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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) 2 D; 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., Competing Interests: J.B. and M.C. are members of the ckj editorial board. M.F. reports other financial or non-financial interest from Amgen, Abiogen, and Vifor. M.Ga. received payment for lectures/presentation from Baxter, Medtronic, Amicus, BD, Sanofi, Vifor Pharma and support for meetings/travel from Astellas, Sanofi. G.C. received payment for lectures/presentation from Amgen, Vifor, AstraZeneca, Boehringer. G.LM. received payment for lectures/presentation fro Astellas, Vifor, Hansa, Biopharma, Eli-Lily, Travere, GlaxoSmithKline. T.N. received grant support from Amgen and consulting fees from Pharmacosmos. S.F. received consulting fees from Amgen, Myovant, UCB, Amolyt, Radius, Agovos and payment for lectures/presentation from Amgen, UCB, Gedeon Richter. J.B. received consulting fees, payment for lectures/presentation and support for attending meetings and/or travel from AMGEN, Abbvie, Sanofi, CSL-Vifor, Astra-Zeneca, Rubió. M.H. received grants from Diaverum, Resverlogix. M.C.M. received payment for lectures/presentation from Amgen, Vifor Pharma, Abiogen. G.T. reports other financial or non-financial interest from Amgen, Biotest, ABBVIE, Janssen-Cilag, Alexion. The remaining authors have no conflicts of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

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.

Both osteoporosis with related fragility fractures and cardiovascular diseases are rapidly outspreading worldwide. Since they are often coexistent in elderly patients and may be related to possible common pathogenetic mechanisms, the possible reciprocal effects of drugs employed to treat these diseases have to be considered in clinical practice. Bisphosphonates, the agents most largely employed to decrease bone fragility, have been shown to be overall safe with respect to cardiovascular diseases and even capable of reducing cardiovascular morbidity in some settings, as mainly shown by real life studies. No randomized controlled trials with cardiovascular outcomes as primary endpoints are available. While contradictory results have emerged about a possible BSP-mediated reduction of overall mortality, it is undeniable that these drugs can be employed safely in patients with high fracture risk, since no increased mortality has ever been demonstrated. Although partial reassurance has emerged from meta-analysis assessing the risk of cardiac arrhythmias during bisphosphonates treatment, caution is warranted in administering this class of drugs to patients at risk for atrial fibrillation, possibly preferring other antiresorptives or anabolics, according to osteoporosis guidelines. This paper focuses on the complex relationship between bisphosphonates use and cardiovascular disease and possible co-management issues.

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.

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

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.

Hyperphosphatemia is a risk factor for vascular calcifications (VCs), which are part of the chronic kidney disease-mineral and bone disorders (CKD-MBD). Vitamin K-dependent proteins such as matrix Gla protein (MGP) and bone Gla proteins (BGP, or osteocalcin) can inhibit VCs and regulate bone mineralization. In this analysis of the Vitamin K Italian (VIKI) study, the relationship between vitamin K status, vertebral fractures (VFs) and VCs in 387 hemodialysis (HD) patients with (N = 163; 42.1%) or without N = 224; 57.9%) sevelamer was evaluated. Levels of vitamin K vitamers K1 and K2 or menaquinones (MK; MK4-7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. Although no differences in clinical characteristics were noted, lower levels of MK4 (0.45 versus 0.6 ng/mL, p = .01) and a greater MK4 deficiency was observed in sevelamer-treated patients (13.5% versus 5.4%, p = .005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (odds ratio [OR] = 2.64, 95% confidence interval [CI] 1.25-5.58, p = .011) and aortic calcification (OR = 8.04, 95% CI 1.07-60.26, p = .04). In the same logistic model, sevelamer amplified the effect of total BGP levels on the odds of VFs in patients with total BGP <150 μg/L compared with those with total BGP ≥150 μg/L (OR = 3.15, 95% CI 1.46-6.76, p = .003). In contrast, there was no such effect in those untreated (total BGP <150 μg/L versus total BGP ≥150 μg/L: OR = 1.21, 95% CI 0.66-2.23, p = .54]; p = .049 for effect modification by sevelamer). Sevelamer may interfere with MK4 levels in HD patients and interact with low BGP levels to increase bone fractures in CKD patients. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Objectives: Obesity is an important risk factor for morbidity and mortality. Vitamin K2 is involved in the production of bone and matrix amino acid g-carboxy-glutamic acid (Gla) proteins (vitamin K-dependent proteins [VKDPs]), regulating bone and vascular calcification (VC). Bone Gla protein (BGP) is involved both in bone mineralization and VCs. We assessed the relationships between vitamin K levels and body mass index (BMI) according to the hypothesis that the impact of BMI on mortality is partly driven by low vitamin K levels., Methods: The Vitamin K Italian (VIKI) study included 387 hemodialysis patients from 18 dialysis centers in Italy. We determined plasma levels of bone markers: vitamin K levels, VKDPs, vitamin 25(OH)D, alkaline phosphatase (ALP), parathyroid hormone (PTH), calcium (Ca), phosphorus (P) and routine biochemistry. BMI was classified into the following categories: underweight (BMI < 18.5 kg/m 2 ), normal weight (18.5 ≤ BMI < 25 kg/m 2 ), overweight (25 ≤ BMI < 30 kg/m 2 ) and obese (BMI ≥ 30 kg/m 2 )., Results: 45.2% of patients were overweight or obese. Stratification by BMI demonstrated lower median menaquinone-7 (MK7)/triglycerides levels in obese patients (0.42 ng/mg [0.19, 0.87], p = 0.005). BGP levels were lower in overweight and obese patients (152 mcg/L [83.2, 251] and 104 mcg/L [62.7, 230], p = <0.001). Furthermore, there was an inverse correlation between MK7/triglycerides levels and BMI (regression coefficient β = -0.159; p = 0.003). In multiple linear regression, there was an inverse relationship between BGP levels and BMI (β = - 0.119; p = 0.012)., Conclusions: These data are the first to report an inverse relationship between Vitamin K2 levels and BMI in hemodialysis patients. Further studies are needed to confirm these findings and to determine if lower levels of Vitamin K are related to greater morbidity and mortality in this at-risk population., (©2020 Walter de Gruyter GmbH, Berlin/Boston.)

Background and Aims: Diabetes mellitus is recognized as one of the major causes of end stage kidney disease. Bone Gla protein (BGP) is a vitamin K-dependent protein involved in bone mineralization and vascular calcifications (VC). Our goal was to characterize BGP and undercarboxylated BGP (ucBGP) in DM patients on HD, compared to HD patients without DM, and their association with vascular and bone disease., Methods: 387 HD patients from 18 dialysis centers in Italy. Associations of DM, levels of BGP, vitamin D and VC were evaluated. Time-to-event analysis for all-cause mortality was performed by the Kaplan-Meier., Results: Patients with DM had lower levels of total BGP (139.00 vs. 202.50 mcg/L, p < 0.001), 25(OH)D (23.4 vs. 30.2 ng/ml, p < 0.001), and ucBGP (9.24 vs. 11.32 mcg/L, p = 0.022). In regression models, the geometric means of total BGP and ucBGP were 19% (p = 0.009) and 26% (p = 0.034) lower in diabetic patients. In univariate Cox regression analysis, DM patients had a higher risk of all-cause mortality (HR:1.83, 95% CI 1.13-2.96, p = 0.014). Adjustment for confounders confirmed the significant DM-mortality link. We included VC and warfarin into the Cox model, the DM-mortality link was no longer significant, suggesting a role of these risk factors as causal mediators leading to increased mortality in dialysis patients., Conclusions: HD patients have an increased mortality risk associated with DM. Furthermore, we found an association between DM and decreased BGP levels. Although our study does not support the notion that BGP levels act as mediator in the DM-mortality link, to our knowledge this is the first study in HD patients suggesting a potential protective role of BGP in the bone, endocrine and vascular pathway.

We herein report on a nationwide survey conducted in Italy to investigate the use of parathyroidectomy (PTX). In spite of the availability of newer and more effective drugs to control chronic kidney disease mineral bone disorder (CKD-MBD) biochemical abnormalities, PTX still remains a resource for nephrologists to use. However, observational analyses suggest that in recent years there has been a constant decline in the number of patients undergoing PTX. The reasons are not clear, though the increasing age and number of comorbidities of dialysis patients may partly explain this trend. Poor adherence to guidelines and/or geographical as well as logistic factors may also contribute to the lower use of PTX. The working group on CKD-MBD of the Italian Society of Nephrology launched a nationwide survey to investigate clinical practice patterns for PTX in Italy and identify modifiable factors that may limit accessibility to surgery.

Background: Lack of adequate management of chronic kidney disease (CKD) often results in delayed diagnosis and inadequate treatment. This study assessed the clinical management and outcome of stages 1-5 CKD patients., Methods: Patients were prospectively followed for 3 years in 25 nephrology centers across Italy. Clinical characteristics were measured at baseline and every 6 months. Outcome measures included CKD staging, presence of comorbidities, treatment, mineral bone disorder (MBD) parameters, and patient outcomes., Results: Of 884 enrolled patients (59.7% males, aged 66.2 ± 14.6 years), 587 (66.4%) completed the study. The majority of patients were referred by a general practitioner (44.7%) and had stage 3 or 4 CKD (40.9 and 23.8% respectively). Data reveal that 91.3% of patients had at least 1 concomitant disease, most frequently hypertension (80.1%) and dyslipidemia (42.5%); 94.6% of patients were receiving cardiovascular medication and 52.6% were receiving lipid-lowering medication. Approximately 40% of patients had proteinuria and intact parathyroid hormone levels outside the normal range. As expected, stages 4 and 5 CKD patients had a higher prevalence of proteinuria (68 and 74%), MBD (59 and 88%) and anemia (28 and 73%), as well as a higher risk of hospitalization (34.3 and 51.9%) and need for dialysis (69.5 and 70%). The overall probability of survival over 36 months was 90.6%., Conclusions: This is the first Italian prospective study performed with a large cohort of CKD patients over a 3-year period. Considering the multifactorial burden of diseases associated with CKD patients, the need for greater attention to CKD and related disorders is paramount., (© 2018 S. Karger AG, Basel.)

Background: Bone Gamma-carboxyglutamic acid (Gla)-protein (BGP or osteocalcin) is a vitamin K-dependent protein involved in the regulation of bone mineralization. Smoking is a risk factor for osteoporosis., Methods: We carried out a secondary analysis of the Vitamin K Italian (VIKI) study to investigate the association between cigarette smoking and BGP levels in patients with end stage renal disease. Data were collected in 370 haemodialysis patients, 37% (136) smokers (or ex-smokers) and 63% (234) nonsmokers. Vascular calcifications and vertebral fractures (quantitative morphometry) were identified on spine radiographs., Results: Smokers had significantly lower BGP levels (152 vs. 204 µg/L, p=0.003). Smokers had lower plasma phosphate levels (4.2 vs. 4.7 mg/dl, p<0.01). Lower BGP levels were associated with aortic calcification (p<0.001), iliac calcification (p=0.042) and vertebral fractures (p=0.023). In addition, the regression model showed that smoking is associated with a significant reduction of total BGP levels by about 18% (p=0.01)., Conclusion: This is the first clinical study in a haemodialysis population, which identifies cigarette smoking as a potential factor that can lower BGP levels, a protective agent in bone and vascular health., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Fragility fractures (FF) are common in patients with chronic kidney disease (CKD), and they occur at a younger age and with a higher frequency than in the general population, producing significant morbidity, mortality and healthcare costs. The pathogenic mechanisms underlying FF in CKD patients have not been completely understood. Behind CKD-MBD, the uremic toxicity should play a role in their pathogenesis, by affecting bone quality (uremic osteoporosis). There are very few prospective studies investigating risk factors for fragility fractures in CKD patients, and available algorithms for fracture risk prediction (FRAX and DeFRA) have never considered CKD. The diagnosis of vertebral fractures (FV), under-diagnosed in CKD patients as well as in general population, should be performed by Quantitative Vertebral Morphometry (QVM) both with DXA or Spine (D4-L5) x-Ray. A recent KDIGO review has qualified the measurement of the Bone Mineral Density by DXA as a predictive tool for fracture risk assessment in patients with stage G3a-G5D. Furthermore, the Trabecular Bone Score (TBS, software applied to DXA) allows the bone quality evaluation as well as the fracture risk prediction. Other techniques, such as Quantitative Computerized Tomography (QCT), especially High Resolution-peripheral QCT (HR-pQCT), have been shown to be useful, although expensive. Finally, some bone biomarkers (PTH and BAP) demonstrated to be informative for the definition of fracture risk in patients with CKD-MBD. In conclusion, there are several different tools and approaches that demonstrated to be useful for the identification of CKD patients at high risk of fracture, when these are appropriately performed and interpreted by expertise clinicians., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Vitamin K is mainly known as an agent involved in blood coagulation, maintaining the activity of coagulation factors in the liver. In addition, epidemiological studies suggested that a lack of vitamin K is associated with several diseases, including osteoporosis and vascular calcification. There are two main kinds of vitamin K: Phylloquinone (or PK) and Menaquinones (MKn), both act as co-enzyme of y-glutamyl carboxylase (GGCX) transforming under-carboxylated in carboxylated vitamin K dependent proteins, such as Bone Gla Protein (or Osteocalcin) and Matrix Gla Protein. Recently, Vitamin K was also identified as a ligand of the nuclear steroid and xenobiotic receptor (SXR) (in murine species Pregnane X Receptor: PXR), expressed in osteoblasts. The purpose of this literature review is to evaluate the protective role of Vitamin K in bone and vascular health.

Background: Hemodiafiltration with on-line endogenous reinfusion (HFR) is an extracorporeal dialytic method that combines diffusion, convection and adsorption. HFR-Supra (HFR-S) is a second-generation system with increased convective permeability and adsorption capability. Previous studies suggested that HFR reduces oxidative stress compared to standard haemodialysis. The principal aim of the present study was to compare antioxidant vitamins behavior and oxidative status of hemodialysis patients treated with HFR and HFR-S., Methods: The study was designed as a multicenter, randomized, crossover trial. Forty-one patients were recruited from 19 dialysis centers and after a 4-month washout stabilization period in on-line hemodiafiltration (ol-HDF), each patient was randomized to a sequence of treatments (HFR-S followed by HFR or viceversa) with each treatment applied over 6 months. Plasma levels of Advanced Oxidation Protein Products, Total Antioxidant Status, vitamins C, A and E and their ligands (Retinol Binding Protein and total lipids) were measured at baseline and at the end of each treatment period., Results: Results show that the higher convective permeability of HFR-S with respect to HFR did not produce additional beneficial effects on the patients' oxidative status, a slight decrease of both Vitamin A and Retinol Binding Protein being the only difference registered in the long-term. However, as compared to ol-HDF, both the re-infusive techniques allowed to reduce the intradialytic loss of Vitamin C and, in the long-term, improve the patients' oxidative status and increase Retinol Binding Protein plasma values. No significant differences were found between the Vitamin C concentration of pre- and post cartridge UF neither in HFR-S nor in HFR showing that the sorbent resin does not adsorb Vitamin C., Conclusion: HFR-S and HFR are almost equivalent in term of impact on antioxidant vitamins and oxidative status of hemodialysis patients. Nonetheless, as compared to ol-HDF, both treatments produced a sensible sparing of Vitamin C and may represent a new approach for reducing oxidative stress and related complications in dialysis patients. Long-term effects of re-infusive treatments on patients' cardiovascular morbidity and mortality need to be evaluated., Trial Registration: ClinicalTrials.gov Identifier NCT01492491 , retrospectively registered in 10 December 2011.

The link between serum parathyroid hormone (iPTH) and cardiovascular (CVS) mortality has not been fully elucidated. The EVOLVE Study was designed to test whether a drug such as cinacalcet, aimed at lowering iPTH, could reduce the astonishingly high cardiovascular risk in patients on maintenance dialysis (CKD-5D). Accordingly, the primary outcome of the study was the combined endpoint of time to death or hospitalization due to CVS factors or from any cause. Time to bone fracture and parathyroidectomy were regarded as secondary endpoints. At study completion, the Intention-To-Treat analysis documented a non- significant 7% (Hazard Ratio: 0.93; 95% Confidence interval: 0.85-1.02; P = 0.11) reduction of the primary composite endpoint. However, the intention to treat analysis does not take into account adherence to drug regimens or control for factors that may potentially jeopardize the conduction of the study. In particular, in spite of a careful pre-planned study sample calculation, the final power of the EVOLVE study was 54% instead of the assumed 90%, greatly reducing the reliability of study results. Furthermore, the pre-planned multivariable adjustment of the primary endpoint suggests a nominally significant reduction of the risk of the primary composite endpoint when age is entered into the statistical model. The sensitivity analysis further corroborates this result. The Lag Time Censoring Analysis (LTCA) evidenced a nominally significant 15% risk reduction of the composite endpoint among patients allocated to cinacalcet if the patients follow-up was terminated 6 months after the study drug discontinuation, as pre-planned in the protocol. It is interesting that the LTCA suggests that the effect of cinacalcet weakened over time and became insignificant after about 1 year from drug discontinuation. Although authors could not detect any effect of cinacalcet on bone fracture associated with cinacalcet use, the secondary analyses of the EVOLVE trial suggest a nominally significant 60-70% risk reduction of parathyroidectomy and a reassuring safety profile of prolonged exposure to cinacalcet. In summary, the EVOLVE study adds to the list of inconclusive randomized clinical trials in Nephrology. However, the preplanned exploratory and sensitivity analyses suggest that when imbalances of patients characteristics at study entry (i.e. age) or study drug discontinuation are considered, a 'nominally' significant risk reduction in CVS and parathyroidectomy associated with cinacalcet treatment is noted.

Background: Haemodialysis patients are ageing and have with a high rate of comorbidities. The impact of this novel clinical setting on intact parathyroid hormone (iPTH) is not well established., Methods: For this observational, prospective multicentre cohort study, incident haemodialysis patients were recruited in 40 Italian centres and followed up for a mean period of 18 +/- 6.7 months. Clinical characteristics and biochemistry were recorded at baseline. Comorbid conditions were scored by the Charlson comorbidity index (CCI)., Results: Data of 411 patients (mean age: 66.5 +/- 14.8 years; 17.3% >80 years old) were recorded. The mean CCI was 4.17 +/- 2.8. In patients with CCI >0, an inverse correlation was observed between CCI (excluding age) and iPTH (P = 0.00002). Independently of CCI, patients with iPTH <150 pg/ml had 76% as high as the risk of all-cause mortality. After multivariable adjustment, the combination of the first tertile of iPTH with second and third tertiles of CCI was significantly associated with all-cause mortality (RR = 3.83, P = 0.02; RR = 3.79, P = 0.01, respectively)., Conclusions: Incident haemodialysis patients suffer from a high rate of clinical complications. In these patients, low iPTH and high CCI are often associated and very likely responsible for an adverse outcome.

Nephrogenic systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) is a recently described disease, occurring only in patients with variable degrees of renal failure (RF) previously exposed to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. Public advisories are consistent on some key points including that no cases of NSF/NFD have been reported in patients with normal renal function, and GBCAs may be toxic in patients with RF due to the prolongation of the half-time allowing dissociation and extravasation of highly toxic gadolinium-free ions, potentially linked to the scleroderma-like NSF/NFD, a systemic disabling disease with a mortality rate of up to 30%. The most intriguing feature remains which cofactor might be at play to explain why the disease occurs only in a minority of exposed patients. Therefore, renal dysfunction (substrate) and gadolinium chelates (trigger agent) are necessary but not sufficient. The challenge for nephrologists includes (a) evidence of transmetallation, such as gadolinium deposits in bone, increased urinary zinc excretion, iron-transferrin dissociation or "spurious hypocalcemia" in exposed people; (b) research for uremic cofactors such as increased serum calcium/phosphate, acidosis, use of phosphate-chelating agents able to act as efficient competitor ligands or other drugs; and (c) identification of at-risk patients (with moderate to severe renal dysfunction) and definition of the role of dialysis in removing gadolinium chelates, if any. Nephrologists are called to action to collect and organize information to identify cofactors for NSF/NFD, and therefore they must be aware of this new pathology, as the eye sees only what the mind knows.

Background: Hyperphosphatemia in the uremic patient undergoing dialysis causes and makes the secondary hyperpharatyroidism progress. Nowadays it has a very important role in predicting mortality. The aim of the study was to assess by "Audit" to analyse adequacy of the Sardinian dialytic patients with reference to the optimal objective of the national and international guidelines., Patients and Methods: The questionnaire of the audit was composed of 11 questions about the percentage distribution of: calcium in the dialysate, values of phosphoremia), Ca x P product, patients treated with vitamin D taking one or more phosphate binders, average dose, spKt/V > or = 1.2, serum aluminium, parathiroidectomy., Results: We examined 1274 dialysis patients (93% on hemodialysis and 7% in CAPD) in 26 dialytic centers in our region (age 63.8 anni +/- 32.4; dialytic age 5.15 +/- 5.06. Phosphorus ranges (mg/dL) P < 5.5: 61.3 +/- 23%; between 5.5 e 6.5: 28.2 +/- 17.7%; and P > 6.5: 10.4 +/- 7.7%; Ca x P (<60): 77.8% +/- 16.6%; between 60-70: 16.8 +/- 13.4%; > 70: 4.99 +/- 4.7%. The more prescribed dialysate calcium was 1.5 mmol/L in HD (58.8%) HF (60.6%), HDF (51.6%) and CAPD (5.6%). PTH levels were: 31.1% (<120); 29.5% (120-250); 21.1% (250-450); 8% (450-600); 10.3% (>600). Patients on vitamin D: os daily 23.04 +/- 28%; post-dialysis boluses: os 32.6 +/- 28, i.v. 10.6 +/- 9%; no therapy 32.7 +/- 22.7%. The percentage use of phosphorus binders: 48.5% calcium carbonate (2.9 g/d); 7.12% calcium acetate (1.34 g/d); 13.5% sevelamer (2.79 g/d); 10% total aluminium based (0.62 g/d). The aluminium is dosed in 11/26 dialysis units (32.3% of the population); 2.3% +/- 0.9% of patients having Aluminium > 30 mcg/L. The dialytic patients have a Kt/V > or = 1.2: 80.1 +/- 19%. Parathyroidectomy incidences 1.8%., Conclusions: The data show good control of the average phosporous, there is a worrying percentage of patients with PTH values compatible with hypodynamic bone condition, lower and therefore safer calcium levels in the dialysate, poor aluminium control and low incidence of parathyroidectomy. In our experience the audit is a good way to verify and to correct the therapeutic choice in uremic osteodistrophy.

Dialysis treatments have allowed 'terminal patients' to live for years and years. However, life expectancy and quality are still consistently reduced in renal dialysis patients. Consequently, all efforts to device alternative treatments to the conventional ones are highly justified. Recently, the Hemo Study showed that neither the use of high flux membranes, nor the increase of the dialysis dose above the conventional, were capable to reduce significantly patient's mortality and morbidity, although 8% reduction of the risk of death was seen in patients treated with high flux vs. patients treated with low-flux dialysis. A relevant question is if convective treatments may offer an overprotection from morbidity and mortality, in comparison with low flux and high flux treatments. Data from the Registro Lombardo di Nefrologia e Trapianto published in 2000 showed a trend toward a better survival (RR= 90) and a significantly better protection from tunnel carpal syndrome (RR= 0.58; p= 0.03) in patients treated with convective treatments (hemofiltration and/or hemodiafiltration) vs. patients treated with diffusive dialysis. Except than a better cardiovascular stability observed on hemofiltration and an higher beta2-microglobuline clearance given by online hemofiltration and hemodiafiltration, evident clinical benefits of convective treatments, over the conventional high flux treatments, are not yet clearly demonstrated. Notwithstanding that, online convective treatments, that are performed with high flux compatible membranes and high technology machines, producing high quality water, offer at the moment the best bases for the improvement of clinical results of dialysis, especially in some category of patients.

Twenty-seven patients, eighteen females and nine males, with chronic renal failure and secondary hyperparathyroidism, were treated by subtotal parathyroidectomy. Bone pain, in 24 patients, hypercalcemia in 2 and severe pruritus in 1 were the main indications to surgery. Result evaluation was possible in twenty four patients. Bone pain disappeared or was reduced in 20/22 patients. Serum alkaline phosphatase and PTH returned to normal in 21/24 patients. There patients had persistent hyperparathyroidism because of inadequate surgical exploration. Another group of seven patients with secondary hyperparathyroidism recalcitant to medical therapy or relapsing after subtotal parathyroidectomy was treated with calcitriol ev. After nine months of follow-up PTH and alkaline phosphatase serum levels were reduced to normal value in all patients.

The distribution of T gamma lymphocytes in the peripheral blood of one group of rheumatoid patients and in the synovial fluid in a second group was determined. The results were compared to those found for peripheral blood (PB) lymphocytes of normal subjects and for synovial fluid lymphocytes of osteoarthrosis and meniscitis patients. Besides recording percentage and absolute number, we also used cytofluorographic analysis to determine individual capacity of PB T gamma cells to bind heat-aggregated IgG (agg-IgG). The following results were found: 1) there is no significant difference between the percentage and absolute number of PB T gamma lymphocytes of rheumatoid arthritis (RA) patients and those of controls, 2) individual RA PB T gamma cells had a greater number and/or avidity of Fc receptor for IgG than those cells of controls, and 3) the percentage of RA T gamma lymphocytes in synovial fluid, revealed by IgG-EA ox rosetting, is significantly lower than that found in control patients. The factors that may determine a similar lymphocyte picture in RA are discussed.

The distribution of T lymphocyte subsets was determined in peripheral blood (PB) of two groups of patients with rheumatoid arthritis by using monoclonal antibodies (OKT). In untreated patients the percentage of OKT4+ cells (helper/inducer) was found to be significantly increased as compared to healthy controls. In patients receiving oral gold therapy a similar increase in OKT4+ cells was confirmed; furthermore, these patients showed a significant decrease in OKT8+ cell population (cytotoxic/suppressor) compared to untreated patients and to normal controls. A small numerical superimposition of values of OKT4+ and OKT8+ lymphocytes was observed in untreated but not in treated patients.

The results of two recent studies of our group have been reported. They regard two immunological parameters of psoriatic arthritis: the proportions of T gamma lymphocytes in peripheral blood and the beta 2 microglobulin in the serum. The data obtained in psoriatic arthritis patients have been compared to those found in normal controls and in rheumatoid arthritis patients. T gamma mean values in psoriatic arthritis were significantly lower than those present in healthy subjects and in rheumatoid patients. These last patients showed beta 2 microglobulin mean values significantly higher than those observed in normal controls and in psoriatic arthritis patients. Conversely, the mean of beta 2 microglobulin levels in psoriatic arthritis has been found to be similar to that observed in normal controls, but a superimposition in the range of individual values of these two groups with the concentrations determined in rheumatoid subjects has been found. These results seem to be of interest in relation to the immunopathogenetic mechanism of psoriatic arthritis, but are of little help in the clinical differentiation of the two rheumatological affections considered.

Two T lymphocyte subpopulations were separated with an immunological method. In fact recently two T cell subsets with receptors for the Fc of IgM (TM) and of IgG (TG) respectively have been described. We have specifically separated TG and T non G lymphocytes by the rosetting technique. Cytological examination was performed on the two cell fractions: the results are in agreement with that already reported. Cytographic analysis was also carried out confirming the cytologic results. The possible practical implications of these acquisitions and those already applied are discussed.