Comparative Effects of Etelcalcetide and Maxacalcitol on Serum Calcification Propensity in Secondary Hyperparathyroidism: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Vitamin D receptor activators and calcimimetics (calcium-sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T50 value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T50 value than a vitamin D receptor activator maxacalcitol. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A randomized, multicenter, open-label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 µg thrice weekly (maxacalcitol group). The primary, secondary, and tertiary outcomes were changes in T50 value, handgrip strength, and score of the Dementia Assessment Sheet for Community-Based Integrated Care System from baseline to 12 months, respectively. RESULTS: In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, n=167; control, n=159), and 321 were included in the intention-to-treat analysis (median age, 66 years; 113 women [35%]). The median (interquartile range) of T50 value was changed from 116 minutes (interquartile range, 90-151) to 131 minutes (interquartile range, 102-176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98-174) to 166 minutes (interquartile range, 127-218) in the etelcalcetide group. The increase in T50 value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; P=0.004). No significant between-group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community-Based Integrated Care System score. CONCLUSIONS: Etelcalcetide was more effective in increasing T50 value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VICTORY; UMIN000030636 and jRCTs051180156.

Higher serum bone alkaline phosphatase as a predictor of mortality in male hemodialysis patients.

AIMS: Higher serum alkaline phosphatase predicts lower mortality in chronic kidney disease and hemodialysis patients without liver dysfunction because it reflects high bone turnover. The purpose of our study was to compare the significance of serum bone alkaline phosphatase (BAP) with that of other bone markers in prediction of all-cause mortality(ACM) in male hemodialysis patients. MAIN METHODS: The study was performed for 5 years. Serum BAP, intact osteocalcin (iOC), ß-CrossLaps (CTX), and intact parathyroid hormone (iPTH) were measured in 196 male hemodialysis patients without radiographic fracture. Their day-to-day variation during 5 consecutive days and diurnal variation were determined in 13 healthy males. KEY FINDINGS: The patients were divided into higher and lower groups based on serum levels of bone markers(mean±SD: iPTH 218.6±214.5 pg/ml, BAP 23.6±12.2 U/L, iOC 42.8±45.2 ng/ml, CTX 1.71±1.23 nmol/L BCE). In Kaplan-Meier analysis, the higher BAP group had significantly higher ACM than the lower BAP group (P=0.013), whereas mortality did not differ between the higher and lower groups in other markers. Cox regression hazard analysis identified higher log BAP as a significant independent predictor [hazard ratio(HR) 8.32(95%CI:1.18-58.98)] for ACM after adjustment for various factors including pre-existing cardiovasucular disease, presence of DM. The significant association of mortality with serum BAP alone, in contrast with other markers including CTX [HR0.64 (95%CI:0.16-2.47)], iOC [HR0.97(95%CI:0.36-2.64)], iPTH [HR0.84(95%CI:0.44-1.60)], it may be due to the narrower day-to-day variation and the absence of diurnal variation in serum BAP compared to other markers. SIGNIFICANCE: Higher serum BAP may be a predictor of ACM in male hemodialysis patients.

Cerebral microbleeds in predialysis patients with chronic kidney disease.

BACKGROUND: Gradient-echo T2*-weighted magnetic resonance imaging (T2*-weighted MRI) is highly sensitive for detecting cerebral microbleeds (CMBs). CMBs have been reported to be a risk factor for future cerebrovascular events and a marker of cerebral small vessel disease in the general population. Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. The relationship between CKD and CMBs, which has not been clarified to date, is examined. METHODS: In this cross-sectional study, T2*-weighted MRI of brain was performed with a 1.5-T MRI system in 162 CKD patients (CKD stages 1-5, excluding CKD stage 5(D)) and 24 normal subjects. RESULTS: CMBs were found in 35 CKD patients (25.6%), but not in control subjects. CMBs were more prevalent in male patients, in those with higher blood pressure, advanced age and poor kidney function. There was a significant association between the prevalence of CMBs and the CKD stage, with higher prevalence of CMBs as the CKD stages advanced (P < 0.01). Estimated glomerular filtration rate was a significant factor associated with the prevalence of CMBs, independent of age, gender and hypertension. There was no significant relationship between CMBs and the presence of diabetes mellitus and dyslipidemia. CONCLUSIONS: Decreased renal function is a significant risk factor for CMBs, independent of the presence of hypertension. Poor kidney function could be associated with future cerebrovascular events.

[Bone metabolic marker for osteoporosis].

The purposes hypothesized for the determination of bone metabolic markers, among which we can measure serum BAP, NTX, TRAP-5b or urinary NTX, DPD, CTX in routine clinical practice, are to predict the rate of bone loss and the resultant fracture risk, and to estimate bone quality. The higher value of bone markers, which might reflect high turnover bone disease, allows us to discriminate those who require early introduction of drug therapy such as bisphosphonate, and raloxifene. Furthermore, early reduction of bone resorption markers, but not bone formation markers, possibly 3-6 month after initiation of bone anti-resorptive drugs, enables us to predict bone gain thereafter. Among various bone resorption markers, TRAP-5b might be the best in that it is not susceptible to between-day variation, day-to-day variation, and renal dysfunction resulting from chronic kidney disease which often occurs in osteoporosis-prone elderly women.

Renal biopsy in a patient with haemophilia A and cryoglobulinaemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection.

A renal biopsy was performed in a 47-year-old man with haemophilia A. Thirty minutes after administration of an intravenous bolus of 4000 units of recombinant factor VIII, which increased the activity to 74-91%, a needle renal biopsy was successfully performed, followed by administration of 3000 units of factor VIII in the evening, and then the subsequent morning and evening. The patient was diagnosed with hepatitis C virus-associated membranoproliferative glomerulonephritis. Treatment with interferon, ribavirin, prednisolone and cyclosporine A improved the nephrotic syndrome. This is the first report of a successful renal biopsy in a patient with haemophilia A after factor VIII injection.

Association of glycated albumin, but not glycated hemoglobin, with peripheral vascular calcification in hemodialysis patients with type 2 diabetes.

AIMS: Elevated HbA(1C) is a predictor of mortality as well as peripheral vascular calcification in hemodialysis (HD) patients with diabetes. However, improved glycemic control as reflected by reduction in HbA(1C) may dismiss the relationship between HbA(1C) and mortality in those patients, due possibly to the underestimation of HbA(1C) by erythropoietin use. This study was to establish the significance of glycated albumin (GA) as a useful marker of peripheral vascular calcification in diabetic HD patients, in comparison with HbA(1C). MAIN METHODS: We examined 49 HD patients with type 2 diabetes (37 men and 12 women). Peripheral vascular calcification at hand arteries was checked on a simple X-ray photograph. GA and HbA(1C) were determined just before HD session. KEY FINDINGS: The prevalence of peripheral vascular calcification was significantly higher in diabetic patients (65.3%) than in non-diabetic patients (27.0%). Multiple regression analyses in diabetic patients showed that both HD duration and GA were significantly associated with the presence of peripheral vascular calcification. When GA was replaced by HbA(1C) in the same model, HbA(1C) failed to show a significant association. However, when a weekly dose of erythropoietin was simultaneously included in addition to HD duration and HbA(1C), both HbA(1C) as well as HD duration emerged as a significant factor associated with the presence of peripheral vascular calcification. SIGNIFICANCE: The present study suggested that GA might be a better indicator of glycemic control, and raise the possibility that improvement of glycemic control might prevent against the development of peripheral vascular calcification in diabetic HD patients.

Serum levels of TRAP5b, a new bone resorption marker unaffected by renal dysfunction, as a useful marker of cortical bone loss in hemodialysis patients.

Tartrate-resistant acid phosphatase (TRAP) 5b is a new marker of bone resorption that is unaffected by renal dysfunction. The significance of TRAP5b was assessed in hemodialysis (HD) patients. Serum concentrations of TRAP5b and cross-linked N-telopeptide of type I collagen (NTX) were determined as bone resorption markers, and those of bone alkaline phosphatase (BAP) and intact osteocalcin (OC) were measured as bone formation markers in 58 HD patients. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry twice in the distal third of the radius, with a 2-year interval between measurements. Serum TRAP5b correlated significantly with BAP, intact OC, intact parathyroid hormone (PTH), and especially serum NTX. TRAP5b, NTX, BAP, and intact OC all correlated significantly with BMD at the time of the second measurement; and TRAP5b, NTX, and intact OC, but not BAP and intact PTH, correlated significantly with the annual change in BMD during the 2-year period. Among the bone markers, patients in the highest tertile for serum TRAP5b and intact OC showed the fastest rate of cortical bone loss. The sensitivity and specificity for detection of rapid bone loss were 57.9% and 76.9%, respectively, for serum TRAP5b. Measurement of serum TRAP5b, as well as intact OC, may be a clinically relevant assay for estimation of bone metabolic status in HD patients, although serum intact OC accumulates in uremic serum.

Utility of serum tartrate-resistant acid phosphatase (TRACP5b) as a bone resorption marker in patients with chronic kidney disease: independence from renal dysfunction.

BACKGROUND: Serum tartrate-resistant acid phosphatase (TRACP) 5b levels were assessed in predialysis patients with chronic kidney disease (CKD). The aim of the study was to establish the usefulness of a new assay for TRACP5b in assessing bone turnover in these patients. METHODS: Serum concentrations of two bone resorption markers, TRACP5b and N-terminal cross-linking telopeptide of type I collagen (NTX); two bone formation markers, bone specific alkaline phosphatase (bone ALP) and intact osteocalcin (OC[1-49]); and PTH were measured in 98 predialysis CKD patients. RESULTS: Log serum TRACP5b and other bone markers were significantly negatively correlated with glomerular filtration rate (GFR) and positively correlated with log serum PTH, suggesting an increase in serum bone markers with development of secondary hyperparathyroidism. Multiple regression analysis including age, gender, BMI, the presence of diabetes, GFR and log serum PTH showed an association of log serum PTH with log serum TRACP5b and other bone markers. GFR was associated with log serum NTX and log OC[1-49], but not with log serum TRACP5b or log bone ALP. These data show that renal dysfunction does not influence serum TRACP5b and bone ALP, but has an influence on NTX and OC[1-49]. CONCLUSION: Serum TRACP5b may be a good marker for serum bone resorption in predialysis CKD patients, as it is not affected by renal dysfunction.

Influence of nutritional status on serum large N-truncated PTH, but not PTH(1-84) in hemodialysis patients.

BACKGROUND: Serum level of parathyroid hormone (PTH), measured by second-generation intact PTH (I-PTH), is known to be associated with nutritional status in hemodialysis (HD) patients. We investigated whether PTH(7-84) and larger N-truncated PTH or PTH(1-84) might be affected by nutritional status in HD patients. METHODS: Serum PTH was determined in 170 male HD patients by either a Bio-intact PTH (Bio-PTH) or I-PTH assay. Lean body mass in the trunk region was measured as a nutritional marker by dual X-ray absorptiometry. RESULTS: The serum PTH(7-84) level was theoretically obtained from the difference between serum I-PTH and Bio-PTH because I-PTH assay cross-reacted with PTH(7-84) with the same degree as PTH(1-84), although N-truncated PTH fragment larger than PTH(7-84) might affect theoretical serum PTH(7-84) level, although slightly. Serum PTH(1-84) was directly obtained from the serum Bio-PTH value because of its exclusive reaction with PTH(1-84). Serum PTH(7-84) correlated significantly with nutritional markers such as body weight, albumin, protein catabolic rate (PCR), TACBUN, BUN, phosphate, and lean body mass in the trunk, whereas PTH(1-84) correlated only with phosphate. Multiple regression analysis revealed that PCR, body weight, and lean body mass in the trunk region are significant factors independently associated with PTH(7-84), but not with PTH(1-84). CONCLUSIONS: The results suggest that serum levels of PTH(7-84) and larger N-truncated PTH fragments, but not PTH(1-84), might be affected by the nutritional state in HD patients, which might explain the reported correlation of serum I-PTH levels with nutritional markers.

[Significance of serum PTH (7-84) as a reliable nutritional marker in hemodialysis patients].

To evaluate the significance of serum PTH (7-84) in hemodialysis patients, correlation of the serum PTH (7-84) level with various nutritional markers was investigated in HD patients. Serum PTH was determined in 170 male HD patients by either a Bio intact PTH assay or a second-generation intact PTH assay. The level of bone formation markers and bone resorption markers were also measured. Lean body mass in trunk region was measured by dual X-ray absorptiometry. The serum PTH (7-84) level was obtained for the difference between serum I-PTH and Bio-PTH. Serum PTH (1-84) was directly obtained from the serum Bio-PTH value. Serum PTH (7-84) correlated significantly with nutritional markers such as body weight, albumin, PCR, TAC BUN, BUN, phosphate and lean body mass in trunk, whereas PTH (1-84) only correlated with phosphate. The correlation of serum PTH (7-84) with bone metabolic markers was no less significant than that for PTH (1-84). The results suggest that serum level of PTH (7-84) may provide clinically useful information, not only of the bone metabolic state but also of the nutritional state in HD patients, in sharp contrast to the exclusive correlation of PTH (1-84) with bone metabolic state.