Abstract: PURPOSE: Chronic kidney disease (CKD) is associated with an impaired endothelial function, which may contribute to cardiovascular events. Whether impairment in endothelial function is involved in the circulatory response to orthostatic stress is unknown. We assessed endothelial function via brachial artery flow-mediated dilation (BAFMD), an index of endothelial-dependent vasodilation. METHODS: We measured changes in brachial artery diameter (BAD) and blood flow by Doppler ultrasound in 35 CKD patients on hemodialysis, 37 young healthy controls (HC) and 50 non-uremic matched controls (MC), in the supine position and after 60 degrees head-up tilting (HUT). Results: In the supine position, endothelial flow-mediated BAD was significantly increased in HC (p<0.001) and MC (p<0.01) while no significant changes were detected in CKD. Mean percent blood flow changes were HC+323.5%, MC+195.1% and CKD+158.8% (HC vs. CKD p<0.001; HC vs. MC p<0.001; MC vs. CKD p=0.04). Similarly, during HUT mean BAD and blood flow increases were significantly impaired in CKD patients. CONCLUSION: In CKD patients, an impaired response in the physiologic vascular reactivity, suggesting endothelial dysfunction, was found in the supine position and after orthostasis by BAFMD. Our results are in favor of a possible adjunctive role of uremia in the abnormal brachial artery response.
Abstract: Mineral metabolism disorders are well-recognized complications in patients with chronic kidney disease (CKD). Furthermore, hyperphosphatemia and secondary hyperparathyroidism are associated with both renal osteodystrophy and cardiovascular disease. During the last 5 years, new therapeutic options have become available to treat these conditions in CKD. We describe the case of a 70-year-old lady with a dialysis history of 5 years and a number of cardiovascular risk factors (hypertension, hypercholesterolemia and obesity). Unfortunately, the patient was poorly compliant with any pharmaceutical treatment. After 2 years, a pharmacological approach with a low dosage of calcium salts and sevelamer HCl, subsequently changed to lanthanum carbonate, intravenous paricalcitol, and cinacalcet HCl reached the goals suggested by the current guidelines. Every nephrologist should look at the pathogenesis and treatment of hyperphosphatemia and secondary hyperparathyroidism. New options are now available and may help the clinician to obtain satisfactory short- and long-term outcomes in the treatment of this disease.
Abstract: Hemodialysis (HD) patients are commonly affected by secondary hyperparathyroidism (SHPT), in which 3 well-known factors are usually involved: hypocalcemia, hyperphosphatemia and calcitriol deficiency. Classically, high parathyroid hormone (PTH) levels cause bone-associated diseases, such as osteitis fibrosa and renal osteodystrophy, but more recently it has been demonstrated the link between SHPT and a systemic toxicity, with a major role in determining cardio-vascular disease, including arterial calcification, endocrine disturbances, compromised immune system, neurobehavioral changes, and altered erythropoiesis. Treatment with calcitriol (CT), the active form of vitamin D, reduces parathyroid hormone (PTH) levels, but may result in elevations in serum calcium (Ca) and phosphorus (P), increasing the risk of cardio-vascular calcification in the HD population. Several new vitamin D analogs have been developed and investigated with the rationale to treat SHPT with a reduced risk of hypercalcemia and hyperphosphatemia in HD patients. Paricalcitol (1,25-dihydroxy-19-nor-vitamin D(2), 19-Nor-D(2)) is a vitamin D analog that suppresses PTH secretion with minimal increases on serum calcium and phosphate levels. It was demonstrated that paricalcitol prevents vascular calcification in experimental models of renal failure, compared with calcitriol. Furthermore, 19-Nor-D(2) is the first analog approved for use in HD patients and is available for i.v. and oral administration, commonly 3 times weekly after HD. The purpose of the present review is to analyze the pathogenesis and treatment of SHPT in HD patients, and the role of paricalcitol in the prevention of arterial calcification.
Abstract: 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 (alpha2-Heremans-Schmid glycoprotein), matrix gamma-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.
Abstract: BACKGROUND: Secondary hyperparathyroidism (SHPT) is common in chronic kidney disease (CKD) patients. Classically, SHPT is induced by hypocalcemia, hyperphosphatemia, and calcitriol deficiency, that cause not only renal osteodystrophy but also systemic toxicity, particularly cardiovascular disease. OBJECTIVE: Treatment with calcitriol, the active form of vitamin D, reduces serum parathyroid hormone (PTH) levels but may result in both hypercalcemia and hyperphosphatemia, increasing the risk of vascular calcification in CKD. Are the new vitamin D receptor activators (VDRAs) more useful in the treatment of SHPT for their reduced risk of hypercalcemia and hyperphosphatemia in haemodialysis (HD) patients? METHODS: In this review, we describe the new VDRA, paricalcitol (1,25-dihydroxy-19-nor-vitamin D2), which suppresses PTH secretion with minimal increases on serum calcium and phosphate levels. RESULTS/CONCLUSIONS: In some animal models of CKD paricalcitol does not cause vascular calcification, while other VDRAs do. These data may account for the results seen in observational studies of HD patients, in which paricalcitol is associated with improved survival compared to calcitriol.
Abstract: BACKGROUND: Vascular calcification (VC) and accelerated atherosclerosis are major causes of cardiovascular (CV) morbidity and mortality in haemodialysis (HD) patients. Inhibitory proteins are associated with reduced VC and may play a key role in preventing CV in chronic kidney disease (CKD) patients. Fetuin-A, also known as alpha(2)-Heremans-Schmid glycoprotein (AHSG), is a circulating plasma protein with inhibitory effects on VC that has been associated with inflammation and CV mortality in HD patients. In the present study, we investigated the associations between serum fetuin-A levels and its gene (AHSG) polymorphisms in an Italian HD population. METHODS: Ninety-six patients on stable chronic HD treatment and 57 healthy controls were genotyped for the common polymorphisms on the AHSG (T256S). In addition, serum fetuin-A levels were tested. RESULTS: In this study, serum fetuin-A levels were lower in HD patients (0.35 +/- 0.11 g/l) compared with healthy controls (0.62 +/- 0.31 g/l, p < 0.05). In both HD patients and the control group, the distribution of the AHSG gene did not show significant association between low serum fetuin-A levels and the Ser/Ser genotype, known to be associated with a higher CV mortality risk in the HD population. Moreover, the distribution of AHSG gene polymorphisms in HD patients and in healthy controls was similar. CONCLUSIONS: In contrast with previous reports, this study suggests that CKD patients on HD treatment have a similar polymorphism distribution of the AHSG gene compared with the normal population and that the reduction in serum fetuin-A levels in Italian HD patients is not associated with an alteration in the distribution of AHSG T256S polymorphisms.
Abstract: 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.
Abstract: 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.
Abstract: Phosphate overload is a dramatic consequence in end-stage renal disease (ESRD) patients. Recent studies have well documented that abnormalities in mineral and bone metabolism in these patients are associated with increased cardiovascular morbidity and mortality. Elevated serum phosphate and calcium-phosphate product levels play an important role in the pathogenesis of secondary hyperparathyroidism and extra-skeletal calcification in dialysis patients. Furthermore, inorganic phosphate may cause vascular calcification directly through a real ""ossification"" of the tunica media in the vasculature of ESRD patients. The ""classical"" treatment of secondary hyperparathyroidism and hyperphosphatemia in ESRD patients consists of either calcium- or aluminum-based phosphate binders and calcitriol administration. Unfortunately, this ""old generation"" therapy is not free of complications. This review paper suggests that new calcium- and aluminum-free phosphate binders, such as lanthanum carbonate, can be used to treat hyperphosphatemia and secondary hyperparathyroidism in ESRD patients.
Abstract: Bisphosphonates are molecules derived from pyrophosphates,but, unlike pyrophosphates, they are resistant to enzymatic hydrolysis. Bisphosphonates are used in the treatment of Paget's disease, cancer-related osteolysis, myeloma, primary hyperparathyroidism, and osteoporosis. In dialysis patients bisphosphonates may be used to reduce bone pain due to renal osteodystrophy. We describe the case of a 60-year-old woman with a history of breast cancer who had been on dialysis for 8 years. She had been receiving clodronic acid at 100 mg per week intravenously for the last 2 years. A year ago, the patient underwent surgical extraction of the lower right second molar. Her jaw pain increased in the following days. An orthopanthograph and a CT scan of the head showed osteolysis, and a surgical osteotomy was performed. Histological examination led to a diagnosis of avascular osteonecrosis of the jaw. Avascular osteonecrosis is typically described in the jaw. In this case, prolonged bisphosphonate treatment may have worsened the osteonecrosis.
Abstract: 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.
Abstract: Since lanthanum carbonate has become available there has been much interest in its use as a non-calcium-containing phosphate binder, but also much speculation among scientists about possible aluminum-like toxicity. This Commentary focuses on the major aspects of this scientific controversy, confirming the safety and efficacy of this new phosphate binder.
Abstract: Background. The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of calcimimetics, phosphate binders, vitamin D and vitamin D analogues for treating secondary hyperparathyroidism in chronic kidney disease (CKD) is presented. Methods. SR of RCT and RCT on interventions for secondary hyperparathyroidism in CKD were identified referring to a Cochrane Library and Renal Health Library search (2005 update). Results. Three SR and 8 RCT were found addressing this intervention issue. Methodological quality of available RCT was suboptimal according to current methodological standards. Calcimimetics used in patients receiving haemodialysis or per-toneal dialysis are more effective than placebo in controlling secondary hyperparathyroidism (reduced parathyroid hormone levels, calcium levels and phosphorus levels). All phosphate binders are effective in controlling hyperphosphatemia but different doses are to be used with different agents to achieve similar targets. Dosing needs to be adjusted according to phosphorus levels. Vitamin D and its analogues are recommended in CKD patients, although there is no significant evience of superiority of individual agents in head-to-head comparisons. Dosing should be based on baseline parathyroid hormone levels, but the risk of hypercalcemia should also be considered. Conclusion. Available evidence suggests that calcimimetics, phosphate binders and vitamin D or its analogues are effective in the treatment of secondary hyperparathyroidism. Superiority of individual agents or doses is still deeply debated. Further studies are necessary to test these issues.
Abstract: Secondary hyperparathyroidism - a common comorbid condition in patients with chronic renal insufficiency - is considered a consequence of critical determinants such as hypocalcemia, phosphate retention and reduced levels of calcitriol production. In this complex mechanism, the skeletal apparatus and the nonskeletal targets such as vascular and heart valves are often involved, thus explaining the increased risk of cardiovascular morbidity and mortality of uremic patients. In this review we will focus on the major role played by Calcitriol deficiency as a trigger of secondary hyperparathyroidism and the crucial need for obiquitous vitamin D receptor activation in order to have an optimal PTH control and to obtain a modulation between inhibitors and inducers of soft tissue calcification. This review will also elucidate the possible role of paricalcitol - a new vitamin D analog - in conditioning morbidity and mortality of patients on renal replacement therapy (RRT).
Abstract: BACKGROUND: In patients on dialysis coronary artery calcification (CAC) rapidly proceeds due to impaired mineral metabolism and/or exogenous calcium load. Progression has not been assessed in patients with chronic kidney disease not yet requiring dialysis (CKD patients). In this study, rate and determinants of CAC progression have been evaluated in CKD patients who are exposed to minor derangement of mineral metabolism and calcium load. METHODS: Consecutive patients were enrolled. Exclusion criteria were: symptomatic coronary disease, arrhythmia, myocardial infarction, and diabetes. Serum calcium, phosphorus, parathyroid hormone, homocysteine, C-reactive protein, triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol were serially measured. Fetuin-A was assessed at entry into the study. CAC progression was detected by measuring total calcium score (TCS) with computed tomography. Initial and final scans were obtained. Predictive factors of progression were investigated. RESULTS: Fifty-three patients had CKD (stage 3-5 CKD; K-DOQI classification) not yet requiring dialysis, and 60 patients had normal renal function (NRF patients). Follow-up lasted 24 +/- 4.2 months (mean +/- SE). Patients with CAC were older with lower serum fetuin-A. TCS increased from 73 +/- 17 to 80 +/- 20 (mean +/- SE; p = NS) in NRF patients, and from 384 +/- 116 to 602 +/- 140 (mean +/- SE; p < 0.01) in CKD patients. Serum phosphorus [OR = 1.97 (1.14-3.41, 95% CI); p = 0.015] was the only variable that was associated with CAC progression. Cardiovascular events occurred in CKD patients with CAC. CONCLUSION: CAC progression was prominent in CKD patients and correlated with serum phosphorus. Fatal and nonfatal cardiovascular events were more frequent in CKD patients. Studies are required to ascertain whether the attainment of serum phosphorus concentration lower than that suggested by current guidelines may reduce CAC progression and ultimately mortality.
Abstract: Vascular calcification is a very common event in patients affected by diabetes and chronic kidney disease (CKD). Recently, it has been well documented that abnormalities in mineral and bone metabolism in CKD patients associate with increased morbidity and mortality. Elevated serum phosphate and calcium-phosphate product levels play an important role in the pathogenesis of vascular mineralization in uremic patients and also appear to be associated with increased cardiovascular mortality. Together with classical passive precipitation of calcium-phosphate in soft tissues, during the last decade it has been demonstrated that inorganic phosphate may cause extraskeletal calcification directly through a real "ossification" of the tunica media in the vasculature of CKD patients. Therefore, control of phosphate retention is now an even more crucial target of treatment in patients affected by chronic kidney disease. The "classical" treatment of secondary hyperparathyroidism and hyperphosphatemia in CKD patients consists of either calcium or aluminium based phosphate-binders and calcitriol administration. Unfortunately, this "old generation" therapy is not free of complications. Patents are also reported discussing the role of derivatives of Lanthanum carbonate hydrates are also used for the treatment of hyperphosphataemia in patients with renal failure. New calcium- and aluminium-free phosphate binders, such as sevelamer hydrochloride and lanthanum carbonate, can be used to treat hyperphosphatemia and secondary hyperparathyroidism, reduce atherosclerotic process, and prevent vascular calcification in CKD patients.
Abstract: 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.
Abstract: Pneumothorax is one of the most frequent complications during percutaneous central vascular cannulation. When choosing a site for central vascular access, the internal jugular vein is preferable to other vessels, for the lower frequency of related complications, including pneumothorax. This review intends to summarize the current state of the art on how to avoid and, if it occurs, to manage this rare but relevant complication. In order to prevent pneumothorax, as well as other relevant complications of central vein cannulation, it is advisable to use ultrasound guidance whenever possible. If pneumothorax occurs, it is important to recognize its signs and symptoms. To exclude the presence of asymptomatic pneumothorax, in the normal clinical routine a chest X-ray should be obtained within 4 hours from the procedure of central vein cannulation of subclavian and internal jugular veins. If promptly recognized, pneumothorax can be managed quickly and in a relatively easy way. Depending on its size and symptoms, and in particular when a tension pneumothorax is suspected, treatment can vary from simple observation to a chest tube insertion or, in the latter case, to an emergency thoracentesis needle insertion in the pleural space.
Abstract: Chronic kidney disease (CKD) patients have an higher incidence of cardiovascular morbidity and mortality compared with the general population. In the past 10 years, several studies pointed out that vascular calcification is a major cause of cardiovascular disease in the dialysis population. In CKD patients, high levels of serum phosphate and parathyroid hormone play a critical role in the pathogenesis of cardiovascular events. Calcium- and aluminum-free phosphate binders provide a new and effective therapeutic tool in preventing cardiovascular calcifications in CKD in animal models and in hemodialysis patients. Moreover, the pathogenesis of vascular and soft-tissue calcification, which traditionally has been associated with a passive calcium-phosphate deposition, certainly also is related to an active, cell-mediated process. In fact, some bone regulatory proteins seem to be able to induce or inhibit mineral deposition in the vasculature. In particular, bone matrix protein 7, alpha2-HS glycoprotein, and matrix GLA protein may be regulatory keys in preventing extraskeletal calcification in uremic conditions. This review presents the current understanding of the pathogenesis of vascular calcification in CKD patients, focusing on these 3 proteins and their protective action on extraskeletal calcification.
Abstract: 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.
Abstract: 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.
Abstract: BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality in hemodialysis (HD). An elevated incidence of cardiovascular calcifications (CVC) is observed in HD. Fetuin-A is an important inhibitor of CVC. Reduced fetuin-A levels associate with inflammation and increased cardiovascular (CV) mortality in HD. In this study we investigated the association of fetuin-A levels and CVC. METHOD: We evaluated a cohort of 115 patients (67 males), aged 63 +/- 16 years with a HD vintage >or=9 months. Presence of CVC was assessed by ultrasound imaging of the abdominal aorta, common carotid arteries, bilateral ilio-femoral axis, aortic and mitral cardiac valves. The presence of CVC was analyzed as a CVC score (CVCS) (0-7) according to the number of CVC sites. Patients were arbitrary stratified in three groups: group I (CVCS = 0), group II (0 < CVCS < 6) and group III (CVCS >or= 6). Patients without CVC were younger, non-diabetic and with a negative history for CV events. RESULTS: Patients with evidence of CVC in more than 5 sites had lower serum fetuin-A levels (0.41 +/- 0.22 g/l) compared to patients with CVCS = 0 (0.51 +/- 0.17 g/l, p = 0.048). In addition a worse CVCS was associated with higher serum levels of C-reactive protein (p = 0.002) and fibrinogen (p < 0.001). Serum fetuin-A levels lower than 0.290 g/l were associated with higher risk of a worse CVCS, independently from traditional risk factors. CONCLUSION: Chronic inflammation in HD patients leads to lower serum fetuin-A levels. The present study confirms the independent and significant association between reduced serum fetuin-A levels and multi-site CVC in HD.
Abstract: 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.
Abstract: Secondary hyperparathyroidism (HPTH) is a common feature in end-stage renal disease (ESRD) patients. The three main factors involved in secondary HPTH pathogenesis are high phosphate levels, hypocalcemia and vitamin D deficiency. Recently, many studies demonstrated a strong association between bone disease and cardiovascular events in chronic kidney disease patients. In addition, cardiovascular events are the most frequent cause of death in patients with chronic renal failure. Increased levels of serum phosphorus and calcium-phosphate product are directly involved in the pathogenesis of extraskeletal calcifications (blood vessels, soft tissues, etc) in dialyzed patients compared to the non-uremic population. Recent studies suggested that vascular calcification is due not only to a passive calcium-phosphate deposition on atherosclerotic arteries, but also to active mechanisms regulated by bone-associated genes. In particular, fetuin and matrix Gla-protein are two 'protective' proteins associated with reduced vascular calcification and could be the regulatory keys in preventing this process in renal failure. The limitations of calcium salts as phosphate-binders in patients with advanced renal failure have been thoroughly evaluated in the last 5 yrs. New phosphate binders, which do not contain aluminum or calcium, have been developed to reduce the risk of extraskeletal calcifications in ESRD.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: BACKGROUND: Uremic patients on regular dialytic treatment (RDT) are often affected by a complex metabolic syndrome leading to osteodystrophy. Bone changes are primarily due to high bone turnover, often combined with a mineralization defect leading to increased bone fractures and bone deformities. Although rarely considered, the craniofacial skeleton represents one of the peculiar targets of this complex metabolic disease whose more dramatic pattern is a form of leontiasis ossea. This complication, although described, has never been evaluated in depth nor quantitatively assessed. In order to assess facial deformities in uremic conditions and to understand the possible relation with hyperparathyroidism, we undertook a quantitative evaluation of soft facial structures in a cohort of uremic patients undergoing RDT. METHODS: The three-dimensional coordinates of 50 soft-tissue facial landmarks were obtained by an electromagnetic digitizer in 10 male and 10 female patients with chronic renal insufficiency aged 53-81 years, and in 34 healthy individuals of the same age, ethnicity and sex. Uremic patients were enrolled according to hyperparathyroid status (PTH < 300 pg/mL and PTH > 500 pg/mL). From the landmarks, facial distances, angles and volumes were calculated according to a geometrical face model. RESULTS: Overall, the uremic patients had significantly larger facial volumes than the reference subjects. The effect was particularly evident in the facial middle third (maxilla), leading to an inversion of the mandibular-maxillary ratio. Facial dimensions were increased in all three spatial directions: width (skull base, mandible, nose), length (nose, mandible), and depth (mid face, mandible). The larger maxilla was accompanied by a tendency to more prominent lips (reduced interlabial angle). Some of the facial modifications (nose, lips, mandible) were significantly related to the clinical characteristics of the patients (age, duration of renal insufficiency and PTH levels). CONCLUSIONS: This report, the first in the literature, shows that facial structures of uremic patients are enlarged in comparison with matched normal subjects and that increased bone turnover could be responsible--at least in part--for facial bone changes.
Abstract: Pathogenesis of vascular calcification in chronic kidney disease. Background. Hyperphosphatemia and hypercalcemia are independent risk factors for higher incidence of cardiovascular events in patients with chronic kidney disease. In addition to increased calcium-phosphate product, hyperphosphatemia accelerates the progression of secondary hyperparathyroidism with the concomitant bone loss, possibly linked to vascular calcium-phosphate precipitation. Results. The control of serum phosphate levels reduces vascular calcification not only by decreasing the degree of secondary hyperparathyroidism and calcium-phosphate product, but also by reducing the expression of proteins responsible for active bone mineral deposition in cells of the vasculature. The calcium and aluminum-free phosphate-binders provide a new and effective therapeutic tool in preventing vascular calcifications in chronic kidney disease in animal models and in hemodialysis patients. Conclusion. Additional investigations are necessary to examine the benefits of different phosphate-binders in reducing mortality from cardiovascular disease.
Abstract: Parathyroid gland growth is a major cause of secondary hyperparathyroidism in renal failure. It is well known that high serum phosphate levels, low serum calcium levels and vitamin D deficiency are the three promoters of parathyroid hyperplasia in renal failure. Recent studies have investigated in depth the potential role of growth factors (transforming growth factor alpha) and their receptors (epidermal growth factor receptor) in the pathogenesis of parathyroid cell hyperplasia in chronic renal failure. The identification of molecular mechanisms involved in calcium, phosphate and vitamin D manipulations in an experimental renal failure model could help design more effective therapy for secondary hyperparathyroidism in uremic patients.
Abstract: 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.
Abstract: 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.
Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Abstract: Elevated serum levels of parathyroid hormone (PTH) contribute to the increased morbidity and mortality in renal failure patients. Parathyroid gland hyperplasia is a major cause of high serum PTH. The present studies used the rat model of renal failure to address the mechanisms underlying uremia-induced parathyroid hyperplasia and the antiproliferative properties of vitamin D therapy (1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)) or its less calcemic analogs). Enhanced TGFalpha/EGFR co-expression is the major mitogenic signal in uremic parathyroid glands. At early stages of renal failure, vitamin D therapy efficiently counteracts uremia- and high phosphorus-induced hyperplasia by inhibiting the increases in parathyroid-TGFalpha/EGFR co-expression. In established hyperparathyroidism, characterized by highly enhanced-TGFalpha/EGFR co-expression, vitamin D therapy arrests growth by suppressing EGFR-growth signals from the plasma membrane and nuclear EGFR actions as a transactivator of the cyclin D1 gene, an important contributor to parathyroid hyperplasia in humans. In advanced renal failure, reduced-parathyroid vitamin D receptor levels limits the antiproliferative efficacy of vitamin D therapy. However, non-antiproliferative doses of 1,25-dihydroxyvitamin D enhance the anti-EGFR actions of EGFR-tyrosine kinase inhibitors (TKI). In fact, combined 1,25-dihydroxyvitamin D/TKI therapy inhibits parathyroid hyperplasia more efficiently than phosphorus restriction, the most powerful promoter of parathyroid growth arrest available at present.
Abstract: BACKGROUND: A high prevalence of bone demineralization occurs in people living with HIV/AIDS. The contribution of HIV itself and its treatment is still unclear. Protease inhibitors (PIs) are potent inhibitors of the cytochrome p450 enzyme system. Three cytochrome p450 mixed function oxygenases control serum levels of 1,25-dihydroxyvitamin D (1,25(OH) D ), which is responsible for vitamin D actions in target tissues including bone. The 25- and 1alpha-hydroxylases regulate 1,25(OH) D synthesis and 24-hydroxylase 1,25(OH) D catabolism. OBJECTIVE: To assess whether HIV-protease inhibitors (ritonavir, indinavir, nelfinavir) impair the activity of the main enzymes involved in 1,25(OH) D homeostasis. DESIGN AND METHODS: Studies were conducted in the human hepatocyte (H3B)- and monocyte (THP-1) cell lines, expressing 25-hydroxylase and 1alpha-hydroxylase, respectively. The 24-hydroxylase expression was induced in macrophages by exposure to 1,25(OH) D. Conversion rates of vitamin D to 25-hydroxyvitamin D [25(OH)D ]; 25(OH)D to 1,25(OH) D or 24,25(OH) D, and 1,25(OH) D degradation were quantified in untreated and HIV-PI-treated cells after C -cartridge extraction and high-performance liquid chromatography purification of 25(OH)D - 24,25(OH) D - and 1,25(OH) D fractions. RESULTS: The PIs impair hepatocyte 25(OH)D - and macrophage 1,25(OH) D synthesis in a reversible, dose-dependent manner. Furthermore, PIs inhibit 1,25(OH) D -degradation in macrophages with lower potency than that elicited on 1alpha-hydroxylase. Thus, reduced macrophage 1,25(OH) D production is the net effect of PIs action. CONCLUSIONS: In intact cells, HIV-PIs markedly suppress the activities of 25- and 1alpha-hydroxylase, which are critical in 1,25(OH) D synthesis, while exerting mild inhibition of 24-hydroxylase, responsible for 1,25(OH) D catabolism. If PIs elicit a similar potency in inhibiting these critical steps for 1,25(OH) D homeostasis, defective 1,25(OH) D production could contribute to the bone demineralization in HIV patients.
Abstract: AIMS: The reversibility of extraskeletal calcifications in dialysis patients is an important and unresolved issue. Although periarticular calcifications have been shown to be reversible, little data are available on vascular or parenchymal calcifications. CASE HISTORY: A patient on maintenance hemodialysis with severe hyperparathyroidism, hypercalcemia and hyperphosphatemia was admitted to undergo parathyroidectomy. A preoperative total body bone scintigraphy was performed to better evaluate a lytic lesion in the pelvis, the histology of which proved to be a "brown tumor". The scan showed the typical findings of renal osteodystrophy, but also a diffuse extra-skeletal uptake of bone tracer in the lungs, kidneys, femoral arteries and myocardium. After surgery, good control of serum calcium, phosphate (Ca x P product < 50 mg2/dl2) and PTH levels was maintained during 4 years of follow-up. Bone scans were repeated after 2 and 4 years, showing marked improvement of periarticular uptake at the ends of long bones. Extraosseous calcium deposition was still markedly evident, but progressively decreased (at 4 years: heart -36%, lungs -18%). CONCLUSION: In this dialysis patient, extraskeletal calcification of visceral organs (particularly in the heart and the lungs) due to prolonged hypercalcemia and hyperphosphatemia was partially reversible by parathyroidectomy followed by good long-term control of serum phosphate and calcium.
Abstract: BACKGROUND: The control of parathyroid hyperplasia and high circulating parathyroid hormone (PTH) levels is crucial in preventing secondary hyperparathyroidism (SH) in renal failure. Parathyroid gland enlargement and elevated levels of PTH are major contributors to increase bone resorption, a feature of renal osteodystrophy. METHODS: These studies assessed the efficacy of the 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (19-Nor), in the prevention (protocol I) and treatment (protocol II) of SH and renal osteodystrophy in uremic rats. In protocol I, normal and uremic rats were fed a high phosphorus diet for 2 months; uremic rats were administered intraperitoneal injections of either vehicle or 19-Nor (200 ng three times a week). In protocol II, normal and uremic rats were fed a high phosphorus diet for 4 months; 2 months after the onset of uremia, rats were administered either intraperitoneal vehicle or 19-Nor (200 ng three times a week). Serum PTH and bone histology were used to assess the degree of SH. RESULTS: 19-Nor was effective in preventing (protocol I) and suppressing (protocol II) the significant SH induced by uremia and further enhanced by a high phosphorus diet. In protocol I, bone histology in uremic controls showed a threefold increase in the cancellous bone mass compared to normal rats. This expansion in unmineralized bone was accompanied by 5-, 1.5-, and 7-fold increases in eroded surface, mineralization lag time (MLT), and bone formation rate (BFR/BS), respectively. Moreover, cortical bone porosity in untreated uremic rats increased 267-fold compared to normal animals. 19-Nor ameliorated these changes in cancellous and cortical bone. In protocol II, the reported indices worsened even further. In contrast, 2 months of 19-Nor treatment improved bone histology by reducing cortical bone porosity, woven bone formation, MLT, and BFR/BS. CONCLUSION: In an experimental model of chronic renal failure (CRF), 19-Nor prevents SH and ameliorates the histomorphometric changes induced by uremia and high phosphorus diet. In addition, 19-Nor suppresses serum PTH and improves bone histology in uremic rats with established severe SH. Further studies in patients with CRF are necessary to define the clinical applicability of 19-Nor on bone histology in humans.
Abstract: The management of secondary hyperparathyroidism is of crucial importance in the treatment of end stage renal disease (ESRD) patients. In particular, hypercalcemia, hyperphosphatemia, and elevated calcium x phosphate (Ca x P) product should be taken into consideration during administration of vitamin D metabolites for the control of PTH secretion. During the last 10 years, many authors have been studying the efficacy of new non-calcemic vitamin D analogs on suppressing secondary hyperparathyroidism in ESRD patients. In this brief review, we analyzed three new vitamin D analogs: 22-oxacalcitriol (Maxacalcitriol), 19-nor-1a, 25(OH)2D2 (Paracalcitriol), and 1a (OH)2D2 (Doxacalciferol). In addition, calcimimetic agents may represent a new pharmacologic choice to the treatment of secondary hyperparathyroidism, binding parathyroid calcium sensing receptors (CaSR) and reducing PTH secretion. These compounds may represent an important tool for the treatment of both secondary hyperparathyroidism and soft tissue calcifications in ESRD patients. In conclusion, a combined use of non calcemic phosphate binders, new vitamin D analogs and calcimimetics should be seriously considered to further improve the already known therapy of secondary hyperparathyroidism in ESRD patients.
Abstract: BACKGROUND: In chronic renal failure (CRF), hyperphosphatemia and an elevated calcium-phosphate product are associated with vascular calcification and increased cardiovascular morbidity and mortality. Previous data have demonstrated that 3-month treatment of uremic rats with sevelamer was associated with less nephrocalcinosis compared to calcium carbonate (CaCO3), despite similar control of serum phosphorus, calcium-phosphorus product (Ca x P product), and secondary hyperparathyroidism. There was no evidence of aortic calcification after 3 months of uremia (J Am Soc Nephrol 13:2299-2308, 2002). The present studies explore the influence of sevelamer and CaCO3 on cardiovascular and kidney calcifications in long-term experimental uremia over 6 months. METHODS: Normal and 5/6 nephrectomized rats (U) were fed a high phosphorus (HP) diet for 6 months. Two phosphate binders, CaCO3 and sevelamer, were administered and their influence on hyperphosphatemia, secondary hyperparathyroidism, kidney/myocardial/aortic calcification, and renal function was compared. RESULTS: All uremic rats began the study with the same degree of renal failure. Sevelamer was as effective as CaCO3 in reducing serum phosphorus, Ca x P product, and attenuating secondary hyperparathyroidism. Despite similar serum cholesterol levels, rats in the U-HP + sevelamer group had markedly lower calcium deposition in the myocardium and aorta (myocardium, 72 +/- 4 microg/g wet tissue; aorta, 736 +/- 156 microg/g wet tissue) compared to rats in either the U-HP + CaCO3 group (myocardium, 179 +/- 48, P < 0.05; aorta, 1308 +/- 343, P < 0.05) or the U-HP group (myocardium, 98 +/- 10, NS; aorta, 2150 +/- 447, P < 0.05). Dual immunohistochemical analysis for calcium and endothelial cell markers demonstrated that myocardial calcium deposition was intravascular within capillaries. Furthermore, calcium deposition in the kidney of uremic rats treated with sevelamer (582 +/- 111 microg/g wet tissue) was lower than that found in uremic rats treated with CaCO3 (1196 +/- 180 microg/g wet tissue). Sevelamer-treated rats had less deterioration in renal function with an associated lower serum creatinine, higher creatinine clearance, and less proteinuria. There was no difference in overall mortality between the three experimental groups. CONCLUSION: In long-term experimental CRF, in addition to controlling serum phosphorus and secondary hyperparathyroidism as efficiently as CaCO3, treatment with the phosphate-binder sevelamer attenuates vascular and kidney calcification.
Abstract: 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.
Abstract: 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.
Abstract: Chronic renal failure is often complicated by altered calcium and phosphate omeostasis. Many patients develop secondary hyperparathyroidism during the course of the disease. Therefore, both prevention and treatment of secondary hyperparathyroidism are central issues in the treatment of uremic patients. Active vitamin D metabolites are important agents in uremic patients, who have a defective activity of the renal 1alpha-hydroxylase responsible for calcitriol synthesis. Howewer, treatment with calcitriol has some limitations, namely an increase in intestinal phosphate absorption, a possible calcium overload and therefore an increase in CaxP ion product. These limitations stimulated an active research on the development of vitamin D analogs with reduced effects on intestinal transport as well as on bone mobilization of calcium and phosphate. Three vitamin D analogs, which have been used in humans, are reviewed in this article: 22-oxacalcitriol (Maxacalcitol), 19-nor-1alpha,25(OH)2 vitamin D2 (Paricalcitol), and 1alpha(OH) Vitamin D2 (Doxercalciferol). In addition, a new pharmacologic approach to the treatment of secondary hyperparathyroidism has been developed: the use of agonists for the parathyroid calcium sensing receptor, or calcimimetics. AMG O73, a second generation agent, is now under clinical evaluation in phase 3 studies, and it will soon be available in clinical practice. Given the different mechanism of action, it will be possible to use it along with vitamin D analogs and non calcemic phosphate binders. A broader spectrum of therapeutic approaches will enable the nephrologist to individually tailor the treatment of secondary hyperparathyroidism.
Abstract: BACKGROUND: Calcitriol, 1,25-(OH)(2)D(3) (1,25D), the most active metabolite of vitamin D, has been used in the treatment of secondary hyperparathyroidism (SH) because it controls parathyroid gland growth and suppresses parathyroid hormone (PTH) synthesis and secretion. Due to the calcemic and phosphatemic actions of 1,25D, two analogs with potentially less side effects, 19-nor-1,25-(OH)(2)D(2) (19-nor) and 1alpha(OH)D(2) (1alphaD(2)) are currently being used in the treatment of SH. METHODS: This study compares the effects of these two analogs on calcium (Ca) and phosphorus (P) metabolism in normal, uremic, and parathyroidectomized (PTX) rats. Using doses of 50 to 250 ng of 19-nor or 1alphaD(2), experiments were conducted in normal and uremic rats. RESULTS: In uremic rats, 19-nor did not increase plasma Ca or P while 1alphaD2 caused a dose-dependent increase in both. In addition, while the Ca x P product remained unchanged in 19-nor-treated rats, it increased progressively with 1alphaD(2)administration. In metabolic studies in normal rats treated with vehicle, 10 ng of 1,25D, 100 ng of 19-nor or 100 ng 1alphaD(2), intestinal calcium absorption and urinary calcium excretion were significantly higher in 1alphaD(2)-treated rats compared to those receiving 19-nor. Similar results were seen for intestinal phosphorus absorption and urinary phosphorus excretion. Finally, the skeletal response to these two analogs was tested in PTX rats fed a calcium-deficient diet and treated daily with 100 ng of 19-nor or 1alphaD(2). The increase in plasma calcium in 1alphaD2-treated rats was markedly higher than in those receiving 19-nor. Similar results were seen in plasma phosphorus when these studies were repeated using a phosphorus-deficient diet. CONCLUSIONS: These studies demonstrate that when given in large doses to rats 19-nor is less calcemic and phosphatemic than 1alphaD(2). The lower Ca x P product in 19-nor treated rats may be an important consideration in patient therapy. Further studies in patients are necessary to define the clinical applicability of these differences.
Abstract: BACKGROUND: Sevelamer HCl, a non-aluminum, non-calcium containing hydrogel, has proved an effective phosphate binder in North American hemodialysis patients. This single-center, open-label, dose titration study assessed the efficacy of sevelamer in a cohort of European hemodialysis patients with different dietary habits, in particular with lower phosphate intake. The aim of the study was to obtain a calcium x phosphate product lower than 60 mg2/dL2 in all patients. METHODS: Administration of calcium- or aluminum-based phosphate binders was discontinued during a two-week washout period. Nineteen patients whose serum phosphate level at the end of washout was greater than 5.5 mg/dL (1.78 mmol/L) qualified to receive sevelamer for six weeks. Based on the degree of hyperphosphatemia during washout, patients were started on 403 mg sevelamer capsules with a dose schedule different from previous studies. Only one capsule was administered at breakfast, and the rest of the phosphate binder was divided equally at the two main meals. Sevelamer could be increased by two capsules per day every two weeks, if necessary. A second two-week washout period followed. RESULTS: Mean serum phosphorus rose from a baseline of 5.3 +/- 1.0 to 7.4 +/- 1.4 mg/dL at the end of washout, then declined to 5.4 +/- 0.8 mg/dL (p < 0.001) by the end of the six-week treatment period and rebounded significantly to 7.1 +/- 1.1 mg/dL after the second two-week washout. Calcium x phosphate product showed a similar pattern, decreasing significantly from 64.1 +/- 14.1 to 46.9 +/- 7.4 mg2/dL2 (p < 0.001) after six weeks of sevelamer. A level of less than 50 mg2/dL2 was reached by 68% of patients, and 95% had less than 60 mg2/dL2. The mean dose of sevelamer at the end of treatment was 3.1 +/- 0.6 g per day. As expected, calcium declined from 9.2 +/- 0.5 to 8.7 mg/dL (p < 0.01) during the initial washout after stopping calcium-based phosphate binders, but remained stable thereafter. Ionized calcium did not change significantly throughout the washout and sevelamer treatment. However, interruption of calcium salts led to a 81% reduction of total calcium intake. CONCLUSIONS: We confirmed in an European sample of hemodialysis patients that sevelamer can reduce phosphate levels without inducing hypercalcemia. The drug can also be successfully used to reduce mean calcium x phosphate levels below 50 mg2/dL2, closer to normal values. Although similar results can be obtained with other phosphate binders, a concomitant accumulation of aluminum, calcium or magnesium could be detrimental to patients.
Abstract: BACKGROUND: High dietary phosphorus (P) worsens uremia-induced parathyroid (PT) hyperplasia through increases in the growth promoter transforming growth factor-alpha (TGF-alpha). In contrast, P restriction prevents PT hyperplasia by inducing the cell cycle inhibitor p21. Since 1,25(OH)2D3-antiproliferative action in various cell types involve increases in p21, we studied whether induction of p21 by 1,25(OH)2D3 or the vitamin D analog, 19-Nor-1,25(OH)2D2, could counteract the PT hyperplasia induced by high dietary P in early uremia. METHODS: Normal (N) and uremic (U; 5/6 nephrectomized) female Sprague-Dawley rats were fed high P (HP), low P (LP) or high Ca (HCa) diets and administered intraperitoneally (IP) either vehicle or vitamin D metabolites for seven days, as follows: N-HP; U-HP + vehicle; U-HP + 1,25(OH)2D3 (4 ng/day); U-HP + 19-Nor-1,25(OH)2D2 (30 ng/day); U-LP; U-HCa. Serum PTH and PT gland weight assessed secondary hyperparathyroidism. Immunohistochemical quantitation of two markers of mitotic activity, Ki67 and PCNA measured PT hyperplasia. Immunohistochemical expression of PT p21 and TGF-alpha addressed potential mechanisms regulating PT cell growth. RESULTS: 1,25(OH)2D3 and 19-Nor-1,25(OH)2D2 were effective in suppressing both PTH secretion and PT hyperplasia induced by uremia and high dietary P independent of increases in ionized Ca. Both vitamin D compounds enhanced PT p21 expression and prevented high P-induced increases in PT TGF-alpha content. Induction of PT p21 and reduction of TGF-alpha content also occurred when uremia-induced PT hyperplasia was suppressed by high dietary Ca. CONCLUSIONS: In early uremia, vitamin D suppression of high P-induced PT hyperplasia and high dietary Ca arrest of PT growth involve induction of PT p21 and prevention of increases in TGF-alpha.
Abstract: BACKGROUND: Administration of intravenous (i.v.) calcitriol three times weekly effectively controls the synthesis and secretion of PTH in most uremic patients. Administration of a single dose of 1.25(OH)2D3 reduces synthesis of PTH-mRNA for 6 days in rats. Moreover, it can lower PTH levels for up to 4 days in chronic hemodialysis patients. Therefore, a good response to the administration of i.v. calcitriol two times weekly can be expected. We studied - in a multicenter randomized study in patients with moderate to severe secondary hyperparathyroidism - the effects of the same doses of intravenous calcitriol, administered two or three times weekly. METHODS: Twenty-two hemodialysis patients were randomized into two frequencies of treatment groups: two times (G-2/w) and three times weekly (G-3/w). Both groups were treated with increasing doses of intravenous calcitriol for 3 months (first month 3 microg, second month 4 microg, third month 6 microg weekly). RESULTS: After 12 weeks of therapy with intravenous calcitriol the G-2/w group showed a significant reduction in serum PTH levels (from 821 +/- 392 to 350 +/- 246 pg/ml; mean reduction = 57.4%) comparable to the decrease observed in the G-3/w group (from 632 +/- 116 to 246 +/- 190 pg/ml; mean reduction = 61.2%). Ionized calcium (G-2/w from 1.13 +/-0.10 to 1.14 +/- 0.08 and G-3/w 1.21 +/- 0.13 to 1.26 +/- 0.18 mmol/l) and phosphate levels (G-2/w from 4.99 +/- 1.01 to 5.99 +/- 1.78 and G-3/w 5.31 +/- 0.73 to 5.81 +/- 1.18 mg/dl) did not change significantly and phosphate binders were not modified during the study. CONCLUSION: This study confirms that intravenous calcitriol is an effective therapy for moderate to severe secondary hyperparathyroidism. The administration of two doses per week of intravenous calcitriol is as efficacious as three doses per week in suppressing PTH secretion.
Abstract: Rifampicin is one of the most effective antibiotics used for the treatment of tuberculosis and severe staphylococcal infections. Intermittent administration of high doses of rifampicin has been associated with frequent adverse reactions, including hepatotoxicity and nephrotoxicity, sometimes resulting in acute renal failure. We describe a case of rifampicin-associated acute renal failure, with biopsy findings of tubulointerstitial nephritis; inflammatory cells were characterized by immunohistochemistry, which showed immunoreactivity for CD3 and CD5 (T lymphocytes) and for CD68 (macrophages). The patient presented with a very rapid systemic reaction to the offending drug and rapid deterioration of renal function, which required dialysis treatment. The response to rifampicin discontinuation was excellent: no further therapy was required, as renal function began to improve within several days and returned to normal values (serum creatinine 1.17 mg/dl) seven months after the onset of symptoms. When prescribing rifampicin the physician should investigate previous use of the drug, because re-exposure is a critical factor in predicting the possibility of drug-induced acute renal failure.
Abstract: Internal jugular vein cannulation has become a routine and clinically important aspect of medical care of critically ill patients. The landmark guided technique usually affords rapid and easy vascular access, but is not always successful and may be complicated by arterial puncture, hematoma, or pneumothorax. Some categories of patients, in particular patients with no external landmarks and patients with coagulopathies, appear to be at an increased risk of complications. We report the experience of internal jugular vein cannulation by a single operator with the external landmark technique in 10 patients and with ultrasound guidance in 31 patients, including 12 high risk patients. These patients had severe coagulopathies due to hepatic failure, HELLP syndrome, excess of anticoagulation treatment, or they had no external anatomic landmarks because of anasarca or obesity, were unable to maintain the horizontal position, or were external landmark catheterization failures. With the availability of the ultrasound device, success and complication rates improved markedly, suggesting that the ultrasound technique is easy to learn and rapidly produces an improvement over the external landmark method. In particular the 13 cannulations performed in 12 high risk patients were all successful at the first attempt, with no complications. In the overall population successful cannulations improved from 80% to 100%, first attempt success from 20% to 87% and carotid punctures decreased from 33% to 3.2%. Our results confirm that ultrasound guided cannulation of the internal jugular vein allows safer operation in high risk patients or when access problems are anticipated.
