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The choice of the dialysate calcium concentration in the management of patients on haemodialysis and haemodiafiltration.

The choice of an appropriate dialysate calcium (Ca) concentration is crucial in the management of dialysis patients: an excessive Ca load has been associated with vascular calcifications, whereas Ca depletion can worsen secondary hyperparathyroidism (HPT) and decrease bone mass. In haemodialysis (HD), Ca transfer by diffusion depends on the concentration gradient between dialysate and blood, and a gain of Ca is expected when the dialysate Ca is >1.5 mmol/l. However, Ca losses by convective transport (ultrafiltration rate) can even exceed the amount of Ca gained by diffusion. Dialysis Ca balances, in normocalcaemic patients with a mean weight loss of 2-4 kg per session, have been shown to be positive, moderately negative or clearly negative using a dialysate Ca of 1.75, 1.50 or 1.25 mmol/l, respectively. Serum ionized Ca increases during sessions with a dialysate Ca of 1.5 and 1.75mmol/l, and decreases to the lower limits of normal after HD with 1.25 mmol/l. In haemodiafiltration (HDF), Ca mass transfer is strongly affected by the Ca content in the replacement solutions. Bicarbonate-containing bags are Ca free so that dialysate Ca needs to be increased above 1.75 mmol/l to overcome the convective losses and avoid markedly negative balances. Ca mass transfer in HDF is also affected by the infusion mode. Ca balance in post-dilution HDF, for a given concentration gradient between blood and dialysate, does not differ from HD. Conversely, in pre-dilution HDF, dialysate Ca concentration should be increased by approximately 0.25 mmol/l to maintain comparable balances. A given dialysate Ca concentration should be prescribed considering the dialysis Ca mass balance, other concomitant therapies (Ca salts, vitamin D metabolites) and the type of bone disease. The current strategy of maintaining normal Ca levels by ensuring an adequate intestinal Ca absorption with large doses of Ca-containing phosphate binders and concomitantly avoiding positive Ca balances from dialysis by using a low Ca dialysate has been questioned recently because of the risk of either worsening HPT or accelerating the progression of vascular calcifications. A dialysate Ca of 1.5 mmol/l seems to be suitable for the majority of patients on HD or post-dilution on-line HDF because the moderately negative dialysis balances can be easily counterbalanced by the administration of mild doses of Ca-containing phosphate binders in order to ensure a neutral total body Ca balance. If necessary, aluminium-free and Ca-free binders can be added to achieve a satisfactory control of hyperphosphataemia, while avoiding an excessive Ca load.

Calcium↗

Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification.

OBJECTIVE: Mineralization-regulating proteins are found deposited at sites of vascular calcification. However, the relationship between the onset of calcification in vivo and the expression of genes encoding mineralization-regulating proteins is unknown. This study aimed to determine the temporal and spatial pattern of expression of key bone and cartilage proteins as atherosclerotic calcification progresses. METHODS AND RESULTS: Using reverse transcription-polymerase chain reaction on a panel of noncalcified and calcified human arterial samples, two classes of proteins could be identified: (1) Matrix Gla protein, osteonectin, osteoprotegerin, and aggrecan were constitutively expressed by vascular smooth muscle cells (VSMCs) in the normal vessel media but downregulated in calcified arteries whereas (2) alkaline phosphatase, bone sialoprotein, osteocalcin, and collagen II were expressed predominantly in the calcified vessel together with Cbfa1, Msx2, and Sox9, transcription factors that regulate expression of these genes. In the calcified plaque in situ hybridization identified subsets of VSMCs expressing osteoblast and chondrocyte-like gene expression profiles whereas osteoclast-like macrophages were present around sites of calcification. CONCLUSIONS: These observations suggest a sequence of molecular events in vascular calcification beginning with the loss of expression by VSMCs, of constitutive inhibitory proteins, and ending with expression by VSMCs and macrophages of chondrocytic, osteoblastic, and osteoclastic-associated proteins that orchestrate the calcification process.

Calcinosis↗

[Management of hyperphosphoremia].

Phosphorus is involved in the pathogenesis of hyperparathyroidism in Chronic Renal Failure (CRF) and in extra-osseous calcifications. Therefore, it is directly related with the morbi-mortality of these patients. The control of phosphorus is of the utmost importance and is often extremely difficult to achieve. A quick overview of the drugs that can bind phosphorus is given in this paper. Iron salts are beginning to come through as a viable possibility in the near future; nevertheless, calcium salts continue to be the most widespread. The problem is the ease with which a positive calcium balance can be produced, as extra-osseous calcifications (and above all, vascular calcifications) can appear and morbid-mortality increases. As a result of all this, calcium-free binders such as lanthanum carbonate and sevelamer are eagerly awaited. The lanthanum is as of yet little and not very well known. Sevelamer possesses good phosphorus-binding properties, as it is insoluble, does not cause intestinal degradation, does not contain traces of other elements and its use has few side effects. Long-term studies and accumulated experience have demonstrated its efficacy as a binder, plus additional advantages such as an improvement in the lipid profile, with a decrease in LDL--and an increase in HDL-cholesterol. As to whether these new binders--or any other compounds that could appear-will be of any real use only time will tell.

Calcinosis↗

Cervical paraspinal calcification in collagen vascular diseases.

Although soft-tissue calcification is common in collagen vascular disease, paraspinal calcification in the cervical spine has not been described before. We studied five women with large, lobulated, predominantly homogeneous calcific masses centered on synovial articulations in the neck. Changes consisting of either osteolysis or erosions were evident. All patients had radiculopathy, focal pain, or stiffness. In two patients, the presence of hydroxyapatite crystals was confirmed on biopsy. Symptomatic cervical paraspinal calcifications in patients with collagen vascular disease cause large soft-tissue masses that mimic tumoral calcinosis.

Aged↗

Fatal soft tissue calcification in suckling puppies.

Renal, pulmonary and vascular calcification was observed in 2 suckling puppies. The lesions were similar to those associated with hypervitaminosis D and possibly hypervitaminosis A. It was suspected that high contents of vitamin D and A in the diet of the lactating bitch had elevated the activity of these vitamins in the milk to levels toxic for the suckling puppies.

Animal Population Groups↗

Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease.

CONTEXT: Calcium deposits in coronary and extracoronary arterial beds may indicate the extent of atherosclerosis. However, the incremental predictive value of vascular calcification, beyond traditional coronary risk factors, is not clearly established. OBJECTIVE: To evaluate risk factors for aortic arch calcification and its long-term association with cardiovascular diseases in a population-based sample. DESIGN AND SETTING: Cohort study conducted at a health maintenance organization in northern California. PARTICIPANTS: A total of 60,393 women and 55,916 men, aged 30 to 89 years at baseline who attended multiphasic health checkups between 1964 and 1973 and for whom incidence of hospitalizations and/or mortality data were ascertained using discharge diagnosis codes and death records through December 31, 1997 (median follow-up, 28 years). MAIN OUTCOME MEASURE: Hospitalization for or death due to coronary heart disease, ischemic stroke, hemorrhagic stroke, or peripheral vascular disease, as associated with aortic arch calcification found on chest radiograph at checkup from 1964-1973. RESULTS: Aortic arch calcification was present in 1.9% of men and 2.6% of women. It was independently associated with older age, no college education, current smoking, and hypertension in both sexes, but it was inversely related to body mass index and family history of myocardial infarction. In women, aortic arch calcification was also associated with black race and elevated serum cholesterol level. After adjustment for age, educational attainment, race/ethnicity, cigarette smoking, alcohol consumption, body mass index, serum cholesterol level, hypertension, diabetes, and family history of myocardial infarction, aortic arch calcification was associated with an increased risk of coronary heart disease (in men, relative risk [RR], 1.27; 95% confidence interval [CI], 1.11-1.45; in women, RR, 1. 22; 95% CI, 1.07-1.38). Among women, it was also independently associated with a 1.46-fold increased risk of ischemic stroke (95% CI, 1.28-1.67). CONCLUSION: In our population-based cohort, aortic arch calcification was independently related to coronary heart disease risk in both sexes as well as to ischemic stroke risk in women. JAMA. 2000;283:2810-2815

Adult↗

Decrease in thoracic vertebral bone attenuation with calcium-based phosphate binders in hemodialysis.

UNLABELLED: We performed a post hoc analysis of a 52-week randomized trial conducted in adult hemodialysis patients that compared the effects of calcium-based phosphate binders and sevelamer, a nonabsorbable polymer, on parameters of mineral metabolism and vascular calcification by electron beam tomography. In this analysis, we evaluated the relative effects of calcium and sevelamer on thoracic vertebral attenuation by CT and markers of bone turnover. Subjects randomized to calcium salts experienced a significant reduction in trabecular bone attenuation and a trend toward reduction in cortical bone attenuation, in association with higher concentrations of serum calcium, lower concentrations of PTH, and reduced total and bone-specific alkaline phosphatase. INTRODUCTION: In patients with chronic kidney disease, hyperphosphatemia is associated with osteodystrophy, vascular and soft tissue calcification, and mortality. Calcium-based phosphate binders are commonly prescribed to reduce intestinal phosphate absorption and to attenuate secondary hyperparathyroidism. Clinicians and investigators have presumed that, in hemodialysis patients, calcium exerts beneficial effects on bone. MATERIALS AND METHODS: We performed a post hoc analysis of a 52-week randomized trial conducted in adult hemodialysis patients that compared the effects of calcium-based phosphate binders and sevelamer, a nonabsorbable polymer, on parameters of mineral metabolism and vascular calcification by electron beam tomography. In this analysis, we evaluated the relative effects of calcium and sevelamer on thoracic vertebral attenuation by CT and markers of bone turnover. RESULTS AND CONCLUSIONS: The average serum phosphorus and calcium x phosphorus products were similar for both groups, although the average serum calcium concentration was significantly higher in the calcium-treated group. Compared with sevelamer-treated subjects, calcium-treated subjects showed a decrease in thoracic vertebral trabecular bone attenuation (p = 0.01) and a trend toward decreased cortical bone attenuation. More than 30% of calcium-treated subjects experienced a 10% or more decrease in trabecular and cortical bone attenuation. On study, sevelamer-treated subjects had higher concentrations of total and bone-specific alkaline phosphatase, osteocalcin, and PTH (p < 0.001). When used to correct hyperphosphatemia, calcium salts lead to a reduction in thoracic trabecular and cortical bone attenuation. Calcium salts may paradoxically decrease BMD in hemodialysis patients.

Aged↗

Arterial calcification in mice after freeze-thaw injury.

Vascular calcification is highly correlated with atherosclerosis and cardiovascular disease and is a significant predictor of cardiovascular morbidity and mortality. Studies in mice indicate a genetic contribution to this dystrophic extra osseous calcification. We sought to elaborate a method to induce dystrophic arterial calcification in mice and further examine the pathogenetical mechanisms involved in the phenotype. We established a method of freeze-thaw injury of the infrarenal aorta producing a limited tissue necrosis and histologically investigated the occurrence of dystrophic calcification within the aortic wall 1, 3 and 7 days after injury in C57BL/6 (a mouse strain shown to be resistant to dystrophic cardiac calcification after injury) and C3H/He (susceptible to dystrophic cardiac calcification). C57BL/6 mice exhibited no dystrophic calcification at all within the vessel wall upon injury of the infrarenal aorta (0/5 mice 1 day after injury and 0/10 animals 7 days after injury). By contrast C3H/He mice displayed a remarkable extent of calcification mainly present within the media of the infrarenal aorta which was evident as early as 24 h (three out of five animals 1 day after injury) and reached its maximum extent 7 days after injury (10 out of 10 animals at the seventh postoperative day, p<0.001 compared to C57BL/6 mice). Upon immuno-histological analysis calcification was accompanied by the occurrence of certain bone-matrix associated proteins. Osteopontin and Bone Morphogenetic Protein 2/4 expression was detected co-localized with the calcified lesions. Our results demonstrate that freeze-thaw injury of the infrarenal aorta is a sufficient method to induce dystrophic arterial calcification in mice. We present evidence that the occurrence of arterial calcification in C3H/He mice seems to be actively regulated by certain bone-matrix associated proteins.

Animals↗

Homocysteine potentiates calcification of cultured rat aortic smooth muscle cells.

Aortic calcification was demonstrated in experimental animal models of hyperhomocysteinemia. Mild hyperhomocysteinemia was associated with aortic calcification, suggesting a relationship between homocysteine (HCY) and the pathogenesis of aortic calcification. In the present study, the effect of HCY on vascular calcification was examined in calcifying and non-calcifying vascular smooth muscle cells (VSMCs). Cell calcification was induced by incubation of VSMCs with beta-glycerophosphate. Proliferation of VSMCs was studied by cell counting, 3H-thymidine (3H-TdR) and 3H-leucine (3H-Leu) incorporation. 45Ca accumulation, cell calcium content, and alkaline phosphatase (ALP) activity were measured as indices of calcification. The results showed that the proliferation of calcifying VSMCs, which was indicated by cell counting, 3H-TdR and 3H-Leu incorporation in calcifying VSMCs, was enhanced as compared with that of non-calcifying VSMCs. HCY promoted increases in cell number, 3H-TdR and 3H-Leu incorporation in both calcifying and non-calcifying VSMCs, but with more prominent effect in calcifying VSMCs. The stimulating effects of HCY on the three parameters in calcifying VSMCs were antagonized by PD98059, a specific inhibitor of mitogen activated protein kinase kinase (MAPKK). The ALP activity, 45Ca uptake, and calcium deposition in the calcifying VSMCs were greater than those in non-calcifying VSMCs. PD98059 had no effect on ALP activity, 45Ca uptake, and calcium deposition in calcifying VSMCs. HCY caused marked increases in 45Ca uptake and calcium deposition both in calcifying and non-calcifying VSMCs. HCY, however, enhanced ALP activity in the calcified VSMCs but not in the non-calcifying VSMCs. The non-calcifying VSMCs treated with HCY showed the same low ALP activity, as did the control VSMCs. In calcifying VSMCs, the HCY-induced increases in 45Ca uptake, calcium deposition, and ALP activity were also attenuated by PD98059. The results demonstrated that HCY potentiated VSMC calcification probably through the mechanisms by which HCY promotes atherosclerosis.

Alkaline Phosphatase↗

Chronic kidney disease-mineral-bone disorder: a new paradigm.

Disturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified on the basis of bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) recently sponsored a Controversies Conference to evaluate this definition. The recommendations were that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD and (2) the term CKD-mineral and bone disorder (CKD-MBD) be used to describe the broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD. CKD-MBD is manifested by an abnormality of any one or a combination of the following: laboratory-abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; bone-changes in bone turnover, mineralization, volume, linear growth, or strength; and calcification-vascular or other soft-tissue calcification. The pathogenesis and clinical manifestations of these components of CKD-MBD are described in detail in this issue of Advances in Chronic Kidney Disease.

Bone Diseases, Metabolic↗

Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia.

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

Bone Diseases↗

Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification.

Thyroid hormones have marked cardiovascular effects in vivo. However, their direct effects on vascular smooth muscle cells have been unclear. Because thyroid hormones play critical roles in bone remodeling, we hypothesized that they are also associated with vascular smooth muscle calcification, one of the pathological features of vascular sclerosis. To test this hypothesis, we examined the effects of 3',3,5-triiodo-L-thyronine (T3) on the expression of calcification-associated genes in rat aortic smooth muscle cells (RAOSMCs). Quantitative RT-PCRs revealed that a physiological concentration of T3 (15 pmol/L free T3) increased mRNA level of matrix Gla protein (MGP), which acts as a potent inhibitor of vascular calcification in vivo, by 3-fold in RAOSMCs, as well as in cultured human coronary artery smooth muscle cells. In RAOSMCs transiently transfected with a luciferase reporter gene driven by the MGP promoter, T3 significantly stimulated luciferase activity. In addition, RNA interference against thyroid hormone receptor-alpha gene diminished the effect of T3 on MGP expression. Aortic smooth muscle tissues from methimazole-induced hypothyroid rats (400 mg/L drinking water; 4 weeks) also showed a 68% decrease in the MGP mRNA level, as well as a 33% increase in calcium content compared with that from the control euthyroid animals, whereas hyperthyroidism (0.2 mg T3/kg IP; 10 days) upregulated MGP mRNA by 4.5-fold and reduced calcium content by 11%. Our findings suggest that a physiological concentration of thyroid hormone directly facilitates MGP gene expression in smooth muscle cells via thyroid hormone nuclear receptors, leading to prevention of vascular calcification in vivo.

Animals↗

Intracerebral vascular occlusion in familial erythrophagocytic lymphohistiocytosis: a case report of two siblings.

Neuropathological findings in two siblings with familial erythrophagocytic lymphohistiocytosis (FEL) are reported. Case 1 showed the typical neuropathological findings of FEL with lymphohistiocytic infiltration of the leptomeninges and perivascular spaces. A characteristic erythrophagocytosis was detected in inguinal lymph nodes, lung and bone marrow. Case 2 revealed calcification and necrotic lesions in the brain. In the necrotic areas, parenchymal calcification, vascular medial calcification, and occlusion of many vessels due to subendothelial fibrosis were detected. The areas of necrosis correlated with the distribution of occluded vessels. These changes were most prominent in putamen, internal capsule, thalamus and dentate nucleus. Hypercytokinemia is suspected to be the underlying mechanism for the clinical and laboratory findings in patients with FEL, although the relationship to the vascular pathology is unclear.

Arterial Occlusive Diseases↗

Effects of excess calcium load on the cardiovascular system measured with electron beam tomography in end-stage renal disease.

Cardiovascular disease is the leading cause of morbidity and mortality in dialysis patients and current research indicates that it might be linked to high serum phosphorus levels and calcium-phosphorus product. The severe osteopathy known to exist in end-stage renal disease (ESRD) patients is often coupled with an inability of bone to handle excess calcium loads. This might predispose to overflow and deposition of calcium and phosphate crystals in various soft tissues and in particular the cardiovascular apparatus. Atherosclerosis is a slow process that expands in the context of the arterial intimal layer and it is for the most part associated with extracellular calcification. Electron beam tomography (EBT) is a radiological technique utilized to non-invasively visualize this silent marker of atherosclerosis: vascular calcification. Several investigations conducted in non-ESRD patients have conclusively demonstrated that coronary calcification indicates a high risk for cardiac events. As EBT allows precise estimates of the extent of vascular and valvular calcification, it might become an important clinical tool in ESRD patients to assess the effect of excess calcium and phosphate load in soft tissues, estimate the cardiovascular risk of events and gauge the effectiveness of therapy.

Calcium↗

[Vascular and tissue calcifications of hemodialysis patients].

The present paper aims to assess radiographic vascular and soft parts calcifications occurrence and its correlation with biochemical profiles. The study was performed in 47 patients (ten diabetic patients), 49 years old, who had been on dialysis for a period of 51 months. Vascular calcifications (VCs) were classified as proximal, distal and soft tissues. In addition, Ca, P, CaxP values in the six months prior to the recruitment period, PTH, FAL and calcium carbonate, calcium acetate, and vitamin D3 intake were determined. A higher frequency of VCs was observed in diabetics, yielding a significant association with proximal 60% (p = 0.05) and almost significant with distal calcifications 70% (p = 0.07). Likewise, a lower CaxP was noted for diabetic VCs in comparison to that seen in non-diabetic VCs (p < 0.05). Proximal and distal VCs in the non-diabetics population were 25% and 20%, respectively; and tissue calcifications were 24%. Age was correlated with proximal and distal VCs (p < 0.01). A higher CaxP was observed in patients with VCs and it yielded an even higher value for tissue calcifications. Lastly, calcium acetate and overall calcium intake was higher in patients with tissue calcifications (p = 0.05). VCs were more frequent in diabetics and they also showed a lower CaxP. VCs in non-diabetics were correlated with CaxP values, whereas tissue calcifications were associated with calcium intake. Therefore, the management of renal osteodystrophy should be changed in order to prevent calcifications as well as to decrease morbidity in hemodialysis patients.

Acetates↗