Alterations in serum phosphate levels predict the long-term response to intravenous calcitriol therapy in dialysis patients with secondary hyperparathyroidism

Calcitriol therapy is a central strategy for the treatment of uremic secondary hyperparathyroidism. Although indiscriminate use of calcitriol may lead to worse outcomes, it is difficult to make a decision to discontinue calcitriol therapy when its parathyroid suppression effect remains unsatisfactory. In this study, intravenous calcitriol was administered to 120 chronic hemodialysis patients. Therapy continued for 48 weeks or until plasma intact parathyroid hormone (iPTH) levels decreased to below 300 pg/ml or until the development of any significant adverse effect. Of the 120 patients, the treatment goal was achieved in 47 patients during the first 4 weeks, in 10 during the next 4 weeks, and in 22 patients thereafter. Logistic regression analysis and stepwise regression analysis revealed that iPTH levels were the only significant predictor of the response to calcitriol therapy at weeks 0 and 4. Besides iPTH, the inorganic phosphate (P) levels were another significant predictor of the ultimate response to calcitriol therapy at week 8. The point of best discrimination for successful treatment was P = 6.0 mg/dl at week 8, or P level at week 8/pretreatment P level = 1.0. In conclusion, the P level at week 8 is a predictor of the response to calcitriol therapy for uremic secondary hyperparathyroidism. Changes in treatment are recommended if patients show unsatisfactory parathyroid suppression with a hyperphosphatemic tendency.     

Pretreatment plasma intact parathyroid hormone and serum calcium levels, but not serum phosphate levels, predict the response to maxacalcitol therapy in dialysis patients with secondary hyperparathyroidism

Background The treatment strategy for secondary hyperparathyroidism is generally determined empirically with regards to present parathyroid function and serum calcium (Ca) and inorganic phosphate (Pi) levels. More evidence is needed to avoid the aimless continuation of active vitamin D therapy.Methods Nondiabetic dialysis patients whose plasma intact parathyroid hormone (iPTH) levels were greater than 300 pg/ml were included in the study. Maxacalcitol was intravenously injected three times a week. The treatment was continued for 48 weeks, unless the iPTH level was reduced to less than 300 pg/ml or unfavorable events occurred. The patients whose plasma iPTH levels were below 300 pg/ml within 48 weeks were defined as those who had been successfully treated.Results Findings for 146 patients were analyzed, and 96 patients were successfully treated. Serum Pi levels did not significantly increase during the therapy. The pretreatment plasma iPTH levels and serum Ca levels were lower in the patients who were successfully treated with maxacalcitol. A logistic regression study and classifying by stratum analyses revealed that the pretreatment serum Ca levels and plasma iPTH levels were significantly related to the result of maxacalcitol therapy, while the serum Pi levels were not. Analyses using a receiver-operating characteristic curve revealed that the areas under curves obtained for iPTH and Ca were significantly greater than those obtained for Pi (P < 0.0001).Conclusions Serum Ca levels and parathyroid function were correlated with the results of maxacalcitol therapy. Pretreatment serum Pi levels could not predict the result.     

Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients

BACKGROUND: Secondary 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. METHODS: One 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 degrees 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. RESULTS: Seventeen 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 x Pi (5670.3, P <.0001). Although the plasma intact PTH levels at the beginning of the observation period were comparable to each other, the intact PTH levels at 2 years after the sample collection were significantly higher in the patients with FGF-23 >/=7500 ng/L than in those with FGF-23 <7500 ng/L (P < .0001). CONCLUSION: Serum FGF-23 level was found to be the most useful factor in predicting future development of refractory secondary hyperparathyroidism in long-term dialysis patients with mild secondary hyperparathyroidism. The measurement of serum FGF-23 levels is a promising laboratory examination that can be applied in the clinical practice of uremic secondary hyperparathyroidism.     

血清FGF-23和Klotho蛋白水平与尿毒症患者骨密度的相关性研究

目的分析尿毒症维持性血液透析(MHD)患者血清成纤维细胞生长因子23(FGF-23)和Klotho蛋白水平与骨密度(BMD)的相关性。方法 2017年1月至2018年6月,我院收治了130例MHD患者。双能X线骨密度仪用于检查MHD患者股骨颈和腰椎的BMD。将患者分为3组:正常骨量组,骨量减少组和骨质疏松组。进行ELISA以测量血清FGF-23,Klotho蛋白和1,25(OH)_2D_3水平。还测量了其他参数,包括钙(Ca),磷(P)和甲状旁腺激素。结果 130例MHD患者中,49.60%的患者合并骨质疏松症,32.80%的患者出现骨量减少。骨质疏松症组血清FGF-23水平最高。然而,根据BMD分组,3组血清FGF-23水平差异无统计学意义(P0.05)。Spearman相关分析还指出血清FGF-23水平与BMD之间缺乏相关性。骨质疏松组血清Klotho蛋白水平明显低于正常骨量组和骨量减少组(P0.05)。血清Klotho蛋白水平与股骨颈和腰椎的BMD和T值呈正相关。多元线性回归分析结果显示,血清Klotho蛋白水平是影响MHD患者BMD的主要因素之一。结论血清FGF-23水平与MHD患者BMD变化无关,而血清Klotho蛋白水平与BMD变化密切相关。     

Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men

INTRODUCTION: Fibroblast growth factor (FGF-23) is a novel phosphaturic factor. Current data suggest that serum phosphate, dietary phosphate and 1,25 dihydroxyvitamin D regulate circulating FGF-23 levels in vivo. We examined if hypogonadism-induced increases in serum phosphate are associated with increases in circulating FGF-23 in healthy men in the absence of dietary manipulation. MATERIALS AND METHODS: 25 healthy men were administered goserelin acetate (GnRH analog) 3.6 mg subcutaneously every 4 weeks for 12 weeks to induce acute testosterone and estrogen deficiency. Subjects consumed an ad libitum diet. Morning fasting blood and urine samples were collected to measure serum phosphate, serum intact FGF-23, PTH, and the maximum tubular reabsorption of phosphate (T(m)P/GFR) at baseline, weeks 4 and 12. The changes in serum FGF-23 and phosphate at weeks 4 and 12 were compared to baseline using paired t-tests. RESULTS: Goserelin therapy decreased mean serum testosterone levels from 543+/-160 ng/dL to 33+/-15 ng/dL at week 4 (p<0.001), and to 20+/-10 ng/dL at week 12 (p<0.001). Serum phosphate increased significantly from 3.4+/-0.6 mg/dL to 3.9+/-0.4 mg/dL at week 4 (p=0.002), and to 4.3+/-0.4 mg/dL at week 12 (p<0.001). T(m)P/GFR increased significantly from 3.2+/-0.6 mg/dL to 3.6+/-0.5 mg/dL at week 4 (p<0.004), and to 4.1+/-0.6 mg/dL at week 12 (p<0.001). FGF-23 levels, however, did not change during the 12-week study. CONCLUSIONS: Gonadal steroid deprivation increased serum phosphate levels in men but did not affect serum FGF-23 concentrations. The absence of any change in circulating FGF-23 suggests that supraphysiologic levels of serum phosphate may be required to stimulate circulating FGF-23 or that FGF-23 production is primarily sensitive to changes in dietary phosphate or 1,25 dihydroxyvitamin D within this physiologic serum phosphate range.     

磷结合剂对于血液透析高磷血症患者成纤维细胞生长因子23水平的影响

目的比较碳酸镧和碳酸钙对于血液透析高磷血症患者血清成纤维细胞生长因子23（fibroblast growth factor-23,FGF-23）水平的影响。方法选择我科56例慢性肾衰竭维持性血液透析患者,入选患者血磷〉1．77mmol／L,血钙〈2．38mmol／L,25-OH—VitDTk平〉30ng／ml,血白蛋白水平〉30g／L。患者限制饮食磷摄人量为1000mg／d左右,将患者随机分为2组,分别接受碳酸镧或碳酸钙治疗16周。每2周常规检测血钙、血磷水平,滴定磷结合剂的使用剂量,使血磷水平达标。在治疗的第0、4、16周检测血清FGF-23及iPTH水平。结果碳酸钙和碳酸镧均能降低血磷水平。2组中,血清校正钙离子水平、甲状旁腺素水平均无明显变化。与碳酸钙相比,碳酸镧能有效降低FGF-23水平,且血磷水平的改变与血清FGF-23水平的改变呈正相关。结论在血液透析患者中应用碳酸镧可以有效降低血磷及血清FGF-23水平,而应用碳酸钙并不能减少血清FGF-23水平。     

Association of serum fetuin-A levels with mortality in dialysis patients

Calcifying atherosclerosis is an active process, which is controlled by calcification inhibitors and inducers. Fetuin-A, an acute phase glycoprotein, is one of the more powerful circulating inhibitors of hydroxyapatite formation. A prospective multicenter cohort study was initiated to include both hemodialysis (HD) and peritoneal dialysis (PD) patients in an evaluation of the association of serum fetuin-A levels with both cardiovascular (CV) and non-CV mortality. An increase in the serum fetuin-A concentration of 0.1 g/l was associated with a significant reduction in all-cause mortality of 13%. There was a significant 17% reduction in non-CV mortality and a near significant reduction in CV mortality. This association of fetuin-A and mortality rates was comparable in both HD and PD patients even when corrected for factors, including but not limited to age, gender, primary kidney disease, C-reactive protein levels, and nutritional status. We conclude that serum fetuin-A concentrations may be a general predictor of mortality in dialysis patients.     

Effect of calcitriol replacement on serum calcitonin and parathyroid hormone levels in CAPD patients

Calcitonin-secreting cells, ‘C cells’, have specificreceptors for calcitriol, thus the calcitriol deficiency inuraemia may affect calcitonin secretion and/or production. Theaim of the present study was to evaluate in CAPD patients theeffect of calcitriol replacement (4 weeks of oral calcitriol,0.5 ng/day) on both, basal calcitonin concentration and calcitoninresponse to calcium infusion (calcium gluconate, 3 mg/kg/h). Calcitriol replacement produced a normalization of serum calcitriollevel without a significant change in serum calcium concentration.After calcitriol replacement, basal calcitonin increased from78 ± 15 to 101 ± 13pg/ml, P<0.05. The incrementin calcitonin induced by a calcium infusion was lower after(15±4pg/ml) than before (29±4pg/ml) calcitriolreplacement. In addition, calcitriol administration induceda decrease in serum PTH level. Replacement of calcitriol in CAPD patients produced an increasein serum calcitonin concentration and a decrease in the calcitoninresponse to hypercalcaemia.     

Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis

PurposeLow 25-hydroxyvitamin D (25D), increased levels of fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were reported to be risk factors for mortality in chronic kidney disease (CKD). However, the independent associations of these factors with cardiovascular disease (CVD), the leading cause of death among CKD patients, remain unclear. Our purpose was to identify which of these factors predict incident CVD in CKD.MethodsIn this prospective cohort study, we enrolled 738 predialysis outpatients in the two nephrology departments. We employed Cox proportional hazards analyses to elucidate predictors of the endpoint, defined as fatal or non-fatal cardiovascular event requiring hospitalization. Multiple imputation was performed for missing values.ResultsMean estimated glomerular filtration rate (eGFR) was 35 mL/min/1.73 m². During a median duration of 4.4 years, 86 patients developed the endpoint, of whom 62 patients achieved it before the initiation of dialysis. Multivariable analyses revealed that high serum intact FGF23 levels predicted the outcome preceding dialysis initiation (hazard ratio (HR) per lnFGF23 (SD), 1.64 (1.27–2.30)), while 25D, PTH, and bone-specific ALP did not. Adding FGF23 to the conventional model of age, sex, diabetes, prior CVD, pulse pressure, and eGFR, led to a net reclassification improvement of 6.87% (P = 0.04). Not censoring the patients at the start of dialysis and continuing follow-up even after dialysis, FGF23 levels did not predict the outcome (HR, 1.16 (0.91–1.48)). Complete case analyses yielded similar results.ConclusionsIntact FGF23 levels in predialysis CKD predicted incident cardiovascular events requiring hospitalization before starting dialysis, but did not predict events during the entire follow-up period, including post dialysis initiation.     

Changes of serum leptin levels and the influential factors in peritoneal dialysis patients

Objective To investigate the changes of serum leptin levels and the influential factors in maintenance peritoneal dialysis patients. Methods Seventy-six peritoneal dialysis patients were chosen at the time before, and 3 months, 6 months, 12 months, 18 months and 24 months after they began the peritoneal dialysis therapy, to examine body mass index (BMI), triceps skinfold thickness (TSF), abdominal circumference, homeostasis model assessment of insulin resistance (HOMA-IR), the plasma lipid profile, and leptin in the same situation. Results For 24 months, these patients showed higher serum leptin level than the values before commencing peritoneal dialysis treatment (P＜0.01). The level of leptin was positively correlated with the BMI(r＝0.412, P＜0.01), TSF(r＝0.308, P＜0.01), abdominal circumference(r＝0.284, P＜0.01), HOMA-IR(r＝0.184, P＜0.01) and TG(r＝0.288, P＜0.01), negatively corelated with the high-density lipoprotein cholesterol(HDL-C)(r＝-0.285, P＜0.01). Multiple logistic regression analysis showed that BMI (β＝0.339, P＜0.01), TG(β＝0.157, P＜0.01) and HDL (β＝-0.126, P＜0.05)were significant predictive factors for the changes of serum leptin levels. Conclusion Leptin maybe involve in the occurrence and the development of cardiovascular events like other metabolic parameters in peritoneal dialysis therapy.     

Pharmacokinetics of calcitriol in continuous ambulatory and cycling peritoneal dialysis patients

Oral calcitriol is commonly used for the treatment of secondary hyperparathyroidism in patients undergoing long-term dialysis, but it has been suggested that intravenous (IV) or intraperitoneal (IP) administration enhances the therapeutic efficacy of the sterol. To examine potential mechanisms for this difference, the bioavailability of calcitriol was evaluated after single oral (PO), IV, and IP doses of 60 ng/kg in each of six adolescent patients with osteitis fibrosa undergoing continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD). Serum calcitriol levels were 3.6 +/- 4.3, 8.2 +/- 7.5, and 2.5 +/- 3.0 pg/mL, respectively, before IV, PO, and IP doses of the sterol; these values increased to similar levels at 24 hours: 55.6 +/- 14.6 pg/mL after PO, 56.4 +/- 17.6 pg/mL after IV, and 53.8 +/- 20.1 pg/mL after IP. Serum calcitriol levels were higher 1, 3, and 6 hours after IV injections than after PO or IP doses; values thereafter did not differ among groups. The bioavailability of calcitriol, determined from the 24-hour area under the curve (AUC0-24) for the increase in serum calcitriol concentration above baseline values was 50% to 60% greater after IV, 2,340 +/- 523 pg.mL-1.h-1, than after PO, 1,442 +/- 467 pg.mL-1.h-1, or IP, 1,562 +/- 477 pg.mL-1.h1, dosages, P less than 0.05. These differences were due to higher values for AUC during the first 6 hours after calcitriol administration. Although IP calcitriol did not increase sterol bioavailability, radioisotope tracer studies indicated that 35% to 40% of the hormone adheres to plastic components of the peritoneal dialysate delivery system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased serum strontium levels in dialysis patients: an epidemiological survey

BACKGROUND: We previously reported on increased bone strontium levels in dialysis patients with osteomalacia versus those presenting other types of renal osteodystrophy. A causal role of strontium in the development of osteomalacia was established in a chronic renal failure rat model. METHODS: To further elucidate the latter issue and to find out whether dialysis patients from particular centers/countries are at an increased risk for strontium accumulation, a worldwide multicenter study was established. In total, 834 patients from 34 dialysis centers in 23 countries were included. In each of the patients, a serum sample was taken for strontium determination, and water and dialysate samples were taken at the various steps of the water purification process. For each patient clinical data and for each center dialysis modalities were recorded. RESULTS: Strontium levels in serum of dialysis patients showed major differences between the various centers, ranging from mean values of 25 +/- 8 microgram/liter in the center with the lowest level up to 466 +/- 90 microgram/liter in the center with the highest concentration. It is of interest that these high levels were mainly found in developing countries. Furthermore, our data point toward a role of the final dialysate in the accumulation of the element, as indicated by the strong correlation (r = 0.74, P < 0.001) between mean serum and dialysate strontium levels. As the high tap water concentration of strontium was adequately reduced during the water purification process, contamination of the final dialysis fluid occurred by the addition of concentrates contaminated with strontium. Besides the dialysate, other factors, such as duration of dialysis, vitamin D supplements, or types of phosphate binders, played a less important role in the accumulation of the element. CONCLUSIONS: Data of this multicenter study indicate patients of particular dialysis centers to be at an increased risk for strontium accumulation, the clinical consequence of which is under current investigation.     

FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis

Concentrations of the phosphate-regulating hormone fibroblast growth factor-23 (FGF-23) are elevated in patients with chronic kidney disease (CKD), but whether higher plasma FGF-23 concentrations associate with all-cause mortality, cardiovascular events, or initiation of chronic dialysis is not completely understood. Here, we measured FGF-23 concentration in stored plasma samples from 1099 patients with advanced CKD who participated in The Homocysteine in Kidney and End Stage Renal Disease study. Mean serum phosphorus concentration was 4.3 mg/dl, median FGF-23 concentration was 392 RU/ml, and mean GFR was 18 ml/min/1.73 m(2). During a median follow-up of 2.9 yr, 453 (41%) patients died from any cause, 215 (20%) had a cardiovascular event, and 615 (56%) initiated chronic dialysis. Compared with the lowest quartile of FGF-23, each subsequent quartile associated with a progressively higher risk for death, adjusted for confounders (HR [95% CI] of 1.24 [0.91 to 1.69], 1.76 [1.28 to 2.44], and 2.17 [1.56 to 3.08] for the second through fourth quartiles, respectively). In addition, compared with the lowest quartile, the two highest quartiles of FGF-23 also associated with a significantly elevated risk for cardiovascular events and initiation of chronic dialysis. In conclusion, in advanced CKD, FGF-23 strongly and independently associates with all-cause mortality, cardiovascular events, and initiation of chronic dialysis.     

Serum beta-2 microglobulin levels predict mortality in dialysis patients: results of the HEMO study

In the randomized Hemodialysis (HEMO) Study, chronic high-flux dialysis, as defined by higher beta-2 microglobulin (beta(2)M) clearance, compared with low-flux dialysis did not significantly alter all-cause mortality in the entire cohort but was associated with lower mortality in long-term dialysis patients. This analysis examined the determinants of serum beta(2)M levels and the associations of serum beta(2)M levels or dialyzer beta(2)M clearance with mortality. In a multivariable regression model that examined 1704 patients, baseline residual kidney urea clearance and dialyzer beta(2)M clearance were strong predictors of predialysis serum beta(2)M levels at 1 mo of follow-up, with regression coefficients of -7.21 (+/-0.69 SE) mg/L per ml/min per 35 L urea volume (P < 0.0001) and -1.94 (+/-0.30) mg/L per ml/min (P < 0.0001),respectively. In addition, black race and baseline years on dialysis correlated positively whereas age, diabetes, serum albumin, and body mass index correlated negatively with serum beta(2)M levels (P < 0.05). In time-dependent Cox regression models, mean cumulative predialysis serum beta(2)M levels but not dialyzer beta(2)M clearance were associated with all-cause mortality (relative risk = 1.11 per 10-mg/L increase in beta(2)M level; 95% confidence interval 1.05 to 1.19; P = 0.001), after adjustment for residual kidney urea clearance and number of prestudy years on dialysis. This association is supportive of the potential value of beta(2)M as a marker to guide chronic hemodialysis therapy.     

FGF-23 in patients with end-stage renal disease on hemodialysis

BACKGROUND: Fibroblast growth factor (FGF)-23 is a recently identified circulating factor which causes renal phosphate wasting disorders. Although the mechanism of regulation of FGF-23 secretion is unknown, plasma FGF-23 level may be regulated or affected by serum phosphate levels because of its hypophosphatemic effect. METHODS: We tested the hypothesis that plasma FGF-23 levels may be increased in hyperphosphatemia in patients with end-stage renal disease (ESRD) on maintenance hemodialysis. We measured plasma FGF-23 levels in 158 male uremic patients on maintenance hemodialysis. Plasma samples were obtained before starting dialysis sessions to determine FGF-23 levels by enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma FGF-23 level exhibited significant and positive correlations with inorganic phosphate, intact parathyroid hormone (PTH), corrected calcium, and duration of hemodialysis on simple regression analyses. All these associations remained significant in multiple regression analyses. CONCLUSION: Serum phosphate, calcium, and intact PTH could be regulators of FGF-23 levels in uremic patients on maintenance hemodialysis. Our results may provide new insights into the pathophysiologic effects of FGF-23 on calcium-phosphate homeostasis.