Evidence-based management of chronic kidney disease in the cat (Proceedings)

Consequences of chronic kidney disease are many and managing them is the hallmark of improving patient quality and quantity of life. Aside from continuous renal replacement therapy and renal transplants, management of azotemia, acid-base disorders, electrolytes, secondary hyperparathyroidism, nutrition, and hypertension are key.

Much has been recommended regarding nutrition in chronic disease and multiple commercial formulations are available. Goals for nutritional management of chronic kidney diseases are to reduce electrolyte and acid-base disorders, provide adequate caloric requirements, and to alleviate the negative effects of accumulating uremic products. As with all adjunctive therapies, the ultimate goal would be to slow progression of disease. There are a few recent studies that would suggest that there is some effect of nutrition on both duration and quality of survival in the feline population with chronic kidney disease.

Elliott et al (JSAP, 2000) showed that those cats fed either a renal diet as compared to a normal maintenance diet had a longer survival time. Electrolyte imbalances were not as prevalent in the renal diet group and BUN was decreased as well. However, one caveat is that those cats that would eat the renal diet were placed in the treatment group, those that would not eat it, were placed in the control group. It is reasonable to be concerned that those cats that would eat a renal diet may have had a better appetite to begin with, biasing the study. Improving upon that study, Ross et al (JAVMA, 2006) conducted a double blinded, randomized controlled clinical trial which showed an improvement in both the number of uremic crises and kidney disease related deaths over the course of the twenty-four month study.

The prior studies simply compared a renal diet compared to maintenance diets. A retrospective of cats on multiple renal diets uncovered a significant improvement in survival time on a particular diet. A significant difference between that diet and the other six studied was the level of eicosapentanoic acid, an omega three fatty acid. There is strong evidence that in the human population, omega three fatty acids have a positive effect on blood pressure levels and the rate of secondary cardiac events in the human population. While high levels have been shown to have a detrimental effects, the levels associated with the diet in this study were beneficial. Since then, most commercial diets have had an increased level of omega three fatty acids.

Renal secondary hyperparathyroidisim is associated with decreased conversion of 25 hydroxycholecalciferol to the more active form, 1,25 dihydroxycholecalciferol (calcitriol), by the hydroxylase enzyme system in the kidney. The decrease in calcitriol leads to hypocalcemia, stimulating release of parathyroid hormone. Without caclcitriol to enhance calcium absorption, the parathyroid hormone is released at higher levels to achieve the same results. While not documented in the feline patient at this time, in other species, continued high levels of parathyroid hormone is associated with immunosuppression, renal toxicity, and glucose intolerance, and hyperlipidemia. The decreased enzyme activity is, to a small degree, associated with decreased renal function, but is more significantly impacted by prolonged hyperphosphatemia. Therefore, either controlling phosphate levels or increasing calcitriol levels should decrease the parathyroid hormone to normal levels. Historically, the benefits associated with calcitriol administration were mainly based on survey based information. However, more recently, an abstract presented at the ACVIM forum (Polzin et al, 2005) in dogs showed a reduction in mortality and improved survival time in dogs with chronic kidney disease. A study in the feline species (Hostutler, JVIM, 2005) did not demonstrate a decrease in parathyroid hormone levels in a small number of cats with naturally occurring kidney disease at either the standard daily dose (2.5 ng/kg PO q 24 hrs) or the extended dose schedule (8.75 ng/kg q 84 hrs). However, the study was short in duration and had only a small number of cats enrolled. It should be noted that parathyroid hormone levels were indeed greater in those cats with chronic kidney disease than those in the healthy control group. At this point, that is the extent of the data for calcitriol supplementation in naturally occurring disease in cats. Certainly optimal dosage levels, intervals, and perhaps formulations must be evaluated before determining if calcitriol therapy should be abandoned.

If we don't have strong evidence at this point for calcitriol therapy in the feline species, what about phosphorous control? As stated before, chronic hyperphosphatemia inhibits conversion of the monohydroxy form of vitamin D3 to the more active calcitriol. This may be one of the major benefits of renal diets. Most are low in protein inherently decreasing phosphorous levels. Without dietary restrictions phosphate binders are useless. The most commonly used phosphate binder in veterinary and human populations has historically been over the counter aluminum hydroxide antacids. They have the advantage of also decreasing gastric acidity that may be associated with uremia. However, palatability is extremely poor which is of course a concern in cats with poor appetites. Compounded aluminum hydroxide powder is available from compounding pharmacies and can be incorporated into the food. A concern in both human and veterinary patients is aluminum toxicity. Neuromuscular disease is a common reported early sign of aluminum toxicity in humans and anecdotally, red cell anomalies are reported to be early signs in veterinary patients. In the later stages of disease, toxicity may be a concern as aluminum is renally excreted. Constipation is also a common side effect at lower, non-toxic doses.

Sucralfate is also an attractive option given its gastric effects as well. Recently, an abstract presented at the ACVIM forum (Quimby et al, 2009) described a short term study in which cats given sucralfate as a phosphate binder was discontinued early as more adverse events and the risk of death was much greater in those cats receiving the drug. Reasons for this aren't readily apparent at this time, however, until other data is available, alternatives should be considered. Because of the risk of aluminum toxicity, alternative phosphate binders have been introduced to the human market. Lanthanum carbonate (Fosrenol) and sevalamer hydrochloride (Renagel) are two of the more commonly prescribed alternatives. Veterinary information at this point is lacking. Mechanisms of actions for Fosrenol are similar to aluminum hydroxide but without the concern for aluminum toxicity. It has been approved in the EU for use in cats with chronic kidney disease but very little data is available. Renagel is an intestinal absorber which has an unfortunate side effect of absorbing other nutrients and medications as well, therefore, care should be taken when using this. The biggest adverse effect of these drugs so far is on the pocket book: they are exponentially more expensive than aluminum hydroxide even in its compounded form.

Two nutraceuticals have recently been marketed as supplement to decrease uremic toxins in cats. Azodyl is a symbiotic: a combination of a prebiotic and probiotic. The strains of bacteria in the product are supposed to metabolize uremic toxins: urea, phosphorous, creatinine, and others. The claim is to utilize enteric dialysis in order to decrease uremia. However, there is little evidence to support this at this point. The company provides data on one series of cats with chronic kidney disease where a small effect on BUN is evident. However, this study was uncontrolled and has not been peer reviewed. Additionally, we don't actually know if there are any beneficial effects to decreasing BUN in feline chronic kidney disease. While it most likely won't hurt, this is an oral medication (capsule) in a disease in which many other orally administered drugs have much more evidence for efficacy behind them and in which inappetance is a major problem. Epakitin is calcium carbonate and chitosan. The biggest concern regarding epakitin is the level of calcium in the product. Those cats with hypercalcemia should not receive it. Again, data in the literature is extremely lacking.