Introduction
Oxygen is essential for aerobic organisms' sustenance. When mitochondria consume oxygen for energy production, reactive oxygen species are released as a byproduct. Oxidative stress is caused when an imbalance between reactive oxygen species and its scavenger system arises. Oxidative stress can lead to tissue damage and induce various diseases. The kidney is highly prone to hypoxia, which leads to end-stage renal disease. Renal hypoxia can aggravate oxidative stress, which could further enhance renal hypoxia, creating a cycle.
What Are Reactive Oxygen Species?
Reactive oxygen species are highly reactive substances. They cause protein alteration, DNA (deoxyribonucleic acid) damage, cellular senescence (stop in cell division), and apoptosis (programmed cell death). Reactive oxygen species in biological tissues have an oxidative effect on lipids, carbohydrates, proteins, and nucleic acid.
What Is the Association Between the Kidney and Oxygen?
Renal blood flow forms 20 percent of cardiac output. Within renal tissue, oxygen tension is low because oxygen shunt diffusion happens between arterial and venous vessels of the kidneys. It is demonstrated by higher oxygen partial pressure within the renal vein than in the renal cortex or efferent arterioles. The reduction of the oxygen gradient from the renal surface to the depth also supports the presence of oxygen shunt diffusion. However, the oxygen shunt increases the susceptibility of the kidney to systemic hypoxia. Even in healthy kidneys, a small drop in blood oxygen levels could lead to a reduction in microvascular oxygen pressure.
What Are the Causes of Hypoxia in Chronic Kidney Disease?
Tubulointerstitial hypoxia develops in chronic kidney disease due to multiple factors. Hypoxia develops parallelly with chronic kidney disease progression and is considered the final step for end-renal disease development. The causes are:
-
Loss of peritubular capillaries.
-
Oxygen diffusion reduces from peritubular capillaries to tubular and interstitial cells due to fibrosis.
-
Decreased blood flow to peritubular capillaries caused by sclerosis of glomeruli.
-
An imbalance in vasoactive substances can reduce blood flow to peritubular capillaries.
-
Increase metabolic demand of tubular cells.
-
Oxidative stress causes inappropriate energy usage.
-
Anemia causes reduced oxygen transport.
How to Measure Oxygen Status in the Kidney?
Several methods to measure oxygen status within the kidney include:
-
Microelectrodes: Based on animal studies, it is a gold standard for measuring oxygen status in solid organs. The limitations of the technique are its invasiveness and ability to measure extracellular regions only.
-
Blood Oxygen Level-Dependent Magnetic Resonance Imaging (BOLD-MRI): A non-invasive technique that measures deoxyhemoglobin but has conflicting results.
-
Nitroimidazole Probes: Used as intracellular oxygen markers.
-
Phosphorescence Lifetime Measurement: Measures oxygen gradient in cortex surface but requires special probes.
Why Is Hypoxia a Critical Factor in Chronic Kidney Disease?
Based on findings from the International Society of Nephrology, ten percent of the world population suffers from chronic kidney disease that results in mortality. Hypoxia-induced renal fibrosis is a hallmark of the disease. Chronic kidney disease aggravates tubulointerstitial hypoxia, which in turn causes chronic kidney disease progression, creating a vicious cycle.
Renal hypoxia can cause acute kidney injury to develop into chronic kidney disease. An incomplete or maladaptive repair of acute kidney injury can lead to kidney fibrosis that causes chronic kidney disease. Recent studies suggest tubulointerstitial hypoxia has a prominent role in acute kidney injury developing into chronic kidney disease.
What Causes Oxidative Stress in Chronic Kidney Disease?
Dysfunctional mitochondrial respiration produces an imbalance between reactive oxygen species production and its removal. Aging, diabetes, and inflammation can induce renal damage that leads to mitochondrial dysfunction.
Oxidative stress is enhanced in chronic kidney disease and diabetic kidney disease. Chronic hyperglycemia enhances reactive oxygen species production in diabetics. Reactive oxygen species-mediated renal inflammation and fibrosis can cause diabetic kidney disease through multiple pathways.
Several markers for oxidative stress, such as 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and advanced glycation products, can determine renal prognosis. 8-OHdG is produced by oxidative DNA damage and is excreted through urine. High serum levels of MDA are present in uremic patients. A high plasma level of MDA indicates graft dysfunction after renal transplantation. Advanced glycation products are deposited on the skin and diagnosed through autofluorescence.
What Is the Association Between Hypoxia and Oxidative Stress in Chronic Kidney Disease?
Oxidative stress is enhanced in chronic kidney disease. Increased oxidative stress enhances kidney oxygen consumption, which leads to kidney tissue hypoxia. Uremic toxins such as Indoxyl sulfate that accumulate within kidneys may cause oxidative stress. Other uremic toxins like phenyl sulfate and p-cresyl sulfate can increase tubular cell susceptibility to oxidative stress by reducing glutathione levels. Hyperuricemia (high uric acid level) can also enhance oxidative stress in chronic kidney disease. Therefore, it is concluded that oxidative stress caused by uremic toxins can enhance renal hypoxia.
Renal hypoxia enhances oxidative stress. Hypoxia and oxidative stress are closely linked and lead to the progression of chronic kidney disease. Both hypoxia and oxidative stress must be treated to disrupt this cycle.
What Is the Treatment Available for Oxidative Stress?
The treatments for oxidative stress are:
-
Angiotensin II Type 1 Receptor Blocker (ARB): Proteinuria (protein in urine) and hypertension determine renal prognosis. ARB has a renoprotective effect that reduces proteinuria independent of changes to blood pressure. Angiotensin II constricts efferent arteriole and decreases peritubular capillary flow, leading to renal hypoxia. ARB blocks the constriction of afferent arterioles.
-
N-Acetylcysteine: The substance is a precursor for glutathione synthesis that directly works as a scavenger for free radicals. It also improves blood flow through nitric oxide-mediated vasodilatation. Antioxidant and vasodilatory mechanisms of substances are needed for treating chronic kidney disease.
-
Antidiabetics: Several studies demonstrate the renoprotective action of antidiabetic agents. The renoprotective effects are independent of glucose-lowering action.
-
Erythropoiesis Stimulating Agent (ESA): Renal anemia induces oxidative stress in chronic kidney disease. ESA is the standard treatment for renal anemia in chronic kidney disease. Studies suggest treatment with ESA can lower oxidative stress and improve the prognosis for cardiovascular morbidity and mortality in patients with chronic kidney disease.
-
Reduction of Indoxyl Sulfate: Indoxyl sulfate can accumulate in chronic kidney disease patients and have cytotoxic effects on renal proximal tubules. Indoxyl sulfate accumulation has a detrimental effect on renal health and enhances oxidative stress. Therefore, reducing indoxyl sulfate may be a therapeutic approach for chronic kidney disease patients.
Conclusion
Hypoxia and oxidative stress are linked to each other. If one increases, it exerts action that increases the effect of the other. Both hypoxia and oxidative stress contribute to the progression of chronic kidney disease. Therefore, both hypoxia and oxidative stress must be simultaneously treated to prevent the progression of renal disease.
