The Gut - Kidney Axis

Increasing evidence from human and veterinary medicine supports a bidirectional relationship between gastrointestinal health and renal function, termed the gut - kidney axis. As a result of this interplay, intestinal dysbiosis, impaired barrier function, and microbial-derived metabolites contribute to CKD progression and systemic complications. This is a relatively new area of focus for veterinary medicine, but recent advancements have highlighted its importance as a potential therapeutic target. (Summers and Quimby 2024).

Dysbiosis and the Intestinal Environment in CKD

The gut microbiome plays an important role in maintaining host health, and alteration of this microbiome has been associated with many illnesses, including CKD. Specifically, the intestinal microbiome is essential for nutrient assimilation, immune modulation, epithelial barrier integrity, bile acid biotransformation, and short-chain fatty acid (SCFA) production, among many other functions. (Qin 2010; Wu & Wu 2012; Meijers 2018) CKD consistently alters gut microbial composition in both human and veterinary species. The uremia associated with CKD has been shown to negatively impact the gut microbiome in humans and rats causing intestinal dysbiosis. (Vaziri 2013; Ramezani 2014) Cats with IRIS stage 2–4 CKD exhibit decreased fecal microbial richness and diversity compared with healthy age-matched controls. (Summers 2019) In dogs, overall diversity changes are less consistent, although specific taxa correlate with disease progression. (Kim 2023) Problematically the shift of the microbiota to a less diverse community then further contributes to the production of colonic-derived uremic toxins such as indoxyl sulfate and p-cresol sulfate, initiating a vicious cycle. (Evenepoel 2009; Nallu 2017; Wong 2014) Reduced diversity and enrichment of the microbiota are potentially driven by a number of factors including uremia-associated changes in luminal pH, ammonia accumulation, epithelial barrier dysfunction, antibiotic exposure, phosphate binders, and low dietary fiber intake. (Vaziri 2013)

Uremic Toxins

The term uremia refers both to the accumulation of substances in the blood that occurs as a result of a decline in GFR, and the clinical manifestations that result. Although this generally refers to abnormal balances in electrolytes, organic solutes and hormones, it also refers to uremic toxins. Creatinine and urea are the best-known uremic toxins, but in reality, are only a couple of approximately 146 organic solutes that are putative uremic toxins. (Rosner 2021) Importantly many of these substances are not actively regulated by the body and so progressively increase with declining GFR. These are particularly problematic for human patients as some uremic toxins are not amenable to removal by hemodialysis. (Rosner 2021) Of particular interest are uremic toxins that are the waste products of protein catabolism (e.g indoxyl sulfate, p-cresyl sulfate) as these are thought to not only have negative pathophysiologic effects, but also to contribute to the clinical syndrome of uremia.

Uremic toxins that are the product of protein catabolism originate from the colon via protein fermentation by intestinal bacteria. (DeMoss 1969; Evenepoel 2009; Nallu 2017) Specifically, indoles are produced by the metabolism of dietary tryptophan by tryptophanase in intestinal bacteria and p-cresol is generated via the partial breakdown of tyrosine and phenylalanine by many intestinal obligate or facultative anaerobes. Indole and p-cresol are then systemically absorbed and sulfated by the liver into the protein-bound uremic toxins indoxyl sulfate and p-cresol sulfate. Protein-bound uremic toxins are excreted into the urine by organic anion and cation transporters in tubular cells and thus accumulate in systemic circulation in patients with renal dysfunction.

Uremic Toxins in Cats and Dogs

In veterinary medicine, the most widely studied gut-derived uremic toxin is IS. Several studies have documented that cats with CKD accumulate IS in systemic circulation. (Summers 2019; Liao 2019; Hall 2020). Although pCS concentrations did not significantly differ between healthy cats and those with CKD, the highest concentrations were noted in CKD cats. (Summers 2019) Similar to cats, dogs with CKD have higher IS concentrations than healthy dogs. (Cheng 2015) In both cats and dogs, IS is associated with disease progression. (Chen 2018; Liao 2019) Several untargeted metabolomics studies have demonstrated deranged uremic toxin profiles in both cats and dogs, with an overall increase in serum or plasma concentrations compared to healthy controls. (Hall 2020; Ephraim and Jewell 2020; Nealon 2024)

Negative Consequences of Uremic Toxins

Although increased concentration of a substance does not imply pathology, numerous uremic toxins that accumulate in CKD are known to have deleterious effects. The accumulation of indoxyl sulfate and p-cresyl sulfate in CKD has been associated with inciting the production of free radicals, activating RAAS, promoting renal fibrosis, inducing inflammation, damaging renal tubular cells, and stimulating the progression of glomerular sclerosis. (Miyazaki 1997; Shimizu 2011; Sun 2013, Watanabe 2013) These uremic toxins also contribute to morbidity and mortality by lowering erythropoietin production and bone turnover, accelerating muscle atrophy, and increasing the risk of cardiovascular disease. (Borges et al., 2016, Enoki et al., 2016, Adesso et al., 2019, Graboski and Redinbo, 2020, Nakano et al., 2021)

Beyond Uremic Toxins: Other Microbial Metabolites

The effects of CKD on microbial dysmetabolism involve more than uremic toxins. Two additional areas that have been studied are short-chain fatty acids (SCFAs) and bile acids. (Summers 2019; Summers 2020; Rowe 2024) Straight-chain SCFAs are major end-products of saccharolytic fermentation of complex polysaccharides (including non-digestible dietary fibers) are essential nutrients vital for both intestinal and host-health. They have several beneficial effects on the host that could benefit patients with CKD including regulation of luminal pH, anti-inflammatory properties and promoting epithelial tight junction assembly, lipid and glucose metabolism, blood pressure regulation. (Fusco 2023) In contrast, BCFAs represent only a small portion of total SCFA production and are produced by microbial fermentation of branched chain amino acids (valine, leucine, isoleucine) in the colon. (Smith and Macfarlane 1998, Aguirre 2016) BCFAs and other products of protein fermentation in the colon are considered deleterious to the gut by promoting inflammation and reducing motility. Cats with CKD have increased fecal concentrations of the BCFA isovaleric acid, particularly in cats with IRIS CKD Stage 3 and 4. CKD cats with muscle atrophy have higher fecal BCFA concentrations compared to CKD cats with normal muscle mass based on physical examination. (Summers 2019)

Dysbiosis of the fecal microbiota can alter bile acid metabolism in variable ways. (Winston and Theriot 2020) In people with end-stage renal disease, genes related to secondary bile acid biosynthesis are increased resulting in fecal enrichment of secondary bile acids and depletion of primary bile acids. (Li 2019; Wang 2020) Poor prognosis and mortality in patients with CKD is correlated with the serum concentration of several taurine conjugated primary and secondary bile acids. (Li 2019)

Cats with CKD exhibit reduced secondary bile acids, including ursodeoxycholic acid, differing from patterns reported in human CKD and resembling post-antibiotic dysmetabolism. (Summers 2020; Rowe 2024)

Constipation: A Clinical Amplifier of the Gut - Kidney Axis

Constipation may also play a role in uremic toxin accumulation due to sustained retention of fecal material in the colon; constipated human patients with CKD have higher serum concentrations of pCS than patients with normal fecal scores. (Ramos et al 2019; Pereira 2020) Delayed colonic transit has the potential to increase microbial protein fermentation and enhance uremic toxin production. Uremic toxins have also been shown to have a negative effect on colonic motility. Furthermore, rodent models demonstrate improvement in renal function and histopathology following treatment with lactulose. (Ramos 2019; Sueyoshi 2019) Constipation is common in feline CKD and likely arises from a combination of impaired urine concentrating ability, chronic dehydration, hypokalemia, and phosphate binder use. (Benjamin & Drobatz 2019; George 2025; Jones 2022; Quimby and Lappin 2016)escription text goes here

Dietary Management

It is common practice in both human and veterinary medicine to reduce protein intake in those with CKD. This practice results in improved survival in both cats and dogs with CKD. (Conroy 2019; Pedrinelli 2020) Since gut-derived uremic toxins are produced by microbial fermentation of dietary amino acids, blood concentrations can be modulated by feeding a diet with a low protein to fiber index. (Ebersolt 2022) In one study in healthy cats, a higher protein diet (10.98 g/100 kcal ME versus 7.44 g/100 kcal ME) was associated with increased concentrations of IS and relatively higher concentrations of pCS. (Summers 2021) Similarly, cats with IRIS Stage 1 CKD had demonstrably higher IS and pCS concentrations when fed a diet higher in protein (8.01 g/100kcal ME versus 6.95 g/100 kcal ME and 5.65 g/100 kcal ME). Similar findings were reported in healthy adult dogs. (Ephraim 2020) Increasing soluble fiber intake is also a strategy to decrease uremic toxin accumulation. (Rossi 2015) In dogs and cats with CKD, feeding a renal therapeutic diet with high soluble fiber decreased plasma concentrations of uremic toxins compared to feeding a renal therapeutic diet alone. (Ephraim and Jewell 2020; Hall 2022)

The degree of restriction of dietary protein intake is controversial, particularly in cats as they are obligate carnivores and have increased protein requirements compared to dogs and humans. Studies suggest that senior cats may require more protein than younger cats and additionally many cats with CKD, body weight, body condition score and/or muscle mass may decline over time. (Freeman 2016) A key concept for successful dietary management in cats with CKD is the maintenance of adequate caloric intake and feeding a modified protein diet with highly digestible and complete source of protein to prevent protein malnutrition and maintain lean body mass. (Hall 2019, Hall 2022) Taking the information known to date into account, recommendations for dietary protein in cats with CKD likely consist of delicately balancing the protein content between limiting uremic toxin production and maintaining lean body mass. (Machado 2022)

Probiotics and Prebiotics

Results of probiotic and synbiotic administration in veterinary CKD are inconsistent, with limited evidence for meaningful reductions in uremic toxins. (Rishniw & Wynn 2011; Summers 2020) Soluble fiber supplementation appears more consistently beneficial in modulating microbial metabolism. (Hall 2022)

Adsorbents

Adsorbents such as AST-120 are used to limit intestinal absorption of IS and pCS in people with CKD and shown to delay progression of disease. (Yamamoto 2015; Asai 2019)  A carbon-based adsorbent designed to bind indole and p-cresol in the intestinal tract is commercially available and marketed for cats with kidney disease (Porus One®, Dechra, USA).  This product has been shown to reduce IS in senior cats and cats with IRIS Stage 2 and 3 CKD after eight weeks of administration. (Mottet and Kowollik 2019, Paschall 2024, Elzenbeck 2026). To the authors’ knowledge, no studies have been published evaluating the effect of adsorbents on gut-derived uremic toxins in dogs.

Management of Constipation

Addressing gut motility may also be a therapeutic target to decrease uremic toxins that are the result of protein catabolism in the colon. Targeted treatment of constipation using hydration, correction of hypokalemia, osmotic laxatives, and promotility agents represents a rational, underutilized strategy to mitigate gut-derived uremic toxin production.cription text goes here