Phosphate binding therapy in dialysis patients: focus on lanthanum carbonate

Hyperphosphatemia is an inevitable consequence of end stage chronic kidney disease and is present in the majority of dialysis patients. Recent observational data has associated hyperphosphatemia with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis prescription practices are not enough to maintain serum phosphate levels within the recommended range so that the majority of dialysis patients require oral phosphate binders. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and side effects. Aluminium-containing agents are highly efficient but no longer widely used because of well established and proven toxicity. Calcium based salts are inexpensive, effective and most widely used but there is now concern about their association with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a large pill burden and high cost are limiting factors to its wider use. In addition, the efficacy of sevelamer as a monotherapy in lowering phosphate to target levels in severe hyperphosphatemia remains debatable. Lanthanum carbonate is a promising new non-aluminium, calcium-free phosphate binder. Preclinical and clinical studies have demonstrated a good safety profile, and it appears well tolerated and effective in reducing phosphate levels in dialysis patients. Its identified adverse events are apparently mild to moderate in severity and mostly GI related. It appears to be effective as a monotherapy, with a reduced pill burden, but like sevelamer, it is significantly more expensive than calcium-based binders. Data on its safety profile over 6 years of treatment are now available

A comparison of clinically useful phosphorus binders for patients with chronic kidney failure

A comparison of clinically useful phosphorus binders for patients with chronic kidney failure. Over the past 30 years it has become apparent that hyperphosphatemia plays a major causative role across the entire spectrum of morbidity associated with advancing kidney dysfunction and failure. A large fraction (60% to 70%) of dietary phosphorus is absorbed and normally excreted by the kidneys. Ideally, as kidney function deteriorates, the net quantity of phosphorus absorbed from the GI tract should be proportionally reduced to match the decrease in kidney function. After initiation of chronic dialysis therapy, the absorbed phosphorus load should match the amount of phosphorus removed via dialysis plus any excreted by residual kidney function. Because it is very difficult to reduce dietary phosphorus to these levels, a variety of oral phosphorus binders have been employed. Currently available binders include alkaline aluminum, magnesium, and calcium salts (primarily calcium carbonate and calcium acetate), various iron salts, and the binding resin sevelamer hydrochloride. Lanthanum carbonate is the newest agent and will probably be released shortly. This review compares the theoretic and in vitro chemistry of these drugs with in vivo data obtained in both normal patients, and in patients with kidney failure. The clinical potency and potential toxicity of the binding agents are compared, and optimal drug administration strategies are also reviewed

Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability

Background. Phosphate binders are required to control serum phosphorus in dialysis patients. A phosphate binder combining calcium and magnesium offers an interesting therapeutic option

Pharmacological Management of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease

Secondary hyperparathyroidism (SHPT) is a common complication of CKD and is part of the chronic kidney disease-mineral bone disorder (CKD-MBD). SHPT is associated with increased risk of fracture and mortality, thus SHPT control is recommended as kidney function declines. Effective SHPT management becomes more difficult once skeletal and cardiovascular adverse effects associated with severe SHPT have become established. However, interventional studies to lower parathyroid hormone (PTH) have so far shown inconsistent results in improving patient-centred outcomes such as mortality, cardiovascular events and fracture. Pharmacological treatment effect on PTH level is also inconsistent between pre-dialysis CKD and dialysis patients which adds to the complexity of SHPT management. This review aims to give an overview on the pathophysiology, pharmacological and non-pharmacological treatment for SHPT in CKD including some of the limitations of current therapeutic options

Management of hyperphosphatemia in patients with end-stage renal disease: focus on lanthanum carbonate

Elevated serum phosphate levels as a consequence of chronic kidney disease (CKD) contribute to the increased cardiovascular risk observed in dialysis patients. Protein restriction and dialysis fail to adequately prevent hyperphosphatemia, and in general treatment with oral phosphate binding agents is necessary in patients with advanced CKD. Phosphate plays a pivotal role in the development of vascular calcification, one of the factors contributing to increased cardiovascular risk in CKD patients. Treatment of hyperphosphatemia with standard calcium-based phosphate binders and vitamin D compounds can induce hypercalcemic episodes, increase the Ca × PO4 product and thus add to the risk of ectopic mineralization. In this review, recent clinical as well as experimental data on lanthanum carbonate, a novel, non-calcium, non-resin phosphate binding agent are summarized. Although lanthanum is a metal cation no aluminium-like toxicity is observed since the bioavailability of lanthanum is extremely low and its metabolism differs from that of aluminium. Clinical studies now document the absence of toxic effects of lanthanum for up to 6 years of follow-up. The effects of lanthanum on bone, vasculature and brain are discussed and put in perspective with lanthanum pharmacokinetics

Phosphorus binders: preferences of patients on hemodialysis and its impact on treatment compliance and phosphorus control

Introducción: En la actualidad disponemos de un amplio abanico de captores del fósforo (CF), pero sabemos poco acerca de las preferencias de los pacientes y de su repercusión sobre el cumplimiento del tratamiento y el control de los niveles de fósforo. Objetivo: Estudiar las preferencias y creencias de los pacientes respecto a los CF, y su influencia sobre el cumplimiento del tratamiento y el control de los niveles de fósforo. Pacientes y métodos: Estudio observacional transversal. Se incluyeron 121 pacientes que respondieron un cuestionario genérico de cumplimiento del tratamiento (SMAQ) y a un cuestionario específico sobre cumplimiento del tratamiento con CF, tipo de CF preferido y razones de dicha preferencia. Todos los pacientes entrevistados habían probado dos o tres CF. Las consecuencias de la falta de cumplimiento del tratamiento con CF se estimaron indirectamente analizando los valores promedio de fósforo sérico. Resultados: El 40% de los pacientes era incumplidor según el cuestionario SMAQ; se encontró una asociación estadísticamente significativa entre la falta de cumplimiento en general y no alcanzar el objetivo de fósforo sérico promedio 5,5 mg/dl (OR = 4,7; IC 95%, 1,1-6,5; p = 0,03). Un 43,8% de los pacientes no refirió tener preferencias entre los diferentes tipos de CF; para el resto de pacientes, el CF preferido fue Royen®, seguido de Fosrenol®, Renagel® y Pepsamar®. Las razones expresadas para el desagrado con el Renagel® fueron las siguientes: incomodidad en la toma por su gran tamaño (28,8%), necesidad de tomar muchos comprimidos y gran consumo de agua (57,7%) e intolerancia gástrica (13,3%). En el caso del Fosrenol®: incómodo de tomar (72,7%) e intolerancia gástrica (27,2%); para el Pepsamar®: mal sabor (54,5%) e intolerancia gástrica (45,4%). Sólo al 9,4% no le gustaba el Royen®. Al analizar los conocimientos de los pacientes respecto a la utilidad de los CF, un 42% sabía que servían para controlar el fósforo; un 52% no lo sabía y un 6% tenía ideas equivocadas. En cuanto a su importancia: un 47% no conocía por qué son importantes; un 2% tenía ideas erróneas; un 9% creía que era beneficioso para la salud; un 11% creía que era bueno «porque lo dice el medico»; un 26% porque controla el fósforo y un 5% lo relacionaba con el hueso. Ningún paciente relacionó los CF con la enfermedad cardiovascular. Un 24,4% no se llevaba los CF cuando salía fuera de casa o estaba con los amigos; eran pacientes más jóvenes a quienes se les habían prescrito un mayor número de comprimidos de CF y que presentaban un mayor riesgo de no cumplir el objetivo de fósforo (OR = 10,5; IC 95%, —1,8 a —16,4; p 5,5 mg/dl (OR = 13.3; IC 95%, 1,1-1,5; p = 0,0001). Paradójicamente, los pacientes que no cumplían con el tratamiento demostraban un mejor conocimiento de su uso (OR = 17,3; IC 95%, 2,2-10,1; p 5.5 mg/dl (χ2: 4.7; 95% CI 1.07-6.5; p = 0.03). Paradoxically, non-adherent patients showed greater knowledge of the use (χ2: 17.3; 95% CI -2.2-10.1; p 5.5 mg/dl) (χ2: 13.3; 95% CI -1.1-1.5; p = 0.0001). Calcium acetate was the prefered PB in 47.1% of patients, lanthanum carbonate in 40%, sevelamer in 20.6% and aluminum hydroxide in 19.4%. The reasons claimed by patients for their negative ratings of PB were the type of dosage form, the taste, the number of tablets and gastric intolerance. Gastric intolerance and bad taste were more frequent in aluminum hydroxide patients (19.4% and 22.2%, respectively). Sevelamer received complaints about its dosage form because the tablets were too large and a large number of tablets were required (27.2%). 17.7% of patient who were taking lanthanum carbonate did not like the chewable tablets. Conclusion: patients who were taking binders that they did not like had worse serum P levels and were prescribed higher doses of binders. Knowing patients’ preferences about the drugs prescribed may be a key factor in achieving adequate adherence to treatment

Uso del sevelamer en la enfermedad renal crónica: Más allá del control del fósforo

Sevelamer is a non-calcium phosphate binder used in advanced chronic kidney disease (CKD) and in dialysis for hyperphosphataemia control. Several experimental, observational studies and clinical trials have shown that sevelamer has pleiotropic effects, beyond hyperphosphataemia control, including actions on inflammation, oxidative stress, lipid profile and atherogenesis, vascular calcification, endothelial dysfunction and the reduction of several uremic toxins. This is the biological basis for its global effect on cardiovascular morbidity and mortality in patients with chronic kidney disease. This review focuses on these pleiotropic actions of sevelamer and their impact on cardiovascular health, with the experience published after more than ten years of clinical expertiseEl sevelamer es un captor no cálcico de fósforo que se utiliza en la ERC avanzada y en diálisis para el control de la hiperfosforemia. Varios estudios experimentales, observacionales y ensayos clínicos han mostrado que el sevelamer tiene efectos pleiotrópicos, más allá del control de la hiperfosforemia, incluyendo acciones sobre la inflamación, el estrés oxidativo, el perfil lipídico y la aterogénesis, la calcificación vascular, la disfunción endotelial y la disminución de diversas toxinas urémicas, todo lo cual sería la base biológica de su efecto global sobre la morbilidad y la mortalidad cardiovascular en pacientes con enfermedad renal crónica. En esta revisión, se hace énfasis en estas acciones pleiotrópicas del sevelamer y su impacto en la salud cardiovascular, con la experiencia publicada después de más de 10 años de experiencia clínicaInstituto de Salud Carlos III [Carlos III Health Institute] (PI10/00072), REDINREN (Red de Investigación Renal [Renal Research Network]) (RD012/0021

Effects of the Use of Non-Calcium Phosphate Binders in the Control and Outcome of Vascular Calcifications: A Review of Clinical Trials on CKD Patients

Vascular calcifications produce a high impact on morbidity and mortality rates in patients affected by chronic kidney disease and mineral bone disorder (CKD-MBD). Effects are manifested from the more advanced stages of CKD (stages 3-4), particularly in patients undergoing dialysis (CKD5D). In recent years, a large number of therapeutic options have been successfully used in the treatment of secondary hyperparathyroidism (SHPT), despite eliciting less marked effects on nonbone calcifications associated with CKD-MBD. In addition to the use of Vitamin D and analogues, more recently treatment with calcimimetic drugs has also been undertaken. The present paper aims to analyze comparative and efficacy studies undertaken to assess particularly the impact on morbidity and mortality rates of non-calcium phosphate binders. Moreover, the mechanism of action underlying the depositing of calcium and phosphate along blood vessel walls, irrespective of the specific contribution provided in reducing the typical phosphate levels observed in CKD largely at more advanced stages of the disease, will be investigated. The aim of this paper therefore is to evaluate which phosphate binders are characterised by the above action and the mechanisms through which these are manifested

Preclinical Pharmacokinetics, Pharmacodynamics and Safety of Sucroferric Oxyhydroxide.

Sucroferric oxyhydroxide (VELPHORO(®)) is a polynuclear iron-based phosphate binder recently approved for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). As a number of the available phosphate binders do not provide the optimal combination of good efficacy, adequate tolerability and low pill burden, sucroferric oxyhydroxide constitutes a promising alternative. Among the attributes of an ideal phosphate binder is minimal absorption and, hence, low risk of systemic toxicity. Accordingly, the iron-releasing properties and absorption, distribution, metabolism and excretion (ADME) profile of sucroferric oxyhydroxide, as well as the possibility of iron accumulation and toxicity, were investigated in a series of preclinical studies. The effect of sucroferric oxyhydroxide on the progression of vascular calcification was also investigated. Sucroferric oxyhydroxide exhibited a high phosphate-binding capacity and low iron-releasing properties across the physiological pH range found in the gastrointestinal tract. In the ADME studies, uptake of (59)Fe-radiolabelled sucroferric oxyhydroxide was low in rats and dogs (<1% from a 50 mg Fe/kg bodyweight dose), with the majority of absorbed iron located in red blood cells. Long-term (up to 2 years) administration of sucroferric oxyhydroxide in rats and dogs was associated with modest increases in tissue iron levels and no iron toxicity. Moreoever, in uraemic rats, sucroferric oxyhydroxide was associated with reduced progression of vascular calcification compared with calcium carbonate. In conclusion, sucroferric oxyhydroxide offers a new option for the treatment of hyperphosphataemia, with a high phosphate-binding capacity, minimal iron release, and low potential for iron accumulation and toxicity