A comprehensive look at the supplements that can help address chronic kidney disease in dogs and cats.

Kidney disease is a common condition in dogs and cats, especially as they get older. Controlling the inflammatory reactions and oxidative stress that contribute to chronic kidney disease can be done with the help of a variety of supplements. This article discusses the pathology of CKD, and how supplements, including antioxidants, can address the inflammatory factors associated with this prevalent disease.

THE DIFFERENCE BETWEEN DRUGS AND SUPPLEMENTS

Drugs with antioxidant effects, developed to try to deal with many of these problems, have “minor” side effects — such as the muscle spasms, nausea, and cardiotoxicity seen with bardoxolone use — restricting their status to investigational drugs only.⁶ In contrast, most nutraceuticals have few to no side effects, although some must be used in a narrow dose spectrum so enough is administered to be beneficial without the effects of overdose.⁷

Nutritional supplements can help address all the factors mentioned above, and increase the longevity of pets with CKD. Antioxidants are the primary way that oxidative stress can be combated naturally. Most kidney supplements have at least some antioxidant effects. When individual supplements are used one at a time, the evidence for their benefits can be slight or even conflicting.

When looking at complete diets, or combinations of nutrients as nutritional interventions in healthy aging trials, additive or multiplicative effects are striking for both humans and animals.^8,9,10 Commercial products for kidney support recognize this, and the best recommendations for pet owners would be to follow that tendency.

NUTRITIONAL KIDNEY SUPPLEMENTS

ANTIOXIDANTS

Reviews of research using a single antioxidant at a time often show mixed or no effects, and doses that are too low. The strongest research support comes from studies that showed the effects of two or more antioxidants used together. Some natural substances, such as vitamins C and E, CoQ10 and N-acetyl-cysteine, already exist in the body as part of the inflammation-limiting effect. In CKD patients, however, they tend to be depleted. Supplementation can help by restoring these antioxidants to a level that can once again fight inflammation from the disease.¹¹

VITAMIN E

A human study showed that vitamin E alleviates renal injury by mediating the inactivation of nitric oxide (NO), but that it has no effect on hypertension¹² Other studies showed a cardio-protective effect as CKD advanced.^13,14 A study of vitamin E²⁰ supplementation in cats showed no difference in oxidative stress.¹⁵ In this author’s opinion, however, the dose used wastoo low, and no vitamin C was administered as a cofactor. So it is possible that the end result was an increase in the pro-oxidant form of vitamin E, which cannot act to reduce oxidative stress.

VITAMIN C

In un-supplemented human CKD patients, renal dysfunction is associated with decreased plasma vitamin C levels, which may cause endothelial dysfunction via an increase in oxidative stress.¹⁶ In humans with CKD, the administration of vitamin C may prevent progression to end stage kidney disease (requiring dialysis and/or a kidney transplant).¹⁷ The majority of studies investigating antioxidant treatments in CKD patients show a reduction in oxidative stress, and many show improved renal function.^11,18 It is possible that vitamin C levels could also be depleted in canine and feline patients. Vitamin C’s beneficial effects in human studies suggest that animals could benefit from its use as well, especially if vitamin E is part of the treatment.

A study involving the use of vitamin E in combination with vitamin C and beta carotene showed significantly reduced DNA damage in cats with renal insufficiency.³ Another study using fish oil, antioxidants (lipoic acid, vitamins C and E), L-carnitine, and botanicals (fruits and vegetables) for six months showed no progression of CKD versus controls.¹⁰

VITAMIN A (NOT BETA CAROTENE)

All-Trans Retinoic Acid (ATRA), a metabolite of retinol, is required for the production of erythropoietin by both the kidneys and liver. As CKD advances, urinary retinol excretion increases and the body’s supply of retinol decreases. Eventually, erythropoietin production is affected.¹⁹ In mice, renal-associated anemia has been reversed by vitamin A. In humans, clinical improvement has been seen in CKD patients treated with retinoids.²⁰ This approach holds promise as a way to maintain the body’s ability to produce erythropoietin in the face of CKD, but research is needed to establish safe doses without causing toxicity.

THIAMIN (B-1)

In humans, functional thiamin deficiency is common in patients with Type II diabetes. Normal top high plasma levels of thiamine are usually found, but are negated by the anti-metabolite oxythiamine. This contributes to microvascular endothelial dysfunction, a part of CKD. Daily thiamin supplements are often recommended for humans on dialysis, and this should be considered for CKD patients being treated with fluid therapy.¹

VITAMIN D (IN THE FORM OF CALCITRIOL)

Calcitriol is the final form of vitamin D used in the body, and is converted from vitamin D by 1-alpha-hydroxylase. Activity of this enzyme is reduced in CKD, so calcitriol is preferred over vitamin D supplementation. The goal of using calcitriol along with phosphorus binders is to restore, as much as possible, the normal balance between calcium and phosphorus in the body. Calcitriol’s primary use is to control renal secondary hyperparathyroidism. It slows both the loss of podocytes and the progression of fibrosis in the kidney, resulting in increased appetite and longer survival times. Calcitriol should be monitored to prevent hypercalcemia, the primary problem seen with vitamin D toxicity.²¹

PHOSPHORUS BINDERS

Calcium carbonate is an inexpensive, over-the-counter agent that is widely used as a phosphorus binder. It also has the benefit of being an antacid, which helps address the problem of metabolic acidosis. Calcium acetate costs a little more but binds twice as much phosphorus per dose.²²

Chitosan is another phosphorus binder that boosts the effect of calcium compounds. At least one supplement on the market combines chitosan and calcium carbonate, and is palatable for cats. This combination has been shown to significantly decrease plasma phosphorus levels and the urinary excretion of phosphorus.²³

Chitosan also adsorbs uremic products and lowers BUN and creatinine levels in humans with CKD. ²³

OMEGA-3 FATTY ACIDS

“Adequate” (according to the NRC) levels of Omega-3 fatty acids can decrease proteinuria, kidney fibrosis, tissue calcification, inflammatory cytokines and inflammation in dogs and cats.^4,25,26 “Higher than adequate” levels (more than twice the NRC “safe” limit) can also protect against malnutrition-inflammation syndrome in cats with CKD.²⁷ Prolonged coagulation time has been reported as a side effect, but primarily at doses higher than the “higher than adequate dose,” so it may be worth trying this dose level in uremic cats who are losing weight. Nausea is a side effect, so it is advisable to start with a low dose and work up to whatever may be tolerated by the cat.

CURCUMIN

Curcumin acts as an antioxidant by reacting directly with free radicals such as superoxide and NO, due to the presence of phenolic groups in its chemical structure. ^{28, 29}

Curcumin protects against kidney fibrosis by downregulating factors, including profibrotic cytokines, vascular endothelial growth factor (VEGF), TGF-β, and connective tissue growth factor (CTGF), among others, and decreasing extracellular matrix proteins such as fibronectin.³⁰

Curcumin also upregulates enzymes and cytoprotective and antioxidant proteins such as superoxide dismutase, due to its ability to upregulate enzymes and cytoprotective and antioxidant proteins such as SOD.^31,32,33

SULFORAPHANE

Nuclear factor erythroid 2 (Nrf-2) is a transcription factor that activates genes containing a DNA sequence known as the antioxidant response element (ARE). AREs are present in the promoter regions of genes, which promote the production of natural antioxidants such as SOD.

When active, genes containing AREs promote increased levels of natural antioxidants. These genes stimulate the production of antioxidant proteins, phase I oxidation, reduction, and hydrolysis genes, phase II detoxifying enzymes such as glutathione s-transferases (GSTs), NADPH-generating enzymes, drug transporters, and stress proteins involved in heme and metal metabolism, such as heme oxygenase 1 (HO-1). In a normal body, a protein (Kelch-like ECH-associated protein 1 known as KEAP 1) keeps Nrf-2 production at low levels as part of the homeostatic pro-oxidant-antioxidant balance.

In CKD, there’s a decrease in natural antioxidants but no decrease in KEAP 1 and no increased ARE activity. Sulforaphane, an isothiocyanate found in cruciferous plants, has a potent Nrf-2 activating effect, which helps restore the body’s own normal levels of antioxidants.³⁴

COQ10

The features of mitochondrial dysfunction seen in CKD include changes in mitochondrial morphology, increased oxidative stress, and significant decrease in ATP production and mitochondrial biogenesis. Mitochondria constantly change their shape and size through fission and fusion processes. Normal shapes range from spherical to hyperfused reticular networks. Normally, there is a balance between fission and fusion, depending on metabolic and signaling cues in the cell.³⁵

Excessive fission activity and increased mitochondrial fragmentation have been seen with increased ROS in CKD.³⁶ This leads to mitochondrial dysfunction and can result in cell death.³⁷

Kidneys have the highest levels of CoQ9 and CoQ10 as compared to all other organs in the body. CoQ10 is required for normal health and functioning of the mitochondria, and is directly involved in ATP generation. It also acts as an antioxidant in preventing lipid peroxidation, and interacts with alpha-tocopherol. CoQ10 supplementation is needed in CKD to ensure mitochondrial health.¹¹

SELENIUM

Selenium is involved with selenoproteins, most importantly (for CKD) glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase (PLGSH-Px), which play an important part in ROS metabolism and prolonged telomere length.³⁸ They inhibit ferroptosis, a non-apoptotic form of cell death seen in cancer, hippocampal, and renal cells.³⁹ They also prevent lipid peroxidation, as long as a normal amount of vitamin E is present in the membranes, and decrease the total amount of vitamin E necessary for this purpose.⁴⁰ Homemade diets may be deficient in selenium, but care must be taken when adding it since an excess amount is toxic.

PREBIOTICS AND PROBIOTICS

Animals with CKD have an imbalance of bacteria in the microbiome: an increase in bacteria such as Clostridium and Bacteroides and a decrease in Lactobacilli and Bifidobacteria.⁴¹ Administration of Lactobacillus acidophilus improves this balance and limits adhesions of pathogens, strengthening the gut barrier.⁴² Probiotics also reduce blood urea and serum phosphate concentration.

Adding prebiotics such as psyllium to probiotics increases the numbers of Bifidobacteria and Lactobacillus, decreases formation of the uremic toxin p-cresol and its plasma levels, decreases blood urea nitrogen, and reduces inflammation and oxidative stress.⁴³

In addition, studies indicate that a diet supplemented with specific antioxidants (e.g. European olea, vitamin E,²³ carotenoids, polyphenols, and flavonoids) is important for limiting renal oxidative stress and the progression of CKD.²

L CARNITINE

L carnitine is associated with improved nitrogen balance, inhibits apoptosis, and has anti-inflammatory and antioxidant effects. Dietary supplementation with L-carnitine is associated with improved nitrogen balance, the inhibition of apoptosis, and improved mitochondrial function. It is needed to transport long-chain FA from the cytosol to sites of FA β-oxidation in the mitochondria.¹⁰

QUERCETIN

Quercetin is a flavonoid with antioxidant and anti-inflammatory properties. It can reduce levels of inorganic phosphate, blood urea nitrogen and creatinine, and increase total antioxidant activity. In one study, rats with CKD were treated with quercetin and showed fewer histopathic renal abnormalities, including fewer signs of chronic interstitial inflammation.¹

RESVERATROL

Resveratrol is a polyphenol that is safe to administer to dogs, and has immunomodulating, anti-inflammatory, antioxidant, and vaso-protective properties. It enhances the production of antioxidant enzymes ⁴⁴and inhibits oxidative stress and renal interstitial fibrosis.⁴⁵ It also decreases muscle atrophy from CKD.⁴⁶

URSOLIC ACID

This supplement is widely found in fruit peels, and in herbs such as rosemary and thyme. It is anti-inflammatory and protects against CKD and renal fibrosis. It inhibits pro-inflammatory cytokines in muscles, which slows the decline of muscle mass associated with the progressive loss of protein in CKD.⁴⁷ Interestingly, ursolic acid has been shown to directly inhibit the expression of pro-inflammatory cytokines in the muscles of mice with CKD.⁴⁸

EGCG

Present in green tea, EGCG neutralizes free radicals, acts as a ROS scavenger, and chelates metal ions. It inhibits oxidative stress in the kidney and decreases the levels of uremic toxins such as methyl guanidine, slowing the progression of kidneydisease.⁴⁹

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