The kidneys are considered the filtration system for various byproducts and toxins. Chronic kidney disease (CKD) is associated with accumulation of waste products due to decreased clearance by the failing kidneys. These “uremic toxins” come from multiple sources.      

Recently, there has been a growing interest in the gut-kidney axis, which refers to the overlapping relationship between gut integrity,  microbiome diversity, resulting inflammatory process and kidney disease. The interaction between the gut and kidneys is very complex and can be divided into two major categories: the gut-derived uremic toxins that can worsen kidney disease, and the inflammatory autoimmune response that can trigger kidney disease. In this blog, we will focus on the gut-derived uremic toxins. 

The gut-kidney dysbiosis cycle

 

Uremic Retention Molecules (URMs)

Uremic toxins, accumulated waste products due to decreased renal clearance, have been linked to systemic inflammation. Recently, researchers have been successful at identifying many of these molecules thanks to a technique called metabolomic analysis. In general, URMs are divided into three categories: 

  1. Small water-soluble molecules
  2. Middle size molecules
  3. Protein-bound uremic molecules

However, for our purpose, it is more helpful to divide these toxins according to their origin:

  1. Endogenous uremic toxins: toxins or waste that naturally and normally occur during metabolism or catabolism
  2. Exogenous uremic toxins: related to dietary intake
  3. Gut-derived uremic toxins: generated by pathogenic gut microbiota in the presence of dysbiosis

 

Gut-derived uremic toxins

The human gut contains trillions of microorganisms, collectively referred to as the gut microbiota or microbiome . The composition of the gut microbiome varies from person to person due to genetics, environmental factors, dietary, and disease state. These microorganisms are in constant communication with the body. They also produce multiple metabolites, nutrients, and cell signals for various physiological functions.  [read more about the microbiome here]

Dysbiosis describes a state where “bad” bacteria (or other organisms like yeast or parasites) outgrow the “good” bacteria. In dysbiosis, we see a rise in inflammatory markers that interact with the lining of the gut and result in damage and increased intestinal permeability (“leaky gut”). This causes shifts in the breakdown of nutrients, including amino acids, which leads to the formation of many gut-derived uremic toxins.

Thanks to recent advances in metabolomic analysis, researchers have identified more than 60 uremic toxins that are derived from the gut. A number of studies have demonstrated that URMs are associated with high cardiovascular burden and mortality in CKD. There are four major gut-derived uremic toxins associated with CKD: Indoxyl sulfate (IS), para-Cresyl sulfate (pCS), Trimethylamine-N-oxide (TMAO), and Indole acetic acid (IAA).

 

Indoxyl sulfate (IS)

IS is a protein-bound uremic toxin. Gut microbiota produce indole from the breakdown of dietary tryptophan, which is then further metabolized to IS in the liver. The majority of IS circulates bound to albumin in the blood. It is excreted by the kidney tubules through organic anion transporters.

IS is one of the most studied uremic toxins. It has been associated with vascular calcifications and increased risk of death from heart disease in patients with advanced kidney disease. Higher levels of circulating IS have also been associated with faster progression of CKD.

 

Para-Cresyl sulfate (pCS)

This is another protein-bound uremic toxin that is produced by the metabolism of amino acids tyrosine and phenylalanine by intestinal bacteria. This leads to the formation of p-cresol which is metabolized in the liver to pCS. pCS also circulates in the blood bound to albumin and is excreted by the kidneys in the same mechanism as IS. 

Serum pCS levels increase with worsening kidney function. Similarly to IS, pCS was also found to predict the progression of kidney disease and is associated with an increased risk of death from heart disease in kidney disease patients.

 

Trimethylamine-N-oxide (TMAO)

TMAO is one of the small water-soluble URMs. It is produced by the metabolism of dietary L-carnitine and choline. The latter two compounds are metabolized into trimethylamine by gut bacteria, which is then absorbed by the gut and oxidized in the liver to form TMAO. The kidneys are the primary source for eliminating TMAO from the body. Dysbiosis and decreased kidney function have been documented to lead to elevated levels of TMAO.

TMAO levels increase with worsening kidney function and are associated with increased progression of kidney disease, increased risk of heart disease and all-cause mortality in kidney patients.

 

The L-carnitine controversy

L-carnitine is a relatively small water-soluble compound that is found abundantly in food sources including in red meat, dairy, poultry, and fish. Lysine, methionine, ascorbate, niacin, pyridoxine, and iron are among the major sources of endogenous carnitine production. 

There is evidence that patients with kidney disease are deficient in L-carnitine and that supplementation leads to improved outcomes. However, there’s seemingly contradictory evidence that, the metabolism of L-carnitine by gut bacteria leads to the production of TMAO which, as described above, is associated with increased mortality in kidney patients.

One explanation for this discrepancy is that research on L-carnitine often fails to distinguish CKD patients who are not on dialysis from those on dialysis. In fact, one study showed L-carnitine levels are actually high in patients with CKD but are low in dialysis patients.

Another reason for the confusion is that most research on L-carnitine supplementation uses intravenous L-carnitine, which bypasses the gut microbiota and liver and, therefore, may not lead to the production of TMAO. Another important consideration is the composition of the microbiome and the intestinal integrity of the gut. Those with certain dysbiotic markers might be at higher risk for producing TMAO and failing to break it down sufficiently, leading to increased kidney injury.

The literature seems to support the need for restricting oral intake of dietary or supplement sources of L-carnitine in patients with kidney disease who are not on dialysis. This might also explain why CKD patients benefit from diets that are dairy-free and low in red meat.

 

Indole acetic acid (IAA)

IAA is yet another protein-bound uremic toxin that results from the metabolism of tryptophan by gut bacteria. Levels of IAA are proportional with CKD stage progression and normalize after kidney transplantation. IAA is linked to vascular inflammation and oxidative stress and has been associated with mortality and increased risk of death from heart disease in patients with CKD.

 

The role of diet

Dietary habits play an important role in gut microbiota composition. Diets high in animal protein are associated with increased dysbiosis and intestinal hyperpermeability and also contain a higher amount of amino acids precursors of uremic toxins. Meanwhile, whole-food and fiber-dense plant-based diets are associated with the growth of healthy gut microbiota, leading to decreased inflammation and better intestinal integrity.

 

Levels of protein intake have been studied in relation to CKD. Interestingly, it is not the amount but the type of protein that is associated with kidney disease. In fact, a large study of 12,000 adults with normal kidney function found no significant association between total protein intake and the incidence of CKD. The same study found that individuals consuming more red and processed meat were at higher risk for CKD compared to those consuming more vegetable protein. Red meat intake has also been reported to increase the risk of worsening kidney function requiring dialysis. 

 

There are various additional factors that should be considered as well, including consumption of processed carbohydrates, simple sugars, and reduced consumption of whole fruits, vegetables, and other fiber sources like whole grains. These nutrient-poor dietary habits can lead to dysbiosis which in turn produce inflammatory molecules that can lead to kidney disease. This can cause further accumulation of inflammatory uremic toxins. 

 

Furthermore, the worsening of kidney function and accumulation of URMs can lead to further dysbiosis, and so on, the cycle repeats. This is what we describe as the dysbiosis cycle in kidney disease.

To date, unfortunately, there are no studies that measure the effectiveness of dietary interventions on URM levels in kidney disease and subsequent prognosis. Studies focusing on the use of prebiotics and probiotics to improve gut health and reduce inflammation and CKD risk have had mixed results. However, a major weakness is that these studies only look at a single intervention that impacts kidney disease when, in reality, the process is much more complex. Future studies should take into consideration the complex interplay of the dietary and lifestyle factors on GI integrity, microbiome balance, genetics, and kidney outcomes.

The bottom line

There is a significant link between the microbiome, gut integrity, genetics, diet, lifestyle, and kidney disease. Most of this can be traced back to the accumulation of URMs in CKD causing a vicious cycle. The conventional approaches to improve gut health and slow the progression of CKD have yielded mixed results.

Casting a wider net to include considerations for all factors that contribute to gut integrity, inflammation, and CKD risk must also be examined, including environmental exposures, genetic risk factors, metabolic factors and changes in body fluid volume, and overlapping factors that contribute to diabetes and hypertension, collectively contribute to increased CKD risk. Hence, we advocate for a comprehensive approach that starts with a gut restoration protocol and addresses the above factors in patients with CKD.