Treatment of secondary hyperparathyroidism by high calcium diet is associated with enhanced resistance artery relaxation in experimental renal failure.
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BACKGROUND: Vasorelaxation is impaired in renal failure (RF) and hypertension. A high calcium diet enhances vasodilatation and reduces blood pressure in experimental hypertension. Oral calcium salts are used as phosphate binders in RF. However, the effect of increased calcium intake on arterial tone in RF is unknown. METHODS: We investigated the influence of an 8-week high calcium diet (0.3 vs 3.0%) on resistance artery tone in 5/6 nephrectomized (NTX) rats. Calcium was supplemented as carbonate salt, blood pressure measured by tail-cuff, urine collected in metabolic cages, and samples taken for blood chemistry and parathyroid hormone (PTH). Functional studies of isolated third-order branches of the mesenteric artery in vitro were performed using the Mulvany multimyograph. RESULTS: Plasma urea was elevated 1.6-fold and systolic blood pressure by 10 mmHg after NTX, while increased calcium intake was without effect on these variables. Plasma PTH and phosphate were raised following NTX, and suppressed by high calcium diet. Vasorelaxations induced by K(+) channel agonists 11,12-epoxyeicosatrienoic acid and levcromakalim were impaired after NTX. Vasorelaxation induced by acetylcholine was also reduced following NTX, and experiments with N(G)-nitro-L-arginine methyl ester, diclofenac and charybdotoxin + apamin suggested that the K(+) channel-mediated component of endothelium-dependent relaxation was deficient after NTX. Increased calcium intake corrected all impairments of vasodilatation in NTX rats. CONCLUSIONS: Deficient vasorelaxation via K(+) channels was normalized by high calcium diet in experimental RF. This effect was independent of the degree of renal impairment and blood pressure, but was associated with improved calcium metabolism: plasma levels of PTH and phosphate were decreased and ionized calcium was increased. (+info)
Importance of hyperphosphataemia in the cardio-renal axis.
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Hyperphosphataemia occurs in nearly all patients with end-stage renal disease (ESRD). In the past, the need to manage hyperphosphataemia focused primarily on its role as a contributor to secondary hyperparathyroidism and renal osteodystrophy. There is now widespread recognition that disturbances in phosphorus metabolism and/or the therapeutic measures used to manage it are important risk factors for cardiovascular calcification. This serious complication of chronic kidney disease may contribute to the very high mortality rate from cardiovascular causes in patients undergoing long-term dialysis. New strategies for controlling serum phosphorus levels and for better management of mineral metabolism in general are required to address these issues in patients with ESRD. (+info)
Improving outcomes in hyperphosphataemia.
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Preclinical studies have shown that lanthanum has a very high phosphate-binding capacity at gastrointestinal pH, while clinical trials have shown lanthanum carbonate to be an effective, well-tolerated phosphate binder for the treatment of hyperphosphataemia in patients with end-stage renal disease. Optimization of bone health is an important issue in these patients, and, based on theoretical grounds, there have been concerns that lanthanum will have toxic effects on bone similar to those of aluminium. However, compared with aluminium, absorption of lanthanum is extremely low and lanthanum treatment is not associated with systemic toxicity. In addition, unlike aluminium, elimination of lanthanum is not through the kidney, but mainly takes place via the biliary route and is, therefore, independent of renal function. This implies that patients with chronic renal failure are not at an increased risk for accumulation of the element, compared with patients with normal renal function. In animal studies, no adverse effects on bone were seen in healthy animals receiving lanthanum carbonate. In 5/6th nephrectomized rats, very high doses of lanthanum (1000-2000 mg/kg) affected bone mineralization. This was not due to a direct toxic effect on bone, but was secondary to phosphate depletion induced by lanthanum and, as with any gastro-intestinal phosphate-binding agent, can be reversed with a phosphate-supplemented diet. In a phase III clinical trial, bone biopsies were taken from dialysis patients at baseline and after 1 year of treatment with either lanthanum carbonate (median dose, 1250 mg/day) or calcium carbonate (median dose, 2000 mg/day). Patients treated with lanthanum carbonate for 1 year did not experience any of the aluminium-like toxic effects on bone expressed as either osteomalacia or adynamic bone disease. (+info)
Improving phosphate-binder therapy as a way forward.
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Aluminium- or calcium-based phosphate-binding agents traditionally have been used to treat hyperphosphataemia in patients with end-stage renal disease. Although these agents effectively lower serum phosphorus levels, they are associated with serious side effects. Aluminium-based agents are associated with bone toxicity, renal osteodystrophy and encephalopathy, and calcium-based agents increase the risk of hypercalcaemia and cardiovascular calcification. Consequently, there remains a need for new, safe and effective non-calcium-, non-aluminium-based alternative treatments. Fortunately, several new agents are now available or are in the late stages of development, including sevelamer hydrochloride and lanthanum carbonate. Although sevelamer hydrochloride represents a step forward in the management of hyperphosphataemia, it has several drawbacks and is far from being the ideal phosphate binder. Lanthanum carbonate is the most recent non-calcium, non-aluminium phosphate binder to be developed for the treatment of hyperphosphataemia. Animal studies have shown it to be as effective as aluminium, without the associated toxicity. In clinical studies, lanthanum carbonate significantly reduced serum phosphorus levels, compared with placebo. It shows a similar efficacy to calcium carbonate in controlling serum phosphorus levels, but requires lower doses. In addition, lanthanum carbonate is at least as well tolerated as calcium carbonate, but is not associated with hypercalcaemia. Importantly, it has a positive effect on bone histology, with no evolution towards low bone turnover. Lanthanum carbonate, therefore, moves closer to the ideal phosphate binder. (+info)
Consequences of hyperphosphatemia in patients with end-stage renal disease (ESRD).
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Hyperphosphatemia is invariably present among patients with end-stage renal disease (ESRD) and is becoming an increasingly important clinical entity. Despite concerted efforts by patients, dietitians, and nephrologists to control serum phosphorus, a recent study by Block et al found that more than 60% of patients on hemodialysis in the United States have serum phosphorus levels above the recommended goal of 5.5 mg/dL. Historically, nephrologists have been concerned about the central role of elevated serum phosphorus in the pathogenesis of secondary hyperparathyroidism and extraosseous calcification. However, the consequences of untreated hyperphosphatemia have assumed more importance in the last few years, largely due to recent clinical studies that revealed a more sinister role of elevated serum phosphorus in increasing the mortality risk among patients with ESRD. Hemodialysis patients with serum phosphorus greater than 6.5 mg/dL were reported to have a 27% higher mortality risk than patients with serum phosphorus between 2.4 and 6.5 mg/dL. The pathophysiologic mechanisms by which persistent hyperphosphatemia enhances the mortality risk in dialysis patients are not yet completely understood. However, given that inadequate control of serum phosphorus contributes to elevated calcium-phosphorus product (Ca x P), untreated hyperphosphatemia may play a key role in cardiovascular calcification. In response to these findings, the National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease have recently recommended more stringent levels for controlling serum phosphorus and Ca x P product in order to improve patients' quality of life and longevity. (+info)
The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification.
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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. (+info)
Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis: results of the CARE study.
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Most patients with end-stage renal disease develop hyperphosphatemia because their dietary intake exceeds phosphorus elimination by intermittent thrice-weekly dialysis. Inadequately treated hyperphosphatemia plays a central role in the pathogenesis of secondary hyperparathyroidism and extraosseous calcification. Moreover, in the last 15 years, this biochemical abnormality has become increasingly important following the publication of two epidemiologic studies that demonstrated an association between elevated serum phosphorus and increased mortality risk in patients with end-stage renal disease. As a result, the National Kidney Foundation Kidney Disease Outcome and Quality Initiative (K/DOQI) Bone Metabolism and Chronic Kidney Disease Guidelines recommend that serum phosphorus levels be maintained between 3.5 and 5.5 mg/dL. Unfortunately, cross-sectional studies have shown a mean serum phosphorus of 6.2 mg/dL in the maintenance hemodialysis population in the United States. An alarming 60% of patients have serum phosphorus in excess of the 5.5 mg/dL level recommended by K/DOQI guidelines. In order to achieve this new target for serum phosphorus, the most efficacious and cost-effective phosphate binders currently available should be utilized. In this review, we discuss the results of the Calcium Acetate Renagel Evaluation (CARE study), which clearly demonstrated the superiority of calcium acetate over sevelamer hydrochloride for controlling serum phosphorus and calcium-phosphate product to the levels recommended by the K/DOQI guidelines. (+info)
Life threatening hyperphosphataemia after administration of sodium phosphate in preparation for colonoscopy.
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An elderly woman developed severe hyperphosphataemia, hypocalcaemia, and cardiac arrest after oral administration of sodium phosphate in preparation for colonoscopy. This is an unusual complication and is attributed to decreased phosphate excretion by the kidneys. At increased risk are patients with impaired renal function, age more than 65 years, and presenting with intestinal obstruction or decreased intestinal motility, increased intestinal permeability, liver cirrhosis, or congestive heart failure. Though there are no accepted guidelines for anticipation and prevention of this adverse effect, it may be desirable to check serum phosphate concentrations before choosing the method for colonic preparation and before giving the second oral dose of sodium phosphate in patients at risk. Hyperphosphataemia should be suspected if a patient develops hypotension or neuromuscular irritability after administration of sodium phosphate. Haemodialysis for direct removal of phosphate and intravenous calcium for treatment of symptomatic hypocalcaemia may be life saving. (+info)