Chronic kidney disease (CKD) is a major public health problem worldwide with continuously
growing epidemic characteristics and heavy cardiovascular (CV) comorbidity. CKD and
CV risk have a parallel course, and CV disease is the leading cause of death in end-stage
kidney disease (ESKD) patients, accounting for about 50% of mortality [1].
During the past decades, atherosclerosis and CV disease have been associated, at least
partially, with excessive overproduction of reactive oxygen species (ROS) and oxidative
stress (OS) has emerged as a novel risk factor for CV mortality in CKD and ESKD patients
[2]. OS occurs when the formation of ROS exceeds the buffering ability of the naturally
occurring endogenous antioxidant defense mechanisms, thus resulting in injury and
oxidation of cells and tissues and ultimately leading to CV disease. Overproduction
and accumulation of ROS is present even at early CKD stages, progresses along with
eGFR decline to ESKD, and is significantly reversed after kidney transplantation.
Due to their high reactivity and ephemeral nature, direct and accurate measurement
of ROS is very difficult. Αn alternative approach for assessing the redox status in
CKD and ESKD is to measure the products resulting from protein, lipid, DNA, or carbohydrate
damage caused by free radicals. Plasma protein carbonyls (PCO) might serve as reliable
biomarkers of OS in CKD; since they are chemically stable with long half-life, their
sampling is relatively easy, and there are several validated accurate detection methods;
and moreover, PCO reflects accurately the state and degree of OS [3]. The oxidation
of biomolecules by ROS starts very early in CKD, progresses in parallel with deterioration
of kidney function, and is further exacerbated in ESKD. Circulating PCO levels are
higher in patients with early CKD compared to healthy individuals and are gradually
increased with reduction of estimated glomerular filtration rate (eGFR) [3]. Compared
to predialysis CKD stage 4, ESKD patients undergoing dialysis present significantly
increased OS. This is attributed to various factors. Typically, in this stage, physicians
give strict dietary restrictions to dialysis patients to avoid consumption of fruits
and vegetables that are rich in potassium to prevent hyperkalemia, thus resulting
in a reduced intake of dietary antioxidants, vitamins, and flavonoids. Moreover, a
certain amount of antioxidants (such as vitamin C and trace elements) is lost during
every hemodialysis (HD) session. However, the main trigger for OS in HD is the contact
of patients' blood with the bioincompatible, artificial dialysate, and membrane, resulting
in activation of white blood cells and overproduction of ROS, after 10 minutes of
every HD session [4]. Other HD-related factors causing overproduction of free radicals
include the infusion of iron, anemia and inflammation, malfunctioning fistulae, the
use of central venous catheters, and the use of heparin and erythropoietin agents
[4]. In PD, where nearly all the above factors are absent, one might expect that the
OS should be minimal. This is not the case at all; PD patients experience increased
OS compared to predialysis CKD patients, but much less than HD patients. In PD, the
main culprit for OS is the bioincompatible dialysate, which progressively damages
the peritoneal membrane. Among proteins that are subjected to oxidative modification
of their structure and function in dialysis patients, albumin is a well-established
marker of nutritional and inflammation status and an independent predictor of all-cause
mortality. Although PD patients present lower PCO levels and oxidized albumin levels
than HD, it should be noted that a certain amount of serum albumin is also lost during
PD procedure [3].
The clinical implications of OS in CKD are serious and cover a vast area of adverse
events, including inflammation, atherosclerosis, CV disease, progression of CKD to
ESKD, and death from any cause. Among these, the association of OS with inflammation
and atherosclerosis is undisputed. Endothelial dysfunction (ED), the hallmark of atherosclerosis
presents early in CKD, is triggered by OS and inflammation and is associated with
CV mortality [5]. Since the first stage of ED is the oxidation of lipids and the formation
of foam cells, it is crucial to investigate the pathophysiologic mechanisms underlying
this process.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), by regulating the expression
of low-density lipoprotein (LDL) cholesterol receptor, is implicated in inflammation
and ED of CKD patients. Dounousi et al. [6] performed a cross-sectional study enrolling
92 predialysis CKD patients (stages II–IV) and found that, although not correlated
with eGFR, proteinuria, OS, and inflammation, plasma PCSK9 levels were associated
with lipid parameters and ED, assessed by soluble intercellular adhesion molecule-1
levels. Moreover, treatment with statins increases circulating PCSK9 levels in this
population and might be of benefit. Another enzyme that is involved in the pathogenesis
and development of OS, inflammation, and ED through regulation of the cholesterol
efflux and oxidative transformation of LDL cholesterol is soluble epoxide hydrolase
2 (EPHX2), a potential therapeutic target for CV disease [7]. In another prospective
study including 118 diabetic kidney disease patients, we found that genetic variations
of the EPHX2 gene (rs27411335 and rs11780592) were associated with increased oxidized
LDL and carotid intima medium thickness and predicted all-cause mortality [8], indicating
thus a possible genetic background in these populations.
Besides CV disease, OS is also implicated in the pathophysiology of CKD progression
and various types of kidney diseases, including Balkan endemic nephropathy (BEN) [9].
The exact pathophysiological mechanisms underlying this chronic tubulointerstitial
nephropathy disease have not yet been fully elucidated. OS, fibrosis, and inflammation
are thought to play a role in the development and progression of BEN, but existing
data are limited. Veljkovic et al. performed a cross-sectional study including 50
patients diagnosed with BEN and 38 healthy controls and found that, compared to controls,
BEN patients exhibited significantly increased systemic lipid and protein oxidation
status, assessed by plasma thiobarbituric acid reactive substances (TBARS) and advanced
oxidation protein products (AOPPs), respectively [10]. However, in urine, only AOPP
levels were significantly higher compared to controls; the urine local lipid oxidation
state was not different among groups, probably due to the reduced urine lipid content.
During the past decade, there is accumulating evidence suggesting that OS plays a
central role in the pathogenesis and development of diabetic kidney disease (DKD)
[11]. However, the exact sites and mechanisms underlying this association have not
yet been fully understood, mainly because most of the existing studies are experimental.
In both in vitro (hyperglycemic kidney tubular epithelial cells) and in vivo (mouse
and human kidney cells with DKD), mitochondrial general control of amino acid synthesis
5-like 1- (GCN5L1-) derived acetylation of the endogenous antioxidant manganese superoxide
dismutase induces OS-mediated kidney injury, suggesting a potential novel pathway
of DKD and a possible new therapeutic target [12]. To counterbalance the deleterious
effects of OS in CKD and ESKD, the supplementation of exogenous antioxidants has been
suggested, with the most promising being to-date the fat-soluble vitamin E in HD patients
and the powerful scavenger N-acetylcysteine (NAC) in PD. An interesting approach to
battle the oxidative burst caused by the exposure of blood to the artificial membrane
was the coating of HD dialyzers with vitamin E. These vitamin E-coated membranes have
been shown to increase the levels of vitamin E, suppress OS and inflammation markers,
and improve anemia status in HD patients [13]. In predialysis CKD, it has been hypothesized
that the disturbance of balance between antioxidants and prooxidants in favor of the
latter might be a risk factor for CKD progression. Ilori et al. performed a large
prospective study including 19,461 participants from the Reasons for Geographic and
Racial Differences in Stroke (REGARDS) cohort study [14]. The authors calculated a
score assessing oxidative balance by combining 13 popular prooxidants and antioxidants
that were determined before enrollment, by using lifestyle and dietary assessment.
After a median follow-up period of 3.5 years, the authors found that a higher score
(which is indicative of higher levels of exogenous antioxidants) was correlated with
significantly lower CKD prevalence. Therefore, it was hypothesized that exogenous
administration of antioxidants might abrogate CKD progression. Among the supplements
that were examined in CKD populations, bardoxolone methyl and pentoxifylline were
shown to significantly protect from deterioration of the kidney function [15]; however,
we need more well-designed trials examining novel and more powerful antioxidants.
In experimental prediabetic animal models, Akinnuga et al. showed that bredemolic
acid improved glucose homeostasis and markers of kidney function, decreased malondialdehyde
(a marker of lipid peroxidation status), and increased the levels of various antioxidants,
including glutathione peroxidase, superoxide dismutase, and total antioxidant capacity
[16]. The authors hypothesized that these findings might suggest a possible renoprotective
effect of this agent, through its antioxidant effects, in an experimental induced
prediabetic state. To further investigate new therapeutic, antioxidant strategies
in DKD, Huang et al. performed a mixed in vitro and in vivo study and examined the
possible beneficial effect of short fatty acid supplementation (acetate, propionate,
and butyrate) in streptozotocin-induced type 2 diabetes/high-fat diet and DKD mice
and in glomerular mesangial cells from high glucose-induced mouse models [17]. Administration
of fatty acids, especially butyrate, decreased insulin resistance, prevented proteinuria
development and eGFR decline in animals, and suppressed the hyperglycemia-derived
OS in mouse glomerular cells, thus suggesting a potential renoprotective effect of
short fatty acids, through improvement of OS.
Antioxidant agents may also have a role in the prevention of acute kidney injury (AKI)
that may result from nephrotoxic agents or treatments, because the main pathophysiologic
pathway in these cases is formation of ROS [18]. NAC has been widely used to prevent
contrast-induced nephropathy, a common complication following the exposure to imaging
iodinated contrast media [19]. To protect tumor patients treated with cisplatin from
AKI, amifostine is usually prescribed as an add-on chemoprotective drug; however,
this drug has several side effects. An experimental antioxidant agent (XH-003) has
been shown to exert chemoprotective properties similar to that of amifostine, but
without causing the adverse side effects of the drug. In the experimental study by
Liu et al., HX-003 was shown to decrease the cisplatin-derived AKI through reduction
of free radicals and upregulation of the activity of the antioxidant enzymes superoxide
dismutase, catalase, and glutathione peroxidase [20].
This special issue is compatible and consistent with our attempt to elucidate the
pathophysiologic mechanisms through which OS affects cells, tissues, organs, and biomolecules
and its impact on health outcomes in CKD and ESKD. The increasing knowledge of the
pathophysiology might provide further insights in the management of OS and in the
evaluation of novel, therapeutic, antioxidant treatments that might benefit CKD and
ESKD patients at the clinical level. This is an ongoing process, and we still need
more evidence and data.
Stefanos Roumeliotis
Vassilios Liakopoulos
Evangelia Dounousi
Patrick B. Mark