Chronic kidney disease (CKD) is a worldwide epidemic. Patients with CKD have a high rate of cardiovascular disease, protein-energy wasting, and mortality. Most of those factors have been linked to inflammation, and low-grade inflammation has been shown to be an integral aspect of chronic kidney disease. In this blog, I will discuss the role of inflammation in CKD and how to identify the root causes, such as vitamin D deficiency, gum disease, gut dysbiosis, and more.
Inflammation in CKD
By Majd Isreb, MD, FACP, FASN, IFMCP
Causes of inflammation in chronic kidney disease
Inflammatory markers were found to be elevated in CKD. The levels of these markers increase with the decrease in kidney function. They also increase with increasing urine protein (albuminuria).
There are several reasons for immune imbalance and inflammation in CKD. Some of these factors are linked directly to the cause of CKD, while others are related to genetic predisposition and epigenetic factors.
Uremic environment
Furthermore, the accumulation of uremic toxins in CKD leads to oxidative stress. We discussed oxidative stress in a previous blog. When oxidative stress (or free radicals) builds up and aren’t handled properly, they can damage enzymes, cells, and tissues. Oxidative stress has been identified as a root cause of many diseases, including heart disease, Alzheimer’s, Parkinson’s, chronic kidney disease, and many more.
The build-up of harmful oxidative toxins in advanced CKD is associated with another problem which is described as “carbonyl stress.” Here, there are irreversible changes in many proteins leading to loss of their function. Higher oxidative and carbonyl stress is linked to inflammation in CKD. It is possible that carbonyl stress is just a biomarker of oxidative stress in CKD and not an independent phenomenon.
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Metabolic acidosis
Metabolic acidosis and high dietary acid load are very common in CKD. In metabolic acidosis, there is an increase in blood acidity. The foods that we eat may generate blood acidity (such as animal proteins) or alkalinity (such as fruits and vegetables). This is described as the dietary acid load We discussed these in a previous blog. They play an important role in the bone disease and protein-energy wasting that are common in CKD. In addition to that, a higher dietary acid load has been linked to faster progression of kidney disease. Metabolic acidosis has been linked to inflammation in CKD. In fact, higher inflammatory cytokines were seen in patients with metabolic acidosis.
Oral disease
Oral and periodontal disease (gum disease) are common in CKD. Over 700 species of microbes reside in the mouth. Together, they are called the oral microbiome. This microbiome produces metabolic by-products in the mouth. Some of these leaks into the bloodstream and lead to low-grade systemic inflammation.
Studies have shown that patients with severe gum disease have elevated levels of pro-inflammatory mediators and increased numbers of white blood cells known as neutrophils in the blood. This suggests that the inflammatory process in the mouth is affecting the whole body and probably injuring organs and tissues. In fact, successful treatment of gum disease was associated with improvement in inflammatory markers.
Intestinal dysbiosis
In CKD there is something called the dysbiosis cycle. We discussed this in a previous blog. Dysbiosis is a state of the intestinal microbiota 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 (also known as “leaky gut”). “Leakiness” of the gut lining allows gut bacteria or bacterial particles from the gut into the bloodstream. It causes shifts in the breakdown of nutrients, including amino acids, which leads to the formation of many gut-derived uremic toxins. Intestinal permeability has been linked to autoimmune disease and systemic inflammation.
Vitamin D deficiency in CKD
Vitamin D deficiency in chronic kidney disease is quite common with 80% of CKD patients having been found to have low levels of 25-hydroxy vitamin D (25 (OH)D) when measured in the serum. Several factors have been implicated in the cause of this deficiency including inadequate outdoor physical activity, inadequate dietary intake, genetic variations, and loss of 25(OH)D in the urine. Vitamin D deficiency has been associated with an imbalanced immune system in CKD. This link between deficiency of vitamin D and kidney disease is important because it can lead to further inflammation in CKD.
Obesity
A higher body mass index is one of the strongest risk factors for CKD. In fact, the incidence of obesity-related kidney disease has increased 10-fold in recent years. Higher visceral fat is linked to increased protein in the urine (albuminuria). Visceral fat was also found to be associated with higher circulating inflammatory cytokines such as IL-6. This is because visceral fat cells produce these inflammatory cytokines.
Decreased clearance of cytokines
It has been well-documented that the levels of circulating inflammatory cytokines are elevated in kidney disease. Cytokines are chemical messengers that are produced by cells of the immune system. There are inflammatory cytokines and anti-inflammatory cytokines. When inflammatory cytokines are high in the blood, it is like a burning fire in the body, damaging and irritating tissues. In addition to the increased generation of cytokines in CKD, decreased renal clearance plays a significant role in the high level of cytokines in the blood.
Symptoms of inflammation in CKD
Higher levels of inflammatory markers such as IL-1beta, IL-6, TNF-alpha, C-reactive protein (CRP), and fibrinogen were found in patients with CKD, according to the Chronic Renal Insufficiency Cohort (CRIC) study. Inflammation is associated with many problems in patients with CKD. These problems include:
- Faster progression of kidney disease
- Increased protein loss in the urine
- Increased risk of heart disease and death
- Increased itching
- Worsening nutrition and protein-energy wasting
- Depression
- Worsening bone-mineral disorder
- Worsening anemia
Healing inflammation in CKD
When thinking about the best treatment for inflammation in CKD, it is crucial to address its root cause. For example, correcting the uremic environment may include strategies to decrease animal protein intake through a plant-dominant dietand a personalized gut restoration protocol. To address vitamin D deficiency, it is always recommended to check for it and correct it in all CKD patients.
Optimizing a person’s nutritional status is fundamental in healing inflammation in CKD and improving all the outcomes mentioned above. In addition, many supplements have been found to improve inflammation in CKD. These include omega-3 fatty acids, decaffeinated green tea extract, pomegranate, soy isoflavones, fiber, and probiotics.
The bottom line on inflammation and CKD
Low-grade inflammation is a common feature of CKD. Multiple root causes can be identified as a source of inflammation in kidney patients. These include decreased clearance of cytokines, oral and intestinal dysbiosis, vitamin D deficiency, uremic toxins, metabolic acidosis, and obesity. It is crucial to address the root causes of inflammation to improve kidney and heart outcomes in these patients.
