Significance of Adipose Tissue Maintenance in Patients Undergoing Hemodialysis.

In the general population, obesity is known to be associated with adverse outcomes, including mortality. In contrast, high body mass index (BMI) may provide a survival advantage for hemodialysis patients, which is known as the obesity paradox. Although BMI is the most commonly used measure for the assessment of obesity, it does not distinguish between fat and lean mass. Fat mass is considered to serve as an energy reserve against a catabolic condition, while the capacity to survive starvation is also thought to be dependent on its amount. Thus, fat mass is used as a nutritional marker. For example, improvement of nutritional status by nutritional intervention or initiation of hemodialysis is associated with an increase in fat mass. Several studies have shown that higher levels of fat mass were associated with better survival in hemodialysis patients. Based on body distribution, fat mass is classified into subcutaneous and visceral fat. Visceral fat is metabolically more active and associated with metabolic abnormalities and inflammation, and it is thus considered to be a risk factor for cardiovascular disease and mortality. On the other hand, subcutaneous fat has not been consistently linked to adverse phenomena and may reflect nutritional status as a type of energy storage. Visceral and subcutaneous adipose tissues have different metabolic and inflammatory characteristics and may have opposing influences on various outcomes, including mortality. Results showing an association between increased subcutaneous fat and better survival, along with other conditions, such as cancer or cirrhosis, in hemodialysis patients have been reported. This evidence suggests that fat mass distribution (i.e., visceral fat and subcutaneous fat) plays a more important role for these beneficial effects in hemodialysis patients.

Cinacalcet may suppress kidney enlargement in hemodialysis patients with autosomal dominant polycystic kidney disease.

A massively enlarged kidney can impact quality of life of autosomal dominant polycystic kidney disease (ADPKD) patients. A recent in vitro study demonstrated that an allosteric modulator of the calcium sensing receptor decreases adenosine-3',5'-cyclic monophosphate, an important factor for kidney enlargement in ADPKD. Therefore, the present study was performed to determine whether cinacalcet, a calcium sensing receptor agonist, suppresses kidney enlargement in hemodialysis patients with ADPKD. Alteration of total kidney volume together with clinical parameters was retrospectively examined in 12 hemodialysis patients with ADPKD treated at a single institution in Japan. In the non-cinacalcet group with longer hemodialysis duration (n = 5), total kidney volume had an annual increase of 4.19 ± 1.71% during an overall period of 877 ± 494 days. In contrast, the annual rate of increase in total kidney volume in the cinacalcet group (n = 7) was significantly suppressed after cinacalcet treatment, from 3.26 ± 2.87% during a period of 734 ± 352 days before the start of cinacalcet to - 4.71 ± 6.42% during 918 ± 524 days after initiation of treatment (p = 0.047). The present findings showed that cinacalcet could be a novel therapeutic tool for suppression of kidney enlargement in hemodialysis patients with ADPKD.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.

Serum ß2-microglobulin correlates positively with left ventricular hypertrophy in long-term hemodialysis patients.

BACKGROUND/AIMS: ß2-Microglobulin (ß2-MG) is a major protein component of dialysis-related amyloidosis. In long-term hemodialysis (HD) patients, ß2-MG amyloid deposits not only in osteoarticular tissues, but also in systemic tissues, including the heart. The purpose of this study was to investigate the relationship between serum ß2-MG concentrations and echocardiographic parameters in long-term HD patients in a cross-sectional study. METHODS: Measurement of serum ß2-MG concentrations and echocardiography were performed in 251 patients who had undergone HD therapy for more than 10 years. RESULTS: The left ventricular mass index (LVMI) of the higher serum ß2-MG (≥30 mg/l) group was significantly higher than that of the lower serum ß2-MG (<30 mg/l) group (151.5 ± 45.7 vs. 137.0 ± 44.5 g/m(2), p = 0.020). In simple regression analyses, serum ß2-MG concentrations correlated significantly and positively with interventricular septum thickness (IVST) (r = 0.215, p < 0.001), posterior left ventricular wall thickness (PWT) (r = 0.249, p < 0.001), left ventricular wall thickness (LVWT) (r = 0.252, p < 0.001), relative wall thickness (RWT) (r = 0.153, p = 0.015) and LVMI (r = 0.171, p = 0.007). Multiple regression analyses revealed that serum ß2-MG concentrations correlated significantly and positively with IVST, PWT, LVWT and RWT. CONCLUSION: Serum ß2-MG concentrations correlated significantly and positively with the echocardiographic parameters of left ventricular hypertrophy (LVH) in long-term HD patients. Thus, deposition of ß2-MG amyloid in the heart may be associated with LVH progression.

Tumor necrosis factor-related apoptosis-inducing ligand as an independent predictor of mortality in hemodialysis patents.

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was originally isolated as an inducer of apoptosis in transformed cells. In addition to tumor surveillance, recent findings suggest that TRAIL and its receptor system have a protective role against infection and cardiovascular disease (CVD). Patients undergoing hemodialysis have a high mortality rate with a unique risk factor profile. Considering that the leading causes of death in these patients are infection and CVD, TRAIL represents an attractive candidate for predicting mortality in this population. We therefore investigated whether TRAIL predicted mortality in hemodialysis patients. METHODS: The study was a retrospective observational cohort design of 45-month duration in 149 male hemodialysis patients. The subjects were divided into two groups according to their baseline TRAIL level measured by ELISA (low or high TRAIL group). The main outcome was all-cause mortality. RESULTS: During the follow-up period, 33 patients died, mostly because of CVD (n=11) or infection (n=9). Crude survival analyses showed that a low TRAIL level was a powerful predictor of all-cause (p=0.011) and infectious mortality (p=0.048). The predictive power of TRAIL remained after adjustment for various confounding factors. CONCLUSIONS: The serum TRAIL level may be a novel biomarker for predicting prognosis in hemodialysis patients.

Greater potency of darbepoetin-α than erythropoietin in suppression of serum hepcidin-25 and utilization of iron for erythropoiesis in hemodialysis patients.

BACKGROUND: The potency of darbepoetin-α (DPO-α) to improve anemia in hemodialysis (HD) patients is greater than that of recombinant human erythropoietin (rHuEPO). DESIGN AND METHODS: To assess the potency of DPO-α to mobilize iron from body stores in comparison with rHuEPO in HD patients without apparent inflammation or infection, serum iron, transferrin saturation (TSAT), ferritin, and hepcidin-25 were measured serially. This study included (i) a long-term crossover study for 3 yr to compare the effects of the two erythropoiesis-stimulating agents (ESA) on serum iron, TSAT, and ferritin, and (ii) a short-term crossover study for 8 wk to examine their effects on serum hepcidin-25 in HD patients. RESULTS: The long-term crossover study demonstrated that the change of ESA from rHuEPO to DPO-α significantly decreased serum ferritin while serum iron and TSAT remained unchanged, while DPO-α as well as rHuEPO maintained hemoglobin level in the target range between 10.0 and 11.0 g/dL. Furthermore, in the short-term crossover study, area under the percent suppression of serum hepcidin-25 time curve for the first 7 d during the DPO-α treatment period was significantly greater than that during the rHuEPO period (348.0 ± 92.4 vs. 178.4 ± 131.5%.day P = 0.030). The greater suppression of hepcidin-25 by DPO-α may facilitate iron mobilization, resulting in diminution of body iron stores without any significant effect on serum iron utilizable for erythropoiesis. CONCLUSION: This study demonstrated that DPO-α has a greater advantage than rHuEPO in that it facilitates iron mobilization from body stores into bone marrow to induce effective erythropoiesis and thus could protect against possible harmful effects caused by excessive iron stores in the body.

[Magnesium disorder and its clinical significance in chronic kidney disease].

Disturbance in mineral and bone metabolism is a common complication of chronic kidney disease (chronic kidney disease - mineral and bone disorder ; CKD-MBD) and closely related to morbidity and mortality. Because magnesium (Mg) is mainly excreted by kidney, Mg homeostasis is disturbed in CKD. Therefore Mg abnormalities in CKD may contribute to pathogenesis of CKD-MBD. The association of Mg with bone metabolism in general population has been demonstrated. There were reported an association with dietary Mg intake and bone mineral density (BMD) and an increased rate of bone loss with dietary Mg intake. In animal models, decreased bone formation, increased bone resorption, decreased bone mass, and increased skeletal fragility were reported in Mg deficiency. Although vascular calcification is frequently seen in CKD patients, contributing factors to vascular calcification are not fully clarified. Mg is considered "a natural calcium antagonist" , and Mg deficiency has been reported to be related to progression of atherosclerosis in several studies. In hemodialysis patients, lower Mg levels were also reported to be associated with increased atherosclerosis of the common carotid artery. Lower serum Mg levels were also found in hemodialysis patients with evidence of increasing arterial calcification. Several studies suggested that Mg plays an important role against the development of cardiovascular disease, infectious disease, and malignant neoplasia so that Mg may relate to mortality. In hemodialysis patients, we demonstrated that low serum Mg level was a predictor for increased mortality.

[Kidney and bone update : the 5-year history and future of CKD-MBD. Bone metabolic marker in hemodialysis patients update].

Disturbances in mineral metabolism and bone disease are common complications of chronic kidney disease (CKD) . There is increasing evidence suggesting that these disorders in mineral and bone metabolism are associated with increased risk for cardiovascular calcification, morbidity, and mortality, especially among those who undergo maintenance hemodialysis. It is very important for hemodialysis patients to assess the mineral and bone abnormalities. Although bone biopsy is necessary to diagnosis of renal osteodystrophy in CKD-mineral and bone disorder (CKD-MBD) classification system, this technique is not recommended of routine evaluation for this bone disease. Thus, the presumption of bone disorder in hemodialysis patients has been essentially based on the parathyroid hormone level. However, it is obvious that measurement of parathyroid hormone dose not provide sufficient information. The parathyroid hormone level basically reflects the degree of activity of parathyroid glands and the CKD state is often associated with resistance of bone to the action of parathyroid hormone. Therefore, measurement of bone metabolic markers, such as bone specific alkaline phosphatase and tartrate-resistant acid phosphatase isoform 5b, is increasingly recognized as a useful tool to assess bone metabolic states in hemodialysis patients. Bone metabolic markers may be useful for assessment in the rate of bone loss, the risk of fracture, and the effects of therapy as in osteoporotic patients without CKD.

Impact of atherosclerosis on the relationship of glycemic control and mortality in diabetic patients on hemodialysis.

OBJECTIVE: The impact of preexisting cardiovascular disease (CVD) on glycemic control-improved survival in hemodialysis patients with diabetes mellitus (DM) was investigated. Glycoalbumin (GA) was used as a glycemic marker. METHODS: A single-center 4-year follow-up study was performed in an observational cohort of 178 DM hemodialysis patients to analyze the relationship between GA and all-cause mortality in patients with (n = 70) and without (n = 108) CVD. The subjects were divided into three categories based on GA value at the start of study. RESULTS: Baseline characteristics did not differ between the two groups of patients. During the 4-year follow-up, 24 of 108 (23.3%) CVD(-) patients and 30 of 70 (42.8%) CVD(+) patients died. The mortality was significantly higher in the CVD(+) group. Multivariate Cox analyses including GA, logCRP, age, gender, hemodialysis duration, albumin, hemoglobin, BMI, SBP, DBP, smoking habit, and SUN as independent variables showed that GA, in addition to logCRP and age, was independently associated with mortality in all patients. Kaplan-Meier analysis showed lower GA levels to be a significant predictor of lower mortality in the CVD(-) group, but not in the CVD(+) group. Multivariable-adjusted Cox proportional hazards models demonstrated a significant association between GA with allcause mortality risk in the CVD(-) group (p = 0.004), in contrast with the CVD(+) group in the same model (p = 0.842). CONCLUSION: These results demonstrate a beneficial effect of improved glycemic control on survival in DM hemodialysis patients, which might be attenuated by the presence of CVD.

[Biochemical markers of bone turnover. New aspect. Dialysis and bone metabolic marker].

Disturbances in mineral metabolism and bone disease are common complications of chronic kidney disease (CKD). There is increasing evidence suggesting that these disorders in mineral and bone metabolism are associated with increased risk for cardiovascular calcification, morbidity, and mortality, especially among those who undergo maintenance dialysis. It is very important for dialysis patients to assess the mineral and bone abnormalities. Although bone biopsy is necessary to diagnosis of renal osteodystrophy in CKD-mineral and bone disorder (CKD-MBD) classification system, this technique is not recommended of routine evaluation for this bone disease. Bone metabolic markers, such as bone specific alkaline phosphatase and tartrate-resistant acid phosphatase isoform 5b, may be useful clinical indicator of bone turnover in CKD-MBD.

Serum beta2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients.

BACKGROUND: Beta(2)-microglobulin (beta(2)-M) is recognized as a surrogate marker of middle-molecule uraemic toxins and is a key component in the genesis of dialysis-associated amyloidosis. Few studies have evaluated the association of beta(2)-M levels with clinical outcome in dialyzed patients. METHODS: The prognostic implication of serum beta(2)-M levels for the survival of haemodialysis patients was examined in 490 prevalent haemodialysis patients (60.1 +/- 11.8 years, haemodialysis duration of 87.4 +/- 75.7 months, 288 males and 202 females; 24% diabetics). The patients were divided into two groups according to their serum beta(2)-M levels: lower beta(2)-M group (n = 245) with serum beta(2)-M <32.2 mg/L (the median serum beta(2)-M) and higher beta(2)-M group (n = 245) with that >or=32.2 mg/L. RESULTS: During the follow-up period of 40 +/- 15 months, there were 91 all-cause deaths, and out of them, 36 were from cardiovascular diseases. Kaplan-Meier analysis revealed that all-cause mortality in the higher beta(2)-M group was significantly higher compared to that in the lower beta(2)-M group (P < 0.001). Multivariate Cox proportional hazards analyses showed that serum beta(2)-M level was a significant predictor for all-cause mortality (hazard ratio, 1.05; 95% CI, 1.01-1.08; P = 0.005), and for non-cardiovascular mortality (hazard ratio, 1.06; 95% CI, 1.02-1.10; P = 0.006), after adjustment for age, gender, haemodialysis duration, the presence of diabetes, serum albumin and serum C-reactive protein. CONCLUSION: These results demonstrate that the serum beta(2)-M level is a significant predictor of mortality in haemodialysis patients, independent of haemodialysis duration, diabetes, malnutrition and chronic inflammation, suggesting the clinical importance of lowering serum beta(2)-M in these patients.

Different risk factors for vascular calcification in end-stage renal disease between diabetics and nondiabetics: the respective importance of glycemic and phosphate control.

Vascular calcification is highly prevalent in dialysis patients, and significantly increases cardiovascular mortality. The presence and progression of vascular calcification is significantly associated with chronic inflammation and malnutrition. Disorders of mineral metabolism, particularly hyperphosphatemia, have been emphasized as risk factors for vascular calcification. Although vascular calcification has been reported to be highly prevalent in diabetic patients with end-stage renal disease (ESRD), the risk factors for vascular calcification in these patients have not been fully explored. Through a review of the literature and our recent studies examining vascular calcification in ESRD patients, hyperphosphatemia is significantly associated with vascular calcification in nondiabetic ESRD patients, while it may not be a significant risk factor for vascular calcification in diabetic ESRD patients. In diabetic patients, vascular calcification occurs long before the initiation of dialysis therapy, and the factors associated with vascular calcification in non-uremic diabetics appear to be hyperglycemia and related metabolic disorders, such as increased glycation and oxidative stress. In diabetic ESRD patients, hyperglycemia is also suggested to be a significant factor associated with the progression of vascular calcification. Thus, the importance of glycemic and phosphate control is suggested to be emphasized in diabetic and nondiabetic ESRD patients, respectively, for prevention of the progression of vascular calcification.

Presence of abdominal aortic calcification is significantly associated with all-cause and cardiovascular mortality in maintenance hemodialysis patients.

BACKGROUND: Although abdominal aortic calcification (AAC) is reported as a predictor for cardiovascular mortality in the general population, it is unknown whether this is also true in hemodialysis patients in whom vascular calcification and cardiovascular diseases are highly prevalent. STUDY DESIGN: Cohort study. SETTINGS & PARTICIPANTS: 515 patients on maintenance hemodialysis therapy at a single center. PREDICTOR: AAC evaluated in a plain roentgenograph of the lateral abdomen at baseline. OUTCOMES & MEASUREMENTS: All-cause and cardiovascular death. RESULTS: Mean age was 60 +/- 12 (SD) years. AAC was present in 291 patients (56.5%). During a mean follow-up period of 51 +/- 17 months, there were 103 all-cause deaths, of which 41 were from cardiovascular diseases. Of patients with and without AAC, 27.8% and 9.8% died, respectively (11.6% and 3.1% of cardiovascular diseases, respectively). Kaplan-Meier analysis showed that all-cause mortality was significantly greater in patients with AAC compared to those without (P < 0.0001, log-rank test). Similarly, cardiovascular mortality was significantly greater in the former than in the latter group (P = 0.0001, log-rank test). Multivariate Cox proportional hazards analysis found that the presence of AAC was significantly associated with increased all-cause mortality (hazard ratio, 2.07; 95% confidence interval, 1.21 to 3.56; P < 0.01) and increased cardiovascular mortality (hazard ratio, 2.39; 95% confidence interval, 1.01 to 5.66; P < 0.05) after adjustment for age, hemodialysis duration, presence of diabetes, serum albumin level, and C-reactive protein level. LIMITATIONS: Nonquantitative assessment of AAC and the lack of information for medication and history of cardiovascular diseases. CONCLUSION: The presence of AAC is significantly associated with both all-cause and cardiovascular mortality in hemodialysis patients, suggesting that careful attention should be given to the presence of AAC in a simple radiograph of the lateral abdomen as a prognostic indicator.

Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels.

Clinical studies have been performed to determine the effect of cinacalcet HCl (cinacalcet), an allosteric modulator of the calcium-sensing receptor (CaR), on primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism of uremia (SHPT). However, no in vitro studies on human parathyroid cells have been reported to date. In this study, the inhibitory effect of cinacalcet on PTH secretion was analyzed in primary cultured parathyroid cells obtained from patients. The investigation involved three PHPT and three SHPT patients subjected to therapeutic parathyroidectomy. Notably, all SHPT patients were resistant to intravenous vitamin D analogue therapy. Removed parathyroid tumors were used for immunohistochemistry and parathyroid cell primary culture. Immunohistochemical analyses revealed diminished expression of CaR and vitamin D receptor (VDR) in all parathyroid tumors. PTH secretion from cultured parathyroid cells of PHPT and SHPT patients was suppressed by extracellular Ca2+ and cinacalcet in a dose-dependent manner. Rates of suppression of PTH secretion in PHPT and SHPT by cinacalcet (1000 nmol/l) were 61% +/- 21% and 61% +/- 19%, respectively. Cinacalcet demonstrates significant potency in the suppression of PTH secretion in primary cultured human parathyroid cells in vitro, despite reduced levels of the target protein, CaR. Data from this in vitro analysis support the clinical application of cinacalcet in PHPT and SHPT therapy.

[Effect of calcium on N-terminal truncation of PTH in human parathyroid cells].

Serum PTH (7-84) is accumulated in patients with secondary hyperparathyroidism. It is also known that serum calcium (Ca) increases the generation of N-terminally truncated forms of parathyroid hormone (PTH). In this study, we examined whether accumulation of PTH (7-84) fraction is a parathyroid glandular origin or not by using primary cultured parathyroid cells from patients with primary and secondary hyperparathyroidism. The Bio-PTH/I-PTH ratio, indicating the ratio of PTH (1-84) to the sum of (1-84) PTH and N-terminally truncated fragment, was suppressed by increase in extracellular Ca2+ concentration for both cultured parathyroid cells prepared from parathyroid adenomas and uremia-associated secondary hyperparathyroidism. There is no difference between the ratios in primary and secondary hyperparathyroidism. These findings suggest that N-terminal truncation is regulated by extracellular Ca2+ concentration in parathyroid cells, but accumulation of PTH (7-84) fragments in patients with secondary hyperparathyroidism is mainly caused by uremia.

Serum concentrations of cross-linked N-telopeptides of type I collagen: new marker for bone resorption in hemodialysis patients.

BACKGROUND: Urinary cross-linked N-telopeptide of type I collagen (NTX) is a reliable bone resorption marker in patients with metabolic bone disease. We assessed a clinically available serum NTX assay suitable for anuric patients on hemodialysis (HD). METHODS: Serum concentrations of NTX, C-terminal telopeptide of type I collagen (beta-CTX), pyridinoline (PYD), and deoxypyridinoline (DPD) were determined as bone resorption markers, and those of bone alkaline phosphatase (BAP) and intact osteocalcin (OC) as bone formation markers, in 113 male HD patients (mean age, 59.3 years; mean HD duration, 67.7 months). Each patient's bone mineral density (BMD) in the distal third of the radius was measured twice, with a 2-year interval between measurements, by dual-energy x-ray absorptiometry. RESULTS: Serum NTX correlated significantly with beta-CTX, PYD, DPD, BAP, and intact OC. NTX, as well as beta-CTX, PYD, DPD, BAP, and intact OC, correlated significantly with BMD at the time of measurement. NTX, beta-CTX, and DPD correlated significantly with the annual change in BMD during the 2-year period thereafter, in contrast to PYD, BAP, and intact OC. Patients in the highest quartile of serum NTX concentrations showed the fastest rate of bone loss. The sensitivity and specificity for detecting rapid bone loss were 48% and 83%, respectively, for serum NTX. CONCLUSION: Serum NTX may provide a clinically relevant serum assay to estimate bone turnover in HD patients.

Direct in vitro evidence of extracellular Ca2+-induced amino-terminal truncation of human parathyroid hormone (1-84) by human parathyroid cells.

CONTEXT: Although serum calcium (Ca2+) concentration regulates the generation of amino-terminally (N-terminally) truncated forms of human PTH (hPTH) degraded from (1-84)hPTH, no studies have yet reported whether the parathyroid gland itself is responsible for this process. OBJECTIVE: Our objective was to determine the site of N-terminal truncation and its roles in PTH metabolism in parathyroid cells in vitro. METHODS: The effect of extracellular Ca2+ concentration was examined on N-terminal truncation in primary cultured parathyroid cells. The parathyroid glands were obtained from the patients with primary and uremia-associated secondary hyperparathyroidisms who underwent therapeutic parathyroidectomies. RESULTS: The N-terminally truncated fragments were detectable with commercially available intact PTH (I-PTH) assays, but not with the bio-intact PTH (Bio-PTH) assay, which detected only the (1-84)hPTH. HPLC revealed that generation of N-terminally truncated fragments detectable by I-PTH increased with extracellular Ca2+ concentration. Suppression of PTH secretion by increasing the extracellular Ca2+ concentration was more evident with the Bio-PTH assay than with the I-PTH assay for both cultured parathyroid cells prepared from parathyroid adenomas and uremia-associated secondary hyperparathyroidism. The Bio-PTH/I-PTH ratio, which is the ratio of (1-84)hPTH to the sum of (1-84)hPTH and N-terminally truncated fragments, decreased in response to increases in extracellular Ca2+. CONCLUSIONS: These findings suggest that the N-terminal truncation is regulated by extracellular Ca2+ concentration and works to suppress the generation of (1-84)hPTH in parathyroid cells.

Serum levels of C-terminal telopeptide of type I collagen: a useful new marker of cortical bone loss in hemodialysis patients.

Renal osteodystrophy is a major complication in hemodialysis patients. Measurement of serum peptide derived from the degradation of bone collagen could potentially provide an indirect estimate of bone resorption. The present study estimated the significance of the C-terminal telopeptide of type I collagen (beta-CTx) as a serum bone resorption marker in male hemodialysis patients. The mean age and hemodialysis duration of the 160 patients were 59.7 years (26-86 years) and 67.2 months (17-142 months), respectively. Bone mineral density (BMD) in the distal third of the radius was measured using dual-energy X-ray absorptiometry twice with a 2-year interval. A blood sample was collected immediately before the hemodialysis session at the time of the second BMD measurement. Other serum bone markers determined were bone-specific alkaline phosphatase (BAP) and intact and N-terminal midfragment (N-Mid) osteocalcin (OC) as bone-formation markers and serum pyridinoline (PYD) and deoxypyridinoline (DPD) as bone resorption markers. Serum beta-CTx correlated significantly in a positive manner with serum PYD, DPD, BAP, intact OC, and N-Mid OC. Serum beta-CTx, as well as PYD, DPD, BAP, intact OC, and N-Mid OC, correlated significantly with BMD in the distal third of the radius at the second measurement and with the rate of BMD reduction during the preceding 2 years. The highest quartile of serum beta-CTx was positively associated with rapid bone loss, defined as a change in the value for BMD in the distal third of the radius falling within the upper tertile of patients, in 55% of cases, and each quartile progress in serum beta-CTx increased the odds ratio of rapid bone loss by a factor of 1.73. Since the Youden index was twice as accurate for beta-CTx, BAP and N-Mid OC as for intact PTH, these bone-remodeling markers may be better risk markers of cortical bone loss than intact PTH. Inclusion in the highest quartile of PTH (above 288 pg/ml) predicted rapid bone loss with a sensitivity of only 26%. This means that the upper limit for serum PTH level recommended by K/DOQI may be too high, since 74% of cases with rapid bone loss showed serum PTH levels of below 288 pg/ml. In conclusion, serum measurement of beta-CTx may provide a new commercially viable and relevant serum assay to reflect cortical bone resorption in hemodialysis patients.

Significance of Bio-intact PTH(1-84) assay in hemodialysis patients.

The aim of the present study was to examine whether the newly developed bio-intact parathyroid hormone (Bio-PTH) assay, which exclusively measures the intact PTH(1-84) molecule, provides a better assay for estimating parathyroid function in hemodialysis (HD) patients, and to evaluate the factors associated with serum PTH levels measured by Bio-PTH assay and by second-generation intact PTH (I-PTH) assay. The study also examined whether Bio-PTH/I-PTH ratio, an index of the active fraction of PTH, could provide information not obtainable from simple PTH results. Serum levels of PTH were measured in 177 male HD patients, together with the bone formation markers bone alkaline phosphatase (BAP), intact osteocalcin (iOC), N-midfragment osteocalcin (N-Mid OC), and N-terminal propeptide of type I collagen (PINP), and the bone resorption markers deoxypyridinoline (DPD), pyridinoline (PYD), and beta-CrossLaps (beta-CTx). Bone mineral density (BMD) was determined twice at distal radius one-third by dual-energy X-ray absorptiometry. Serum Bio-PTH was significantly elevated in HD patients compared to normal controls. Serum Bio-PTH and I-PTH correlated significantly in a positive manner with serum bone formation markers (BAP, iOC, N-Mid OC, PINP), and resorption markers (DPD, PYD, beta-CTx), and in a negative manner with BMD and annual change therein at distal radius one-third. The degree of correlation of Bio-PTH was not significantly different from that of I-PTH. The Bio-PTH/I-PTH ratio was significantly lower in HD patients than in normal individuals, due probably to accumulation of N-truncated PTH fragments in the former. The Bio-PTH/I-PTH ratio correlated significantly in a negative manner with serum calcium (Ca) (r=-0.251, P<0.001) and nutritional marker serum urea nitrogen, protein catabolic rate and serum creatinine. Multiple regression analysis further revealed that serum I-PTH, but not Bio-PTH, was significantly associated with each of these nutritional markers, and that the Bio-PTH/I-PTH ratio was negatively associated with serum Ca. It was also found that I-PTH, but not Bio-PTH, was influenced by nutritional state. It is concluded that serum Bio-PTH assay could be of similar value to I-PTH assay in evaluating parathyroid function in HD patients and that their combined use in the form of the Bio-PTH/I-PTH ratio could provide information not obtainable from simple PTH results.