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PubMed1985

Interaction of dietary fat and protein in spontaneous diseases of Syrian golden hamsters.

The influence of interactions between dietary fat and protein on spontaneous diseases was investigated in Syrian golden hamsters fed two levels of corn oil [4.5 or 18 g/385 kilocalories (kcal)] with each of two levels of casein (9 or 36 g/385 kcal). The four diets were fed to separate groups in two different sequences: 1) Diets were given during weeks 3-7 and followed by control diet (9 g corn oil and 18 g casein/385 kcal), or 2) control diet was fed during weeks 3-7, and the four diets were fed from week 8 until death. Dietary interactions of fat and protein modified spontaneous degenerative, inflammatory, and proliferative diseases in hamsters. For example, amyloidosis in the liver, kidneys, spleen, and adrenal glands was reduced in females by feeding high-fat-high-protein (HF-HP) diet in comparison with low-fat-high-protein (LF-HP) diet during weeks 3-7 or by feeding LP diets at either fat level after 8 weeks. The incidence of hepatic abscess was highest in males consuming HP diet at either fat level after 8 weeks, and hepatic necrosis was observed most often in hamsters fed HF-HP diet after 8 weeks. Gastric and renal vascular calcification and nephrocalcinosis incidences were reduced by 50-100% in hamsters fed HF-HP diet after 8 weeks, and HF diet fed at this time reduced vascular calcification in the heart in both sexes and in the lungs in males. Inflammation was generally influenced similarly by diets fed either during weeks 3-7 or after 8 weeks. In the prostate gland, inflammation was observed most frequently in males fed HF-LP diet; however, in the vagina inflammation was elevated in females fed HF-HP diet and found in the gallbladder more commonly in hamsters fed HF-HP than in those given LF-HP. The incidence of colitis was decreased by giving HF-LP diet during weeks 3-7 or LF-LP diets after week 8. The incidence of gastric ulcer was high in males fed HF diets during weeks 3-7, and intestinal ulcers were high in those fed LF-LP at this time. The adrenal hyperplasia incidence was highest in males given HF-HP diet before or after 8 weeks and in females given this diet after 8 weeks. Similarly, ovarian and hepatic ductal hyperplasia was highest in females fed HF-HP diet after 8 weeks, and gastric and intestinal hyperplasia increased with the rise in fat at both protein levels in both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animal Feed↗

PubMed2005

Plasma osteoprotegerin is associated with mortality in hemodialysis patients.

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Regulating molecules such as osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) could play a key role in bone-vascular calcification imbalance. This study investigated the contribution of these proteins as well as mineral metabolism disorders in hemodialysis (HD) patient outcome. A total of 185 HD patients were followed up prospectively for 2 yr. In addition to clinical characteristics, mineral metabolism markers as well as OPG and soluble RANKL (sRANKL) were measured at baseline. After 2 yr, survival rates were described with Kaplan-Meier and compared with Cox regression analyses; 50 patients died (27 from cardiovascular diseases). Calcium, phosphate, and calcium x phosphate product were not associated with mortality. Both hyperparathyroidism (parathyroid hormone > or =300 pg/ml) and hypoparathyroidism (parathyroid hormone <150 pg/ml) were poorly associated with all-cause and cardiovascular mortality. By contrast, elevated OPG levels predicted all-cause (relative risk [RR] 2.67; 95% confidence interval [CI] 1.32 to 5.41; P = 0.006) and cardiovascular mortality (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03). Low levels of sRANKL were associated with a protective effect for all-cause mortality (RR 0.45; 95% CI 0.21 to 0.94; P = 0.03). The association of OPG with all-cause mortality was stronger in patients with C-reactive protein > or =12.52 mg/L. In this condition, both highest (RR 5.68; 95% CI 1.48 to 22.73; P = 0.01) and lowest tertiles (RR 5.37; 95% CI 147 to 1968; P = 0.01) significantly predicted poor outcome. These results show that regulating-bone molecules, especially OPG, are strong predictors of mortality in HD patients, suggesting that OPG is a vascular risk factor, in particular in patients who have high C-reactive protein levels. OPG determination therefore should be added to the biologic follow-up of these patients.

Adult↗

PubMed2004

Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro.

BACKGROUND: Hyperphosphatemia, elevated calcium x phosphorus product (Ca x P), and calcium burden, major causes of vascular calcification, are correlated with increased cardiovascular morbidity and mortality in dialysis patients. METHODS: To address the underlying mechanisms responsible for these findings, we have utilized an in vitro human smooth muscle cell (HSMC) model of vascular calcification. Previous studies using this system demonstrated enhanced calcification of HSMC cultures treated with phosphorus levels in the hyperphosphatemic range, and implicated a sodium-dependent phosphate cotransport-dependent mechanism in this effect. In the present study, we examine the effect of increasing calcium concentrations on HSMC calcification in vitro. RESULTS: Increasing calcium to levels observed in hypercalcemic individuals increased mineralization of HSMC cultures under normal phosphorus conditions. Importantly, at these total calcium concentrations, ionized calcium levels increased from 1.2 mmol/L to 1.7 mmol/L, consistent with levels observed physiologically in normocalcemic and hypercalcemic individuals, respectively. Furthermore, increasing both calcium and phosphorus levels led to accelerated and increased mineralization in the cultures. Calcium-induced mineralization was dependent on the function of a sodium-dependent phosphate cotransporter, since it was inhibited by phosphonoformic acid (PFA). While elevated calcium did not affect short-term phosphorus transport kinetics, long-term elevated calcium treatment of HSMCs induced expression of the sodium-dependent phosphate cotransporter, Pit-1. CONCLUSION: These studies suggest that elevated calcium may stimulate HSMC mineralization by elevating Ca x P product and enhancing the sodium-dependent phosphate cotransporter-dependent mineralization pathway previously observed in HSMCs.

Aorta↗

PubMed1998

Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression.

The cellular and molecular events leading to calcification in atherosclerotic lesions are unknown. We and others have shown that bone-associated proteins, particularly matrix Gla protein (MGP) and osteopontin (OP), can be detected in atherosclerotic lesions, thus suggesting an active calcification process. In the present study, we aimed to determine whether human vascular smooth muscle cells (VSMCs) could calcify in vitro and to determine whether MGP and OP have a role in vascular calcification. We established that human aortic VSMCs and placental microvascular pericytes spontaneously form nodules in cell culture and induce calcification, as detected by von Kossa's method, Alizarin red S staining, and electron microscopy. The cells in calcifying nodules differed from those in monolayer cultures by expressing higher levels of the SMC markers alpha-SM actin, SM22alpha, and calponin. In addition, Northern blot analysis revealed that in human VSMCs, calcification was associated with increased levels of MGP mRNA. In contrast, OP mRNA was barely detectable in calcified human VSMCs and pericyte nodules, nor was OP protein detected, suggesting that OP was not necessary for calcification to occur. These studies reveal that human VSMCs are capable of inducing calcification and that MGP may have a role in human vascular calcification.

Adolescent↗

PubMed1998

Dementia associated with hyperphosphatemic tumoral calcinosis.

Hyperphosphatemic tumoral calcinosis (HTC) is a rare inherited metabolic disorder manifested by pararticular calcification and hyperphosphatemia, caused by an elevated renal phosphate reabsorption threshold and elevated serum 1,25-dihydroxyvitamin D levels. The disorder usually affects African-American subjects, but has also been described in Caucasians and Hispanics. Vascular calcifications and angioid streaks have been reported to be associated with the disorder; however, dementia has not been previously reported. Our medical center has followed two African-American siblings, with HTC for over 30 years, who have developed dementia at 56 years and 67 years of age. Neither man has been hypertensive, however, magnetic resonance imaging (MRI) scans in both cases revealed multiple periventricular infarcts, suggestive of infarcts caused by vascular calcification in the central nervous system. These two brothers with HTC suggest that periventricular infarcts with dementia may be a long term complication of this disorder.

Aged↗

PubMed2004

Kidney-bone, bone-kidney, and cell-cell communications in renal osteodystrophy.

The relationship between bone and the kidney in renal osteodystrophy is a complex interplay of kidney to bone connections, bone to kidney connections, and cell to cell connections. In addition, such interactions have a profound effect on the vasculature. In this review, we discuss the role of the bone morphogenetic proteins (BMPs) in the skeleton, kidney, and vasculature. In addition, we propose that deficiencies of these BMPs seen in chronic kidney disease (CKD) result in decreased bone remodeling and a compensatory secondary hyperparathyroidism (high turnover state). Treatment of the hyperparathyroidism blocks this compensatory arm and thus decreased bone remodeling occurs (low turnover). We review animal models of CKD in which treatment with BMP-7 resulted in normalization of both high and low turnover states. Finally, we discuss vascular calcification as it relates to bone metabolism. We discuss the roles of BMP-7 and 2 other bone regulatory proteins, osteoprotegerin (OPG) and alpha2-HS glycoprotein (AHSG, human fetuin), in the human vasculature and their implications for vascular calcification.

Bone Morphogenetic Proteins↗

PubMed2005

Cartilage formation in growth plate and arteries: from physiology to pathology.

Vascular calcifications are the consequence of several pathological conditions such as atherosclerosis, diabetes, hypercholesterolemia and chronic renal insufficiency. They are associated with risks of amputation, ischemic heart disease, stroke and increased mortality. A growing body of evidence indicates that vascular smooth muscle cells (VSMCs) undergo chondrogenic commitment eventually leading to vascular calcification, by mechanisms similar to those governing ossification in the cartilage growth plate. Our knowledge of the formation of cartilage growth plate can therefore help us to understand why and how arteries calcify and, consequently, develop new therapeutic strategies. Reciprocally, thorough consideration of the events leading to ectopic chondrocyte differentiation appears crucial to further increase our understanding of growth plate formation. In this context, we will review the effects of known or suspected factors that promote chondrogenic differentiation in growth plate and arteries.

Animals↗

PubMed1996

Cutaneous gangrene due to hyperparathyroidism secondary to chronic renal failure (uraemic gangrene syndrome)

Cutaneous and subcutaneous gangrene are serious sequelae of secondary or tertiary hyperparathyroidism which may accompany chronic renal failure. Based on analysis of the present typical case and a retrospective survey of similar cases in the literature, we propose the term 'uraemic gangrene syndrome' for this association. These skin lesions in chronic renal failure patients represent the most serious clinical manifestation of calciphylaxis, a condition originally described by Selye. The appearance of early skin lesions should be regarded as an indication for subtotal parathyroidectomy. The association of cutaneous gangrene with vascular calcification was first described by Bryandt and White in 1989, and was termed by these authors as 'gangrenous calcification'. A total of 80 cases of this rare complication of chronic renal disease had been reported up to early 1994. A retrospective review of these reports has strongly suggested a close interrelationship between renal failure, secondary hyperparathyroidism, vascular calcification and cutaneous gangrene. The present report concerns a characteristic case to draw attention to this syndrome which is accompanied by serious, predominantly cutaneous, changes.

Adult↗

PubMed2005

[New therapy strategies in secondary hyperparathyroidism on dialysis (I): new concepts, new treatments].

Secondary hyperparathyroidism (SHP) is still an early and frequent complication of chronic renal disease (CRD). Currently, CRD is an independent cardiovascular risk factor, and calcium-phosphorus metabolism is one of the modifiable related factors. In this first article, we summarize the recent SHP treatment paradigm shift in dialysis patients, derived from the better knowledge and understanding of vascular calcification. We analyze the most recent guidelines (K/DOQI), and describe the general implications of hyperphosphatemia, as well as our therapeutic approach with phosphorus-binders. Since sevelamer additionally presents some pleiotropic effects and it attenuates the progression of vascular calcification, we consider it in the first-line of treatment despite it is not yet demonstrated a survival benefit. We also minimize the use of elemental calcium to a maximum of 1000 to 1500 mg/day. Lanthanum carbonate may well be an important therapeutic agent in the near future, especially if security concerns related to metal accumulation are overcome. Ferric citrate, colestilan and nicotinamide may soon play a role. All these drugs, isolated or in combination, are important in the treatment of SHP since a great deal of its success and the avoidance of some dialysis-related complications depend on an efficient phosphorus control.

Algorithms↗

PubMedDate not supplied

Renal transplantation and secondary hyperparathyroidism.

Secondary hyperparathyroidism (2'HPT) improves after renal transplantation (RTx) along with recovered function of the renal allograft. However, normal renal function does not last long due to rejection, drug-induced nephrotoxic nepthropathy, or recurrence of post-transplant glomerulonephritis. Therefore, improved calcium and phosphate metabolism, and parathyroid function after RTx fluctuate in accordance with the function of the renal allograft. In cases with severe 2'HPT, parathyroidectomy should be performed before RTx because hypercalcemia due to secondary or tertiary hyperparathyroidism aggravates the renal allograft function. In the follow-up of mild 2'HPT after RTx, hypercalcemia and vascular calcification should be monitored carefully by serum parathyroid hormone, calcium and phosphate concentrations, alkaline phosphatase activity, and bone X-ray film. If serum calcium level exceeds 12 mg/dl, parathyroidectomy (PTx) should be performed to prevent the acceleration of vascular calcification. Total PTx with forearm allograft is a preferred surgical procedure for 2'HPT even after RTx.

Cholecalciferol↗

PubMed2003

Phosphate binder usage in kidney failure patients.

Phosphorus binders are used in patients with kidney failure because of the incomplete removal of phosphorus with dialysis and the inability to exclude phosphorus from the diet. Aluminium was the initial phosphorus binder used, but was replaced by calcium-containing binders because of the development of aluminium toxicity. Calcium-based binders have been the mainstay of therapy for many years, but recent investigations have pointed to increased rates of vascular calcification in patients taking calcium-containing binders. For this reason, alternative agents have been developed. Sevelamer (Renagel), GelTex Pharmaceuticals Inc.) is a polymer which has been found to effectively bind phosphorus. It has resulted in a decreased rate of vascular calcification compared to calcium-containing binders. Other agents under development include lanthanum carbonate and iron-complex preparations. Further research will likely concentrate on identifying binders that bind phosphate more efficiently, have minimal gastrointestinal side effects and provide other benefits to dialysis patients.

Acetates↗

PubMed2005

A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis.

Gain-of-function mutations in fibroblast growth factor-23 (FGF23) are responsible for autosomal dominant hypophosphatemic rickets, a disorder of isolated renal phosphate wasting. Patients with the disorder display hypophosphatemia with normocalcemia as well as inappropriately normal 1,25-dihydroxyvitamin D [1,25(OH)2D3] concentrations. Reciprocally tumoral calcinosis (TC) patients are often hyperphosphatemic with inappropriately normal or elevated serum 1,25(OH)2D3 levels and have ectopic and vascular calcifications, a phenotype similar to that of Fgf23 null mice. Therefore, the goal of the present studies was to test whether FGF23 was a candidate gene for TC. Two sisters in a consanguineous TC family had hyperphosphatemia and normal 1,25(OH)2D3 levels with characteristic ectopic and vascular calcifications. Interestingly, these patients had low-normal intact serum FGF23 levels but demonstrated FGF23 concentrations approximately 40 times normal when assessed with a C-terminal FGF23 serum assay. Mutational analyses identified a homozygous S71G mutation in FGF23 in the TC patients, which was not found in control alleles. Finally, modeling demonstrated that the S71G mutation most likely destabilizes full-length FGF23. In summary, recessive FGF23 mutations can lead to TC. Additionally, our findings indicate that FGF23 may adopt an unstable conformation in some TC patients, possibly leading to nonfunctional FGF23 protein.

Adult↗

PubMed1973

Evolution of bone disease over 10 years in 135 patients with terminal renal failure.

An objective radiographic study of erosions, fractures, and periarticular and vascular calcification was made in a series of 135 patients over 10 years of maintenance haemodialysis therapy. The four lesions progressed at different rates, consistent with variation in the response of tissues to a changing biochemical milieu and deficiency in vitamin D metabolites. The half time for development of individual radiographic signs was 3.4 years for vascular calcification, 9 years for fractures, 16 years for periarticular calcification, and 22.9 years for erosions. Calcification of the dorsalis pedis artery seen as a developing ring or tube was an early and valuable sign of disturbed calcium metabolism. In these patients renal osteodystrophy is a chronic condition with a prolonged time course.

Adolescent↗

PubMed2004

Reduced coronary artery and abdominal aortic calcification in Hispanics with type 2 diabetes.

OBJECTIVE: To compare lifestyle factors, cardiovascular risk factors, and coronary artery calcium (CAC) and abdominal aortic calcium (AAC) levels in Hispanic and non-Hispanic white (NHW) individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: We recently demonstrated in a small group of nonreferred, healthy, nondiabetic subjects that CAC was reduced in Hispanics compared with NHWs, despite a worse cardiovascular risk factor profile. In this study, we evaluated whether this ethnic disparity in vascular calcification was present in individuals with type 2 diabetes and in several different arterial beds. Hispanic and NHW subjects (n = 245) with type 2 diabetes were evaluated for cardiovascular risk factors using questionnaires and assays of plasma biomarkers. CAC and AAC were measured by electron-beam computer-assisted tomography. RESULTS: Although Hispanics were slightly younger than NHWs, other standard risk factors and novel cardiovascular risk factors, including plasminogen activator-1 and fibrinogen levels, were similar between the groups. Despite the similar risk factor profile, the prevalence of cardiovascular disease (CVD) and mean and median levels of CAC and AAC were lower in Hispanics. Furthermore, the distribution of these calcium scores differed from that of NHWs (P < 0.05), with significantly fewer Hispanic subjects having high CAC or AAC scores. These differences were not explained by differences in CVD prevalence or any measured lifestyle or risk factor. CONCLUSIONS: Hispanics with type 2 diabetes have reduced CAC and AAC levels compared with NHW subjects, suggesting a reduction in the overall burden of vascular calcification and atherosclerosis. These data are consistent with the notion that Hispanics are protected against the development of CVD.

Aorta, Abdominal↗

PubMed2000

Cutaneous calciphylaxis. An underrecognized clinicopathologic entity.

Calciphylaxis (CPX), an uncommon syndrome characterized, in part, by progressive cutaneous vascular calcification, is seen principally in the setting of renal failure-associated hyperparathyroidism and is difficult to distinguish histologically from other microvasculopathies. We assessed histologic specimens from 13 cases of clinicopathologically classic CPX of the skin and reviewed documented histologic findings in the literature. Our series included 7 "early" and 6 "late" lesions (absence or presence of tissue necrosis, respectively). Histologically, early lesions were subtle and almost inapparent microscopically. Late lesions were easier to recognize because of obvious epidermal ulceration, dermal necrosis, and easily seen mural vascular calcification. The most common finding in both groups was acute and chronic calcifying septal panniculitis. Endovascular fibroblastic proliferation was more common in advanced lesions. Necrosis of dermal collagen was identified in only a few early lesions. Frank luminal vascular thrombosis was infrequent in both groups. The cited histologic findings largely were mirrored by those in the literature. Although they are relatively nonspecific when considered in isolation, the cited histopathologic features of cutaneous CPX allow for the diagnosis of this potentially lethal disorder when they are seen in combination with one another, particularly if detailed clinical data also are available.

Adult↗

PubMed2003

Effect of hypertension before beginning dialysis on survival of hemodialysis patients.

BACKGROUND: The role of hypertension as a predictor of mortality in hemodialysis patients is controversial. The purpose of this study is to investigate the effect of hypertension before starting hemodialysis therapy on survival of patients without diabetes during renal replacement therapy. METHODS: We reviewed 184 patients starting hemodialysis therapy. Variables studied were age, sex, renal disease, hypertension, comorbidity, vascular calcifications, left ventricular hypertrophy, body mass index, and albumin, cholesterol, and alkaline phosphatase levels. Regarding blood pressure control, three groups were considered: normotensive (NH), controlled hypertensive (c-HT), and uncontrolled hypertensive (uc-HT). RESULTS: The Cox model was performed considering all-cause and cardiovascular mortality. The model was adjusted for age, sex, serum albumin level, vascular calcifications, history of hypertension, and comorbidity. Comorbidity included cardiovascular comorbidity. For all-cause mortality, comorbidity and history of uncontrolled hypertension were independent risk factors (comorbidity relative risk, 1.95; 95% confidence interval, 1.26 to 3.1; P = 0.003; uncontrolled hypertension relative risk, 1.79; 95% confidence interval, 1.15 to 2.8; P = 0.01). For cardiovascular mortality, uncontrolled hypertension was the main risk factor (relative risk, 2.93; 95% confidence interval, 1.68 to 5.12; P = 0.000). Mortality rates were 7.9/100 patient-years for NH, 8.7/100 patient-years for c-HT, and 14.1/100 patient-years for uc-HT patients. CONCLUSION: This study suggests that uncontrolled hypertension in renal patients before starting dialysis therapy is a major risk factor for cardiovascular mortality during hemodialysis. Because hypertension usually starts in the initial stages of renal disease, we emphasize the importance of prompt and adequate control of blood pressure in this population.

Adolescent↗

PubMed2004

The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification.

The role of abnormal phosphorus metabolism in the progression of renal disease and metastatic calcification. Hyperphosphatemia is a common biochemical abnormality in advanced renal failure. The resulting increase serum calcium x phosphorus product results in the deposition of hydroxyapatite crystals. The crystalline properties of these deposits incite an inflammatory response manifested by encapsulated tumoral deposits around joints, acute inflammatory arthritis, and irritative conjunctivitis. These deposits occur in association with marked elevation of serum phosphorus levels, and are prevented and eradicated by normalizing serum phosphorus levels. The calcium-phosphate deposits which occur in heart and lungs are nonapatitic. These deposits were never clearly related to hyperphosphatemia. They are mainly of historic interest because currently they are rarely seen. Their eradication appears to be more of a result of improved dialytic techniques than correction of serum phosphorus levels. The presence, persistence, and progression of vascular calcification are more closely related to patient age and duration of dialysis than hyperphosphatemia. This suggests that these deposits are a result of dystrophic calcification occurring de novo in a diseased or damaged vessel wall. Phosphorous restriction has also been shown to be protective of renal functional deterioration in experimental renal disease. It is unclear whether the protective effect is mediated through phosphate restriction or phosphate depletion. In conclusion, control of serum phosphorus levels in dialyzed uremic patients has clearly decreased morbidity associated with periarticular, articular, and conjunctiva hydroxyapatite deposits. In contrast, phosphorous control has had little effect on the presence or severity of vascular calcification.

Calcinosis↗

PubMed1991

Calcium deposition in the skin of a hemodialysis patient with widespread skin necrosis.

Rapidly progressive skin necrosis involving large areas of the skin associated with extensive vascular calcification was observed in a 39-year-old male patient on chronic hemodialysis. Histological examination of the periphery of a skin ulcer showed that subepidermal arterioles were occluded with fibrin deposits and that calcification was demonstrated in subcutaneous small arteries and arterioles. Electron microscopically, electron-dense materials, granular, crystal-like, vacuolar, or laminated, were found not only in arterial walls of the periphery of an ulcer but also, to a lesser extent, in those of normal-appearing skin. The skin necrosis gradually healed with antiseptic topical treatments and the injection of recombinant erythropoietin. The relationship between the vascular lesions in hemodialysis patients and progressive skin necrosis is not well known, although a combination of local and systemic factors may play an important role in the development of vascular calcification and skin necrosis in uremic and hemodialysis patients.

Adult↗