The Gut as a Source of Inflammation in Chronic Kidney Disease

Abstract

Chronic inflammation is a non-traditional risk factor for cardiovascular mortality in the chronic kidney disease (CKD) population. In recent years, the gastrointestinal tract has emerged as a major instigator of systemic inflammation in CKD. Postmortem studies previously discovered gut wall inflammation throughout the digestive tract in chronic dialysis patients. In CKD animals, colon wall inflammation is associated with breakdown of the epithelial tight junction barrier ('leaky gut') and translocation of bacterial DNA and endotoxin into the bloodstream. Gut bacterial DNA and endotoxin have also been detected in the serum from CKD and dialysis patients, whereby endotoxin levels increase with the CKD stage and correlate with the severity of systemic inflammation in the dialysis population. The CKD diet that is low in plant fiber and symbiotic organisms (in adherence with low potassium, low phosphorus intake) can alter the normal gut microbiome, leading to overgrowth of bacteria that produce uremic toxins such as cresyl and indoxyl molecules. The translocation of these toxins from the 'leaky gut' into the bloodstream further promotes systemic inflammation, adverse cardiovascular outcomes and CKD progression. Data are lacking on optimal fiber and yogurt consumption in CKD that would favor growth of a more symbiotic microbiome while avoiding potassium and phosphorus overload. Prebiotic and probiotic formulations have shown promise in small clinical trials, in terms of lowering serum levels of uremic toxins and improving quality of life. The evidence points to a strong relationship between intestinal inflammation and adverse outcomes in CKD, and more trials investigating gut-targeted therapeutics are needed.

Figure 1

Pathways by which altered microbiome and chronic gut inflammation lead to systemic inflammation in chronic kidney disease (CKD). The low potassium and low phosphorus CKD diet leads to inadequate intake of plant fiber and symbiotic bacteria, and there is influx of urea from the blood circulation in the gut lumen. These factors promote expansion of bacteria that express urease, as well as overgrowth of bacteria that produce uremic toxins including p-cresyl and indoxyl sulfates. Urea is degraded by urease-producing bacteria to form ammonia that is hydrolyzed to caustic ammonium hydroxide (NH₄OH) which causes degradation of tight junction proteins. Concurrently, the changed microbiome alters the symbiotic balance and competes with gut epithelial cells for short-chain fatty acids (SCFAs) for source of energy. This may impact colonocyte integrity and impair the protective mucosal barrier, with influx of inflammatory leukocytes and cytokine production. Gut inflammation further promotes epithelial barrier degradation via induction of endocytosis of tight junction proteins. Decreased tissue levels of the anti-inflammatory transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) further contributes to tight junction breakdown. Ultimately, there is translocation of bacteria, endotoxin and uremic toxins from the gut lumen into the circulation which drives systemic inflammation, a known non-traditional risk factor for cardiovascular mortality and CKD progression. Progression of kidney disease feeds into further elevation of blood urea levels, further propagating alterations in gut microbiome and forming a vicious circuit.