Cognitive Function in Stage 5 Chronic Kidney Disease Patients on Hemodialysis: No Adverse Effects of Lanthanum Carbonate Compared with Standard Phosphate-Binder Therapy

P Altmann; M E Barnett; W F Finn

Disclosures

Kidney Int. 2006;71(3):252-259. 

In This Article

Abstract and Introduction

Abstract

Patients with Stage 5 chronic kidney disease who have hyperphosphatemia require treatment with phosphate binders to lower serum phosphorus levels. Existing binders are effective but may be associated with important safety disadvantages. Lanthanum carbonate is a phosphate binder with demonstrated efficacy, safety, and tolerability in clinical trials. Changes in cognitive function were evaluated over time using the Cognitive Drug Research computerized cognitive assessment system (Simple Reaction Time, Digit Vigilance Task, Choice Reaction Time, Numeric Working Memory, and Delayed Picture Recognition) in 360 hemodialysis patients who were enrolled in a 2-year, multicenter, comparative study of lanthanum carbonate versus standard therapy. A decline in cognitive function from baseline was observed in both groups. The deterioration in cognitive function was similar in both the lanthanum carbonate and standard therapy groups. One parameter- Numeric Working Memory- showed a statistically significant between-group difference in favor of lanthanum carbonate (P=0.02). Given the magnitude of the changes, however, and the differences that were observed at baseline between treatment groups, the clinical significance of this difference is doubtful. This study demonstrates that cognitive function deteriorates in hemodialysis patients over a 2-year time period. Use of lanthanum carbonate as a phosphate binder does not adversely affect cognitive function compared with standard therapy.

Introduction

Hyperphosphatemia is a common complication seen in patients with Stage 5 chronic kidney disease (CKD). Uncontrolled hyperphosphatemia contributes to the development of secondary hyperparathyroidism, renal osteodystrophy, and vascular calcification. The latter has also been linked with an increased risk of cardiovascular mortality.[1,2] To reduce serum phosphorus levels, patients are treated with phosphate-binding agents. A number of effective agents are currently available, but all have certain disadvantages. Calcium salts, including calcium carbonate and calcium acetate, are currently the mainstay of therapy, but recent evidence suggests that high doses of ingested calcium over prolonged periods of time are associated with hypercalcemia and vascular calcification.[3,4] Sevelamer hydrochloride is a non-calcium, non-aluminum phosphate binder that has proven to be a useful addition to the current choices available. There are, however, some concerns, including gastrointestinal side effects, a tendency to metabolic acidosis, and a high pill burden.[5,6] A number of new agents are currently being investigated but little is known about their long-term safety and tolerability.[7,8]

Aluminum hydroxide is the most potent phosphate binder that is currently available, but its toxic effects include brain disease, bone disease, parathyroid suppression, and anemia.[9,10] The toxicity of aluminum in experimental animals was first observed in 1897,[11,12] with the earliest report in 1921 outlining similar effects in industrially exposed workers.[13] In 1976, the link between aluminum exposure and encephalopathy was first observed in dialysis patients.[14] Abnormalities in psychomotor function related to aluminum status have been observed in hemodialysis patients even though they had no overt clinical signs of aluminum toxicity.[15]

Studies of the cognitive effects in dialysis patients are particularly relevant, as there is anecdotal evidence and cross-sectional data to support a role for uremia and dialysis in reducing cognitive function.[16,17,18,19,20] Longitudinal data are limited, although a study in elderly individuals found that those with CKD (glomerular filtration rate <60 ml/min/1.73 m2) experienced a significantly greater decline in cognitive function compared with those with preserved renal function.[20] In addition, it has been demonstrated that cognitive brain dysfunction in hemodialysis patients may be fully reversed by successful renal transplantation.[16]

Lanthanum carbonate (Fosrenol®) is a phosphate binder that is effective and well tolerated in patients with Stage 5 CKD[21,22,23,24] and has similar phosphate-binding potency to aluminum hydroxide (Damment SJP, Webster I, Presented at the 36th Annual Meeting of the American Society of Nephrology, San Diego, CA, USA, 2003). Importantly, the bioavailability of lanthanum (0.00089%)[25] is substantially lower than that of aluminum (0.01%). There is no evidence from animal studies that lanthanum can cross the blood-brain barrier.[26,27] In fact, the impermeability of a number of other blood-tissue barriers to lanthanum has also been demonstrated, including the placenta and retina.[28,29] No functional or histopathological evidence of central nervous system toxicity of lanthanum has been identified in oral or intravenous studies with lanthanum carbonate in animals (Damment SJP, Greaves P, Downes N, Presented at the 36th Annual Meeting of the American Society of Nephrology, San Diego, CA, USA, 2003; Jones C, Webster I, Damment SJP, Presented at the 19th Congress of the ERA-EDTA, Lisbon, Portugal, 2004). Although brain lanthanum deposition has been reported recently in an animal model of renal failure,[30] this finding has been challenged as a contamination artifact,[31] as the mode of administration chosen (diet admixture) carried a high risk of sample contamination during autopsy. To allay fears about the potential for lanthanum to cause cognitive dysfunction in a similar manner to aluminum, we evaluated changes in cognitive function over time in hemodialysis patients who were receiving lanthanum carbonate or standard phosphate-binder therapy.

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