cCa Levels Research Articles

SAT229 Symptomatic Hypocalcemia In The Setting Of Crohn’s Disease With Severe Hypomagnesemia

Abstract Disclosure: K. Cuan: None. T. Reisman: None. Introduction: People with Crohn’s Disease (CD) are at risk for various nutritional deficiencies due to decreased oral intake, malabsorption, and increased intestinal losses. CD often causes a negative calcium balance, which does not usually cause hypocalcemia because the bones serve as a reservoir for calcium. However, symptomatic hypocalcemia may occur if a concurrent severe hypomagnesemic state is present. The factors resulting in hypocalcemia in patients with magnesium deficiency are impaired PTH secretion, PTH resistance, and vitamin D deficiency. Clinical Case: A 33-year-old man with CD and rheumatoid arthritis presented following a seizure with additional symptoms of hand cramping and facial twitching. He had previously undergone three small bowel resections and had a history of hypocalcemia due to malabsorption. Although this patient had previously been admitted due to a hypocalcemic seizure, he did not start oral calcium supplements at that time. No issues with magnesium were identified previously. On this encounter, he was found to have a corrected calcium (cCa) of 5.3 mg/dL, undetectably low magnesium at <0.7 mg/dL, normal phosphorus, 25-hydroxyvitamin D at 3.5 ng/mL, and an elevated intact PTH (iPTH) at 169 pg/mL. Aggressive intravenous calcium and magnesium repletion improved cCa to 7.4 mg/dL and magnesium to 2 mg/dL with no further seizure activity. He was discharged on calcium carbonate, calcitriol, and ergocalciferol. A month later, he presented to our endocrinology clinic asymptomatic but with a cCa of 6 mg/dL and magnesium at <0.7 mg/dL. Further biochemical workup revealed normal phosphorus, 25-hydroxyvitamin D at 7.9 ng/mL, and an inappropriately normal iPTH at 49 pg/mL. He was readmitted to the hospital where intravenous repletion improved cCa to 8.1 mg/dL and magnesium to 1.9 mg/dL. His recurrent hypomagnesemia was attributed to malabsorption. An increased dose of calcitriol and oral magnesium were added to his discharge medication regimen, in addition to his ergocalciferol and calcium carbonate. Three days later, he had a cCa level of 7.1 mg/dL as an outpatient. Conclusion: Patients with CD often have nutrient deficiencies, especially if they have had surgical resection within the intestinal tract. Our patient initially developed hypocalcemia from malabsorption, which was then exacerbated by the severely hypomagnesemic state. During his initial hospital encounter, the elevated iPTH level indicated PTH resistance. On his second encounter, the normal iPTH level suggested hypoparathyroidism. Given the relationship between magnesium and calcium homeostasis, addressing the hypomagnesemia eventually aided in achieving stabilization of serum calcium levels. Thus, in patients who are at risk for malabsorption and have recurrent symptomatic hypocalcemia, it is prudent to check magnesium levels as it can affect long term management of hypocalcemia. Presentation: Saturday, June 17, 2023

Associations of calcium, phosphate and intact parathyroid hormone levels with mortality, residual kidney function and technical failure among patients on peritoneal dialysis.

Associations of calcium, phosphate and intact parathyroid hormone (iPTH) levels with outcomes may be different between patients on peritoneal dialysis (PD) and hemodialysis (HD). The aim of the study is to evaluate these associations among PD patients. In this prospective cohort study on the Japan Renal Data Registry, adults on PD at the end of 2009 were included. The observation period was until the end of 2018 and the data were censored at the time of transplantation or transition to HD. Exposures were time-averaged or time-dependent albumin-corrected calcium (cCa), phosphate and iPTH levels. Outcomes were all-cause and cardiovascular mortality, transition to HD and urine output. Data were analyzed using Cox regression models or linear mixed-effects models and the results were shown as cubic spline curves. Among 7393 patients, 590 deaths and 211 cardiovascular deaths were observed during a median follow-up of 3.0 years. Higher cCa and phosphate levels were associated with higher mortality. Lower cCa levels were associated with a faster decline, whereas lower phosphate was associated with a slower decline in urine output. Lower phosphate and iPTH levels were associated with a lower incidence of transition to HD. Among PD patients, the observed associations of cCa, phosphate and iPTH with mortality, residual kidney function and technical failure suggest that avoiding high cCa, phosphate and iPTH levels might improve outcomes.

Phase 2 study of upacicalcet in Japanese haemodialysis patients with secondary hyperparathyroidism: an intraindividual dose-adjustment study.

Upacicalcet is a novel small-molecule calcimimetic agent developed for intravenous injection. Here, we evaluated the long-term efficacy and safety of upacicalcet treatment via intraindividual dose adjustment in haemodialysis patients with secondary hyperparathyroidism (SHPT). A phase 2, multicentre, open-label, single-arm study was conducted. Upacicalcet was administered for 52weeks; the starting dose was 50μg thrice a week, and then adjusted to 25, 50, 100, 150, 200, 250, or 300μg, according to the dose-adjustment method set in the protocol. The primary endpoint was the percentage of patients with serum intact parathyroid hormone (iPTH) level achieving a target range of 60-240pg/mL (target achievement rate) at week 18. A total of 58 patients were administered upacicalcet. The target achievement rate of serum iPTH level at week 18 was 57.9%, which increased to 80.8% at week 52. The serum-corrected calcium (cCa) level decreased immediately after upacicalcet administration, but no further decrease was observed. Adverse events were observed in 94.8% of patients, and adverse drug reactions (ADRs) occurred in 20.7% of patients. The most common ADR was decreased adjusted calcium in eight patients; dizziness occurred as a serious ADR in one patient. The serum cCa level of patients who interrupted upacicalcet treatment at a serum cCa level of <7.5mg/dL recovered to ≥7.5mg/dL immediately after the interruption. In haemodialysis patients with SHPT, upacicalcet doses of 25-300μg for 52 weeks were found to be highly effective and well-tolerated, with minor safety concerns.

ODP102 Indicators for the effects of calcimimetics on hypercalcemia in the elderly patients with primary hyperparathyroidism.

Abstract Primary hyperparathyroidism (PHPT) is the most common disorder causing hypercalcemia, in which parathyroid hormone (PTH) is excessively secreted from a parathyroid tumor. PHPT occurs mainly in elderly women, and patient with PHPT present symptoms including nephrolithiasis, bone fracture, and cognitive impairment or can be asymptomatic. Excessive secretion of PTH leads to elevated serum levels of alkaline phosphatase as well as calcium and decreased serum inorganic phosphate level. Parathyroid surgery is the only established treatment, and the treatment reduces elevated serum levels of calcium and PTH, increases bone mineral density, reduces the occurrence of bone fractures, and decreases the risk of renal stones. However, some PHPT patients, especially elderly patients, refuse to undergo surgical therapy for various reasons including perceived risk. Calcimimetic treatment, including cinacalcet and evocalcet administration, has also been reported to be effective for reducing serum calcium level in patients with PHPT. However, the relationship between the efficacy of calcimimetic treatment for PHPT and patient characteristics related to the effectiveness of calcimimetics remains to be elucidated. To investigate the relevance of clinical parameters to the effectiveness of calcimimetics for PHPT, we retrospectively analyzed patients with PHPT who received calcimimetic treatment in our department. We included nine patients including 8 females (88.9%) and one male (11.1%) in the study. The median age of the patients was 81 years (interquartile range (IQR): 61-86 years). Laboratory tests before calcimimetic treatment revealed that median level of serum corrected calcium (cCa) was high (11.1 (IQR: 10.5-12.7) mg/dL), serum inorganic phosphate was low (2.3 (2.3-2.4) mg/dL), and plasma intact PTH was high (251. 0 (198.3-498.5) pg/mL). The fractional excretion of calcium was higher than 1% (1.3% (1.12-1.48%)), %tubular reabsorption of phosphate was low (79.9% (77.1-83.9%)), nephrogenous cyclic adenosine monophosphate (cAMP) was high (3.4 (2.4-4. 0) nmoL/dL GF), and urinary cAMP was normal (4.3 (4. 0-5.3) μmoL/day). Median reduction rate of serum cCa level due to calcimimetic treatment was 5.8% (0-13.4%) at the first follow-up (median treatment duration: 22 (20-29) days). Notably, reduction rate of serum cCa level had significant correlations with age (R=0.95), dual energy X-ray absorptiometry % young adult mean (DEXA %YAM) in the femoral neck (R=-0.92), and urinary cAMP level (R=-0.85). Thus, the present study suggested that elevated serum cCa levels may be reduced by treatment with calcimimetics more effectively in PHPT patients of relatively advanced age, patients with low DEXA %YAM, and patients with low urinary cAMP. Presentation: No date and time listed

A Phase I, Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Pharmacokinetics, Safety, and Tolerability of Etelcalcetide Administered Intravenously to Chinese Patients With Chronic Kidney Disease Undergoing Hemodialysis

PurposeThis study reports data from the first evaluation of etelcalcetide treatment in Chinese adults with chronic kidney disease and secondary hyperparathyroidism. MethodsThis phase I, randomized study compared thrice-weekly etelcalcetide (5 mg per dose intravenously) and placebo in 33 Chinese adults (aged 18-70 years) receiving hemodialysis. Patients in both treatment groups received standard-of-care treatment with a total of 12 doses of the investigational product during a 4-week treatment period, followed by 4 weeks of washout and follow-up. Pharmacokinetic (PK) parameters (primary endpoint), tolerability (secondary endpoint), and changes in intact parathyroid hormone (iPTH) and corrected calcium (cCa) concentrations (exploratory endpoints) were assessed. PK parameters, ie, the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–last), assessed over the interdialytic interval following the first and last doses were evaluated. The incidence of treatment-emergent adverse events (AEs) and anti-etelcalcetide antibodies was assessed. FindingsEtelcalcetide administered to 25 patients was compared with placebo administered to 8 patients. Etelcalcetide exposure, assessed by Cmax and AUC0–last, increased after multiple-dose administration of etelcalcetide through day 27, with a mean (SD) accumulation ratio of 3.02 (0.61) based on AUC. At least one AE was reported for all patients in the etelcalcetide group and for 87.5% of patients in the placebo group. Serious AEs were reported in 12% of patients in the etelcalcetide group only. No deaths occurred, and a single discontinuation because of patient withdrawal of consent was reported in the etelcalcetide group. Preexisting anti-etelcalcetide antibodies were detected in one patient. The mean serum cCa level for all patients was maintained at >1.75 mmol/L. The iPTH and cCa concentrations decreased as expected, and a maximum mean decrease from baseline of 35.13% in iPTH levels was detected on day 27. ImplicationsMultiple doses of 5 mg etelcalcetide were well tolerated, and observed etelcalcetide PK and safety profiles were similar to those in reports in adults of ethnicities other than Chinese. Changes in serum iPTH and serum calcium levels were consistent with expected responses to etelcalcetide. ClinicalTrials.gov identifier: NCT03283098.

The relationship between disease prognosis and serum calcium and corrected calcium levels in COVID-19 patients

Objectives: The present study aimed to evaluate whether low serum calcium (Ca) and corrected calcium (cCa) levels could predict disease prognosis and mortality in patients with COVID-19. Methods: In this study, we retrospectively enrolled 206 eligible patients with COVID-19, diagnosed at Turkey Kanuni Sultan Süleyman Training and Research Hospital between March 12, 2020 and June 15, 2020. Results: Serum Ca level was 8.8 ± 0.57 mg/dL and the serum cCa level was 8.99 ± 0.53 in all patients. The patients were divided into two groups, such as hypocalcemic and non-hypocalcemic patients. We observed that serum Ca levels of patients who died were significantly lower than that of surviving patients. A significant negative correlation was found between serum cCa level and albumin level. A significant positive correlation was found between serum cCa level and C-reactive protein, lactate dehydrogenase, ferritin, procalcitonin, troponin, CURB-65 score, and quick Sepsis-related Organ Failure Assessment (q-SOFA) score. Univariate logistic regression analysis revealed that age, respiratory rate, saturation, heart rate, lymphocyte, serum calcium, D-dimer, CURB-65 score, and q-SOFA score were independent predictors of high-risk group of mortality. Conclusions: This study confirms that the severity of COVID-19 is associated with lower concentrations of serum Ca. The cCa levels were associated with certain prognostic factors. Serum Ca and cCa levels could be an early and helpful marker to improve management of patients with COVID-19. We recommend evaluation of calcium in patients on initial presentation and serial monitoring during hospitalization in order to perform timely and appropriate corrective actions.

Hypocalcemia and bone mineral changes in hemodialysis patients with low bone mass treated with denosumab: a 2-year observational study.

Increases in bone mineral density (BMD) following a single dose of denosumab and increased incidence of denosumab-associated acute hypocalcemia (DAAH) have been reported in chronic kidney disease patients. Little is known about clinical risk factors related to DAAH and the long-term effect of denosumab on BMD in hemodialysis patients. An observational noncontrolled study involving 47 hemodialysis patients was conducted to determine the independent risk factors related to percentage changes in serum calcium (Ca) levels associated with denosumab using multivariate regression analysis. Optimal predictive markers for DAAH were explored by receiver operating characteristic analysis. Percentage changes of BMD at the lumbar spine (LS) and femoral neck (FN) at 24 months were investigated. The incidence of DAAH [serum corrected Ca (cCa) ≤8 mg/dL] following denosumab was 25.5%. Multivariate regression analysis showed that baseline bone alkaline phosphatase was independently related to percentage changes in cCa levels (β = -0.407, P = 0.008). Tartrate-resistant acid phosphatase-5b was found to be the most accurate marker to predict DAAH, with an area under the curve of 0.750 (95% confidence interval 0.546-0.954; P = 0.02), and the optimal cut-off level was 670 mU/mL with sensitivity: 0.727 and specificity: 0.733. BMD significantly increased by 5.9 ± 1.7% (P = 0.01) at LS and 4.2 ± 1.5% (P = 0.04) at FN at 24 months. In hemodialysis patients, high bone turnover was an independent risk factor for the Ca declines induced by denosumab. Denosumab significantly increased BMD at LS and FN at 24 months.

Effect of switching from cinacalcet to etelcalcetide on secondary hyperparathyroidism in patients undergoing hemodialysis: an ESCORT trial

BackgroundEtelcalcetide is the first intravenously administered calcimimetic agent used to manage secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients. We evaluated the safety and efficacy of replacing cinacalcet with etelcalcetide in HD patients.MethodsOne hundred and thirty-three patients HD on cinacalcet were screened, and 93 patients with serum-intact parathyroid hormone (iPTH) level of ≥ 60 pg/mL and serum albumin-corrected calcium (cCa) level of ≥ 8.4 mg/dL were enrolled. The patients were divided into three groups based on the dose of cinacalcet (i.e., 25, 50, and ≥ 75 mg) and switched to etelcalcetide. Etelcalcetide was administered three times per week for 24 weeks. The primary and secondary endpoints were etelcalcetide conversion dose and etelcalcetide effectiveness for iPTH levels (target range: 60–240 pg/mL), respectively.ResultsOf the 68 patients whose iPTH level was within the management target at screening, 60 patients maintained the target level at the end of the study. Among patients whose iPTH level exceeded 240 pg/mL at screening, it decreased from 401 ± 246 pg/mL to 220 ± 209 pg/mL (p < 0.001) at the end of the study. Among 22 patients with the iPTH level of ≥ 240 pg/mL, 17 achieved the target level. The mean dose of cinacalcet was 41.4 ± 22.2 mg/day and that of etelcalcetide at the end of the study was 6.4 ± 3.7 mg/session in all patients. In 45 patients whose iPTH level was within the management target throughout the study and active vitamin D agent and calcium-based phosphate binder doses were constant, the mean dose of cinacalcet was 45.0 ± 22.4 mg/day and that of etelcalcetide at the end of the study was 6.1 ± 3.1 mg/session. The spKt/V might affect the ratio of etelcalcetide per session to oral cinacalcet per day (45 patients, p = 0.087; 90 patients, p < 0.05) in the generalized linear model. Etelcalcetide-induced severe adverse events were not observed.ConclusionsThis study reports the conversion dose of etelcalcetide and demonstrates its safety and efficacy in HD patients with SHPT previously treated with cinacalcet.Trial registrationUMIN, UMIN000027637; Registered on June 5, 2017.

Factors affecting the relationship between ionized and corrected calcium levels in peritoneal dialysis patients: a retrospective cross-sectional study

BackgroundChronic kidney disease-mineral and bone disorder (CKD-MBD) management in patients with end-stage renal disease is important owing to the risk of cardiovascular diseases. In clinical practice, we manage patients not by monitoring the levels of biologically active ionized calcium (iCa) but by monitoring total serum calcium or corrected calcium (cCa). We previously reported that iCa/cCa ratio was different between patients with hemodialysis and those with peritoneal dialysis (PD). In PD patients, several factors are expected to affect iCa/cCa ratio. Therefore, modifying the strategy to achieve better CKD-MBD management might be necessary; however, no reports have studied this to date. Therefore, we investigated the factors influencing iCa/cCa ratio in PD patients.MethodsThis retrospective cross-sectional study examined background and laboratory data, including iCa, collected at routine outpatient visits. The patients were divided into the first, second, and third tertile of iCa/cCa ratio groups to compare patient background and laboratory data. Multiple regression analysis was used to investigate the factors influencing iCa/cCa ratio. We used multiple imputation to deal with missing covariate data.ResultsIn total, 169 PD patients were enrolled. In PD patients with lower iCa/cCa ratio, PD duration was longer and pH was higher. Urine volume and weekly renal Kt/V were lower in the patients with lower iCa/cCa ratio than in those with higher iCa/cCa ratio. iCa/cCa ratio and weekly renal Kt/V were directly correlated (r = 0.41, p < 0.01), and weekly renal Kt/V and pH were independent factors affecting iCa/cCa ratio (t = 2.86, p < 0.01 and t = − 5.42, p < 0.01, respectively).ConclusionsiCa levels were lower in PD patients with lower residual renal function (RRF) even though their cCa levels were equal to those with maintained RRF, warranting caution in the assessment and management of CKD-MBD in PD patients.

Safety and efficacy of etelcalcetide, an intravenous calcimimetic, for up to 52\xa0weeks in hemodialysis patients with secondary hyperparathyroidism: results of a post-marketing surveillance in Japan

BackgroundEtelcalcetide is a second-generation calcimimetic for the management of secondary hyperparathyroidism (SHPT) in patients on dialysis. We performed a post-marketing surveillance (PMS) to obtain information on the safety and efficacy of etelcalcetide in clinical practice in Japan.MethodsThis PMS enrolled SHPT patients who started initial treatment with etelcalcetide between April 1, 2017 and February 28, 2018 in Japan. Safety [adverse drug reactions (ADRs)] and efficacy [serum intact parathyroid hormone (iPTH), corrected calcium (cCa), phosphorous (P), and alkaline phosphatase (ALP)] were recorded for up to 52 weeks or until treatment discontinuation. Treatment decisions were at the physician’s discretion.ResultsOf 1226 patients enrolled across 282 centers, safety and efficacy data were available for 1195 and 1192, respectively, while 933 continued treatment to Week 52. The starting dose was 5 mg in 82.0% of patients. There were 218 ADRs in 169 patients (14.1%). Metabolism and nutrition disorders (8.8%), adverse laboratory test results (1.8%), and gastrointestinal disorders (1.6%) were the most frequent classes of ADRs. Hypocalcemia-related ADRs occurred in 104 patients (8.7%). The percentage of patients with iPTH levels within the target range (60–240 pg/mL) steadily increased from 19.5% at Week 0 to 64.1% at Week 52 or last dose. cCa, P, and ALP levels remained well controlled.ConclusionThis was the first real-world, large-scale, long-term observational PMS of etelcalcetide in Japan. We did not observe any new safety concerns. Etelcalcetide was associated with clinically relevant improvements in serum iPTH and maintenance of serum cCa, P, and ALP levels.

P0902DAILY TERIPARATIDE TREATMENT AND PHARMACOKINETICS IN HEMODIALYSIS PATIENTS WITH LOW BONE MASS

Abstract Background and Aims Daily 20µg teriparatide (PTH1-34) is an osteoanabolic agent approved for use treating osteoporosis. However, there are few reports about concerning use of this agent in hemodialysis patients. Method We conducted an observational study, single centre study on 5 patients with low bone mineral density (BMD) and low iPTH levels defied as iPTH below 60 pg/mL, who were treated with recombinant human PTH1-34; teriparatide 20 µg 3 times per week between January 2012 and January 2015. All patients were 20 years of age or older, had undergone regular hemodialysis treatment and were without skeletal malignancies and bone metastasis. Low BMD in this study was defined either as BMD T-score -2.5 at the lumbar spine (LS) or /and femoral neck (FN) and distal one –third radius (RS) analyzed by dual-energy X-ray absorptiometry (DXA), or BMD T-score of -2.5 to -1.0 with history of fragility fractures. We analyzed the biochemical data including bone metabolic makers (intact amino-terminal propeptide of type I collagen (iP1NP), bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) at baseline, and after 3, 6, and 12 months of teriparatide treatment. BMD at LS and FN were evaluated at 6months of treatment. Results Data from five patients (mean age: 69.2±7.4years; mean hemodialysis time: 23.2±6.2years) were reviewed. Laboratory data at baseline were iPTH: 34.2±24.2 pg/mL, BAP: 13.0±4.9 µg/L, iP1NP: 45.3±14.3 ng/mL, TRACP-5b: 350±201 mU/dL, corrected Ca (cCa): 9.7±0.3 mg/dL, and P:4.1±0.7 mg/dL. Baseline BMD T-score at LS and FN were -2.8±1.7 and -3.0±0.6, respectively. During a 12 month- teriparatide treatment, mean cCa levels significantly decreased from 9.7±0.3 to 9.1±0.2 mg/dL at 3 months (P &amp;lt; 0.05) and returned to 9.5±0.4 mg/dL at 12 months. As for bone metabolic markers, BAP and iP1NP significantly increased from baseline by 31.3±12.9 (P &amp;lt; 0.05) and 47.4±14.5% (P &amp;lt; 0.05) at 6 months of teriparatide treatment, while TRACP-5b significantly decreased by 10.5±2.5% at 3 months, which did not reach a statistical significance. BMD changes from baseline at LS and FN were 2.1±2.5% and 1.2±1.5% at 6 months of treatment with a significant change at LS. Pharmacokinetics of Teriparatide The time-course of changes in plasma teriparatide acetate concentration was evaluated in one patient who had undergone parathyroidectomy 20 years before enrollment in this study and her serum endogenous iPTH level was undetectable at baseline. After teriparatide injection, serum teriparatide acetate levels peaked at 30 minutes at 157.2 pg/mL, and then rapidly decreased to undetectable levels at 240 minutes. Conclusion We report that teriparatide improved LS and FN BMD in hemodialysis patients with low iPTH. Pharmacokinetics showed this agent might not accumulate in dialysis patients and can be used safely. Adequate Ca supplementation might be needed to adjust serum Ca levels.

Two-year retrospective study of the effect of preemptive kidney transplantation and pretransplant mineral bone factors on calcium in post-kidney transplant recipients.

Preemptive kidney transplantation (PEKT) incidence has recently increased in Japan. The effect of PEKT and mineral bone factors before kidney transplantation (KTx) on long-term calcium (Ca) levels remains unknown. Eighty-one consecutive patients at Nagoya Daini Red Cross Hospital were included in this study (PEKT group with 41 patients and non PEKT group with 40 patients). Ca metabolism, including intact fibroblast growth factor 23 (iFGF23), were measured before KTx and intact parathyroid hormone (iPTH), and corrected Ca (cCa) were measured before KTx and 6months (M), 12M, and 24M after KTx. In PEKT group, cCa levels at 24M were higher from the baseline level. At baseline, cCa levels had a positive correlation with iFGF23 levels (r = 0.51; p < 0.001) and a negative correlation with iPTH levels (r = 0.51; p < 0.001). The cCa difference between baseline and 24M was 0.8 ± 0.6mg/dL in PEKT group and 0.3 ± 0.7mg/dL in non-PEKT group (p = 0.001). A multivariate linear regression analysis showed iFGF23 and iPTH at baseline in entire groups were useful markers on calcium levels at 24M. However, in PEKT group, both markers were found to be not associated with Ca at 24M, whereas in non PEKT group, iPTH was the only effective marker. This study suggested that iFGF23 and iPTH may be useful markers of the calcium status after KTx. However, no correlation was noted in PEKT group.

Effects of denosumab on hypercalcemia and bone mineral density loss in kidney transplant recipients .

Hypercalcemia and bone mineral density (BMD) loss are serious problems associated with post-transplant chronic kidney disease-mineral and bone disorder. The present study aimed to clarify the effects of denosumab on hypercalcemia complicated with BMD loss in kidney transplant recipients. Among 100 consecutive adult kidney transplant recipients, 16 patients with serum corrected Ca (cCa) levels ≥11.0mg/dL were included in a severe hypercalcemia group. In 14 patients (excluding 2 patients who underwent parathyroidectomy) with severe hypercalcemia and low BMD at the lumbar spine (T-score < -1.0), 60mg of denosumab were administered by subcutaneous injection at 6-month intervals. Serum cCa and alkaline phosphatase (ALP) levels were analyzed before and after denosumab administration. Lumbar spinal BMD was compared between, before, and 12months after denosumab administration. Both serum cCa (11.7mg/dL) and ALP (525U/L) levels declined promptly after denosumab administration, with only the cCa level showing rebound. Additionally, serum cCa and ALP levels were significantly lower after denosumab administration (all time points) than before denosumab administration. Lumbar spinal BMD increased significantly 12 months after denosumab administration when compared with the value before denosumab administration in both anterior-posterior (increase rate: 5.0%) and lateral (increase rate: 5.4%) projections. Denosumab could improve hypercalcemia and BMD loss in kidney transplant recipients. Therapeutic intervention involving denosumab should be considered for hypercalcemia and BMD loss associated with post-transplant chronic kidney disease-mineral and bone disorder.

Prognostic Value of Corrected Levels of Serum Calcium and Serum Lactate Dehydrogenase for Newly Diagnosed Multiple Myeloma Patients

To investigate the prognostic value of the serum calcium level corrected by serum albumin (cCA) and corrected serum lactate dehydrogenase (LDH) level for the risk stratification for newly diagnosed multiple myeloma (MM) patients. The clinical data and survival of 186 newly diagnosed MM patients admitted to our hospital from June 1, 2015 to November 1, 2017 were collected. The patients's survival time was obtained by telephone and follow-up visits to patients and their families. The value of the prognostic system consisting of cCA levels and LDH levels in the survival time of MM patients was retrospectively analyzed. Moreover, the post-corrected hypercalcemia and high LDH as 2 factors were used for risk stratification, then according to these 2 factors, the MM patients were divided into 3 groups: group 1 (no risk factor), group 2 (1 risk factor) and group 3 (2 risk factors), and the effect of risk factors on the prognosis of MM patients was analyzed. The median follow-up time was 16 months. The cumulative OS rate of the post-corrected hypercalcemia group was lower than that of the non-hypercalcemia group. The 1-year cumulative OS rate in the 2 groups was 79.0%±6.7% and 88.6%±3.0%, the 3-year cumulative OS rate was 53.0%±10.5% and 74.6%±6.6% (P=0.016), respectively. The cumulative OS rate of the high LDH group [LDH ＞upper limit of normal (ULN), ULN=250 U/L] was lower than that in the normal LDH group. The 1-year cumulative OS rate in the 2 groups was 71.6%±8.6% and 90.0%±2.8%, the 2-year cumulative OS rate was 44.9%±12.1% and 83.1%±4.0%, respectively, and the median OS time was 19 months (95%CI: 15.32-23.34) and not reached (P=0.001). The risk stratification analysis showed that the median OS time of the 3 group was not reached (n=103, 57%), not reached (n=70, 39%) and 17 months (n=7, 4%, 95%CI: 5.19-28.41, P＜0.001). Patients with two risk factors had a prognosis worse than patients with 0-1 risk factor. The prognostic combination of corrected serum calcium and LDH levels may provide a basis for risk stratification and prognosis in MM patients in clinical practice.

Evaluation of initial results of naïve HIV-infected patients regarding bone health

Aim: HIV-infected patients have increased risk of osteoporosis due to both HIV and the treatment regimens in HIV. Our aim was to reveal the need of screening for bone health in HIV-infected patients, and to reveal the relationship between indirect serum markers of bone-condition, CD4+ T lymphocyte counts and HIV RNA viral loads and DEXA screening results.Methods: Naïve HIV positive patients over 18 years old who were under follow-up in our hospital between January 2014 and December 2018 were included in this retrospective cohort study. CD4+ T cell counts, HIV RNA viral loads, body mass indexes (BMI), 25 (OH) vitamin D, serum calcium and corrected calcium (cCa) levels and DEXA screening results of these patients were recorded. For statistical analysis and interpretation, e-picos (https://www.e-picos.com) and SPSS (version 20.0; SPSS Inc., Chicago, IL, USA) were used.Results: A total of 101 naive HIV-infected patients were included in the study. Vitamin D levels were within normal limits in only 9 (10.8%) patients, while 42 (50.6%) patients had insufficiency and 32 (38.5%) patients had deficiency. Serum calcium and cCa values were significantly lower in patients with &lt; 40 years of age (P=0.04). According to the T-score assessment in DEXA screening, 19 patients (47.5%) had osteopenia findings in at least one of three regions (femoral neck, total hip and lumbar spine). A total of three male patients (7.5%) had osteoporosis. In terms of viral load, only BMD and T-score in women with viral load &gt; 100,000 IU/mL were significantly lower in lumbar spine (P=0.01 and P=0.01, respectively). In terms of CD4 counts, only Z-scores in only lumbar spine and femoral neck were statistically lower in women with CD4 counts &gt; 200 cells/µl (P=0.04 and P=0.03, respectively). There were not any significant differences in any other groups and region in terms of viral load and CD4 count. None of the factors including high viral load, low CD4 + count, low 25 (OH) vitamin D level or low cCa levels were directly related to T, Z-score and low BMD.Conclusion: Osteopenia and osteoporosis are observed more frequently and at younger ages in HIV-infected patients than in the general population. Since we cannot make any prediction on bone health using one of the indirect markers in serum including 25 (OH) vitamin D levels and Ca levels or viral loads and CD4 counts in HIV-infected patients, BMD screening at younger ages may be beneficial.

Effects of Denosumab and Alendronate on Bone Health and Vascular Function in Hemodialysis Patients: A Randomized, Controlled Trial.

Mineral and bone disorders including osteoporosis are common in dialysis patients and contribute to increased morbimortality. However, whether denosumab and alendronate are effective and safe treatments in hemodialysis patients is not known. Thus, we conducted a prospective, three-center study of 48 hemodialysis patients who were diagnosed as having osteoporosis and had not received anti-osteoporotic agents previously. Participants were randomized to either denosumab or intravenous alendronate, and all subjects received elemental calcium and calcitriol during the initial 2 weeks. The primary endpoint was the percent change in lumbar spine bone mineral density (LSBMD) at 12 months of treatment. The secondary endpoints included the following: change in BMD at other sites; change of serum bone turnover markers (BTM), coronary artery calcium score (CACS), ankle-brachial pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), flow mediated dilation (FMD), and intima-media thickness at the carotid artery (CA-IMT); change from day 0 to day 14 in serum levels of Ca and P; time course of serum calcium (Ca), phosphorus (P), and intact parathyroid hormone (i-PTH); new fractures; and adverse events. Initial supplementation with elemental calcium and calcitriol markedly ameliorated the decrease of serum corrected calcium (cCa) levels induced by denosumab during the first 2 weeks, whereas serum cCa levels in the alendronate group were increased. Denosumab and alendronate markedly decreased serum levels of BTM and increased LSBMD at 12 months compared with baseline. However, no significant differences were found in the changes in LSBMD between the two groups. The serum cCa, P, and i-PTH levels in the two groups were maintained within the appropriate range. In contrast to the anti-osteoporotic effects, no significant differences after 12 months of treatment were found in the CACS, CA-IMT, ABI, baPWV, and FMD compared with pretreatment in both groups. Denosumab and alendronate treatment improved LSBMD, reduced BTM, and appeared to be safe in hemodialysis patients with osteoporosis. © 2019 American Society for Bone and Mineral Research.

Determining Efficacy and Persistence of the Wood Preservative Copper Chrome Arsenate Type C against The Wood Destroying Insects and Treated Wood Durability

The wood preservative Copper chrome arsenate (CCA type C) is one of the most common wood preservatives in the world, its effectiveness depends on performance, leach resistance, depth of penetration and persistence within treated wood tissue. The persistence of the preservative copper chrome arsenate typeC within four species of treated wood using full-cell pressure technique (double vacuum and pressure) and fixation of the preservative at 45˚C and 75% R.H was investigated. Bioassay tests were carried out to evaluate the performance of CCA-C treated wood against biological destruction and wood borers infestation using the powder post beetles Lyctus africanus (Lyctidae: Coleoptera).The treated wood samples at a concentration of 3% showed high resistance and durability against L. africanus attack through a period of four years, also the treated wood exposed to leaching process for two weeks showed resistance to L. africanus, which confirms the successful fixation of the CCA within the wood tissue and was not affected by leaching process. For all the tested treated wood species, the samples were free of L. africanus attack and no exit holes were recorded. It was found that, despite the cutting off treated wood blocks and exposing the internal parts (cross-section) of the wood to the beetles to lay eggs, wood is still resistant to beetles’ infestation, which confirms the deepening of the preservative into treated wood, also the penetration depth of the preservative (CCA) inside the wood tissue was measured using Ferro-Cyanide Potassium as a copper reagent. It was observed that, the internal tissue color (cross-section) of the treated wood has been changed to brown as a result of the penetration of copper into the treated wood. According to elemental analysis of the concentration of CCA components within treated wood after 48 months, very large differences among all wood species in retaining of elements were observed. Arsenic is clearly the least stable element in wood tissue. copper was the most affected element by leaching for all wood species. However, the residual CCA level was sufficient enough to prevent attacks and decay by L. africanus. ), Consequently, the full-cell pressure technique with (vacuum 30 in Hg) and the positive pressure of (10 bar) can be considered successful to preserve hardwood species against wood borers attack and maximize the penetration depth of the preservative within wood tissue.

Tetraspanin 1 promotes epithelial-to-mesenchymal transition and metastasis of cholangiocarcinoma via PI3K/AKT signaling

BackgroundNumerous studies have demonstrated that tetraspanin 1 (TSPAN1), a transmembrane protein, functions as an oncoprotein in many cancer types. However, its role and underlying molecular mechanism in cholangiocarcinoma (CCA) progression remain unclear.MethodsIn the present study, the expression of TSPAN1 in human CCA and adjacent nontumor tissues was examined using real-time PCR, western blot and immunohistochemistry. The effect of TSPAN1 on proliferation and metastasis was evaluated by functional assays both in vitro and in vivo. A luciferase reporter assay was performed to investigate the interaction between microRNA-194-5p (miR-194-5p) and TSPAN1 3′-untranslated region. Co-immunoprecipitation (co-IP) was used to confirm the interaction between TSPAN1 protein and integrin α6β1 and western blot was used to explore TSPAN1 mechanism.ResultsWe found that TSPAN1 was frequently upregulated in CCA and high levels of TSPAN1 correlated with TNM stage, especially metastasis in CCA. TSPAN1 overexpression promoted CCA growth, metastasis, and induced epithelial-to-mesenchymal transition (EMT), while its silencing had the opposite effect both in vitro and in vivo. To explore the differential expression of TSPAN1, we screened miR-194-5p as the upstream regulator of TSPAN1. A combination of high-level TSPAN1 and low-level miR-194-5p predicted poor prognosis in patients with CCA. Furthermore, in accordance with the functional characteristics of the TSPAN superfamily, we proved that TSPAN1 interacted with integrin α6β1 to amplify the phosphoinositide-3-kinase (PI3K)/AKT/glycogen synthase kinase (GSK)-3β/Snail family transcriptional repressor (Snail)/phosphatase and tensin homolog (PTEN) feedback loop.ConclusionThe results indicate that TSPAN1 could be a potential therapeutic target for CCA.

Impaired residual renal function predicts denosumab-induced serum calcium decrement as well as increment of bone mineral density in non-severe renal insufficiency.

Although denosumab-induced hypocalcemia has been frequently observed in patients with chronic kidney disease (CKD) stages 4-5D being treated with denosumab for osteoporosis, few studies have assessed the risk factors for serum-corrected calcium (cCa) reductions in patients with non-severe renal insufficiency. This study assessed the risk factors for reduced cCa concentration following denosumab administration and analyzed factors predictive of changes in bone mineral density (BMD). Seventy-seven osteoporotic patients, not including those with CKD stages 4-5D, were treated with 60mg denosumab once every 6months. Biochemical parameters and BMD were analyzed from prior to the initial dose until 1month after the second dose. Following the first administration of denosumab, cCa levels decreased, reaching a minimum on day 7. Multiple linear regression analyses showed that baseline cCa, estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2, tartrate-resistant acid phosphatase-5b (TRACP-5b), and bone alkaline phosphatase (BAP) or pretreatment with antiresorptive agents were significant factors independently associated with the absolute reduction in cCa from baseline to day 7 (ΔcCa0-7days). ΔcCa0-7days after the second dose of denosumab was significantly lower than that after the first dose. After 6months of denosumab treatment, both LS-BMD and FN-BMD significantly increased from baseline. LS-BMD and FN-BMD correlated significantly with baseline TRACP-5b or BAP and eGFR, respectively. Both low eGFR and high bone turnover were independent risk factors for denosumab-induced cCa decrement, and for increases in BMD. Pretreatment with antiresorptive agents may reduce the risk of hypocalcemia.

Prevalence and predictors of early hypercalcemia after kidney transplantation: a nested case-control study within a cohort of 100 patients.

Hypercalcemia (HC) after kidney transplantation (KTx) can deteriorate both graft and patient survival. However, HC as a clinical condition and its clinical significance after KTx remain unknown. We evaluated the prevalence and risk factors of early HC after KTx. We performed a nested case-control study using a cohort of 100KTx patients. KTx patients were divided into the HC and normocalcemia (NC) groups based on the baseline serum-corrected calcium (cCa) levels (≥ 10.5 and < 10.5mg/dL) within 1year after KTx. Overall, the median value of maximum serum cCa level within 1year after KTx was 10.1 (9.1-13.8) mg/dL. Of the 100 KTx patients within the cohort, 31 patients (31.0%) were classified as the HC group. The maximum serum cCa level was reached significantly earlier in the HC group compared with the NC group (2 vs. 4months, p = 0.024). In univariate analysis, the risk factors of early HC after KTx were dialysis duration ≥ 10years, serum cCa level the day before KTx, and cinacalcet administration before KTx. Among these risk factors, serum cCa level the day before KTx and cinacalcet administration before KTx were identified as significant independent risk factors of early HC after KTx in multivariate analysis. One-third of the KTx patients presented early HC within 1year after KTx. Early HC after KTx resulted from persistent hyperparathyroidism. Therapeutic strategies to manage HC after KTx must be established.