Role of Antitroponin Antibodies and Macrotroponin in the Clinical Interpretation of Cardiac Troponin.

Cardiac troponin is extensively used as a biomarker in modern medicine due to its diagnostic capability for myocardial injury, as well as its predictive and prognostic value for cardiac diseases. However, heterophile antibodies, antitroponin antibodies, and macrotroponin complexes can be observed both in seemingly healthy individuals and patients with cardiac diseases, potentially leading to false positive or disproportionate elevation of cTn (cardiac troponin) assay results and introducing discrepancies in clinical interpretations with impact on medical management. In this review article, we describe the possible mechanisms of cTn release and the sources of variations in the assessment of circulating cTn levels. We also explore the pathophysiological mechanisms underlying antitroponin antibody development and discuss the influence exerted by macrotroponin complexes on the results of immunoassays. Additionally, we explore approaches to detect these complexes by presenting various clinical scenarios encountered in routine clinical practice. Finally, unsolved questions about the development, prevalence, and clinical significance of cardiac autoantibodies are discussed.

Pre-operative levels of angiopoietin protein-like 3 (ANGPTL3) in women diagnosed with high-grade serous carcinoma of the ovary.

Cancer cells need constant supplies of lipids to survive and grow. Lipid dependence has been observed in various types of cancer, including high-grade serous ovarian carcinomas (HGSOC), which is a lethal form of gynecological malignancy. ANGPTL3, PCSK9, and Apo CIII are pivotal lipid-modulating factors, and therapeutic antibodies have been developed against each one (Evinacumab, Evolocumab and Volanesorsen, respectively). The roles -if any- of ANGPTL3, PCSK9, and Apo CIII in HGSOC are unclear. Moreover, levels of these lipid-modulating factors have never been reported before in HGSOC. In this study, circulating levels of ANGPTL3, PCSK9, and Apo CIII, along with lipid profiles, are examined to verify whether one or many of these lipid-regulating factors are associated with HGSOC. Methods ELISA kits were used to measure ANGPTL3, PCSK9 and Apo CIII levels in plasma samples from 31 women with HGSOC and 40 women with benign ovarian lesions (BOL) before treatment and surgery. A Roche Modular analytical platform measured lipid panels, Apo B and Lp(a) levels.Results ANGPTL3 levels were higher in women with HGSOC (84 ng/mL, SD: 29 ng/mL, n = 31) than in women with BOL (67 ng/mL, SD: 31 ng/mL, n = 40; HGSOC vs. BOL P = 0.019). Associations between the lipid panel and ANGPTL3, and the inverse relationship between HDL-cholesterol and triglycerides, were present in women with BOL but not with HGSOC. PCSK9 and Apo CIII were not associated with HGSOC.Conclusions In this cohort of 71 women, ANGPTL3 levels were increased in HGSOC patients. The presence of HGSOC disrupted the classic inverse relationship between HDL and triglycerides, as well as the association between the lipid panel and ANGPTL3. These associations were only maintained in cancer-free women. Given the availability of Evinacumab, a therapeutic antibody against ANGPTL3, the current finding prompts an assessment of whether ANGPTL3 inhibition has therapeutic potential in HGSOC.

The Progression of Interstitial Fibrosis and Tubular Atrophy at 6 Months Is an Independent Predictor of Poor Graft Outcomes in Kidney Transplant Recipients.

Interstitial fibrosis and tubular atrophy (IFTA) found on 1-y surveillance biopsies has been associated with poor graft outcomes. However, its progression over time and relationship to outcomes are less well defined. Methods: We studied implantation and 6-mo surveillance biopsies and examined the association between the progression of IFTA (ΔIFTA) and a composite of censored graft loss or doubling of serum creatinine in 248 adult kidney recipients. Results: The percentage of patients with ΔIFTA of 1 or ≥2 was 35% and 22%, respectively. Positive ΔIFTA was a risk factor for the composite endpoint (hazard ratio, 1.36; 95% confidence interval, 1.03-1.79). This estimate was robust to adjustment for recipient and donor baseline characteristics, baseline IFTA, tacrolimus levels, and rejection status. ΔIFTA was associated with decreased estimated glomerular filtration rate at 3 and 5 y. IFTA+i was a predictor in the cohort; however, IFTA progression was not limited to those with a mononuclear cell interstitial inflammation (Banff "i") score above zero. Notably, donor age was a predictor of IFTA at 6 mo, but not of ΔIFTA, whereas rejection, donor diabetes, and recipient smoking status were. Conclusions: Progression of IFTA at 6 mo can predict outcomes. ΔIFTA was not related to donor age but may be linked to other risk factors influencing decision-making for donor versus recipient selection.

Current use of bone turnover markers in the management of osteoporosis.

The adult bone is continuously being remodelled to repair microdamage, preserve bone strength and mechanical competence as well as maintain calcium homeostasis. Bone turnover markers are products of osteoblasts (bone formation markers) and osteoclasts (bone resorption markers) providing a dynamic assessment of remodelling (turnover). Resorption-specific bone turnover markers are typically degradation products of bone collagen molecules (N- [NTX] and C-telopeptide cross-linked type 1 collagen [CTX]), which are released into the circulation and excreted in urine; or enzymatic activities reflecting osteoclastic resorption, tartrate-resistant acid phosphatase [TRACP]. Formation-specific bone turnover markers embrace different osteoblastic activities: type 1 collagen synthesis (Procollagen type I N- propeptide [PINP]), osteoblast enzymes (bone-specific alkaline phosphatase [BALP]), or bone matrix proteins [osteocalcin]. Among individuals not receiving osteoporosis treatment, resorption and formation markers are tightly linked and highly correlated (r = 0.6-0.8). Significant biological variability was reported in the past, but these issues have been greatly improved with automated assays and attention to pre-analytical and analytical factors that are known to influence bone turnover marker levels. Bone turnover markers are not useful in the diagnosis of osteoporosis, the individual prediction of bone loss, fracture, or rare complications, or in the selection of pharmacological treatment. Despite remaining issues with reference intervals and assays harmonization, bone turnover markers have proven to be useful in elucidating the pharmacodynamics and effectiveness of osteoporosis medications in clinical trials. As an alternative to BMD testing, BTMs may be useful to monitor osteoporosis therapies.

Low BRCA1 and BRCA2 Germline Mutation Rates in a French-Canadian Population with a Diagnosis of Epithelial Tubo-Ovarian Carcinoma.

OBJECTIVE: Universal genetic testing has become increasingly important in the management of epithelial tubo-ovarian and peritoneal carcinoma. Worldwide, reported incidences of deleterious BRCA mutations vary between 12% and 15%. We sought to evaluate the incidence in our population, given its specific genetic background (French-Canadian ancestry). METHOD: Mainstream genetic testing was implemented in our service in May 2017 and offered to all patients with epithelial tubo-ovarian or peritoneal carcinomas, except mucinous and borderline tumours. Data were prospectively collected in a database and retrospectively analyzed. RESULTS: We tested 222 patients in our centre, of whom 183 (82.4%) had high-grade serous carcinoma (HGSC). Overall, 139 patients had no identified mutation (62.6%). Deleterious BRCA1 and BRCA2 mutations were found in 12 patients (5.4%): 6 had BRCA1, and 6 BRCA2 mutations; 11 of these patients had HGSC. Other non-BRCA mutations (ATM, RAD51C, RAD51D, BRIP1, CDH1, MRE11, MSH6, MUTYH, PALB2, and PMS2) were observed in an additional 20 patients (9.0%), of whom 18 had HGSC. A total of 63 different variants of unknown significance (VUS) were found, of which 4 were in the BRCA1 and BRCA2 genes. Deleterious mutations were not identified in clear cell carcinomas, and only 1 was found in low-grade serous carcinoma. CONCLUSION: In our French-Canadian population, the incidence of deleterious germline BRCA mutations was surprisingly low at 5.4%-less than half that reported in the literature. This may affect patient response to poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy. Mainstream genetic testing was successfully implemented in our service and facilitated access to genetic testing in our patient population.

Impact of the 2016 Canadian Lipid Guidelines on Daily Practice at a Community Hospital.

OBJECTIVES: The aim of this study was to determine the impact of the 2016 Canadian cardiovascular society guidelines for the management of dyslipidemia. More specifically, we assessed the use of 1) alternate lipid targets when triglyceride (TG) levels are high; and 2) nonfasting lipid testing. METHODS: Lipid profiles and pharmacy data were obtained from patients with a history of myocardial infarction and from patients ≥40 years of age with a diagnosis of diabetes. RESULTS: As TG increased to >1.5 mmol/L, percent within target for non-high-density lipoprotein cholesterol and apolipoprotein B 18 months after guideline release remained low in both patients with atherosclerotic cardiovascular disease (40%) and patients with diabetes in primary prevention (30%). Approximately 50% of patients were fasting when presenting for lipid testing. Use of high-intensity statin was suboptimal in both groups. CONCLUSIONS: The concept of alternate lipid targets may not be well understood by many physicians, leading to undertreatment of patients. Progress was made in the promotion of routine nonfasting lipid testing.

Impact of the Martin/Hopkins modified equation for estimating LDL-C on lipid target attainment in a high risk patient population.

OBJECTIVE: To evaluate the Martin/Hopkins equation for estimating LDL-C as target in a population composed of high cardiac risk patients. METHODS: Lipid profile data from patients with TG ≤ 4.52 mmol/L (<400 mg/dl) were used. The high cardiac risk group (N 4150) consisted of patients over 40 years of age that had an A1C level of 6.5% or above and patients with a history of atherosclerotic cardiovascular disease (ASCVD). Comparisons were made between the Martin/Hopkins formula (MH-LDL-C), the Friedewald formula (F-LDL-C), Non-HDL-C and ApoB. RESULTS: Higher LDL-C values (0.15 mmol/L or 7.3%) were obtained using MH-LDL-C compared to the F-LDL-C. The % within target (%WT) values for F-LDL-C, MH-LDL-C, Non-HDL-C and ApoB were similar when TG levels were ≤ 1.5 mmol/L with a high degree of concordance as measured by the kappa statistic. When compared to F-LDL-C, Non-HDL-C and ApoB showed a profound decrease in the WT value as TG levels increased from normal (67.7%) to intermediate (39.1%) and high levels (20.8%). MH-LDL-C showed an attenuated decrease in the WT value as TG increased from normal (61.4%) intermediate (43.4%) and high levels (32.7%). Concordance with the alternate target parameters was higher for MH-LDL-C than for F-LDL-C when triglycerides levels were increased. CONCLUSION: The Martin/Hopkins modified equation for estimating LDL-C is a significant improvement on the decade's old Friedewald formula; however it remains an imperfect tool to estimate the atherogenic load in patients with high TG levels.

Performance of preoperative plasma tumor markers HE4 and CA125 in predicting ovarian cancer mortality in women with epithelial ovarian cancer.

Clinical utility of new biomarkers often requires the identification of their optimal threshold. This external validation study was conducted to assess the performance of the preoperative plasma tumor markers HE4 and CA125 optimal cut-offs to predict cancer mortality in women with epithelial ovarian cancer (EOC). Participating women had upfront debulking surgery in the University Hospital of Quebec City (Canada) between 1998 and 2013. A total of 136 women participated in the training cohort (cohort 1) and 177 in the validation cohort (cohort 2). Preoperative plasma HE4 and CA125 levels were measured by Elecsys. Optimal thresholds were identified in the cohort 1 using time-dependent receiver operating characteristic (ROC) curves. Multivariate Cox models were used to validate the biomarkers using their optimal cut-offs in the cohort 2. The likelihood ratio (LR) test was done to test whether the biomarkers added prognostic information beyond that provided by standard prognostic factors. The Areas Under the Curves (AUC) for HE4 and CA125 were respectively 64.2 (95% CI: 54.7-73.6) and 63.1 (95%CI: 53.6-72.6). The optimal thresholds were 277 pmol/L for HE4 and 282 U/ml for CA125. Preoperative plasma HE4 (≥277 pmol/L) was significantly associated with EOC mortality (adjusted hazard ratio (aHR): 1.90; 95% CI:1.09-3.29). The prognostic effect of HE4 was strongest in the subgroup of women with serous ovarian cancer (aHR: 2.42; 95% CI: 1.25-4.68). Using a multivariate model including all standard prognostic factors, this association was maintained (aHR: 2.21; 95% CI: 1.15-4.23). In addition, preoperative plasma HE4 added prediction for death over the standard prognostic markers in women with serous tumors (p-value for LR-test: 0.01). Preoperative CA125 was not associated with cancer mortality, both in women with EOC and in those with serous tumors. Preoperative HE4 is a promising prognostic biomarker in EOC, especially in serous tumor.

Predictors of circulating INTERLEUKIN-6 levels in head and neck cancer patients.

BACKGROUND: Circulating interleukin-6 (IL-6) improves outcome prediction for second primary cancer (SPC) in head and neck cancer (HNC) patients. This study aimed to identify factors associated with IL-6 serum levels in HNC patients. METHODS: This study was conducted as part of a phase III chemoprevention trial. IL-6 was measured using chemiluminescent immunometric assay on pretreatment serum sample obtained from 527 stage I-II HNC patients. Patients' lifestyle habits, sociodemographic, medical and tumor characteristics were evaluated before radiation therapy (RT). Factors independently associated with IL-6 levels before RT were identified using multiple linear regression. RESULTS: The median IL-6 serum level was 3.1 ng/L. In the multivariate analysis, eight factors were significantly associated (p < 0.05) with IL-6: age, gender, marital status, body mass index, tobacco consumption, comorbidities, Karnofsky Performance Status and HNC site. Smoking duration and lifetime pack-years were positively associated with IL-6 serum levels in a dose-response relationship (p-value for trend ≤0.03). CONCLUSIONS: Circulating IL-6 is a strong predictor of the occurrence of SPC in HNC patients. We identified eight factors independently associated with serum IL-6 levels in 527 stage I-II HNC patients.The dose-response relationship between lifetime smoking and IL-6 serum levels suggested a causal role of tobacco exposure on IL-6 production. Further studies are needed to establish whether the effect of tobacco exposure on SPC could be partly mediated by IL-6, a pro-inflammatory cytokine.

Variability of High-Sensitivity Troponin T Concentrations in Emergency Settings: Impact for the Diagnosis of Myocardial Infarction.

OBJECTIVES: To assess biological variation of troponin T in emergency settings and establish limits for interpretation of serial results. METHODS: We studied 6,557 consecutive patients with troponin measurements. A stable reference subset was selected to estimate biological variation and threshold limits. RESULTS: The first troponin level was elevated in 32% of patients, and 2,490 had a second troponin level with a myocardial infarction (MI) prevalence of 16.2%. In the stable reference group with at least one abnormal value, the 99th percentile of the absolute delta between the first two samples was 16 ng/L. For MI diagnosis, the area under the receiver operating characteristic curve was 0.85 (confidence interval [CI], 0.83-0.87) for the first troponin level and 0.94 (CI, 0.93-0.95) for the absolute delta. CONCLUSIONS: An absolute delta of 16 ng/L has good specificity in the emergency setting. This threshold is valid for any sex, age, and sampling interval between 3 and 24 hours and is higher than published limits found in healthy outpatients.

Serum Parathyroid Hormone and 25-Hydroxyvitamin D Concentrations Before and After Biliopancreatic Diversion.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) decreases vitamin D and calcium absorption, which may result in secondary hyperparathyroidism. This study aimed at evaluating the prevalence of vitamin D deficiency and secondary hyperparathyroidism before and after BPD-DS. METHODS: A retrospective analysis of patients who had undergone BPD-DS at a tertiary bariatric center between 2003 and 2010 and for whom simultaneous measurements of serum 25-hydroxyvitamin D and parathyroid hormone were available within 5 years post-op was performed. The prevalence of vitamin D deficiency (< 20 ng/ml) and secondary hyperparathyroidism (> 65 pg/mL) at different time points was calculated. RESULTS: Included were 1436 patients (mean ± SD, age 42.7 ± 10.4 years; BMI 51.5 ± 8.6 kg/m2; 69.8% women). Prevalence of vitamin D deficiency decreased up to 6-12 months after surgery (from 35.8% at baseline down to 6-9%) then rose progressively, plateauing at 15.5% after 36 months. Prevalence of hyperparathyroidism was 28.5% before surgery and rose progressively after surgery, reaching 68.6% at 5 years. Mean serum corrected calcium increased from 0 to 6 months then decreased up to 36 months. Preoperatively, the prevalence of hypocalcemia was 7.3%. It increased after 12 months, attaining 26.9% at 48 months. CONCLUSIONS: Prevalence of vitamin D deficiency and secondary hyperparathyroidism is high before BPD-DS. Despite a low prevalence of vitamin D deficiency after surgery, prevalence of hyperparathyroidism increased steadily 1 year after surgery, preceded by a decrease in serum calcium. Factors explaining the high prevalence of secondary hyperparathyroidism after BPD-DS and its long-term impact on bone health should be addressed.

Comparison of fasting and non-fasting lipid profiles in a large cohort of patients presenting at a community hospital.

OBJECTIVE: To compare the fasting and non-fasting lipid profile including ApoB in a cohort of patients from a community setting. Our purpose was to determine the proportion of results that could be explained by the known biological variation in the fasting state and to examine the additional impact of non-fasting on these same lipid parameters. METHODS: 1093 adult outpatients with fasting lipid requests were recruited from February to September 2016 at the blood collection sites of the Moncton Hospital. Participants were asked to come back in the next 3-4days after having eaten a regular breakfast to have their blood drawn for a non-fasting lipid profile. RESULTS: 91.6% of patients in this study had a change in total cholesterol that fell within the biological variation expected for this parameter. Similar results were seen for HDL-C (94.3%) non-HDL-C (88.8%) and ApoB (93.0%). A smaller number of patients fell within the biological variation expected for TG (78.8%) and LDL-C (74.6%). An average TG increase of 0.3mmol/L was observed in fed patients no matter the level of fasting TG. A gradual widening in the range of change in TG concentration was observed as fasting TG increased. Similar results were seen in diabetic patients. CONCLUSION: Outside of LDL-C and TG, little changes were seen in lipid parameters in the postprandial state. A large part of these changes could be explained by the biological variation. We observed a gradual widening in the range of increase in TG for patients with higher fasting TG. Non-HDL-C and ApoB should be the treatment target of choice for patients in the non-fasting state.

The Effect of Triglyceride Concentration on Attainment of Lipid Targets in Patients with Diabetes.

OBJECTIVES: To evaluate the effects of triglyceride (TG) and glycated hemoglobin (A1C) concentrations in the percentage of patients with diabetes who are within target (WT) for low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (ApoB), as defined by the Canadian Lipid Guidelines, in a cohort of outpatients presenting at a 350-bed community hospital. METHODS: Laboratory samples from 1919 patients, 18 years or older, who had A1C levels of 6.5% or above were used. Fasting lipid profiles were retrieved, and ApoB was measured. RESULTS: We found no significant difference in the percentage of those WT for LDL-C as TG increased from normal to intermediate and high levels. For non-HDL-C, we saw a substantial decrease in the percentage of patients WT as TG levels increased from normal (61%) to intermediate (30.4%) and high levels (14.0%). ApoB showed a similar pattern to non-HDL-C: decreasing from normal (68.8%) to intermediate (40.7%) and high levels (21.0%). No significant difference was seen in the percentage of patients WT for the 3 lipid parameters studied with the increase in A1C levels. CONCLUSIONS: As TG increases, we saw discordance in the percentage of patients WT for LDL-C in relation to non-HDL-C and ApoB. Alternative targets to LDL-C should preferentially be used when the TG concentration is elevated.

Prediction and validation of the duration of hemodialysis sessions for the treatment of acute ethylene glycol poisoning.

The duration of hemodialysis (HD) sessions for the treatment of acute ethylene glycol poisoning is dependent on concentration, the operational parameters used during HD, and the presence and severity of metabolic acidosis. Ethylene glycol assays are not readily available, potentially leading to undue extension or premature termination of HD. We report a prediction model for the duration of high-efficiency HD sessions based retrospectively on a cohort study of 26 cases of acute ethylene glycol poisoning in 24 individuals treated by alcohol dehydrogenase competitive inhibitors, cofactors and HD. Two patients required HD for more than 14 days, and two died. In 19 cases, the mean ethylene glycol elimination half-life during high-efficiency HD was 165 minutes (95% confidence interval of 151-180 minutes). In a training set of 12 patients with acute ethylene glycol poisoning, using the 90th percentile half-life (195 minutes) and a target ethylene glycol concentration of 2 mmol/l (12.4 mg/dl) allowed all cases to reach a safe ethylene glycol under 3 mmol/l (18.6 mg/dl). The prediction model was then validated in a set of seven acute ethylene glycol poisonings. Thus, the HD session time in hours can be estimated using 4.7 x (Ln [the initial ethylene glycol concentration (mmol/l)/2]), provided that metabolic acidosis is corrected.

Predictive factors for sentinel lymph nodes and non-sentinel lymph nodes metastatic involvement: a database study of 1,041 melanoma patients.

BACKGROUND: Sentinel lymph node (SLN) biopsy may identify patients who may need completion lymphadenectomy and adjuvant therapy. METHODS: Univariate and multivariate analysis were conducted for SLN status in a prospective cohort of 1,041 patients. A biopsy was recommended for melanoma greater than or equal to 1 mm thick or greater than or equal to .75 mm with poor prognostic features. RESULTS: For sentinel node status, mitotic rate is very significant in univariate analysis. In multivariate analysis, Breslow, lymphovascular invasion, and primary site were significant. Breslow thickness greater than or equal to 2 mm and SLN with macroscopic burden greater than or equal to 2 mm are the only statistically significant variables predicting the non-SLN status in multivariate analysis. CONCLUSIONS: The data confirm the importance of Breslow, lymphovascular invasion, and body site for SLN status. The cutoff of 2 mm for tumor load in SLN appears to be a simple technique to find the high-risk patients with further lymph node disease.

Prediction and validation of hemodialysis duration in acute methanol poisoning.

The duration of hemodialysis (HD) in methanol poisoning (MP) is dependent on the methanol concentration, the operational parameters used during HD, and the presence and severity of metabolic acidosis. However, methanol assays are not easily available, potentially leading to undue extension or premature termination of treatment. Here we provide a prediction model for the duration of high-efficiency HD in MP. In a retrospective cohort study, we identified 71 episodes of MP in 55 individuals who were treated with alcohol dehydrogenase inhibition and HD. Four patients had residual visual abnormality at discharge and only one patient died. In 46 unique episodes of MP with high-efficiency HD the mean methanol elimination half-life (T1/2) during HD was 108 min in women, significantly different from the 129 min in men. In a training set of 28 patients with MP, using the 90th percentile of gender-specific elimination T1/2 (147 min in men and 141 min in women) and a target methanol concentration of 4 mmol/l allowed all cases to reach a safe methanol of under 6 mmol/l. The prediction model was confirmed in a validation set of 18 patients with MP. High-efficiency HD time in hours can be estimated using 3.390 × (Ln (MCi/4)) for women and 3.534 × (Ln (MCi/4)) for men, where MCi is the initial methanol concentration in mmol/l, provided that metabolic acidosis is corrected.

Reversal of Severe and Refractory Humoral Hypercalcemia With 177Lu-Octreotate Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumor of the Pancreas.

A 48-year-old Caucasian male patient with newly diagnosed neuroendocrine tumor of the pancreas with multiple liver metastases developed severe and refractory hypercalcemia. Complementary investigations were compatible with humoral hypercalcemia with high parathyroid hormone-related peptide (PTHrP) levels. Hypercalcemia was refractory to medical treatments for more than 2 years. Serum calcium returned to normal values only after 4 cycles of peptide receptor radionuclide therapy with Lu-octreotate, with concomitant reduction of PTHrP level and tumor regression. The use of radionuclide therapy could be an option for the management of severe humoral hypercalcemia in patients with inoperable metastatic pancreatic neuroendocrine tumor.

The impact of warfarin on the rate of progression of aortic stiffness in hemodialysis patients: a longitudinal study.

BACKGROUND: Accelerated progression of aortic stiffness in patients with advanced chronic kidney disease is not well explained by the traditional cardiovascular risk factors. We hypothesized that vitamin K deficiency may result in an accelerated progression of aortic stiffness in the pro-calcifying uremic milieu. METHOD: Eighteen hemodialysis (HD) patients on warfarin were matched to 54 HD patients without warfarin (control). Aortic stiffness was determined by carotid-femoral pulse wave velocity (cf-PWV) at baseline and after a mean follow-up of 1.2 years. In the control group, spontaneous vitamin K deficiency was defined as proteins induced by vitamin K deficiency/absence-II >median. RESULTS: At baseline, clinical characteristics and cf-PWV were similar. Adjusted cf-PWV increased by 0.86 ± 1.87 m/s in control and by 2.24 ± 2.68 m/s in warfarin group (P = 0.024). After adjustments for confounders, warfarin therapy was independently associated with progression of aortic stiffness (P = 0.016). The rate of progression of aortic stiffness showed a linear trend in response to vitamin K status and warfarin therapy, suggesting that at least part of the effects are mediated through reduced availability of vitamin K. The unadjusted and adjusted hazard ratio (HR) of warfarin therapy on mortality were, respectively, 2.40 (P = 0.006) and 2.53 (P = 0.006). In a forward conditional Cox regression analysis, age, albumin, augmentation index (AIx) and a cf-PWV > 13.8 m/s at the time of follow-up (HR: 2.11, P = 0.05) were independent determinants of mortality, whereas warfarin use was not retained as an independent factor. Finally, control patients with poor vitamin K status had an intermediate survival as compared with controls with better vitamin K status and patients with warfarin (P = 0.01). CONCLUSION: This is the first study to show a temporal association between warfarin, functional vitamin K deficiency and progression of aortic stiffness in HD patients. These findings suggest that the net cardiovascular benefit of long-term warfarin therapy may need to be reevaluated in this population.

Active vitamin D and accelerated progression of aortic stiffness in hemodialysis patients: a longitudinal observational study.

BACKGROUND: We hypothesized that high-dose active vitamin D therapy in the form of alphacalcidol (α-calcidol), used to treat secondary hyperparathyroidism in chronic kidney disease, could lead to vascular calcification and accelerated progression of aortic stiffness. METHODS: We conducted an observational study in 85 patients on chronic hemodialysis, among which 70 were taking a weekly dose of α-calcidol of <2 µg and 15 were taking a weekly dose of ≥2 µg (pharmacological dose). Parathyroid hormone, 25-hydroxyvitamin D, fibroblast growth factor 23, and α-klotho were determined. Aortic stiffness was assessed by determination of carotid-femoral pulse wave velocity (cf-PWV) at baseline and after a mean follow-up of 1.2 years. A multivariable regression model was used to evaluate the impact of pharmacological dose of α-calcidol on the progression of aortic stiffness. RESULTS: At baseline, clinical, biological, and hemodynamic parameters were similar. At follow-up, cf-PWV increased more in patients with pharmacological dose of α-calcidol (0.583±2.291 m/s vs. 1.948±1.475 m/s; P = 0.04). After adjustment for changes in mean blood pressure and duration of follow-up, pharmacological dose of α-calcidol was associated with a higher rate of progression of cf-PWV (0.969 m/s; 95% confidence interval = 0.111-1.827; P = 0.03), and this association persisted after further adjustments for parameters of mineral metabolism. CONCLUSIONS: In this study, pharmacological dose of α-calcidol was associated with accelerated progression of aortic stiffness. This study suggest that the vascular safety of active vitamin D posology may need to be specifically addressed in the treatment of chronic kidney disease-related bone mineral disorder.