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In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.

In the manuscript by Di Lullo et al. [1], the authors evaluate the association between cardiac valve calcification extent and biochemical markers of mineral metabolism and inflammation, such as parathyroid hormone (PTH), phosphate (P), calcium (Ca), fibroblast growth factor 23 (FGF23), Klotho, vitamin D and C-reactive protein, in a population of incident chronic kidney disease (CKD) stage 3–4 patients. Interestingly, in the multivariate analysis, high serum PTH and FGF23 levels associated with aortic valve calcification. Authors' conclusions are that further studies ‘should examine whether FGF23 assay should be included in routine clinical evaluation of CKD, as part of CV risk stratification’. How far away are we from suggesting routinely screening for FGF23 in the CKD population? CKD patients have a dramatically higher incidence of cardiovascular morbidity and mortality compared with the general population [2]. In the last 10 years, several studies have pointed out that vascular calcification is a major cause of cardiovascular disease in the dialysis population. In CKD patients, high levels of plasma Ca, serum P, PTH and FGF23 play a critical role in the pathogenesis of cardiovascular events [3]. Patients develop extensive medial calcification, which causes increased arterial stiffness and high morbidity and mortality due to cardiovascular events [4, 5]. A variety of risk factors are associated with vascular calcification in dialysis patients (time on dialysis, uraemic toxins, history of diabetes and inflammation), but abnormalities in bone mineral metabolism may play a critical role [6]. In fact, elevated serum P, Ca–P product, PTH and FGF23 levels contribute to vascular calcification, although their roles are incompletely understood [7, 8]. Elevations of serum P and Ca–P product levels may worsen cardiovascular events in the uraemic population, through a progressive increase in Ca deposition in the coronary arteries and heart valves [9]. Recent insights into novel roles of bone biomarkers, such as FGF23, in vascular biology make this primarily kidney-derived protein a possible candidate to form a link between bone and cardiovascular morbidity and mortality [10]. A central aspect of FGF23 and α-Klotho is regulation of their expression and the apparent disconnect between tissue level and concentration in blood. FGF23 is regulated by several feedback loops consistent with endocrine systems: it reduces serum P, 1,25-dihydroxyvitamin D and PTH, and these factors stimulate FGF23 expression in bone. Active vitamin D is the most potent regulator of FGF23 and acts directly on FGF23 gene transcription by binding a vitamin D-responsive element in the gene promoter region [11]. FGF23 is now considered a major determinant of circulating levels of P and vitamin D metabolites. This role is accomplished by regulation of the expression of transmembrane P carriers and by modulating activity of the hydroxylases that activate or catabolize vitamin D. All of these FGF23 effects are obtained through activation of specific receptors. Significantly, however, the presence of a co-receptor is essential. Intriguingly, this co-receptor, Klotho, besides contributing to FGF23 actions, also has specific biological effects that may be relevant for cardiovascular disease in CKD. Several small clinical studies report on the association between higher levels of FGF23 and vascular calcification. Increased serum levels of FGF23 have been recognized as a risk factor for mortality either in conservative or in maintenance haemodialysis populations [12, 13]. Recently, a prospective study of patients with CKD stages 3–5D, with a follow-up of 35 ± 3 months, showed a significant positive correlation between serum FGF23 levels and coronary calcification (CAC) score, with a 62.5% sensitivity and a 75.9% specificity. In this study, regression analysis identified FGF23 levels together with severe CAC (>400) as independent risk factors for all-cause mortality [14]. Cardiac valve calcification is a common finding in CKD with a high rate of cardiovascular mortality [15]. Even if in the preclinical setting the role of FGF23 in vascular calcification pathogenesis is still unclear, interestingly, high FGF-23 levels were independent predictors of mitral valve calcification and a risk factor for cardiovascular mortality in 150 diabetic patients with mild to moderate CKD [16]. A relevant contribution on the possible pathogenetic role of FGF23 in the development of cardiovascular disease in renal patients comes from the work by Faul et al. [17]. In this study, increased levels of FGF23 were independently associated with left ventricular hypertrophy (LVH) in a large CKD population. Importantly, with in vivo experimental data, LVH was induced by an intramyocardial or intravenous injection of FGF23 in wild-type mice. LVH developed also in transgenic Klotho-deficient mice with mildly elevated FGF23 levels. Finally, in ex vivo studies (isolated cardiomyocytes), these authors demonstrated a direct hypertrophic effect of FGF23 through interaction with an FGF receptor that activates the calcineurin–nuclear factor of activated T-cells signalling pathway, independently of the presence of the co-receptor Klotho. In an established animal model of CKD, treatment with an FGF receptor blocker attenuated LVH, with no significant change in blood pressure. All of these data point to a causal role for FGF23, which seems to be Klotho-independent, in the pathogenesis of LVH. Accordingly, chronically elevated FGF23, as described in CKD, could directly contribute to LVH and high rates of cardiovascular mortality in these patients [17]. Lower levels of FGF23 resulting from therapies aimed at controlling CKD-MBD were associated with lower rates of cardiovascular events [18]. The clinical significance of FGF23 as a biomarker of CKD-MBD or of cardiovascular risk in renal patients is thus waiting for definite settlement. Besides FGF23, also its co-receptor Klotho is now widely investigated for potential involvement with cardiovascular disease through direct or indirect mechanisms. Available data indicate the strict pathophysiological link existing between FGF23 and Klotho. Even very early reduction in renal function associates with reduced circulating levels of Klotho (which is mainly produced by the kidney). It is currently accepted that this reduction prompts an increment of FGF23 secretion tentatively aimed at balancing the peripheral resistance secondary to reduction of the co-receptor. As a result, it may well be that at least some of the cardiovascular disease of CKD is secondary to reduced Klotho systemic activity. In fact, Klotho exists in a membrane-bound form and a soluble form (s-Klotho). Transmembrane α-Klotho (TM-Klotho), expressed in renal tubules, is mainly regarded as the cofactor for FGF23 receptor. Circulating soluble α-Klotho (s-Klotho) results from TM-Klotho shedding and is regarded as the component of Klotho that is responsible for its systemic, specific and FGF23-independent effect. Decreased TM-Klotho expression, described in both experimental and human CKD, lowers FGF23 effects on kidney tubules, but also lessens circulating s-Klotho [19]. In CKD patients, circulating s-Klotho is lower than normal and its reduction is detectable from CKD stage 2. s-Klotho positively correlates with eGFR, but also with serum Ca and, negatively, with serum P, PTH and FGF23. In this setting, serum levels of FGF23 are also higher than normal, with increments detectable from CKD stage 2. Assuming that s-Klotho mirrors TM-Klotho synthesis, low-circulating s-Klotho somehow describes the ensuing tubular resistance to FGF23, which, accordingly, is increased as a secondary response [20]. Thus, levels of s-Klotho can be regarded as an early marker of CKD-MBD, but more reliability of current assays for s-Klotho is needed. In conclusion, since FGF23 is reliably measured in serum or plasma, a wealth of epidemiological studies have explored cross-sectional and longitudinal relationships between FGF23 and clinical outcomes. The outcome of these studies unequivocally points to FGF23 as a robust marker of disease surrogate markers as well as hard clinical end points including mortality and cardiovascular events. Such relationships should be confirmed in CKD patients as well as in community-dwelling adults and in populations with a high occurrence of pre-existing cardiovascular disease.

Vitamin D in CKD Important mineral homeostasis disorders occur from the early stages of chronic kidney disease (CKD), despite patients may be completely asymptomatic. These disorders, affecting the serum levels of calcium, phosphorus, parathyroid hormone, and vitamin D, have a striking impact on the patient's prognosis as they affect the cardiovascular system. The new term “Chronic Kidney Disease-Mineral Bone Disease” (CKD-MBD) was created to define bone disease during CKD as a systemic disorder tightly linked to cardiovascular calcifications and disabilities. Vitamin D deficiency has a main role in the pathogenesis of CKD-MBD through the pleiotropic actions of this hormone. Vitamin D receptors (VDRs) are ubiquitarious, and their activation has shown protective effects against the development of secondary hyperparathyroidism as well as anti-hypertensive, anti-inflammatory, anti-fibrotic, immunomodulating, anti-proliferative, anti-diabetic, and anti-proteinuric properties. These mechanisms can explain, at least in part, the influence of vitamin D status for avoiding and delaying cardiovascular disease and CKD progression. These findings strongly support the importance of an early diagnosis of mineral homeostasis disorders in CKD and the need for a correction of vitamin D deficiency to prevent the disabilities and major events related to it.

Patients with chronic kidney disease (CKD) have markedly higher rates of severe vitamin D deficiency and reduced ability to convert 25-(OH)vitamin D into the active form, 1,25-dihydroxyvitamin D [1]. In the setting of CKD, secondary hyperparathyroidism develops as a consequence of reduced renal production of active vitamin D and phosphate retention resulting in hypocalcaemia and hyperphosphataemia. This is a process that is dangerously linked with metabolic bone disease, arterial calcifications and cardiovascular mortality [2]. Therefore, the conventional rationale for vitamin D treatment in CKD is to slow the progression of secondary hyperparathyroidism. In addition to the classical pathway for activation of 25-(OH)vitamin D to 1,25-(OH)2 vitamin D, a peripheral autocrine pathway exists and results in calcitriol synthesis in a variety of peripheral extra-renal tissues [3]. By binding with its intracellular vitamin D receptor (VDR) in these tissues, calcitriol can regulate cellular proliferation and differentiation, inflammation, the immune system and the endocrine system, including insulin resistance, lipid metabolism and renin–angiotensin system (RAS) [4]. Interestingly, active vitamin D analogues have shown demonstrably favourable effects on proteinuria, likely through interference with RAS [5, 6]. The discovery of this non-classical pathway has brought new significance to the importance of addressing nutritional vitamin D deficiency [7]. Vitamin D deficiency has been associated with all-cause and cardiovascular mortality in patients with CKD, whereas therapies with vitamin D and analogues have been associated with reduced mortality, recently also in meta-analysis of observational studies (Table 1). However, evidence from randomized controlled trials (RCTs) supporting a survival benefit from active and/or pre-active vitamin D administration in CKD patients is still lacking. Moreover, it is not even known whether different types of active vitamin D, selective or non-selective VDR activators, or precursors have a diversified effect on mortality in the CKD population. Table 1. Systematic literature reviews on vitamin D in patients with CKD In the present issue of the Clinical Kidney Journal, Mann et al. [8] present a meta-analysis of RCTs to investigate the effect of oral vitamin D therapy versus placebo on mortality and cardiovascular outcomes among adults with CKD, whereas vitamin D supplementation was not found to exert any significant effect on these hard outcomes. Analysis of pooled data displayed a substantial overlap in confidence intervals and homogeneity between study results. Stratification of trials by CKD stage, weekly vitamin D dose, proportion of diabetic subjects and vitamin D compound displayed similar results. In detail, 13 trials that, overall, enrolled 1469 patients with CKD stage 1–5D were selected for analysis and none of them had mortality as a primary outcome. These studies were mainly designed to test biochemical or bone histological end points and consequently had a rather short follow-up. On the whole 41 all-cause deaths (2.8%) were recorded during a follow-up ranging from 3 to 104 weeks (mean 41 weeks). Of note, about two-thirds of the patients (n= 1087) had been followed for

Vascular calcification (VC) represents a major cardiovascular risk factor in chronic kidney disease patients. High phosphate (Pi) levels are strongly associated with VC in this population. Therefore, Pi binders are commonly used to control high Pi levels. The aim of this work was to study the mechanism of action of lanthanum chloride (LaCl3) on the progression of Pi-induced VC through its direct effect on vascular smooth muscle cells (VSMCs) in vitro. High Pi induced VSCM Ca deposition. We evaluated the action of LaCl3, compared to gadolinium chloride (GdCl3), and found different effects on the modulation of VSMC lineage markers, such as α-actin and SM22α. In fact, only LaCl3 preserved the expression of both VSMC lineage markers compared to high Pi-treated cells. Interestingly, both LaCl3 and GdCl3 reduced the high Pi-induced elevations of bone morphogenic protein 2 mRNA expression, with no reduction of the high core binding factor-alpha 1 mRNA levels observed in calcified VSMCs. Furthermore, we also found that only LaCl3 completely prevented the matrix GLA protein mRNA levels and osteonectin protein expression elevations induced by high Pi compared to GdCl3. Finally, LaCl3, in contrast to GdCl3, prevented the high Pi-induced downregulation of Axl, a membrane tyrosine kinase receptor involved in apoptosis. Thus, our results suggest that LaCl3 prevents VC by preserving VSMC lineage markers and by decreasing high Pi-induced osteoblastic differentiation.

Vitamin D is a common treatment against secondary hyperparathyroidism in renal patients. However, the rationale for the prescription of vitamin D sterols in chronic kidney disease (CKD) is rapidly increasing due to the coexistence of growing expectancies close to unsatisfactory evidences, such as (1) the lack of randomized controlled trials (RCTs) proving the superiority of any vitamin D sterol against placebo on patients centered outcomes, (2) the scanty clinical data on head to head comparisons between the multiple vitamin D sterols currently available, (3) the absence of RCTs confirming the crescent expectations on nutritional vitamin D pleiotropic effects even in CKD patients, (4) the promising effects of vitamin D receptors activators (VDRA) against proteinuria and myocardial hypertrophy in diabetic CKD cohorts, and (5) the conflicting data on the impact on mortality of VDRA versus calcimimetic centered regimens to control CKD-MBD. The present review arguments these issues focusing on the opened questions that nephrologists should consider dealing with the prescription of nutritional vitamin D or VDRA and with the choice of a VDRA versus a calcimimetic based regimen in CKD-MBD patients.

Chronic kidney disease mineral bone disorders (CKD-MBD) encompass laboratory, vascular and bone abnormalities that might portend a poor prognosis in CKD. In spite of a great effort in elucidating the CKD-MBD natural history and pathogenesis, the underlying mechanisms are still largely unknown. However, a deficit in vitamin D is commonly reported as one of the first steps in CKD-MBD, and numerous epidemiological studies have associated serum vitamin D levels with different markers of cardiovascular disease and the risk of death in different populations. We herein summarize current evidence that links vitamin D deficiency to an adverse outcome and the results of the most recent clinical trials that have investigated the impact of paricalcitol supplementation on hard outcome in CKD patients.

Background: In non-dialysis patients (ND-CKD), C.E.R.A. has been extensively investigated in ESA-naïve subjects but no data are available on its efficacy after switch from other ESA. Methods: In this prospective, multicenter, open-label study lasting 24 weeks, ND-CKD patients (n = 157) receiving ESA were converted to C.E.R.A. at doses lower than recommended. Primary outcome was the prevalence of Hb target (11-12.5 g/dl). Results: Age was 73 ± 13 years and GFR was 26.2 ± 9.4 ml/min/1.73 m2; male gender, diabetes and prior cardiovascular disease were 49, 33 and 19%, respectively. Doses of darbepoetin (25 ± 16 µg/week, n = 124) and epoetin (5,702 ± 3,190 IU/week, n = 33) were switched to low dose C.E.R.A. (87 ± 17 µg/month). During the study, prevalence of Hb target increased from 60% to 68% at week-24, while that of Hb < 11 g/dl declined from 32% to 16% (p < 0.001). Hb increased from 11.3 ± 0.8 at baseline to 11.7 ± 0.9 g/dl at week-24 (p = 0.01) without changes in C.E.R.A. dose. Significant predictors of Hb increase were low BMI, low Hb and longer dosing intervals before switch. These factors also predicted the risk of Hb overshooting (Hb > 12.5 g/dl) occurring in 57 patients. Conclusions: In ND-CKD, conversion from other ESAs to C.E.R.A. is associated with a better anemia control induced by a greater Hb increase in patients previously treated with ESAs at extended dosing interval. This parameter should be considered when switching to long-acting ESA for its potential impact on the risk of overshooting.

The existing body of evidence suggests that cinacalcet isan effective drug for secondary hyperparathyroidism(SHPT) control in patients undergoing maintenance dialy-sis (CKD-5D) [1–10]. Indeed, available evidence suggeststhat by modulating the parathyroid calcium-sensing re-ceptor affinity to serum calcium, cinacalcet lowers by40–50% (250–350 pg/mL) serum parathyroid hormone(PTH) (Table 1). A consensual reduction in calcium [∼0.5–0.8 mg/dL (0.125–0.200 mmol/L); 5–8%] (Table 1) is alsoreported and expected due to the calcium-PTH set pointchange induced by this drug [11, 12]. However, some,albeit not all, reports (Table 1) have described a consen-sual reduction in serum phosphorus, which is more com-plicated to explain and often confounded by theconcomitant use of other agents such as vitamin D andphosphate binders that significantly affect phosphorousmetabolism [13, 14].Serum phosphorous represents a minimal part (∼1%) ofthe total body pool and is regulated by the net amount ab-sorbed in the intestine, the quota excreted by the kidneysand the net amount exchanged by the bones in the timeunit [13]. Notably, serum phosphorous does not alwaysclosely mirror the total body pool and phosphorousbalance in CKD, since different hormones regulate renaltubular (i.e. FGF-23, FGF-7, PTH) and bone (i.e. PTH) phos-phate handling to avoid excessive fluctuations of serumphosphorous concentration [13–15]. However, in CKD-5Dpatients the amount excreted by the kidneys is minimal ifnot absent. Hence, the reported tendency of cinacalcet toreduce serum phosphorous cannot be explained bya ‘renalcompensation’, but rather by the PTH effect on bones.We read with interest the manuscript by Zitt et al. [16].The aim of their study was to elucidate the mechanismsby which cinacalcet may lower serum phosphorous. Inthis observational study (ECHO study) [16], the authorsreport an overall tendency towards phosphate reduction(median change −9.1%, interquartile range: −25% to+10%), after 12 months of cinacalcet therapy [16]. Each10% serum PTH reduction correlates with a 3% decreasein serum phosphorous in the ECHO study cohort [16].However, at least 25% of the study population experi-enced an increase in serum phosphorous (median change−9.1%, interquartile range: −25% to +10%) [16] in spiteof the treatment with cinacalcet. The use of othercompounds such as vitamin D or phosphate binders aswell as the lack of diet control might explain why not allpatients treated with cinacalcet exhibit a consensualserum phosphorous reduction, but authors documentthat among 45% of patients in which serum phosphorousdecreases [defined as a change of at least 0.1 mg/dL(0.0323 mmol/L)], the use of concomitant medicationscannot explain this trend (vitamin D either increased orremained unchanged and phosphate binders were eitherreduced or left unchanged during follow-up). Finally, thelack of association between cinacalcet dose and serumphosphorous corroborates the hypothesis that bonemetabolism may playa role at least in some patients whoexperience a phosphate reduction while on cinacalcettreatment, similarly to what was seen after surgical para-thyroidectomy [17]. The role of bone metabolism couldalso be hypothesized by the multivariable-adjusted andsensitivity analyses. Adjustment for factors associatedwith serum phosphorus in CKD-5D patients documentsthat baseline serum phosphorous, dialysis vintage andPTH change from baseline to month 12 are the major de-terminants of phosphorus reduction at follow-up [16].However, sensitivity analyses document that a significantserum phosphate reduction is noted in all but the lowestbaseline PTH quartile and PTH change at Month 12 [17],suggesting that the quota of phosphate removed fromthe bone is relevant among subjects with severe SHPT oramong patients with parathyroid gland tissue still respon-sive to a calcimimetic drug (i.e. greater PTH reduction).The findings reported by Zitt et al. are consistent withprevious reports (Table 1 ). Though all studies recruited sub-jects with on average a poorly controlled PTH (in the rangeof 500–700 pg/mL), not all patients experienced a de-crease in serum phosphate. However, no study has con-trolled the use of phosphate binders and vitamin Dchanges during follow-up. In this regard, Zitt et al. furtherexpand the body of knowledge showing this trend amongpatients who did not decrease vitamin D or increase phos-phate binder usage at follow-up. Nonetheless, the obser-vational nature and the potential of imbalance amongdifferent groups (data not reported) and the lack of phos-phate intake evaluation at baseline and during follow-up,caution against definitive conclusions about the role ofPTH and the generalizability of the authors’ results.

Secondary hyperparathyroidism (SHPT) is one of the most frequent and deleterious complication of chronic kidney disease (CKD). SHPT is also one of the principal components of the now called CKD-mineral and bone disorders (MBD) syndrome. It is usually prevented and treated by vitamin D derivatives. However, the rationale for the prescription of vitamin D sterols in those patients is still a matter of hotly debates, mainly because of unsatisfactory results from numerous observational and not well-controlled studies. Scanty clinical data on head-to-head comparisons between the multiple vitamin D sterols are currently available. Moreover, there is crescent expectations on nutritional vitamin D, as well as vitamin D receptor activators (VDRA), regarding their putative pleiotropic effects even in CKD patients, and the promising effects of VDRA against proteinuria and myocardial hypertrophy in diabetic CKD cohorts. Nevertheless, additional randomized controlled trials (RCT) are needed to answer to many open questions and incertitude considering the effect of nutritional vitamin D and VDRA on hard end points including the risk of skeletal fractures and of mortality in CKD patients. RCT comparing VDRA to calcimimetics in the control of SHPT are also needed in dialysis patients. The present review will visit these open questions that nephrologists should ask before starting a treatment by nutritional vitamin D or VDRA.

The new or direct oral anticoagulants [new oral anticoagulants (NOAC) or direct oral anticoagulants (DOAC)] were launched in the Italian market in 2013. Although these compounds share common pharmacological indications with vitamin K antagonists (warfarin or acenocumarol), they have different mechanisms of action, do not require a constant anticoagulant monitoring but are more efficacious and safer than vitamin K antagonists. The use of these molecules (Dabigatran, Apixaban, Rivaroxaban, Betrixaban, Edoxaban) is constantly rising in daily practice. However, while available data suggest that NOAC/DOAC use is safe, dosage should be adjusted based on renal or liver function. It should be acknowledged that commonly available blood tests [Prothrombin Time (PT) and partial thromboplastin time (PTT)] are not indicated to monitor the anticoagulant activity of these compounds. With the exception of dabigatran, we currently lack of an antidote to reverse the anticoagulant effect of NOAC/DOAC. We herein review available evidence on NOAC/DOAC pharmacokinetic, risk factors for bleeding, interventions to reverse the anticoagulant activity in case of hemorrhages or need of urgent surgery and/or NOAC/DOAC overdose or side effects.

Several factors influence the choice of phosphate binder for patients, including older age, male gender, post-menopause, diabetes, low bone turnover, vascular/valvular calcification and inflammation. Unlike calcium-based phosphate binders, non-calcium-based phosphate binders, such as sevelamer and lanthanum carbonate, have been able to reduce the progression of bone disease to adynamic bone among patients with CKD. New iron-based phosphate binders are now available. With multiple options available for the reduction of phosphate, the focus has been on agents that do not contain calcium. This is because it is thought that calcium itself functions as a substrate for calcification.

A high prevalence of vascular calcification (VC) and a high incidence of cardiovascular events are two key complications of chronic kidney disease. Since most observational studies found a positive association between these two complications, a causal relationship has been assumed. If so, this would render VC a target of therapy. Recent studies, however, suggested this assumption might be an oversimplification. The fundamental aspects of these recent studies are two-fold. The first novel insight is that VC is not a single entity. VC can be the consequence of a wide range of different biological processes, but also of pharmacological interventions. Sometimes it is the underlying process that carries the additional risk, and sometimes it is tissue calcification itself. Both calcium-containing phosphate binders and statin therapy are associated with an increase in VC, but with divergent effects on cardiovascular risk. Moreover, VC can have different anatomical and histological locations. The second novel insight is that the assumption of a straightforward linear association between the amount of VC and risk for clinical events can be challenged. In this review we summarize recent literature that should lead to reconsidering the implications of VC in CKD. This includes an overview of the many different pathways underlying the ultimate occurrence of VC. Finally, we present a nuanced view concerning the pathophysiologic and therapeutic implications of the different types of calcification in patients with chronic kidney disease.

Cardiovascular disease and major cardiovascular events represent main cause of death in both acute and chronic kidney disease patients. Kidney and heart failure are common and frequently co-exist This organ-organ interaction, also called organ cross-talk, leads to well-known definition of cardiorenal syndrome (CRS). Here we will describe cardiovascular involvement in patients with acute kidney injury (AKI). Also known as Type-3 CRS or acute reno-cardiac CRS, it occurs when AKI contributes and/or precipitates development of acute cardiac injury. AKI may directly or indirectly produces an acute cardiac event and it can be associated with volume overload, metabolic acidosis and electrolytes disorders such as hyperkalemia and hypocalcemia, coronary artery disease, left ventricular dysfunction and fibrosis which has been also described in patients with AKI with the consequence of direct negative effects on cardiac performance.

During the last decade, a new view into the molecular mechanisms of chronic kidney disease-mineral bone disorder (CKD-MBD) has been proposed, with fibroblast growth factor 23 (FGF23) as a novel player in the field. Enhanced serum FGF23 levels cause a reduction in serum phosphate, together with calcitriol suppression and consequent hyperparathyroidism (HPT). In contrast, reduced serum FGF23 levels are associated with hyperphosphatemia, higher calcitriol levels and parathyroid hormone (PTH) suppression. In addition, serum FGF23 levels are greatly increased and positively correlated with serum phosphate levels in CKD patients. In this population, high serum FGF23 concentration seems to predict the occurrence of refractory secondary HPT and to be associated with higher mortality risk in incident haemodialysis patients. In living-donor kidney transplant recipients, a faster normalization of FGF23 and phosphate levels with a lower prevalence of HPT, may be considered a major pathway to investigate.

FGF23 is a hormone that appears as the core regulator of phosphate metabolism. Great deal of data has accumulated to demonstrate increased FGF23 secretion from the bone to compensate for even subtle increases in serum phosphorus long before intact PTH. However, recent evidence points to the fact that actions and interactions of FGF23 are not limited solely to phosphate metabolism. FGF23 may be implicated in iron metabolism and erythropoiesis, inflammation, insulin resistance, proteinuria, acute kidney injury and left ventricular hypertrophy. In this review, we will summarize latest experimental and clinical data examining impact of FGF23 on aforementioned pathophysiologic pathways/disorders.

Chronic kidney disease (CKD) patients demonstrate higher rates of cardiovascular mortality and morbidity; and increased incidence of sudden cardiac death (SCD) with declining kidney failure. Coronary artery disease (CAD) associated risk factors are the major determinants of SCD in the general population. However, current evidence suggests that in CKD patients, traditional cardiovascular risk factors may play a lesser role. Complex relationships between CKD-specific risk factors, structural heart disease, and ventricular arrhythmias (VA) contribute to the high risk of SCD. In dialysis patients, the occurrence of VA and SCD could be exacerbated by electrolyte shifts, divalent ion abnormalities, sympathetic overactivity, inflammation and iron toxicity. As outcomes in CKD patients after cardiac arrest are poor, primary and secondary prevention of SCD and cardiac arrest could reduce cardiovascular mortality in patients with CKD.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is common in kidney transplant recipients (KTRs), where secondary hyperparathyroidism (HPTH) and post-transplantation bone disease (PTBD) are potential effectors of both graft and vascular aging. Reduced 25(OH)D levels are highly prevalent in KTRs. Experimental and clinical evidence support the direct involvement of deranged vitamin D metabolism in CKD-MBD among KTRs. This review analyzes the pathophysiology of vitamin D derangement in KTRs and its fall out on patient and graft outcome, highlighting the roles of both nutritional and active vitamin D compounds to treat PTBD, cardiovascular disease (CVD) and graft dysfunction. Fibroblast growth factor-23-parathyroid hormone (PTH)-vitamin D axis, immunosuppressive therapy and previous bone status have been associated with PTBD. Although several studies reported reduced PTH levels in KTRs receiving nutritional vitamin D, its effects on bone mineral density (BMD) remain controversial. Active vitamin D reduced PTH levels and increased BMD after transplantation, but paricalcitol treatment was not accompanied by benefits on osteopenia. Vitamin D is considered protective against CVD due to the widespread pleiotropic effects, but data among KTRs remain scanty. Although vitamin deficiency is associated with lower glomerular filtration rate (GFR) and faster estimated GFR decline and data on the anti-proteinuric effects of vitamin D receptor activation (VDRA) in KTRs sound encouraging, reports on related improvement on graft survival are still lacking. Clinical data support the efficacy of VDRA against HPTH and show promising evidence of VDRA's effect in counteracting post-transplant proteinuria. New insights are mandatory to establish if the improvement of surrogate outcomes will translate into better patient and graft outcome.

Vascular calcification, occurring during late-stage vascular and valvular disease, is highly associated with chronic kidney disease-mineral and bone disorders (CKD-MBD), representing a major risk factor for cardiovascular morbidity and mortality. The hallmark of vascular calcification, which involves both media and intima, is represented by the activation of cells committed to an osteogenic programme. Several studies have analysed the role of circulating calcifying cells (CCCs) in vascular calcification. CCCs are bone marrow (BM)-derived cells with an osteogenic phenotype, participating in intima calcification processes and defined by osteocalcin and bone alkaline phosphatase expression. The identification of CCCs in diabetes and atherosclerosis is the most recent, intriguing and yet uncharted chapter in the scenario of the bone–vascular axis. Whether osteogenic shift occurs in the BM, the bloodstream or both, is not known, and also the factors promoting CCC formation have not been identified. However, it is possible to recognize a common pathogenic commitment of inflammation in atherosclerosis and diabetes, in which metabolic control may also have a role. Currently available studies in patients without CKD did not find an association of CCCs with markers of bone metabolism. Preliminary data on CKD patients indicate an implication of mineral bone disease in vascular calcification, as a consequence of functional and anatomic integrity interruption of BM niches. Given the pivotal role that parathyroid hormone and osteoblasts play in regulating expansion, mobilization and homing of haematopoietic stem/progenitors cells, CKD-MBD could promote CCC formation.

In the late 1970s, calcitriol was introduced into clinical practice for the management of secondary renal hyperparathyroidism in chronic kidney disease (CKD). Since then, the use of calcifediol or other native forms of vitamin D was largely ignored until the publication of the 2009 Kidney Disease Improving Global Outcomes (KDIGO) recommendations. The guidelines suggested that measurement of circulating levels of 25(OH)D (calcifediol) and its supplementation were to be performed on the same basis as for the general population. This indication was based on the fact that the precursors of active vitamin D had provided to CKD patients considerable benefits in survival, mainly due to their pleiotropic effects on the cardiovascular system. However, despite the long-term use of various classes of vitamin D in CKD, a clear definition is still lacking concerning the most appropriate time for initiation of therapy, the best compound to prescribe (active metabolites or analogs), the proper dosage, and the most suitable duration of therapy. The aim of this position statement is to provide and critically appraise the current plentiful evidence on vitamin D in different clinical settings related to CKD, particularly focusing on outcomes, monitoring and treatment-associated risks. However, it should be taken in account that position statements are meant to provide guidance; therefore, they are not to be considered prescriptive for all patients and, importantly, they cannot replace the judgment of clinicians.

Vitamin D is a common treatment against secondary hyperparathyroidism in renal patients. However, the rationale for the prescription of vitamin D sterols in chronic kidney disease (CKD) is rapidly increasing due to the coexistence of growing expectancies close to unsatisfactory evidences, such as the lack of randomized controlled trials (RCTs) proving the superiority of any vitamin D sterol against placebo on patient-centered outcomes, the scanty clinical data on head-to-head comparisons between the multiple vitamin D sterols currently available, the absence of RCTs confirming the crescent expectations on nutritional vitamin D pleiotropic effects even in CKD patients and the promising effects of vitamin D receptors activators (VDRA) against proteinuria and myocardial hypertrophy in diabetic CKD cohorts. The present chapter arguments these issues focusing on the opened questions that nephrologists should consider dealing with the prescription and the choice of a VDRA.

This is a case report on a patient with non-dialysis chronic kidney disease (CKD) in whom several nutritional issues are briefly discussed from a practical point of view. The article is accompanied by an editorial published in this Journal in relation to the 2nd International Conference of the European Renal Nutrition working group at ERA-EDTA—“Retarding CKD progression: readily available through comprehensive nutritional management?”— and focuses on several practical topics associated with the nutritional approach for the conservative treatment of non-dialysis CKD. The article is divided into 3 sections—basic nutritional assessment, nutritional targets, and nutritional follow-up in non-dialysis CKD—linked to 3 consecutive steps of the clinical follow-up of the patient and the related nutritional concerns and intervention. First visit: Baseline nutritional assessment and basic nutritional considerations in non-dialysis chronic kidney disease (CKD) • What nutritional assessment/monitoring for protein-energy wasting (PEW) should be employed? • Is a body mass index (BMI) of 21 kg/m2 adequate? • What phosphate target should be pursued? • What are the nutritional habits in patients with incident CKD? • What protein needs and amount of dietary protein should be pursued? • Does the quality of protein matter? • What amount of dietary salt should be employed? How should this be obtained? • How should normal serum phosphate be achieved? • What diet should be recommended? Is a vegetarian diet an option? Second visit: Major nutritional targets in non-dialysis CKD • Consequences of unintentional weight loss • What is the role of the renal dietitian in helping the patient adhere to a renal diet? Intermediate visits: Nutritional follow-up in non-dialysis CKD • What treatment for calcium/parathyroid hormone (PTH) will affect CKD progression? Final visits: • Would a dietary recall/intensive dietary education improve adherence with the diet? • Would a very-low-protein diet (VLPD)/ketodiet be indicated for this patient?

Background. Optimal treatment for secondary hyperparathyroidism (SHPT) has not been defined. The IMPACT SHPT (ClinicalTrials.gov identifier: NCT00977080) study assessed whether dose-titrated paricalcitol plus supplemental cinacalcet only for hypercalcaemia is superior to cinacalcet plus low-dose vitamin D in controlling intact parathyroid hormone (iPTH) levels in patients with SHPT on haemodialysis. Methods. In this 28-week, multicentre, open-label Phase 4 study, participants were randomly selected to receive paricalcitol or cinacalcet plus low-dose vitamin D. Randomization and analyses were stratified by mode of paricalcitol administration [intravenous (IV) or oral]. The primary efficacy end point was the proportion of subjects who achieved a mean iPTH value of 150–300 pg/mL during Weeks 21–28. Results. Of 272 subjects randomized, 268 received one or more dose of study drug; 101 in the IV and 110 in the oral stratum with two or more values during Weeks 21–28 were included in the primary analysis. In the IV stratum, 57.7% of subjects in the paricalcitol versus 32.7% in the cinacalcet group (P ¼ 0.016) achieved the primary end point. In the oral stratum, the corresponding proportions of subjects were 54.4% for paricalcitol and 43.4% for cinacalcet (P ¼ 0.260). Cochran–Mantel–Haenszel analysis, controlling for stratum, revealed overall superiority of paricalcitol (56.0%) over cinacalcet (38.2%; P ¼ 0.010) in achieving iPTH 150–300 pg/mL during Weeks 21–28. Hypercalcaemia occurred in 4 (7.7%) and 0 (0%) of paricalcitol-treated subjects in the IV and oral strata, respectively. Hypocalcaemia occurred in 46.9% and 54.7% of cinacalcet-treated subjects in the IV and oral strata, respectively. Conclusion. Paricalcitol versus cinacalcet plus low-dose vitamin D provided superior control of iPTH, with low incidence of hypercalcaemia.

Calcific uraemic arteriolopathy (CUA), or calciphylaxis, is a rare disease predominantly occurring in comorbidity with dialysis. Due to the very low frequency of CUA, prospective studies on its management are lacking and even anecdotal reports on treatment remain scarce. Therefore, calciphylaxis is still a challenging disease with dismal prognosis urgently requiring adequate strategies for diagnosis and treatment.In an attempt to fill some of the current gaps in evidence on various, highly debated and controversial aspects of dialysis-associated calciphylaxis, 13 international experts joined the 1st Consensus Conference on CUA, held in Leuven, Belgium on 21 September 2015. The conference was supported by the European Calciphylaxis Network (EuCalNet), which is a task force of the ERA-EDTA scientific working group on Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD). After an intense discussion, a 9-point Likert scale questionnaire regarding 20 items on calciphylaxis was anonymously answered by each participant. These 20 items addressed unsolved issues in terms of diagnosis and management of calciphylaxis. On the one hand, the analysis of the expert opinions identified areas of general consensus, which might be a valuable aid for physicians treating such a disease with less experience in the field. On the other hand, some topics such as the pertinence of skin biopsy and administration of certain treatments revealed divergent opinions. The aim of the present summary report is to provide some guidance for clinicians who face patients with calciphylaxis in the current setting of absence of evidence-based medicine.? The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Uremic subjects, in addition to accelerated atherosclerosis, develop diffuse media vascular calcification (VC) which, in turn, is associated with increased vascular stiffness and mortality risk. Two sets of risk factors for VC can be considered: passive deposition of calcium-phosphate and active transformation of vascular smooth muscle cells into osteoblastic- like cells. The former is linked with the metabolic imbalance in divalent ions that affects renal patients at any stage of the disease; the latter is secondary to a recently discovered mechanism of cellular trans-differentiation caused by deranged local concentration of divalent ions. Also, the role of inhibitors of calcification is under investigation. These include circulating or local, substances like fetuin, matrix GLA protein or osteoprotegerin. Their biologic importance is supported by the occurrence of calcification in transgenic animals lacking these factors. Accordingly, VC is a complex biologic and incompletely understood process that deserves further research, in order to develop specific therapeutic strategies. In general, once established, these calcifications are not considered to be reversible; therefore, prevention is the main treatment option. With this aim, in uremic patients it is now recommended to adopt restricted ranges of serum concentrations for calcium, phosphate and parathyroid hormone which are associated with a lower rate of calcification. To target these recommended ranges, new drugs, like selective vitamin D receptor activators, calcium sensing receptor modulators and calcium free intestinal phosphate binders, have been introduced. Moreover new possible pathogenetic pathways are considered (e.g. vitamin K deficiency). Further, in patients with calciphylaxis, the most severe form of VC, experimental therapies are suggested, with drugs like sodium thiosulphate or bisphosphonates. Drugs capable of reversing the process of trans-differentiation from osteoblast-like to vascular smooth muscle cells could be developed in the future.

Background. Paricalcitol and cinacalcet are common therapies for patients on haemodialysis with secondary hyperparathyroidism (SHPT). We conducted a multi-centre study in 12 countries to compare the safety and efficacy of paricalcitol and cinacalcet for the treatment of SHPT. Methods. Patients aged ≥18 years with Stage 5 chronic kidney disease receiving maintenance haemodialysis and with intact parathyroid hormone (iPTH) 300–800 pg/mL, calcium 8.4–10.0 mg/dL (2.09–2.49 mmol/L) and phosphorus ≤6.5 mg/dL (2.09 mmol/L) were randomized within two strata defined by the mode of paricalcitol administration to treatment with paricalcitol- (intra-venous, US and Russian sites, IV stratum; oral, non-US and non-Russian sites, oral stratum) or cinacalcet-centred therapy. The primary endpoint is the proportion of patients in each treatment group who achieve a mean iPTH value of 150–300 pg/mL during Weeks 21–28 of treatment. Assuming efficacy response rates of 36 and 66% for cinacalcet and paricalcitol, respectively, and a 20% discontinuation rate, 124 subjects in each stratum were estimated to provide 81% power to detect a 30% absolute difference in the primary endpoint. Results. Of 746 patients screened, 272 (mean age, 63 years; mean iPTH, 509 pg/mL) were randomized. Mean duration of haemodialysis at baseline was 3.7 years. Comorbidities included hypertension (90.4%), Type 2 diabetes (40.4%), congestive heart failure (17.3%), coronary artery disease (34.6%) and gastrointestinal disorders (75%). Conclusions. The study participants are representative of a multinational cohort of patients on haemodialysis with elevated iPTH. The study results will provide valuable information on the best available treatment of SHPT in patients on haemodialysis.

Progressive loss of kidney function leads to reduced production of calcitriol (1,25-dihydroxyvitamin D; active vitamin D) and an imbalance in serum calcium (Ca) and phosphorus (P) levels, which are associated with progression of renal failure as well as increased rates of cardiovascular (CV) events and mortality. In addition, multifactorial hypocalcemia and resistance to parathyroid hormone (PTH) can lead to prolonged and excessive synthesis and secretion of PTH, eventually leading to development of secondary hyperparathyroidism and renal osteodystrophy. These changes associated with chronic kidney disease (CKD), extending beyond bone and related biochemical abnormalities, have prompted the development of the term CKD–mineral and bone disorder to describe its systemic nature. Excessive P loading, among other factors, will promote vascular calcification (VC), and PTH production will affect bone remodeling. Although administration of calcitriol increases serum Ca levels and decreases PTH, it is also associated with elevated Ca × P product. Therefore, compounds that selectively activate vitamin D receptors (VDR activators), potentially reducing Ca–P toxicity and distinctly affecting pathogenic mechanisms of VC, might enhance CV and renal protection, increase the vitamin D therapeutic window, and thus provide a significant clinical benefit. Moreover, selective VDR activators have been associated with improvement in survival, at least among dialysis patients. Thus, selective VDR activators should be considered a novel and interesting approach to enhance the standard of care in CKD patients.

textabstractAims: Considering the growing relevance of fibroblast growth factor-23 (FGF-23) in the pathogenesis of chronic kidney disease bone and mineral disorder (CKD-MBD), an analysis was performed to determine the relative importance of C-ter-minal (cFGF-23) and intact (iFGF-23) assays in assessing CKD-MBD status in the first place and the relationship between FGF-23 and mortality as a secondary aim. Methods: In 77 patients (15 peritoneal dialysis and 62 hemodialysis), levels of calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvi-tamin-D (25D), 1,25D, FGF-23 (C-terminal and intact molecule) were measured and their correlations were analyzed. The relationship between FGF-23 levels and patient survival was also analyzed. Results: A significant correlation was found between cFGF-23 and 1,25D, PTH and 25D while iFGF-23 was significantly correlated with phosphate, 25D and PTH. PTH and 1,25D were independent predictors of cFGF-23, while for iFGF-23 independent predictors were phosphate and 25D. No significant relationship was found between FGF-23 and mortality. Conclusions: C-terminal or intact FGF-23 levels are weakly correlated and thus not clearly indicative of FGF-23 effects on PTH, P and vitamin D metabolism in dialysis patients. Assays for cFGF-23 and iFGF-23 showed a good correlation, but the intact molecule was not superior in defining interactions with CKD-MBD molecules. Measuring FGF-23 on a regular basis with the current assays in CKD and dialysis patients does not yet seem clinically useful.

Vascular calcification (VC) is one of the most dramatic consequences of chronic kidney disease (CKD). It has been considered a passive process, resulting essentially from mineral metabolism disorders and alterations in calcium and phosphate balance. But during the last decade, it has been elucidated how VC is not only a passive but more properly an active process, in which different factors are deeply involved. The progression of vessel wall mineralization is commonly associated with factors that promote VC, such as age, dialysis vintage and mineral metabolism abnormalities. Furthermore, many substances seem to be dynamically implicated in the regulation of the molecular mechanisms of VC. Between them, the matrix Gla protein and fetuin-A have recently been investigated in CKD. In this review, along with the most promising possible treatments, the new molecular mechanisms involved in the VC process will be elucidated.

Recently, a new view of the molecular mechanisms of phosphate homeostasis and secondary hyperparathyroidism pathogenesis has been proposed, with fibroblast growth factor 23 (FGF23) as a novel player in the field. FGF23 is a 32-kDa peptide secreted by the osteocytes involved in the control of phosphate homeostasis and calcitriol metabolism. FG23 is constantly elevated in advanced chronic kidney disease (CKD) patients, and recent studies have indicated that high levels are associated with the progression of CKD and with higher mortality rates in hemodialysis patients. In the CKD population, high serum FGF23 concentration seems to predict the occurrence of refractory secondary hyperparathyroidism, by inducing a resistance of the parathyroid glands to FGF23, and to be associated with higher mortality risk in incident hemodialysis patients. FGF23 appears to be involved in bone metabolism, but a direct effect of FGF23 on bone disease in humans has not yet been elucidated, even if the inhibitory effect of FGF23 on osteoblast activity that has been described in animal models and hereditary rickets is clearly connected with FGF23 deficiency. The association between altered levels of FGF23 and bone disease could be mainly due to the dysregulation of phosphate-handling and vitamin D metabolism, more than to a direct antiosteoblastic activity of FGF23. FGF23 appears to be a new biomarker, which is independently associated with several cardiovascular risk factors such as endothelial dysfunction, arterial stiffness and left ventricular hypertrophy, in the general population as well as in early CKD. All of the above have been related to cardiovascular and general mortality. Until now, we know that elevated FGF23 levels in dialysis patient are associated with several cardiovascular adverse outcomes mentioned above; the clinical relevance of high FGF23 values in dialysis patients remains unclear, because therapy with active vitamin D sterols further increases FGF23 levels but, on the other hand, is associated with a survival benefit in dialysis patients. This paradox highlights the need for future prospective randomized trials to evaluate the correlation between vitamin D therapy and FGF23 levels in dialysis patients. In the clinical setting, there are still different FGF23 actions that need investigation. In this sense, increased knowledge of mineral metabolism disorder alterations in CKD may be used to improve diagnostics and select future treatments.

Introduction Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare disease most frequently occurring in patients with advanced chronic kidney disease (CKD). The clinical picture is typically characterized by very painful skin lesions and ulcerations following calcification and occlusion of small cutaneous arterioles. CUA is life-threatening due to infections and concomitant cardiovascular diseases. Methods We performed a literature search for the terms calciphylaxis and calcific uremic arteriolopathy and summarized current state-of-the-art knowledge about pathophysiology, clinical picture, course of the disease, as well as treatment options. We have filled out the literature data with our personal treatment experiences. Results A combination of various local and systemic risk factors are necessary to cause the development of calciphylaxis. This pathophysiological cascade is still incompletely understood. Patients with advanced CKD and dialysis patients are especially at risk to develop CUA. Regarding therapy, no randomized prospective trials are available, and treatment is rather based on pathophysiological considerations as well as on evidence derived from case reports or case series. Therapy focuses on optimized dialysis treatment, control of chronic kidney disease-mineral and bone disorder parameters, experimental anticalcification strategies and wound care. Conclusion Facing the still deleterious outcome of patients with calciphylaxis, further studies on prophylaxis as well as treatment are urgently needed. Current treatment strategies may help ameliorate the course of the disease in some patients. However, it is still unclear if they are able to decrease mortality.

Background: The very high cardiovascular (CV) mortality and morbidity rates in hemodialysis (HD) patients are greatly related to atherosclerosis. CCN2 (connective tissue growth factor/CTGF) is a profibrotic factor that is secreted by endothelial cells, involved in atherogenesis, promoting fibroblast proliferation and matrix production. CCN2 protein is significantly increased in complicated fibrous plaques and enhances monocyte migration into atherosclerotic lesions. The aim of this study was to investigate a possible association between CCN2 gene polymorphism and CV morbidity and mortality in HD patients. Methods: 98 HD patients, followed for 24 months, were genotyped for the common polymorphism on the CCN2 gene (G-945C). HD patient characteristics were: age 64 ± 13 years, males 64%, diabetes 24%, hypertension 62%, smokers 38%, dyslipidemia 28%, all undergoing standard HD three times weekly. Results: All-cause mortality was not associated with CCN2 polymorphism (G-945C). In contrast, however, the GG genotype was strongly associated with CV mortality: OR 13 (1.49–155), p = 0.0048. Interestingly, the GG genotype was also greatly associated with the serious CV events of stroke and myocardial infarction in surviving HD patients: OR 13.3 (2.5–87.08), p = 0.0001. Conclusions: We demonstrate for the first time that CCN2 gene polymorphism is a prognostic risk factor for CV morbidity and mortality in HD patients. These data may have important implications for better understanding the link between accelerated atherosclerosis and increased mortality in HD population.

Modern strategies to prevent secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients give great relevance to vitamin D replacement therapy. However, a sound approach to treatment requires taking into account many factors, including stage of CKD, underlying renal disorder, levels of circulating PTH, bone status, vitamin D deposits, and serum calcium (Ca) and phosphate (P) levels. The aim of vitamin D replacement therapy should be to prevent SHPT from the early stages of CKD, because once parathyroid hyperplasia and osteodystrophy develop, they cannot be completely reverted. The therapeutic strategies for SHPT are now changing. The availability of VDRAs allows inhibition of parathyroid glands with less effect on calcium and phosphate levels, and perhaps reduces the mortality of dialysis patients. Actual objectives for treating CKD patients with new generation VDRAs are to retain or amplify the effects of calcitriol on PTH suppression, with no effects on serum Ca and P levels. Paricalcitol is such a new VDRA with minimal impact on serum Ca and P levels. Since cardiovascular disease is the leading cause of morbidity and mortality in dialysis patients, these data suggest that the beneficial effect associated with paricalcitol injection on patient survival is at least partially related to its effect on the cardiovascular system.

Arterial hypertension and proteinuria are risk factors for chronic kidney disease. A mobile clinic was parked in a central plaza of 11 Italian cities to check blood pressure (BP), prescribe antihypertensive drugs, assess for proteinuria, and provide awareness about hypertension. Among 3757 patients, 56% were hypertensive, 37% were not diabetic nor proteinuric with BP >or=140/90 mm Hg, 17% were diabetic or proteinuric with BP >or=130/80 mm Hg, and 11% were on treatment with BP at target. Among 1204 treated patients, 400 (33%) had controlled BP. Among all 2114 hypertensive patients, only 1344 (64%) were aware of their hypertension. Awareness was greater among treated patients at target (99%). As many as 523 (14%) patients had proteinuria >or=30 mg/dL. The authors conclude that awareness of people walking in the street about their BP and proteinuria is insufficient. Mobile screening clinics may increase public awareness and detection of hypertension and proteinuria in the general community and detect patients at risk for chronic kidney disease.

Secondary hyperparathyroidism (SHPT) is a classical feature of chronic kidney disease (CKD). Commonly, hypocalcemia, hyperphosphatemia, and vitamin D deficiency are involved into the pathogenesis of SHPT. Parathyroid (PT) glands are characterized by a low turnover and rarely undergo mitoses. However, in the presence of low calcium, high phosphorus, vitamin D deficiency, and uremia, PT cells leave quiescence. In the last decade, both new molecular and cellular mechanisms have been investigated in the pathophysiology of SHPT, between them the emerging role of the PT vitamin D receptor and calcium-sensing receptor. Furthermore, recent studies indicate that the fibroblast growth factor-23 may play a central role in the regulation of phosphate-vitamin D metabolism in CKD. Certainly, in the next future, these new insights into the pathogenesis of SHPT will give the possibility to improve the treatment of this condition in the CKD population.