The beneficial effects of dietary P restriction have been demonstrated in experimentally induced and in naturally occurring feline CKD. In cats with surgically reduced renal mass, dietary restriction of P intake markedly decreased renal pathology [13
]. In a prospective study in cats with naturally occurring CKD, the mean survival time of the animals fed a veterinary diet restricted in P and protein was 2.4 times longer than that of cats maintained on a normal non-restricted maintenance diet. The beneficial effect was mainly attributable to P restriction [11
]. In a retrospective study, Plantinga et al.
] found similar effects on the survival time of cats fed different renal diets. A low level of dietary P was one of the main characteristics of the most effective diet.
In a prospective clinical trial, King et al.
] found a highly significant negative correlation between plasma P concentration and survival time. The relevance of serum P in CKD was further confirmed in a retrospective study on predictors of survival time: Boyd et al.
] found serum P concentration at time of diagnosis to be the only clinicopathologic variable tested that was predictive of survival.
Nutritional intervention to restrict P intake is considered as potentially effective to interrupt the vicious circle of inherent, progressive decline in renal function. In particular, the available evidence strongly supports the notion that this intervention is able to prevent renal secondary hyperparathyroidism and its sequelae [10
]. A number of kidney friendly diets for cats and dogs specifically designed to restrict P intake are commercially available. They have a reduced content of protein and P and are adapted to further support nutritional needs of CKD patients. Restriction of protein is an important means to reduce P content because animal protein sources are intrinsically rich in P. However, the palatability of protein-restricted diets appears to be reduced, and consequently they are often less well accepted [5
]. Dietary protein restriction must be carefully weighed against the risk of malnutrition and exacerbation of azotaemia, particularly in CKD patients where anorexia is already one of the most common signs.
Regular commercial maintenance diets for cats still remain relatively rich in P. In addition, the recommended daily requirement of P for adult cats appears to be overestimated [19
]. This is particularly true for older animals with a reduced renal capacity for P clearance. With progression of CKD, the degree of P restriction needs to increase accordingly [8
] which is difficult to achieve by mere restriction of P content in the feed through protein restriction.
As a potential alternative to dietary P restriction, or as an aid to further reduce the dietary burden of absorbable P beyond the technical and acceptance limits of restriction, an intestinal P binder can be added to the feed. Such agents bind diet-borne phosphate in the gastrointestinal tract and thereby reduce apparent P digestibility and systemic P availability.
In a recent review on the management of feline hyperphosphataemia, seven such P binding agents were listed: aluminium carbonate, aluminium hydroxide, aluminium oxide, calcium carbonate (with or without chitosan), calcium acetate, sevelamer hydrochloride, and lanthanum carbonate [10
]. These compounds are derived from human treatment of renal hyperphosphataemia. With the exception of Lantharenol®
(lanthanum carbonate octahydrate), none of the P binders listed above has so far undergone any formal assessment by regulatory agencies for safety and efficacy as P binders for veterinary use, be it as a feed additive or as a pharmaceutical drug. Lanthanum carbonate tetrahydrate (Fosrenol®
) is approved as a drug for treating hyperphosphataemia in human patients with end-stage CKD. Extensive trials proved that in this target population this P binder has few side-effects, which were mainly restricted to gastrointestinal tolerability [20
]. It is an effective agent without significant risk of hypercalcaemia or worsening metabolic acidosis, and clinical studies in humans have demonstrated its tolerability for short- and long-term administration [21
In the studies reported in the present paper, Lantharenol® was found to be well tolerated and efficacious to reduce systemic P availability in healthy cats as well. It was well accepted and tolerated by healthy cats fed standard moist feline maintenance diets non-restricted in P and protein. General health status, P balance, feed acceptance, body weight changes and serum P levels were used as the main indicators for tolerability and systemic tolerability of Lantharenol® in the range of feed concentrations tested, whereas the shift of P excretion from urinary to faecal excretion was used to assess efficacy.
Supplementation of feed with Lantharenol® produced no adverse effects on feed acceptance and behaviour up to a dose of 1 g/kg body weight (corresponding to 84 g/kg complete feed). During a total of more than 800 individual feeding sessions in both studies, feed supplementation with Lantharenol® was well accepted up to this maximal tolerated dose.
In the dose escalation study, vomiting first occurred at a dosage of 2 g/kg body weight in 7 out of 10 cats. As there had been an overall acceptance of the supplemented feed in all cats at dosages up to the maximal tolerated dose, it is assumed that acute gastrointestinal irritation and resulting gastrointestinal intolerability is the limiting factor for Lantharenol®
overdosing, consistent with findings reported in studies with Fosrenol®
in human patients [20
General health status and serum P levels were unaffected within the total dose range of Lantharenol® applied, including the maximal tolerated dose and beyond. Furthermore, there were no adverse effects on P balance, clinical haematology and blood chemistry values as determined in the dose-effect study.
In all groups including controls, body weights increased in the dose escalation study, and significantly decreased in the dose-effect study, even though the dosage of Lantharenol® amounted to only 2-20% of the maximal tolerated dose determined and daily feed intakes were unchanged. The most likely explanation for the observed weight loss is the inevitably stressful individual housing during the three day urine and faeces sampling period. Another possible explanation is that the cats in the dose-effect study were not fed according to their actual needs. The energy density was not declared on the feed label, and ad libitum feeding was recommended by the manufacturer. To avoid potential conflicts with nutritional demands, the cats were switched to this feed about a month before the official acclimatisation period to ensure that they were given an appropriate daily ration during the study. In any case, an effect of the test item on body weight can be excluded, as all groups including the control group that did not receive Lantharenol® were similarly affected, and feed intake was not affected by feed supplementation with Lantharenol®.
Lantharenol® proved to be an effective P binder with a dose dependent effect. Dosages of 1.6, 4.8 and 16 g/kg complete feed resulted in a dose related increase in faecal P excretion. This increase appeared to be accompanied by a decrease in urinary P excretion, but statistical evaluation failed to support this impression. This failure is likely related to the large standard deviations for urinary P excretion. Part of this variability could potentially have been overcome by longer sampling times and/or within subject analysis of changes in P excretion patterns from baseline. However, the experimental design of the dose-effect study did not foresee a baseline phase and hence did not allow for a within subject analysis.
Feed supplementation with Lantharenol®
reduced mean apparent P digestibility by up to 22%. Slightly lower but significant effects were observed with the lowest dosage tested (-15% mean apparent P digestibility at 1.6 g/kg complete feed). The results of a study by Wagner et al.
] showed a similar absolute reduction of P digestibility in a balance trial with healthy adult cats fed a commercial canned diet for senior cats supplemented with a formulation of calcium carbonate and chitosan. Positive effects of this formulation on serum P and parathyroid hormone levels in cats with surgically reduced renal mass were also described by Brown et al.
]. However, until prospective data on the safety and tolerability of calcium-based P binders become publicly available, the risk of hypercalcaemia with vascular and soft tissue calcification should be considered before using such agents in nutritional management of CKD in cats [9
]. In fact, where serum calcium concentrations are elevated, alternative calcium-free P binders are preferable.
Phosphorus binders based on aluminium have already been disfavoured for use in CKD because of the potential for development of aluminium toxicity [10
]. Possible adverse side effects have not yet been systematically evaluated in companion animals, but recently, two cases of aluminium toxicity following administration of aluminium-based P binders have been reported in dogs [24
Sevelamer hydrochloride (Renagel®
), an organic polymer, is a relatively new P binder used in human patients on renal dialysis. In rats with experimentally induced CKD, sevelamer significantly inhibited the occurrence of hyperphosphataemia and protected against deterioration of renal function, although the mode of action for the protective effect remains unclear [25
]. Its effects in companion animals have not yet been reported to our knowledge.