Estimated glomerular filtration rate in observational and interventional studies in chronic kidney disease.

Estimated glomerular filtration rate is considered the principal measure of kidney function and, together with albuminuria, is a relevant prognostic factor for the development of end-stage kidney disease. Due to the strong association between estimated glomerular filtration rate and clinical events, such as commencement of dialysis, cardiovascular outcomes and all-cause death, estimated glomerular filtration rate is crucial for clinical decision-making in terms of scheduling follow-up and pharmacological interventions, and planning renal replacement therapies in advanced chronic kidney disease. In this review we discuss the available methods for measuring glomerular filtration rate and for estimating it through mathematical equations developed over the last few decades. We summarize the prognostic association of different percentages of estimated glomerular filtration rate decline and the main clinical outcomes, and how treatments modify estimated glomerular filtration rate decline and the risk of future endpoints. We also examine the role of pre-clinical trial slope and that of estimated glomerular filtration rate as a useful biomarker when evaluating patients for inclusion into both observational and interventional studies.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Background: Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. Methods: A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. Results: One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n = 55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Conclusion: Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

Effect of Antidiabetic Drugs on Bone Health in Patients with Normal Renal Function and in Chronic Kidney Disease (CKD): Insight into Clinical Challenges in the Treatment of Type 2 Diabetes.

Among the metabolic changes occurring during the course of type 2 diabetes (T2DM) and diabetic kidney disease (DKD), impaired bone health with consequent increased fracture risk is one of the most complex and multifactorial complications. In subjects with diabetic kidney disease, skeletal abnormalities may develop as a consequence of both conditions. In the attempt to define a holistic approach to diabetes, potential effects of various classes of antidiabetic drugs on the skeleton should be considered in the setting of normal kidney function and in DKD. We reviewed the main evidence on these specific topics. Experimental studies reported potential beneficial and harmful effects on bone by different antidiabetics, with few data available in DKD. Clinical studies specifically designed to evaluate skeletal effects of antidiabetics have not been performed; notwithstanding, data gleaned from randomized controlled trials and intervention studies did not completely confirm observations made by basic research. In the aggregate, evidence from meta-analyses of these studies suggests potential positive effects on fracture risk by metformin and glucagon-like peptide-1 receptor agonists, neutral effects by dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, and sulfonylureas, and negative effects by insulin and thiazolidinediones. As no clinical recommendations on the management of antidiabetic drugs currently include fracture risk assessment among the main goal of therapy, we propose an integrated approach with the aim of defining a patient-centered management of diabetes in chronic kidney disease (CKD) and non-CKD patients. Future clinical evidence on the skeletal effects of antidiabetics will help in optimizing the approach to a personalized and more effective therapy of diabetes.

Future treatment of vascular calcification in chronic kidney disease.

INTRODUCTION: Cardiovascular disease (CVD) is one of the global leading causes of morbidity and mortality in chronic kidney disease (CKD) patients. Vascular calcification (VC) is a major cause of CVD in this population and is the consequence of complex interactions between inhibitor and promoter factors leading to pathological deposition of calcium and phosphate in soft tissues. Different pathological landscapes are associated with the development of VC, such as endothelial dysfunction, oxidative stress, chronic inflammation, loss of mineralization inhibitors, release of calcifying extracellular vesicles (cEVs) and circulating calcifying cells. AREAS COVERED: In this review, we examined the literature and summarized the pathophysiology, biomarkers and focused on the treatments of VC. EXPERT OPINION: Even though there is no consensus regarding specific treatment options, we provide the currently available treatment strategies that focus on phosphate balance, correction of vitamin D and vitamin K deficiencies, avoidance of both extremes of bone turnover, normalizing calcium levels and reduction of inflammatory response and the potential and promising therapeutic approaches liketargeting cellular mechanisms of calcification (e.g. SNF472, TNAP inhibitors).Creating novel scores to detect in advance VC and implementing targeted therapies is crucial to treat them and improve the future management of these patients.

Impact of Baseline Clinical Variables on SGLT2i's Antiproteinuric Effect in Diabetic Kidney Disease.

INTRODUCTION: Proteinuria is a major risk factor for the progression of chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated a nephroprotective and antiproteinuric effect in people with type 2 diabetes (T2DM) and proteinuric CKD. We conducted a retrospective study to evaluate clinical and laboratory variables that can help predict proteinuria reduction with SGLT2i therapy. MATERIALS AND METHODS: Patients affected by T2DM and CKD who started any SGLT2i were included in the study. Patients were stratified into two subgroups, Responder (R) and non-Responder (nR), based upon the response to the therapy with SGLT2i, namely the reduction in a 24 h urine proteins test (uProt) of ≥30% from baseline levels. The aim of the study is to analyse differences in baseline characteristics between the two groups and to investigate the relationship between them and the proteinuria reduction. A Kruskal-Wallis test, unpaired t-test and Chi2 test were used to test the difference in means and the percentage (%) between the two groups. Linear and logistic regressions were utilized to analyse the relationship between proteinuria reduction and basal characteristics. RESULTS: A total of 58 patients were enrolled in the study: 32 patients (55.1%) were in the R group and 26 patients (44.9%) in the nR group. R's patients had a significant higher uProt at baseline (1393 vs. 449 mg/24 h, p = 0.010). There was a significant correlation between baseline uProt and proteinuria reduction with SGLT2i in both univariate (ß = -0.43, CI -0.55 to -031; p < 0.001) and multivariate analyses (ß = -0.46, CI -0.57 to -0.35, p < 0.001). In the multivariate analysis, there was a significant positive correlation between the estimated glomerular filtration rate (eGFR) and proteinuria reduction (ß = -17, CI -31 to -3.3, p = 0.016) and a significant negative correlation with body mass index (BMI) (ß = 81, CI 13 to 50, p = 0.021). The multivariate logistic regressions show a positive correlation of being in the R group with diabetic retinopathy at baseline (Odds Ratio (OR) 3.65, CI 0.97 to 13.58, p = 0.054), while the presence of cardiovascular disease (CVD) at baseline is associated with being in the nR group (OR 0.34, CI 0.09 to 1.22, p = 0.1), even if these statements did not reach statistical significance. CONCLUSIONS: In this real-life experience, following the administration of SGLT2i, a reduction of more than 30% in proteinuria was observed in more than half of the patients, and these patients had a significantly higher baseline proteinuria value. Variables such as eGFR and BMI are variables that, considered in conjunction with proteinuria, can help predict treatment response before therapy initiation. Different phenotypes of diabetic kidney disease may have an impact on the antiproteinuric response.

Real-World Analysis of Outcomes and Economic Burden in Patients with Chronic Kidney Disease with and without Secondary Hyperparathyroidism among a Sample of the Italian Population.

This real-world analysis evaluated the clinical and economic burden of non-dialysis-dependent CKD patients with and without secondary hyperparathyroidism (sHPT) in Italy. An observational retrospective study was conducted using administrative databases containing a pool of healthcare entities covering 2.45 million health-assisted individuals. Adult patients with hospitalization discharge diagnoses for CKD stages 3, 4, and 5 were included from 1 January 2012 to 31 March 2015 and stratified using the presence/absence of sHPT. Of the 5710 patients, 3119 were CKD-only (62%) and 1915 were CKD + sHPT (38%). The groups were balanced using Propensity Score Matching (PSM). Kaplan-Meier curves revealed that progression to dialysis and cumulative mortality had a higher incidence in the CKD + sHPT versus CKD-only group in CKD stage 3 patients and the overall population. The total direct healthcare costs/patient at one-year follow-up were significantly higher in CKD + sHPT versus CKD-only patients (EUR 8593 vs. EUR 5671, p < 0.001), mostly burdened by expenses for drugs (EUR 2250 vs. EUR 1537, p < 0.001), hospitalizations (EUR 4628 vs. EUR 3479, p < 0.001), and outpatient services (EUR 1715 vs. EUR 654, p < 0.001). These findings suggest that sHPT, even at an early CKD stage, results in faster progression to dialysis, increased mortality, and higher healthcare expenditures, thus indicating that timely intervention can ameliorate the management of CKD patients affected by sHPT.

Vitamin D and the Kidney: Two Players, One Console.

Vitamin D belongs to the group of liposoluble steroids mainly involved in bone metabolism by modulating calcium and phosphorus absorption or reabsorption at various levels, as well as parathyroid hormone production. Recent evidence has shown the extra-bone effects of vitamin D, including glucose homeostasis, cardiovascular protection, and anti-inflammatory and antiproliferative effects. This narrative review provides an overall view of vitamin D's role in different settings, with a special focus on chronic kidney disease and kidney transplant.

A roadmap to parathyroidectomy for kidney transplant candidates.

Chronic kidney disease mineral and bone disorder may persist after successful kidney transplantation. Persistent hyperparathyroidism has been identified in up to 80% of patients throughout the first year after kidney transplantation. International guidelines lack strict recommendations about the management of persistent hyperparathyroidism. However, it is associated with adverse graft and patient outcomes, including higher fracture risk and an increased risk of all-cause mortality and allograft loss. Secondary hyperparathyroidism may be treated medically (vitamin D, phosphate binders and calcimimetics) or surgically (parathyroidectomy). Guideline recommendations suggest medical therapy first but do not clarify optimal parathyroid hormone targets or indications and timing of parathyroidectomy. There are no clear guidelines or long-term studies about the impact of hyperparathyroidism therapy. Parathyroidectomy is more effective than medical treatment, although it is associated with increased short-term risks. Ideally parathyroidectomy should be performed before kidney transplantation to prevent persistent hyperparathyroidism and improve graft outcomes. We now propose a roadmap for the management of secondary hyperparathyroidism in patients eligible for kidney transplantation that includes the indications and timing (pre- or post-kidney transplantation) of parathyroidectomy, the evaluation of parathyroid gland size and the integration of parathyroid gland size in the decision-making process by a multidisciplinary team of nephrologists, radiologists and surgeons.

Erratum to: A roadmap to parathyroidectomy for kidney transplant candidates.

[This corrects the article DOI: 10.1093/ckj/sfac050.].

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism.

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis.

Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease.

Alkaline phosphatase (ALP) is an evolutionary conserved enzyme and widely used biomarker in clinical practice. Tissue-nonspecific alkaline phosphatase (TNALP) is one of four human isozymes that are expressed as distinct TNALP isoforms after posttranslational modifications, mainly in bone, liver, and kidney tissues. Beyond the well-known effects on bone mineralization, the bone ALP (BALP) isoforms (B/I, B1, B1x, and B2) are also involved in the pathogenesis of ectopic calcification. This narrative review summarizes the recent clinical investigations and mechanisms that link ALP and BALP to inflammation, metabolic syndrome, vascular calcification, endothelial dysfunction, fibrosis, cardiovascular disease, and mortality. The association between ALP, vitamin K, bone metabolism, and fracture risk in patients with chronic kidney disease (CKD) is also discussed. Recent advances in different pharmacological strategies are highlighted, with the potential to modulate the expression of ALP directly and indirectly in CKD-mineral and bone disorder (CKD-MBD), e.g., epigenetic modulation, phosphate binders, calcimimetics, vitamin D, and other anti-fracture treatments. We conclude that the significant evidence for ALP as a pathogenic factor and risk marker in CKD-MBD supports the inclusion of concrete treatment targets for ALP in clinical guidelines. While a target value below 120 U/L is associated with improved survival, further experimental and clinical research should explore interventional strategies with optimal risk-benefit profiles. The future holds great promise for novel drug therapies modulating ALP.

The Role of Vitamin K in CKD-MBD.

PURPOSE OF REVIEW: We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD). RECENT FINDINGS: Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.

An update on tenapanor to treat hyperphosphatemia.

Hyperphosphatemia is a common feature in patients with chronic kidney disease (CKD), especially in those with end-stage renal disease (ESRD). Commonly, high serum phosphate levels are observed only in later stages of CKD. The control of hyperphosphatemia plays a key role in the management of CKD patients. However, the optimal range for serum phosphate levels in CKD patients is still controversial. Currently, phosphate binders are the only medications available to reduce elevated serum phosphate levels in patients with ESRD receiving hemodialysis. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), acts via a non-phosphate-binding mechanism, reducing paracellular phosphate transport in the intestine. Has tenapanor the potential to improve management of mineral bone disorder in CKD?

Bone Mineral Density Changes in Long-Term Kidney Transplant Recipients: A Real-Life Cohort Study of Native Vitamin D Supplementation.

Vitamin D insufficiency has been associated with reduced bone mineral density (BMD) in kidney transplant patients (KTRs). However, the efficacy of vitamin D supplementation on BMD remains poorly defined, especially for long-term KTRs. We aimed to investigate the effect of native vitamin D supplementation on the BMD of KTRs during a 2-year follow-up. Demographic, clinical, and laboratory data were collected. BMD was evaluated with standard DEXA that was performed at baseline (before vitamin D supplementation) and at the end of study period. BMD was assessed at lumbar vertebral bodies (LV) and right femoral neck (FN) by a single operator. According to WHO criteria, results were expressed as the T-score (standard deviation (SD) relative to young healthy adults) and Z-score (SD relative to age-matched controls). Osteoporosis and osteopenia were defined as a T-score ≤ -2.5 SD and a T-score < -1 and a > -2.5 SD, respectively. Based on plasma levels, 25-OH-vitamin D (25-OH-D) was supplemented as recommended for the general population. Data from 100 KTRs were analyzed. The mean study period was 27.7 ± 3.4 months. At study inception, 25-OH-D insufficiency and deficiency were recorded in 65 and 35 patients. At the basal DEXA, the percentage of osteopenia and osteoporosis was 43.3% and 18.6% at LV and 54.1% and 12.2% at FN, respectively. At the end of the study, no differences in the Z-score and T-score gains were observed. During linear mixed model analysis, native vitamin D supplementation was found to have a negative nitration with Z-score changes at the right femoral neck in KTRs (p < 0.05). The mean dose of administered cholecalciferol was 13.396 ± 7.537 UI per week; increased 25-OH-D levels were found (p < 0.0001). Either low BMD or 25-OH-vitamin D concentration was observed in long-term KTRs. Prolonged supplementation with 25-OH-D did not modify BMD, Z-score, or T-score.

Calcifediol supplementation in adults on hemodialysis: a randomized controlled trial.

BACKGROUND: Vitamin D deficiency is associated with increased risks of mortality in people with chronic kidney disease. The benefits and harm of vitamin D supplementation on cardiovascular outcomes and mortality are unknown. We aimed to assess the effectiveness of calcifediol in reducing mortality in patients with vitamin D insufficiency on hemodialysis compared to no additional therapy. METHODS: A phase III, multicenter, randomized, open-label trial was conducted including 284 adults with vitamin D insufficiency undergoing hemodialysis who were randomly assigned to receive oral calcifediol or standard care for 24 months. RESULTS: Two hundred eighty-four participants were enrolled (143 assigned to the calcifediol group and 141 to the no additional therapy group). The primary outcome (mortality) occurred in 34 and 31 participants in the calcifediol and control group, respectively [hazard ratio (HR) 1.03; 95% confidence interval (CI) 0.63-1.67]. Calcifediol had no detectable effects on cardiovascular death (HR 1.06; 95% CI 0.41-2.74), non-cardiovascular death (HR 1.13; 95% CI 0.62-2.04), nonfatal myocardial infarction (HR 0.20; 95% CI 0.02-1.67) or nonfatal stroke (HR could not be estimated). The incidence of hypercalcemia and hyperphosphatemia was similar between groups. None of the participants underwent parathyroidectomy. CONCLUSIONS: In adults treated with hemodialysis and who had vitamin D insufficiency, calcifediol supplementation for 24 months had inconclusive effects on mortality and cardiovascular outcomes. TRIAL REGISTRATION NUMBER: NCT01457001.

Impact of nutritional vitamin D supplementation on parathyroid hormone and 25-hydroxyvitamin D levels in non-dialysis chronic kidney disease: a meta-analysis.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a common and major complication in chronic kidney disease (CKD), reflecting the increase of parathyroid hormone (PTH) in response to reduced vitamin D signalling and hypocalcaemia. This meta-analysis evaluated the impact of nutritional vitamin D (NVD) (cholecalciferol or ergocalciferol) on SHPT-related biomarkers. METHODS: A systematic literature search was performed in PubMed to identify relevant randomized control trials to be included in the meta-analysis. Fixed- and random-effects models were used to pool study-level results. Effects were studied within NVD study arms and relative to control groups (placebo/no treatment); the former in order to identify the effect of actively altering biomarkers levels. RESULTS: Reductions in PTH from supplementation with NVD were small when observed within the NVD study arms (pooled reduction: 10.5 pg/mL) and larger when compared with placebo/no treatment (pooled reduction: 49.7 pg/mL). NVD supplementation increased levels of 25-hydroxyvitamin D [25(OH)D] in both analyses (increase within NVD study arm: 20.6 ng/mL, increase versus placebo/no treatment: 26.9 ng/mL). While small and statistically non-significant changes in phosphate and fibroblast growth factor 23 were observed, NVD supplementation caused calcium levels to increase when compared with placebo/no treatment (increase: 0.23 mg/dL). CONCLUSIONS: Our results suggest that supplementation with NVD can be used to increase 25(OH)D to a certain extent, while the potential of NVD to actively reduce PTH in non-dialysis-CKD patients with SHPT is limited.

Oral Calcitriol Use, Vertebral Fractures, and Vitamin K in Hemodialysis Patients: A Cross-Sectional Study.

Fractures and vascular calcifications (VCs) are common in patients with chronic kidney disease (CKD). They are related to abnormalities in vitamin D metabolism, calcium, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23)/Klotho that occur with CKD. Impaired vitamin D metabolism and abnormal levels of calcium, phosphate, parathyroid hormone (PTH), and FGF23/Klotho drive bone and vascular changes in CKD. It is unclear if oral calcitriol safely mitigates fracture risk without increasing the burden of calcifications. Therefore, we investigated whether treatment with calcitriol affected the prevalence of fractures and VC progression in hemodialysis (HD) patients. This report is a secondary analysis of the Vitamin K Italian (VIKI) study, a cross-sectional study involving 387 HD patients. We assessed vitamin 25(OH)D, alkaline phosphatase, PTH, calcium, phosphate, osteocalcin or bone Gla protein, matrix Gla protein, and vitamin K levels. Vertebral fractures (VFs) and VCs were determined by spine radiograph. A reduction of >20% of vertebral body height was considered a VF. VCs were quantified by the length of calcific lesions along the arteries. The patients treated with oral calcitriol were 177 of 387 patients (45.7%). The prevalence of VF was lower in patients receiving oral calcitriol than in those untreated (48.6% versus 61.0%, p = 0.015), whereas the presence of aortic and iliac calcifications was similar (aortic: 81.9% versus 79.5%, respectively, p = 0.552; iliac: 52.0% and 59.5%, respectively, p = 0.167). In multivariable logistic regression analysis, oral calcitriol was associated with a 40.2% reduced odds of fracture (OR 0.598; 95% confidence interval [CI], 0.363-0.985; p = 0.043). In conclusion, we found a significant association between oral calcitriol and lower VF in HD patients without an increase in the burden of VC. Further prospective and interventional studies are needed to confirm these findings. © 2021 American Society for Bone and Mineral Research (ASBMR).

The Vessels-Bone Axis: Iliac Artery Calcifications, Vertebral Fractures and Vitamin K from VIKI Study.

Vascular calcification and fragility fractures are associated with high morbidity and mortality, especially in end-stage renal disease. We evaluated the relationship of iliac arteries calcifications (IACs) and abdominal aortic calcifications (AACs) with the risk for vertebral fractures (VFs) in hemodialysis patients. The VIKI study was a multicenter cross-sectional study involving 387 hemodialysis patients. The biochemical data included bone health markers, such as vitamin K levels, vitamin K-dependent proteins, vitamin 25(OH)D, alkaline phosphatase, parathormone, calcium, and phosphate. VF, IACs and AACs was determined through standardized spine radiograms. VF was defined as >20% reduction of vertebral body height, and VC were quantified by measuring the length of calcium deposits along the arteries. The prevalence of IACs and AACs were 56.1% and 80.6%, respectively. After adjusting for confounding variables, the presence of IACs was associated with 73% higher odds of VF (p = 0.028), whereas we found no association (p = 0.294) for AACs. IACs were associated with VF irrespective of calcification severity. Patients with IACs had lower levels of vitamin K2 and menaquinone 7 (0.99 vs. 1.15 ng/mL; p = 0.003), and this deficiency became greater with adjustment for triglycerides (0.57 vs. 0.87 ng/mL; p < 0.001). IACs, regardless of their extent, are a clinically relevant risk factor for VFs. The association is enhanced by adjusting for vitamin K, a main player in bone and vascular health. To our knowledge these results are the first in the literature. Prospective studies are needed to confirm these findings both in chronic kidney disease and in the general population.

Denosumab-Induced Hypocalcemia and Hyperparathyroidism in de novo Kidney Transplant Recipients.

INTRODUCTION: Denosumab represents a realistic treatment option to increase bone mineral density in kidney transplant recipients (KTRs). It is still unknown how and at what extent posttransplantation bone disease and graft function influence the effects of denosumab on mineral metabolism indexes. In this study, we analyze risk factors of hypocalcemia and parathyroid hormone (PTH) increase after denosumab administration in eighteen de novo KTRs and its management before and after this treatment. METHODS: We conducted a monocentric, observational, prospective study on de novo KTRs. All KTRs enrolled received a single 60 mg subcutaneous dose of denosumab every 6 months. Before kidney transplantation, no patients were treated with calcio-mimetic. After kidney transplantation and before antiresorptive therapy, no patients were treated with calcio-mimetic drugs and/or vitamin D receptor agonists, while all patients received nutritional vitamin D supplementation (from 1,000 IU to 1,500 IU daily). RESULTS: Hypocalcemia was related to the degree of lumbar osteoporosis (p = 0.047); the increase in the PTH level was correlated to baseline bone turnover markers (bone alkaline phosphatase, serum osteocalcin, and ß-C-terminal telopeptide), the 25 OH status, and eGFR. The introduction of calcitriol, after the PTH increase, in addition to cholecalciferol was necessary to ensure an adequate control of serum calcium and PTH during a follow-up of 15 months. Following the treatment with denosumab, it was observed an improvement of areal bone mineral density both at lumbar and femoral sites with a mean percentual increase of 1.74% and 0.25%, respectively. CONCLUSIONS: Denosumab is an effective treatment for bone disease in KTRs. In our study, the increase in PTH is not a transient event but prolonged throughout the follow-up period and requires continuous supplementation therapy with calcitriol.

The link between homocysteine, folic acid and vitamin B12 in chronic kidney disease.

Patients with chronic kidney disease or end-stage renal disease experience tremendous cardiovascular risk. Cardiovascular events are the leading causes of death in these patient populations, thus the interest in non-traditional risk factors such as hyperhomocysteinemia, folic acid and vitamin B12 metabolism is growing. Hyperhomocysteinemia is commonly found in CKD patients because of impaired renal metabolism and reduced renal excretion. Folic acid, the synthetic form of vitamin B9, is critical in the conversion of homocysteine to methionine like vitamin B12. Folic acid has also been shown to improve endothelial function without lowering homocysteine, suggesting an alternative explanation for the effect of folic acid on endothelial function. Whether hyperhomocysteinemia represents a reliable marker of cardiovascular risk and cardiovascular mortality or a therapeutic target in this population remains unclear. However, it is reasonable to consider folic acid with or without methylcobalamin supplementation as appropriate adjunctive therapy in patients with CKD. The purpose of this review is to summarize the characteristics of homocysteine, folic acid, and vitamin B12 metabolism, the mechanism of vascular damage, and the outcome of vitamin supplementation on hyperhomocysteinemia in patients with CKD, ESRD, dialysis treatment, and in kidney transplant recipients.