong phosphaturic action and an inhibition of vitamin D 1-alpha hydroxylase activity. Fourty-six patients undergoing maintenance hemodialysis therapy participated in the study. They were randomly divided into 2 groups, and treated with either 3 g sevelamer hydrochloride+3 g of calcium bicarbonate (CaCO3), or 3 g of CaCO3 alone. Serum FGF23 levels were determined by a sandwich enzyme-linked immunosorbent assay (ELISA) system that detects the intact form of FGF23 molecules. Although the serum inorganic phosphate (Pi) levels were comparable before treatment, the levels were significantly lower in the patients treated with sevelamer hydrochloride+CaCO3 than those with CaCO3 alone after 4 weeks of treatment (P

Electron-dense deposits are often found around glomerular capillary lumens in patients with glomerulonephritis, forming a portion of the blood-urine barrier (BUB).Four hundred and four patients with primary glomerular diseases or donors for living-related kidney transplantation who underwent both percutaneous renal biopsy and renal clearance tests were included in the study. Sodium thiosulfate and paraamino hippurate double-clearance studies were performed with catheterized urinary collection. The filtration fraction (FF) was determined as follows: FF = sodium thiosulfate clearance/paraamino hippurate clearance (CPAH: ). Histomorphometric analyses were performed in 53 patients with overt para-capillary electron-dense deposits (PCEDD) by electron microscopic observations.Patients with membranous nephropathy and membranoproliferative glomerulonephritis showed significantly lower levels of FF than the donors for living-rebated kidney transplantation (normal controls). FF levels were significantly lower in patients with PCEDD than in those without (P0.001), while the levels of mean blood pressure and CPAH: were comparable in the two groups. The PCEDD/BUB ratio demonstrated a significant negative correlation with FF (P0.0001; r(2) = 0.331). Patients with a ratio of 0.5 or more showed significantly lower FF levels than those with a ratio of 0.25 or less.PCEDD significantly affected FF levels in patients with primary glomerular diseases. FF may not be an accurate indicator of intraglomerular blood pressure in patients with overt PCEDD.

This review summarizes the molecular properties and biological roles of a new phosphaturic factor, fibroblast growth factor 23 (FGF23). Significant roles of FGF23 are discussed, especially in terms of its effects on the kidney, the main target organ.FGF 23 is a recently discovered phosphaturic factor. Several animal experiments including overexpression or ablation of the FGF23 gene have recently revealed the significant effects of this factor on phosphate excretion and on vitamin D synthesis in the kidney. Although FGF23 was originally identified as a factor responsible for several hypophosphatemic disorders, recent data indicate its role in the physiological regulation of phosphate homeostasis. In chronic kidney disease, FGF23 plays a crucial role in the pathogenesis of secondary hyperparathyroidism. Effects of FGF23 on other organs including bone and intestine remain to be elucidated.FGF23 is a physiological regulator of phosphate homeostasis. Excessive activity of FGF23 with normal renal function results in hypophosphatemia, low 1,25-dihydroxyvitamin D levels, and rickets/osteomalacia. By contrast, excessive FGF23 activity suppresses 1,25-dihydroxyvitamin D synthesis, but may not be sufficient to excrete the phosphate load appropriately with deteriorating renal function, both of which contribute to the development of hyperparathyroidism.

Objective: Hyperthyroidism is a well-described cause of hyperphosphatemia. We aimed to clarify the physiological role of fibroblast growth factor (FGF)-23 in serum phosphate homeostasis in patients with Graves’ disease during the course of treatment for hyperthyroidism. Context: The study group comprised 56 patients (45 for a cross-sectional study and 11 for a longitudinal study) with Graves’ disease. For the cross-sectional study, patients were assigned, on the basis of their serum phosphate level, to a hypophosphatemia group (n = 14), a normophosphatemia group (n = 16), or a hyperphosphatemia group (n = 15). Serum FGF-23, calcium, phosphate, PTH, and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels were compared between the three groups. For the longitudinal study, we assessed changes in these biochemical indices before and after antithyroid treatment. Results: In the cross-sectional study, the serum FGF-23 level was significantly higher (P < 0.05) in the hyperphosphatemia group than in the other groups (61 ± 36 ng/liter vs. 31 ± 22 ng/liter and 30 ± 9 ng/liter). In the longitudinal study, serum levels of FGF-23 decreased significantly (P < 0.05) from a high of 54 ± 12 ng/liter before treatment to 29 ± 14 ng/liter after treatment. In contrast, the serum 1,25(OH)2D level increased significantly (P < 0.005) from 55 ± 22 pmol/liter before treatment to 185 ± 76 pmol/liter 3 months after treatment. Serum FGF-23 levels were positively correlated with serum phosphate levels (P < 0.0001) and negatively correlated with serum 1,25(OH)2D levels (P < 0.0001). Conclusions: The significant positive correlation between serum levels of phosphate and FGF-23 indicates that FGF-23 may play an important role in serum phosphate homeostasis by its up-regulation in the hyperphosphatemic condition.

Adynamic bone disease is characterized by an extremely low bone turnover bone due to the lack of osteoid formation. An abnormal calcium metabolism refractory to hypocalcemia lies behind the development of adynamic bone. Extraskeletal calcification is often seen in patients with adynamic bone disease. Hypoparathyroidism appeared to be an life prognosis limiting factor in dialysis patients. Most of them are considered to be with adynamic bone disease.

The skeletal resistance to PTH is a phenomenon specifically found in uremia which is considered to be a back ground abnormality associated with the development of renal bone diseases. The skeletal resistance to PTH appears as an anti-calcemic effect against exogenous PTH load in the physiological aspect, and as the discrepancy between serum PTH level and bone turnover in the morphological aspect. Therefore, it can be a common pathogenesis of both secondary hyperparathyroidism and adynamic bone. The break through in osteoclastology largely attributed to understand the pathophysiology of the skeletal resistance. As a result, circulating osteoprotegerin appeared to be one of the factors to promote the skeletal resistance to PTH in uremia through suppressing osteoclastogenesis/activation. However, the mechanism why circulating osteoprotegerin level is elevated remains unknown. Further investigations are certainly needed.

The skeletal resistance to PTH is a phenomenon specifically found in uremia. The skeletal resistance to PTH appears as an anti-calcemic effect against exogenous PTH load in the physiological aspect, and as the discrepancy between serum PTH level and bone turnover in the morphological aspect. Therefore, it can be a common pathogenesis of both secondary hyperparathyroidism and adynamic bone. Osteoprotegerin, a newly found osteoclastogenesis inhibitory factor, may be one of such uremic toxins that promote the skeletal resistance to PTH in uremia. However, the mechanism why circulating osteoprotegerin level is elevated remains unknown.

Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients.BackgroundSecondary hyperparathyroidism is a common complication among long-term dialysis patients. The method of predicting future parathyroid function has not yet been established. Fibroblast growth factor-23 (FGF-23) is a newly found humoral phosphaturic factor.MethodsOne hundred and three nondiabetic dialysis patients whose plasma intact parathyroid hormone (PTH) levels were below 300 pg/mL were included in the study. Blood samples were stored at -80°C for 2 years. Meanwhile, each physician in charge decided upon the strategy of medical therapy for maintaining intact PTH levels between 150 and 300 pg/mL. Patients were judged 2 years after the sample collection with regard to whether the hyperparathyroidism responded to the medical therapy. The definition of refractory secondary hyperparathyroidism was either (1) retaining intact PTH levels greater than 300 pg/mL 2 years after sample collection, or (2) having received the parathyroid intervention therapy during the observation period. Serum FGF-23 levels were determined with a sandwich enzyme-linked immunosorbent assay system that detects biologically active human FGF-23.ResultsSeventeen patients with intact PTH levels greater than 300 pg/mL were judged as having secondary hyperparathyroidism refractory to medical therapy. A stepwise regression analysis revealed that only serum levels of FGF-23 were significantly related to the prognosis of parathyroid function. A receiver-operated characteristic analysis demonstrated that the area under the curves obtained from FGF-23 (7099.9) was significantly greater than that obtained from intact PTH (6306.4, P < .01) and Ca × Pi (5670.3, P

Background and aim We have developed a new rat model that mimics the natural course of diabetic nephropathy seen in type 2 diabetes. Methods Nine days after intravenous injection of streptozotocin (STZ) (40 mg/kg) or vehicle to 8-week-old male Sprague–Dawley rats, the animals’ right kidneys were surgically removed. Two weeks after surgery, the STZ-injected rats were fed on either a high-fat (ST + HF) or a normal (ST) diet, while the vehicle-injected rats were fed on the high-fat diet (HF). Results Baseline biochemical markers did not differ between the three groups. Only the ST + HF group showed a significant increase in plasma glucose levels after 15 weeks, and simultaneously plasma insulin levels started to decrease, followed by an increase in plasma total cholesterol and triglyceride levels at 25 weeks and slightly later by an increase in blood pressure. In the ST + HF group, significant microalbuminuria was detected at 15 weeks followed by overt proteinuria, both of which were absent in the other two groups. Also in ST + HF, the creatinine clearance rate increased until week 15, and then gradually decreased. Histologically, ST + HF rats showed mesangial expansion at week 25, and diffuse glomerular sclerosis at the end of the experiments. Conclusion The chronological changes in biochemical, physiological and histological markers in ST + HF rats are reminiscent of human type 2 diabetes and nephropathy. Our new model of type 2 diabetic nephropathy should help us to understand the pathophysiology of the disease and serve to explore measures to prevent and treat diabetic nephropathy.

Many investigators used to believe that active vitamin D is a promotive factor for bone resorption. However, active vitamin D shows an osteoprotective action when administrated as an anti-osteoporotic agent. Recently, active vitamin D agents are considered as an inhibitor for bone resorption. However, it is difficult to evaluate if it is also the case in chronic renal failure, since high-turnovered osteopenia found in uremic patients are brought about by secondary hyperparathyroidism.

PURPOSE OF REVIEW: This review focuses on the impact of a recent breakthrough in bone cell biology for understanding the pathophysiology of bone/vascular abnormalities associated with uraemia. RECENT FINDINGS: Osteoprotegerin is a humoral osteoclastogenesis/osteoclast activation inhibitory factor, which belongs to the TNF-alpha receptor superfamily. Serum osteoprotegerin levels are elevated along with the deterioration of the glomerular filtration rate. The circulating osteoprotegerin molecules were likely to preserve the activity of osteoclastogenesis inhibition, and the levels in many dialysis patients were high enough to inhibit osteoclastogenesis. The higher serum osteoprotegerin levels were related to the development of vascular calcification. SUMMARY: Osteoprotegerin is a potential uraemic toxin that increases the skeletal resistance to PTH. However, the roles of increased circulating osteoprotegerin on bone and/or vascular abnormalities in uraemia remain to be clarified.

Patients who have renal failure and are on dialysis therapy experience serious complications caused by low-molecular-weight uremic toxin proteins normally filtered by glomeruli and metabolized by proximal tubule cells (PTC). Dialysis-related amyloidosis is one such complication induced by systemic deposition of amyloid proteins derived from 12-kD β 2 -microglobulin (β 2 -m). Despite the use of high-flux membrane hemodialysis devices and direct absorbent columns, the removal of β 2 -m is suboptimal, because the effects are transient and insufficient. Megalin is expressed in the apical membranes of PTC and recognized as a multiligand endocytic receptor that binds numerous low-molecular-weight proteins, including β 2 -m. This study tested the feasibility of an intracorporeal therapeutic model of continuous β 2 -m removal using megalin-expressing cell implantation. By cell association and degradation assays, rat yolk sac-derived L2 cells were identified to internalize and degrade β 2 -m via megalin. The cells were effectively implanted within the subcutaneous tissues of nude mice using a type I collagen scaffold and a method inducing local angiogenesis. After nephrectomy and intraperitoneal injection with 125 I-β 2 -m, it was found that the implanted cells took up the labeled ligand, efficiently removing it from the blood. Bioengineered implantation of megalin-expressing cells may represent a new supportive therapy for dialysis patients to compensate for the loss of renal protein metabolism and remove uremic toxin proteins. E-mail: akisaito@med.niigata-u.ac.jp

Background/Aims: Little is known about the microstructural changes in bone tissue in the early phase of chronic renal failure (CRF). In this study, we analyzed the bone tissue in a rat model of early CRF using a high-resolution X-ray tomographic system, i.e. microfocus computed tomography (MXCT), which is capable of detecting microscopic structural changes in bone tissue. Methods: CRF rats were created by 7/8 nephrectomy by ligation of the renal artery branches, and were sacrificed 24 weeks after surgery. MXCT and bone mineral densitometry by single-energy X-ray absorptiometry (SXA) were performed using extracted bone samples. Images obtained by MXCT were further analyzed by node-strut morphometry. Results: Biochemical analysis confirmed that CRF was induced in 7/8-renal artery-ligated rats. MXCT demonstrated a significant decrease in trabecular bone in uremic rats, whereas SXA was unable to detect the difference. The node-strut method revealed decreased trabecular connectivity, with little change in the thickness of the trabecular bone in uremic rats. Conclusion: MXCT was able to detect significant changes in trabecular bone at an early stage of renal failure. The observed structural changes differed from those found in long-term dialysis patients. MXCT is a practical and promising device used for the non-invasive evaluation of early bone changes in uremic patients.

The so-called "intact parathyroid hormone (iPTH)" assay detects large C-terminal PTH fragments that are lacking several N-terminal amino acid residues in addition to 1-84 PTH molecules.Blood samples were obtained from 65 predialysis patients (male, 35; female, 30) and 109 dialysis patients (male, 73; female, 36). The plasma 1-84 PTH levels were determined by a specific immunoradiometric assay (IRMA).The ratio of 1-84 PTH/iPTH did not show a significant correlation with glomerular filtration rate (GFR) among patients with a GFR of more than 80 ml/min, while it showed a positive correlation with GFR among patients with a GFR of less than 80 ml/min. The ratio of 1-84 PTH/iPTH demonstrated a significant tendency to decrease in the order of patients with normal renal function (0.928 +/- 0.182), those with renal dysfunction (0.836 +/- 0.186; P0.05 vs patients with GFR80 ml/min [i.e., normal renal function]), and those with maintenance hemodialysis (0.618 +/- 0.123; P0.01 vs patients with GFR80 ml/min). The plasma levels of 1-84 PTH and conventional iPTH showed a close correlation in dialysis patients. Neither 1-84 PTH levels nor secondary parameters calculated from them showed a better correlation with bone metabolic markers than iPTH levels.Circulating large C-terminal PTH fragment levels are increased in uremic patients. However, this noninvasive study failed to demonstrate the superiority of the specific 1-84 assay compared with the conventional iPTH assay to evaluate bone metabolism.

Skeletal resistance to parathyroid hormone (PTH) is one of the major abnormalities underlying bone diseases in uremia, the mechanism of which has not yet been fully elucidated. Osteoclastogenesis inhibitory factor (OCIF), or osteoprotegerin, is a natural decoy receptor for osteoclast differentiation factor (ODF), produced by osteoblasts in response to PTH. To elucidate the kinetics and roles of OCIF in chronic renal failure, serum OCIF levels were measured in 46 predialysis patients and 21 dialysis patients by means of enzyme-linked immunosorbent assay (ELISA). Serum OCIF levels in predialysis patients increased as renal function declined (OCIF = 1.178 + 0.233 x creatinine; r2 = 0.413; P < 0.0001). Twenty-four-hour creatinine clearance and 1/OCIF in predialysis patients showed a clear positive correlation and a straight line regression (1/OCIF = 0.443 + 0.004 x creatinine clearance; r2 = 0.425; P < 0.0001). In dialysis patients, serum OCIF levels were significantly elevated (5.18 +/- 1.48 ng/mL) to a level that would inhibit 50% osteoclast formation in vitro. These findings suggest that OCIF accumulates in serum of patients with renal dysfunction. Because serum levels of OCIF with the ability to bind ODF in vitro (active OCIF) correlated well with those of OCIF detected by standard ELISA (active OCIF = 0.251 + 0.877 x OCIF; r2 = 0.829; P < 0.0001), OCIF accumulated in serum may be a candidate uremic toxin responsible for the skeletal resistance to PTH seen in chronic renal failure. Further studies with serum parameters and bone histological evaluation are needed to assess this possibility.

Osteoprotegerin (OPG) is a newly identified glycoprotein that belongs to the tumor necrosis factor receptor superfamily and regulates bone mass by inhibiting osteoclastic bone resorption. The regulatory mechanism of OPG is still unclear after successful renal transplantation (RTX), however, resulting in resolution of uremia. The present study was designed to clarify the potential role of OPG in uremia and after RTX under immunosuppressive therapy. We evaluated circulating OPG levels by measuring them before and after RTX (postoperative days 2, 14, and 28). Our protocol of immunosuppressive drugs was dual therapy using cyclosporine and steroids. Serum OPG was quantitated using enzyme-linked immunosorbent assay. After successful RTX, serum OPG levels decreased significantly on day 14 and day 28 compared with the baseline level (P < 0.05). Creatinine clearance dramatically increased until day 14 and decreased thereafter. Serum OPG declines for the first 2 weeks after RTX owing to functioning allograft and decreases again for the next 2 weeks because of steroids and possible immunosuppressive agents.

Skeletal resistance to parathyroid hormone (PTH) was suggested initially as a mechanism of PTH hypersecretion in uremia. Because of the effective suppression of PTH by recently developed therapeutic modalities, this background abnormality has been uncovered and currently recognized as relative hypoparathyroidism in terms of its relation to bone turnover. Thus, PTH levels two to three times greater than normal are usually required to keep bone turnover normal in uremia. Recent studies suggested that PTH activity may be overestimated using the conventional intact PTH assay. In addition, several steps to osteoclastogenesis are suspected to be disturbed in uremia. Additional studies at cellular and molecular levels are needed to establish preventive and therapeutic modalities for this abnormality.

Generally, dialysis patients are under potential risk for iron deficiency because they lose a small amount of blood during every hemodialysis session. Iron deficiency is a major cause of anemia that is resistant to erythropoietin therapy in dialysis patients (1); therefore, iron agents are often administered to dialysis patients, in most cases intravenously. Conversely, aimless continuation of iron administration to dialysis patients sometimes causes iron overload, which is also clearly harmful. Iron overload has been thought to induce the accumulation of iron in the organs and subsequent organ dysfunctions (2). In addition, the risk for immunologic disturbance through reticuloendoplasmic suppression (3) and the promotion of atherosclerosis through the induction of oxidative stress (4) were recently suggested. Thus, the total amount of iron storage in dialysis patients should be controlled to within a certain physiologic range. A precise marker with which to monitor iron …

Dialysis related amyloidosis (DRA) is a major complication of long term hemodialysis therapy. It is well recognized that scintigraphic study using radioisotope-labeled beta 2-microglobulin (beta 2M) as a tracer is a sensitive and specific technique to diagnose DRA non-invasively. The aim of this study is to clarify the mechanism of 131I-beta 2M accumulation around the amyloid tissue. Three dialysis patients with carpal tunnel syndromes were examined for consecutive 131I-beta 2M scintigraphies every 24 hours for 3 days till the carpal tunnel synovectomy. Removed synovial tissues were processed for histological study. The scintigraphic study demonstrated tracer accumulations in the joints involved with DRA and the intensity increased in a time dependent fashion. Microscopic observations revealed many inflammatory cells presenting CD68-monocytes/macrophages antigen infiltrated into the synovial tissues. 131I-beta 2M was evident in the cytoplasm of the infiltrating cells, while no radioactivity was detected above background in the amyloid tissues. In conclusion, the tracer accumulations observed in the 131I-beta 2M scintigraphic studies were the consequence of circulating beta 2M assimilated by the infiltrating monocytes/macrophages. Thus, the undetermined elimination pathway of circulating beta 2M in the dialysis patients was identified as the storage pool in those inflammatory cells. The inflammatory change may play a crucial role in the local progression of DRA through the accumulation of circulating beta 2M around the established amyloid tissues.

A 24-year-old woman undergoing chronic dialysis therapy who had been diagnosed as having ‘heparin allergy’ presented acute allergic reaction after the intracatheter injection of a heparin agent. Further investigation revealed that mild eosinophilia had persisted for more than 3 years before this incidence despite avoiding the use of heparin agents. The leukocyte migration inhibition test (LMIT) showed that heparin agent A which was used for the patient showed positive reaction while heparin agent B which was not used for the patient showed a negative reaction. Paraoxybenzoic acid esters (parabens) are contained in heparin agent A but not in heparin agent B. Parabens showed positive reactions on LMIT. Parabens are the most common preservatives in drugs, foods, and cosmetics and they sometimes induce allergic reactions through percutaneous and possibly ingestive sensitization. However, they cause more severe allergic reactions when used intravenously. We concluded that the allergen in this patient was not heparin but parabens. Hypereosinophilia of unknown origin often occurs in dialysis patients. Such patients may be hypersensitive to parabens.

Summary Subarachnoid hemorrhage (SAH) often accompanies cardiac abnormalities. Sudden cardiac arrest is also known to occur after SAH. A 32-year-old woman was admitted to our hospital because of cardiac arrest immediately after the onset of SAH. Return of spontaneous circulation was obtained by conventional advanced cardiovascular life support. After resuscitation, her echocardiogram showed left ventricular apical ballooning, which improved within 7 days. This is the first report presenting both sudden cardiac arrest and transient left ventricular apical ballooning after SAH.

Pretreatment serum FGF-23 levels predict the efficacy of calcitriol therapy in dialysis patients. Background The predictor for the result of calcitriol therapy would be useful in the clinical practice of secondary hyperparathyroidism. Fibroblast growth factor-23 (FGF-23) is a newly found circulating phosphaturic factor. Its circulating level is elevated in uremia. Methods Dialysis patients with plasma intact parathyroid hormone (iPTH) levels greater than 300 pg/mL were included in the study. Calcitriol was intravenously injected three times a week. The patients whose plasma iPTH levels dropped below 300 pg/mL within 24 weeks were defined as those who had been successfully treated. A sandwich enzyme-linked immunosorbent assay (ELISA) system that detects human FGF-23 was applied. Results Sixty-two patients were analyzed. The pretreatment FGF-23 levels were related to the iPTH levels, calcium × phosphate product levels, and history of active vitamin D therapy. The pretreatment FGF-23, iPTH, and calcium levels were lower in the patients who would be successfully treated with calcitriol. A logistic regression study revealed that the pretreatment iPTH and FGF-23 levels significantly affected the therapy results. Analyses using a receiver-operated curve revealed that FGF-23 was the best screening test for identifying patients with future refractory response to calcitriol therapy. The treatment would be successful in 88.2% of those with FGF-23 ≤9860 ng/L and iPTH ≤591 pg/mL, while it would be successful in only 4.2% of those with FGF-23 >9860 ng/L and iPTH >591 pg/mL. Conclusion Pretreatment serum FGF-23 levels were a good indicator in predicting the response to calcitriol therapy. The measurement of serum FGF-23 levels, especially in combination with iPTH levels, is a promising laboratory examination for the clinical practice of secondary hyperparathyroidism.

BACKGROUND Osteoprotegerin is a natural glycoprotein which plays a critical role in osteoclast physiology. Elevated levels of circulating osteoprotegerin may account for the development of bone and mineral metabolic abnormalities in uremia. Little is known about the effects of vitamin D therapy on the circulating osteoprotegerin levels in dialysis patients. PATIENTS AND METHODS Fifty chronic dialysis patients whose plasma intact PTH levels were greater than 300 pg/ml were analyzed for the study. Following a four-week washout time during which all vitamin D administration was halted, 10 microg of maxacalcitol was intravenously injected thrice a week. RESULTS The circulating intact PTH, bone-specific alkaline phosphatase and intact osteocalcin levels were significantly lowered, while the serum calcium levels were elevated after the therapy. The osteoprotegerin levels significantly decreased after the therapy (p < 0.0001). CONCLUSION Maxacalcitol therapy reduced the circulating osteoprotegerin levels and improved secondary hyperparathyroidism. The observed effects were the opposite of those expected from previous in vitro studies. Osteoprotegerin may mediate and/or modify the effect of active vitamin D therapy in dialysis patients.