Dietary considerations for dogs and cats with renal disease
William J. Burkholder, DVM, PhD, DACVN
The JAVMA welcomes contributions to this feature.
Articles submitted for publication will be fully reviewed with the American College of Veterinary Nutrition (ACVN) acting in an advisory capacity to the editors. Inquiries should be sent to Dr. John E. Bauer, Chairman ACVN, Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4474.
It is estimated that 15 to 20% of older cats and dogs have some degree of renal azotemia, and approximately 5% of all deaths in dogs and 3% of all deaths in cats are attributable to renal failure.1-3 Only neoplasia is responsible for the deaths of more dogs and cats.3 Most dogs and cats die within 2 to 3 years after the diagnosis of renal disease is made, although there is considerable variation in the duration of the survival period.4 Renal disease has many causes, with both the cause and the amount of time that the disease remains undiagnosed and untreated contributing to the duration of the survival period of the animal after renal disease is recognized.
Self-perpetuating Destruction of Nephrons
Although there are many causes of renal disease, it is believed that a common, self-perpetuating set of events induces progression from renal injury to renal insufficiency to renal failure and death.5-6 When nephrons become nonfunctional, homeostasis is maintained by the remaining nephrons, which undergo compensatory changes including increases in size and length of glomerular and tubular segments as well as increases in perfusion and fractional clearance of blood flowing through the kidneys. Mechanisms responsible for the compensatory changes are beneficial in the short term but ultimately are damaging to the kidneys, eventually causing more nephrons to be destroyed and shifting the filtration and processing load to fewer and fewer nephrons. The self-perpetuation theory of renal disease states that renal failure is inevitable after a critical number of nephrons are destroyed, even when the original cause of destruction is corrected or eliminated. When formulating diets for animals with renal disease, alterations are made to nutrient proportions in an effort to prevent or decrease the self-perpetuating destruction of nephrons. For the purpose of understanding the rationale behind specific nutrient alterations, various contributory events can be lumped into the following 3 categories: secondary renal hyperparathyroidism, acidosis, and glomerular changes. The end result of these components is destruction of tubules or glomeruli by inflammation, mineralization, and scarring. Understanding the way in which nutrients promote or inhibit components of self-perpetuating nephron destruction will enable clinicians to form a better appreciation for the reasons that nutrient alterations are made in an attempt to counter the effects of these components and delay progression to renal failure.
Maintaining Hydration
Water is always the most important nutrient, especially for animals with renal disease that are at risk of becoming dehydrated and are unable to compensate for lack of water in a state of renal insufficiency, with dehydration leading to uremia and renal failure. Dehydration decreases renal perfusion and delivery of oxygen to nephrons that have increased their metabolic activity and, thus, their requirement for delivery of oxygen and nutrients, as well as the requirement for removal ofmetabolic waste products, to enable them to continue to maintain systemic homeostasis. Thus, maintenance of hydration and adequate renal perfusion is paramount in animals with renal disease, and dehydration can lead to acute, extensive nephron destruction.
Secondary Renal Hyperparathyroidism
The first category contributing to chronic ongoing destruction of nephrons involves events leading to development of secondary renal hyperparathyroidism (2o HPTH). Although the mechanisms for development of 2o HPTH are complex, part of the etiopathogenesis results because the kidneys are responsible for regulating concentrations of phosphorus and phosphate (HPO4 2-) in the blood, reabsorbing HPO4 2- when the serum concentration of HPO4 2- is low or excreting excess HPO4 2- when the concentration is high.
Excretion of HPO4 2- is the difference between glomerular filtration and tubular reabsorption of HPO4 2-.
Destruction of nephrons causes a decrease in filtration and an increase in serum HPO4 2- concentration, which stimulates the parathyroid gland to secrete additional amounts of parathyroid hormone (PTH). One effect of PTH is to decrease reabsorption of HPO4 2- in the prox- imal convoluted tubules such that more of the filtered HPO4 2- is excreted and the serum concentration of HPO4 2- is maintained within the physiologic range.7 As more nephrons are destroyed, a greater concentration of PTH is required to maintain the serum concentration of HPO4 2-.
This mechanism is appropriate for maintaining serum concentrations of HPO4 2-; however, PTH has 2 other effects on the balance of HPO4 2- and renal tissue. First, PTH stimulates reabsorption and release of minerals from bone, 1 of which is HPO4 2-. This increases the amount of HPO4 2- the remaining nephrons must eliminate. Second, in animals used in experimental models of renal disease, the concentration of PTH correlates with histologic evidence of inflammation and mineralization of renal tissue.8-11 In fact, primary hyperparathyroidism can cause inflammation and mineralization of renal tissue in humans.12 Thus, an increased concentration of PTH is believed to be damaging to the kidneys in the long term.
Because an increased serum concentration of HPO4 2- stimulates PTH secretion, controlling the serum concentration of HPO4 2- becomes the primary strategy for preventing 2o HPTH. Serum concentration of HPO4 2- is directly affected by dietary intake; therefore, restricting the amount of HPO4 2- in diets formulated for animals with renal disease is a central component of dietary therapy. In several studies in dogs and cats,8-11-13 investigators have documented that restriction of dietary HPO4 2- is beneficial for lessening the severity of inflammation and mineralization in the kidneys, decreasing the concentration of PTH, maintaining filtration capacity of the kidneys, and, ultimately, prolonging longevity of the animals.8-11-13 Current dietary therapeutic formulas for animals with renal disease contain between 0.03 and 0.11 g of HPO4 2- /100 kcal, (0.14 to 0.63% of dry matter [DM]). Another strategy for controlling serum concentration of HPO4 2- is to use a HPO4 2- binder. Phosphate binders will not be effective unless dietary restriction of HPO4 2- is used concurrently. The goal should be to maintain serum concentration of HPO4 2- for animals with renal disease in the mid to low end of the reference range to maximally suppress stimulation of PTH secretion.
In addition to effects and interactions with HPO4 2-, PTH is also regulated by, and interacts with, serum concentrations of calcium and vitamin D. Parathyroid hormone causes increases in serum concentrations of calcium by reabsorption and release of minerals from bone and by stimulating the kidneys to produce additional amounts of 1-25 dihydroxycholecalciferol (active vitamin D). Increases in serum concentrations of calcium and vitamin D typically provide negative feedback on PTH secretion. However, there is evidence that increases in serum concentrations of calcium may not suppress PTH secretion effectively in animals with renal disease, and because there is less functional renal tissue, there will be less vitamin D produced in response to increased concentrations of PTH. Therefore, the end result is less vitamin D to inhibit PTH secretion. Providing vitamin D to an animal with renal disease in conjunction with HPO4 2- restriction can markedly decrease PTH concentration, but the animal’s animal’s serum calcium concentration must be monitored frequently to ensure the animal does not develop hypercalcemia as a result of vitamin D administration. 13-14 Iatrogenic hypercalcemia as a result of administration of vitamin D will increase the chance of mineralization and destruction of renal tissue because of an increase in calcium-HPO4 2- product.
Acidosis
Acidosis is the second category of self-perpetuating events causing nephron destruction. The kidneys are responsible for eliminating the daily acid load produced by normal cellular metabolism and dietary intake. One way the kidneys eliminate acid is by using ammonia (NH3) produced from glutamine to trap hydrogen ions as ammonium ions (NH4+). When nephrons are destroyed, the remaining nephrons increase production of NH3. Increased concentrations of NH3 and NH4+ stimulate activation of complement proteins (C5b to C9, the membrane attack complex), which promotes inflammation of renal tissue by causing release of cytokines. Those cytokines generate free radicals, recruit inflammatory cells, and, ultimately, destroy functional renal tissue.15 Also, as the ability of the kidneys to eliminate acid decreases, the body’s bicarbonate buffering system becomes saturated. To maintain physiologic pH, more carbonate (CO3 2-) and HPO4 2- buffers are recruited by mobilizing CO3 2- and HPO4 2- from bone. It is an established fact that chronic acidosis causes mobilization, remodeling, and loss of bone. Additional release of HPO4 2- from bone leads to the aforementioned 2o HPTH. Chronic acidosis also can disrupt electrolyte homeostasis, particularly for potassium. Dietary intake of potassium, as well as the ability of the kidneys to eliminate acid and respond to rennin and aldosterone for electrolyte conservation, will interact to produce hyper- and hypokalemia, depending on the influence of each factor in a given animal.
Dietary contributions to the daily acid load come primarily from intake of sulfur-containing amino acids (methionine and cysteine) and secondarily from strong anions (Cl-, SO4 2-, PO4 2-). Animal proteins tend to provide more sulfur-containing amino acids and be more acidifying than plant proteins, regardless of whether the animal protein is supplied by the diet or comes from catabolism of the animal’s own body proteins. Acidosis stimulates catabolism of body proteins, which, in turn, generates more acid.16-17 Furthermore, an affected animal will catabolize body proteins to meet energy and protein needs when they are not consuming sufficient calories and dietary protein to maintain body weight and physiologic processes.18-19 Therapeutic diets formulated for animals with renal disease tend to use combinations of ingredients that will alkalinize the urine and blood, minimizing the dietary contribution to acid load. The diets are limited in protein ingredients, especially those that are high in sulfur-containing amino acids, but still attempt to meet daily protein needs to minimize protein catabolism and its associated acid load. Protein content of commercial diets formulated for dogs with renal disease ranges from 1.9 to 5.2 g of protein/100 kcal (9 to 28% of DM), and protein content of commercial diets formulated for cats with renal disease ranges from 5.4 to 7.2 g/100 kcal (25 to 31% of DM). These diets include various amounts of potassium (from 0.08 to 0.21 g of potassium/ 100 kcal (0.36 to 1.12% of DM), which is 50 to 150% of the normal requirements. Potassium requirements increase as dietary protein increases, partially as a result of acidosis and potassium wasting. Cats with renal disease are particularly at risk for hypokalemia induced by metabolic acidosis.20
Glomerular Changes
The final category of self-perpetuating events are glomerular changes. These include glomerular hypertrophy and increased perfusion, which help maintain total glomerular filtration with fewer nephrons.
Increased perfusion has the potential to increase pressure within vessels entering the glomeruli. Increased pressure will help maintain total glomerular filtration by increasing the fraction of plasma filtered by each glomerulus. Increased pressure also can stimulate mesangial cells in the glomeruli to secrete a cytokine (transforming growth factor ?) that causes collagen to be deposited in the glomerular basement membrane; this alters the basement membrane’s permeable selectivity and allows proteins to cross.21
Dietary Protein
Renal perfusion increases with increasing amounts of dietary protein, and, thus, it can be speculated that increasing the amount of dietary protein could cause glomerular hypertension. Serum proteins that cross the glomerular basement membrane are taken up and degraded by epithelial cells lining the tubules. In some in vitro cell-culture systems, proteins are toxic to tubular epithelial cells, either by stimulating release of cytokines and attracting inflammatory cells or by overloading the normal protein degradation pathways and causing leakage of lysosomal enzymes that then damage the tubular epithelial cells.22-24Data supporting the toxic effect of proteins on renal tubular cells and overall damage to renal function have come from studies conducted on rodents and humans. Studies in which investigators have created renal failure by surgically removing all but a small fraction of renal tissue in dogs and cats (ie, remnant-kidney model) have revealed little or no association between dietary protein and lesions in renal tissue or effects on longevity.9-19 This has led some investigators to conclude that dietary protein does not matter in dogs and cats with renal disease.
One variable that dietary protein does impact is BUN concentration. It is an established fact that an increase in dietary protein correlates directly with greater concentrations of BUN.9-19 Urea by itself does not account for all, if any, of the clinical signs of uremia, and some clinicians argue that it is simply a marker compound for other more important uremic toxins. However, a decrease in BUN concentration often will correspond to improvement in clinical condition of an animal. For this reason, some manufacturers have incorporated fermentable fiber into their renal therapeutic diets that allegedly will create a nitrogen trap in the colon by producing an acidic pH through bacterial fermentation of the fiber. Urea freely diffuses into all body compartments, and bacteria in the colon can split urea into CO2 and NH3. Similar to the situation in the kidneys, hydrogen in the colon is trapped by conversion of NH3 to NH4 + , with the net result being an increase in fecal content of nitrogen and, perhaps, a decrease in BUN concentration. If dietary protein does not matter in animals with renal disease, then the need for and relevancy of nitrogen trapping by fiber also should be questioned, given the questionable role of BUN in uremia.
The conclusion that dietary protein does not matter in animals with renal disease may prove short sighted from 3 standpoints. First, it fails to account for the contributory effects of dietary protein on acidosis. In fact, some investigators studying the potential effects of dietary protein have used alkalinizing agents to correct acidosis in animals in their studies.19 Second, it dismisses the possibility that dietary protein may be more important in animals with renal disease that are losing protein in their urine. Use of the remnant-kidney model produces mild proteinuria, compared with that observed for animals with several naturally occurring renal diseases that cause proteinuria.9,19,25 Furthermore, the perfusion and hypertensive effects of dietary protein could be more important in the early progression of renal disease than in later stages. Third, as a practical matter, it is hard to achieve the degree of PO4 2- restriction desired in renal therapeutic diets by use of typical ingredients without also restricting the amount of dietary protein.
Caloric and Fat Content of Diets
Dietary effects are relatively easy to detect, compared with nutrient effects that are much more difficult to isolate. What was believed to be a possible protein effect on progression of renal lesions in earlier studies that used the remnant-kidney model in cats26,27 appears to be a calorie effect.19 On better isolation of the effects of protein and calories, researchers have documented that cats fed an amount of calories close to that needed to meet resting energy requirements (50 to 55 kcal/kg of body weight) develop fewer lesions in the remnantkidney model than cats fed a maintenance amount of calories (70 to 75 kcal/kg).19 However, cats fed fewer total calories, but in which more calories were from protein, had evidence of more protein catabolism than those on a diet moderately restricted in calories and protein, which indicates the need for an adequate amount of nonprotein calories to provide energy and spare the protein from catabolism for energy.19
In terms of nonprotein calories, the composition of fat-containing polyunsaturated fatty acids (PUFA) is important in preventing progression of renal disease and extending longevity.28 Dogs with a remnant-kidney model fed fat containing increased concentrations of omega-3 (ie, n-3) PUFA lived significantly longer than dogs fed fat containing increased concentrations of omega-6 (ie, n-6) PUFA. Dogs fed the increased n-3 diet had better preservation of glomerular filtration and less glomerular changes, less inflammatory infiltrate, and less interstitial fibrosis. It was speculated that these findings resulted because n-3 PUFA tend to be less pro-inflammatory, compared with the effects of n-6 PUFA. Most renal therapeutic diets have increased amounts of fat to increase the caloric density, thus enhancing palatability and decreasing the amount of food required to provide a specific number of calories in an attempt to counter anorexia associated with uremia. Most manufacturers of therapeutic renal diets have included n-3 PUFA in those diets.
Sodium Content of Diet
Consideration should be given to dietary sodium content, because sodium affects circulating plasma volume and, thus, blood pressure. Furthermore, diseased kidneys are suspected of being less efficient at regulating sodium and plasma volume. However, to the author’s knowledge, sodium restriction has not been proven definitively to be beneficial in dogs or cats with renal disease. It has been postulated that too much or too little sodium can have adverse hemodynamic effects.29 There also is evidence that the effects are not attributable solely to sodium; rather, the effects on blood volume and pressure may be attributable to the combination of sodium and chloride.30 Commercial renal therapeutic diets range from 0.03 to 0.14 g of sodium/100 kcal (0.15 to 0.85% DM), which is about 2 times the recommended minimum requirement.
Overcoming Anorexia
Finally, animals with renal disease will not benefit from malnutrition, and it is known that animals with renal failure commonly are anorexic. Also, renal therapeutic diets are of marginal palatability. Diseased renal tissues need adequate amounts of energy and protein to meet the increased work demands that result because of less functional tissue. Several strategies exist for optimizing food intake of animals with renal disease. One advantage to having several commercially available formulations from various companies is that an animal with renal disease often will not eat formulations produced by a specific company but will eat a similar formulation produced by another of the companies. Other affected animals may have a rotational preference among 3 or 4 formulations, preferring to eat 1 diet for a few weeks, then preferentially eating another diet for a few weeks before preferentially eating still another diet for a few weeks, at which point the animal prefers the original diet again. Many veterinary nutritionists can attempt to formulate homemade diets that approximate nutrient profiles of commercially available renal therapeutic formulations, using foods that a particular animal prefers. However, it does not take much substitution of ingredients to cause the nutrient profile to deviate substantially from the intended formulation. It has been stated31 that animals with renal disease do not eat what they are supposed to eat and do not eat a sufficient amount of what they are not supposed to eat to maintain body weight and physiologic functions. When such an animal is encountered, permanent placement of a gastrostomy tube can be used to provide the appropriate diet in the appropriate amount for an owner who wishes to do everything possible to maximize longevity and health of their pet. However, to maximize longevity and health of an animal with renal disease, it is best to institute nutritional therapy early during the course of renal disease (ie, as soon as it is documented to exist). For this reason, early diagnosis and treatment is a key component to successful treatment and optimal outcome.
From the Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4474
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