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Background In chronic kidney disease, the activation of the renin–angiotensin–aldosterone system (RAAS) and renal inflammation stimulates renal fibrosis and the progression to end-stage renal disease. The low levels of vitamin D receptor (VDR) and its activators (VDRAs) contribute to worsen secondary hyperparathyroidism and renal fibrosis. Methods The 7/8 nephrectomy model of experimental chronic renal failure (CRF) was used to examine the anti-fibrotic effects of treatment with two VDRAs, paricalcitol and calcitriol, at equivalent doses (3/1 dose ratio) during 4 weeks. Results CRF increased the activation of the RAAS, renal inflammation and interstitial fibrosis. Paricalcitol treatment reduced renal collagen I and renal interstitial fibrosis by decreasing the activation of the RAAS through renal changes in renin, angiotensin receptor 1 (ATR1) and ATR2 mRNAs levels and renal inflammation by decreasing renal inflammatory leucocytes (CD45), a desintegrin and metaloproteinase mRNA, transforming growth factor beta mRNA and protein, and maintaining E-cadherin mRNA levels. Calcitriol showed similar trends without significant changes in most of these biomarkers. Conclusions Paricalcitol effectively attenuated the renal interstitial fibrosis induced by CRF through a combination of inhibitory actions on the RAAS, inflammation and epithelial/mesenchymal transition.

BackgroundIn chronic kidney disease, serum phosphorus (P) elevations stimulate parathyroid hormone (PTH) production, causing severe alterations in the bone–vasculature axis. PTH is the main regulator of the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, which is essential for bone maintenance and also plays an important role in vascular smooth muscle cell (VSMC) calcification. The discovery of a new RANKL receptor, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), which is important for osteoblast differentiation but with an unknown role in vascular calcification (VC), led us to examine the contribution of LGR4 in high P/high PTH–driven VC.MethodsIn vivo studies were conducted in subtotally nephrectomized rats fed a normal or high P diet, with and without parathyroidectomy (PTX). PTX rats were supplemented with PTH(1–34) to achieve physiological serum PTH levels. In vitro studies were performed in rat aortic VSMCs cultured in control medium, calcifying medium (CM) or CM plus 10−7 versus 10−9 M PTH.ResultsRats fed a high P diet had a significantly increased aortic calcium (Ca) content. Similarly, Ca deposition was higher in VSMCs exposed to CM. Both conditions were associated with increased RANKL and LGR4 and decreased OPG aorta expression and were exacerbated by high PTH. Silencing of LGR4 or parathyroid hormone receptor 1 (PTH1R) attenuated the high PTH–driven increases in Ca deposition. Furthermore, PTH1R silencing and pharmacological inhibition of protein kinase A (PKA), but not protein kinase C, prevented the increases in RANKL and LGR4 and decreased OPG. Treatment with PKA agonist corroborated that LGR4 regulation is a PTH/PKA-driven process.ConclusionsHigh PTH increases LGR4 and RANKL and decreases OPG expression in the aorta, thereby favouring VC. The hormone’s direct pro-calcifying actions involve PTH1R binding and PKA activation.

Background In chronic kidney disease (CKD), increases in serum phosphate and parathyroid hormone (PTH) aggravate vascular calcification (VC) and bone loss. This study was designed to discriminate high phosphorus (HP) and PTH contribution to VC and bone loss. Methods Nephrectomized rats fed a HP diet underwent either sham operation or parathyroidectomy and PTH 1-34 supplementation to normalize serum PTH. Results In uraemic rats fed a HP diet, parathyroidectomy with serum PTH 1-34 supplementation resulted in (i) reduced aortic calcium (80%) by attenuating osteogenic differentiation (higher α-actin; reduced Runx2 and BMP2) and increasing the Wnt inhibitor Sclerostin, despite a similar degree of hyperphosphataemia, renal damage and serum Klotho; (ii) prevention of bone loss mostly by attenuating bone resorption and increases in Wnt inhibitors; and (iii) a 70% decrease in serum calcitriol levels despite significantly reduced serum Fgf23, calcium and renal 24-hydroxylase, which questions that Fgf23 is the main regulator of renal calcitriol production. Significantly, when vascular smooth muscle cells (VSMCs) were exposed exclusively to high phosphate and calcium, high PTH enhanced while low PTH attenuated calcium deposition through parathyroid hormone 1 receptor (PTH1R) signalling. Conclusions In hyperphosphataemic CKD, a defective suppression of high PTH exacerbates HP-mediated osteogenic VSMC differentiation and reduces vascular levels of anti-calcifying sclerostin.

The causes of the high cardiovascular mortality observed in chronic kidney disease (CKD) are unknown. Here, we report data on prevalence of subclinical atherosclerosis in the NEFRONA population and a stratified multivariate logistic analysis of factors associated with the presence of plaque.We analysed 2445 patients with an estimated glomerular filtration rate (eGFR)60 mL/min (CKD 3: 937; CKD 4-5: 820; CKD 5D: 688) and 559 non-CKD subjects (eGFR60 mL/min), 18-75 years old, without previous cardiovascular events. An itinerant team of professionals performed carotid and femoral arterial ultrasound.The already high prevalence of plaques in CKD 3 is even higher in more severe CKD. Multivariate logistic analysis showed that, at any CKD stage, age and being male are independently associated with the presence of plaques. In CKD 3, there was a significant interaction of the smoking status and triglycerides levels which were independently associated with the presence of plaque. Furthermore, being diabetic was also associated with the presence of subclinical atherosclerosis. In stage 4-5 there was a significant association with smoking, high phosphate and hsCRP levels. In dialysis patients, being diabetic, having low levels of 25(OH)-vitamin D3 and smoking status also showed a significant association with the presence of plaque. Furthermore, the association of phosphate levels with the presence of subclinical atheromatosis showed a U-shaped curve.This analysis demonstrates the magnitude of subclinical atheromatous disease in a large CKD population. The patient characteristics associated with the presence of plaque differ in every CKD stage.

Background. Left ventricular hypertrophy (LVH), a common complication in chronic kidney disease (CKD), is associated with high cardiovascular mortality. The aim of this experimental study was to analyze the effect of different vitamin D receptor activators (VDRAs) on both LVH and myocardial fibrosis in chronic renal failure (CRF). Methods. Male Wistar rats with CRF, carried out by 7/8 nephrectomy, were treated intraperitoneally with equivalent doses of VDRAs (calcitriol, paricalcitol and alfacalcidol, 5 days per week) during 4 weeks. A placebo group (CRF + vehicle) and a Sham group with normal renal function served as controls. Biochemical, morphological, functional and molecular parameters associated with LVH were evaluated, as well as cardiac fibrosis, collagen I, transforming growth factor β1 (TGFβ1) and matrix metalloproteinase-1 (MMP1) expression. Results. All VDRAs treatment prevented LVH, with values of cardiomyocyte size, LV wall and septum thickness and heart– body weight ratio similar to those observed in the Sham group. At molecular levels, all VDRAs attenuated atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression compared with CRF+ vehicle. The phosphorylation of ERK1/2, a signal for activating growth, was stimulated in the CRF+ vehicle group; VDRAs use prevented this activation. Paricalcitol was the only VDRA used that maintained in the normal range all parameters associated with myocardial fibrosis (total collagen, collagen I, TGFβ1 and MMP1). Conclusions. Our findings demonstrated that the three VDRAs used induced similar changes in bone metabolic parameters and LVH. In addition, paricalcitol was the only VDRA which showed a relevant beneficial effect in the reduction of myocardial fibrosis, a key factor in the myocardial dysfunction in CKD patients.

Mineral metabolism parameters may play a role in the survival of patients with chronic kidney disease (CKD).In the CORES Study, we analysed the association between calcium, phosphorus and PTH and mortality (all-cause and cardiovascular) in 16 173 haemodialysis (HD) patients over 18 years from six Latin American countries, who underwent haemodialysis up to 54 months. Unadjusted, case-mix-adjusted and time-dependent multivariable-adjusted hazard ratio (HR) of death were calculated for categories of serum albumin-corrected calcium (Ca(Alb)), phosphorus and PTH using as 'reference values' the range in which the lowest death rate was observed. Age, gender, vitamin D treatment, diabetes, vintage, vascular access, weight, blood pressure and laboratory variables (serum albumin, haemoglobin, creatinine, ferritin and Kt/V) were used as confounding variables.Low (9.5 mg/dL) and high (10.5 mg/dL) Ca(Alb) increased the HR for all-cause mortality. Low (9.0 mg/dL) Ca(Alb) increased the HR for cardiovascular mortality. High phosphorus (5.5 mg/dL) increased the HR for both all-cause and cardiovascular mortality. Low phosphorus (4.0 and3.0 mg/dL) increased the HR for both all-cause and cardiovascular mortality. Furthermore, low (150 pg/mL) and high (500 and300 pg/mL) PTH increased the HR for both all-cause and cardiovascular mortality. In addition, only phosphorus6.0 mg/dL increased the HR for cardiovascular hospitalizations. No effect was observed with Ca(Alb) or PTH.In summary, in 16,173 HD patients, elevated and reduced serum levels of albumin-corrected calcium, phosphorus and PTH levels were associated with increments in all-cause mortality. Similar results were obtained when only cardiovascular mortality was analysed.

Background The regulatory mechanisms of parathyroid hormone (PTH) synthesis are complex, involving calcium, calcitriol, the calcium-sensing receptor (CaR) and the vitamin D receptor (VDR). In this study, the effects of calcium and calcitriol on the simultaneous expression of CaR and VDR mRNA and protein levels were assessed in parathyroid glands cultured in vitro. Methods Parathyroid glands (N = 424) were removed and cultured for 24 h to study the effect of calcium on the CaR, VDR and PTH. In addition, the effect of calcitriol at low calcium concentrations (0.6 mM) on CaR and VDR levels was studied after 48 h of incubation. CaR, VDR and PTH mRNAs were measured by quantitative real-time PCR (qRT-PCR), and CaR and VDR protein levels were measured by immunohistochemistry. Results PTH gene expression was reduced by high calcium concentration. No differences were found in the CaR mRNA levels among the different calcium concentrations tested (0.6 mM calcium: 100%; 1.2 mM calcium: 120%; 2.0 mM calcium: 112%; median values), but VDR gene expression rose when calcium increased (0.6 mM calcium: 100%; 1.2 mM calcium: 164%; 2.0 mM calcium: 195%; median values). Calcitriol increased both CaR (control: 100%; 10(-8) M calcitriol: 196%; median values) and VDR genes expression (control: 100%; 10(-8) M calcitriol: 176%; median values). The same findings were corroborated at protein levels for both CaR and VDR. Conclusions In parathyroid glands cultured in vitro, calcium up-regulates VDR but not CaR. Conversely, calcitriol up-regulates both VDR and CaR mRNAs and protein levels, even at low calcium concentrations.

Although medical guidelines generally are graded according to their evidence level, low evidence 'judgement' are generally perceived as much as absolute truth by the medical community as high evidence 'guidelines' are. Being aware of this bias, a workgroup appointed by the European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA), the members of which are the authors of the current publication, decided that European nephrology guidelines issued by the Association should be published only as 'guidelines' in the case of high-level evidence; otherwise they should be named 'recommendations' or 'position statements' and be published in a different format. Acknowledging that in nephrology, high levels of evidence are often lacking, it was also decided to rename the responsible body from European Best Practice Guidelines (EBPG) to European Renal Best Practice (ERBP). The present publication reviews the arguments based on which this decision was taken.

Hyperphosphataemia is a frequent and important cardiovascular risk factor in patients with chronic kidney disease (CKD). High phosphate levels may influence vascular calcifications by two separate mechanisms: by worsening secondary hyperparathyroidism, which in turn facilitates calcification, and by promoting calcium phosphate deposition in pre-formed endothelial plaques and in the arterial wall. Recent studies have shown that hyperphosphataemia induces the proliferation and differentiation of endothelial vascular cells into osteoblast-like cells, promoting vascular calcification. High phosphate levels also increase the risk of mortality in patients with CKD. To reduce the negative impact of high phosphate, serum phosphate levels should be

Background. Disturbances of calcium-phosphate (Ca-P) metabolism in chronic renal insufficiency (CRI) play an important role not only in bone disease (renal osteodystrophy) but also in soft tissue calcification, with an increased risk of vascular calcification, arterial stiffness, and worsening of atherosclerosis. Methods. Discussion in order to achieve a consensus on key points relating to pathogenesis, clinical assessment, and management of renal osteodystrophy in dialysis patients. Results. Secondary hyperparathyroidism develops primarily as a consequence of reduced active vitamin D production by the kidneys and phosphate retention, with the development of hyperphosphataemia, hypocalcaemia, and increased parathyroid hormone (PTH) levels. The same factors over the long term cause parathyroid gland hyperplasia and autonomous PTH production (tertiary hyperparathyroidism). As hyperphosphataemia and increased Ca 3P product have been associated with increased mortality in dialysis patients, hyperparathyroidism should be prevented and managed, starting in the pre-dialysis period, by calciumuvitamin D supplementation. Hyperphosphataemia is usually treated by means of intestinal phosphate binders, but different types of binders have been used. The traditional aluminiumbased phosphate binders are certainly effective, but have the drawback of side effects due to aluminium absorption (osteomalacia, encephalopathy, microcytic anaemia). Calcium-containing phosphate binders (calcium carbonate or calcium acetate) have mainly been used for the last 10‐15 years. However, they aggravate metastatic calcification, particularly if they are taken together with vitamin D analogues and a high calcium dialysate concentration. New calcium- and aluminiumfree phosphate binders have recently been developed and may be useful, particularly in patients with metastatic calcification anduor hypercalcaemic episodes, in order to reduce the phosphate burden in the absence of an additional calcium load. New vitamin D analogues and calcimimetic drugs are also being developed for PTH suppression, with the goal to minimize or even entirely avoid hypercalcaemia anduor hyperphosphataemia. A suitable dialysate calcium concentration is important and must take into consideration the medical therapy and the calcium balance on an individual patient basis. Surgical parathyroidectomy is the ultimate means of treating hypercalcaemic hyperparathyroidism, when medical therapy has failed. Conclusion. Achieving an evidence-based consensus can give clinicians a useful tool for the treatment of disturbances of Ca-P metabolism in CRI: this has become an important objective in nephrological care, particularly as ageing and increased risk of atherosclerosis have become major issues in the dialysis population.

Background. Malnutrition is common in dialysis patients and closely related to morbidity and mortality. Therefore, assessment of nutritional status and nutritional management of dialysis patients play a central role in everyday nephrological practice. Methods. Achieving a consensus on key points relating to pathogenesis, clinical assessment, and nutritional management of dialysis patients. Results. The assessment of nutritional status should be based on clinical assessment and biochemical parameters, including history of weight loss, per cent standard weight, body mass index, muscle mass, subcutaneous fat mass, and plasma albumin, creatinine, bicarbonate and cholesterol. Co-morbid conditions should be assessed and C-reactive protein (CRP) measured—as a marker of inflammation—as there is a close relation between malnutrition, on one side, and co-morbid conditions and inflammation on the other. For a more detailed assessment, subjective global assessment of nutritional status is a well-validated tool, and dual-energy X-ray absorptiometry (DEXA) is a useful method for routine assessment of lean body mass. Anthropometric methods are also useful. They are cheap and easy to apply, although less precise than DEXA. The recommended daily protein intake is at least 1.2 gukg standard body weight and the energy intake 35 kcalukg standard body weight (BW), in patients -60 years, and 30 kcalukg standard BW in patients )60 years. The standard bicarbonate level should be at least 22 mmolul. If CRP is )10 mgul, it is important to seek and treat the underlying cause. Adequate dialysis (for haemodialysis: KtuV )1.2) should be ensured and, although no definite evidence of the importance of dialysis water quality is available, the opinion of the authors is that the water quality should be high. The role of the biocompatibility of the dialysis membrane is still not clear. The dietitian plays a pivotal role in the nutritional care of dialysis patients, and patients should be provided with dietary counselling from the start of substitutive treatment in order to meet the recommended nutritional intakes. Dietary counselling can also play an important role in an integrated treatment of hyperphosphataemia, although most patients will also need phosphate binders if they have an adequate protein intake. Conclusion. Malnutrition assessment and treatment is a great challenge for nephrological care. Achieving evidence-based consensus can help in implementing the progress of knowledge in clinical practice.

Chronic aluminium exposure and toxicity related to aluminium absorption and contaminated dialysis fluid continue to be a problem for many patients with renal failure, particularly in South America and in some developing countries. The two most prevalent sources of aluminium in this population are water used to prepare dialysate and aluminium-containing phosphate binders. Of particular concern is the effect of aluminium at the level of the bone, the haematopoietic system and the brain. Here we focus mainly on the adverse effects of aluminium on bone, the preferred organ of aluminium accumulation in the body. Unfortunately, aluminium has a cumulative effect, thus even short-term exposure to aluminium in phosphate binders adds to the total load and may contribute to the risk of aluminium-related bone disease. Even a bone biopsy does not allow a precise determination of total bone aluminium content. We examine the mechanisms by which aluminium contributes to abnormal bone remodelling. Studies indicate that aluminium has a direct effect, inhibiting bone formation and resorption. There is also evidence for an indirect effect through the action of aluminium on parathyroid hormone synthesis and by its modulation of calcium activity. We discuss commonly used techniques for identifying aluminium load and review studies of chelation therapy as a method to lower aluminium load. It is apparent that aluminium overload has serious consequences for patients with chronic renal failure, yet this problem can be largely prevented by the use of aluminium-free phosphate binders. The deleterious effects on bone remodelling caused by chronic exposure to aluminium suggest that caution should be observed when using other metals as phosphate binders.