การรับมือกับความผิดพลาดอย่างมีประสิทธิภาพ

Introduction

A growing body of research supports the concept that there is significant connection in multiple species between the gut and the kidney (also known as the “gut-kidney axis”) (Figure 1), and that both systems have important influences upon the other, with potential significant clinical implications. Cats with chronic kidney disease (CKD) have dysbiosis, supporting the notion that the gut is a therapeutic target to potentially improve longevity and comorbidities. This article reviews the current understanding of the gut-kidney axis and strategies available to veterinarians to potentially improve the health of the gut microbial community and thus reduce accumulation of harmful gut-derived uremic toxins.

The microbiome and dysbiosis

The intestinal microbiome is defined as the collection of microorganisms that consists primarily of bacteria. These microorganisms reside in the gastrointestinal tract and form an ecosystem that has complex interactions both with each other and the host. In cats, there are thousands of gut bacterial phylotypes, amounting to trillions of cells with an extensive functional capacity. This wide array of microorganisms plays an important role in maintaining host health via products of bacterial metabolism and by influencing gene expression in the gut. A healthy bacterial microbiota and communication between host and bacterial metabolites is vital for the development and maintenance of a healthy immune system, assimilation of nutrients from the diet, maintenance of the gut barrier, nutrient synthesis (e.g., short-chain fatty acids, vitamin B12), and protection against invading enteric pathogens 1.

Dysbiosis is defined as an imbalanced intestinal microbial community, with alteration in the composition of the microbiota and its metabolic activities. In many conditions dysbiosis is not just a marker of disease, it also actively contributes to the pathology 2. Intestinal dysbiosis has been extensively documented in people with CKD and in laboratory modelling; uremia has been shown to negatively impact the microbiome, shifting the intestinal microbiota from a more evenly distributed and complex community to one that is simpler and dominated by certain bacterial families 2. Proposed reasons for intestinal dysbiosis in CKD patients – in addition to the direct effect of urea and subsequent increased production of ammonia by gut bacteria – include frequent use of antibiotics and phosphate binders, and dietary changes such as decreased fiber intake 2.

Uremic toxins

The term uremia refers both to the accumulation of substances in the blood that occurs as a result of a decline in glomerular filtration rate (GFR), and the clinical manifestations that result. Although this generally refers to imbalances in electrolytes, organic solutes and hormones, it also refers to uremic toxins. Creatinine and blood urea nitrogen (BUN) are the best-known uremic toxins from a clinical perspective, but in reality these are only two of approximately 146 organic solutes that are putative uremic toxins 3. Importantly, many of these substances are not actively regulated by the body, and so progressively increase with declining GFR. Even for human patients these are particularly problematic, as some toxins are not amenable to removal by hemodialysis 3. Of particularly interest are uremic toxins that are waste products of protein catabolism by colonic microbiota (e.g., indoxyl sulfate [IS], p-cresol sulfate [pCS]), as these are thought to not only have negative pathophysiologic effects, but also to contribute to the clinical syndrome of uremia.

Indole and p-cresol, which are uremic toxin precursors, are both products of protein catabolism which are produced in the colon via protein fermentation by microbiota 4,5. Indoles are derived from the metabolism of dietary tryptophan by tryptophanase in intestinal microbiota such as Escherichia coli (E. coli), Proteus vulgaris, and Bacteroides spp. (Figure 2). P-cresol is generated via the partial breakdown of tyrosine and phenylalanine by many intestinal obligate or facultative anaerobes, including the genera Bacteroides, Lactobacillus, Enterobacter, Bifidobacterium, and Clostridium. Indol and p-cresol are absorbed and then sulfonated in the liver into the protein-bound uremic toxins IS and pCS respectively. These toxins are usually excreted by the kidneys, and thus accumulate in the systemic circulation of patients with renal disease. Dysbiosis further contributes to the production of colonic-derived uremic toxins, initiating a vicious cycle 4,5. The protein malassimilation in the small intestine that occurs in CKD patients increases protein substrate in the intestinal lumen, which promotes the expansion of proteolytic bacteria that produce the uremic toxin precursors. Constipation may also play a role due to sustained retention of fecal material in the colon; constipated human patients with CKD have higher levels of uremic toxins than patients with normal fecal scores 6.

Deleterious effects 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. For example, the accumulation of IS and pCS in CKD has been associated with inciting the production of free radicals, activating the renin angiotensin aldosterone system (RAAS) which then promotes renal fibrosis, inducing inflammation and damaging renal tubular cells, and stimulating the progression of glomerular sclerosis 7. Other unwanted effects of uremic toxins also contribute to morbidity and mortality; these include impairment of the neurologic system, lowered erythropoietin production and bone turnover, accelerated muscle atrophy, and increased risk of cardiovascular disease 7 (Figure 3).

Fecal fatty acids in CKD

Additional metabolites of colonic microbiota that could be disrupted by intestinal dysbiosis are fatty acids. The short-chain fatty acids (SCFA) produced by the colonic microbiota consist of the straight-chain SCFAs acetic acid, propionic acid, butyric acid and valeric acid, and the branched-chain (BCFA) SCFAs isovaleric acid and isobutyric acid (Figure 4). Straight-chain SCFAs are major end-products of saccharolytic fermentation of complex polysaccharides (including non-digestible dietary fibers) and epithelial-derived mucus, and are essential nutrients vital for both intestinal and host health 8. They have several beneficial local and systemic effects, including promotion of colonic motility, lipid and glucose metabolism, blood pressure regulation, and anti-inflammatory properties. In contrast, BCFAs represent only a small portion of total SCFA production, and are produced when protein passes through the small intestine unabsorbed and protein-derived branched chain amino acids are fermented by microbiota in the colon 8. BCFAs and other products of protein fermentation in the colon are considered deleterious to the gut, and may serve as an instigator of inflammation as well as having negative effects on gut motility 8. In humans, dysbiosis in CKD is associated with a decrease in microbiota that produce SCFAs, but to the best of the authors’ knowledge BCFAs have not been studied.

What do we know in cats?

There is relatively limited information regarding the microbiome and uremic toxins and their link to kidney disease in veterinary medicine, but our knowledge is more advanced in cats. In comparison to healthy cats (≥ 8 years), cats with CKD have been documented to have a dysbiosis characterized by decreased fecal microbial diversity and richness based on 16S rRNA gene sequencing 9. Additionally, cats with CKD accumulate gut-derived uremic toxins in the systemic circulation. Significantly elevated levels of IS have been shown to be present in feline CKD (Figure 5), which is associated with disease progression 10,11,12. Although pCS concentrations did not significantly differ between healthy and CKD groups in one study, the highest concentrations were noted in CKD cats 9. Interestingly, even IRIS CKD Stage 2 cats have been documented to have uremic toxin concentrations that are significantly higher than control cats, implying this imbalance occurs relatively early in the disease process.

When fecal concentrations of straight-chain SCFAs (acetic acid, propionic acid, butyric acid, valeric acid) and BCFAs (isobutyric acid, isovaleric acid) were assessed in CKD cats and healthy controls, the first group had increased fecal isovaleric acid, and in particular the IRIS CKD Stage 3 and 4 cats 9. Cats with muscle atrophy had higher fecal BCFA concentrations compared to cats without muscle atrophy. Additional studies have demonstrated cats with CKD have a deranged fecal bile acid profile 13, and a deficiency in several essential amino acids in the serum 14. Together these findings support malassimilation of protein in CKD cats, but additional investigation is needed to more thoroughly understand the interplay between the gut and kidney in this species. However, these studies support the idea that the gut microbiome is a therapeutic target in CKD cats, with the goal of reducing production of detrimental gut-derived uremic toxins and restoring a healthier gut microbial community.

The gut as a potential therapeutic target

Uremic toxins

Due to the potential negative effects of gut-derived uremic toxins, and their poor ability to be removed via hemodialysis due to protein binding, human medicine has focused on strategies to decrease production of IS and pCS, including modulation of microbial growth in the colon by dietary management, prebiotics, probiotics, and target adsorption of uremic toxins by the use of adsorbents 4,5. Generation of IS and pCS can be modulated by selectively increasing saccharolytic and reducing proteolytic bacteria in the colon, and by optimizing intestinal transit time (and hence addressing constipation is an important consideration). Prebiotics and probiotics have been shown to influence the composition of the colonic microbiota and have been successfully used to decrease IS and pCS concentrations in human CKD patients. In addition, increasing dietary levels of carbohydrate and fiber, and decreasing protein intake, have been shown to decrease IS and pCS concentrations. Adsorbents such as sevelamer hydrochloride and AST-120 are also used to limit intestinal absorption of these toxins 15,16. However, there has been little published on strategies to decrease gut-derived uremic toxins in veterinary CKD patients, and further exploration as a potential therapeutic target seems warranted.

The concept of decreasing uremic toxins and clinical signs of uremia through palliation of the dietary protein load is the central tenet behind the historical protein modification in veterinary renal therapeutic diets. However due to lack of studies, no strong evidence currently exists that show limiting protein results in palliation of uremic toxins or clinical signs of uremia, hence the more recent controversies, particularly in cats, about the ideal protein content in renal diets 17,18. Limited data on the effects of differing protein contents on uremic toxins in cats exists. 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 19. Similarly, a study on cats with IRIS Stage 1 CKD that were fed three diets of differing protein levels showed that they had demonstrably higher IS and pCS concentrations when fed the highest protein diet (8.01 g/100kcal ME versus 6.95 g/100 kcal ME and 5.65 g/100 kcal ME) 20.

There is still a debate regarding the ideal protein content of renal diets for cats, as they are considered to be obligate carnivores and thus have increased protein requirements compared to dogs and humans. Studies suggest that senior cats may require more protein than younger cats and, in addition, many cats with CKD will show a decline in body weight, body condition score and/or muscle mass over time. 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. A key concept for success when feeding a modified protein diet is to ensure that an adequate caloric intake is also provided.

Prebiotic and probiotic treatments have been used in CKD cats in the hope that they will improve the health of the gut microbiome and reduce blood concentrations of gut-derived uremic toxins. The use of a commercial probiotic supplement (Enterococcus faecium SF68) was evaluated in cats with CKD, with the study reporting that it had no appreciable effect on the gut microbiome and serum concentrations of the major gut-derived uremic toxins 21. Another study evaluated the effect of fermentable fiber (a prebiotic) in experimental diets on the fecal microbiota in cats with CKD, and found that their microbiome was resistant to change when compared to healthy cats 22. The fiber did reduce relative concentrations of plasma uremic toxins in the CKD cats in comparison to healthy cats, which supports the notion that alteration of the gut microbiome can reduce the production of gut-derived uremic toxins, but species-specific evidence-based strategies are needed.

Some commercially available products are now available in many countries; these include a probiotic/prebiotic intended to beneficially target the microbiome by creating an environment with less uremic toxin production, and a carbon-based adsorbent designed to bind indole in the digestive tract to prevent uptake into the body. The latter product has been shown to reduce indoxyl sulfate in senior cats after eight weeks of administration 23, but data on the effectiveness of either product to decrease IS concentrations in cats with CKD is still forthcoming.

Constipation

The prevalence of constipation associated with feline CKD has not been reported, but anecdotally this appears to be a common medical concern (Figure 6). Preliminary results of a survey studying fecal habits in cats suggest that defecation is less regular in CKD, and the cause of constipation in these cats is likely a dysfunction of water balance, possibly combined with abnormal GI motility. As the kidneys fail to provide appropriate urine concentrating ability, and the patient fights with chronic subclinical dehydration, water is reabsorbed from the colon to compensate. Hypokalemia and the use of phosphate binders may also contribute to constipation 24,25. Therapy for constipation may include correction of dehydration and electrolyte imbalance, diet, fiber, osmotic stool softeners or promotility agents such as lactulose. In addition to its clinical effects, constipation may have other negative consequences and is likely a classic example of the gut-kidney axis. As previously mentioned, constipated human patients with CKD have higher concentrations of uremic toxins than patients with normal fecal scores, and conversely such toxins may have negative effects on gastrointestinal motility 8. Laboratory modelling of CKD has demonstrated significant improvement in uremic toxins, creatinine and even kidney histopathology subsequent to a regimen of lactulose 26.

Conclusion

Although much work remains to be done, there is emerging evidence that the gastrointestinal tract and the kidneys interact and influence each other in both health and disease. Given that many cats with chronic kidney failure have dysbiosis of the microbiome, it is likely that the gut will become seen as a major focus to be proactively targeted with specific therapeutics in order to improve longevity and quality of life in affected cats.