Objectives of the Presentation
Following this presentation, the attendee should be able to
- Define low, adequate, and high dietary protein for dogs and cats
- Compare and contrast potential benefits and detriments of dietary protein restriction with CKD
- Describe role of dietary protein in managing patients with CKD
For decades, dietary protein restriction has been a cornerstone of nutritional management of pet dogs and cats with chronic kidney disease (CKD). Whether dietary protein restriction is beneficial or necessary, however, has been controversial for decades as well. Chronic kidney disease is defined as kidney damage present for at least three months, with or without decreased glomerular filtration rate (GFR) or greater than 50% reduction in GFR persisting for at least three months. Kidney damage is further defined as either 1) microscopic or macroscopic pathologic changes detected by histologic or direct visualization of the kidneys or 2) markers of damage detected by blood or urine tests or imaging studies. The International Renal Interest Society (IRIS; www.iris-kidney.com) recommends that the appropriate term is chronic kidney disease and proposes a dynamic staging system based on serum/plasma creatinine concentration, presence of proteinuria, and presence and degree of systemic arterial hypertension. Before staging is undertaken, the patient must be proven to have kidney disease that is chronic in nature. Based on staging, therapeutic interventions may be undertaken including nutritional.
Dietary Protein and Protein Metabolism
Proteins are large, complex molecules composed of amino acids. Amino acids are composed of carbon, hydrogen, oxygen, nitrogen, and sometimes sulfur and phosphorus. Although hundreds of amino acids exist, only 20 are commonly found in protein of which 10 are essential for dogs and 11 are essential for cats. Essential amino acids must be supplied by diet as they cannot be synthesized endogenously in sufficient amounts. Proteins provide structure (e.g., collagen, muscle, keratin, hemoglobin), function (e.g., enzymes, hormones, antibodies), and are an energy source after the amino group is removed by deamination or transamination. Proteins also provide a source of nitrogen for synthesis of nitrogen-containing compounds such as nucleic acids, creatinine, and some neurotransmitters.
Dietary proteins are digested and absorbed from the gastrointestinal tract with digestion beginning in the stomach by acid hydrolysis and pepsin. Pancreatic and brush border enzymes further metabolize protein so that amino acids, di-peptides, and tri-peptides are absorbed primarily. Amino acids are absorbed by a sodium-dependent energy-requiring process using one of 6 transporters for neutral, basic, acidic, tricarboxylic acid, imino, and beta- amino acids. Absorbed amino acids and di- and tri-peptides are reassembled into "new" proteins by the liver and other tissues. Amino acids are used for tissue protein synthesis; synthesis of enzymes, albumin, and hormones, and other nitrogencontaining compounds; and deamination and use of carbon skeletons for energy. Amino acids and proteins not absorbed in the small intestine may be fermented in the large intestine to produce fecal odor compounds and utilized by colonic bacteria. There is no storage pool of amino acids, per se, although structural and functional proteins can be catabolized and in essence represent a storage pool; however, their utilization results in depletion of such protein. In catabolic situations, the amine group is removed and the carbon skeleton of the amino acid used for glucose and/or ketone body production. The amine group can be converted to urea via the urea cycle or used for urinary ammonia excretion (glutamine) or purine synthesis.
When discussing dietary protein, it is not only the quantity provided, but the quality of the protein. Protein quality refers to the efficiency by which amino acids from food are converted into tissue. The efficiency depends on the protein source, concentration of essential amino acids in the food, and their availability.1 High-quality proteins provide all essential amino acids in high amounts and in proportion, whereas poor-quality proteins have low amounts or lack one or more essential amino acids (limiting amino acid(s)). Poor protein quality can also result from an excess of certain amino acids that interfere with availability or usage of essential amino acids. Other factors affect protein quality as well.
Protein requirements for healthy pet dogs and cats depend on whether a high-quality protein or commonly used protein sources are used. When using a high-quality protein, growing dogs require approximately 18% protein (dry matter basis; DMB) and adult dogs require approximately 8% protein (DMB), while growing kittens require 18% protein (DMB) and adult cats require approximately 16% protein (DMB). The Association of American Feed Controls Officials provides daily allowances for dietary protein where common dietary protein sources are used. Allowances for growing dogs are 22% protein (DMB), adult dogs are 22% protein (DMB), growing kittens are 30% (DMB), and adult cats are 26% (DMB).
Protein Metabolism and Requirements with Chronic Kidney Disease
The kidney is a highly metabolic organ; therefore, CKD would be expected to have a variety of adverse systemic effects in addition to renal effects. In general terms, renal function includes filtration, reabsorption, and secretion of endogenous and exogenous substances; maintaining homeostasis of water, acid-base, minerals, electrolytes, and other substances; neurohumoral regulation of vitamins (such as vitamin D), red blood cell production, blood pressure, and others; and energy metabolism including gluconeogenesis and reabsorption of amino acids. There is little to no information on protein metabolism in dogs and cats with chronic kidney disease or the incidence of cachexia and sarcopenia in these patients although it is assumed to occur in at least some. It has been shown that dogs with CKD that are underconditioned have a decreased survival compared to dogs who are optimally or overconditioned;2 however, no information was provided in this study as to muscle condition scoring and lean body mass (LBM).
In uremic rodent models, 3-methylhistidine release, an index of myofibrillar protein degradation, is elevated to a greater degree than in rodents without CKD. During in vivo infusion of 14C leucine, protein synthesis following fasting was less in rats with CKD than in healthy rats. Muscle protein synthesis was lower in rats with CKD following a period of stress than in rats without CKD. There is also increased muscular alanine and glutamine release and a decrease in leucine incorporation in rats with CKD and increased muscular tyrosine and phenylalanine release. It has been shown in rodent studies that metabolic acidosis, excess angiotensin II, and inflammation increases muscular protein degradation and decreases muscular protein synthesis, primarily through insulin resistance and impaired insulin/IGF-I signalling. Data in human beings suggest that CKD, even when advanced, does not in itself engender net protein breakdown. Many nitrogen balance studies in human beings with CKD who are not undergoing chronic dialysis have demonstrated that they are able to maintain neutral or positive nitrogen balance studies with low protein intakes. Thus, uremia, per se, does not stimulate net protein catabolism and human pre-dialytic patients fed low-protein diets are able to conserve protein if metabolic acidemia is not present or if there is no concurrent illness. Protein turnover kinetic studies suggest that the mechanism of protein conservation includes downregulation of protein degradation, and amino acid oxidation and maintenance of protein synthesis at near normal levels. If chronic inflammation, increased cytokine levels and activity, and/or metabolic acidosis exists, then protein requirements may be increased.
So, if protein restriction is not detrimental with CKD in many patients, the question is whether there is an advantage over not restricting dietary protein with CKD. In evaluating the veterinary literature, no clear consensus is derived. There are potentially several reasons for this. Studies evaluating only a dietary protein effect have used induced CKD models in dogs and cats, which may or may not adequately represent naturally occurring disease. Some studies demonstrate histologic changes while others have only evaluated blood biochemical parameters. Most induced CKD studies evaluated a small number of animals. Finally, CKD is a complex disease and optimal treatment of patients with CKD involves modifying multiple dietary factors. Nonetheless, dietary protein restriction, if not detrimental, has potential benefits. Decreased dietary protein intake inhibits secretion of TGF-β a cytokine involved in progression of CKD. Decreased dietary protein intake reduces tubular hyperfunction by decreasing renal acid load and renal ammoniagenesis. Sulfur-containing amino acids in dietary protein contributes to renal acid load. If proteinuria is present, dietary protein restriction is beneficial as proteinuria induces inflammatory and fibrogenic pathways and increases oxidative stress.
Two studies evaluated effects of dietary protein on progression of induced CKD for one year in cats.3,4 In one study, renal function did not progressively decrease, regardless of dietary protein amount and caloric intake; however, cats fed the higher-protein diet had more severe glomerular and tubulointerstitial changes.3 The cats in the higher-protein diet group also consumed more calories. In the other study, no difference in renal function or glomerular lesions were found in cats consuming the high-protein diet.4 These studies were of short duration and progression of spontaneous CKD in cats may occur slowly.
Clinical trials of naturally occurring CKD in pet dogs and cats have utilized dietary modification including but not limited to dietary protein restriction. The effectiveness of diet therapy in minimizing uremic episodes and mortality in dogs and cats with naturally occurring IRIS CKD stages 2 and 3 have been established in double-blinded randomized controlled clinical trials.5-7 These studies compared a renal diet to a maintenance diet. The renal diets contained reduced quantities of dietary protein, but also contained reduced quantities of phosphorus and sodium and were supplemented with omega-3 fatty acids when compared with the maintenance diet. In the canine study, the risk of developing a uremic crisis was reduced by approximately 75% in dogs fed the renal diet when compared with dogs fed the adult maintenance diet.5 The median symptom-free interval in dogs fed the renal diet was 615 days compared with 252 days in dogs consuming the maintenance diet. Furthermore, the risk of death irrespective of cause was reduced by 66% and the risk of death from renal causes was reduced by 69%. Median survival time for dogs consuming the renal diet was 594 days compared with 198 days for dogs consuming the maintenance diet. In the feline trial, cats in IRIS CKD stage 2 and 3 were evaluated.6The risks of uremic crises and renal deaths were significantly reduced. Among the cats fed the renal diet, there were no uremic crises or renal deaths and only three deaths from non-renal causes over the 2-year study period. In contrast, among the cats consuming the maintenance diet, 6 developed uremic crises, 5 died of renal causes, and 5 died of non-renal causes. In another study of cats with CKD, feeding a renal diet was associated with a significantly longer survival with a median survival time of 633 days for cats fed the renal diet versus 264 days for cats fed the maintenance diet.8
There are no clear cut recommendations concerning dietary protein with CKD; however, some recommendations can be made. Limiting dietary protein intake may help ameliorate clinical signs in patients. Although currently available evidence fails to support a recommendation for or against limiting dietary protein intake alone in non-uremic patients, with CKD, there are potential benefits assuming that patients maintain adequate caloric intake, body condition, and muscle condition. Patients may be more likely to accept a new renal diet if offered before uremia develops.9 Although not discussed, dietary phosphorus restriction has been shown by itself to slow progression of CKD and it is difficult to achieve this degree of phosphorus restriction using typical ingredients without limiting dietary protein.10 But it is not impossible. In determining how much protein to recommend for dogs and cats with CKD, patients should be monitored for signs of protein malnutrition and nutritional management adjusted to maintain optimal body condition and muscle condition minimally. For cats with CKD, the minimum dietary protein requirement was 20% of calories,11 which equates to 24% protein (on a dry matter basis; DMB). Similar studies have not been reported in dogs. The Association of American Feed Control Officials recommends a minimum of 18% (DMB) for dogs and 26% (DMB) for cats. Recommendations for dogs with CKD are 14–20% (DMB) and for cats with CKD they are 28–35% (DMB). It is emphasized that less total dietary protein can be fed if high biologic value proteins are fed.
Uremic gastrointestinal complications may be present in patients with CKD. These may be overt (e.g., vomiting, anorexia), but may be more covert with only hyporexia being present. Patients with CKD may benefit from antiemetics, antacids, and/or gastroprotectant pharmacologic therapy. Hypokalemia, which occurs more frequently in cats with CKD than in dogs, is not only associated with muscle weakness but hyporexia to anorexia. If necessary, nutritional therapy can be facilitated through use of feeding tubes.
In patients with CKD that experience sarcopenia, a thorough physical examination and biochemical evaluation should be undertaken. Metabolic acidosis does not occur until late in progression of CKD in cats; however, if present, it induces protein metabolism and loss of lean body mass. In patients with sarcopenia, an attempt should be made to increase dietary protein while monitoring response. If azotemia or acidosis worsens or if electrolyte and mineral imbalances occur, then the nutritional plan should be re-evaluated and adjusted.
There are several novel treatments for CKD. In pre-dialytic human patients with CKD, feeding a low-protein diet supplemented with ketoanalogues of essential amino acids (keto-diet) proved effective in ameliorating metabolic disturbances of advanced CKD and delaying the initiation of dialysis without deleterious effects on nutritional status. Several recent studies report that the keto-diet could also slow down the rate of decline in renal function, with better outcomes after the initiation of dialysis. Enteric dialysis using an oral sorbent may also permit feeding of higher-protein diets. A probiotic formula is currently available for use in dogs and cats with CKD and is marketed as enteric dialysis although no data substantiate this claim. These treatments especially use of keto-acids represent unexplored territory in the treatment of CKD in pet dogs and cats.
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