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Digestive tract tumors (DTT), particularly gastric cancer (GC) and colorectal cancer (CRC), remain among the leading causes of cancer-related morbidity and mortality worldwide. Accumulating epidemiological evidence indicates that patients with chronic kidney disease (CKD) exhibit a significantly increased risk of developing gastrointestinal malignancies and experience worse clinical outcomes. However, the biological mechanisms underlying this association have not been comprehensively synthesized. In this review, we integrate clinical and experimental evidence to delineate how CKD functions as a systemic pro-tumorigenic condition rather than a passive comorbidity. We highlight three interrelated mechanistic axes linking CKD to DTT: (i) persistent systemic inflammation and oxidative stress, (ii) metabolic and endocrine dysregulation driven by uremic toxin accumulation, vitamin D deficiency, and mineral imbalance, and (iii) immune perturbations associated with dialysis modalities and post-transplant immunosuppression. These processes converge to disrupt gastrointestinal barrier integrity, reshape the gut microbiota, impair antitumor immune surveillance, and promote malignant transformation and tumor progression. Importantly, we discuss how CKD-specific interventions, including dialysis strategies, kidney transplantation, dietary management, and modulation of gut microbiota, may further modify gastrointestinal cancer risk. Finally, we propose CKD-oriented preventive and screening strategies for GC and CRC, emphasizing the need for risk stratification based on renal function, proteinuria, and metabolic profiles. By framing CKD as an active driver of gastrointestinal carcinogenesis, this review provides a novel integrative framework that synthesizes interconnected mechanistic pathways and explicitly links them to CKD-specific clinical management strategies, a translational perspective that informs early detection, prevention, and integrated care of DTT in patients with CKD.
1 IntroductionDigestive tract tumors (DTT) refer to primary and metastatic malignancies arising in the oral cavity, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, and ileum), and large intestine. Globally, the overall burden of DTT is increasing and shows a shift toward younger onset; both incidence and mortality continue to rise, particularly among males (Schell et al., 2022; Huang et al., 2024; Danpanichkul et al., 2024). This pattern may reflect multiple direct or indirect drivers, including population aging, the growing prevalence of the “three highs” (high blood glucose, hyperlipidemia, and hypertension), and the non-specific and insidious symptoms at early stages (Ahn et al., 2024; Li et al., 2018; Hashimoto et al., 2025). Among these factors, chronic kidney disease (CKD) has emerged as a clinically significant contributor to the development of gastric cancer (GC) and colorectal cancer (CRC). This association underscores the need to clarify CKD-related mechanisms and to investigate why patients with CKD are more susceptible to these cancers, particularly GC and CRC.
CKD refers to a group of kidney disorders of any etiology characterized by structural or functional abnormalities that adversely affect health (Romagnani et al., 2025). According to Kidney Disease: Improving Global Outcomes 2024 (KDIGO 2024), a diagnosis requires kidney abnormalities persisting for at least 3 months, as evidenced by imaging or urine abnormalities, a history of kidney transplantation, or a glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 (KDIGO, 2024, 2024). CKD is staged from G1 to G5, and early clinical manifestations are often subtle (Francis et al., 2024). With disease progression, multisystem symptoms emerge. These include anorexia, weight loss, and an increased predisposition to gastrointestinal bleeding. Advanced stages may involve severe uremic complications such as pericarditis, acute pulmonary edema, severe anemia, and uremic encephalopathy (Zoccali et al., 2023; Wang et al., 2025; Rhee et al., 2022; Kalantar-Zadeh et al., 2022; Frąk et al., 2024). Emerging evidence indicates that patients with CKD are particularly susceptible to DTT, which may be driven by inflammatory, metabolic, and treatment-related factors; however, the mechanistic basis remains incompletely defined. While previous articles have individually addressed inflammation, uremic toxins, or microbiota alterations in CKD, a comprehensive synthesis is currently lacking. Such a synthesis would need to integrate these interconnected mechanisms and explicitly translate them into CKD-oriented screening and management strategies. This review synthesizes observational evidence on DTT in CKD, delineates plausible mechanistic pathways, and proposes practical, CKD-specific strategies to preserve kidney and gastrointestinal health and optimize management to improve outcomes.
2 Observational evidences suggest a strong association between CKD and DTTRecent observational studies indicate that patients with renal insufficiency exhibit an increased risk of DTT (Table 1). In a Korean cohort study, Hyung Jung Oh et al. enrolled 35,443 pre-dialysis CKD patients and determined the risk of DTT using the standardized incidence ratio (SIR). Over a 54.9-month follow-up, the risk of DTT in pre-dialysis CKD patients was significantly higher than in the general population (SIR 1.54, 95% CI 1.46–1.62), with respective SIRs for GC and CRC of 1.60 and 1.25 (Oh et al., 2018). Importantly, among CKD patients younger than 40, the incidence of CRC increased markedly compared to their peers in the general population (SIR 4.58) (Oh et al., 2018). While this study provides robust evidence of an association, it is important to acknowledge that such registry-based comparisons may not fully account for the uneven distribution of traditional risk factors. For instance, the higher prevalence of metabolic syndrome components, such as diabetes and obesity, in the general population, and their potential under-documentation in registry data, could confound the observed SIRs, potentially either inflating or masking the true effect of CKD.
CountryFirst author/YearSample sizePopulation typeCancer typeMain outcomesReferenceKoreaHyung Jung Oh/201835,443Pre-dialysisGC/CRC1. CKD patients before dialysis had a significantly higher risk of developing DTT compared to the cohort population (SIR 1.54, 95% CI 1.46–1.62).Observational studies reveal a close association between CKD and DTT.
Abbreviation: CKD, chronic kidney disease; DTT, digestive tract tumor; GC, gastric cancer; CRC, colorectal cancer; PD, peritoneal dialysis; HD, hemodialysis; SIR, standardized incidence ratio; FIT, fecal immune test; eGFR, estimated glomerular filtration rate.
A multicenter retrospective cohort study in Japan analyzed 2,161 dialysis patients and 158,964 non-dialysis cancer patients. It found that GC and CRC were diagnosed at earlier stages in the dialysis group. Additionally, cox proportional hazards models revealed that dialysis patients with CRC or GC had significantly higher mortality compared to their non-dialysis counterparts (both p < 0.05) (Kida et al., 2022). Additionally, in a retrospective cohort study by Lee et al., 13,473 dialysis patients and 22,455 non-dialysis patients were included. After propensity score matching, the dialysis group demonstrated a significantly higher risk of both GC and CRC. Moreover, patients receiving peritoneal dialysis (PD) presented approximately double the risk of GC compared to those receiving hemodialysis (HD), while no significant difference in CRC risk was observed (Lee et al., 2018). This suggests dialysis modality may influence DTT risk. In South Korea, a cohort study followed 14,382 dialysis patients, among whom 1,124 (7.82%) were diagnosed with cancer during follow-up. Notably, CRC was identified as the most common primary cancer site in both males and females, while stomach cancer ranked third in men and fourth in women (Myung et al., 2020). Additionally, a retrospective analysis of 48,315 dialysis patients and healthy controls similarly identified CRC as the most prevalent malignancy, and the risk of malignancy was observed to be higher in peritoneal dialysis patients than in those undergoing hemodialysis (adjusted HRs: 1.91; 95% CI: 1.59–1.79 vs. 1.69; 95% CI: 1.66–2.2, respectively) (Kwon et al., 2019). Despite adjustments, confounding by indication remains a concern in studies comparing dialysis modalities. Patients are typically selected for PD or HD based on specific clinical profiles, such as age, cardiovascular stability, and diabetic status. These very factors, particularly diabetes and its associated microvascular complications, are also independent risk factors for carcinogenesis. Therefore, the higher GC risk observed in PD patients might be partially attributable to a higher baseline prevalence of diabetes or other unmeasured metabolic disturbances in this group, rather than the dialysis modality itself.
Furthermore, in a prospective cohort study by Eric H. Au et al. involving 1,706 patients with CKD stages 3–5 who underwent fecal immunochemical test (FIT)-based screening, advanced colorectal neoplasia was detected in 117 individuals (6.9%). Subsequent multivariate analysis identified several independent risk factors, including older age (OR, 1.05 per year; 95% CI, 1.03–1.07; p < 0.001), male sex (OR, 2.27; 95% CI, 1.45–3.54; p < 0.001), azathioprine use (OR, 2.99; 95% CI, 1.40–6.37; p = 0.005), and the use of erythropoiesis-stimulating agents (OR, 1.92; 95% CI, 1.22–3.03; p = 0.005) (Au et al., 2022). These factors appear to collectively contribute to an elevated risk, suggesting that such patient profiles warrant careful consideration when devising screening protocols. This study is notable for its prospective design and adjustment for multiple variables. However, it also highlights the difficulty of disentangling the effects of CKD from those of its treatments (e.g., immunosuppressants, erythropoiesis-stimulating agents [ESAs]). Furthermore, lifestyle factors notoriously difficult to measure precisely in epidemiological studies, such as smoking status and dietary patterns, were not included in the final multivariate model, representing a potential source of residual confounding.
Moreover, de novo malignancies (DNM) are regarded as serious complications following transplantation, with the risk of developing such malignancies in solid organ transplant recipients being 2 to 3 times higher than in the general population (Mazzucotelli et al., 2017; Pradere et al., 2020). In a Korean cohort study comprising 10,085 kidney transplant recipients, Park et al. reported that kidney transplantation was associated with an increased risk of DTT, with GC occurring at a notably higher rate among male recipients (Park et al., 2019). In a retrospective study, Zorn et al. observed that, among kidney transplant patients, the incidence of DTT was second only to that of urological tumors during 9.9 years, and that both GC and CRC were significantly more prevalent than other types in both males and females (Apel et al., 2013). Additionally, a Swedish cohort study analyzing 7,952 CKD patients who underwent kidney transplantation between 1970 and 2008 reported a cumulative cancer incidence of 12% within 20 years after surgery. However, the SIRs for GC and CRC reached 1.8 and 2.3, respectively (Krynitz et al., 2013). Furthermore, mounting evidence indicates that the overall cumulative exposure to immunosuppression remains the key determinant of cancer risk after kidney transplantation, superseding the role of individual drug classes (Vallianou et al., 2025; Sprangers et al., 2018). While the link between immunosuppression and cancer is well-established, interpreting post-transplant cancer risks requires careful consideration of pre-transplant exposures. The elevated SIRs for GC and CRC could reflect not only the oncogenic effects of immunosuppressive drugs but also the legacy of pre-existing uremia, dialysis vintage, and the accumulation of traditional risk factors like smoking, all of which are highly prevalent in this population. The lack of detailed data on pre-transplant lifestyle factors and the duration and severity of prior CKD in many registry studies limits the ability to definitively isolate the contribution of transplantation from the patients' cumulative exposure history. This understanding warrants further investigation into the potential differential effects of specific agents, particularly mTOR inhibitors, on oncogenic outcomes. Collectively, these observational studies suggest that CKD patients exhibit significant gastrointestinal health disparities compared to healthy individuals, and they experience a higher risk of malignancy. Furthermore, CKD-related treatments, including dialysis and kidney transplantation, appear to be associated with the occurrence and progression of DTT. Conversely, evidence from the opposite perspective exists. In a large prospective study, Miyamoto et al. found that low eGFR was not significantly associated with an increased risk of overall cancers or specific cancers (such as GC and CRC) in CKD patients. This null finding may be explained by several limitations, including inadequate sample size and an eGFR estimation based solely on serum creatinine without information on quantitative albuminuria or serum cystatin C (Miyamoto et al., 2023), which underscores the critical need for future studies to incorporate more precise measures of kidney damage, such as proteinuria, alongside comprehensive data on confounders like smoking, obesity, and diabetes, to accurately delineate the independent role of CKD. Meanwhile, there is no research indicating an association between CKD and specific DTT subtypes, and further research is needed.
3 Potential mechanisms underlying the multifaceted effects of CKD and DTTEmerging evidence suggests that the association between CKD and DTT is not driven by a single pathogenic pathway but instead arises from a network of interrelated systemic disturbances. Conceptually, CKD establishes a pro-tumorigenic milieu through three converging mechanistic axes: (i) persistent systemic inflammation and oxidative stress, (ii) metabolic and endocrine dysregulation resulting from uremic toxin accumulation, vitamin D deficiency, and mineral imbalance, and (iii) immune perturbations induced by renal replacement therapies, including dialysis and kidney transplantation. These axes do not operate in isolation; rather, they interact to disrupt gastrointestinal barrier integrity, reshape the gut microbiota, impair antitumor immune surveillance, and promote malignant transformation and tumor progression. In the following sections, we delineate these mechanisms in detail, thereby understanding how CKD actively contributes to the initiation and progression of gastrointestinal malignancies.
3.1 CKD-mediated chronic inflammation and oxidative stress elevate the risk of carcinogenesisCKD is a state of chronic systemic inflammation and oxidative stress, which drives both renal deterioration and increases the risk of GC and CRC. In patients with CKD, hypertension arises from activation of the renin–angiotensin–aldosterone system (RAAS), water and sodium retention, and sympathetic overactivity; sustained hypertension further accelerates renal fibrosis through glomerular hypertension and endothelial injury (De Pascalis et al., 2024; Ku et al., 2019). Within these pathways, angiotensin II (Ang II) and aldosterone play pivotal roles. Excess Ang II and aldosterone activate NADPH oxidase and the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome via the angiotensin II type 1 receptor (AT1R) and the mineralocorticoid receptor (MR), respectively. The resulting activation of NF-κB (nuclear factor kappa-B) and JAK–STAT signaling drives the production of reactive oxygen species (ROS) and pro-inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-αlpha (TNF-α), and interleukin-1 beta (IL-1β), thereby establishing an inflammation–oxidation amplification loop (Zhang X. et al., 2019; Huang et al., 2021; Bruder-Nascimento et al., 2016; Es et al., 2022; Patel et al., 2019). Mechanistically, Ang II promotes assembly of the NLRP3 inflammasome by facilitating NLRP3–ASC (apoptosis - associated speck - like protein containing a CARD) complex formation and upregulating caspase-1 through AT1R and a Ca2+-dependent pathway, leading to IL-1β processing and secretion (Zhang X. et al., 2019; Es et al., 2022). By contrast, aldosterone induces vascular injury through interleukin-1 receptor (IL-1R) activation (Bruder-Nascimento et al., 2016). Consistent with these mechanisms, Espitia-Corredor et al. showed that 16-h Ang II exposure in myocardial fibroblasts induces pronounced perinuclear/nuclear colocalization of NLRP3 and ASC, increases caspase-1 activity by approximately 30%, and triggers IL-1β secretion via an AT1R/PLC/IP3R/Ca2+-dependent mechanism (Es et al., 2022). Moreover, Nascimento et al. reported that IL-1R−/− and NLRP3−/− mice infused with aldosterone for 2 weeks are protected from aldosterone-induced vascular dysfunction, evidenced by suppression of VCAM-1 and ICAM-1 expression, thereby highlighting essential roles for IL-1β and NLRP3 in aldosterone-induced vascular damage and underscoring the contribution of hypertension and aldosterone to inflammasome activation (Bruder-Nascimento et al., 2016). However, extrapolating these findings from animal models to humans requires caution.
Moreover, evidence indicates that inflammatory mediators enter the gastrointestinal mucosa via the circulation, increasing local microvascular permeability and driving structural remodeling, thereby exacerbating gastrointestinal barrier dysfunction (Figure 1) (Britzen-Laurent et al., 2023; Li et al., 2025). Convergent data from cellular, animal, and human tissue studies demonstrate that inflammatory stimuli heighten barrier permeability through mechanisms that include overexpression of MLCK (myosin light-chain kinase) and mediation by STAT6 (signal transducer and activator of transcription 6) (Meyer et al., 2023; Jin and Blikslager, 2020; Lin et al., 2019). Concurrently, infiltration of inflammatory cells (e.g., neutrophils and macrophages) into the gastrointestinal mucosa markedly elevates oxygen consumption, while microvascular injury diminishes oxygen delivery; together, these processes induce tissue hypoxia, which stabilizes hypoxia-inducible factor-1α (HIF-1α) and establishes a positive feedback loop (Lun et al., 2023). In a rat model of sepsis, Lei et al. reported significantly higher HIF-1α expression in septic animals versus controls (p < 0.05), along with pronounced hyperplasia of the intestinal lamina propria and extensive protrusion and sloughing of villus epithelium. They further observed significantly reduced expression of the tight junction proteins ZO-1, occludin, and claudin-1, underscoring the pivotal role of HIF-1α in barrier impairment (Lei et al., 2022). Under chronic inflammatory hypoxia, HIF-1α also promotes the expansion and activation of myeloid-derived suppressor cells (MDSCs) (Köstlin-Gille et al., 2019). By secreting inhibitory mediators (e.g., interleukin-10 [IL-10], inducible nitric oxide synthase [iNOS], and vascular endothelial growth factor [VEGF]) and depleting local arginine, MDSCs suppress T-cell function and create an immunosuppressive microenvironment (Tran et al., 2020; Daniel et al., 2019), thereby undermining immune surveillance and increasing the risk of tissue carcinogenesis. Moreover, a hypoxic and inflammatory intestinal environment reduces butyrate-producing bacteria, which both impairs effective downregulation of HIF-1α and diminishes the energy supply and anti-inflammatory capacity of intestinal epithelial cells. These changes exacerbate inflammation and markedly increase the risk of DTT (He et al., 2022; Dengler et al., 2021). In in vitro studies, butyrate lowers HIF-1α levels, likely preventing its accumulation by inhibiting lactate dehydrogenase A (LDHA) activity (Zhao et al., 2024; Nishioku et al., 2025; Xiong et al., 2025; Yan et al., 2024). Furthermore, chronic inflammation critically modulates cancer stemness to drive tumor initiation and malignant progression (Wang T. et al., 2019). Specifically, inflammatory mediators induce deacetylation of FOS-related antigen 1 (FRA1), imparting stem-like properties to CRC cells—enhancing self-renewal, differentiation, and therapy resistance (Wang T. et al., 2019)—thereby directly promoting CRC progression.
Inflammatory mediators disrupt gastrointestinal homeostasis. Inflammatory factors increase the permeability of the gastrointestinal barrier through mechanisms that involve MLCK overexpression and STAT6-mediated effects, among others. Subsequently, MLCK-dependent phosphorylation of the regulatory MLC is responsible for the activation of myosin II and the contraction of the peri-junction actin ring. STAT6 activates downstream target MLCK1, leading to disruption of tight junction structures in epithelial cells. In addition, infiltration of neutrophils, macrophages, and other cells into the gastrointestinal mucosa markedly increases oxygen consumption, while microvascular damage reduces oxygen delivery; together, these changes lead to tissue hypoxia, which further stabilizes HIF-1α. Moreover, inflammatory factors regulate the expression of tight junction proteins, with significant reductions in occludin and claudin-1 levels. At the same time, HIF-1α induces the expansion and activation of MDSCs, which subsequently secrete inhibitory mediators, creating an immunosuppressive microenvironment and increasing the likelihood of tumorigenesis. Furthermore, the inflammatory–hypoxic environment in the gut also affects microbiota homeostasis, characterized by a decrease in butyrate-producing bacteria. This prevents the effective downregulation of HIF-1α and simultaneously weakens the energy supply and anti-inflammatory capacity of intestinal epithelial cells, thereby exacerbating inflammation and markedly elevating the risk of DTT. MLCK, myosin light-chain kinase; STAT6, signal transducer and activator of transcription 6; MLC, myosin light-chain; MLCK1, myosin light-chain kinase 1; MDSC, myeloid-derived suppressor cells; HIF-1α, hypoxia-inducible factor-1α; DTT, digestive tract tumor; SCFAs, short-chain fatty acids; IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1 beta (By Figdraw).
Patients with CKD exhibit a marked imbalance in oxidative stress, characterized by the accumulation of ROS and diminished antioxidant capacity; this state persists across all stages of CKD (Roumeliotis et al., 2024; Tsinari et al., 2025). The gastrointestinal tract is a primary site of ROS generation. Excess ROS perturbs cellular metabolism by inducing DNA damage, lipid peroxidation, and protein oxidation. It can directly attack DNA, giving rise to carcinogenic mutations (Ohno et al., 2024; Li J. et al., 2024). At the tissue level, Scalise et al. showed that DNA damage may induce TP53 mutations, thereby initiating CRC (Scalise et al., 2016). Moreover, ROS may compromise base excision repair glycosylases (hOGG1, MUTYH), leading to mutation accumulation and promoting the progression of DTT (Vodicka et al., 2020). In gastrointestinal cells, lipid peroxidation damages mitochondrial membranes, lowering mitochondrial membrane potential and impairing electron transport chain function, thereby reducing energy supply (Zheng et al., 2025). Furthermore, growing evidence highlights the central role of cardiolipin in mitochondrial regulation, including the assembly of complexes III and IV and the maintenance of cristae architecture. However, cardiolipin’s conical geometry and specific localization to negatively curved membranes render it highly susceptible to oxidative modification, resulting in mitochondrial dysfunction (El-Hafidi et al., 2020). In addition, ROS also induces carbonylation of protein side chains, leading to enzyme inactivation and structural protein denaturation. Consequently, antioxidant enzyme activities in the gastrointestinal mucosa (e.g., superoxide dismutase and catalase) are suppressed, promoting oxidant accumulation and exacerbating tissue injury (Vona et al., 2021; Choudhary et al., 2022). Inflammation and oxidative stress form a vicious cycle: CKD-associated inflammation amplifies oxidative stress, which in turn enhances the release of inflammatory mediators. This cycle not only damages the kidneys but also accelerates the initiation and progression of DTT.
3.2 CKD-related metabolic alterations promote the development of DTTMetabolic factors associated with CKD, including uremic toxin accumulation, disordered vitamin D (VD) metabolism, mineral metabolism disturbances, and CKD-specific dietary patterns, collectively contribute, to varying degrees, to the initiation and progression of DTT (Figure 2). Declining renal function in CKD frequently leads to the buildup of uremic toxins. These intestinal uremic toxins alter the gut microenvironment and promote dysbiosis in CKD patients. Characteristically, dysbiosis involves an expansion of aerobic bacterial strains, which drives the production of three major uremic toxins: p-cresol, p-cresyl sulfate, and indoxyl sulfate (Ramezani and Raj, 2014; Di et al., 2023). Notably, Ichisaka et al. linked CKD progression to worsening CRC. Treating HCT-116 CRC cells with indoxyl sulfate for 24 h elevated c-Myc protein levels and promoted cell proliferation via activation of the Akt/β-catenin/c-Myc signaling pathway (Ichisaka et al., 2025). In addition, experiments have shown that indoxyl sulfate significantly enhances the proliferation ability of CRC cells at concentrations exceeding 62.5 µ M, which is inhibited by the aryl hydrocarbon receptor (AhR) antagonist CH223191, demonstrating the direct role of the AhR/c-Myc signaling pathway in proliferation (Ichisaka et al., 2025; Ichisaka et al., 2024). These findings indicate that uremic toxins play a critical mediating role in the CKD–CRC axis and highlight them as potential therapeutic targets in CKD. Furthermore, dysbiosis induced by CKD-related uremic toxin accumulation undermines anti-tumor defenses and can directly compromise genomic stability through multiple mechanisms, including depletion of protective metabolites (e.g., short-chain fatty acids, SCFAs), induction of oxidative DNA damage, mutations in key genes (e.g., APC or KRAS), and activation of oncogenic signaling pathways (e.g., NF-κB) (Kuru-Yaşar and Üstün-Aytekin, 2024; García et al., 2024; Li Y. et al., 2024), thereby promoting DTT.
Metabolic alterations in CKD drive the development of DTT. CKD–related metabolic alterations, including the accumulation of uremic toxins, disrupted VD metabolism, mineral metabolism disorders, and CKD-specific dietary practices, collectively contribute, to varying degrees, to the initiation and progression of DTT. Intestinal uremic toxins, notably p-cresol, p-cresyl sulfate, and indoxyl sulfate, reshape the gut microenvironment, promote dysbiosis, weaken anti-tumor defenses, and may directly compromise genomic stability, while simultaneously depleting protective metabolites such as SCFAs. Perturbations in VD metabolism further undermine gastrointestinal homeostasis by impairing epithelial integrity, dysregulating anti-inflammatory immune responses, and permitting aberrant cellular proliferation. In parallel, mineral disorders characterized by hyperphosphatemia, hypocalcemia, and elevated PTH indirectly accelerate DTT progression, and increased FGF23 has been implicated as a meaningful marker for CRC diagnosis and screening. Additionally, dietary regimens common in CKD care (low potassium, low phosphorus, and protein restriction) may influence DTT risk via altered nutrient intake and absorption; notably, the relationship between phosphorus intake and DTT risk remains to be clarified and warrants further investigation. Collectively, these CKD-associated metabolic disturbances appear to partially drive the development of DTT. CKD, chronic kidney disease; DTT, digestive tract tumor; CRC, colorectal cancer; VD, vitamin D; SCFAs, short-chain fatty acids; PTH, parathyroid hormone; FGF23, fibroblast growth factor 23 (By Figdraw).
In addition, VD plays a critical role in maintaining intestinal epithelial integrity, modulating immune responses (predominantly anti-inflammatory), and suppressing aberrant cellular proliferation. Patients with CKD frequently present with VD deficiency (<20 ng/mL) or insufficiency (20–29 ng/mL) (Jean et al., 2017). Impaired renal function diminishes the conversion of 25-hydroxyvitamin D to its active metabolite, 1,25-dihydroxyvitamin D, resulting in reduced circulating levels of active VD (Tang et al., 2025). Active VD binds the vitamin D receptor (VDR) in intestinal epithelial cells to regulate the expression of tight junction proteins, such as occludin and claudins, thereby preserving mucosal barrier integrity and permeability (Assa et al., 2015; Yang et al., 2024). In states of deficiency, this barrier is compromised; translocation of bacteria and endotoxins across the mucosa exacerbates chronic inflammation and elevates cancer risk. In a cross-sectional study, Kwak et al. reported that sufficient VD levels were associated with a reduced risk of Helicobacter pylori infection, a major etiological factor for GC (Kwak and Paik, 2020). Furthermore, using CRC mouse models and clinical serum samples, Zhou et al. showed that VD supplementation improved disease indices and inhibited CRC initiation and progression. Their work also highlighted VD’s key regulatory role in maintaining colonic barrier integrity via gut probiotics and A. muciniphila (Zhou et al., 2020). Notably, some researchers found that VDR-deficient mouse models exhibited reduced colonic expression of the barrier protein claudin-5, along with significantly increased levels of the proliferation marker PCNA (proliferating cell nuclear antigen), compared with controls (Zhang et al., 2022; Sun and Zhang, 2022). In addition, the VD/VDR signaling axis also helps regulate gut microbial homeostasis and promotes colonization by probiotics such as Bifidobacterium and Lactobacillus (Sharma et al., 2023). Consequently, CKD-associated reductions in probiotic diversity, together with a loss of SCFA-producing taxa (Zeb et al., 2025), further impair the epithelial barrier, amplify inflammation, and foster a tumor-promoting microenvironment.
Moreover, disturbances in mineral metabolism, specifically hyperphosphatemia, hypocalcemia, and elevated parathyroid hormone (PTH), are important drivers of DTT in patients with CKD. Previous studies have shown that elevated phosphate stimulates secretion of fibroblast growth factor 23 (FGF23) (Vogt et al., 2019; Zhou W. et al., 2023; Hamid et al., 2024). High circulating FGF23 has been implicated, particularly in CRC, as a clinically relevant factor for diagnosis and screening, and may promote carcinogenesis by enhancing inflammation and angiogenesis or by directly stimulating epithelial cell proliferation (Wang et al., 2014). Additionally, phosphate excess and calcium deficiency also trigger PTH release (Ketteler et al., 2025). Hyperparathyroidism states may increase cancer risk indirectly by modulating calcium-dependent signaling, including the Wnt/β-catenin pathway, or by promoting cellular proliferation (Wang W. et al., 2019; Takeda et al., 2017; Zhang K. et al., 2019). Notably, Jacklyn N. Hellwege and colleagues evaluated the joint effects of VD deficiency and PTH responsiveness on CRC risk in a prospective cohort. Under VD deficiency, PTH hypo-responsivity was associated with a 2.56-fold increase in CRC risk, whereas PTH hyperresponsiveness conferred only a non-significant 1.65-fold increase (Hellwege et al., 2021). These findings suggest that the combined VD–PTH status may represent a potential biomarker.
Distal to renal pathology, dietary management strategies for CKD, including low-potassium, low-phosphorus, and protein-restricted regimens, also appear to be associated with DTT. Clinicians commonly advise patients to limit potassium-rich fruits and vegetables (e.g., bananas, oranges, tomatoes, spinach, potatoes), which are rich in dietary fiber and antioxidants such as vitamin C and carotenoids. Such restrictions may reduce fiber intake and decrease consumption of antioxidant vitamins and phytochemicals. Evidence suggests that inadequate fiber intake is a significant risk factor for DTT, particularly CRC (Gianfredi et al., 2018; Cifuentes and O'Keefe, 2024). By lowering the inflammatory potential of the diet, as reflected in reduced E-DII (Energy-adjusted Dietary Inflammatory Index) scores, fiber may attenuate CRC-related Wnt signaling activity and thereby inhibit CRC progression (Malcomson et al., 2021). Besides, antioxidant vitamins (A, C, and E) and phytochemicals (e.g., polyphenols and carotenoids) further contribute by neutralizing free radicals and enhancing DNA repair (Fenech et al., 2023). Multiple studies reported that vitamins and polyphenols significantly lowered the oxidative stress biomarker 8-OHdG (El et al., 2023; Ilari et al., 2025; Tratenšek et al., 2024), which may indirectly reduce cancer risk. High-phosphorus foods such as dairy products and nuts are likewise often limited. However, a recent cross-sectional study observed an inverse association between phosphorus intake and CRC risk (Qin et al., 2025). In contrast, Ye et al. demonstrated in a CKD rat model that high-phosphorus feeding induces detrimental alterations in the gut microbiota and adversely affects long-term health outcomes (Ye et al., 2021). Taken together, the relationship between dietary phosphorus and DTT risk remains inconsistent across populations and disease stages, particularly in CKD; high-quality CKD-specific prospective data are needed. Protein intake is also commonly restricted to reduce renal workload and the generation of uremic toxins. To meet energy and essential amino acid requirements under such constraints, some patients may rely more heavily on animal protein, particularly red and processed meats. Yet high consumption of these foods is a well-established risk factor for CRC (Ungvari et al., 2025). Quantitatively, Knuppel et al. reported that each 50 g increment in red meat intake confers an approximately 36% higher CRC risk (HR 1.36, 95% CI: 1.13–1.64) (Knuppel et al., 2020). Collectively, CKD-related metabolic and dietary changes may promote DTT progression through multiple pathways, while simultaneously revealing potential opportunities to manage DTT through intervention in CKD. Notably, most mechanistic data derive from preclinical models; prospective human studies integrating inflammatory and metabolic biomarkers are needed to validate causality and therapeutic targets in CKD-associated GC/CRC.
3.3 Dialysis and kidney transplantation further increase the riskDialysis is a non-physiologic intervention in which blood contacts bioincompatible membranes and dialysate components, repeatedly activating the immune system and triggering the release of inflammatory cytokines, including IL-1β, IL-6, and TNF-α (Chang et al., 2020). Dialysis may also induce an acquired immunodeficiency, reflected by abnormal monocyte activation driven by dialysis membranes and dialysate (Carracedo et al., 2002). Despite this, cellulose membranes, particularly cellulose acetate derivatives, remain widely used in clinical practice because of their favorable biocompatibility and distinctive advantages for heparin-free dialysis (Puerta et al., 2025; Ragab et al., 2023). Evidence indicated that monocyte exposure to cellulose dialysis membranes promoted robust IL-1β and TNF-α release in vivo and in vitro, fostering persistent low-grade inflammation. Meanwhile, repeated activation yields a CD14+CD32+ senescent phenotype and marked telomere shortening in monocytes; during dialysis, complement activation and trace bacterial endotoxin residues further exacerbate monocyte dysfunction (Carracedo et al., 2002; Paul et al., 2022). Collectively, these alterations blunt acute stress immune responses while enhancing the release of pro-tumorigenic factors, thereby increasing cancer risk. Notably, in polysulfone-based dialysis sessions, Vassilios Liakopoulos and colleagues reported a skewing of monocyte subsets in HD patients toward pro-inflammatory CD16+ Mo2 and Mo3 populations. They also observed significantly reduced CX3CR1 expression (receptors that promote monocyte migration) in Mo2/Mo3 subsets, specifically to approximately 0.7-fold of the level in healthy controls, with further downregulation post-dialysis. Additionally, leukocyte adhesive capacity was diminished after dialysis compared with pre-dialysis. These findings, however, derive from a relatively small cohort (n = 15) and warrant confirmation in larger studies (Liakopoulos et al., 2018).
Post-transplant immunosuppression is widely recognized to facilitate the development of multiple cancers. Immunosuppressive agents diminish T-cell and natural killer (NK) cell activity, impairing immune surveillance; for instance, this can predispose to Epstein–Barr virus (EBV) infection and subsequent lymphoepithelioma-like gastric carcinoma (Hirabayashi et al., 2023). Immunosuppressants may also exert direct mutagenic effects. Using comet and micronucleus assays, Cilião et al. evaluated DNA instability
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