A confusional state associated with use of lanthanum carbonate in a dialysis patient: a case report

Sir, Muller and colleagues report a case of febrile confusion and ‘diverticular flare-up’ with abdominal pain and speculate an association with lanthanum carbonate (LC) because discontinuation of LC treatment and initiation of antibiotic therapy led to recovery [1]. They support their argument with the radiographic detection of lanthanum particles in the gastrointestinal tract, a reduction of plasma lanthanum levels following discontinuation of treatment and a selective review of the literature. However, there is no convincing argument for an association with LC treatment. The only available presentation of LC (FOSRENOL®, Shire Pharmaceuticals, Basingstoke, UK) is a chewable tablet containing no excipients to aid dispersal. Tablets should be taken with or immediately after meals and should be chewed completely; intact tablets should not be swallowed [2]. The size of the lanthanum particles evident in the radiograph is consistent with that of chewed LC, as has been seen in other published reports and not been associated with gastrointestinal obstruction [3,4]. As expected, and noted by the authors, the lanthanum particles ‘continued to migrate through the digestive tract’. In contrast, the case report by Kurtz (sic) et al. (Kongress der Gesellschaft fur Nephrologie, Tubingen, Germany, 2008) cited by Muller clearly showed the presence of un-chewed tablets. Speculation that deposition of lanthanum in the central nervous system (CNS) resulted in the confusional state draws on controversial evidence from in vivo studies [5,6]. Recent data from a study examining the potential for contamination of tissue samples in dietary studies of LC leads one to question the validity of this evidence [7]. In this study comparing dietary, oral gavage and intravenous administration, lanthanum was only detectable in brain tissue from rats administered LC in their diet. It appears that despite stringent efforts to limit contamination, lanthanum is still transferred to tissue samples during autopsy [7]. In another recent study, Bervoets et al. demonstrated no difference in the brain concentrations of lanthanum between healthy rats and those with chronic renal failure treated by oral gavage with LC for 20 weeks [8]. Levels remained around the lower limit of quantification for the assay. The results of these studies add to the weight of evidence in the literature that lanthanum does not cross the blood–brain barrier, even in the uraemic inflammatory and other disease states [8–10]. In the study by Feng et al., which suggests alteration of CNS function with lanthanum treatment, changes in biochemical parameters were not dose dependent and not predictive of effects in humans as discussed in the literature [6,11]. In addition, the authors do not consider the clinical data on the effects of LC on cognitive function [12]. Altmann et al. found no difference in the rate of cognitive decline in dialysis patients randomized to LC or standard phosphate-binder therapy (mainly calcium based) [12]. In this study, the median plasma lanthanum level of LC-treated patients stabilized at ∼0.3 (range 0.0–3.1) ng/mL. Therefore, the plasma lanthanum value of 2.13 μg/L noted by Muller et al. is neither ‘higher than normal’ compared with a population treated with LC for 2 years, nor is it associated with excessive cognitive decline. Extrapolation from in vivo tissue deposition data [8] based on human plasma lanthanum levels [13] is not scientifically sound and the conclusion that toxic levels of lanthanum can be reached in patients with renal failure is purely speculative, with no human or animal evidence provided. This patient was elderly and had diffuse cerebral atrophy on CT scan. Her presenting symptoms included dizziness with falling and confusion. Infection is commonly implicated with the etiology of several conditions that cause confusion in the elderly, and therapy of the underlying condition leads to recovery [14]. Benzodiazepine use is also commonly associated with confusion in the elderly. Either of these factors are plausible explanations for the confusion experienced by this patient. In summary, this patient with known diverticular disease presented with a febrile episode that responded to antibiotic treatment. The authors noted the expected radio-opaque appearance of lanthanum in the gastrointestinal tract and plasma lanthanum levels within the range observed in pivotal clinical trials. Neither finding has been convincingly linked to the patient's presentation; therefore, there are no grounds for revising the benefit–risk profile for LC. Conflict of interest statement. MS and RDP are employees of Shire Pharmaceuticals.