Protein restriction for cats with chronic kidney disease

Introduction

Chronic kidney disease (CKD) is a commonly encountered problem in feline practice 1 2, and the prevalence of the condition in cats over 15 years of age has been shown to be more than 30% 3. In the majority of cases an underlying etiology is not identified at the time of diagnosis, even when histopathological examination is performed 1. While CKD in all species is often progressive in nature, it is also a surprisingly dynamic and heterogenous disease process, being influenced – particularly in cats – by multiple factors, many of which remain to be discovered 1 4.

Despite this variability, dietary therapy has remained the cornerstone of management for feline CKD for the past 60 years 4 5 6 7. Feeding a renal diet (either a diet formulated by a veterinary nutritionist or manufactured specifically for managing animals with kidney disease) to cats with International Renal Interest Society (IRIS) CKD stages 2-4¹ (Table 1) is currently considered the standard of care 8. In fact, nutritional management is regarded as the therapeutic intervention most likely to enhance the long-term survival and quality of life for cats with IRIS CKD stages 3 and 4 8. Renal diets also help to ameliorate or prevent the clinical consequences of CKD and uremia, slow the progression of the disease, minimize electrolyte, mineral, and acid-base balance abnormalities, and maintain adequate body weight, body condition and muscle condition. Initiating therapy with a renal diet is also considered part of the standard of care for management of proteinuria in cats (Table 2) 8.

¹ http://iris-kidney.com/guidelines/index.html

Despite its widely accepted role, there is controversy surrounding the use of renal diets for cats, and in particular the restriction of dietary protein. The increasing popularity of feeding raw and protein-rich, grain-free diets has reduced public interest in the use of protein-restricted renal diets, and there is also increased awareness of the potential risks, such as protein-energy wasting. It is a challenge to evaluate the potential benefits of protein restriction and whether they outweigh any risks, as there is insufficient research in cats, and some reference to studies in dogs, humans or other species is required, which is obviously not ideal. There are therefore three main questions that need to be answered;

1. Should we restrict dietary protein intake for cats with CKD?

2. If yes, how much should we restrict protein intake?

3. When should we restrict protein intake?

To answer these questions, we need to consider the benefits versus the risks of protein restriction, the protein requirements of both healthy cats and cats with CKD, and a range of individual factors such as the pet’s appetite, concurrent medical conditions and their associated prognoses, as well as the cat’s age.

What are the benefits of protein restriction?

Limiting protein intake to ameliorate the clinical signs of uremia has been considered best practice for many years and is well-supported by evidence for cats with advanced renal disease. Multiple studies have demonstrated that feeding a renal diet to cats with CKD is associated with a reduction in blood urea nitrogen and observable clinical benefit, along with an increased survival time, although whether protein restriction (rather than other features of a renal diet) contributes to this increase in survival is the subject of ongoing and sometimes heated debate. It is uncertain how toxic urea is in cats, whilst in humans, though once thought of as being biologically inert, it is now considered to be directly toxic at concentrations seen in CKD 9. Altered insulin sensitivity, increased free radical production and induction of apoptosis have been directly attributed to the concentration of urea, although urea-derived metabolites may also contribute. Whether the concentration of urea in plasma reaches sufficient concentrations to have a direct effect in cats with CKD remains to be shown 2 4 7 10

Protein restriction may also be of benefit if proteinuria is present, although even this is controversial. Restricted dietary protein is thought to alter glomerular hemodynamics and permselectivity, thus reducing glomerular filtration pressure and protein loss into the filtrate. In other species a linear relationship between reduction in dietary protein intake and a decrease in proteinuria has been demonstrated 11. However, in a study where cats with naturally occurring stage 2 and 3 CKD were fed either a protein-restricted renal diet or a maintenance diet, there was no difference in proteinuria levels 7. It may be that the renal hemodynamic response is over-ridden as renal function declines, or that it depends on the specific amino acids in the proteins, or other as yet unknown factors.

Dietary protein restriction has been shown experimentally to reduce the gene expression of several proteins believed to play an important role in the progression of chronic kidney disease, such as platelet-derived growth factor and transforming growth factor ß within the glomerulus 12. It is unknown whether this decreased gene expression is a direct consequence of an improvement in proteinuria, or due to some other effect of dietary protein restriction such as reduced renal ammoniagenesis 13.

What about uremic toxins?

Most interestingly, recent research has focused on the benefits of protein restriction with respect to reducing uremic toxin formation. Uremic toxins are solutes normally excreted by the kidneys that accumulate in patients with CKD and have detrimental effects. Uremic toxins have been associated with accelerated progression of renal disease, the development or progression of cardiovascular disease, bone disorders and neurological complications, both in humans and in many other species.

Urea was the first toxin identified and is now known to have both direct and indirect toxic effects 14, but to date over 130 different uremic toxins have been identified. Ingested nutrients, such as L-carnitine, tryptophan and tyrosine, can be metabolized by the gut microbiota to generate uremic toxins, or precursors that are metabolized to toxins in the body (Figure 1). Trimethylamine N-oxide, p-cresyl-sulfate, and indoxyl sulfate are important uremic toxins that originate from dietary-derived nutrients. Methylguanidine (a nephro- and neurotoxin) has been shown to increase oxidative stress and accelerate neutrophil apoptosis in dogs 15.

Indoxyl sulfate is produced by hepatic sulphation of indole, which is absorbed from the gut where it is produced by bacterial metabolism of dietary tryptophan, and has been extensively studied. It has been reported to induce mitochondrial dysfunction, leading to increased production of reactive oxygen species and oxidative damage in the renal vasculature 16. This results in induction of inflammation and renal tubular cell injury, promotion of renal fibrosis, and progression of glomerular sclerosis 17. In addition accumulation of indoxyl sulfate can contribute to sarcopenia; therefore, feeding more protein in an attempt to maintain lean mass may actually promote and worsen sarcopenia, contributing to patient morbidity and ultimately mortality 18. However, the production of indole is dependent on both the mass of available tryptophan, and the number of indole-producing bacteria in the intestine, thus the effect of protein restriction will vary greatly between cats with different intestinal microbiota.

While the clinical impact of different uremic toxins requires further investigation in cats, it has been shown that indoxyl sulfate is increased in cats with CKD when compared with healthy controls 17. Importantly, cats with IRIS stage 2 (and also stages 3 and 4) CKD have been found to have significantly higher-serum indoxyl sulfate concentrations, implying that some degree of protein restriction may be of benefit from IRIS stage 2 onwards. Human patients on very low-protein diets have been found to have a significant decrease in protein-derived uremic toxins – in one study, indoxyl sulfate was reduced by 69% 19. There is a lot more to learn about uremic toxins and their effects in cats with kidney disease; however, current research provides some compelling evidence for early and controlled reduction of non-essential protein.

What are the risks of protein restriction?

Despite the benefits of protein restriction detailed above, reasonable concern has been raised that low-protein renal diets may predispose feline patients to weight loss and loss of lean muscle mass. Protein-energy wasting, an under-appreciated condition in CKD, is undoubtedly the biggest fear surrounding dietary protein restriction 4. The International Society of Renal Nutrition and Metabolism expert panel has defined protein-energy wasting as “a state of decreased body stores of protein and energy fuels (body protein and fat mass)” 20. The proposed causes of protein-energy wasting are multifactorial, and include both nutritional and non-nutritional mechanisms.

In humans, concerns regarding protein-restricted diets and protein-energy wasting have been largely alleviated by a number of studies demonstrating that carefully planned low-protein diets (as followed by motivated and adherent patients) are effective and do not cause protein-energy wasting 21. It is well-established that protein restriction to the recommended minimum intake for a healthy human adult is very unlikely to promote protein-energy wasting, so long as the protein sources are highly digestible and have high biological value, and the patient is eating enough to meet their energy requirement 22.

Similarly, studies in cats with naturally occurring CKD that were fed therapeutic diets with restricted protein have found no detrimental effect on body weight or body condition score over a greater than two-year period 6. It is common for ageing cats and cats with CKD to experience a loss of body weight and lean body mass, but it is important to understand that increasing dietary protein is not necessarily the obvious solution, as some amino acid-derived uremic toxins are anorexigenic and, as noted previously, can also promote uremic sarcopenia and accelerate the kidney disease 23 (Figure 2).

Another concern with protein restriction is that it can be challenging to objectively assess the protein status of a cat in clinical practice; muscle condition scoring is relatively subjective and careful nutritional assessment is often not performed regularly enough. Recommendations for humans with CKD involve a careful, monthly assessment of nutritional status, which includes appetite, dietary protein intake, energy intake, body weight and muscle mass, and urinary and serum biomarkers. Routinely monitoring nutritional status, particularly energy intake, in cats with CKD would be similarly beneficial, in order to allow any problems to be detected promptly. It is known that muscle-derived amino acids are used for gluconeogenesis if there is inadequate caloric intake, which decreases protein utilization for maintenance of lean muscle mass. When energy requirements are not met, catabolism occurs, leading to loss of lean mass and potentially resulting in clinical deterioration.

What degree of protein restriction is warranted?

Cats have a high requirement for dietary protein relative to omnivores in order to support both protein turnover and a relatively high rate of gluconeogenesis 24. When considering the degree of protein restriction that might be appropriate, it is important to understand what the protein requirement of a healthy adult cat is, and then how the requirement for cats with CKD might vary from this.

The National Research Council (NRC) minimum requirements for protein and amino acids were established based on data from growing kittens, nitrogen balance studies, and other parameters. The NRC recommended intake of dietary protein for adult cats, 50 grams/1000 kcal ME (metabolizable energy), represents a 25% increase over the absolute physiological minimum requirement to account for variations in digestibility and bioavailability. In order to account for losses during processing and storage, and the low digestibility of some commercially available ingredients, the Association of American Feed Control Officials (AAFCO) Dog and Cat Food Nutrient Profiles were created. Therefore, the AAFCO minimum requirement adds a further “safety margin”, and the minimum protein requirement for adult cats is 65 grams/1000 kcal ME. This margin helps ensure adequate intake of protein and amino acids for the majority of cats if calorie requirements are met.

Unfortunately, there is insufficient clinical research to confidently establish the minimum protein requirement of cats with naturally occurring CKD, and certainly no studies that have compared different stages of CKD; however, it is believed to be similar to the minimum protein requirement of healthy cats 4. In one study, the dietary protein requirement of cats with spontaneous chronic kidney disease was found to be approximately 20% metabolizable energy 25. Commercial renal diets typically contain around 55-95 g protein/1000 kcal ME 26, or approximately 22-24% protein ME. This amount is above the NRC recommended allowance (50 g protein/1000 kcal ME) for adult cats, but is below that commonly employed in typical maintenance diets, which are around 80-120 g/1000 kcal ME.

Many owners do not realize that most commercial renal diets meet the AAFCO recommended minimum for protein, with a few exceptions. Furthermore, diligent manufacturers can optimize the digestibility and amino acid profile of commercial renal diets to ensure high-protein quality and nutritional adequacy. More research on the protein requirement of cats in different stages of naturally occurring CKD would, of course, be desirable. However, there is no reason to currently believe that the degree of protein restriction used in commercial renal diets is inappropriate or excessive, or that it will increase the risk of protein-energy wasting, assuming that the cat’s caloric intake is adequate.

When should dietary protein be restricted in a cat with CKD?

Severe protein restriction is unlikely to be necessary in the very early stages of non-proteinuric feline CKD (IRIS stage 1). However, this may be a good time to transition cats that are fed a very high-protein diet onto a diet with more moderate protein levels. It is also sensible to ensure that canned and/or dry diets will be accepted, if the cat is usually fed a dehydrated, raw or freeze-dried diet.

Delaying protein restriction until the cat begins to display clinical signs of uremia, typically during late IRIS CKD Stage 3 or IRIS CKD Stage 4, is likely too late and may result in harmful metabolic derangements due to undetected accumulation of uremic toxins or even development of an overt uremic crisis. Thus, the introduction of protein-restrition at the level of veterinary renal diets should begin in IRIS CKD Stage 2 (along with dietary phosphorus restriction), because it may slow the progression of CKD, delay the onset of uremic signs, and facilitate better acceptance of dietary adjustment. In addition, given that most commercial renal diets still exceed the minimum protein requirement for adult maintenance, there is no reason to avoid feeding them at the earliest stage, nor any compelling argument for gradually increasing restriction as the disease progresses.

Home-prepared or commercial renal diets?

One study evaluated the appropriateness of 28 home-prepared diets used in cats with CKD, and found that no single recipe that was utilized met all the NRC nutrient recommended allowances for adult animals 5. Importantly, with respect to the protein content of these diets, the authors reported that concentrations of either crude protein or at least one amino acid were low in 42.9% of the recipes evaluated. This is not to suggest that home-prepared diets cannot be the equal of commercial diets, but only that they need to be formulated with great care. Therefore, when considering use of a home-prepared diet, consultation with a board-certified veterinary nutritionist^® for advice on formulation of an age- and disease-appropriate diet is strongly recommended (Figure 3).

Raw meat-based diets for cats with CKD

With the rising popularity of raw feeding practices for both dogs and cats, there is increasing interest in feeding raw meat-based diets to cats with CKD. A willingness to acknowledge the benefits of phosphorus restriction is commonplace, but protein restriction of any kind is often regarded by proponents as unnecessary and potentially harmful. Many owners believe the only necessary change to their feeding practices to be the exchange of phosphorus-rich bone for ground eggshell. Most raw diets are quite palatable, which can certainly be advantageous, but they are often very high in protein (greater than 50% ME) and phosphorus. Providing a very high-protein diet, well in excess of the cat’s requirement, is likely to increase production of uremic toxins, as previously discussed, and may advance disease progression. Moreover, meat-rich diets are acidifying, and some cats with CKD already have metabolic acidosis, which is why commercial renal diets are formulated to be alkalinizing. It is also challenging to adequately reduce phosphorus in meat-rich diets, especially if lean meats such as kangaroo, turkey or venison are being fed as a significant part of the diet (Figure 4).

Despite the controversy, the well-researched benefits of dietary protein restriction in CKD include reducing the accumulation of nitrogenous wastes and harmful uremic toxins, improving proteinuria, decreasing renal oxidative stress, and limiting the metabolic disturbances characteristic of CKD. Although the ideal degree of protein restriction for cats with CKD is not yet known, commercial renal diets provide a moderate amount of high-quality dietary protein, which meets and slightly exceeds the established minimum requirement for an adult cat, to allow a reasonable margin of safety. No research suggests that protein-restricted renal diets increase the risk of protein-energy wasting, but careful attention to ensuring adequate energy intake is essential. Available evidence suggests that protein-restriction may be of value from IRIS CKD stage 2, or potentially earlier if proteinuria is documented in cats with IRIS CKD stage 1. As with the management of any chronic disease in cats, careful attention should also be given to monitoring appetite, body weight, body condition and muscle condition, in order to reduce the risk of catabolism and loss of lean mass.