12/09/2024
Chronic Inflammation
The inflammatory state of CKD was multifactorial, including increased susceptibility to infection (especially dialysis pathway-related infections), oxidative stress and acidosis, metabolic changes of adipose tissue, and intestinal disorders (Bloembergen and Port, 1996; Dai et al., 2017; Mihai et al., 2018; Ebert et al., 2020). Persistent low-grade inflammation had been identified as a significant pathological feature of CKD (Ebert et al., 2020). On one hand, inflammatory overload of the kidney caused by increased production of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α might be manifested as impaired renal excretion function, which might prolong plasma half-life of these pro-inflammatory cytokines and be associated with persistent low-grade inflammation in CKD (Gupta et al., 2012). On the other hand, susceptibility to infection might be one of the significant, easily being overlooked, clinical characteristics of the CKD population. Community-population follow-up study showed a crude incidence of infectious events of 23.6 (95% CI, 22.8-24.6) per 1,000 person-years in CKD patients, with an increased risk of hospitalization for infection in both those on dialysis therapy and those with less severe renal insufficiency who did not require dialysis (Ishigami et al., 2017). Another report indicated that the incidence of common infectious complications in CKD patients who had not yet started dialysis was about 3 times that of the general population (Naqvi and Collins, 2006). And the admission rate due to this infection event in CKD population was 4 times higher than that in non-CKD population, and in dialysis patients it become 10 times higher than non-CKD population (Naqvi and Collins, 2006).
It has been recognized that chronic inflammation was one of the most common features of infection (Kovalchuk et al., 2014). Similarly, inflammation has long been considered as one of the risk factors and one of the important participants in the process of cancer formation, as inflammatory environment might enable tumor cells to escape host immune surveillance, leading to subsequent angiogenesis, tumor growth, invasion, and metastasis (Coussens and Werb, 2002). Also, chronic inflammation was likely to lead to DNA mutation and deregulation and release of carcinogenic cytokines, a key step implicated during the development of cancer (Wong et al., 2012). Chronic inflammation due to infection could directly induce DNA damage through production of nitric oxide derivative nitrogen dioxide by phagocytes, and indirectly by mutagen peroxynitrite generated by the reaction of nitric oxide with superoxide anion (Kovalchuk et al., 2014). The DNA-damaged cells were likely to cause mutations in oncogenes or tumor suppressor genes, resulting in a clonal population of cells with a proliferative advantage (Basu, 2018).
Interestingly, inflammation and oxidative stress might interact with each other and play pivotal roles in CKD. Chen et al. detected significant upregulation of inflammatory factors including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (INOS) and monocyte chemotactic protein-1 (MCP-1), downregulation of pro-oxidant genes p47phox, and downregulation of antioxidant systems [nuclear factor erythroid related factor 2 (Nrf2), catalase, heme oxygenase 1 (HO-1), glutathione peroxidase (GPx), glutamate transporter protein-1 (GSH-1)] in blood and urine specimens from 180 CKD patients (Chen et al., 2017). And this inflammatory/oxidative process was accompanied by activation of Wnt/β-catenin signaling pathway (Chen et al., 2017). Multiple evidence has indicated that Wnt/β-catenin signaling pathway was involved in the development and progression of solid tumors and hematologic malignancies (Zhang and Wang, 2020). In mice, it was reported that β-catenin activated by Wnt pathway synergized with other oncogenic pathways or chemicals to induce liver cancer (He and Tang, 2020). Wnt/β-catenin signaling pathway has also been indicated to regulate differentiation, proliferation, apoptosis and migration of multiple myeloma cells (Hu and Hu, 2018).
Besides, in renal tubular epithelial cells, aldosterone could induce trans-activation of epidermal growth factor receptor (EGFR) via ADAM17, followed by the release of transforming growth factor-α, which regulated the expression of pro-inflammatory factors such as chemokine ligand 2 (CCL-2) and chemokine ligand 5 (CCL-5) (Morgado-Pascual et al., 2015). The pro-inflammatory factors CCL-2 and CCL-5 were reportedly associated with tumor growth, angiogenesis, and invasion of breast cancer, while CCL-2 could indirectly stimulate tumorigenic activity of normal breast cells (Yu et al., 2018; Yamaguchi et al., 2021). CCL-5 secreted by tumor-associated macrophages (TAMs) might promote the progression of prostate, gastric and colorectal cancers. However, the carcinogenic effects of both in CKD need to be further explored in the future (Yamaguchi et al., 2021).
Interestingly, it was found that angiotensin II (Ang-II) might stimulate superoxide production through NAD(P)H oxidase, while angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) might reduce superoxide production by blocking Ang-II production or by preventing AngII from binding to the receptor (de Cavanagh et al., 2004); and the authors suggested that these drugs might hold an antioxidant effect and might improve the oxidative stress state of diseases (de Cavanagh et al., 2004). However, it seemed to be contradictory to the clinical data that the incidence rate of cancer in CKD patients was relatively higher than non-CKD patients, although ARB/ACEI have been frequently used in CKD patients. This inconsistency might be due to other potential risk factors or molecular mechanisms in CKD patients, which we would discuss later in this review, and might be resulted from the potential effects or impacts of common application of other drugs in these CKD patients such as erythropoietin (EPO) for the treatment of anemia in CRF patients, which has been implicated to be related to promotion of tumor growth with undetermined mechanisms (González Vitores et al., 1999; Ribatti, 2010). These factors might outweigh the potential antioxidant effect of ACI/ARB and further explorations are in need in the complex setting of CKD.
Accumulation of Carcinogenic Compounds
In ESKD patients, due to impaired renal function, nitrogen-containing substances and carcinogenic compounds accumulated in the blood, which put the body in a uremic environment (Masereeuw et al., 2014). It was found that levels of carcinogenic compounds 2-amino-6-methyldipyrido [1,2-a:3′,2′-d]imidazole (Glu-P-1) and 2-aminodipyrido [1,2-a:3′,2′-d]imidazole (Glu-P-2) were relatively higher in plasma of uremic patients on dialysis than in normal population and levels of both compounds remained high after 1 month of dialysis treatment, indicating that uremic patients might be persistently exposed to high levels of carcinogenic compounds (Manabe et al., 1987). Animal studies had shown that several oncogenic heterocyclic amines, including Glu-P-1, 2-amino-3,8-dimethylimidazo [4,5f]quinoxaline (MeIQx), and 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), might be moderately carcinogenic to the liver, breast and intestine, but limited to dietary acquisition and exposure at certain doses and times (Dooley et al., 1992). Mechanistically, this might be related to activation of these oncogenic chemicals as electrophilic species during metabolism through binding to DNA or causing DNA damage (Basu, 2018). These studies suggested that reduced excretion of partial renal excretion of carcinogenic compounds in renal failure led to accumulation of such substances in plasma, and it was plausible to infer that a certain dose and duration of exposure to carcinogenic compounds in uremic environment might be associated with a high incidence of malignancy in patients with chronic renal failure.
Aromatic hydrocarbon receptor (AHR) was a ligand-activated transcription factor, which was well known for regulating the toxicity of carcinogen “dioxin” and has been implicated in tumorigenesis (Opitz et al., 2011). There were studies showing levels of serum aryl hydrocarbon receptor-activating potential (AHR-AP) were elevated before dialysis but decreased after dialysis in CKD patients (Dou et al., 2018). The authors indicated that in these patients high levels of AHR-AP reflected the accumulation of uremic toxins, the latter of which were AHR agonists, and that AHR might be activated under such conditions (Dou et al., 2018). Animal studies showed 5/6 nephrectomy approach induced an approximately 3-fold increase in serum urea concentration and in AHR-AP in CKD mice compared to the sham-operated group (Dou et al., 2018). AHR could also mediate transcriptional upregulation of cytochrome P450 Phase 1 hydrocylases CYP1A1, CYP1A2 and CYP1B1, the latter of which has been implicated to be a risk factor for the carcinogensis of certain cancers (Lao et al., 2014; Wang Z. et al., 2020). These studies suggested that uremic toxins may be involved in tumorigenesis in CKD through its interaction with activation of this AHR signaling.
Oxidative Stress
Oxidative stress is a state of imbalance between oxidation and antioxidant action in the body, which has been implicated in CKD, manifested as increased oxidative activity and decreased antioxidant system (Morena et al., 2002; Putri and Thaha, 2014). In early stages of CKD, continuous low and chronic inflammation in CKD patients might trigger the generation of NADPH oxidase and MPO by polymorphonuclear neutrophils and monocyte-macrophages, which promoted formation of reactive oxygen species (ROS) and synergistically participated in the oxidative stress process (Locatelli et al., 2003; Putri and Thaha, 2014). A study of 87 patients with CKD whose plasma levels of the oxidative stress indicator 8-epiPGF2a were significantly increased with the progression of CKD staging showed that oxidative stress levels were increased in late renal insufficiency stage of CKD (Dounousi et al., 2006). At the same time, excess ROS reduced clearance of pro-oxidant substances and decreased antioxidant function presented in patients with CKD would combine to increase oxidative stress levels, and thereby create a pro-oxidant environment (Locatelli et al., 2003). Under physiological conditions, transcription factor Nrf2 played a significant role in antioxidant responses through nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway (Shaw and Chattopadhyay, 2020), whereas in uremic and hemodialysis patients, the antioxidant effect was reduced (Stockler-Pinto et al., 2018). Upon stimulation by oxidative stress, dissociation of covalently bound nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein1 (Nrf2-keap1) in the cytoplasm allowed free translocation of Nrf2 to the nucleus, where it heterodimerized with Maf (musculoaponeurotic fibrosarcoma oncogene homolog) proteins to form the Nrf2/Maf complex, which subsequently initiated ARE-dependent gene expression of antioxidant and cytoprotective proteins (Tu et al., 2019). In peripheral blood mononuclear cells of uremic and hemodialysis patients, Nrf2-associated antioxidant genes, such as heme oxygenase-1(HO-1), glutamate-cysteine ligase modifier subunit (GCLM) and catalase, were downregulated, whereas NF-κB activation showed opposite effects, leading to upregulated expression of oxidant genes and proteins and increased oxidative stress levels (Pedruzzi et al., 2015; Feng et al., 2019). Activation of NF-κB might be associated with certain T cell lymphoma (Giri and Aggarwal, 1998).
During oxidative stress, ROS was constantly generated by aerobic metabolism in mitochondria, which may contribute to serious damage to cell structure and function and induce somatic mutation and tumor transformation (Loft and Poulsen, 1996; Reuter et al., 2010), including increasing DNA mutations or inducing DNA damage, genomic instability, and malignant cell proliferation (Reuter et al., 2010). In addition, ROS itself was involved in cancer migration as an important component of certain signaling pathways. In vitro experiments showed that bladder cancer cell line TSGH-8301 was more dispersed and separated from each other after stimulation with uremic toxin p-cresyl (P-CS), and indicated that ROS was a key signal for cell migration induced by P-CS which further induced bladder cancer cell migration and epithelial mesenchymal transition (EMT) through reactive oxygen species/Src/focal adhesion kinase (ROS/Src/FAK) signaling pathway (Peng et al., 2020). It was indicated that activation of Src could contribute to the growth, survival, migration, and metastasis of malignant tumors (breast, prostate, and lung cancers), as well as FAK, which could also regulate migration and invasion of a variety of cancer cells, under the regulation of ROS signals (Lim et al., 2012).
Impairment of DNA Repair
Low DNA damage repair capacity was associated with the risk of cancer development and has long been considered a cause of malignancy (Sevilya et al., 2014). Experiments on repair capacity of lymphocytes from normal people or patients with chronic renal failure (CRF) treated with or without dialysis showed that DNA repair capacity of lymphocytes in CRF patients on dialysis was similar to that of normal control population, which, in contrast, was significantly reduced after UV or gamma irradiation in the latter population, suggesting that patients with CRF might have a reduced capacity to repair DNA damage and might regain this capacity through dialysis (Malachi et al., 1993). Unrepaired or improperly repaired DNA damage would lead to mutable genes and aberrations in the chromosome, which might be responsible for cancer susceptibility, that was, the malignant and pathological transformation of cells (Schupp et al., 2010; Helena et al., 2018). Irreparable genomic damage, such as sister chromatid exchanges and chromosome breaks, and abnormal distribution of entire chromosomes, has been found in lymphocytes of dialysis patients, correlated to an increased incidence of cancer in these patients, particularly in kidney, prostate, liver, and uterine cancers and lymphoma (Stopper et al., 1999; Buemi et al., 2006). Polymorphism studies of DNA repair enzyme genes Xeroderma pigmentosum complementation group D (XPD) and X-ray cross-complementing group 1 (XRCC1) in dialysis patients and healthy controls indicated these DNA damage repair variants were significantly associated with susceptibility to the development of ESKD (Trabulus et al., 2012).
Excessive Parathyroid Hormone
With the gradual decline of renal function, urinary phosphorus excretion was reduced and increased blood phosphorus was increased. Blood phosphorus and calcium combine to form calcium phosphate, which lowered blood calcium. Low blood calcium, high blood phosphorus, and lack of active vitamin D were all recognized as the main causes of secondary hyperparathyroidism (SHPT) (Lau et al., 2018). It had been reported that parathyroid hormone (PTH) and parathyroid hormone receptors stimulated the proliferation of some tumor cells, such as osteoblasts, human renal carcinoma cell and breast cancer cells, indicating excessive parathyroid hormone might be pro-carcinogenic to some extent (Birch et al., 1995). In an experimental study in uremic rats, rats in the sham-surgery group with preserved parathyroid glands showed high PTH and high FGF-23 during renal failure induced by feeding the adenine high-phosphorus diet, compared to control rats with destroyed parathyroid glands, implicating that hyperparathyroidism secondary to CKD could induce increased serum levels of FGF-23 (Lavi-Moshayoff et al., 2010). High expression of FGF-23 in CKD patients might be associated with regulation of FGF-23 production by bone remodeling through release of low molecular weight FGFs (Silver and Naveh-Many, 2013). Although there was a lack of research on tumor-promoting effects of high expression of FGF-23, the important role of FGF/FGFR signaling in prostate cancer and paraneoplastic diseases mediated by FGF23 overexpression, such as hypophosphatemia, also suggested a link between FGF-23 and tumors (Lee et al., 2014).
Deficiency of vitamin D (VD) was often observed in CKD patients (Diniz et al., 2012; Feldman et al., 2014). VD is the precursor to the potent steroid hormone calcitriol (also known as 1,25-dihydroxy- vitamin D3 (1,25(OH)2D3)), widely involved in a series of physiological processes in the body and multiple cellular signaling pathways in relation to cancer risk and prognosis (Jones, 2010). In vitro studies suggested some potential anti-tumor mechanisms of calcitriol, one of the active metabolites of VD, including stagnation of tumor cell cycle, promotion of tumor cell apoptosis, inhibition of tumor angiogenesis and invasion, etc (Trump and Aragon-Ching, 2018). Several controlled experimental studies have suggested that DV deficiency (VDD) might be associated with the development of several malignancies (breast, colorectal and bladder, etc) (Palmieri et al., 2006; Jacobs et al., 2013; Chandler et al., 2015). Others demonstrated that VDD might be associated with an increased risk of esophageal squamous cell cancer, oral cancer, and throat cancer, and the expression of VD receptor was increased in precancerous lesions and oral cancers (Botelho et al., 2020). From this point of view, it might be reasonable to expect a potential anti-cancer role of supplementation of VD. And there were some studies implicated that supplementation of VD might be correlated with a reduced risk of cancer (Feldman et al., 2014; Theodoratou et al., 2014). However, a meta analysis concluded that there was still a lack of sufficiently convincing evidence for a significant association between VD and cancer (Theodoratou et al., 2014). And randomized control trials in humans did not yet exist to supportively conclude a beneficial role for VD supplementation in the clinical setting (Feldman et al., 2014). It would be of importance to conduct further experiments and trials to identify the role of VDD and VD supplementation in cancer development and treatment in CKD patients.
In the treatment of secondary hyperparathyroidism, some first-line drug treatments included vitamin D preparations, calcimimetics, etc. For refractory secondary hyperparathyroidism, parathyroidectomy (PTx) might be considered an effective treatment. Observational studies have shown a 34% reduction in all-cause mortality in patients with SHPT treated with PTx compared to patients with SHPT not treated with PTx, suggesting that parathyroidectomy might be beneficial to the survival of CKD patients with SHPT (Komaba et al., 2015). Nevertheless, large observational studies of tumor morbidity and mortality in CKD patients with combined SHPT after surgical treatment are still lacking.
Changes in Intestinal Microbiota
Uremia might directly or indirectly influence the composition of intestinal microbiota and intestinal barrier (Syed-Ahmed and Narayanan, 2019). Some researchers used antibiotics to eradicate the facultative anaerobic microbiota in the intestinal tract of CKD mice, which effectively prevented bacterial translocation, significantly reduced the levels of serum endotoxin, and completely reversed all markers of systemic inflammation to the level of non-CKD control mice (Andersen et al., 2017). A large number of studies reported that lactobacilli decreased in the intestinal microbiota of CKD animals and patients, while Enterobacteriaceae with a gene encoding tryptophan tyrosine phenol lyase increased, demonstrating they might come into play in production of uremic toxins (Kikuchi et al., 2017).
As mentioned earlier, AHR was a ligand activated transcription factor known for its tumor-promoting effects, and uremic toxins derived from intestinal microbiota have been recognized as effective endogenous ligands for AHR activation (Murray et al., 2014). Other mechanisms have been proposed that the imbalance of intestinal flora might aggravate the development of intestinal tumors and inhibit antitumor immunity, and might be related to the followings: 1) destruction of DNA: This might arise by the injury induced by intestinal flora producing specific toxins like Colibactin; 2) activation of carcinogenic signal pathways, including PI3K/Akt, Wnt and NF-κB signaling pathways, which were activated by the toxins expressed by Helicobacter pylori; and 3) production of tumor-promoting metabolites such as secondary bile acids, secreted or produced by coupled binding of bile acids by intestinal microbiota (Mima et al., 2017). Intestinal microbiota also communicated with the brain by regulating levels of some metabolites including tryptophan, 5-hydroxytryptamine and short-chain fatty acids, changed the central higher-order behavior, and indirectly participated in the regulation of body emotion and cognition (Jenkins et al., 2016; Mohajeri et al., 2018). Emotional and cognitive regulation disorders caused by changes in intestinal microbiota might also play a role in mental diseases such as anxiety and depression, which were closely related to cancer (Spiegel and Giese-Davis, 2003; Skonieczna-Zydecka et al., 2018; Wang Y.-H. et al., 2020). Very recently, novel examination method has been developed, such as the addition of f***l F nucleatum quantitation to f***l immunochemical test for screening characteristics of the intestinal microbiome, which greatly improved the sensitivity of early detection of gastrointestinal tumors (Song et al., 2020). The changes in intestinal microbiota suggested that regulating intestinal microbiota might be an interesting and promising target to lower toxins of uremic patients and thereby the incidence of cancer.
