Heavy metals, Oxidative stress and Inflammation in Pathophysiology of Chronic Kidney disease - A Review
Samir Derouiche*, Taissir Cheradid, Messaouda Guessoum
Department of Cellular and Molecular Biology, Faculty of the Sciences of Nature and Life, El-Oued University, El Oued 39000, El Oued, Algeria.
*Corresponding Author E-mail: dersamebio@gmail.com
ABSTRACT:
This review aims at identifying the role of oxidative stress and inflammation as factors associated with chronic kidney disease pathophysiology. some risk factorsof chronic kidney disease which can be non-modifiable including; age, gender, ethnicity and family history and may be modified by pharmacotherapy or lifestyle such as Diabetes, hypertension, inflammation, anemia. Oxidative stress is associated with kidney disease progression. Inflammation is a redox-sensitive mechanism able to activate transcriptor factors such as NF-kB, which regulates inflammatory mediator gene expression. There is a strong relationship between oxidative stress and inflammation in chronic kidney disease, both are related to endothelial dysfunction, and reactive oxygen species (ROS), lipid and protein oxidation products as well as advanced glycation end-products (AGEs) are generated in response to inflammatory stimuli.As a conclusion, oxidative stress and inflammation are essential factors in the development and complication of the CKD, and therefore it is necessary to take into account the mitigation of these two phenomena in any approved treatment program.We suggest also that exposure to heavy metals can negatively alter the function of the remaining functional nephrons, which can lead to faster and additional cell death and glomerulosclerosis and from it to chronic renal failure.
KEYWORDS: CKD, Oxidative stress, Inflammation, Glomerular filtration, heavy metals.
1. INTRODUCTION:
Chronic kidney disease (CKD) also called chronic kidney failure is defined as the presence of kidney damage and can’t filter blood the way they should [1], it is manifested by abnormal albumin excretion or decreased kidney function [2] shown by glomerular filtration rateGFR<60ml/min/1.73m2 for 3 months or more which is less than half of normal value in young adult men and women of approximately 125 ml/min/1.73m2 and the ACR >30mg/g [3]. The glomerular filtration rate (GFR) is the best overall index of kidney filtration in healthy and disease [4] when the volume of plasma that is filtered by the glomeruli per unit of time,it is measured by the clearance of creatinine [5] also the age and gender are used to estimate the GFR. It became normal when it's number is more 90ml/min but in kidney damage it divided depending the CKD stage whereas it become less than 15 ml/min in ESRD. [6] a consequently the acute renal failure or acute kidney injury (AKI) is associated with acute decline of GFR [7]. The most risk factors for causing kidney disease are environment toxicity, heart disease, high blood pressure, diabetes, and a family history [8]. The inflammatory cells are then a source of free radicals in the forms of reactive oxygen and nitrogen species [9]. Many of recent landmarks in scientific research have shown that in human beings, Oxidative stress is an important factor causing metabolic and physiological alterations and various diseases in the body [10], it is as a consequence of increase a reactive oxygen species and decrease in antioxidant defenses in prevalent in many health problems like CKD [11]. Faced with this data, this review aims at identifying the role of oxidative stress and inflammation as factors associated with chronic kidney disease. Also, we will focus on some of the most prevalent environmental heavy metal toxicants: nickel, cadmium, and lead.
2. Risk factors and progression of chronic kidney disease:
The determination of factors predisposing an individual to CKD is essential in terms of personal and community health as some risk factors which can be non-modifiable including; age, gender, ethnicity and family history [12]. In addition, a number of independent risk factors have been identified that may be modified by pharmacotherapy or lifestyle changes to reduce the rate of CKD progression such as Diabetes, hypertension, inflammation,anemia and smoking ,obesity , physical activity [13], also metabolic syndromes, dyslipidemia, agricultural occupation and contact with agrochemicals can lead to kidney disease [14]. In addition, at the histopathological state, renal damage has been shown in humans, including intranuclear inclusion bodies and cellular necrosis in the proximal and interstitial tubule fibrosis [15]. Furthermore, The contamination of water resources has important repercussions for the environment and human health [16,17]. While that Drinking water contamination with different chemicals and heavy metals, released from different anthropogenic sources has become a global concern. [18]. On the other hand, acute kidney injury (AKI) is considered a risk factor for developing end-stage renal disease (ESRD) [19]. In the results of a study conducted on the blood/ rat ischemia model, acute renal impairment is characterized by a temporary but significant decrease in GFR, risk of high urine concentration, proteinuria and interstitial fibrosis. Also, the affected kidneys in this model show a significant increase in the lack of oxygen and renal fibrosis, as well as the glomerular capillary density and vascular density inside the tube increase with age and the ability to repair and regenerate tissues after a reduced infection is weak [20]. CKD progression may not be a smooth and continuous pathway as it is a gradual function characterized by frequent fits of acute kidney injury [21].
3. Oxidative stress in chronic kidney disease
The kidney is a highly energetic organ. This makes it more vulnerable to damage caused by oxidative stress (OS). In turn, OS is associated with kidney disease progression [22]. Furthermore, several complications of chronic kidney disease (CKD) such as inflammation , the major cause of death in patients with CKD, are also linked to increased levels of OS [23]. The kidneys maintain persistently high levels of mitochondrial oxidative phosphorylation and arterial blood flow, making them an environment in which ROS formation is expected [24]. In end-stage renal disease (ESRD) patients the antioxidant-pro-oxidant balance is shifted toward an increased oxidative stress. Several antioxidant systems have been shown to be deficient in patients with chronic renal insufficiency [25]. There is a complex interaction between antioxidants and oxidants such as reactive oxygen species, which modulates the generation of oxidative stress [26]. Reduced levels of vitamin C are present, in part due to a dietary restriction of fresh fruits and vegetables to avoid hyperkalemia, and vitamin E intracellular levels are low, selenium levels are reduced, and there is a deficiency in the glutathione system [27]. The imbalance in pro- and anti-oxidant capacities in kidney disease results in excess production of ROS in the blood [28]. The oxidant stress in dialysis patients causes increases in Malondialdehyde, oxidized LDL, and increases in antibodies against oxidized LDL [29].
4. Inflammation induced oxidative stress in kidney disease:
Oxidative stress in renal failure has been associated with hypertension endothelial dysfunction, decreased erythrocyte lifespan, atherosclerosis and inflammation [30]. The inflammatory cells are then a source of free radicals in the forms of reactive oxygen and nitrogen species. The highly reactive oxygen species (ROS) are capable of damaging various structures and functional pathways in cells [31]. Moreover the inflammation is a redox-sensitive mechanism, as oxidative stress is able to activate transcriptor factors such as NF-kB, which regulates inflammatory mediator gene expression. NF-kB is a dimer factor maintained inactivated in the cytoplasm by binding to inhibitory proteins (members of I-kB family) [32]. The causes of inflammation in dialysis patients include both factors arising from dialysis itself (efficiency and biocompatibility issues) as well as others that are non-dialysis related, such as advanced age and diabetes, renal disease and uremia parse [33]. ESRD patients have increased levels of inflammation-related proteins, such as interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a) and C-reactive protein(CRP) and are subjected to enhanced oxidative stress as aresult of both insufficient anti-oxidant defense mechanisms and excessive generation of oxidant compounds [34]. Components of the inflammatory response associated with hemodialysis (HD) method include neutrophil activation due to interaction between blood and dialysis membraneswith consequent increased synthesis and releaseof pro-inflammatory cytokines (IL-1â, IL-6, TNF-a) [35]. In addition, there is a strong relationship between inflammation and oxidative stress in hemodialysis patient population, as both are related to endothelial dysfunction, reactive oxygen species (ROS), lipid and protein oxidation products as well as advanced glycation end-products (AGEs) are generated in response to inflammatory stimuli [36].
5. Heavy metals and chronic kidney disease:
Heavy metals are those metals with higher atomic number and weight. They constitutedifferent groups of elements with variations in their biological functions and chemical properties [37]. They are a large group of elements with anatomic density of greater than six grams percubic centimeter, and are both biologically andindustrially important [38]. Generally, drinking water containing different anions and heavy metals including Cd, Cr, Co, Hg, Ni, Pb, Zn etc, has significant adverse effects on human health either through deficiency or toxicity due to excessive intake. Chronic low fluoride supplementation of drinking water on normal or decreased kidneys is insufficiency. While the kidneys are the target organs for fluoride toxicity [39,40]. Exposure to Nickel results in dysfunction of kidney function. An increase in serum creatinine and uremia levels appears after treatment with NiCl2 in drinking water [41], which indicates the installation of transient renal failure, confirmed by a structural alteration of the kidney, which would make the renal functions of filtration and tubular secretion difficult [42]. Nickel also induces a drop in the expression of the stress protein (Hsp72) and in the synthesis of metallothionein (MT) in the kidney tissue [43]. In rats exposed to nickel sulphate in drinking water show a change in the urine albumin level in both the female and the male, while the glucose content decreases [44]. As the kidneys play an important role in the excretion of lead, there are changes in the proximal tubules. The increase in urea and creatinine indicates a malfunction of the kidney linked to lead poisoning [45]. During acute intoxication, there will be irritation and necrosis of the digestive mucosa causing the digestive signs observed during lead poisoning as well as degeneration of the renal tubules [46]. Involvement of the proximal renal tubules is reversible if the poisoning is minor and there is then aminoaciduria, glycosuria and relative hyper phosphaturia with hypophosphatemia [47]. It appears that mitochondria play an important role in Pb-mediated injury. Oxidative stress within the cell may lead to alterations in the regulation of the mitochondria permeability transition pore [48]. However, if the exposure is chronic and prolonged, chronic interstitial nephritis can lead to kidney failure [49]. Chronic Exposure of cells to Pb also leads to structural alterations in the mitochondria such as distortion of the mitochondrial cristae and swelling and rupture of the outer membrane which is characteristic alteration in chronic kidney disease [50]. Epidemiological studies have demonstrated a positive correlation between kidney disease and the renal accumulation of Cd in individuals exposed chronically to this metal [51]. Moreover, exposure to Cd or other nephrotoxicants may further reduce or completely eliminate the renal functional reserve and the ability of the remaining functional renal mass to maintain normal homeostasis when challenged [52]. Following chronic exposure to Cd, approximately 50% of the total body stores accumulate in the kidney. Thus, it is not surprising to find that this organ is one of the primary targets of Cd intoxication [53]. Renal accumulation of Cd leads to reduced GFR, polyuria, and generalized tubular dysfunction (i.e., Fanconi’s syndrome). GFR falls if a disease causing albuminuria also destroys glomeruli, or if toxic substances destroy tubular cells after reabsorption from filtrate [54]. One of the earliest signs of renal damage is the presence of urinary biomarkers such as kidney injury molecule-1 (Kim-1), β2-microglobulin, N-acetyl-β-d-glucosamidase (NAG), and cystatin C [55]. β2-microglobulin is a low molecular weight protein that is filtered freely at the glomerulus and is absorbed normally by proximal tubules [56].
6. CONCLUSION:
Oxidative stress and inflammation are essential factors in the development and complication of the CKD, and therefore it is necessary to take into account the mitigation of these two phenomena in any approved treatment program which contributes to the prevention or limitation of disease development. We suggest also that exposure to heavy metals can negatively alter the function of the remaining functional nephrons, which can lead to faster and additional cell death and glomerulosclerosis and from it to chronic renal failure.
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Received on 19.04.2020 Modified on 21.05.2020
Accepted on 16.06.2020 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Tech. 2020; 10(3):202-206.
DOI: 10.5958/2231-5713.2020.00033.1