Feline chronic kidney disease (CKD) is a common condition with the prevalence increasing with advancing age. Reduction in the number of functioning nephrons affects the homeostasis of a number of solutes primarily excreted in the urine, including phosphorus. Hyperphosphataemia is thought to be the initiating factor in the development of secondary renal hyperparathyroidism with parathyroid hormone (PTH) concentrations increased in 84% of cats with CKD. As serum phosphorus concentration is associated with survival of cats with CKD, it is an important consideration when treating these cases.
Complex interactions between circulating ionised calcium, inorganic phosphorus, PTH, calcidiol, calcitriol, and fibroblast growth factor 23 (FGF-23) occur during CKD. Relative and absolute deficits of calcitriol are central in the genesis of renal secondary hyperparathyroidism. Though not emphasized until very recently, deficits of calcidiol are also common in CKD and may contribute to renal secondary hyperparathyroidism. Total body phosphorus burden and increasing concentration of circulating phosphorus play a pivotal role in the development of renal secondary hyperparathyroidism and are intimately related to dynamics of calcitriol and FGF-23.
The kidney plays a pivotal role in regulating phosphorus balance, as it is the primary route of phosphorus excretion. Serum phosphorus concentrations represent the net balance between dietary intake and renal excretion of phosphorus. If dietary phosphorus intake remains constant, a decline in glomerular filtration rate (GFR) will lead to phosphorus retention and ultimately hyperphosphataemia. However, during the early stages of CKD, serum phosphorus concentrations typically remain within the normal range because of a compensatory decrease in phosphorous reabsorption in the surviving nephrons. This renal tubular adaptation is a consequence of the phosphaturic effects of FGF-23 and PTH. Renal excretion of phosphorous is enhanced by reducing the tubular transport maximum for phosphorous reabsorption in the proximal tubule via the adenyl cyclase system. When the GFR declines below 20% of normal, this adaptive effect reaches its limit and hyperphosphataemia ensues. In CKD, serum phosphorus concentrations typically parallel serum urea concentration. Thus hyperphosphataemia is common in azotaemic but not in non-azotaemic renal disease.
The primary consequence of phosphorus retention and hyperphosphatemia is progression of CKD with serum phosphorus concentrations directly proportional to increased mortality.
The combination of hyperphosphataemia and a normal serum calcium concentration produces an elevated calcium-phosphate product (Ca × PO4). If the calcium phosphate product exceeds approximately 6 (SI units), there is a tendency for calcium to precipitate in blood vessels, joints, and soft tissues. Metastatic calcification is especially prominent in the stomach, kidneys, myocardium, lung, and liver.
Control of Hyperphosphataemia
Maintaining serum phosphorus concentrations within the normal range, as renal function is lost requires modification of phosphorus intake. In theory, optimum control of hyperphosphatemia would be achieved by reducing dietary phosphorus intake proportionally to the decrease in GFR. Without treatment, phosphorus retention, and subsequently hyperphosphataemia and renal secondary hyperparathyroidism, occurs in most cats with CKD stages 2–4. Minimizing phosphorus retention and hyperphosphataemia appears to slow progression of CKD and prolong survival.
Impaired renal perfusion (prerenal azotaemia) promotes increased serum phosphorus concentrations, so the first step in correcting hyperphosphataemia is to assure adequate hydration. Minimizing hyperphosphataemia may be accomplished by limiting dietary phosphorus intake, oral administration of agents that bind phosphorus within the lumen of the intestines, or a combination of these methods. The usual approach is to start with dietary therapy with the addition of phosphorous-binding agents if dietary therapy is ineffective. It remains unclear whether normalization of PTH levels is an important therapeutic goal in cats with CKD.
Intervention to manage serum phosphorus concentration is indicated for cats with stages 2–4 CKD when serum phosphorus concentration rises above the therapeutic target concentration. Ideally, serum phosphorus concentration should be maintained below the target values of 1.45 mmol/l (4.5 mg/dL) in stage 2, 1.61 mmol/l (5 mg/dL) in stage 3, and 1.94 mmol/l (6 mg/dL) in stage 4.
Blood samples for serum phosphorus concentration should be collected after a 12-hour fast to avoid postprandial effects. Sample haemolysis should be avoided as erythrocytes contain significant quantities of phosphorus.
Dietary Phosphorus Restriction
Dietary therapy with or without phosphate-binding agents normalises serum phosphorus levels in most stage 2 and many stage 3 cats.
Typical commercial cat foods contain from 1–4% phosphorus on a dry matter basis and provide about 2.9 mg/kcal or more phosphorus. Modified protein diets designed for cats with CKD may contain as little as 0.5% phosphorus on a dry-matter basis and provide about 0.9 mg/kcal of phosphorus. High dietary phosphorus content may greatly limit the effectiveness of phosphorus-binding agents, or substantially increase the dosage required to achieve the desired therapeutic effect. Because of the high phosphorus content of typical maintenance cat foods, it is unlikely that treatment targets can be achieved solely by using phosphate-binding agents with maintenance diets.
As dietary phosphorus restriction reduces serum phosphorus levels, phosphorus leaches out of tissues, which delays the overall reduction in serum phosphorus concentration. Thus the overall efficacy of dietary phosphorus restriction in reducing serum phosphorus concentrations may not occur for several weeks after instituting a phosphorus-restricted diet.
Intestinal Phosphate Binders
If after 4–8 weeks dietary therapy alone fails to maintain the serum phosphorus concentrations below the target value, addition of an intestinal phosphate-binding agent should be used to reduce serum phosphorus concentration below the target concentration.
The most commonly used intestinal phosphate binder contains aluminium as hydroxide, oxide, or carbonate salts. Because of concern about aluminium toxicity in humans, aluminium-containing agents are becoming more difficult to obtain. Although aluminium-containing binding agents usually appear to be well tolerated and safe in animals, aluminium toxicity has been reported in dogs with advanced CKD treated with high doses of aluminium-containing binding agents, but not in cats.
Alternative drugs that do not contain aluminium include calcium carbonate, calcium acetate, sevelamer hydrochloride, lanthanum carbonate, or sucralfate. Experience with these drugs in cats is, however, limited and hypercalcaemia can be a problem with the calcium-based products, particularly when administered with calcitriol. Lanthanum carbonate and other salts of lanthanum appear to be quite effective and are associated with minimal side effects. Lanthanum is reportedly minimally absorbed from the intestinal tract, thus may be of reduced toxicity risk compared with aluminium salts; however, they are substantially more expensive.
Phosphate binders need to be given around feeding, as the goal is to bind the phosphorus in the diet. Given away from feeding markedly reduces their effectiveness. Calcium-based phosphate-binding agents that are given between meals function primarily as a calcium supplement rather than as a phosphate binder.
Phosphate binders are generally administered "to effect" with the dose adjusted to ensure that the serum phosphorus target is achieved. The starting dose is usually within the recommended dose range and adjusted upward as needed every 4–6 weeks until the therapeutic target is reached. Different types of phosphate binders may be combined in order to minimise the risk of overdosage. If the dose substantially exceeds the recommended dosage range, then it is best to add different phosphate binders rather than risk overdosage.
Aluminium-Containing Phosphate Binders
These include aluminium hydroxide, aluminium carbonate, and aluminium oxide with an initial dose of 30–100 mg/kg/day. They are available in liquid, tablet, or capsule forms as antacid preparations. In humans, capsules and tablets are less effective than liquids, but liquid preparations are generally unpalatable in cats. A powder form is available, which has the advantage of being relatively free from taste or texture that may adversely affect appetite.
Calcium-Based Phosphate Binders
These include calcium acetate, calcium carbonate, or calcium citrate with an initial dose of 60–90 mg/kg/day for calcium acetate and 90–150 mg/kg/day for calcium carbonate. As calcium-based products may promote hypercalcaemia, it is recommended that the serum calcium concentration be regularly monitored and are contraindicated with hypercalcaemia. They may also be used as a source of additional dietary calcium. Reduced dosages of calcium carbonate and calcium acetate may be used concurrently with aluminium-based binding agents to limit risks of hypercalcaemia. Calcium acetate is the most effective calcium-based phosphate binder as well as least likely to induce hypercalcaemia because it releases the least amount of calcium compared to the amount of phosphorus it binds. Some calcium carbonate preparations may not be effective because they fail to dissolve within the gastrointestinal tract.
The initial dose is 30 mg/kg/day divided with meals and it largely remains within the lumen of the gut and not absorbed; increasing the dose to achieve the therapeutic target would be a reasonable goal.
An initial dose of 30–135 mg/kg per day divided and given with meals is indicated. As sevelamer can expand in water, it is recommended that the tablet or capsule not be crushed, chewed, broken into pieces, or taken apart prior to administration. Like lanthanum, sevelamer does not promote hypercalcaemia; however, it is more expensive and potentially can induce vitamin K deficiency with subsequent haemorrhage.
The kidneys are responsible for converting 25-hydroxycholecalciferol to its most active metabolite, 1,25-dihydroxycholecalciferol, or calcitriol. As CKD impairs the production of calcitriol, calcitriol deficiency may be one factor promoting renal secondary hyperparathyroidism. Calcitriol supplementation has been advocated as a means of normalising hyperparathyroidism. In a randomized controlled clinical trial examining the effect of calcitriol therapy in CKD, calcitriol was effective in reducing renal mortality, but did not appear to influence appetite, activity, or quality of life. A potential adverse effect of calcitriol supplementation is the development of hypercalcaemia. Although hypercalcaemia reportedly occurs in 30–57% of humans treated with calcitriol, hypercalcaemia appears to be an uncommon side effect in dogs.
Protocol for Calcitriol Therapy in CKD
Collect baseline serum creatinine, serum urea, phosphorus, calcium, and ideally an intact PTH level.
Serum phosphorus concentrations must be reduced to less than 2 mmol/l before initiating calcitriol therapy as hyperphosphataemia increases the chances of calcitriol promoting renal mineralisation and further renal damage.
Calcitriol should not be given with meals because it enhances intestinal absorption of calcium and phosphorus.
A starting dose of 2.5–3.5 ng/kg body weight per day given orally.
The optimum maintenance dose for calcitriol must be determined for each animal and based on serial evaluation of serum calcium and phosphorus and PTH. It is recommended to evaluate serum phosphorus, calcium, creatinine, and urea levels 1 week and 1 month after initial calcitriol therapy and monthly thereafter if the animal's condition is stable.
The recommended endpoint of calcitriol therapy is normalization of PTH activity in the absence of hypercalcaemia. If the dose of calcitriol necessary to normalise PTH levels is associated with hypercalcaemia, the daily dose may be doubled and given every other day. This approach may be less likely to induce hypercalcaemia because the effect of calcitriol on intestinal calcium absorption is related to the duration of exposure of intestinal cells to calcitriol. The onset of hypercalcaemia after initiation of calcitriol therapy is unpredictable because of the dynamic nature of CKD. Persistent monitoring is highly recommended because hypercalcaemia may occur days to months after starting treatment.