Control del fósforo y prevención de fracturas en el paciente renal / Control of phosphorus and prevention of fractures in the kidney patient

El paciente con enfermedad renal tiene incrementado el riesgo de fracturas, y a los factores habituales de la población general se suman otros propios de la uremia. Los mecanismos que favorecen las fracturas en la uremia no son suficientemente conocidos, aunque es ampliamente aceptado que la disminución del contenido mineral óseo y la alteración en la arquitectura ósea son responsables de un aumento en la fragilidad ósea. Con la progresión de la enfermedad renal crónica (ERC), el riesgo de fractura aumenta, siendo especialmente evidente cuando el paciente requiere diálisis. Dentro de las numerosas causas implicadas en el aumento de fracturas óseas se encuentran la edad avanzada, la amenorrea, la exposición a esteroides, el descenso de la vitamina D, el aumento de la hormona paratiroidea (PTH) y también la desnutrición y la inflamación crónica. La concentración de fósforo sérico ya sea alto o muy bajo también se ha correlacionado con el riesgo de fractura. El aumento del fosfato sérico puede afectar el metabolismo óseo directamente e indirectamente a través del desarrollo de mecanismos hormonales adaptativos que tratan de prevenir la hiperfosfatemia, como el aumento de PTH y el factor de crecimiento de fibroblastos 23 (FGF23), y la disminución del calcitriol. Estos mecanismos de adaptación son de menor intensidad si la absorción intestinal de fosforo se disminuye con el uso de captores de fósforo; los cuales parecen tener un impacto positivo en la reducción del riesgo de fracturas. En este documento se describirán los posibles mecanismos que relacionan el riesgo de fracturas con: los niveles de fósforo sérico, los mecanismos adaptativos propios de la enfermedad renal y el uso de fármacos para controlar la hiperfosfatemia. No existen estudios que proporcionen evidencia sobre la influencia de diversos tratamientos en el riesgo de fracturas en pacientes con enfermedad renal crónica. Sugerimos que el control del fósforo debería ser un objetivo a tener en cuenta

Patients with chronic kidney disease have a higher risk of fractures than the general population due to the added factor of uraemia. Although the mechanisms behind uraemia-associated fractures are not fully understood, it is widely accepted that the decrease in bone mineral content and alteration in bone architecture both increase bone fragility. As chronic kidney disease progresses, the risk of fracture increases, especially once the patient requires dialysis. Among the many causes of the increased risk are advanced age, amenorrhoea, steroid exposure, decreased vitamin D, increased parathyroid hormone (PTH), malnutrition and chronic inflammation. Serum phosphorus, whether high or very low, seems to correlate with the risk of fracture. Moreover, increased serum phosphate is known to directly and indirectly affect bone metabolism through the development of adaptive hormonal mechanisms aimed at preventing hyperphosphataemia, such as the increase in PTH and fibroblast growth factor 23 (FGF23) and the reduction in calcitriol. These adaptive mechanisms are less intense if the intestinal absorption of phosphorus is reduced with the use of phosphorus captors, which seem to have a positive impact in reducing the risk of fractures. We describe here the possible mechanisms associating serum phosphorus levels, the adaptive mechanisms typical in kidney disease and the use of drugs to control hyperphosphataemia with the risk of fractures. We found no studies in the literature providing evidence on the influence of different treatments on the risk of fractures in patients with chronic kidney disease. We suggest that control of phosphorus should be an objective to consider

Impacts of parathyroidectomy on calcium and phosphorus metabolism disorder, arterial calcification and arterial stiffness in haemodialysis patients.

BACKGROUND: Secondary hyperparathyroidism (SHPT) and calcium and phosphorus metabolism disorder are important complications in haemodialysis patients. Parathyroidectomy (PTX) may prevent or delay the progress of vascular calcification in haemodialysis patients. OBJECTIVE: To investigate the impacts of PTX on calcium and phosphorus metabolism, arterial calcification and arterial stiffness in haemodialysis patients with SHPT. METHODS: Twenty-one SHPT-haemodialysis patients were selected for PTX. The preoperative and postoperative 1-year scores of coronary artery calcification were measured via multislice spiral CT, along with the brachial-ankle pulse wave velocity (baPWV), and preoperative and postoperative 1-year indexes such as calcium, phosphorus, calcium-phosphorus product concentration and parathyroid hormone (PTH) level were compared. RESULTS: Compared with the preoperative score, the postoperative 1-year coronary artery calcification score was significantly reduced; the mean baPWVs of the bilateral limbs were reduced; and the levels of serum calcium, phosphorus, calcium-phosphorus product concentration and PTH were all reduced; all differences were statistically significant (P < 0.05). CONCLUSIONS: PTX can be used to correct calcium and phosphorus metabolism disorder, reduce arterial calcification, and improve arterial stiffness.

The phosphate binder equivalent dose.

Phosphate binders include calcium acetate or carbonate, sevelamer hydrochloride or carbonate, magnesium and lanthanum carbonate, and aluminum carbonate or hydroxide. Their relative phosphate-binding capacity has been assessed in human, in vivo studies that have measured phosphate recovery from stool and/or changes in urinary phosphate excretion or that have compared pairs of different binders where dose of binder in each group was titrated to a target level of serum phosphate. The relative phosphate-binding coefficient (RPBC) based on weight of each binder can be estimated relative to calcium carbonate, the latter being set to 1.0. A systematic review of these studies gave the following estimated RPBC: for elemental lanthanum, 2.0, for sevelamer hydrochloride or carbonate 0.75, for calcium acetate 1.0, for anhydrous magnesium carbonate 1.7, and for "heavy" or hydrated, magnesium carbonate 1.3. Estimated RPBC for aluminum-containing binders were 1.5 for aluminum hydroxide and 1.9 for aluminum carbonate. The phosphate-binding equivalent dose was then defined as the dose of each binder in g × its RPBC, which would be the binding ability of an equivalent weight of calcium carbonate. The phosphate-binding equivalent dose may be useful in comparing changes in phosphate binder prescription over time when multiple binders are being prescribed, when estimating an initial binder prescription, and also in phosphate kinetic modeling.

[The French clinician's guide to the Kidney disease: Improving global outcomes (KDIGO) for chronic kidney disease-mineral and bone disorders (CKD-MBD)]. / L'essentiel des nouvelles recommandations des kidney disease: improving global outcomes (KDIGO) pour les désordres du métabolisme minéral et osseux à l'usage du clinicien francophone.

The new recommendations of "Kidney disease: improving global outcomes" for the definition and classification of chronic kidney disease and mineral and bone disorders were released in August 2009. We report the most important of these recommendations and a brief comment from a clinician's point of view. The main points to be noted with regard to the new recommendations are as follows: serum calcium should be in the normal range; phosphorus concentration should be lowered toward the normal range and serum parathyroid hormone (PTH) levels should be two to nine times the upper limit of the normal range; bone remodelling can be assessed using alkaline phosphatase; the use of calcium-phosphorus (Ca x P) product as an index is not recommended anymore; at any stage of CKD, vitamin D deficiency and insufficiency must be corrected; vascular calcification should be detected in a simple way using lateral abdominal radiography and echocardiography; a bone biopsy should be performed before therapy with bisphosphonates; the prescription of dialysate calcium should be individualized within the range of 1.25-1.5 mmol/l; the phosphate binder (calcium- or non-calcium-based) and the other treatments for secondary hyperparathyroidism should be individualized based on a global strategy. A majority of these recommendations are not based on evidence and their feasibility and relevance need to be assessed.

[Prevalence and quality of control of calcium and phosphorus metabolism disorders among Lithuanian hemodialysis patients in 2004 and 2005]. / Kalcio ir fosforo apykaitos sutrikimu paplitimas, pobudis bei kontroles kokybe tarp Lietuvos hemodializuojamu ligoniu (2004-2005 metu duomenimis).

UNLABELLED: The aim of the study was to determine the prevalence and quality of control of disorders of calcium and phosphorus metabolism among patients on hemodialysis in Lithuania during the period of 2004-2005 and to assess rarely used methods of treatment such as parathyroidectomy and administration of calcimimetics. MATERIAL AND METHODS: All Lithuanian hemodialysis centers were visited, and data on disorders of calcium-phosphorus metabolism were collected in December 2004 and 2005. The quality of control was evaluated according to Kidney Disease Outcome Quality Initiative recommendations. RESULTS: According to Kidney Disease Outcome Quality Initiative guidelines, normal parathyroid hormone levels were found in 20.4% of hemodialysis patients in 2004 and 18.8% of hemodialysis patients in 2005; normal levels of phosphate were in 41.9% and 39.4%, respectively; normal levels of calcium were observed in 44.7% of patients in 2004 and in 42.3% of patients in 2005. In 2005 as compared to 2004, there were statistically significantly more patients with low parathyroid hormone level (39.9% and 45.8%, respectively, P<0.05). Only in 5.6% of patients in 2004 and 3.9% of patients in 2005, all four parameters of calcium-phosphate metabolism (calcium, phosphate, and of parathyroid hormone levels and calcium-phosphate product) were within the normal range. No parameters in the normal range were found in 17-20% of patients. The use of alfacalcidol significantly increased: 316 (30.8%) patients in 2004 and 388 (35.7%) patients in 2005 were treated with alfacalcidol (P<0.05). Alfacalcidol was prescribed for 16.5% of patients in 2004 and for 17% of patients in 2005, in whom parathyroid hormone level was below the normal range in the presence of hypercalcemia and hyperphosphatemia. The use of calcimimetics was considered rational in 142 (13.8%) patients in 2004 and 119 (10.9%) patients in 2005. According to the data of our study, parathyroidectomy was indicated in 19 (1.85%) patients in 2004 and 17 (1.56%) patients in 2005. CONCLUSIONS: According to Kidney Disease Outcome Quality Initiative recommendations, the control of disorders of calcium-phosphate metabolism in Lithuanian hemodialysis patients was insufficient in 2004 and 2005. One-third of the patients were treated with alfacalcidol when parathyroid hormone level was low and hypercalcemia and hyperphosphatemia persisted. Calcimimetics for the treatment of secondary hyperparathyroidism were administered in about 10% of patients.

Sevelamer and other anion-exchange resins in the prevention and treatment of hyperphosphataemia in chronic renal failure.

Sevelamer, or more precisely 'sevelamer hydrochloride', is a weakly basic anion-exchange resin in the chloride form that was introduced in 1997 for the treatment of the hyperphosphataemia of patients with end-stage renal failure, usually those on long-term haemodialysis. The rationale for this therapy was that sevelamer would sequester phosphate within the gastrointestinal tract, so preventing its absorption and enhancing its faecal excretion. Over the succeeding years, large numbers of patients have been treated with sevelamer, and it has fulfilled expectations in helping to control the hyperphosphataemia of end-stage renal failure. However, it is only one of many anion-exchange resins that could be used for this purpose, some of which are currently available for clinical use and are much less costly than sevelamer. Theoretical considerations suggest that some of these other resins might be at least as efficient as sevelamer in sequestering phosphate in the gastrointestinal tract. Neither sevelamer, nor any of these other agents, has been submitted to a proper metabolic balance study to measure the amount of phosphate sequestered by the resin in the bowel, and without this information it is impossible to judge which is the ideal resin for this purpose.

Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake.

Elevated serum phosphorus has been identified as a cardiovascular risk factor in chronic kidney disease (CKD) patients and a clear understanding of phosphorus homeostasis is very important for practicing nephrologists. At any particular point, serum phosphorus levels reflect the balance between movements of this mineral from and into the intestine, bone, intracellular space, and kidneys. We briefly review here all these exchanges with a particular emphasis on dietary phosphorus intake. Despite all the oral phosphorus binders currently available in the market, dietary restriction of this mineral remains a cornerstone for the prevention and treatment of hyperphosphatemia. An effective restriction of dietary intake of phosphorus requires prescription of a moderate protein intake (0.9-1.0 g/kg/day) and restricted consumption of highly processed fast and convenience foods. Phosphorus added during food processing is an important source of this mineral because of its magnitude and high bioavailabilty. Moreover, as food manufacturers are not required to label the amount of phosphorus added during food processing, a significant amount of the current daily phosphorus intake remains unaccounted when estimating phosphorus intake in CKD patients. The recent development of low phosphorus-containing food products represents a very useful addition for CKD patients.

Phosphorus balance with daily dialysis.

Hyperphosphatemia is an almost universal finding in patients with end-stage renal disease and is associated with increased all-cause mortality, cardiovascular mortality, and vascular calcification. These associations have raised the question of whether reducing phosphorus levels could result in improved survival. In light of the recent findings that increased per-session dialysis dose, as assessed by urea kinetics, did not result in improved survival, the definition of adequacy of dialysis should be re-evaluated and consideration given to alternative markers. Two alternatives to conventional thrice weekly dialysis (CHD) are nocturnal hemodialysis (NHD) and short daily hemodialysis (SDHD). The elimination kinetics of phosphorus as they relate to these alternative daily dialysis schedules and the clinical implications of overall phosphorus balance are discussed here. The total weekly phosphorus removal with NHD is more than twice that removed by CHD (4985 mg/week +/- 1827 mg vs. 2347 mg/week +/- 697 mg) and this is associated with a significantly lower average serum phosphorous (4.0 mg/dl vs. 6.5 mg/dl). In spite of the observed increase in protein and phosphorus intake seen in patients on SDHD, phosphate binder requirements and serum phosphorus levels are generally stable to decrease although this effect is strongly dependent on the frequency and overall treatment time.

Control of hyperphosphatemia beyond phosphate.

Hyperphosphatemia is a prevalent condition in the dialysis population and is associated with bad outcome. Block et al. present data from a post hoc analysis indicating that sevelamer, a noncalcium-containing phosphate binder, may confer a survival benefit in incident hyperphosphatemic hemodialysis patients. This is the first intervention study in the field of mineral metabolism showing a beneficial effect on a hard end point.

Multidisciplinary approach for prescriptive management of mineral and bone metabolism in chronic kidney disease: development of a dietetic led protocol.

BACKGROUND: A number of mineral metabolism abnormalities occur as kidney function declines, these include hyperphosphatemia, hyperparathyroidism and altered vitamin D metabolism. These derangements are associated with increased morbidity and mortality amongst the chronic kidney disease patient group. Treatment requires a multidisciplinary team approach in which the dietitian plays a pivotal role. OBJECTIVES: The development of protocols to aid implementation of various international, national and local treatment strategies is described. Audit the protocol to evaluate their clinical effectiveness. RESULTS: A prescriptive Protocol for the management of mineral and bone metabolism abnormalities in chronic kidney disease was developed and implemented. Initial audit findings suggest the protocol has had a positive effect on the control of phosphate, corrected calcium and parathyroid (PTH) levels. CONCLUSION: The development and implementation of a dietetic-led prescriptive therapy protocol allows dietitians and clinicians to adopt an integrated approach for the diagnosis and timely management of these complicated conditions.

The case against calcium-based phosphate binders.

Disturbances of mineral metabolism are associated with significant morbidity and mortality in patients with chronic kidney disease. Unfortunately, some of the treatments for these disturbances also have been found to be associated with morbidity. More recently, there is increasing evidence in the form of prospective, randomized trials that the use of calcium-based phosphate binders contributes to progressive coronary artery and aorta calcification compared with the non-calcium-containing binder sevelamer. Moreover, there is compelling biologic plausibility that hyperphosphatemia and excess exogenous calcium administration can accelerate vascular calcification. Unfortunately, there is no bedside test that can determine whether there is a dose of calcium salts (either as maintenance or as cumulative dose) that can be administered safely, and, unfortunately, the serum calcium concentration does not reflect calcium balance. Therefore, calcium-based phosphate binders should be avoided in many, if not most, patients who are undergoing dialysis.

Calcium-based phosphate binders are appropriate in chronic renal failure.

Many nephrologists feel threatened by the allegation that, in patients with chronic renal failure, treatment with calcium-based phosphate binders (calcium acetate and calcium carbonate) may induce coronary artery and cardiac calcification, thereby imposing a greater risk for death compared with sevelamer, a non-calcium-based binder. Acknowledging that drug manufacturers are not unaware of the marketing advantage to their product consequent to destabilizing demand for competing drugs, the case for and against abandoning calcium-based phosphate binders in favor of sevelamer is reviewed in this study. The case for continuing prescription of calcium-based phosphate binders stands on the following: (1) flawed clinical trials that favor sevelamer as a replacement; (2) weak evidence that oral calcium intake modulates vascular and/or cardiac calcification; (3) clinical trials that reinforce the safety and efficacy of calcium-based phosphate binders; and (4) the inordinate relative cost of sevelamer. Recognizing that established as well as novel phosphate binders are currently undergoing clinical evaluation, an open mind and an awareness of developing literature are necessary when deciding how to manage hyperphosphatemia in renal failure.