Aluminum-based Phosphate Binders Research Articles

Aluminum overload in the reverse osmosis dialysis era: does it exist?

Background Aluminum accumulation is a well-described complication in dialysis patients. Improvements in hemodialysis technology have possibly eliminated the occurrence of aluminum overload. Limited evidence suggests that aluminum overload may decline in the era of aluminum removal from dialysis fluids, even with the use of aluminum binders. Methods We examined the data from January 2014 to June 1, 2020, identified through our electronic records, to evaluate the desferrioxamine (DFO) test results for aluminum overload. The presentation and treatment of aluminum overload were recorded. Results Ninety-nine dialysis patients were enrolled for the DFO test. Forty-seven patients (47.5%) were identified as DFO test positive for aluminum overload, of which 14 (14/47) patients had symptoms, including one patient with an unexplained fracture, eight patients with unexplained anemia despite high-dose erythropoiesis-stimulating agents, and five patients with hypercalcemia (serum calcium >11 mg dL-1). None of the patients with aluminum overload developed encephalopathy. Only four of the 47 patients had microcytic anemia. Patients requiring longer treatments (>10 months versus <10 months) had similar basal serum aluminum (p = 0.219) but had an increase in serum aluminum after DFO (p = 0.041). Furthermore, the treatments decreased erythropoietin doses in the aluminum overload group, with serum total alkaline phosphatase levels <60 U L-1 (p = 0.028). Conclusion We concluded that aluminum overload existed in the reverse osmosis dialysis era. In light of non-obvious symptoms, such as anemia and bone turnover change, serum aluminum in dialysis patients should be monitored in countries using aluminum-based phosphate binders, despite reverse osmosis dialysis.

MP692ELEVATED FGF23-LEVELS IN DIALYSIS PATIENTS TREATED WITH ALUMINUM BASED PHOSPHATE BINDERS

MP692ELEVATED FGF23-LEVELS IN DIALYSIS PATIENTS TREATED WITH ALUMINUM BASED PHOSPHATE BINDERS

Hemodialysis practice patterns in the Russia Dialysis Outcomes and Practice Patterns Study (DOPPS), with international comparisons.

There is little comparable information about hemodialysis (HD) practices in low- and middle income countries, including Russia. Evaluation of HD in Russia and its international comparisons could highlight factors providing opportunities for improvement. We examined treatment patterns for 481 prevalent HD patients in 20 Russian facilities, and compared them to contemporary data for 8512 patients from 311 facilities in seven European countries, Japan, and North America. Data were collected according to the uniform methodology of the Dialysis Outcomes and Practice Patterns Study, phase 5. Compared to other regions, Russian patients were younger (mean age 53.4 years), had a lower percent of males (52.5%), higher arteriovenous fistula use (89.7%), and longer treatment time (mean: 252 minutes, SD: 37 minutes). Mean single pool Kt/V was 1.49 (SD 0.58). Prescription of dialysate calcium 3.5 mEq/L and aluminum-based phosphate binders were high (15.2% and 17.6% of patients, respectively), while intravenous vitamin D and cinacalcet were low (3.3% and 2.2%, respectively). The percents with parathyroid hormone >600 pg/mL (30.9%) and serum phosphate >1.78 mmol/L (37.7%) were high. Use of erythropoetin stimulating agents (78%) was lower, but hemoglobin, ferritin, and transferrin saturation were generally comparable to North America and Europe. These detailed data for hemodialysis in Russia demonstrate that many practice patterns contrasted sharply to those in Europe, Japan, and North America, while other features were similar. Our analysis revealed several positive and some less favorable treatment patterns in Russia that represent opportunities for improving patient care and outcomes.

Phosphate levels in patients treated with low-flux haemodialysis, pre-dilution haemofiltration and haemodiafiltration: post hoc analysis of a multicentre, randomized and controlled trial

Whether convective therapies allow better control of serum phosphate (P) is still undefined, and no data are available concerning on-line haemofiltration (HF). The objectives of the study are to evaluate the effect of convective treatments (CTs) on P levels in comparison with low-flux haemodialysis (HD) and to evaluate the correlates of serum phosphate in a post hoc analysis of a randomized clinical trial. This analysis was performed in the database of a multicentre, open label and randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: on-line pre-dilution HF (36 patients) or on-line pre-dilution haemodiafiltration (40 patients). CTs did not affect P (P = 0.526), calcium (Ca) (P = 0.849) and parathyroid hormone levels (P = 0.622). P levels were associated with the use of phosphate binders including aluminium-based phosphate binders (P < 0.001) and sevelamer (P < 0.001), pre-dialysis bicarbonate levels (P < 0.001) and pre-dialysis blood K levels (P < 0.001). On multivariate analysis (generalized linear model), serum P was again largely unassociated with CTs (P = 0.631). Notably, participating centres were by far the strongest independent correlate of serum P, explaining 45.3% of the variance of serum P over the trial and this association was confirmed at multivariate analysis. Bicarbonate (P < 0.001) and, to a weaker extent, serum K (P = 0.032) were independently related to serum P. In comparison with low-flux HD, CTs did not significantly affect serum P levels. Participating centres were the main source of P variability during the trial followed by treatment with phosphate binders, serum bicarbonate and, to a weak extent, serum potassium levels (ClinicalTrials.gov Identifier: NCT011583309).

New thoughts concerning the epidemic of rickets: was the role of alum overlooked?

Recent emphasis on the re-emergence of nutritional rickets has renewed interest in the etiology and therapy of this devastating disorder. At its peak in the 19th and 20th century, rickets was a major area of study for countless experts in childhood disorders and numerous theories abounded as to its cause. These included, among others, infections, confinement or intestinal disturbances, and were largely discarded after the discovery of the role of vitamin D and the importance of ultraviolet irradiation. Once a good explanation had been found for the cause of the disorder and the curative power of vitamin D proven, whether it was obtained from the diet or through exposure to sunlight, there was no apparent need to look any further into the etiology of rickets. But in fact there may have been other contributory factors, recognition of which might have lessened the severity of the disease or hastened recovery. One of these theories might be of particular interest to pediatric nephrologists because it relates to insoluble aluminum-based phosphate binders. Namely, alum used as an adulterant in bread in certain locations may have contributed to metabolic bone disease during the great epidemic of rickets.

Do aluminium-based phosphate binders continue to have a role in contemporary nephrology practice?

BackgroundAluminium-containing phosphate binders have long been used for treatment of hyperphosphatemia in dialysis patients. Their safety became controversial in the early 1980's after reports of aluminium related neurological and bone disease began to appear. Available historical evidence however, suggests that neurological toxicity may have primarily been caused by excessive exposure to aluminium in dialysis fluid, rather than aluminium-containing oral phosphate binders. Limited evidence suggests that aluminium bone disease may also be on the decline in the era of aluminium removal from dialysis fluid, even with continued use of aluminium binders.DiscussionThe K/DOQI and KDIGO guidelines both suggest avoiding aluminium-containing binders. These guidelines will tend to promote the use of the newer, more expensive binders (lanthanum, sevelamer), which have limited evidence for benefit and, like aluminium, limited long-term safety data. Treating hyperphosphatemia in dialysis patients continues to represent a major challenge, and there is a large body of evidence linking serum phosphate concentrations with mortality. Most nephrologists agree that phosphate binders have the potential to meaningfully reduce mortality in dialysis patients. Aluminium is one of the cheapest, most effective and well tolerated of the class, however there are no prospective or randomised trials examining the efficacy and safety of aluminium as a binder. Aluminium continues to be used as a binder in Australia as well as some other countries, despite concern about the potential for toxicity. There are some data from selected case series that aluminium bone disease may be declining in the era of reduced aluminium content in dialysis fluid, due to rigorous water testing.SummaryThis paper seeks to revisit the contemporary evidence for the safety record of aluminium-containing binders in dialysis patients. It puts their use into the context of the newer, more expensive binders and increasing concerns about the risks of calcium binders, which continue to be widely used. The paper seeks to answer whether the continued use of aluminium is justifiable in the absence of prospective data establishing its safety, and we call for prospective trials to be conducted comparing the available binders both in terms of efficacy and safety.

Treating mineral metabolism disorders in patients undergoing long hemodialysis: A search for an optimal strategy

In hemodialysis (HD) patients, mineral metabolism (MM) disorders have been associated with an increased mortality rate. We report the evolution of MM parameters in a stable HD population undergoing long hemodialysis by performing an annual cross-sectional analysis for every year from 1994 to 2008. The therapeutic strategy has changed: the dialysate calcium concentration has decreased from a mean of 1.7 +/- 0.1 to 1.5 +/- 0.07 mmol/L and has been adapted to parathyroid hormone serum levels (from 1 to 1.75 mmol/L). The use of calcium-based and aluminum-based phosphate binders has decreased and they have been replaced by sevelamer; alfacalcidol has partly been replaced by native vitamin D. The percentage of patients with a parathyroid hormone serum level between 150 and 300 pg/mL has increased from 9% to 67% (P<0.001); the percentage of patients with phosphataemia between 1.15 and 1.78 mmol/L has increased from 39% to 84% (P<0.001). The percentage of those with albumin-corrected calcemia between 2.1 and 2.37 mmol/L has increased from 29% to 61% (P<0.001), and that of patients with a calcium-phosphorous product (Ca x P) level >4.4 mmol/L decreased from 8.8% to 2% (P=0.02). Although patients undergo long and intensive HD treatment, MM disorders are common. However, an appropriate strategy, mostly consisting of native vitamin D supplementation, progressive replacement of calcium-based phosphate binders with non-calcium-based ones, and individualization of dialysis session duration and dialysate calcium concentration, would result in a drastic improvement.

Management of Secondary Hyperparathyroidism in the Elderly Patient with Chronic Kidney Disease

Patients with chronic kidney disease (CKD) are generally affected by secondary hyperparathyroidism (SHPT). High phosphate, low calcium and vitamin D deficiency represent the classical 'triad' involved into the pathogenesis of SHPT in renal insufficiency, in which downregulation of the parathyroid vitamin D receptor and calcium-sensing receptor represents a critical step. Recently, new studies indicate that fibroblast growth factor 23 may play a central role in the regulation of phosphate-vitamin D metabolism in patients with CKD. These new insights into the pathogenesis of SHPT will possibly improve the treatment of this condition in patients with CKD. The 'modern' treatment of SHPT in CKD patients consists of free-calcium and aluminium phosphate binders, vitamin D receptor activators and calcimimetics. However, calcium- and aluminium-based phosphate binders and calcitriol are therapeutic tools that are not without complications, including increasing the risk of cardiovascular calcification in patients with CKD. This review summarizes the current understanding and evidence supporting strategies for SHPT treatment in CKD patients, with particular focus on the elderly, although specific guidelines for control of this disorder in this age group are lacking.

Optimising the treatment of hyperphosphatemia and vascular calcification in chronic kidney disease

Accelerated atherosclerosis and vascular calcifications (VC) play a central role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD) patients. Mineral metabolism disorders and increased serum calcium-phosphate product have been recently investigated as inducing factors of cardiovascular calcification. In fact, cardiovascular disease in renal failure appears greatly associated with bone metabolism alterations. Recently, the treatment of hyperphosphatemia in CKD patients changed from either calcium- or aluminium-based phosphate-binders to new free-calcium and aluminium phosphate binders, such as sevelamer hydrochloride and lanthanum carbonate. Therefore, control of serum phosphate in CKD patients becomes crucial in preventing increases in calcium-phosphate product, secondary hyperparathyroidism and ultimately VC.

Hyperphosphatemia in Dialysis Patients: The Therapeutic Role of Lanthanum Carbonate

Phosphate overload is a dramatic consequence in end-stage renal disease (ESRD) patients. Recent studies have well documented that abnormalities in mineral and bone metabolism in these patients are associated with increased cardiovascular morbidity and mortality. Elevated serum phosphate and calcium-phosphate product levels play an important role in the pathogenesis of secondary hyperparathyroidism and extra-skeletal calcification in dialysis patients. Furthermore, inorganic phosphate may cause vascular calcification directly through a real ""ossification"" of the tunica media in the vasculature of ESRD patients. The ""classical"" treatment of secondary hyperparathyroidism and hyperphosphatemia in ESRD patients consists of either calcium- or aluminum-based phosphate binders and calcitriol administration. Unfortunately, this ""old generation"" therapy is not free of complications. This review paper suggests that new calcium- and aluminum-free phosphate binders, such as lanthanum carbonate, can be used to treat hyperphosphatemia and secondary hyperparathyroidism in ESRD patients.

Lanthanum carbonate

Controlling hyperphosphatemia in patients with chronic renal failure on renal dialysis is a major problem. None of the available calcium- or aluminum-based phosphate binders match the requirements for an ideal agent, each having its own limitations. The introduction of sevelamer hydrochloride represented a step change in management. Lanthanum carbonate is an alternative nonaluminium, noncalcium phosphate binder. Taken with food, it is well tolerated. It is poorly absorbed and does not require functioning kidneys to be removed from the body. There is no evidence from current studies that it accumulates to biologically significant levels in tissues, but despite the large numbers of patients included in clinical trials, experience with long-term dosing is limited and, as with every new drug used in this type of clinical setting, patients should be carefully monitored as experience with the drug increases. Lanthanum carbonate binds phosphate effectively across the physiological pH range of the upper gastrointestinal tract, and has no detrimental effect on calcium, vitamin D or parathyroid hormone metabolism. From the extensive trial data it seems that lanthanum carbonate is an effective and practical phosphate binder. Lanthanum carbonate and sevelamer are two new oral phosphate binding agents that with others currently in preclinical trials, such as stabilized polynuclear iron idroxide, could well represent a significant breakthrough in the management of hyperphosphatemia in patients with chronic renal failure in whom dietary phosphate restriction and cheaper oral phosphate binding agents prove unsatisfactory. Comparative trials and enhanced clinical experience are needed before the exact place of these competing and complementary therapies can be properly identified in patient management.

Hyperphosphatemia and phosphate binders

The pathophysiology of hyperphosphatemia associated with end-stage renal disease and treatment with phosphate binders are discussed. Phosphorus is an essential element necessary for the normal function of the human body, required for skeletal construction and synthesis of DNA, proteins, and adenosine triphosphate. In healthy individuals, serum phosphorus concentrations are maintained between 2.5 and 4.5 mg/dL through diet and renal excretion. In renal insufficiency, phosphorus excretion declines and hyperphosphatemia develops. The body's compensation mechanisms cause secondary hyperparathyroidism and renal osteodystrophy. Phosphate binders provide an effective means for managing serum phosphate. Commercially available phosphate binders include calcium carbonate, calcium acetate, sevelamer, lanthanum, and, rarely, aluminum hydroxide. Because of aluminum's known toxicities, aluminum-based phosphate binders have a limited place in therapy. Calcium carbonate's benefits are seen over a narrow gastric pH range, thereby limiting the drug's utility. Calcium acetate is effective over a wide pH range. Other phosphate binders, including sevelamer hydrochloride and lanthanum carbonate, have recently entered the market, but their use remains controversial. If left untreated, hyperphosphatemia can result in secondary hyperparathyroidism, renal osteodystrophy, and metastatic calcification of blood vessels and soft tissue. The treatment of hyperphosphatemia in patients with chronic renal failure includes dialysis, dietary phosphorus restrictions, phosphate-binding medications, and vitamin D analogs. Selection of phosphate binders should be based on patient characteristics, including serum phosphate, serum calcium, and intact parathyroid hormone concentrations, and patient tolerability.

Plasma aluminium: a redundant test for patients on dialysis?

Aluminium toxicity as a cause of dementia, osteodystrophy and anaemia in patients receiving renal dialysis was first described in the 1970s and led to the regular monitoring of aluminium in plasma and dialysate water. However, aluminium phosphate binders have now been replaced by calcium-based binders or sevelamer and reverse osmosis (RO) water is used in the preparation of dialysate fluid. This has reduced the exposure of dialysis patients to aluminium and it is therefore opportune to review aluminium monitoring in patients undergoing regular renal dialysis. Plasma and water aluminium results were audited over the period January 2000-January 2004, with results obtained from nine renal dialysis units in the UK. Patients with a plasma aluminium concentration in the toxic range (>3.7 micromol/L) were followed up by contacting the relevant consultant. Plasma aluminium results were collected on 1626 patients over the four-year period (mean=0.47 micromol/L, median=0.3 micromol/L, range 0.07-30.26 micromol/L, n=5918). Forty-six patients had an aluminium concentration >3.7 micromol/L and nine were not retested. Only three patients had a repeat aluminium concentration >2.2 micromol/L, one being a result of desferrioxamine treatment, with no further clinical information available on the other two. All renal units are using RO water to prepare dialysate and aluminium-based phosphate binders are no longer prescribed. Only one of 212 RO water aluminium concentrations measured was >10 microg/L. Patients with clinical symptoms of overt aluminium toxicity were not identified in this population. The role of aluminium monitoring in long-term renal dialysis patients needs re-evaluation. Regular monitoring of plasma aluminium may not be required, but should be considered in any patient showing signs or symptoms of aluminium toxicity or exposed to a contaminated water supply. It is more important that RO water supplies are maintained and monitored. Environmental aluminium as a source of sample contamination should be considered and eliminated during blood collection and sample processing.

Safety and Efficacy of Sevelamer in the Treatment of Uncontrolled Hyperphosphataemia of Haemodialysis Patients

Background/Aim: The treatment of hyperphosphataemia is of major importance in the management of patients on dialysis. Traditional phosphate binders can be associated with undesirable effects. Recently, a new non-absorbable phosphate-binding polymer, sevelamer hydrochloride, has been available. Clinical information is scarce, and its cost could be a limiting factor for its wider use. No studies have evaluated its usefulness in uncontrolled hyperphosphataemic patients. Methods: We identified 34 patients with a maintained serum phosphorus concentration >6.5 mg/dl and/or toxicity related to standard phosphorus-binding treatment (aluminium or calcium based). Sevelamer was added and titrated up fortnightly to achieve phosphorus control. Previous phosphate binders were decreased, whenever possible. The period of the study was 6 months. Results: Thirteen patients (38%) dropped out because of side effects, mainly related to the gastro-intestinal tract. The efficacy analysis disclosed that the phosphorus concentration decreased from 2.39 ± 0.48 to 1.84 ± 0.48 mmol/l (p < 0.001). The mean dose of sevelamer was stabilised at 3.4 ± 1.8 g/day. The amount of calcium- and aluminium-based phosphate binders could be decreased from 5.1 ± 3.5 to 3.1 ± 2.7 g/day (38% decrease) and from 2.4 ± 1.5 to 1.5 ± 1.7 g/day (36% decrease), respectively. The Ca × P product was significantly decreased from 5.83 ± 1.19 to 4.36 ± 1.12 mmol/l² (p < 0.001). The total cholesterol concentration decreased from 4.34 ± 0.9 to 3.98 ± 0.9 mmol/l (p < 0.01) and the low-density lipoprotein cholesterol level from 2.61 ± 0.98 to 2.20 ± 0.77 mmol/l (p < 0.03). Conclusions: Sevelamer is an effective phosphate binder that allows a better serum phosphorus control, while allowing a decrease in the dose of calcium- and aluminium-based phosphate binders in these difficult patients. The drawbacks are the high intolerance rate and the price of the product.

Nicotinamide suppresses hyperphosphatemia in hemodialysis patients

The use of calcium- or aluminum-based phosphate binders against hyperphosphatemia is limited by the adverse effects of hypercalcemia or aluminum toxicity in long-term hemodialysis. Because nicotinamide is an inhibitor of sodium-dependent phosphate cotransport in rat renal tubule and small intestine, we examined whether nicotinamide reduces serum levels of phosphorus and intact parathyroid hormone (iPTH) in patients undergoing hemodialysis. Sixty-five hemodialysis patients with a serum phosphorus level of more than 6.0 mg/dL after a 2-week washout of calcium carbonate were enrolled in this study. Nicotinamide was administered for 12 weeks. The starting dose was 500 mg/day, and the dose was increased by 250 mg/day every 2 weeks until serum phosphorus levels were well controlled at less than 6.0 mg/dL. A 2-week posttreatment washout period followed the cessation of nicotinamide. Blood samples were collected every week for measurement of serum calcium, phosphorus, lipids, iPTH, and blood nicotinamide adenine dinucleotide (NAD). The mean dose of nicotinamide was 1080 mg/day. The mean blood NAD concentration increased from 9.3 +/- 1.9 nmol/105 erythrocytes before treatment to 13.2 +/- 5.3 nmol/105 erythrocytes after treatment (P < 0.01). The serum phosphorus concentration increased from 5.4 +/- 1.5 mg/dL to 6.9 +/- 1.5 mg/dL with the pretreatment washout, then decreased to 5.4 +/- 1.3 mg/dL after the 12-week nicotinamide treatment (P < 0.0001), and rose again to 6.7 +/- 1.6 mg/dL after the posttreatment washout. Serum calcium levels decreased during the pretreatment washout from 9.1 +/- 0.8 mg/dL to 8.7 +/- 0.7 mg/dL with the cessation of calcium carbonate. No significant changes in serum calcium levels were observed during nicotinamide treatment. Median serum iPTH levels increased with pretreatment washout from 130.0 (32.8 to 394.0) pg/mL to 200.0 (92.5 to 535.0) pg/mL and then decreased from the maximum 230.0 (90.8 to 582.0) pg/mL to 150.0 (57.6 to 518.0) pg/mL after the 12-week nicotinamide treatment (P < 0.05). With nicotinamide, serum high-density lipoprotein (HDL) cholesterol concentrations increased from 47.4 +/- 14.9 mg/dL to 67.2 +/- 22.3 mg/dL (P < 0.0001) and serum low-density lipoprotein (LDL) cholesterol concentrations decreased from 78.9 +/- 18.8 mg/dL to 70.1 +/- 25.3 mg/dL (P < 0.01); serum triglyceride levels did not change significantly. Nicotinamide may provide an alternative for controlling hyperphosphatemia and hyperparathyroidism without inducing hypercalcemia in hemodialysis patients.

The importance of bone health in end-stage renal disease: out of the frying pan, into the fire?

In the early stages of renal failure, hyperparathyroidism develops as a compensatory mechanism to control serum levels of calcium, phosphorus and calcitriol. As kidney disease progresses, this ability to maintain mineral homeostasis is lost, leading to the development of renal osteodystrophy (ROD). Over the past decade, the pattern of ROD seen in patients with chronic kidney disease (CKD) has changed. Previously, the majority of patients had mixed uraemic osteodystrophy or aluminium-related osteomalacia. The decreased use of aluminium-based phosphate binders, coupled with improvements in the management of hyperphosphataemia, led to a reduction in the prevalence of these types of ROD. Since the mid-1990s, there has been an increase in the prevalence of adynamic bone disease as a result of increased suppression of parathyroid hormone through the use of calcium-based phosphate binders and calcitriol therapy. Adynamic bone disease is also associated with several clinical factors, such as older age, use of continuous ambulatory peritoneal dialysis and the presence of diabetes mellitus, as well as the use of calcitriol therapy. Studies of calcium metabolism in patients with CKD have shown that adynamic bone disease is a distinct clinical condition that leads to hypercalcaemia via mechanisms different from that seen in high-turnover bone disease. As high calcium x phosphorus product has been associated with soft tissue and vascular calcifications, and increased mortality, optimizing bone health may be an important way of reducing cardiovascular risk in patients with CKD. To do this, novel, effective, non-calcium, non-aluminium phosphate binders will be necessary.

Aluminium in over-the-counter drugs: risks outweigh benefits?

In the early 1970s, aluminium toxicity was first implicated in the pathogenesis of clinical disorders in patients with chronic renal failure involving bone (renal osteomalacia) or brain tissue (dialysis encephalopathy). Before that time the toxic effects of aluminium ingestion were not considered to be a major concern because absorption seemed unlikely to occur. Meanwhile, aluminium toxicity has been investigated in countless epidemiological and clinical studies as well as in animal experiments and many papers have been published on the subject. It is now commonly acknowledged that aluminium toxicity can be induced by infusion of aluminium-contaminated dialysis fluids, by parenteral nutrition solutions, and by oral exposure as a result of aluminium-containing pharmaceutical products such as aluminium-based phosphate binders or antacid intake. Over-the-counter antacids are the most important source for human aluminium exposure from a quantitative point of view. However, aluminium can act as a powerful neurological toxicant and provoke embryonic and fetal toxic effects in animals and humans after gestational exposure. Despite these facts, the patient information leaflets from European antacids that are available OTC show substantial differences regarding warnings from aluminium toxicity. It seems advisable that all patients should receive the same information on aluminium toxicity from patient information leaflets, in particular with regard to the increased absorption through concomitant administration with citrate-containing beverages and the use of such antacids during pregnancy.

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

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. Discussion in order to achieve a consensus on key points relating to pathogenesis, clinical assessment, and management of renal osteodystrophy in dialysis patients. 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. 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.

Aluminium and bone disease in chronic renal failure.

Aluminium is absorbed by the intestines and is rapidly transported into bone, where it disrupts mineralization and bone cell growth and activity. Its toxicities result in or exacerbate painful forms of renal osteodystrophy, most notably adynamic bone disease and osteomalacia, but also other forms of the disease. Because aluminium is sequestered in bone for long periods, its toxic effects are cumulative. As a result, even intermittent or low-dose use of aluminium-based phosphate binders adds to the total load of this toxin in the bone; thus, aluminium use is inadvisable, even for a 'rescue indication'. Aluminium blood levels are not a reliable marker of aluminium absorption or organ load in dialysis patients: only stainable aluminium at the mineralization front reflects the histopathological changes observed in bone. Therefore, bone biopsies remain the only approach for definitive diagnosis of aluminium-related bone disease. Most importantly, lack of correlation between overall organ concentrations of a toxin, such as aluminium, and pathological changes does not rule out toxicity. Thus, the specific localization of the toxin is more important than overall organ concentration. What has been observed with aluminium during 25 years of research might be reproduced with other metals that are absorbed, transported and accumulated in bone. What we have learned about the toxicity of aluminium should inform our interpretation of data from studies of other metal-based therapeutics for renal patients. This calls for careful evaluation of any newly introduced therapeutic agents for bone disease in patients lacking excretory kidney function.

Dementia in patients undergoing long-term dialysis: aetiology, differential diagnoses, epidemiology and management.

Dementia in patients undergoing long-term dialysis has not been clearly defined; however, four different entities have been described. Uraemic encephalopathy is a complication of uraemia and responds well to dialysis. Dialysis encephalopathy syndrome, the result of acute intoxication of aluminium caused by the use of an aluminium-containing dialysate, was a common occurrence prior to 1980. However, using modern techniques of water purification, such acute intoxication can now be avoided. Dialysis-associated encephalopathy/dementia (DAE) is always associated with elevated serum aluminium levels. Pathognomonic morphological changes in the brain have been described, but the mechanism for the entry of aluminium into the CNS is incompletely understood. The mechanisms involved in the pathogenesis of the neurotoxicity associated with aluminium are numerous. Although only a very small fraction of ingested aluminium is absorbed, the continuous oral aluminium intake from aluminium-based phosphate binders, and also of dietary or environmental origin, is responsible for aluminium overload in dialysis patients. Age-related dementia, especially vascular dementia, occurs in patients undergoing long-term dialysis as frequently as it does in the general population. The differential diagnoses of dialysis-associated dementias should include investigation for metabolic encephalopathies, heavy metal or trace element intoxications, and distinct structural neurological lesions such as subdural haematoma, normal pressure hydrocephalus, stroke and, particularly, hypertensive encephalopathy and multi-infarct dementia. To prevent DAE, dietary training programmes should aim to achieve the lowest phosphate intake and pharmacological tools should be used to keep serum phosphate levels below 2 mmol/L. To prevent vascular dementia, lifestyle modification should be undertaken, including optimal physical activity and fat intake, nicotine abstinence, and targeting optimal blood glucose, cholesterol and triglyceride levels, and blood pressure, to those outlined in current recommendations.