Coronary artery calcification and aortic valve calcification in patients with kidney failure: a sex-disaggregated study.

BACKGROUND: Chronic kidney disease (CKD) is linked to an increased cardiovascular disease (CVD) burden. Albeit underappreciated, sex differences are evident in CKD with females being more prone to CKD development, but males progressing more rapidly to kidney failure (KF). Cardiovascular remodelling is a hallmark of CKD with increased arterial and valvular calcification contributing to CKD. However, little is known regarding sex differences in calcific cardiovascular remodelling in KF patients. Thus, we hypothesise that sex differences are present in coronary artery calcification (CAC) and aortic valve calcification (AVC) in patients with KF. METHODS: KF patients, males (n = 214) and females (n = 107), that had undergone computer tomography (CT) assessment for CAC and AVC were selected from three CKD cohorts. All patients underwent non-contrast multi-detector cardiac CT scanning, with CAC and AVC scoring based on the Agatston method. Baseline biochemical measurements were retrieved from cohort databases, including plasma analyses for inflammation markers (IL-6, TNF, hsCRP) and oxidative stress by skin autofluorescence measuring advanced glycation end-products (AGE), amongst other variables. RESULTS: Sex-disaggregated analyses revealed that CAC score was associated with age in both males and females (both p < 0.001). Age-adjusted analyses revealed that in males CAC was associated with diabetes mellitus (DM) (p = 0.018) and CVD (p = 0.011). Additionally, for females CAC associated with IL-6 (p = 0.005) and TNF (p = 0.004). In both females and males CAC associated with AGE (p = 0.042 and p = 0.05, respectively). CAC was associated with mortality for females (p = 0.015) independent of age. AVC in females was not reviewed due to low AVC-positive samples (n = 14). In males, in multivariable regression AVC was associated with age (p < 0.001) and inflammation, as measured by IL-6 (p = 0.010). CONCLUSIONS: In female KF patients inflammatory burden and oxidative stress were associated with CAC. Whereas in male KF patients oxidative stress and inflammation were associated with CAC and AVC, respectively. Our findings suggest a sex-specific biomarker signature for cardiovascular calcification that may affect the development of cardiovascular complications in males and females with KF.

Chronic kidney disease (CKD) is a condition that affects the kidneys and increases the risk of heart problems. Males and females may experience CKD differently, and our study aimed to understand the differences in the development of calcification in the blood vessels of the heart (coronary artery calcification, or CAC) and the heart valves (aortic valve calcification, or AVC) between males and females with CKD.We analysed 214 males and 107 females with CKD who had undergone a heart scan (computer tomography, or CT) to measure CAC and AVC. We collected information on age, diabetes, cardiovascular disease, and markers of inflammation and oxidative stress.Our results showed that in both males and females CAC was associated with age. In males, CAC was associated with diabetes and cardiovascular disease, while in females, it was linked to markers of inflammation. In females, CAC was also associated with mortality regardless of age. Unfortunately, we had insufficient samples of females with AVC for analysis. However, in males AVC was associated with age and inflammation.Overall, our study indicates sex-specific differences in the development of calcification in the blood vessels and heart valves of CKD patients. In females, inflammation and oxidative stress are associated with CAC, while in males, oxidative stress and inflammation are associated with CAC and AVC, respectively. These findings underscore the importance of considering these differences when assessing cardiovascular complications in CKD patients. It may help in developing personalised treatment approaches for both males and females with CKD.

Central obesity as assessed by conicity index and a-body shape index associates with cardiovascular risk factors and mortality in kidney failure patients.

Background: Anthropometric indices of central obesity, waist circumference (WC), conicity index (CI), and a-body shape index (ABSI), are prognostic indicators of cardiovascular (CV) risk. The association of CI and ABSI with other CV risk indices, markers of nutritional status and inflammation, and clinical outcomes in chronic kidney disease (CKD) stage 5 (CKD5) patients was investigated. Methods: In a cross-sectional study with longitudinal follow up of 203 clinically stable patients with CKD5 (median age 56 years; 68% males, 17% diabetics, 22% with CV disease, and 39% malnourished), we investigated CI and ABSI and their associations with atherogenic index of plasma (AIP), Framingham CV risk score (FRS), Agatston scoring of coronary artery calcium (CAC) and aortic valve calcium (AVC), handgrip strength (HGS), high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). CV events (CVE) and all-cause mortality during up to 10-years follow up were analyzed by multivariate survival analysis of restricted mean survival time (RMST). Results: Chronic kidney disease patients with middle and highest CI and ABSI tertiles (indicating greater abdominal fat deposition), compared to those with the lowest CI and ABSI tertiles, tended to be older, more often men and diabetic, had significantly higher levels of hsCRP, IL-6, AIP, FRS, CAC and AVC scores. CI and ABSI were positively correlated with CAC, FRS, AIP, hsCRP and IL-6. Both CI and ABSI were negatively correlated with HGS. In age-weighted survival analysis, higher CI and ABSI were associated with higher risk of CVE (Wald test = 4.92, p = 0.027; Wald test = 4.95, p = 0.026, respectively) and all-cause mortality (Wald test = 5.24, p = 0.022; Wald test = 5.19, p = 0.023, respectively). In RMST analysis, low vs. high and middle tertiles of CI and ABSI associated with prolonged CVE-free time and death-free time, and these differences between groups increased over time. Conclusion: Abdominal fat deposit indices, CI and ABSI, predicted CV outcomes and all-cause mortality, and were significantly associated with the inflammatory status in CKD patients.

Scoring of medial arterial calcification predicts cardiovascular events and mortality after kidney transplantation.

BACKGROUND: Progression of vascular calcification causes cardiovascular disease, which is the most common cause of death in chronic kidney failure and after kidney transplantation (KT). The prognostic impact of the extent of medial vascular calcification at KT is unknown. METHODS: In this prospective cohort study, we investigated the impact of medial calcification compared to a mix of intimal and medial calcification represented by coronary artery calcification (CAC score) and aortic valve calcification in 342 patients starting on kidney failure replacement therapy. The primary outcomes were cardiovascular events (CVE) and death. The median follow-up time was 6.4 years (interquartile range 3.7-9.6 years). Exposure was CAC score and arteria epigastrica medial calcification scored as none, mild, moderate, or severe by a pathologist at time of KT (n = 200). We divided the patients according to kidney failure replacement therapy during follow-up, that is, living donor KT, deceased donor KT, or dialysis. RESULTS: Moderate to severe medial calcification in the arteria epigastrica was associated with higher mortality (p = 0.001), and the hazard ratio for CVE was 3.1 (95% confidence interval [CI] 1.12-9.02, p < 0.05) compared to no or mild medial calcification. The hazard ratio for 10-year mortality in the dialysis group was 33.6 (95% CI, 10.0-113.0, p < 0.001) compared to living donor recipients, independent of Framingham risk score and prevalent CAC. CONCLUSION: Scoring of medial calcification in the arteria epigastrica identified living donor recipients as having 3.1 times higher risk of CVE, independent of traditional risk factors. The medial calcification score could be a reliable method to identify patients with high and low risk of CVE and mortality following KT.

Role of GDF-15, YKL-40 and MMP 9 in patients with end-stage kidney disease: focus on sex-specific associations with vascular outcomes and all-cause mortality.

BACKGROUND: Sex differences are underappreciated in the current understanding of cardiovascular disease (CVD) in association with chronic kidney disease (CKD). A hallmark of CKD is vascular aging that is characterised, amongst others, by; systemic inflammation, microbiota disbalance, oxidative stress, and vascular calcification-features linked to atherosclerosis/arteriosclerosis development. Thus, it is the necessary to introduce novel biomarkers related to athero-/arteriosclerotic damage for better assessment of vascular ageing in patients CKD. However, little is known about the relationship between uraemia and novel CVD biomarkers, such as growth differentiation factor-15 (GDF-15), cartilage glycoprotein-39 (YKL-40) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesise that there are sex-specific relationships between GDF-15, YKL-40, MMP-9 levels in end-stage kidney disease (ESKD) patients in relation to gut microbiota, vascular calcification, inflammation, comorbidities, and all-cause mortality. METHODS: ESKD patients, males (n = 151) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective ESKD cohorts. GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay kits. Biomarker levels were analysed in the context of gut microbiota-derived trimethylamine N-oxide (TMAO), vascular calcification, inflammatory response, oxidative stress, comorbidities, and all-cause mortality. RESULTS: Increased GDF-15 correlated with higher TMAO in females only, and with higher coronary artery calcification and IL-6. In females, diabetes was associated with elevated GDF-15 and MMP-9, whilst males with diabetes only had elevated GDF-15. No associations were found between biomarkers and CVD comorbidity. Deceased males and females had higher GDF-15 concentrations (p = 0.01 and p < 0.001, respectively), meanwhile only YKL-40 was increased in deceased males (p = 0.02). CONCLUSIONS: In conclusion, in males GDF-15 and YKL-40 were related to vascular calcification, inflammation, and oxidative stress, whilst in females GDF-15 was related to TMAO. Increased levels of YKL-40 and GDF-15 in males, and only GDF-15 in females, were associated with all-cause mortality. Our findings suggest that sex-specific associations of novel CVD biomarkers have a potential to affect development of cardiovascular complications in patients with ESKD.

Functional vitamin K insufficiency, vascular calcification and mortality in advanced chronic kidney disease: A cohort study.

Patients with chronic kidney disease (CKD) suffer from vitamin K deficiency and are at high risk of vascular calcification (VC) and premature death. We investigated the association of functional vitamin K deficiency with all-cause mortality and whether this association is modified by the presence of VC in CKD stage 5 (CKD G5). Plasma dephosphorylated-uncarboxylated matrix Gla-protein (dp-ucMGP), a circulating marker of functional vitamin K deficiency, and other laboratory and clinical data were determined in 493 CKD G5 patients. VC was assessed in subgroups by Agatston scoring of coronary artery calcium (CAC) and aortic valve calcium (AVC). Backward stepwise regression did not identify dp-ucMGP as an independent determinant of VC. During a median follow-up of 42 months, 93 patients died. Each one standard deviation increment in dp-ucMGP was associated with increased risk of all-cause mortality (sub-hazard ratio (sHR) 1.17; 95% confidence interval, 1.01-1.37) adjusted for age, sex, cardiovascular disease, diabetes, body mass index, inflammation, and dialysis treatment. The association remained significant when further adjusted for CAC and AVC in sub-analyses (sHR 1.22, 1.01-1.48 and 1.27, 1.01-1.60, respectively). In conclusion, functional vitamin K deficiency associates with increased mortality risk that is independent of the presence of VC in patients with CKD G5.

Sparing effect of peritoneal dialysis vs hemodialysis on BMD changes and its impact on mortality.

INTRODUCTION: Bone loss in end stage renal disease (ESRD) patients associates with fractures, vascular calcification, cardiovascular disease (CVD) and increased mortality. We investigated factors associated with changes of bone mineral density (ΔBMD) during the initial year on dialysis therapy and associations of ΔBMD with subsequent mortality in ESRD patients initiating dialysis. MATERIALS AND METHODS: In 242 ESRD patients (median age 55 years, 61% men) starting dialysis with peritoneal dialysis (PD; n = 138) or hemodialysis (HD; n = 104), whole-body dual-energy X-ray absorptiometry (DXA), body composition, nutritional status and circulating biomarkers were assessed at baseline and 1 year after dialysis start. We used multivariate linear regression analysis to determine factors associated with ΔBMD, and fine and gray competing risk analysis to determine associations of ΔBMD with subsequent mortality risk. RESULTS: BMD decreased significantly in HD patients (significant reductions of BMDtotal and BMDleg, trunk, rib, pelvis and spine) but not in PD patients. HD compared to PD therapy associated with negative changes in BMDtotal (ß=- 0.15), BMDhead (ß=- 0.14), BMDleg (ß=- 0.18) and BMDtrunk (ß=- 0.16). Better preservation of BMD associated with significantly lower all-cause mortality for ΔBMDtotal (sub-hazard ratio, sHR, 0.91), ΔBMDhead (sHR 0.91) and ΔBMDleg (sHR 0.92), while only ΔBMDhead (sHR 0.92) had a beneficial effect on CVD-mortality. CONCLUSIONS: PD had beneficial effect compared with HD on BMD changes during first year of dialysis therapy. Better preservation of BMD, especially in bone sites rich in cortical bone, associated with lower subsequent mortality. BMD in cortical bone may have stronger association with clinical outcome than BMD in trabecular bone.

Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease.

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0-1312]) compared to patients carrying a T allele (median 0 [range 0-966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.

Copeptin is independently associated with vascular calcification in chronic kidney disease stage 5.

BACKGROUND: Vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD) present in 30-70% of patients with chronic kidney disease (CKD). Copeptin is a sensitive surrogate marker of arginine vasopressin (AVP), which is involved in many pathophysiologic processes in CKD. The aim of the present study was to explore the association of copeptin with VC in CKD stage 5. METHODS: Copeptin was investigated in conjunction with living donor kidney transplantation in 149 clinically stable CKD stage 5 patients (CKD5), including 53 non-dialyzed (CKD5-ND) and 96 dialysis patients treated by peritoneal dialysis (PD) (n = 43) or hemodialysis (HD) (n = 53). We analyzed the association of copeptin with presence and extent of VC ascertained both histologically in biopsies from the inferior epigastric artery (n = 137) and by coronary artery calcification (CAC) score measured by computed tomography. RESULTS: Patients with higher copeptin were older, had higher systolic blood pressure, higher prevalence of CVD and their preceding time on chronic dialysis was longer. In Spearman's rank correlations (Rho), copeptin concentrations were significantly associated with CAC score (Rho = 0.27; p = 0.003) and presence of medial VC (Rho = 0.21; p = 0.016). Multivariate logistic regression analysis showed that 1-SD higher age, male gender, diabetes and 1-SD higher copeptin were significantly associated with the presence of moderate-extensive VC. CONCLUSIONS: High circulating levels of copeptin in CKD5 patients are independently associated with the degree of medial calcification ascertained by histology of arterial biopsies. Thus, plasma copeptin may serve as a marker of the uremic calcification process.

Aortic Valve Calcium Associates with All-Cause Mortality Independent of Coronary Artery Calcium and Inflammation in Patients with End-Stage Renal Disease.

BACKGROUND: Aortic valve calcium (AVC) and coronary artery calcium (CAC) are common complications in end-stage renal disease (ESRD). We investigated the prognostic significance of overlapping presence of AVC and CAC, and whether AVC was associated with all-cause mortality independent of the presence of CAC in ESRD. METHODS: 259 ESRD patients (median age 55 years, 67% males) undergoing cardiac computed tomography were included. Framingham risk score (FRS), presence of cardiovascular disease (CVD), statin use, nutritional status and other relevant laboratory data were determined at baseline. During follow-up for median 36 months, 44 patients died, and 68 patients underwent renal transplantation. RESULTS: The baseline overlap presence of AVC and CAC was 37%. Multivariate regression analysis showed that FRS (odds ratio (OR) 2.25; 95% confidence interval (95% CI), 1.43-3.55) and CAC score (OR (95% CI), 2.18 (1.34-3.59)) were independent determinants of AVC. In competing-risk regression models adjusted for presence of CAC, inflammation, nutritional status, CVD, FRS and statin use, AVC remained independently associated with all-cause mortality (sub-hazard ratio (95% CI), 2.57 (1.20-5.51)). CONCLUSIONS: The overlap of AVC and CAC was 37% in this ESRD cohort. AVC was associated with increased all-cause mortality independent of presence of CAC, traditional risk factors and inflammation.

Inverse J-shaped relation between coronary arterial calcium density and mortality in advanced chronic kidney disease.

BACKGROUND: The coronary artery calcium (CAC) score from cardiac computed tomography (CT) is a composite of CAC volume and CAC density. In the general population, CAC volume is positively and CAC density inversely associated with cardiovascular disease (CVD) events, implying that decreased CAC density reflects atherosclerotic plaque instability. We analysed associations of CAC indices with mortality risk in patients with end-stage renal disease [chronic kidney disease Stage 5 (CKD5)]. METHODS: In 296 CKD5 patients undergoing cardiac CT (median age 55 years, 67% male, 19% diabetes, 133 dialysed), the Framingham risk score (FRS), presence of CVD and protein-energy wasting (PEW; subjective global assessment) and high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were determined at baseline. During follow-up for a median of 35 months, 51 patients died and 75 patients underwent renal transplantation. All-cause mortality risk was analysed with competing-risk regression models. Vascular calcification was analysed in biopsies of the arteria epigastrica inferior in 111 patients. RESULTS: Patients in the middle tertile of CAC density had the highest CAC score, CAC volume, age, CVD, PEW, FRS, hsCRP and IL-6. In competing risk analysis, the middle {subhazard ratio [sHR] 10.7 [95% confidence interval (CI) 2.0-57.3]} and high [sHR 8.9 (95% CI 1.5-51.8)] tertiles of CAC density associated with increased mortality, independent of CAC volume. The high tertile of CAC volume, independent of CAC density, associated with increased mortality [sHR 8.9 (95% CI 1.5-51.8)]. Arterial media calcification was prominent and associated with CAC volume and CAC density. CONCLUSIONS: In CKD5, mortality increased linearly with higher CAC score and CAC volume whereas for CAC density an inverse J-shaped pattern was observed, with the crude mortality rate being highest for the middle tertile of CAC density. CAC volume and CAC density were associated with the extent of arterial media calcification.

Bone mineral density at different sites and 5 years mortality in end-stage renal disease patients: A cohort study.

BACKGROUND: Bone disease with osteoporosis and renal osteodystrophy is common in end stage renal disease (ESRD) patients and associates with cardiovascular disease (CVD) and increased morbimortality. We investigated associations of low bone mineral density (BMD) at various bone sites with five year all-cause and CVD mortality in ESRD patients. METHODS: In a post hoc analysis of 426 ESRD patients (median age 56 years, 62% men) starting dialysis, BMD (whole-body dual-energy X-ray absorptiometry, DXA), body composition, nutritional status (subjective global assessment, SGA), handgrip strength (%HGS), Framingham CVD risk score (FRS) and biochemical biomarkers of nutrition and inflammation were assessed. We used the Fine and Gray competing risk regression analysis to assess survival analysis. RESULTS: In multivariate logistic regression analysis, %HGS and intact parathyroid hormone associated with low tertile of: BMDtotal, BMDhead and BMDpelvis, after adjusting for FRS, SGA, %HGS, s-albumin, hsCRP, lean body mass index and year of recruitment. Patients with high FRS had low BMDhead (p<0.001). Low tertile of BMDtotal (sHR, 1.53), BMDhead (sHR 1.54) and BMDpelvis (sHR 1.60) associated with increased all-cause mortality whereas no such associations were found for the trabecular bone rich sites BMD arm, leg, trunk, rib or spine. Low tertile of BMDtotal (sHR 1.94), BMDhead (sHR 1.68), BMDleg (sHR 2.25) and BMDpelvis (sHR 2.45) associated with increased CVD mortality whereas BMD at other sites did not associate with CVD mortality. CONCLUSION: Low head and pelvis BMD, and low total BMD, as assessed by whole-body DXA, were independent predictors of increased risk of all-cause and CVD mortality. Cortical BMD appeared to have stronger association to survival in ESRD than trabecular BMD.

Differences in association of lower bone mineral density with higher coronary calcification in female and male end-stage renal disease patients.

BACKGROUND: Risk of cardiac events and cardiovascular disease (CVD) in end-stage renal disease (ESRD) patients are predicted by coronary artery calcification (CAC) independently. It is not clear to what extent low bone mineral density (BMD) is associated with higher risk of CAC and if sex interacts. We investigated the sex-specific associations of CAC score with total body BMD (tBMD) as well as with BMD of different skeletal sub-regions. METHODS: In 174 ESRD patients, median age 57 (10th-90th percentiles 29-75) years, 63% males, BMD (measured by dual-energy X-ray absorptiometry; DXA), CAC score (measured by cardiac CT) and circulating inflammatory biomarkers were analysed. RESULTS: A total of 104 (60%) patients with CAC > 100 AUs were older, had higher prevalence of both clinical CVD and diabetes, higher level of high sensitivity C-reactive protein, tumour necrosis factor, interleukin-6 and lower T-score of tBMD. Female patients had significantly lower tBMD and BMD of all skeletal sub-regions, except head, than male patients. Female patients with high CAC (> 100 AUs) had significantly decreased T-score of tBMD, and lower BMD of arms, legs than those low CAC (≤ 100 AUs); elevated CAC score were associated with tBMD, T-score, Z-score of tBMD and BMD of arms and legs, while no such differences was observed in males. Multivariate generalized linear model (GLM) analysis adjusted for age, diabetes and hsCRP showed that in females per SD higher CAC score (1057 AUs) was predicted by either per SD (0.13 g/cm2) lower tBMD or per SD (0.17 g/cm2) lower BMD at legs. No such associations were found in male ESRD patients. CONCLUSIONS: In female, but not male, lower BMD, in particular sub-regions of legs, was associated with higher CAC score independently. Low BMD has the potential to identify increased risk for high CAC score in ESRD patients.

Method comparison for cardiac image registration of coronary computed tomography angiography and 3-D echocardiography.

Treatment decision for coronary artery disease (CAD) is based on both morphological and functional information. Image fusion of coronary computed tomography angiography (CCTA) and three-dimensional echocardiography (3DE) could combine morphology and function into a single image to facilitate diagnosis. Three semiautomatic feature-based methods for CCTA/3DE registration were implemented and applied on CAD patients. Methods were verified and compared using landmarks manually identified by a cardiologist. All methods were found feasible for CCTA/3DE fusion.

CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease.

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-ß-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-ß-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence.

Bone mineral density of extremities is associated with coronary calcification and biopsy-verified vascular calcification in living-donor renal transplant recipients.

Chronic kidney disease (CKD) mineral and bone disorders (CKD-MBD) may lead to low bone mineral density (BMD) and vascular calcification (VC), but links to the latter are unclear. Here we investigated associations between BMD, coronary artery calcium (CAC) scores, and histological signs of VC in end-stage renal disease (ESRD) patients undergoing living-donor kidney transplantation (LD-Rtx). In 66 ESRD patients (median age 45 years, 68% males), BMD (by dual-energy X-ray absorptiometry, DXA), CAC score (by computed tomography, CT; n = 54), and degree of VC score (graded by histological examination of epigastric artery specimens collected at LD-Rtx; n = 55) were assessed at the time of LD-Rtx. Of the patients, 26% had osteopenia and 7% had osteoporosis. Of those undergoing artery biopsy, 16% had extensive VC, and of those undergoing CT 28% had high CAC score (>100 Agatston units). CAC scores correlated with BMD of legs and pelvis. BMDs of leg and pelvic sub-regions were significantly lower in patients with extensive VC. In multivariate regression analysis adjusted for age and gender, lower BMD of leg sub-region was associated with CAC score >100 AUs and extensive VC, and patients with extensive VC had significantly higher CAC score. Both high CAC and extensive VC were independently predicted by low BMD of legs. Low BMD has the potential to identify ESRD patients at risk of vascular calcification.

Does statins promote vascular calcification in chronic kidney disease?

BACKGROUND: In end-stage renal disease (ESRD), coronary artery calcification (CAC) and inflammation contribute to cardiovascular disease (CVD). Statins do not improve survival in patients with ESRD, and their effect on vascular calcification is unclear. We explored associations between CAC, inflammatory biomarkers, statins and mortality in ESRD. MATERIALS AND METHODS: In 240 patients with ESRD (63% males; median age 56 years) from cohorts including 86 recipients of living donor kidney transplant (LD-Rtx), 96 incident dialysis patients and 58 prevalent peritoneal dialysis patients, associations of CAC score (Agatston Units, AUs), interleukin-6 (IL-6) with high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor (TNF), use of statins and all-cause mortality were analysed. Cardiac CT was repeated in 35 patients after 1·5 years of renal replacement therapy. In vitro, human vascular smooth muscle cells (hVSMCs) were used to measure vitamin K metabolism. RESULTS: Among 240 patients, 129 (53%) had a CAC score > 100 AUs. Multivariate analysis revealed that independent predictors of 1-SD higher CAC score were age, male gender, diabetes and use of statins. The association between CAC score and mortality remained significant after adjustment for age, gender, diabetes, CVD, use of statins, protein-energy wasting and inflammation. Repeated CAC imaging in 35 patients showed that statin therapy was associated with greater progression of CAC. In vitro synthesis of menaquinone-4 by hVSMCs was significantly impaired by statins. CONCLUSION: Elevated CAC score is a mortality risk factor in ESRD independent of inflammation. Future studies should resolve if statins promote vascular calcification and inhibition of vitamin K synthesis in the uremic milieu.

Vertebral bone density associates with coronary artery calcification and is an independent predictor of poor outcome in end-stage renal disease patients.

OBJECTIVE: Chronic kidney disease-mineral bone disorder (CKD-MBD) is a major complication of end-stage renal disease (ESRD). Reduced bone mineral density (BMD) is associated with vascular calcification. Here we investigated associations between vertebral bone density (VBD) and coronary artery calcification (CAC), quantified by cardiac computed tomography (CT), and BMD quantified by dual-energy X-ray absorptiometry (DXA), and their relations with mortality. METHODS: In 231 ESRD patients (median age 56years, 63% males) comprising incident dialysis patients, prevalent peritoneal dialysis patients and recipients of living donor kidney transplant, VBD (Hounsfield units, HUs) and CAC scores (Agatston units, AUs) were quantified by cardiac CT, and, in 143 of the patients, BMD was measured by DXA of total body. Metabolic and inflammation biomarkers potentially linked to CKD-MBD were also analysed. RESULTS: Patients with low tertile of VBD were older and had more often cardiovascular disease (CVD), and higher HbA1c (non-diabetics), interleukin-6 and CAC score. Low VBD was independently associated with higher CAC score (>100 AUs) after adjustment for age, gender, diabetes, CVD, inflammation and cohorts. In Cox proportional hazards analysis, low VBD was independently associated with all-cause mortality after adjustment for age, gender, diabetes, CVD, inflammation and subjective global assessment (SGA). The root mean-squared error of prediction (RMSE) showed a good degree of association between VBD and BMD evaluated from DXA. In receiver-operator characteristics curve (ROC) analysis, lower VBD was more strongly associated with higher CAC score and all-cause mortality than BMD evaluated from DXA. CONCLUSIONS: While assessments of BMD by DXA and CT showed good degree of agreement, associations of high CAC, and mortality, with low VBD were stronger than those based on low BMD by DXA. The strong independent associations of low VBD with high CAC score and increased mortality risk suggest that VBD may serve as an important prognosticator in ESRD patients.

Increased circulating sclerostin levels in end-stage renal disease predict biopsy-verified vascular medial calcification and coronary artery calcification.

Sclerostin, an osteocyte-derived inhibitor of bone formation, is linked to mineral bone disorder. In order to validate its potential as a predictor of vascular calcification, we explored associations of circulating sclerostin with measures of calcification in 89 epigastric artery biopsies from patients with end-stage renal disease. Significantly higher sclerostin levels were found in the serum of patients with epigastric and coronary artery calcification (calcification score 100 or more). In Spearman's rank correlations, sclerostin levels significantly associated with age, intact parathyroid hormone, bone-specific alkaline phosphatase, and percent calcification. Multivariable regression showed that age, male gender, and sclerostin each significantly associated with the presence of medial vascular calcification. Receiver operating characteristic curve analysis showed that sclerostin (AUC 0.68) predicted vascular calcification. Vascular sclerostin mRNA and protein expressions were low or absent, and did not differ between calcified and non-calcified vessels, suggesting that the vasculature is not a major contributor to circulating levels. Thus, high serum sclerostin levels associate with the extent of vascular calcification as evaluated both by coronary artery CT and scoring of epigastric artery calcification. Among circulating biomarkers of mineral bone disorder, only sclerostin predicted vascular calcification.

Associations between Thyroid Hormones, Calcification Inhibitor Levels and Vascular Calcification in End-Stage Renal Disease.

INTRODUCTION: Vascular calcification is a common, serious and elusive complication of end-stage renal disease (ESRD). As a pro-calcifying risk factor, non-thyroidal illness may promote vascular calcification through a systemic lowering of vascular calcification inhibitors such as matrix-gla protein (MGP) and Klotho. METHODS AND MATERIAL: In 97 ESRD patients eligible for living donor kidney transplantation, blood levels of thyroid hormones (fT3, fT4 and TSH), total uncarboxylated MGP (t-ucMGP), desphospho-uncarboxylated MGP (dp-ucMGP), descarboxyprothrombin (PIVKA-II), and soluble Klotho (sKlotho) were measured. The degree of coronary calcification and arterial stiffness were assessed by means of cardiac CT-scans and applanation tonometry, respectively. RESULTS: fT3 levels were inversely associated with coronary artery calcification (CAC) scores and measures of arterial stiffness, and positively with dp-ucMGP and sKlotho concentrations. Subfractions of MGP, PIVKA-II and sKlotho did not associate with CAC scores and arterial stiffness. fT4 and TSH levels were both inversely associated with CAC scores, but not with arterial stiffness. DISCUSSION: The positive associations between fT3 and dp-ucMGP and sKlotho suggest that synthesis of MGP and Klotho is influenced by thyroid hormones, and supports a link between non-thyroidal illness and alterations in calcification inhibitor levels. However, the absence of an association between serum calcification inhibitor levels and coronary calcification/arterial stiffness and the fact that MGP and Klotho undergo post-translational modifications underscore the complexity of this association. Further studies, measuring total levels of MGP and membrane bound Klotho, should examine this proposed pathway in further detail.

Coronary plaque burden, as determined by cardiac computed tomography, in patients with myocardial infarction and angiographically normal coronary arteries compared to healthy volunteers: a prospective multicenter observational study.

OBJECTIVES: Patients presenting with acute myocardial infarction and angiographically normal coronary arteries (MINCA) represent a diagnostic and a therapeutic challenge. Cardiac computed tomography (CT) allows detection of coronary artery disease (CAD) even in the absence of significant stenosis. We aimed to investigate whether patients suffering from MINCA had a greater coronary plaque burden, as determined by cardiac CT, than a matched group of healthy volunteers. METHODS: Consecutive patients, aged 45 to 70, with MINCA were enrolled in the Stockholm metropolitan area. Patients with myocarditis were excluded using cardiovascular magnetic resonance imaging. Remaining patients underwent cardiac CT, as did a reference group of healthy volunteers matched by age and gender, with no known cardiovascular disease. Plaque burden was evaluated semi-quantitatively on a per patient and a per segment level. RESULTS: Despite a higher prevalence of smoking and hypertension, patients with MINCA did not have more CAD than healthy volunteers. Among 57 MINCA patients and 58 volunteers no signs of CAD were found in 24 (42%) and 25 (43%) respectively. On a per segment level, MINCA patients had less segments with stenosis ≥ 20% (2% vs. 5%, p<0.01), as well as a smaller proportion of large (2% vs. 4%, p<0.05) and mixed type plaques (1% vs. 4%, p<0.01). The median coronary calcium score did not differ between MINCA patients and healthy volunteers (6 vs. 8, ns). CONCLUSIONS: MINCA patients with no or minimal angiographic stenosis do not have more coronary atherosclerosis than healthy volunteers, and a large proportion of these patients do not have any signs of CAD, as determined by cardiac CT. The MINCA patient group is probably heterogeneous, with a variety of different underlying mechanisms. Non-obstructive CAD is most likely not the most prevalent cause of myocardial infarction in this patient group.