Extraosseous Calcification Research Articles

Arterio-Venous Fistula Calcifications—Risk Factors and Clinical Relevance

(1) Background: Arterio-venous fistulas (AVFs) are considered the gold-standard vascular access (VA) in patients on maintenance hemodialysis (HD) therapy. AVF calcifications represent a less studied VA related complication, even though HD patients are at a higher risk for extraosseous calcifications. The aim of this study is to assess the prevalence and risk factors of AVF calcifications, as well as the 5-year impact on AVF functionality and on overall mortality. (2) Methods: We conducted a 5-year prospective study including 161 patients on maintenance HD therapy. At baseline, we collected data related to VA history, comorbidities, demographics, subjective global assessment scale (SGA), and biochemical parameters. All patients underwent a complete AVF ultrasound and we recorded AVF blood flow and the presence of AVF calcifications, stenoses, and aneurysms. (3) Results: In our study, we found an AVF calcification prevalence of 39%. In a univariate analysis, we found that patients with AVF calcifications were associated with other AVF complications as well (stenoses, aneurysms), had longer AVF and HD vintage, as well as higher serum calcium and PTH values. In a multivariate analysis, we found that patients with a longer HD vintage and higher calcium values were independently associated with AVF calcifications. AVF calcifications did not affect 5-year fistula patency, nor were they associated with a higher mortality risk in our group of patients. (4) Conclusions: AVF calcifications were a frequent finding in our analysis, but their presence does not seem to affect the 5-year AVF patency.

Calcifications et métabolisme phosphocalcique

Extraosseous calcifications correspond to ubiquitous deposits of intra-tissue calcium salts leading to dysfunction of the affected tissue or organ. There are two types: metastatic calcifications and dystrophic calcifications. Their formation mechanism is by mimicking the physiological mineralization process with an "osteoblast-like" cell. The cause of extra-osseous calcification is variable and depends on risk factors. If the subject is young, you will have to think about a genetic syndrome!

Tc-99m-MDP Uptake in Extraosseous Metastases from Ovarian Papillary Serous Adenocarcinoma.

The uptake of Tc-99m-uptake of Tc-99m-methylene diphosphonate (MDP) on bone scintigraphy can be seen at sites other than bone in a varying number of benign and malignant conditions. Extraosseous metastatic calcifications can occur in ovarian papillary serous adenocarcinoma (PSAC). These extraosseous calcifications show Tc-99m-MDP uptake. We report a case of a female in her sixties who had a previous history of PSAC of the ovary. The patient had undergone neoadjuvant chemotherapy (NACT) followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy. She also received adjuvant chemotherapy. Tc-99m-MDP bone scan was performed post chemotherapy because the patient complained of lower backache. The scan showed increased uptake in the lower thoracic and lumbar vertebral regions. However, single-photon emission computed tomography/computed tomography (CT) localizes the uptake to metastatic calcified peritoneal deposits. Further 18F-fluorodeoxyglucose positron emission tomography/CT confirmed widespread peritoneal and omental metastatic disease with increased uptake.

Biochemical Clusters as Substitutes of Bone Biopsies in Kidney Transplant Patients.

Bone and mineral metabolism abnormalities are frequent in kidney transplant recipients and have been associated with cardiovascular morbidity. The primary aim of this study was to analyse the association between routine clinically available biochemical evaluation, non-routine histomorphometric bone evaluation, and vascular disease in kidney transplanted patients. A cross-sectional analysis was performed on 69 patients, 1-year after kidney transplantation. Laboratory analysis, radiography of hands and pelvis, bone biopsy, bone densitometry, and coronary CT were performed. One-year post-transplantation, nearly one-third of the patients presented with hypercalcemia, 16% had hypophosphatemia, 39.3% had iPTH levels > 150pg/mL, 20.3% had BALP levels > 40 U/L, and 26.1% had hypovitaminosis D. Evaluation of extraosseous calcifications revealed low Adragão and Agatston scores. We divided patients into three clusters, according to laboratory results routinely used in clinical practice: hypercalcemia and hyperparathyroidism (Cluster1); hypercalcemia and high BALP levels (Cluster2); hypophosphatemia and vitamin D deficiency (Cluster 3). Patients in clusters 1 and 2 had higher cortical porosity (p = 0.001) and osteoid measurements, although there was no difference in the presence of abnormal mineralization, or low volume. Patients in cluster 2 had a higher BFR/BS (half of the patients in cluster 2 had high bone turnover), and most patients in cluster 1 had low or normal bone turnover. Cluster 3 has no differences in volume, or turnover, but 60% of the patients presented with pre-osteomalacia. All three clusters were associated with high vascular calcifications scores. Vascular calcifications scores were not related to higher bone mineral density. Instead, an association was found between a higher Adragão score and the presence of osteoporosis at the femoral neck (p = 0.008). In conclusion, inferring bone TMV by daily clinical biochemical analysis can be misleading, and bone biopsy is important for assessing both bone turnover and mineralization after kidney transplantation, although hypophosphatemia combined with vitamin D deficiency is associated with abnormal mineralization. The presence of hypercalcemia with high levels of PTH or high levels of BALP, or hypophosphatemia and vitamin D deficiency should remind us to screen vascular calcification status of patients.Clinical Research: ClinicalTrials.gov ID NCT02751099.

When Woman Turns to Stone: Extraosseous Calcification in a Dialysis Patient

When Woman Turns to Stone: Extraosseous Calcification in a Dialysis Patient

Simultaneous Uptake of 18F-NaF and 18F-FDG by Bladder and Prostate Calculi.

Calcification and formation of calculi in the genitourinary system such as the bladder, kidney, and prostate are common processes of aging. Despite being in different parts of the body, these calculi can share risk factors; for instance, bladder and prostate calculi are seen in older men with benign prostatic hyperplasia. There have been increasing reports of detection of calculi using PET tracers such as 18F-NaF and 18F-FDG, suggesting their role for detection of extraosseous calcification. In this report, we present simultaneous detection of bladder and prostate calculi with both 18F-NaF and 18F-FDG avidity in a 74-year-old man with multiple myeloma.

Phosphate Toxicity and Vascular Calcification in Chronic Kidney Disease: A Closer Look Utilizing Transmission Electron Microscopy.

Hyperphosphatemia is independently linked with vascular calcification, cardiovascular disease, bone-mineral disease, progression of renal insufficiency, and all-cause mortality in chronic kidney disease (CKD) and end-stage renal disease (ESRD). The emerging importance of fibroblast growth factor-23 (FGF-23) and its co-factor Klotho play very important roles as phosphaturic hormones; however, phosphate levels rise due to a loss of renal Klotho production and the phosphaturic effects of the FGF-23/Klotho axis. Hyperphosphatemia is also associated with calciphylaxis, acceleration of renal tubulointerstitial disease, renal osteodystrophy, and uremic cardiomyopathy. This review incorporates ultrastructural remodeling of the thoracic aorta to provide a different perspective on vascular calcification. Nine-week-old male heterozygous (mRen2) 27 (Ren2) rat models of hypertension, insulin resistance, vascular oxidative stress and albuminuria are utilized to demonstrate aortic remodeling associated with vascular calcification. Nine-week-old male Zucker obese (fa/fa) rat models are utilized to better understand nephrolith formation. Phosphate homeostasis, toxicity, multiple metabolic and uremic toxicities, renal osteodystrophy, and vascular calcification are also discussed. Additionally, the role of the endothelium, vascular smooth muscle cells, inflammatory monocytes/macrophages and mast cells, pericytes, oxidative stress, hydrogen sulfide, and extraosseous calcification in the kidney are discussed as they relate to CKD, ESRD and calciphylaxis.

68Ga-bisphosphonates for the imaging of extraosseous calcification by positron emission tomography

Radiolabelled bisphosphonates (BPs) and [18F]NaF (18F-fluoride) are the two types of radiotracers available to image calcium mineral (e.g. bone), yet only [18F]NaF has been widely explored for the non-invasive molecular imaging of extraosseous calcification (EC) using positron emission tomography (PET) imaging. These two radiotracers bind calcium mineral deposits via different mechanisms, with BPs chelating to calcium ions and thus being non-selective, and [18F]NaF being selective for hydroxyapatite (HAp) which is the main component of bone mineral. Considering that the composition of EC has been reported to include a diverse range of non-HAp calcium minerals, we hypothesised that BPs may be more sensitive for imaging EC due to their ability to bind to both HAp and non-HAp deposits. We report a comparison between the 68Ga-labelled BP tracer [68Ga]Ga-THP-Pam and [18F]NaF for PET imaging in a rat model of EC that develops macro- and microcalcifications in several organs. Macrocalcifications were identified using preclinical computed tomography (CT) and microcalcifications were identified using µCT-based 3D X-ray histology (XRH) on isolated organs ex vivo. The morphological and mineral analysis of individual calcified deposits was performed using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). PET imaging and ex vivo analysis results demonstrated that while both radiotracers behave similarly for bone imaging, the BP-based radiotracer [68Ga]Ga-THP-Pam was able to detect EC more sensitively in several organs in which the mineral composition departs from that of HAp. Our results strongly suggest that BP-based PET radiotracers such as [68Ga]Ga-THP-Pam may have a particular advantage for the sensitive imaging and early detection of EC by being able to detect a wider array of relevant calcium minerals in vivo than [18F]NaF, and should be evaluated clinically for this purpose.

ITGAM rs1143679 Variant in Systemic Lupus Erythematosus Is Associated with Increased Serum Calcification Propensity.

CD11B/ITGAM (Integrin Subunit α M) mediates the adhesion of monocytes, macrophages, and granulocytes and promotes the phagocytosis of complement-coated particles. Variants of the ITGAM gene are candidates for genetic susceptibility to systemic lupus erythematosus (SLE). SNP rs1143679 (R77H) of CD11B particularly increases the risk of developing SLE. Deficiency of CD11B is linked to premature extra-osseous calcification, as seen in the cartilage of animals with osteoarthritis. Serum calcification propensity measured by the T50 test is a surrogate marker for systemic calcification and reflects increased cardiovascular (CV) risk. We aimed to assess whether the CD11B R77H gene variant is associated with a higher serum calcification propensity (i.e., a lower T50 value) in SLE patients compared to the wild-type allele (WT). Cross-sectional study incorporating adults with SLE genotyped for the CD11B variant R77H and assessed for serum calcification propensity with the T50 method. Participants were included in a multicenter trans-disciplinary cohort and fulfilled the 1997 revised American College of Rheumatology (ACR) criteria for SLE. We used descriptive statistics for comparing baseline characteristics and sequential T50 measurements in subjects with the R77H variant vs. WT CD11B. Of the 167 patients, 108 (65%) were G/G (WT), 53 (32%) were G/A heterozygous, and 6 (3%) were A/A homozygous for the R77H variant. A/A patients cumulated more ACR criteria upon inclusion (7 ± 2 vs. 5 ± 1 in G/G and G/A; p = 0.02). There were no differences between the groups in terms of global disease activity, kidney involvement, and chronic renal failure. Complement C3 levels were lower in A/A individuals compared to others (0.6 ± 0.08 vs. 0.9 ± 0.25 g/L; p = 0.02). Baseline T50 did not differ between the groups (A/A 278 ± 42' vs. 297 ± 50' in G/G and G/A; p = 0.28). Considering all sequential T50 test results, serum calcification propensity was significantly increased in A/A individuals compared to others (253 ± 50 vs. 290 ± 54; p = 0.008). SLE patients with homozygosity for the R77H variant and repeated T50 assessment displayed an increased serum calcification propensity (i.e., a lower T50) and lower C3 levels compared to heterozygous and WT CD11B, without differing with respect to global disease activity and kidney involvement. This suggests an increased CV risk in SLE patients homozygous for the R77H variant of CD11B.

The WNT/β-catenin system in chronic kidney disease-mineral bone disorder syndrome.

The WNT/β-catenin system is an evolutionarily conserved signaling pathway that plays a crucial role in morphogenesis and cell tissue formation during embryogenesis. Although usually suppressed in adulthood, it can be reactivated during organ damage and regeneration. Transient activation of the WNT/β-catenin pathway stimulates tissue regeneration after acute kidney injury, while persistent (uncontrolled) activation can promote the development of chronic kidney disease (CKD). CKD-MBD is a clinical syndrome that develops with systemic mineral and bone metabolism disorders caused by CKD, characterized by abnormal bone mineral metabolism and/or extraosseous calcification, as well as cardiovascular disease associated with CKD, including vascular stiffness and calcification. This paper aims to comprehensively review the WNT/β-catenin signaling pathway in relation to CKD-MBD, focusing on its components, regulatory molecules, and regulatory mechanisms. Additionally, this review highlights the challenges and opportunities for using small molecular compounds to target the WNT/β-catenin signaling pathway in CKD-MBD therapy. We conducted a comprehensive literature review using various scientific databases, including PubMed, Scopus, and Web of Science, to identify relevant articles. We searched for articles that discussed the WNT/β-catenin signaling pathway, CKD-MBD, and their relationship. We also reviewed articles that discussed the components of the WNT/β-catenin signaling pathway, its regulatory molecules, and regulatory mechanisms. The WNT/β-catenin signaling pathway plays a crucial role in CKD-MBD by promoting vascular calcification and bone mineral metabolism disorders. The pathway's components include WNT ligands, Frizzled receptors, and LRP5/6 co-receptors, which initiate downstream signaling cascades leading to the activation of β-catenin. Several regulatory molecules, including GSK-3β, APC, and Axin, modulate β-catenin activation. The WNT/β-catenin signaling pathway also interacts with other signaling pathways, such as the BMP pathway, to regulate CKD-MBD. The WNT/β-catenin signaling pathway is a potential therapeutic target for CKD-MBD. Small molecular compounds that target the components or regulatory molecules of the pathway may provide a promising approach to treat CKD-MBD. However, more research is needed to identify safe and effective compounds and to determine the optimal dosages and treatment regimens.

Systemic inflammation factors influence on the risk of detecting signs of cardiovascular calcification in a patient with stage 5D chronic kidney disease

BACKGROUND. Chronic kidney disease (CKD) is a common pathology influencing mortality risk in the world population. Calcification of aorta and heart structures (valves, coronary arteries) is a risk factor for cardiovascular complications. The influence of cytokines, integrin proinflammatory indices, acute phase proteins and other inflammatory factors on the risk of extravasal calcification is promising. THE AIM: to study the effect of cytokines, integrative proinflammatory indices, acute phase proteins and other inflammatory factors on the risk of extra-osseous calcification. PATIENTS AND METHODS. A one-stage, cohort study of 85 patients with CKD 5D treated with programmed hemodialysis was conducted. General clinical examination was carried out according to the protocol. Blood levels of C-reactive protein (CRP) were determined by immunoturbodimetry. A Glasgow Prognostic Score (GPS) risk index for systemic inflammation was calculated using CRP and plasma albumin concentrations. Interleukin-6 (IL-6), interleukin-3 (IL-3) were assessed by enzyme immunoassay. Blood leukocyte shift index (BLI) was calculated. Echocardioscopy was performed using Doppler mode. The presence of cardiac valve calcification (CAC) was registered, its severity was assessed. To estimate the abdominal aortic calcification, the abdominal radiography was carried out in the left lateral projection. The severity of manifestations of aortic calcification was assessed using the L.I. Kauppilla Calcification Scale. Statistical analysis was performed using STATISTICA 12.6. toolkit (StatSoft, USA). RESULTS. Systemic inflammatory factors negatively affected the severity of cardiovascular calcification. An increased GPS value was found to correlate with the severity of CAC and CSA. In the case of calcification severity analysis considering IL-3 and IL-6 values, it was also shown that high levels of these pro-inflammatory cytokines are associated with severe manifestations of anterior aortic wall calcification and aortic calcification at the L3 level. Inclusion of ISLC in the analysis had no effect on the severity of calcification of the aortic wall and no effect on the intensity of cardiac valve calcification in general, the aortic valve and the mitral valve in particular.

Bone Mineral Density and Vascular Calcification in Children and Young Adults With CKD 4 to 5 or on Dialysis

Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. Mineral accrual by the growing skeleton may protect young people with CKD from extraosseous calcification. Our hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. This was a multicenter longitudinal study in children and young people (5-30 years) with CKD stages 4 to 5 or on dialysis. BMD was assessed by tibial peripheral quantitative computed tomography (pQCT) and lumbar spine dual-energy X-ray absorptiometry (DXA). The following cardiovascular imaging tests were undertaken: cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima media thickness z-score (cIMTz), pulse wave velocity z-score (PWVz), and carotid distensibility for arterial stiffness. All measures are presented as age-adjusted and sex-adjusted z-scores. One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed up after a median of 1.45 years. Trabecular BMD z-score (TrabBMDz) decreased (P= 0.01), and there was a nonsignificant decrease in cortical BMD z-score (CortBMDz) (P= 0.09). Median cIMTz and PWVz showed nonsignificant increase (P= 0.23 and P= 0.19, respectively). The annualized increase in TrabBMDz (ΔTrabBMDz) was an independent predictor of cIMTz increase (R 2= 0.48, β= 0.40, P= 0.03). Young people who demonstrated statural growth (n= 33) had lower ΔTrabBMDz and also attenuated vascular changes compared with those with static growth (n= 24). This hypothesis-generating study suggests that children and young adults with CKD or on dialysis may develop vascular calcification even as their BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraosseous calcification.

Role of Calcimimetics in Treating Bone and Mineral Disorders Related to Chronic Kidney Disease.

Renal osteodystrophy is common in patients with chronic kidney disease and end-stage renal disease and leads to the risks of fracture and extraosseous vascular calcification. Secondary hyperparathyroidism (SHPT) is characterized by a compensatory increase in parathyroid hormone (PTH) secretion in response to decreased renal phosphate excretion, resulting in potentiating bone resorption and decreased bone quantity and quality. Calcium-sensing receptors (CaSRs) are group C G-proteins and negatively regulate the parathyroid glands through (1) increasing CaSR insertion within the plasma membrane, (2) increasing 1,25-dihydroxy vitamin D3 within the kidney and parathyroid glands, (3) inhibiting fibroblast growth factor 23 (FGF23) in osteocytes, and (4) attenuating intestinal calcium absorption through Transient Receptor Potential Vanilloid subfamily member 6 (TRPV6). Calcimimetics (CaMs) decrease PTH concentrations without elevating the serum calcium levels or extraosseous calcification through direct interaction with cell membrane CaSRs. CaMs reduce osteoclast activity by reducing stress-induced oxidative autophagy and improving Wnt-10b release, which promotes the growth of osteoblasts and subsequent mineralization. CaMs also directly promote osteoblast proliferation and survival. Consequently, bone quality may improve due to decreased bone resorption and improved bone formation. CaMs modulate cardiovascular fibrosis, calcification, and renal fibrosis through different mechanisms. Therefore, CaMs assist in treating SHPT. This narrative review focuses on the role of CaMs in renal osteodystrophy, including their mechanisms and clinical efficacy.

A 31-year-old female patient with chronic kidney disease presenting with persistent cough

Can you diagnose this 31-year-old woman with end-stage renal disease and a persistent cough? https://bit.ly/3s7n5VU.

Differential diagnosis of hypercalcemia in a patient with CKD G5D

Patients with chronic kidney disease are characterized by the development of mineral disorders due to a decrease in the number of functioning nephrons. These changes manifest by the development of secondary hyperparathyroidism (the overproduction of intact parathyroid hormone (PTH) associated with the serum hypocalcemia, hyperphosphatemia), dysfunctional vitamin D metabolism, bone mineralization and also extraosseous calcifications. Decreased serum PTH levels associated with hypercalcemia are suspicious for adynamic bone disease, but at the same time requires an extended differential diagnostic search (e.g. metastatic processes). One of the rare causes of hypercalcemia is a defect in 24-hydroxylase (CYP24A1). We present a case of a patient on hemodialysis with atypical secondary hyperparathyroidism and an established CYP24A1 defect.

Extraosseous calcification in kidney disease.

A consequence of chronic and end-stage kidney disease is a higher risk of calcium deposition in sites other than the bones. The authors of this review outline current understanding of the pathogenesis, presentation, diagnosis, and treatment of this group of disorders.

The Role of Bone Volume, FGF23 and Sclerostin in Calcifications and Mortality; a Cohort Study in CKD Stage 5 Patients.

Chronic kidney disease-mineral and bone disorder has been associated with increasing morbid-mortality. The aim of this study was to determine the prevalence and phenotype of bone disease before transplantation and to correlate FGF23 and sclerostin levels with bone histomorphometry, and study possible associations between FGF23, sclerostin, and bone histomorphometry with cardiovascular disease and mortality. We performed a cross-sectional cohort study of a sample of 84 patients submitted to renal transplant, which were prospectively followed for 12months. Demographic, clinical, and echocardiographic data were collected, laboratory evaluation, bone biopsy, and X-ray of the pelvis and hands were performed. Patient and graft survival were recorded. We diagnosed low bone turnover in 16 patients (19.5%); high bone turnover in 22 patients (26.8%); osteomalacia in 1 patient (1.2%), and mixed renal osteodystrophy in 3 patients (3.7%). At the end of 12months, 5 patients had graft failure (5.9%), 4 had a cardiovascular event (4.8%), and 4 died. Age was associated with low remodeling disease, whereas high BALP and phosphorus and low sclerostin with high turnover disease. Sclerostin was a risk factor for isolated low bone volume. High BALP, low phosphorus, and low FGF23 were risk factors for abnormal mineralization. FGF23 appears as an independent factor for severity of vascular calcifications and for cardiovascular events, whereas the presence of valve calcifications was associated with low volume and with turnover deviations. Sclerostin was associated a higher HR for death. Sclerostin and FGF23 seemed to provide higher cardiovascular risk, as well as low bone volume, which associated with extra-osseous calcifications.

EVALUATION OF THE EFFECTS OF BIOCHEMICAL MARKERS LIKE CALCIUM, PHOSPHORUS AND PARATHORMONE IN PREDICTING THE COMPLICATIONS & MORTALITY IN CHRONIC KIDNEY DISEASE

Introduction: Chronic kidney disease (CKD) is an international public health problem affecting about 5–10% of the population. As kidney function declines, there is a progressive deterioration in mineral homeostasis with disruption of normal serum concentrations of phosphorus, calcium and changes in circulating levels of hormones like parathyroid hormone (PTH) and Vitamin D3. Hyperparathyroidism plays a vital role in the excess morbidity and mortality in chronic kidney disease. As a result; patients are at increased risk of bone disease, extraosseous calcification, and death. Aims and Objectives: To estimate the serum Calcium, Phosphorus, Parathyroid Hormone levels in patients with CKD and to compare them with healthy individuals. To know the association between Calcium, phosphorus and PTH in CKD patients. Material & Methods: 50 cases of CKD and 50 controls were included in the study. Serum calcium, phosphorus and PTH were measured in both cases and controls. Statistically significant increases in levels of all parameters were seen in cases as compared to controls. Conclusion: The levels of PTH, calcium & phosphorus are used as surrogate markers of disease progression. Abnormalities can occur subtly, usually without any symptoms, and may progress to cause more complications if not detected early. The ultimate goals of treating secondary hyperparathyroidism are to normalize mineral metabolism, prevent bone disease, and prevent extra skeletal manifestations of the altered biochemical processes. Various CKD Guidelines recommend targets and early treatment strategies to correct serum levels of phosphorus, calcium, and PTH levels. Keywords: CKD – Chronic kidney disease, PTH – Parathyroid hormone, ESRD – End stage renal disease, Glomerular filtration rate -GFR

MO574MINERAL AND BONE DISORDERS CHANGES IN RENAL TRANSPLANTED PATIENTS

Abstract Background and Aims Successful renal transplant restores many physiologic abnormalities, including improvement of chronic kidney disease- mineral and bone disorder (CKD-MBD) syndrome. The primary aims of this study were: analyse the changes and evolution of the 3 components of CKD-MBD pre and 1 year post renal transplantation: the mineral abnormalities, the bone disorders and the vascular calcifications; and to correlate fibroblast grow factor 23 (FGF23), klotho and sclerostin serum levels with bone histomorphometric parameters and CV disease. The secondary aims were to study the evolution of other bone related parameters and correlate those with bone biopsies data, as well as to validate Adragão vascular calcification score in a population of renal transplant patients. Method We performed a prospective cohort study of a consecutive sample of de novo single renal transplanted patients in our unit. At inclusion, demographic, clinical and transplant-related data were collected, X-ray of the pelvis and hands (for Adragão score) and echocardiographic findings were recorded. All patients were submitted to a bone biopsy and laboratorial evaluation at baseline (time 0 – T0). Patients were followed for 12 months (time 1 – T1), after which performed laboratorial evaluation, a 2nd bone biopsy, echocardiogram, X-ray of pelvis and hands, bone densitometry and non-contrast cardiac CT (Agatston score). Continuous variables are presented as medians and categorical variables as frequencies. Differences between T0 and T1 were accessed by Wilcoxon matched-pairs test and paired McNemar test. Correlations between bone histomorphometric findings and severity of vascular calcifications with demographic and laboratorial parameters were obtained with Wilcoxon rank-sum test or Kruskall Wallis test. STATA software was used and p < 0.05 was considered statistically significant. Results We recruited 84 patients in a 28 month-period. At the end of 12 months, 69 patients performed a 2nd evaluation. Median age 53 years, 48 men, 53 caucasian, median dialysis vintage 55 months. We observe a significant reduction on phosphorus, magnesium, PTH, calcitonin, sclerostin, bone alkaline phosphatase and FGF23. Both calcium and alpha-klotho serum levels increase, with no significant changes in vitamin D levels. 68% of the patients presented renal osteodystrophy at the 2nd bone biopsy, and we observed a significant increase in the development of low turnover bone disorder, with no major changes in volume or mineralization. Changes in alpha-klotho, bAP and sclerostin (from T0 to T1) were important determinants of changes in turnover, mineralization and volume, respectively. Despite not being statistically significant, we were able to observe an improvement in the cortical bone porosity. Vascular calcifications and echocardiographic findings weren’t different comparing to the baseline (Median Adragão score was 1 in both evaluations, and valve calcifications were present in 22% and 23% of patients, with no changes in LVMI). The median Agatston score was 48.5, being the median adjusted percentile of 82%. FGF23 and sclerostin were found to be independent risk factors for extra-osseous calcifications, as well as low bone volume, cortical porosity and osteoid volume. Adragão score and valve calcifications correlated well with the increased severity of coronary calcifications determined by Agatston score (absolute and percentile). Conclusion In conclusion, renal transplantation improves two of the three components of CKD-MBD (biochemical and bone disorders), slowing the progression of vascular calcifications. FGF23, sclerostin and bAP seemed to be key parameters in understanding the bone changes observed in post transplant period, and these hormones also interfere with extra osseous calcification severity. Adragão score seems to be a good tool to access vascular calcifications in renal transplanted patients.

Apoptosis in the Extraosseous Calcification Process.

Extraosseous calcification is a pathologic mineralization process occurring in soft connective tissues (e.g., skin, vessels, tendons, and cartilage). It can take place on a genetic basis or as a consequence of acquired chronic diseases. In this last case, the etiology is multifactorial, including both extra- and intracellular mechanisms, such as the formation of membrane vesicles (e.g., matrix vesicles and apoptotic bodies), mitochondrial alterations, and oxidative stress. This review is an overview of extraosseous calcification mechanisms focusing on the relationships between apoptosis and mineralization in cartilage and vascular tissues, as these are the two tissues mostly affected by a number of age-related diseases having a progressively increased impact in Western Countries.