Omega 3 and the management of renal insufficiency

Nutrition has an essential role in the management of chronic kidney disease.

The goals of the nutrition intervention in these patients are:

The prevention or improvement of the clinical sign
The reduction of the progression rate of the disease and extension of the survival time
The reduction of electrolyte (calcium and phosphorus) and acid-base imbalances
The provision of adequate nutrition.

Renal diets are specially designed to achieve these goals and, in general, their adaptations include:

Reduced phosphorus content
Reduced protein content with an increase in protein quality
Controlled sodium level
Increased B vitamins, potassium and antioxidant content
A moderate base excess
An increase in long chain omega-3 polyunsaturated fatty acid (LC omega-3 PUFA) content, more specifically, an increased content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Increased caloric density

Nutritional imbalance - risks of feeding raw food to dogs

EPA & DHA sources

EPA DHA Conversaion pathways diagram

Figure 1. Pathways for conversion of the omega-6 linoleic acid (LA) into arachidonic acid (AA) and the conversion of the omega 3 family linolenic acid (ALA) into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Δ-5, Δ-6 and Δ-4 are desaturases. Δ-6 has low affinity for ALA, thus conversion of ALA into EPA is inefficient in cats and dogs. Adapted from NRC 2006.¹

Both, EPA and DHA derive from another omega 3 fatty acid, the α‐linolenic acid (ALA) through the enzymatic action of desaturases (Δ-5 and Δ-6) and elongases (Figure 1). Unfortunately, cats and dogs have low Δ-6 desaturase activity, which prevents ALA from being an efficient source of EPA and DHA for these species.

ALA is considered an essential fatty acid for cats and dogs, in particular during growth and reproduction due to its role in supporting normal development, and it is expected that when EPA and DHA are included in the diet, the dietary requirement of ALA is reduced.

All these omega 3s (ALA, EPA and DHA) can be found in pet foods, but while ALA is provided by vegetable oils - like flaxseed oil, soya oil or rapeseed oil - EPA and DHA are fatty acids that can only be provided in adequate amounts from marine sources - like fish oil, crustaceans such as krill, or microorganisms such as algae.

EPA & DHA effects

EPA DHA General pathways diagram

Figure 2. General pathways of eicosanoid formation from n-3 and n-6 PUFAs (polyunsaturated fatty acids). Eicosapentaenoic acid (EPA) and arachidonic acid (AA) compete with one another for incorporation into cell membranes and as substrates for cyclooxygenase (CO) and 5-lipoxygenase (5-LO). EPA is the precursor of the less active leukotriene B5 (LTB₅₎ and can form hydroxyl fatty acids via 15-lipoxygenase (15-LO), which is a potent inhibitor of leukotriene B4 (LTB₄). Source NRC 2006.

The most well reported mechanisms by which EPA and DHA can achieve their beneficial outcomes is by EPA direct effects. Namely:

competition for the active sites of many cyclooxygenase (CO) and lipoxygenase (LO) enzymes - preventing the production of more potent pro-inflammatory eicosanoids produced from arachidonic acid (AA) - by using the same pathways2 (Figure 2);
inhibition of AA synthesis, through inhibition of delta-5-desaturase1 (Figure 1);
competition with AA for the enzyme phospholipase A - reducing its release from the membrane and thus its bioavailability. DHA can contribute to these effects because it can be retro-converted to EPA (Figure 1).

EPA & DHA role in renal diets for cats and dogs

Since it was found that myocardial infarction and ischemic heart disease rarely occurred in the Eskimo human populations that were fed high quantities of long chain omega-3 PUFAs (polyunsaturated fatty acids) from marine sources, these fatty acids have been intensively researched. The intense research on their physiologic functions showed that EPA and DHA can influence inflammation, immune response, gene expression and, ultimately, renal disease.

fish oil

The results of studies done in humans, rats^, dogs and the results of a retrospective study in cats, show that long chain omega-3 PUFA supplementation can have a beneficial role as an adjunctive treatment for chronic kidney disease (CKD) patients.

In dogs with experimentally induced CKD, high dosages of EPA and DHA were able to reduce proteinuria, prevent glomerular hypertension and decrease the production of proinflammatory eicosanoids - with reduction of histopathologic lesions (decreased mesangial matrix expansion, glomerulosclerosis, and renal interstitial cellular infiltrates).

Data on the effect of EPA and DHA in cats is limited to one retrospective study where cats with CKD fed a maintenance diet were compared to the ones fed 1 of 7 renal diets. In this study, the renal diet with the highest EPA content (2g/1000kcal) was associated with the longest survivaltime.

The EPA and DHA beneficial effects are attributed not only to their ability to reduce inflammation and oxidative stress - by interfering with the production of pro-inflammatory eicosanoids (see above EPA and DHA effects) - but also to the synthesis of different metabolites known as resolvins and protectins. These metabolites act as potent anti-inflammatory mediators by blocking the actions of eicosanoids, and also by helping to clear the site of inflammation. The long chain omega-3 PUFA supplementation also increases the bioavailability of nitric oxide, which contributes to the reduction in proteinuria. In summary, there is evidence that higher intake of EPA and DHA improves kidney function and potentially slows down the progression of renal disease.

EPA & DHA dosage for renal patients

Although EPA and DHA are omega 3- fatty acids, not all sources of omega 3s have the same effects. α‐Linolenic acid (18:3n‐3, ALA) is an omega- 3 fatty acid found in many vegetable oils and, although it could be a precursor of eicosapentaenoic acid (20:5n‐3, EPA), as explained above, cats and dogs have very limited capacity to synthesise EPA and DHA from α‐linolenic acid and so they must be obtained pre‐formed from the diet.

The minimum amount of total EPA + DHA that showed a reduction in glomerular hypertension and proinflammatory eicosanoids in dogs was 0.41% on a dry matter basis together with a total omega-6: total omega-3 ratio of 5:1. This would be equivalent to a dose of approximately 130 to 140 mg of EPA and DHA /kg0.75 body weight for a dog.

From the retrospective study in cats with CKD, the minimum effective beneficial dosage of EPA in cats with CKD cannot be defined. However, the EPA content of the renal diet which was associated with increased survival time compared to the other renal diets would be equivalent to a dosage of approximately 95 to 127 mg EPA per kg body weight (based on a 4-kg cat eating 75 to 100 kcal/kg^0.67). As the ratio of EPA:DHA in fish oil is roughly 1:1, this would mean that the dosage of combined EPA and DHA in the cats fed the diet associated with the longest survival time was around 190 to 254 mg/kg body weight.

The omega-3 / omega-6 ratio is also important to consider, due to their metabolic competitive behaviour.

Higher dosages might give an extra benefit, but the NRC (2006)safe upper limit for dogs is 760 mg of EPA and DHA/kg^0.75 body weight, since high dosages might be responsible for secondary side effects, for instance: gastrointestinal upset, decreased wound healing, decreased platelet function, and altered immune function^.It should be noted that the FEDIAF’s Nutritional Guidelines do not indicate a nutritional maximum for EPA and DHA. Any risk of gastrointestinal upset can be reduced by a slow transition to higher EPA + DHA in the diet and these fatty acids should always be accompanied by a fat-soluble antioxidant like vitamin E.

Therapeutic kidney diets are often supplemented with high concentrations of the omega-3 fatty acids, which include EPA, DHA, and ALA. Although ALA is considered an essential fatty acid (as already mentioned), its conversion to EPA and DHA is residual in these species. Therefore, information on the specific concentration of EPA and DHA in the diet is important for the clinician. If this information is not readily available in the food package or support information, it is possible to obtain it by contacting the manufacturer or the distributor.

Concentrations of eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) in SPECIFIC and other renal diets (December 2023.

FOR DOGS		FOR CATS
	EPA + DHA (g/1000 kcal)		EPA + DHA (g/1000 kcal)
SPECIFIC CKD Heart & Kidney Support	5.0	SPECIFIC FKD Kidney Support	3.7
SPECIFIC CKW Heart & Kidney Support	5.1	SPECIFIC FKW Kidney Support	4.8
		SPECIFIC FKW-P Kidney Support	3.1
Other renal diets (n=22)	1.0 - 4.2	Other renal diets (n=23)	1.0- 2.2

References

1. National Research Council (NRC), 2006. Chap 5. Fat and fatty acids. Nutrient requirements of dogs and cats. Washington, DC: Ad Hoc Committee on Dog and Cat Nutrition. p. 85-110.

2. Hadley KB, Guimont-Desrochers F, Bailey-Hall E, et al 2017. Supplementing dams with both arachidonic and docosahexaenoic acid has beneficial effects on growth and immune development. Prostaglandins, Leukotrienes and Essential Fatty Acids, 126:55-63.

3. Dunbar BL, Bigley KE, Bauer JE, 2010. Early and sustained enrichment of serum n-3 long-chain polyunsaturated fatty acids in dogs fed a flaxseed supplemented diet. Lipids 45:1–10.

4. Hu J, Liu Z, Zhang H, 2017. Omega-3 fatty acid supplementation as an adjunctive therapy in the treatment of chronic kidney disease: a meta-analysis. Clinics, 72:58-64.

5. Zanetti M, Gortan Cappellari G, Barbetta D, et al 2017. Omega 3 Polyunsaturated Fatty Acids Improve Endothelial Dysfunction in Chronic Renal Failure: Role of eNOS Activation and of Oxidative Stress. Nutrients,9: 895.

6. Brown SA, Brown CA, Crowell WA, et al, 1998. Beneficial effects of chronic administration of dietary omega-3 polyunsaturated fatty acids in dogs with renal insufficiency. J Clin Lab Med, 131:447–455.

7. Brown SA, Brown CA, Crowell WA, et al, 2000. Effects of dietary poly-unsaturated fatty acid supplementation in early renal insufficiency in dogs. J Lab Clin Med, 135:275–286.

8. Plantinga EA, Everts H, Kastelein AM, Beynen AC, 2005. Retrospective study of the survival of cats with acquired chronic renal insufficiency offered different commercial diets. Vet Rec, 157:185-187.

9. Serhan CN, Hong S, Gronert K, Colgan SP, et al, 2002. “Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.” J Exp Med , 196:1025-1037.

10. Lenox CE, Bauer JE, 2013. Potential adverse effects of omega-3 Fatty acids in dogs and cats. J Vet Intern Med, 27:217-26.

11. FEDIAF (2021) Nutritional Guidelines for Complete and Complementary Pet Food for Cats an Dogs

Omega 3 and the management of renal insufficiency

Renal diets are specially designed to achieve these goals and, in general, their adaptations include:

EPA & DHA role in renal diets for cats and dogs

EPA & DHA dosage for renal patients

Concentrations of eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) in SPECIFIC and other renal diets (December 2023.

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Omega 3 and the management of renal insufficiency

Renal diets are specially designed to achieve these goals and, in general, their adaptations include:

EPA & DHA role in renal diets for cats and dogs

EPA & DHA dosage for renal patients

Concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in SPECIFIC and other renal diets (December 2023.

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Concentrations of eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) in SPECIFIC and other renal diets (December 2023.

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