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Background Vascular calcification and accelerated atherosclerosis are major causes of death in haemodialysis (HD) patients. Matrix metalloproteinases (MMPs) are a family of enzymes, involved in the biology of extracellular matrix and in atherogenesis. MMP1 and MMP3 contribute to the enlargement and instability of atherosclerotic plaque, respectively. The common polymorphisms on MMP1 (2G/2G) and MMP3 (6A/6A) gene promoters have been related to increased coronary artery calcification and to carotid artery stenosis. The aim of this study was to evaluate the association of MMP1 and MMP3 polymorphisms with end-stage renal failure (ESRD) and all-cause mortality risk in HD. Methods Ninety-nine HD patients, followed-up for 36 months, and 133 matched controls were genotyped for the two polymorphisms. HD patients' characteristics were age 64 +/- 13 years, males 64%, diabetic 24%, hypertensive 62%, smokers 38%, dyslipidaemic 28%, all undergoing standard HD thrice weekly. Results ESRD was strongly associated with the combination of 2G/2G and 6A/6A homozygosity: OR 2.57 (0.95-7.4), P = 0.037, but not with isolated 2G/2G and 6A/6A homozygosity (P = 0.09 and P = 0.11, respectively). Isolated 2G/2G was associated with all-cause mortality risk independently from age, gender, diabetes, hypertension, smoking, dyslipidaemia, C-reactive protein, albumin, dialysis vintage and history of cardio-vascular disease: HR 2.96 (1.29-6.80), P = 0.01. A trend for the association of mortality and isolated 6A/6A homozygosity was also observed: HR 3.01 (0.88-10.26), P = 0.078. Combination of 2G/2G and 6A/6A homozygosity significantly increased the mortality risk in the same Cox regression model: HR 4.69 (1.72-12.81), P = 0.003. Conclusions In this study, we demonstrated for the first time that MMP-1 and MMP-3 gene polymorphisms are negative prognostic risk factors for all-cause mortality in HD patients, independently from traditional risk factors. These data may have important implications for better understanding the pathogenesis of the increased mortality in HD patients.

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

Secondary hyperparathyroidism is a serious complication of chronic renal disease when function decline and is characterized by abnormalities in serum calcium and phosphate profile, along with a decline in calcitriol synthesis. A reduced density of specific receptors for vitamin D and calcium in several tissues and organs are also present, thus contributing to parathyroid hyperplasia and abnormal parathyroid hormone synthesis and secretion. This metabolic derangement is observable early in the course of chronic renal failure (stages 3 and 4) and on this basis it should also be treated early in order to avoid important clinical consequences. To afford secondary hyperparathyroidism, several strategies should be considered: phosphate oral intake control (diet and phosphate binders), adequate calcium oral intake, vitamin D receptor activation. More specifically, the concept of selective vitamin D receptor activation will be considered as well as its biological effects, the use of paricalcitol (a selective vitamin D receptor activator) given orally to patients on peritoneal dialysis, and stages 3 and 4 of chronic renal failure. Finally, we will consider a series of nonclassical interesting potential mechanisms of selective vitamin D receptor activation leading to reduced cardiovascular and all-cause mortality.

Continuously emerging evidence indicates that defi ciencies in 25-hydroxyvitamin D and consequently vitamin D receptor (VDR) activation play crucial roles in adversely affecting cardiovascular (CV) he

Chronic kidney disease (CKD) patients in dialysis (HD) show peculiar, atypical features of clinical presentation and diseases (cardiovascular, metabolic, hematologic). This is also true for viral hepatitis infections, for which CKD patients represent an important risk group. In the past, hepatitis B virus (HBV) was the major cause of viral hepatitis in end-stage renal disease (ESRD). However, the introduction of a rigorous infection-control strategy, routine screening of patients and staff for hepatitis B serologic markers, vaccination of susceptible patients and staff, use of separate rooms and dedicated machines for HD of HbsAg-positive patients have all led to a decline in the spread of HBV infection in dialysis. Despite the prevalence of the antibody-hepatitis C virus (HCV), there has been a marked decrease in HD patients; after the introduction of routine screening for HCV and the use of erythropoietin, its occurrence ranges from 5% to 25% in the United States, with a prevalence of 6.8% in Europe. In CKD and in HD patients, the presence of HBV and HCV is an independent and significant risk factor for death and this risk may be at least partially attributed to chronic liver disease with its attendant complications. Liver disease can progress with modest hepatic inflammation and prominent fibrosis; the natural history of viral hepatitis in these patients is dependent on the immune dysfunction typical of kidney disease. Despite recent advances in antiviral therapy, there are still many uncertainties in regards to the efficacy and long-term outcomes of treatment with antiviral agents.

Abnormalities of bone mineral parameters (calcium, phosphate, vitamin D, and parathyroid hormone) are nearly omnipresent in patients with advanced chronic kidney disease (CKD). These typically consist of hypocalcemia, hyperphosphatemia, abnormalities of vitamin D metabolism, and secondary hyperparathyroidism (SHPT). Currently, several lines of evidence suggest that these abnormalities may have consequences beyond the typical consequence of renal bone disease, with a major role in determining cardiovascular disease, including arterial calcification. The 'classical' treatment of SHPT and hyperphosphatemia in HD patients consists of phosphate binders, vitamin D receptor activators (VDRAs), and/or calcimimetics. Calcium- or aluminum-based phosphate binder prescriptions and calcitriol administration are therapeutic tools not free of complications, increasing the risk of cardiovascular calcification in the HD population. New calcium- and aluminum-free phosphate binders, such as lanthanum carbonate and sevelamer hydrochloride, new VDRA (paricalcitol), and cinacalcet hydrochloride can be used to treat SHPT, slow down the atherosclerotic process, and prevent vascular calcification in HD patients.

Abnormalities of bone mineral parameters (calcium, phosphate, vitamin D, and parathyroid hormone) are nearly omnipresent in patients with advanced chronic kidney disease (CKD). These typically consi

In the last decade, the nephrology community has focused its attention on the main cause of morbidity and mortality in chronic renal failure patients: cardiovascular disease. In addition, recent studies pointed out that vascular calcification (VC) is a major cause of cardiovascular disease in the dialysis population. Interestingly, the pathogenesis of VC and soft tissue calcification in chronic kidney disease (CKD) has been extensively investigated. Nowadays we know that VC is associated not only with passive calcium phosphate deposition, but also with an active, cell-mediated process. To better understand the pathogenesis of VC in CKD, numerous regulatory proteins have been studied, because of their ability to inhibit mineral deposition in the vessels. We here examine the state of the art of those substances recognized as regulatory key factors in preventing VC in uremic conditions, such as fetuin A (α2-Heremans-Schmid glycoprotein), matrix γ-carboxyglutamic acid protein, pyrophosphate, osteoprotegerin and bone morphogenetic protein. We conclude that at present it is too early to introduce these novel markers into clinical practice.

It is commonly accepted that the first cause of morbidity and mortality in chronic kidney disease (CKD) is the cardiovascular (CV) disease, in which vascular calcification (VC) plays a central pathogenetic role. In CKD population, mineral metabolism disorders have been recently investigated not only as key factors on renal osteodystrophy but also as inducing players on extra-skeletal calcification. Clearly, either high phosphate (P) or high calcium (Ca) concentration induce vascular smooth muscle cells mineralization in vitro studies. In fact, VC is induced by a cell-mediated process, which actively accompanies the traditional and passive Ca-P deposition in arterial walls. Interestingly, lack of inhibitory proteins, such as fetuin-A (alpha2-HS glycoprotein, AHSG), matrix GLA protein (MGP), osteoprotegerin (OPG), and bone morphogenetic protein 7 (BMP-7) are the regulatory key factors in preventing VC in uremic conditions.

Accelerated atherosclerosis and vascular calcifications (VC) play a central role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD) patients. Mineral metabolism disorders and increased serum calcium-phosphate product have been recently investigated as inducing factors of cardiovascular calcification. In fact, cardiovascular disease in renal failure appears greatly associated with bone metabolism alterations. Recently, the treatment of hyperphosphatemia in CKD patients changed from either calcium- or aluminium-based phosphate-binders to new free-calcium and aluminium phosphate binders, such as sevelamer hydrochloride and lanthanum carbonate. Therefore, control of serum phosphate in CKD patients becomes crucial in preventing increases in calcium-phosphate product, secondary hyperparathyroidism and ultimately VC.

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Parathyroid (PT) hyperplasia is a major feature of secondary hyperparathyroidism (SH) in uremia. The transforming growth factor-alpha (TGFalpha) / epidermal growth factor receptor (EGFR)Ethgrowth loop is the main contributor to uremia-induced PT hyperplasia. Since integrin beta1 and focal adhesion kinase (FAK) are known to directly activate cell growth and enhance EGFR-driven growth, these studies examined their contribution to PT hyperplasia in uremia. Western blot analysis was used to measure the expression of EGFR, integrin beta1, and the non-receptor integrin-sensitive FAK, in PT glands from 8 hemodialysis patients with various degrees of SH at the time of the surgery, and in a normal human PT gland. In all patients, PT EGFR expression was higher than in the normal control. Integrin beta1, a direct activator of EGFR-driven growth, was increased in 5 of the 8 hyperplastic glands, whereas 7 out of 8 PT glands showed a marked enhancement in FAK expression, an elevation unrelated to increases in integrin beta1, but directly associated to time in hemodialysis. Similar increases in PT FAK content were observed after 1 month after the onset of uremia by 5/6 nephrectomy in rats. These findings suggest that in kidney disease, the increased PT cell growth driven by enhanced EGFR could be further aggravated through elevations in integrin beta1 and FAK expression.

Introduction S econdary hyperparathyroidism, a frequent complication of chronic renal failure, is characterized by parathyroid hyperplasia and enhanced synthesis and secretion of parathyroid hormone (PTH). As summarized in Figure 1, high circulating PTH levels are not only a major contributor to osteitis fibrosa and bone loss, typical features of renal osteodystrophy, but also to a variety of systemic defects including cardiovascular complications which increase mortality in renal failure patients. A link between the mechanisms controlling proliferation and hormonal production also exists in normal parathyroid cells, which respond to the stimulus of chronic hypocalcemia not only by an increase in PTH release but with a secondary expansion in cell mass. The mechanisms responsible for this link, however, remain poorly understood. In renal failure, hypocalcemia, hyperphosphatemia and vitamin D deficiency are the three main direct causes of hyperparathyroidism. Hyperphosphatemia and 1,25-dihydroxyvitamin D (l,25(OH)2D3) deficiency also enhance parathyroid function indirectly by lowering serum calcium (Ca).^'^'^ The regulation of PTH synthesis by Ca, phosphate (P) and vitamin D has been extensively studied. PTH-gene transcription is tightly controlled by Ca and l,25(OH)2D3 through mechanisms that involve the calcium sensing receptor (CaSR) and the vitamin D receptor (VDR), respectively. ' As renal disease progresses, a reduction in parathyroid content of both proteins renders the parathyroid glands more resistant to suppression of PTH synthesis and secretion in response to Ca and l,25(OH)2D3.^'^^ Serum Ca and P levels also control PTH synthesis through post-transcriptional mechanisms that involve the binding of cytosolic proteins to the 3'-untranslated region of the PTH mRNA, thus regulating transcript stability and consequently, PTH translation rates. ' ' Changes in the levels of serum Ca, P, l,25(OH)2D3 and in the parathyroid content of the CaSR and the VDR also have a dramatic impact on parathyroid tissue growth. ' ' However, the lack of an appropriate parathyroid cell line has precluded a better understanding of the pathogenic mechanisms mediating the potent effects of the three main regidators on the rate of parathyroid cell proliferation already induced by uremia. This chapter summarizes the current understanding of parathyroid tissue growth and presents new insights, emerging from the 5/6 nephrectomized rat model, into the molecular mechanisms contributing to the regulation of parathyroid hyperplasia in early uremia by Ca, P and l,25(OH)2D3.

This paper reports on human hepatocytes cultured in a galactosylated membrane bioreactor in order to explore the modulation of the effects of a pro-inflammatory cytokine, Interleukin-6 (IL-6) on the liver cells at molecular level. In particular the role of IL-6 on gene expression and production of a glycoprotein, fetuin-A produced by hepatocytes, was investigated by culturing hepatocytes in the membrane bioreactor, both in the absence and presence of IL-6 (300 pg/ml). IL-6 modulated the fetuin-A gene expression, synthesis and release by primary human hepatocytes cultured in the bioreactor. A 75% IL-6-induced reduction of fetuin-A concentration in the medium was associated with a 60% increase of C-reactive protein in the same samples. Real-time-PCR demonstrated an 8-fold IL-6-induced reduction of fetuin-A gene expression. These results demonstrate that the hepatocyte galactosylated membrane bioreactor is a valuable tool to study IL-6 effects and gave evidence, for the first time, that IL-6 down-regulates the gene expression and synthesis of fetuin-A by primary human hepatocytes. The human hepatocyte bioreactor behaves like the in vivo liver, reproducing the same hepatic acute-phase response that occurs during the inflammatory process.

The incidence and prevalence of congestive heart failure are actually increasing worldwide, especially in Western countries. In Europe and the United States, congestive heart failure represents a disabling clinical disease, accountable for increased hospitalization and health care costs. European guidelines have underlined the importance of pharmacological treatment to improve both patients' outcomes and quality of life. The latest clinical trials to evaluate ivabradine's efficacy have underlined its usefulness as a stand-alone medication and in combination with conventional congestive heart failure therapy, including in chronic kidney disease patients.

Chronic kidney disease (CKD) causes alterations in mineral metabolism inducing the development of secondary hyperparathyroidism (HPT) and renal osteodystrophy. Recently, it has been suggested that these alterations play an important role in determining extraskeletal calcification and thus cardiovascular morbidity and mortality among CKD patients. An impaired 1 alfa -hydroxylation of 25-hydroxycholecalciferol (25(OH)D3) to 1,25-dihydroxycholecalciferol (1,25(OH)2 D3) with decreased circulating 1,25(OH)2 D3 levels is commonly observed in patients with creatinine clearance below 70 ml/min. The reduction in 1,25(OH)2 D3 production triggers the up-regulation of parathyroid hormone (PTH) synthesis, through a decreased suppression on PTH gene transcription and a decreased intestinal calcium absorption. A reduced expression of vitamin D receptor (VDR) and a less efficient binding of the complex 1,25(OH)2 D3 -VDR to specific DNA segments account for the resistance to 1,25(OH)2 D3 in target cells. Thus, absolute and relative 1,25(OH)2 D3 deficiency is one of the causes of secondary HPT in patients with CKD, together with phosphate retention and skeletal resistance to PTH. Consistently with these pathophysiological mechanisms, the therapeutic use of 1,25(OH)2 D3 still represents a milestone for the treatment of secondary HPT and renal osteodystrophy, even though hypercalcemia and hyperphosphatemia are common adverse events and may increase the risk of cardiovascular calcifications. To reduce the impact of such adverse effects while retaining anti-PTH activity, 1,25(OH)2 D3 analogues with lower calcemic effects have been synthesized and are now available for clinical use.

In the last 10 years, it has been well documented that mineral metabolism abnormalities in dialysis patients are associated with an enhanced risk of morbidity and mortality for cardiovascular disease. Extraskeletal calcifications represent one of the major risk factors involved in the pathogenesis of cardiovascular disease in this population. In fact, secondary hyperparathyroidism and hyperphosphatemia associate with increased cardiovascular mortality in uremic patients for two reasons: first for the passive deposition of calcium and phosphate in soft tissues; second for the active role of inorganic phosphate on direct induction of extraskeletal mineralization of the tunica media in the vasculature of these patients. In peritoneal dialysis patients, many unbalances of calcium and phosphate metabolism are present. In particular, recent cohort studies indicate that most patients do not reach targets indicated by clinical practice guidelines. Further efforts to control hyperphosphatemia are essential, in order to reduce the impact of secondary hyperparathyroidism both on bone and cardiovascular system.

In the last 10 years, it has been well documented that mineral metabolism abnormalities in dialysis patients are associated with an enhanced risk of morbidity and mortality for cardiovascular disease. Extraskeletal calcifications represent one of the major risk factors involved in the pathogenesis of cardiovascular disease in this population. In fact, secondary hyperparathyroidism and hyperphosphatemia associate with increased cardiovascular mortality in uremic patients for two reasons: first for the passive deposition of calcium and phosphate in soft tissues; second for the active role of inorganic phosphate on direct induction of extraskeletal mineralization of the tunica media in the vasculature of these patients. In peritoneal dialysis patients, many unbalances of calcium and phosphate metabolism are present. In particular, recent cohort studies indicate that most patients do not reach targets indicated by clinical practice guidelines. Further efforts to control hyperphosphatemia are essential, in order to reduce the impact of secondary hyperparathyroidism both on bone and cardiovascular system.

Daniela Paola Roggeri,1 Mario Cozzolino,2 Sandro Mazzaferro,3 Diego Brancaccio,4 Ernesto Paoletti,5 Alessandro Roggeri,1 Anna Maria Costanzo,6 Umberto di Luzio Paparatti,6 Vincenzo Festa,6 Piergiorgio Messa7 1ProCure Solutions, Nembro, Bergamo, 2Department of Health Sciences, University of Milan, Milan, 3Department of Cardiovascular, Respiratory, Nephrologic and Geriatric Sciences, Sapienza University of Rome, Rome, 4Dialysis Unit NephroCare Simone Martini, Milan, 5Department of Nephrology, San Martino Hospital, Genoa, 6AbbVie Italy, Campoverde, Latina, 7Nephrology, Dialysis and Renal Transplant, Fondazione Ca Granda IRCCS Policlinico, Milan, Italy On behalf of the FARO Study Group Background: The aim of this analysis was to estimate biochemical parameters and the costs of treatment of secondary hyperparathyroidism (SHPT) in a subpopulation of the FARO-2 study. Methods: The FARO-2 observational study aimed at evaluating the patterns of treatment for SHPT in naïve hemodialysis patients. Data related to pharmacological treatments and biochemical parameters (parathyroid hormone [PTH], calcium, phosphate) were recorded at entry to hemodialysis (baseline) and 6 months later (second survey). The analysis was performed from the Italian National Health Service perspective. Results: Two prominent treatment groups were identified, ie, one on oral calcitriol (n=105) and the other on intravenous paricalcitol (n=33); the intravenous calcitriol and intravenous paricalcitol + cinacalcet combination groups were not analyzed due to low patient numbers. At baseline, serum PTH levels were significantly higher in the intravenous paricalcitol group (P

The parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor-alpha (TGF-alpha). TGF-alpha stimulates growth through activation of its receptor, the epidermal growth factor receptor (EGFR), normally expressed in the parathyroid glands. Because enhanced coexpression of TGF-alpha and EGFR causes aggressive cellular growth, these studies utilized highly specific inhibitors of EGFR tyrosine kinase, a step mandatory for TGF-alpha-induced EGFR activation, to assess the contribution of growth signals from enhanced expression of TGF-alpha exclusively or both TGF-alpha and EGFR to the rapid parathyroid growth induced by kidney disease and exacerbated by high-phosphorus (P) and low-calcium (Ca) diets in rats. The enhancement in parathyroid gland weight and proliferating activity (proliferating cell nuclear antigen/Ki67) induced by kidney disease and aggravated by either high P or low Ca intake, within the first week after 5/6 nephrectomy, in rats, coincided with simultaneous increases (2- to 3-fold) in TGF-alpha and EGFR content. Conversely, prevention of the increases in both TGF-alpha and EGFR paralleled the efficacy of either P restriction or high-Ca intake in ameliorating uremia-induced parathyroid hyperplasia. More importantly, suppression of TGF-alpha/EGFR signaling, through prophylactic administration of potent and highly selective inhibitors of ligand-induced EGFR activation, completely prevented both high-P- and low-Ca-induced parathyroid hyperplasia as well as TGF-alpha self-upregulation. Thus enhanced parathyroid TGF-alpha/EGFR expression, self-upregulation, and growth signals occur early in kidney disease, are aggravated by low-Ca and high-P intake, and constitute the main pathogenic mechanism of the severity of parathyroid hyperplasia.

Background: Increased vascular calcification plays an important role in the pathogenesis of cardiovascular events in chronic kidney disease (CKD) patients. It is the result of an active ossification process counteracted by ‘protective’ proteins, such as matrix GLA protein (MGP). Polymorphisms of MGP have been identified. Methods: The aim of this study was to define the distribution of two MGP polymorphisms (–7, –138) in 99 hemodialysis (HD) patients, in 26 patients with CKD stage 3 and in 135 age- and sex-matched healthy controls. Patients were followed up for 12 months to record any cardiovascular deaths. The cause of death was determined by medical doctors, considering the medical history of each patient. The primers were designed with Primer Express software. Results: MGP –138TT homozygotes were more frequent in the HD group versus controls (p = 0.0004). Additionally, the frequency of the T allele was significantly higher in the HD group (p = 0.0006). The frequency of the A allele of MGP-7 was significantly higher both in the HD group (p = 0.033) and in the CKD group (p = 0.0017) versus controls. MGP-7 GG homozygotes were significantly less common in the CKD group than in controls (p = 0.037). Combination –138TT –7AA was significantly more frequent in both CKD patients (p = 0.001) and in HD patients (p = 0.029) than in controls. Seventeen out of 99 HD patients experienced fatal cardiovascular events. Sixteen (94.1%) were –138TT homozygotes and either –7AA homozygotes or –7GA heterozygotes. Conclusion: This study suggests that CKD and HD patients have a different distribution of MGP gene polymorphism as compared with the normal population. Altered MGP gene polymorphism may be a negative prognostic factor for the progression to end-stage renal disease and for cardiovascular events in CKD patients.

The current understanding of the mechanisms of calcium deposition in soft tissues in chronic kidney disease (CKD) patients has been deeply investigated in the last ten years. Because of higher morbidity and mortality due to cardiovascular disease in dialysis patients compared to general population, several studies showed that extraskeletal calcification may play a major role in the pathogenesis of cardiovascular events in CKD patients. Traditionally, the pathogenesis of vascular and soft tissue calcification has been associated with a passive calcium-phosphate deposition. Actually, it is well known that extraskeletal calcification is also related to an active process. In this review, we analyzed some of the factors potentially involved in the pathogenesis of vascular calcification in CKD patients.

Cardiovascular disease is the first cause of morbidity and mortality in dialysis patients. Hyperphosphatemia and elevated serum calcium-phosphate levels have recently been investigated as inducing factors on extraskeletal calcification in this population. In vitro studies demonstrated that human aortic smooth muscle cells calcify when incubated in a high phosphate medium, where calcium and calcitriol are not changed. Furthermore, the lack of inhibitory proteins, such as fetuin and matrix Gla protein, is a possible main determinant of calcium-phosphate deposition in soft tissues. The classical treatment of hyperphosphatemia and secondary hyperparathyroidism in dialysis patients consists of calcium-based phosphate binders and calcitriol administration. Unfortunately, this "first-generation" therapy is not free of dramatic side effects. New free-calcium and -aluminum phosphate binders, new vitamin D metabolites, and calcimimetics are examples of "second-generation" therapies that may prevent vascular calcification and possibly prevent some of the burden of cardiovascular disease in uremia.

In chronic kidney disease, secondary hyperparathyroidism (HPTH) is characterized by parathyroid hyperplasia and enhanced synthesis and secretion of parathyroid hormone (PTH). Elevated PTH levels cause renal osteodistrophy and cardiovascular complications, with significantly increased morbidity and mortality in renal failure. The three main direct causes of renal HPTH are hypocalcemia, hyperphosphatemia and vitamin D deficiency. A link between the mechanisms controlling proliferation and hormonal production also exists in normal parathyroid cells which respond to the stimulus of chronic hypocalcemia, not only by an increase in PTH release but also with a consequent parathyroid cell proliferation. The mechanisms responsible for this link, however, remain poorly understood. In this review, we analyze the current understanding concerning the new insights into the molecular mechanisms of parathyroid hyperplasia and PTH secretion in renal failure regulated by calcium, phosphate and vitamin D.

The current understanding of the mechanisms of calcium deposition in soft tissues in chronic kidney disease (CKD) patients has been deeply investigated in the last ten years. Because of higher morbidity and mortality due to cardiovascular disease in dialysis patients compared to general population, several studies showed that extraskeletal calcification may play a major role in the pathogenesis of cardiovascular events in CKD patients. Traditionally, the pathogenesis of vascular and soft tissue calcification has been associated with a passive calcium-phosphate deposition. Actually, it is well known that extraskeletal calcification is also related to an active process. In this review, we analyzed some of the factors potentially involved in the pathogenesis of vascular calcification in CKD patients.

Management of post-parathyroidectomy hypocalcemia in dialysis patients is not well defined. We reviewed published approaches to treatment in an effort to define a clinical algorithm for controlling serum calcium levels post-operatively.We conducted a PubMed search for the years 1980-2003 with the keywords "hypocalcemia" and "parathyroidectomy". Only English language and human subject abstracts were analyzed, and only those articles dealing with secondary or tertiary hyperparathyroidism (HPTH) were reviewed further. Other articles were extracted from cross-referencing.We initially examined 146 articles. This review summarizes the findings of the relevant articles along with our own practice regarding post-parathyroidectomy hypocalcemia management in dialysis patients. The vast majority of patients require intravenous (i.v.) calcium supplements after surgery. There are no available controlled studies on calcium supplementation for post-parathyroidectomy hypocalcemia in this patient population. Calcitriol supplementation proved valuable in two studies.Post-parathyroidectomy hypocalcemia is a common complication, which can be prevented and treated with oral and i.v. calcium supplementation and/or active vitamin D metabolites. Daily follow-up of both serum calcium and phosphorus are mandatory to prevent this major post-operative complication. Based on the available evidence, we propose a protocol for the prevention and treatment of post-parathyroidectomy hypocalcemia, for use in clinical practice. This approach requires validation by a controlled clinical trial.

Several factors are involved in conditioning renal anemia, and a critical role is attributed to parathyroid hormone (PTH) oversecretion, which has some direct effects on endogenous erythropoietin (EPO) synthesis, bone marrow erythroid progenitors, and red cell survival. Indirect effects are mainly based on the induction of bone marrow fibrosis. Indirect evidence of the role of PTH is based on the observation that parathyroidectomy, when performed in uremic patients, is often followed by restoration of the hematocrit. The interpretations of such positive results are based on the observation of the restored bone marrow space after operation and also in a rise of immunoreactive EPO serum concentrations observed in the first weeks after gland removal. Another field of clinical interest is the possible beneficial effects of vitamin D therapy in controlling PTH secretion, which in turn determines an improvement of anemia of uremic subjects. Several uncontrolled studies confirmed this possibility, indicating that patients who respond to calcitriol or its analogs also show an increase of their hemoglobin levels. Thus, a combined therapeutic approach to PTH oversecretion and anemia is possible by intravenous calcitriol or parathyroidectomy pointing to the possible reversibility of bone marrow fibrosis, which is a common feature of secondary hyperparathyroidism. The increased sensitivity to EPO therapy can also induce a successful reduction of its dosage, thus allowing an interesting reduction of costs.

The control of serum phosphorus (P) and calcium-phosphate (Ca x P) product is critical to the prevention of ectopic calcification in chronic renal failure (CRF). Whereas calcium (Ca) salts, the most commonly used phosphate binders, markedly increase serum Ca and positive Ca balance, the new calcium- and aluminum-free phosphate binder, sevelamer hydrochloride (RenaGel), reduces serum P without altering serum Ca in hemodialysis patients. Using an experimental model of CRF, these studies compare sevelamer and calcium carbonate (CaCO(3)) in the control of serum P, secondary hyperparathyroidism (SH), and ectopic calcifications. 5/6 nephrectomized rats underwent one of the following treatments for 3 mo: uremic + high-P diet (U-HP); UHP + 3% CaCO(3) (U-HP+C); UHP + 3% sevelamer (U-HP+S). Sevelamer treatment controlled serum P independent of increases in serum Ca, thus reducing serum Ca x P product and further deterioration of renal function, as indicated by the highest creatinine clearances. Sevelamer was as effective as CaCO(3) in the control of high-P-induced SH, as shown by similar serum PTH levels, parathyroid (PT) gland weight, and markers of PT hyperplasia. Also, both P binders elicited similar efficacy in reducing the myocardial and hepatic calcifications induced by uremia. However, sevelamer caused a dramatic reduction of renal Ca deposition (29.8 +/- 8.6 micro g/g wet tissue) compared with both U-HP (175.5 +/- 45.7 micro g/g wet tissue, P < 0.01) and the U-HP+C (58.9 +/- 13.7 micro g/g wet tissue, P < 0.04). Histochemical analyses using Von Kossa and Alizarin red S staining of kidney sections confirmed these findings. The high number of foci of calcification in the kidney of uremic controls (108 +/- 25) was reduced to 33.0 +/- 11.3 by CaCO(3) and decreased even further with sevelamer (16.4 +/- 8.9, P < 0.02 versus CaCO(3)). Importantly, the degree of tubulointerstitial fibrosis was also markedly lower in U-HP+S (5%) compared with either U-HP+C (30%) or U-HP (50%). It is concluded that in experimental CRF in rats, despite a similar control of serum P and SH, sevelamer is more effective than CaCO(3) in preventing renal Ca deposition and tubulointerstitial fibrosis, including better preservation of renal function. These findings cannot be extrapolated to human disease, and further studies in patients are necessary to determine the benefits of either P binder.

1,25(OH)(2)D(3) antiproliferative properties are widely known. However, the molecular bases of these properties are only partially elucidated. Since 1,25(OH)(2)D(3) effectively arrests growth in many tumors and hyperplastic tissues whose growth is driven by co-expression of EGFR and its ligand TGF-alpha, it was hypothesized that 1,25(OH)(2)D(3) could affect the TGF-alpha/EGFR-autocrine growth loop. This study examined 1,25(OH)(2)D(3) regulation of EGFR-growth signals, using human epidermoid A431 cells, in which the overexpression of EGFR and TGF-alpha constitute the major autocrine mitogenic signal. 1,25(OH)(2)D(3) inhibited autocrine and EGF-induced A431 cell proliferation. Furthermore, 1,25(OH)(2)D(3) changed the cellular localization of both TGF-alpha and EGFR and inhibited ligand-dependent phosphorylation of EGFR and ERK1/2. In addition, 1,25(OH)(2)D(3) impaired autocrine and EGF-induced nuclear translocation of activated EGFR and, consequently, its binding to AT-rich DNA sequences and transcriptional activation of the cyclin D1 promoter. These results demonstrate that 1,25(OH)(2)D(3) alters EGFR membrane trafficking and down-regulates EGFR growth signaling.

Matrix-Gla protein and vascular calcification: The negative role of oral anticoagulant therapy