Chronic Kidney Disease, Postbiotics and the Gut Microbiome Therapeutics

The kidneys are vital organs that play crucial functions in filtering waste products from the blood, regulating blood pressure, conserve electrolyte levels and maintain fluid balance.

Kidney disease (acute or chronic) is one of the most common diseases in companion animals. In fact, Chronic Kidney Disease (CKD) is the most prevalent renal conditions in elderly cats and dogs, affecting up to 50% of cats of all ages and over 80% of cats over the age of 15 years.¹

Although CKD prevalence in canine fares better than in feline, dogs with CKD are generally considered to have a worse prognosis and shorter survival times. Possible reason is that canine generally has shorter life span especially the larger breed dogs.²

While CKD is a progressive and irreversible deterioration of kidney function over time, it can be managed effectively to improve quality of life and slow its progression.

What is CKD?

CKD is characterized by lasting structural or functional impairment of the kidneys (reduced total kidney glomerular filtration rate) that persist for at least 3 months.

The disease can develop due to wide variety of factors such as age, genetic predisposition, infections, toxins, and immune-mediated conditions.³

Early clinical signs might be non-specific symptoms such as weight loss, vomiting, lethargy. It could even be inapparent until at least 75% impairment of nephron function which is when the development of azotemia or elevated levels of nitrogen-containing compounds such as creatinine and blood urea nitrogen (BUN) is often detected.

According to the guidelines set forth by the International Renal Interest Society (IRIS), CKD is generally classified into 4 stages.

What happens in CKD?

The relationship between CKD and gut microbiome disorders is an emerging field of research in both human medicine and veterinary science.

The gut microbiome plays a pivotal role in modulating the health of companion animals.⁴

On the other hand, an imbalanced gut microbiome composition or dysbiosis are associated with myriad of diseases such as CKD, obesity, diabetes mellitus, cardiovascular disease, and neurologic disorders.⁵

When it comes to CKD, gut disorders have preceded long before kidney disease becomes chronic.

It is important to establish these four conditions occur in onset CKD6

1. Microbial dysbiosis or imbalanced gut microbiome composition
2. Increased gut permeability aka leaky gut
3. Excessive production of microbiota-generated nephrotoxins such as the uremic toxins
4. Gut and systemic level inflammation

Unlocking the Gut-Kidney Connection

The gut-kidney interaction is still poorly understood in today’s medicine and veterinary care.

The current treatment protocols in CKD are focused on slowing disease progression and protecting renal function.⁷

While standard CKD medication regime such as phosphate binders, ACE inhibitors, fluid therapy, anti-nausea medications, appetite stimulants, and prescription kidney diet are essential in managing symptoms, they lack the tools to address the roots of the problem: correcting the gut.

Understanding the gut-kidney axis or the link between CKD and gut microbiome disorders leads to one direction: management of CKD requires treatment of the gut microbiome.

This is where postbiotics come in.

Remedy CKD with postbiotics

Since our inception in 2021, we at Sirius Pet Biologics have been introducing biotherapeutic approach targeting restoration of the gut microbiome to alleviate the progression of CKD in companion animals.

Incorporating RenaCor, our functional postbiotics innovation specifically targeted on improving the renal health and gut health, has yielded much improved prognoses among the patient cohorts of our veterinary partners.

Rapid normalization of renal markers namely serum creatinine level, BUN, as well as the symmetric dimethylarginine (SDMA) level have been documented in various stages of CKD.

How do Postbiotics Remedy CKD?

Postbiotics are bioactive compounds produced by the metabolic activity of probiotics during fermentation. These beneficial compounds include substances like short-chain fatty acids (SCFAs) – namely acetate, butyrate, and propionate; enzymes; peptides; bacteriocins, exopolysaccharides; other organic acids; inactivated microbial cells, and cell wall fragments.

The bioactivities of postbiotics below are highly essential to address the very problems in CKD8

• Strengthening gut barrier integrity
• Anti-inflammatory
• Immunomodulatory
• Antimicrobial activity against gut pathogens
• Anti-oxidative

The mechanisms of action of postbiotics in remedying onset CKD are as follows^9,10,11

1. Improve the Gut Health
   
   Dysbiosis or imbalanced gut microbiome, and leaky gut lead to increased gut permeability that preceded onset CKD.
   • Mechanism: postbiotics help restore the gut microbiota balance and enhance the gut barrier integrity.
   • Benefit: a healthier gut and enhanced gut barrier integrity reduce the absorption of pathogenic microbes and harmful toxins into the bloodstream, hence easing the burden on the kidneys.
2. Anti-Inflammatory Properties
   
   Translocation of harmful microbes and their pro-inflammatory properties induce gut level and systemic level inflammation.
   • Mechanism: postbiotics, particularly SCFAs, have anti-inflammatory properties that can modulate the immune response to reduce inflammation at the gut level and systemic level, which are key drivers of CKD progression.
   • Benefit: with inflammation in control, postbiotics will help slow the progression of kidney damage and improve overall kidney function.
3. Reduce Uremic Toxins
   Build-up of harmful bacteria in the gut, bloodstream and their uremic toxins impair kidney functions.
   • Mechanism: postbiotics can suppress the proliferation of pathogenic bacteria and their uremic toxins.
   • Benefit: reduced levels of uremic toxins in the bloodstream can alleviate symptoms like nausea, lethargy, and poor appetite, improving the quality of life of the companion animals.
4. Antioxidative Activity
   Oxidative stress is one major contributor to kidney damage in CKD.
   • Mechanism: postbiotics possess antioxidative properties that help neutralise oxidative stress.
   • Benefit: reducing oxidative stress can protect kidney cells from further damage and slow CKD progression.
5. Improve Metabolic Health
   CKD often disrupts insulin sensitivity and irregulates metabolism.
   • Mechanism: postbiotics help improve insulin sensitivity and irregulates metabolism from disruption.
   • Benefit: improved metabolic health can reduce CKD-associated complications such as hypertension and proteinuria.
6. Better Nutrition Absorption
   Malnutrition is a common issue in onset CKD.
   • Mechanism: postbiotics help improve gut health and enhances the absorption of essential nutrients like minerals and vitamins.
   • Benefit: improved nutrient uptake can help address malnutrition.
7. Strengthen the Immune System
   Infections and complications are risk factors in onset CKD.
   • Mechanism: postbiotics are well established for their immunomodulating factor.
   • Benefit: a stronger immune system can reduce risks of infections and other complications that may arise in pets with CKD; the gut holds the key for a strong immune system.

Postbiotics for Renal Health Maintenance Post-recovery 

Postbiotics are natural occurring bioactive compounds in the gut of companion animals.

These beneficial properties have a profound role in achieving the gut homeostasis which is the state of balance between the gut microbiota composition, gut function, and immune regulation.

The gut homeostasis plays a central role in the systemic health. The same axis applies in gut-kidney connection.

Postbiotics intervention in CKD not only paves the way for next-generation microbial therapeutics but it also provides a sustainable solution to manage long-term gut health and renal health post azotemia, as well as future preventive strategies.

References
1. Marino CL, Lascelles BD, Vaden SL, et al. Prevalence and classification of chronic kidney disease in cats randomly selected from four age groups and in cats recruited for degenerative joint disease studies. J Feline Med Surg. 2014;16(6):465–472
2. Kokkinos, Y., Morrison, J., Bradley, R. et al. An early prediction model for canine chronic kidney disease based on routine clinical laboratory tests. Sci Rep 12, 14489 (2022). https://doi.org/10.1038/s41598-022-18793-6
3. Yu H, Lee IG, Oh JY, Kim J, Jeong JH, Eom K. Deep learning-based ultrasonographic classification of canine chronic kidney disease. Front Vet Sci. 2024 Sep 4;11:1443234. doi: 10.3389/fvets.2024.1443234. PMID: 39296582; PMCID: PMC11408351.
4. Jordan E Rindels, Brett R Loman, Gut microbiome – the key to our pets’ health and happiness?, Animal Frontiers, Volume 14, Issue 3, June 2024, Pages 46-53, https://doi.org/10.1093/af/vfae015
5. Suchodolski J. Analysis of the gutmicrobiome in dogs and cats. Vet Clin Pathol.2022;50(Suppl. 1):6–17. https://doi.org/10.1111/vcp.13031
6. Kim K-R, Kim S-M and Kim J-H (2023) A pilot study of alterations of the gut microbiome in canine chronic kidney disease. Front. Vet. Sci. 10:1241215. doi: 10.3389/fvets.2023.1241215
7. He, M., Wei, W., Zhang, Y. et al. Gut microbial metabolites SCFAs and chronic kidney disease. J Transl Med 22, 172 (2024). https://doi.org/10.1186/s12967-024-04974-6
8. Jordan E Rindels, Brett R Loman, Gut microbiome – the key to our pets’ health and happiness?, Animal Frontiers, Volume 14, Issue 3, June 2024, Pages 46-53, https://doi.org/10.1093/af/vfae015
9. Scott, E.; De Paepe, K.; Van de Wiele, T. Postbiotics and Their Health Modulatory Biomolecules. Biomolecules 2022, 12, 1640. https://doi.org/10.3390/biom12111640
10. Magliocca, G.; Mone, P.; Di Iorio, B.R.; Heidland, A.; Marzocco, S. Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation. Int. J. Mol. Sci. 2022, 23, 5354. https://doi.org/10.3390/ijms23105354
11. Deng M, Li X, Li W, Gong J, Zhang X, Ge S and Zhao L (2021) Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins. Front. Nutr. 8:756730. doi: 10.3389/fnut.2021.756730