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
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
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.
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.
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
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 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
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
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 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 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 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 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
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
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
1Rapa SF, Di Iorio BR, Campiglia P, Heidland A, Marzocco S. Inflammation and Oxidative Stress in Chronic Kidney Disease-Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites. Int J Mol Sci. 2019 Dec 30;21(1):263.
2Halfen DP, Caragelasco DS, Nogueira JPS, Jeremias JT, Pedrinelli V, Oba PM, Ruberti B, Pontieri CFF, Kogika MM, Brunetto MA. Evaluation of Electrolyte Concentration and Pro-Inflammatory and Oxidative Status in Dogs with Advanced Chronic Kidney Disease under Dietary Treatment. Toxins (Basel). 2019 Dec 19;12(1):3.
3Yu S, Paetau-Robinson I. Dietary supplements of vitamins E and C and beta-carotene reduce oxidative stress in cats with renal insufficiency. Vet Res Commun. 2006 May;30(4):403-13.
4Brown SA, Brown CA, Crowell WA, et al. Beneficial effects of chronic administration of dietary omega-3 polyunsaturated fatty acids in dogs with renal insufficiency. J Lab Clin Med. 1998;131:447–455.
5Quimby J, Erickson A, Mcleland S, Cianciolo R, Maranon D, Lunn K, Elliott J, Lawson J, Hess A, Paschall R, Bailey S. Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease. Vet Sci. 2021 Dec 8;8(12):314.
6Rayego-Mateos S, Valdivielso JM. New therapeutic targets in chronic kidney disease progression and renal fibrosis. Expert Opin Ther Targets. 2020 Jul;24(7):655-670.
7Padayatty SJ, Levine M. Vitamin C: the known and the unknown and Goldilocks. Oral Dis. 2016 Sep;22(6):463-93.
8Lin JL, Fung TT, Hu FB, Curhan GC. Association of dietary patterns with albuminuria and kidney function declinein older white women: A subgroup analysis from the Nurses’ Health Study. Am J Kidney Dis. 2011;57(2):245–54. 10.1053
9(3)Hall JA, MacLeay J, Yerramilli M, Obare E, Yerramilli M, Schiefelbein H, Paetau-Robinson I, Jewell DE. Positive Impact of Nutritional Interventions on Serum Symmetric Dimethylarginine and Creatinine Concentrations in Client-Owned Geriatric Dogs. PLoS One. 2016 Ap
10(4) Hall JA, Jewell DE. Feeding healthy beagles medium-chain triglycerides, fish oil, and carnitine offsets age-related changes in serum fatty acids and carnitine metabolites. PLoS One. 2012;7(11):e49510
11Small DM, Coombes JS, Bennett N, Johnson DW, Gobe GC. Oxidative stress, antioxidant therapies and chronic kidney disease. Nephrology (Carlton). 2012 May;17(4):311-21.
12Tamay-Cach F, Quintana-Pérez JC, Trujillo-Ferrara JG, Cuevas-Hernández RI, Del Valle-Mondragón L, García-Trejo EM, Arellano-Mendoza MG. A review of the impact of oxidative stress and some antioxidant therapies on renal damage. Ren Fail. 2016;38(2):171-5.
13Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, FainaruM, Green MS. Secondary prevention with antioxidants of cardiovascular disease in end stage renal disease (SPACE): randomized placebo-controlled trial. Lancet. 2000 Oct 7;356(9237):1213-8.
14Meagher EA. Treatment of atherosclerosis in the new millennium: is there a role for vitamin E? Prev Cardiol. 2003 Spring;6(2):85-90.
15Timmons RM, Webb CB. Vitamin E supplementation fails to impact measures of oxidative stress or the anemia
of feline chronic kidney disease: a randomized, double-blinded placebo control study. Vet Med Sci. 2016 Jan 22;2(2):117-124.
16Takahashi, N.; Morimoto, S.; Okigaki, M.; Seo, M.; Someya, K.; Morita, T.; Matsubara, H.; Sugiura, T.; Iwasaka, T. Decreased plasma level of vitamin C in chronic kidney disease: Comparison between diabetic and non-diabetic patients. Nephrol. Dial. Transpl. 2011, 26, 1252–1257
17Jun M, Venkataraman V, Razavian M, Cooper B, Zoungas S, Ninomiya T, Webster AC, Perkovic V. Antioxidants for chronic kidney disease. Cochrane Database Syst Rev. 2012 Oct 17;10(10):CD008176.
18Sung CC, Hsu YC, Chen CC, Lin YF, Wu CC. Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease. Oxid Med Cell Longev. 2013;2013:301982
19Rojo-Trejo MH, Robles-Osorio ML, Sabath E. Liposoluble vitamins A and E in kidney disease. World J Nephrol. 2022 May 25;11(3):96-104.
20Kinoshita K, Kishimoto K, Shimazu H, Nozaki Y, Sugiyama M, Ikoma S, Funauchi M. Successful treatment with retinoids in patients with lupus nephritis. Am J Kidney Dis. 2010;55:344–347
21Corbee R. J. Vitamin D in Health and Disease in Dogs and Cats Advances in Small Animal Care 1 (2020) 265–277
22Emmett, M. A Comparison of Calcium-Based Phosphorus Binders for Patients with Chronic Kidney Disease Dialysis & Transplantation May 2006
23Wagner E, Schwendenwein I, Zentek J. Effects of a dietary chitosan and calcium supplement on Ca and P metabolism in cats. Berl Munch Tierarztl Wochenschr. 2004 Jul-Aug;117(7-8):310-5. PMID: 15298059
24Jing SB, Li L, Ji D, Takiguchi Y, Yamaguchi T. Effect of chitosan on renal function in patients with chronic renal failure. J Pharm Pharmacol. 1997 Jul;49(7):721-3.
25Roudebush P, Polzin DJ, Adams LG, Towell TL, Forrester SD. An evidence-based review of therapies for canine chronic kidney disease. J Small Anim Pract 2010; 51(5): 244–52.
26Maniaki E, Finch N Chronic Kidney Disease in cats and Dogs, managing proteinuria In Practice London Vol. 40, Iss. 7, (Sep 2018): 266.
27Harris M, Lunn K, Quimby J, etal Omega 3 fatty acids mitigate inflammation in felines with chronic kidney disease FASEB April 2012 Vol 26 Iss 51
28Pan, Y.; Zhu, G.; Wang, Y.; Cai, L.; Cai, Y.; Hu, J.; Li, Y.; Yan, Y.; Wang, Z.; Li, X.; et al. Inhibition of high glucose-induced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic rats. Br. J. Pharm. 2012, 166, 1169–1182
29Barzegar, A.; Moosavi-Movahedi, A.A. Intracellular ROS protection efficiency and free radical-scavenging activity of curcumin. PLoS ONE 2011, 6, e26012.
30Soetikno, V.; Watanabe, K.; Sari, F.R.; Harima, M.; Thandavarayan, R.A.; Veeraveedu, P.T.; Arozal, W.; Sukumaran, V.; Lakshmanan, A.P.; Arumugam, S.; et al. Curcumin attenuates diabetic nephropathy by inhibiting PKC-α and PKC-β1 activity in streptozotocin-induced type I diabetic rats. Mol. Nutr. Food Res. 2011, 55, 1655–1665.
31Leong, G.S.; Oh, G.S.; Pae, H.O.; Jeong, S.O.; Kim, Y.C.; Shin, M.K.; Seo, B.Y.; Han, S.Y.; Lee, H.S.; Jeong, J.G.; et al. Comparative effects of curcuminoids on endothelial heme oxygenase-1 expression: Ortho-methoxy groups are essential to enhance heme oxygenase activity and protection. Exp. Mol. Med. 2006, 38, 393–400
32Ye, S.F.; Hou, Z.Q.; Zhong, L.M.; Zhang, Q.Q. Effect of curcumin on the induction of glutathione
S-transferases and NADP(H): Quinone oxidoreductase and its possible mechanism of action. Yao Xue Xue Bao 2007, 42, 376–380.
33Rushworth, S.A.; Ogborne, R.M.; Charalambos, C.A.; O’Connell, M.A. Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes. Biochem. Biophys. Res. Commun. 2006, 341, 1007–1016.
34Liebman SE, Le TH. Eat Your Broccoli: Oxidative Stress, NRF2, and Sulforaphane in Chronic Kidney Disease. Nutrients. 2021 Jan 18;13(1):266.
35Mishra P, Chan DC. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol. 2014; 15:634–646.
36Brooks C, Wei Q, Cho SG, et al. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest. 2009; 119:1275–1285.
37Galvan DL, Green NH, Danesh FR. The hallmarks of mitochondrial dysfunction in chronic kidney disease. Kidney Int. 2017 Nov;92(5):1051-1057.
38Cai Z, Zhang J, Li H. Selenium, aging and aging-related diseases. Aging Clin Exp Res. 2019
39Cardoso BR, Hare DJ, Bush AI, Roberts BR. Glutathione peroxidase 4: a new player in neurodegeneration? Mol Psychiatry. 2017 Mar;22(3):328-335.
40Ursini F, Bindoli A. The role of selenium peroxidases in the protection against oxidative damage of membranes. Chem Phys Lipids. 1987 Jul-Sep;44(2-4):255-76.
41Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D, 2017. Gut microbiome in chronic kidney disease: challenges and opportunities. Transl Res. 179:24–37.
42Hall JA, MacLeay J, Yerramilli M, Obare E, Yerramilli M, Schiefelbein H, Paetau-Robinson I, Jewell DE, 2016. Positive impact of nutritional interventions on serum symmetric dimethylarginine and creatinine concentrations in client-owned geriatric dogs. PLoS One. 11(4):e0153653.
43Lopes RCSO, Balbino KP, Jorge MP, Ribeiro AQ, Martino HSD, Alfenas RCG. Modulation of intestinal microbiota, control of nitrogen products and inflammation by pre/probiotics in chronic kidney disease: a systematic review. Nutr Hosp. 2018 Apr 27;35(3):722-730.
44Saldanha, J.F.; Leal, V.O.; Rizzetto, F.; Grimmer, G.H.; Ribeiro-Alves, M.; Daleprane, J.B.; Carraro-Eduardo, J.C.; Mafra, D. Effects of Resveratrol Supplementation in Nrf2 and NF-κB Expressions in Nondialyzed Chronic Kidney Disease Patients: A Randomized, Double-Blind, Placebo-Controlled, Crossover Clinical Trial. J. Ren. Nutr. 2016, 26, 401–406
45Liang, J.; Tian, S.; Han, J.; Xiong, P. Resveratrol as a therapeutic agent for renal fibrosis induced by unilateral ureteral obstruction. Ren. Fail. 2014, 36, 285–291. .
46Sun, L.J.; Sun, Y.N.; Chen, S.J.; Liu, S.; Jiang, G.R. Resveratrol attenuates skeletal muscle atrophy induced by chronic kidney disease via MuRF1 signaling pathway. Biochem. Biophys. Res. Commun. 2017, 487, 83–89.
47Kunkel, S.D.; Suneja, M.; Ebert, S.M.; Bongers, K.S.; Fox, D.K.; Malmberg, S.E. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell Metab. 2011, 13, 627–638.
48Stenvinkel, P.; Ketteler, M.; Johnson, R.J.; Lindholm, B.; Pecoits-Filho, R.; Riella, M. IL-10, IL-6 and TNF-alpha: Central factors in the altered cytokine network of uremia–the good, the bad and the ugly. Kidney Int. 2005, 67, 1216–1233.
49Yamabe, N.; Yokozawa, T.; Oya, T.; Kim, M. Therapeutic potential of (-)-epigallocatechin 3-O-gallate on renal damage in diabetic nephropathy model rats. J. Pharmacol. Exp. Ther. 2006, 319, 228–236.