Stage-dependent rise of maresin 1 in pediatric chronic renal failure: Toward a novel diagnostic and therapeutic target

Stage-dependent rise of maresin 1 in pediatric chronic renal failure: Toward a novel diagnostic and therapeutic target | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Stage-dependent rise of maresin 1 in pediatric chronic renal failure: Toward a novel diagnostic and therapeutic target Muhammet Akif Guler, Muhammet Celik, Hamza Halici, Zafer Bayraktutan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8333931/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Chronic renal failure (CRF) in children is characterized by persistent inflammation and oxidative stress, contributing to progressive loss of renal function and multisystem involvement. Maresin 1 (MaR1), a specialized pro-resolving lipid mediator derived from docosahexaenoic acid (DHA), plays a role in the resolution of inflammation and tissue repair. However, its circulating concentrations in pediatric CRF have not been examined. This study aimed to determine serum MaR1 levels across CRF stages in children and to assess its potential relevance as a biomarker reflecting disease severity. Methods Children were categorized as healthy controls or assigned to CRF stages 1–5 according to estimated glomerular filtration rate (eGFR). Serum MaR1 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Group comparisons were performed using one-way ANOVA with Tukey’s post-hoc test (p < 0.05). Results Serum MaR1 levels differed significantly among the six groups (p < 0.001). Compared with healthy controls (≈ 110 ± 15 pg/mL), levels were substantially reduced in CRF stages 1–3 (25–70 pg/mL). In contrast, MaR1 concentrations increased in advanced stages, with marked elevations in stage 4 (≈ 200 ± 20 pg/mL) and stage 5 (≈ 300 ± 30 pg/mL). Conclusions Serum MaR1 concentrations show a stage-dependent, biphasic pattern in pediatric CRF, with suppression in early disease and elevation in advanced stages. These findings suggest that MaR1 may reflect underlying inflammatory dynamics in CRF and could merit further investigation as a potential biomarker and therapeutic target. Maresin 1 Chronic renal failure Pediatric nephrology Figures Figure 1 Introductıon The kidneys play a central role in maintaining internal homeostasis and supporting normal growth in children. Consequently, pediatric renal disorders require specialized diagnostic and therapeutic frameworks. Despite this need, healthcare systems in many regions remain under-resourced, contributing to delayed diagnosis and suboptimal management of chronic kidney disease (CKD) in children [ 1 , 2 ]. Chronic renal failure (CRF) has emerged as a major global cause of pediatric morbidity and mortality [ 3 ]. Its prevalence varies geographically and is largely shaped by congenital anomalies of the kidney and urinary tract (CAKUT), hereditary nephropathies, and glomerulonephritis [ 4 ]. In low- and middle-income settings, late presentation is common, with many children first evaluated at end-stage renal disease (ESRD) [ 5 ]. Accurate staging of CRF through estimated or measured glomerular filtration rate (GFR) remains fundamental for assessing disease severity, monitoring complications, and guiding therapy [ 6 ]. Although CRF encompasses diverse etiologies, inflammation represents a unifying pathogenic mechanism. Systemic inflammation and oxidative stress are well-established hallmarks of CRF and intensify progressively with renal function decline. 7 Persistent immune activation—driven by uremic toxin accumulation, cytokine excess, oxidative stress, and impaired immune regulation—creates a chronic low-grade inflammatory milieu that promotes tubulointerstitial fibrosis, glomerular ischemia, and ongoing nephron loss. 7 In children, this chronic inflammatory state contributes to impaired growth, anemia, bone–mineral disturbances, protein–energy wasting (PEW), and accelerated cardiovascular risk [ 7 , 8 ]. Pro-inflammatory mediators such as IL-6, TNF-α, and high-sensitivity C-reactive protein (hsCRP) correlate strongly with GFR decline and cardiovascular events [ 7 , 9 ]. Multiple immune pathways and immune cell subsets contribute both to inflammatory activation and to the fibrotic progression characteristic of advanced CRF [ 10 ]. Up to half of adults with stage 5 CRF display evidence of inflammatory activation even prior to dialysis initiation [ 11 , 12 ], and this inflammatory burden may worsen with hemodialysis(HD) or peritoneal dialysis(PD) due to membrane bio-incompatibility, oxidative stress, and infectious complications [ 13 ]. Chronic inflammation is a major predictor of mortality in dialysis populations [ 14 ]. Among upstream inflammatory regulators, the IL-1β/IL-18 axis plays a particularly important role. Elevated IL-18 concentrations correlate with monocyte chemoattractant protein-1 (MCP-1) levels, which are independently associated with reduced GFR and progressive vascular injury [ 14 , 15 ]. Beyond classical inflammatory mediators, a growing body of interest surrounds specialized pro-resolving mediators (SPMs)—lipid-derived autacoids that actively orchestrate the resolution phase of inflammation. Maresins, biosynthesized from omega-3 fatty acids, are among the most potent SPM families [ 16 , 17 ]. Maresin 1 (MaR1; 7,14-dihydroxydocosahexaenoic acid) is produced in macrophages through the 12-lipoxygenase (12-LOX) pathway, generating the intermediates 14S-hydroperoxy-DHA and 13S,14S-epoxy-maresin prior to conversion into MaR1 [ 1 ]. MaR1 exerts pleiotropic anti-inflammatory and tissue-regenerative actions, including reducing neutrophil infiltration, enhancing macrophage efferocytosis, promoting tissue repair, and attenuating inflammatory pain [ 16 , 17 , 19 ]. In contrast to steroids or NSAIDs, SPMs—including MaR1—resolve inflammation without inducing global immunosuppression, presenting a favorable therapeutic profile [ 20 ]. Experimental evidence indicates that MaR1 is renoprotective across diverse models of kidney injury. In acute kidney injury, MaR1 attenuates neutrophil-driven renal inflammation and accelerates tissue recovery [ 21 ]. In diabetic nephropathy, MaR1 reduces reactive oxygen species (ROS) generation, suppresses NLRP3 inflammasome activation, and downregulates IL-1β expression [ 22 ]. In ischemia–reperfusion injury, MaR1 protects renal tissue by inhibiting TLR4-mediated MAPK signaling cascades [ 23 ]. Taken together, these data suggest that MaR1 may function as an important endogenous mediator modulating inflammation, oxidative stress, and fibrosis. However, circulating MaR1 levels have not been systematically studied in pediatric CRF, and the stage-dependent behavior of MaR1 remains unknown. Considering the central role of chronic inflammation in CRF, we aimed to investigate serum MaR1 levels across the full spectrum of pediatric CRF. Establishing this relationship may identify MaR1 as a candidate diagnostic biomarker and a novel therapeutic target for resolution-based intervention strategies. Methods Study Design and Setting This prospective, controlled, cross-sectional study was conducted in the pediatric nephrology departments of a university hospital and a state hospital. Approval was obtained from the Local Ethics Committee of Atatürk University Faculty of Medicine. Study Population A total of 90 children aged 24–220 months were enrolled and distributed into six groups: five CRF groups categorized according to the Kidney Disease: Improving Global Outcomes (KDIGO) pediatric staging system (stages 1–5) and one control group of healthy children with similar demographic characteristics. Each group consisted of 15 participants. Exclusion Criteria Exclusion criteria included: acute infection or inflammatory disease; receipt of steroids or immunosuppressants within the preceding three months; presence of another chronic illness; and lack of parental consent or subsequent withdrawal of consent. Data Collection and Laboratory Measurements Clinical and laboratory data—including age, sex, past medical history, serum creatinine, serum electrolytes, and serum MaR1 levels—were recorded for all participants. Serum samples were obtained at random time points in controls and in CRF patients not requiring dialysis. For patients undergoing hemodialysis, blood sampling occurred 48 hours after the last dialysis session, immediately before the subsequent session. For MaR1 measurement, venous blood was collected into biochemical tubes, allowed to clot for 10–20 minutes, and centrifuged at + 4°C for 10 minutes at 4,500 rpm. Serum aliquots were stored at − 80°C until analysis. MaR1 concentrations were determined using a commercially available ELISA kit (Human Maresin 1 ELISA Kit, YL Biont, Cat. No. YLA4082HU, China), following the manufacturer’s instructions. Sample Size Calculation Assuming a medium effect size (Cohen, 2013), an alpha level of 0.05, and 80% power, a total sample size of 90 participants was deemed sufficient for within-group and between-group comparisons (G*Power 3.1). Statistical Analysis Statistical analyses were conducted using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were presented as frequency (n), percentage (and mean ± standard deviation. Normality was assessed using the Shapiro–Wilk test and Q–Q plots. As the data were normally distributed, group comparisons were performed using one-way analysis of variance (ANOVA), followed by Tukey’s HSD test for post hoc analyses. A p-value < 0.05 was considered statistically significant. Artificial Intelligence Disclosure: ChatGPT (OpenAI) was used to support clarity and improve grammar during the writing of this article. No content, analysis, or interpretation was generated by AI. Results No significant differences were observed among the six groups in median age or sex distribution (p = 0.999 and p = 0.922, respectively) (Table 1 ). All patients in CRF stage 5 were receiving hemodialysis every other day; none of the other CRF groups required dialysis. Table 1 Demographic characteristics of the groups. Group Age (months) Median ± SE Gender (F/M) (n) Healthy 91 ± 17.63 7/8 CRF-Stage1 96 ± 17.91 8/7 CRF-Stage2 90 ± 17.72 6/9 CRF-Stage3 88 ± 17.86 8/7 CRF-Stage4 85 ± 17.47 9/6 CRF-Stage5 94 ± 17.62 8/7 F: Female, M: Male, SE: Standard error,Age: No significant difference among groups (Kruskal–Wallis, p = 0.999), Gender: No significant difference among groups (Chi-square test, p = 0.922) Serum MaR1 levels displayed a significant stage-dependent pattern (p < 0.05). Compared with healthy controls, MaR1 levels were markedly reduced in CRF stages 1–3, with stage 1 exhibiting the lowest values. Beginning at stage 3, MaR1 levels increased progressively, reaching the highest concentrations in stage 5. Pairwise comparisons confirmed significant differences between all stages (Fig. 1 ). Overall, MaR1 demonstrated a biphasic distribution: an initial decline in early CRF followed by a pronounced increase in advanced stages. Discussion In this study, we evaluated serum MaR1 concentrations across different stages of pediatric CRF and identified a distinct stage-dependent, biphasic pattern. MaR1 levels were significantly suppressed in early CRF (stages 1–3) and progressively elevated in later stages (stages 4–5). These findings provide new insight into the dynamic interplay between inflammatory activation and resolution pathways in pediatric CRF. CRF is characterized by persistent low-grade inflammation and oxidative stress extending beyond the kidney, contributing to systemic metabolic and cardiovascular complications [ 24 , 25 ]. The inflammatory cascade begins early and is sustained by interactions among uremic toxins, dysregulated cytokine signaling, intestinal dysbiosis, and oxidative stress [ 26 , 27 ]. Elevated cytokines—including IL-1β, IL-6, TNF-α, and MCP-1—promote endothelial dysfunction, vascular calcification, and tubulointerstitial fibrosis. Proteinuria is a major prognostic marker in CRF [ 28 ]. Even asymptomatic proteinuria is associated with early endothelial activation [ 29 ]. Persistent proteinuria triggers podocyte expression of TGF-β, promoting epithelial and mesangial cell transdifferentiation into fibroblasts and stimulating extracellular matrix (ECM) production [ 19 , 30 ]. Additional factors—albuminuria, complement activation, cytokine leakage, and hypoxia from endothelial dysfunction—further intensify tubular inflammation [ 31 – 33 ]. Early Decline in MaR1 The observed reduction in MaR1 levels in early CRF likely reflects impaired resolution mechanisms under conditions of heightened inflammatory stress. Sustained elevations of IL-1β, IL-6, and TNF-α, together with oxidative stress, favor M1 macrophage polarization and prolonged NF-κB activation, limiting the M2 phenotype and reducing MaR1 synthesis [ 15 , 26 ]. This failure of intrinsic resolution may allow unchecked inflammation and accelerate nephron injury. Later Elevation in MaR1 In advanced CRF, chronic inflammation becomes intertwined with fibrosis, driven largely by TGF-β/SMAD2/3 signaling [ 34 , 36 ]. Partial macrophage repolarization and feedback activation of lipid mediator synthesis may contribute to the rise in MaR1 observed in stages 4–5. Experimental studies demonstrate that MaR1 attenuates renal fibrosis by inhibiting SMAD phosphorylation, reducing collagen I and fibronectin expression, and suppressing epithelial-to-mesenchymal transition [ 23 , 37 ]. MaR1 also downregulates NLRP3 inflammasome activation, reduces oxidative stress, and modulates MAPK pathways [ 37 , 38 ]. Thus, elevated MaR1 levels in late CRF may represent a compensatory attempt to counterbalance persistent inflammation and fibrosis. Nrf2–MaR1 Interaction Recent evidence highlights a critical role for the Nrf2 pathway in renal pathophysiology [ 39 – 45 ]. Reduced Nrf2 expression and increased NF-κB activity have been observed in advanced CRF [ 46 ]. Nrf2 deficiency enhances ROS generation, DNA damage, inflammation, and fibrosis, whereas activation of Nrf2 signaling mitigates renal injury [ 46 – 48 ]. Emerging data suggest that MaR1 activates Nrf2 signaling, thereby enhancing antioxidant defenses and attenuating inflammation [ 49 , 50 ]. MaR1 also modulates cytokine production, reduces fibrosis, and restores redox balance through interactions with NF-κB and TGF-β pathways [ 51 – 53 ]. These findings support a cooperative relationship between MaR1 and Nrf2 that may become more prominent in advanced CRF. Interpretation Taken together, our findings indicate that MaR1 exhibits a dual, stage-dependent role in pediatric CRF: early suppression is associated with unchecked inflammatory signaling, whereas later elevation reflects compensatory activation of anti-inflammatory and antifibrotic pathways. This biphasic behavior underscores a transition from a predominantly pro-inflammatory state to a chronic, partially resolution-driven phase. Conclusion Serum MaR1 levels demonstrate a striking biphasic pattern across pediatric CRF stages—suppressed in early disease and elevated in advanced stages. Dominant inflammatory signaling likely suppresses MaR1 production in early CRF, whereas progressive inflammation and fibrosis in later stages may trigger compensatory activation of MaR1-mediated resolution pathways. These findings suggest that MaR1 may serve both as a biomarker for CRF staging and as a potential therapeutic target for resolution-based interventions. Limitations This study has several limitations that should be considered when interpreting the results. First, the relatively modest sample size, particularly within individual CKD stages, may limit statistical power and the generalizability of the findings. This constraint is partly inherent to pediatric CKD research, given the heterogeneity of disease etiologies and the limited availability of well-characterized patient cohorts. Second, the cross-sectional design precludes definitive conclusions regarding causality or temporal relationships. Although the observed suppression of Maresin-1 in early CKD stages and its elevation in advanced stages suggest a stage-dependent regulatory pattern, longitudinal studies are needed to determine whether these changes represent adaptive, compensatory, or disease-driven mechanisms during CKD progression. In addition, potential confounding factors, including medication use, nutritional status, and residual renal function, could not be fully controlled and may have influenced circulating Maresin-1 levels. Despite these limitations, this study provides the first clinical evidence of stage-dependent alterations in Maresin-1 in pediatric CKD, supporting its potential role as both a biomarker and a mechanistically relevant mediator of disease progression. Abbreviations AKI : Acute kidney injury ANOVA : Analysis of variance CAKUT : Congenital anomalies of the kidney and urinary tract CKD : Chronic kidney disease CRF : Chronic renal failure DHA : Docosahexaenoic acid ECM : Extracellular matrix eGFR : Estimated glomerular filtration rate ELISA : Enzyme-linked immunosorbent assay ESRD : End-stage renal disease GFR : Glomerular filtration rate HD : Hemodialysis hsCRP : High-sensitivity C-reactive protein IL : Interleukin IL-1β : Interleukin-1 beta IL-6 : Interleukin-6 LOX : Lipoxygenase MaR1 : Maresin 1 MAPK : Mitogen-activated protein kinase MCP-1 : Monocyte chemoattractant protein-1 NLRP3 : NOD-like receptor family pyrin domain-containing 3 NF-κB : Nuclear factor kappa-light-chain-enhancer of activated B cells NSAIDs : Non-steroidal anti-inflammatory drugs Nrf2 : Nuclear factor erythroid 2–related factor 2 PD : Peritoneal dialysis PEW : Protein–energy wasting ROS : Reactive oxygen species SMAD : Mothers against decapentaplegic homolog (SMAD2/3 signaling pathway) SPM : Specialized pro-resolving mediator TGF-β : Transforming growth factor-beta Declarations Author contributions Conceptualization, investigation, visualization, project administration and writing: Muhammet Akig Guler; writing - review & editing: Halil Keskin (Both Muhammet Akig Guler and Halil Keskin contributed equally to this work as co-first authors); methodology and investigation: Muhammet Celik and Zafer Bayraktutan; software and validation, data curation, conceptualization, supervision: Hamza Halici, Emir Enis Yurdgulu and Yusuf Anil Ay; funding acquisition: All authors. All authors read and approved the final manuscript. Funding The authors did not receive any financial support for the research, authorship, or publication of this article. Data availability The raw datasets analyzed in this study are available from the corresponding author upon reasonable request and with permission from the institutional review board. Ethics approval and consent to participate This prospective, controlled, cross-sectional study was conducted in accordance with the Declaration of Helsinki and approved by the Local Ethics Committee of Atatürk University Faculty of Medicine (Approval No: B.30.2.ATA.0.01.00/639). Written informed consent to participate was obtained from the parents or legal guardians of all patients. Consent for publication Not applicable. Conflicts of interest The authors declare no conflicts of interest relevant to this study. References Wise PH. The Future Pediatrician: The Challenge of Chronic Illness. 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University","correspondingAuthor":false,"prefix":"","firstName":"Muhammet","middleName":"","lastName":"Celik","suffix":""},{"id":571522124,"identity":"e316b192-de74-4d24-8206-25356823f921","order_by":2,"name":"Hamza Halici","email":"","orcid":"","institution":"Ataturk University","correspondingAuthor":false,"prefix":"","firstName":"Hamza","middleName":"","lastName":"Halici","suffix":""},{"id":571522125,"identity":"e6971a68-eabd-45e8-becf-ab3e1ed55528","order_by":3,"name":"Zafer Bayraktutan","email":"","orcid":"","institution":"Ataturk University","correspondingAuthor":false,"prefix":"","firstName":"Zafer","middleName":"","lastName":"Bayraktutan","suffix":""},{"id":571522126,"identity":"b63fc00a-44fc-4f15-8277-6ec036f50932","order_by":4,"name":"Emir Enis Yurdgulu","email":"","orcid":"","institution":"Ataturk 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07:12:58","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":105741,"visible":true,"origin":"","legend":"","description":"","filename":"09ff9762244241c1b5b526cdff6837281structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8333931/v1/5124594e572c5fe9e4a20025.xml"},{"id":100017874,"identity":"b0263fc4-82db-46b4-97b8-e8b06c64eac5","added_by":"auto","created_at":"2026-01-12 07:12:58","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":119778,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8333931/v1/abd79391ca5517ccebe837c8.html"},{"id":100017868,"identity":"0ca1948a-40d8-433e-b6f1-5345dbf8ef3e","added_by":"auto","created_at":"2026-01-12 07:12:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":186799,"visible":true,"origin":"","legend":"\u003cp\u003eSerum maresin 1 levels Results are presented as mean ± standard deviation. Tukey's post hoc test was applied to the one-way ANOVA tests. Different letters on the graph indicate statistically significant differences (p\u0026lt;0.05). The same letters indicate no statistically significant differences (p\u0026gt;0.05). (CRF: chronic renal failure)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8333931/v1/abf0a8b4cafdf7ed8d730e2c.png"},{"id":100381264,"identity":"fcf4e237-1fac-4220-b028-1d8d1c662fa6","added_by":"auto","created_at":"2026-01-16 10:37:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":833987,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8333931/v1/a02316b5-f308-44ba-a6d0-6bb35d28fac6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Stage-dependent rise of maresin 1 in pediatric chronic renal failure: Toward a novel diagnostic and therapeutic target","fulltext":[{"header":"Introductıon","content":"\u003cp\u003eThe kidneys play a central role in maintaining internal homeostasis and supporting normal growth in children. Consequently, pediatric renal disorders require specialized diagnostic and therapeutic frameworks. Despite this need, healthcare systems in many regions remain under-resourced, contributing to delayed diagnosis and suboptimal management of chronic kidney disease (CKD) in children [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eChronic renal failure (CRF) has emerged as a major global cause of pediatric morbidity and mortality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Its prevalence varies geographically and is largely shaped by congenital anomalies of the kidney and urinary tract (CAKUT), hereditary nephropathies, and glomerulonephritis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In low- and middle-income settings, late presentation is common, with many children first evaluated at end-stage renal disease (ESRD) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Accurate staging of CRF through estimated or measured glomerular filtration rate (GFR) remains fundamental for assessing disease severity, monitoring complications, and guiding therapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough CRF encompasses diverse etiologies, inflammation represents a unifying pathogenic mechanism. Systemic inflammation and oxidative stress are well-established hallmarks of CRF and intensify progressively with renal function decline.\u003csup\u003e7\u003c/sup\u003e Persistent immune activation\u0026mdash;driven by uremic toxin accumulation, cytokine excess, oxidative stress, and impaired immune regulation\u0026mdash;creates a chronic low-grade inflammatory milieu that promotes tubulointerstitial fibrosis, glomerular ischemia, and ongoing nephron loss.\u003csup\u003e7\u003c/sup\u003e In children, this chronic inflammatory state contributes to impaired growth, anemia, bone\u0026ndash;mineral disturbances, protein\u0026ndash;energy wasting (PEW), and accelerated cardiovascular risk [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePro-inflammatory mediators such as IL-6, TNF-α, and high-sensitivity C-reactive protein (hsCRP) correlate strongly with GFR decline and cardiovascular events [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Multiple immune pathways and immune cell subsets contribute both to inflammatory activation and to the fibrotic progression characteristic of advanced CRF [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Up to half of adults with stage 5 CRF display evidence of inflammatory activation even prior to dialysis initiation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and this inflammatory burden may worsen with hemodialysis(HD) or peritoneal dialysis(PD) due to membrane bio-incompatibility, oxidative stress, and infectious complications [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Chronic inflammation is a major predictor of mortality in dialysis populations [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong upstream inflammatory regulators, the IL-1β/IL-18 axis plays a particularly important role. Elevated IL-18 concentrations correlate with monocyte chemoattractant protein-1 (MCP-1) levels, which are independently associated with reduced GFR and progressive vascular injury [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBeyond classical inflammatory mediators, a growing body of interest surrounds specialized pro-resolving mediators (SPMs)\u0026mdash;lipid-derived autacoids that actively orchestrate the resolution phase of inflammation. Maresins, biosynthesized from omega-3 fatty acids, are among the most potent SPM families [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Maresin 1 (MaR1; 7,14-dihydroxydocosahexaenoic acid) is produced in macrophages through the 12-lipoxygenase (12-LOX) pathway, generating the intermediates 14S-hydroperoxy-DHA and 13S,14S-epoxy-maresin prior to conversion into MaR1 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMaR1 exerts pleiotropic anti-inflammatory and tissue-regenerative actions, including reducing neutrophil infiltration, enhancing macrophage efferocytosis, promoting tissue repair, and attenuating inflammatory pain [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In contrast to steroids or NSAIDs, SPMs\u0026mdash;including MaR1\u0026mdash;resolve inflammation without inducing global immunosuppression, presenting a favorable therapeutic profile [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExperimental evidence indicates that MaR1 is renoprotective across diverse models of kidney injury. In acute kidney injury, MaR1 attenuates neutrophil-driven renal inflammation and accelerates tissue recovery [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In diabetic nephropathy, MaR1 reduces reactive oxygen species (ROS) generation, suppresses NLRP3 inflammasome activation, and downregulates IL-1β expression [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In ischemia\u0026ndash;reperfusion injury, MaR1 protects renal tissue by inhibiting TLR4-mediated MAPK signaling cascades [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTaken together, these data suggest that MaR1 may function as an important endogenous mediator modulating inflammation, oxidative stress, and fibrosis. However, circulating MaR1 levels have not been systematically studied in pediatric CRF, and the stage-dependent behavior of MaR1 remains unknown. Considering the central role of chronic inflammation in CRF, we aimed to investigate serum MaR1 levels across the full spectrum of pediatric CRF. Establishing this relationship may identify MaR1 as a candidate diagnostic biomarker and a novel therapeutic target for resolution-based intervention strategies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003eThis prospective, controlled, cross-sectional study was conducted in the pediatric nephrology departments of a university hospital and a state hospital. Approval was obtained from the Local Ethics Committee of Atat\u0026uuml;rk University Faculty of Medicine.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population\u003c/h3\u003e\n\u003cp\u003eA total of 90 children aged 24\u0026ndash;220 months were enrolled and distributed into six groups: five CRF groups categorized according to the Kidney Disease: Improving Global Outcomes (KDIGO) pediatric staging system (stages 1\u0026ndash;5) and one control group of healthy children with similar demographic characteristics. Each group consisted of 15 participants.\u003c/p\u003e\n\u003ch3\u003eExclusion Criteria\u003c/h3\u003e\n\u003cp\u003eExclusion criteria included: acute infection or inflammatory disease; receipt of steroids or immunosuppressants within the preceding three months; presence of another chronic illness; and lack of parental consent or subsequent withdrawal of consent.\u003c/p\u003e\n\u003ch3\u003eData Collection and Laboratory Measurements\u003c/h3\u003e\n\u003cp\u003eClinical and laboratory data\u0026mdash;including age, sex, past medical history, serum creatinine, serum electrolytes, and serum MaR1 levels\u0026mdash;were recorded for all participants.\u003c/p\u003e \u003cp\u003eSerum samples were obtained at random time points in controls and in CRF patients not requiring dialysis. For patients undergoing hemodialysis, blood sampling occurred 48 hours after the last dialysis session, immediately before the subsequent session.\u003c/p\u003e \u003cp\u003eFor MaR1 measurement, venous blood was collected into biochemical tubes, allowed to clot for 10\u0026ndash;20 minutes, and centrifuged at +\u0026thinsp;4\u0026deg;C for 10 minutes at 4,500 rpm. Serum aliquots were stored at \u0026minus;\u0026thinsp;80\u0026deg;C until analysis. MaR1 concentrations were determined using a commercially available ELISA kit (Human Maresin 1 ELISA Kit, YL Biont, Cat. No. YLA4082HU, China), following the manufacturer\u0026rsquo;s instructions.\u003c/p\u003e\n\u003ch3\u003eSample Size Calculation\u003c/h3\u003e\n\u003cp\u003eAssuming a medium effect size (Cohen, 2013), an alpha level of 0.05, and 80% power, a total sample size of 90 participants was deemed sufficient for within-group and between-group comparisons (G*Power 3.1).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were conducted using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were presented as frequency (n), percentage (and mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Normality was assessed using the Shapiro\u0026ndash;Wilk test and Q\u0026ndash;Q plots. As the data were normally distributed, group comparisons were performed using one-way analysis of variance (ANOVA), followed by Tukey\u0026rsquo;s HSD test for post hoc analyses. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eArtificial Intelligence Disclosure:\u003c/h3\u003e\n\u003cp\u003eChatGPT (OpenAI) was used to support clarity and improve grammar during the writing of this article. No content, analysis, or interpretation was generated by AI.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eNo significant differences were observed among the six groups in median age or sex distribution (p\u0026thinsp;=\u0026thinsp;0.999 and p\u0026thinsp;=\u0026thinsp;0.922, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All patients in CRF stage 5 were receiving hemodialysis every other day; none of the other CRF groups required dialysis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of the groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (months) Median\u0026thinsp;\u0026plusmn;\u0026thinsp;SE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGender (F/M) (n)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHealthy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e91\u0026thinsp;\u0026plusmn;\u0026thinsp;17.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7/8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRF-Stage1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e96\u0026thinsp;\u0026plusmn;\u0026thinsp;17.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRF-Stage2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e90\u0026thinsp;\u0026plusmn;\u0026thinsp;17.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRF-Stage3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e88\u0026thinsp;\u0026plusmn;\u0026thinsp;17.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRF-Stage4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e85\u0026thinsp;\u0026plusmn;\u0026thinsp;17.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRF-Stage5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e94\u0026thinsp;\u0026plusmn;\u0026thinsp;17.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eF: Female, M: Male, SE: Standard error,Age: No significant difference among groups (Kruskal\u0026ndash;Wallis, p\u0026thinsp;=\u0026thinsp;0.999), Gender: No significant difference among groups (Chi-square test, p\u0026thinsp;=\u0026thinsp;0.922)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSerum MaR1 levels displayed a significant stage-dependent pattern (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Compared with healthy controls, MaR1 levels were markedly reduced in CRF stages 1\u0026ndash;3, with stage 1 exhibiting the lowest values. Beginning at stage 3, MaR1 levels increased progressively, reaching the highest concentrations in stage 5. Pairwise comparisons confirmed significant differences between all stages (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOverall, MaR1 demonstrated a biphasic distribution: an initial decline in early CRF followed by a pronounced increase in advanced stages.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we evaluated serum MaR1 concentrations across different stages of pediatric CRF and identified a distinct stage-dependent, biphasic pattern. MaR1 levels were significantly suppressed in early CRF (stages 1\u0026ndash;3) and progressively elevated in later stages (stages 4\u0026ndash;5). These findings provide new insight into the dynamic interplay between inflammatory activation and resolution pathways in pediatric CRF.\u003c/p\u003e \u003cp\u003eCRF is characterized by persistent low-grade inflammation and oxidative stress extending beyond the kidney, contributing to systemic metabolic and cardiovascular complications [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The inflammatory cascade begins early and is sustained by interactions among uremic toxins, dysregulated cytokine signaling, intestinal dysbiosis, and oxidative stress [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Elevated cytokines\u0026mdash;including IL-1β, IL-6, TNF-α, and MCP-1\u0026mdash;promote endothelial dysfunction, vascular calcification, and tubulointerstitial fibrosis.\u003c/p\u003e \u003cp\u003eProteinuria is a major prognostic marker in CRF [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Even asymptomatic proteinuria is associated with early endothelial activation [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Persistent proteinuria triggers podocyte expression of TGF-β, promoting epithelial and mesangial cell transdifferentiation into fibroblasts and stimulating extracellular matrix (ECM) production [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Additional factors\u0026mdash;albuminuria, complement activation, cytokine leakage, and hypoxia from endothelial dysfunction\u0026mdash;further intensify tubular inflammation [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEarly Decline in MaR1\u003c/h2\u003e \u003cp\u003eThe observed reduction in MaR1 levels in early CRF likely reflects impaired resolution mechanisms under conditions of heightened inflammatory stress. Sustained elevations of IL-1β, IL-6, and TNF-α, together with oxidative stress, favor M1 macrophage polarization and prolonged NF-κB activation, limiting the M2 phenotype and reducing MaR1 synthesis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This failure of intrinsic resolution may allow unchecked inflammation and accelerate nephron injury.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eLater Elevation in MaR1\u003c/h2\u003e \u003cp\u003eIn advanced CRF, chronic inflammation becomes intertwined with fibrosis, driven largely by TGF-β/SMAD2/3 signaling [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Partial macrophage repolarization and feedback activation of lipid mediator synthesis may contribute to the rise in MaR1 observed in stages 4\u0026ndash;5. Experimental studies demonstrate that MaR1 attenuates renal fibrosis by inhibiting SMAD phosphorylation, reducing collagen I and fibronectin expression, and suppressing epithelial-to-mesenchymal transition [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. MaR1 also downregulates NLRP3 inflammasome activation, reduces oxidative stress, and modulates MAPK pathways [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Thus, elevated MaR1 levels in late CRF may represent a compensatory attempt to counterbalance persistent inflammation and fibrosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eNrf2\u0026ndash;MaR1 Interaction\u003c/h2\u003e \u003cp\u003eRecent evidence highlights a critical role for the Nrf2 pathway in renal pathophysiology [\u003cspan additionalcitationids=\"CR40 CR41 CR42 CR43 CR44\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Reduced Nrf2 expression and increased NF-κB activity have been observed in advanced CRF [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Nrf2 deficiency enhances ROS generation, DNA damage, inflammation, and fibrosis, whereas activation of Nrf2 signaling mitigates renal injury [\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEmerging data suggest that MaR1 activates Nrf2 signaling, thereby enhancing antioxidant defenses and attenuating inflammation [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. MaR1 also modulates cytokine production, reduces fibrosis, and restores redox balance through interactions with NF-κB and TGF-β pathways [\u003cspan additionalcitationids=\"CR52\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. These findings support a cooperative relationship between MaR1 and Nrf2 that may become more prominent in advanced CRF.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eInterpretation\u003c/h2\u003e \u003cp\u003eTaken together, our findings indicate that MaR1 exhibits a dual, stage-dependent role in pediatric CRF: early suppression is associated with unchecked inflammatory signaling, whereas later elevation reflects compensatory activation of anti-inflammatory and antifibrotic pathways. This biphasic behavior underscores a transition from a predominantly pro-inflammatory state to a chronic, partially resolution-driven phase.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSerum MaR1 levels demonstrate a striking biphasic pattern across pediatric CRF stages\u0026mdash;suppressed in early disease and elevated in advanced stages. Dominant inflammatory signaling likely suppresses MaR1 production in early CRF, whereas progressive inflammation and fibrosis in later stages may trigger compensatory activation of MaR1-mediated resolution pathways. These findings suggest that MaR1 may serve both as a biomarker for CRF staging and as a potential therapeutic target for resolution-based interventions.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis study has several limitations that should be considered when interpreting the results. First, the relatively modest sample size, particularly within individual CKD stages, may limit statistical power and the generalizability of the findings. This constraint is partly inherent to pediatric CKD research, given the heterogeneity of disease etiologies and the limited availability of well-characterized patient cohorts.\u003c/p\u003e \u003cp\u003eSecond, the cross-sectional design precludes definitive conclusions regarding causality or temporal relationships. Although the observed suppression of Maresin-1 in early CKD stages and its elevation in advanced stages suggest a stage-dependent regulatory pattern, longitudinal studies are needed to determine whether these changes represent adaptive, compensatory, or disease-driven mechanisms during CKD progression.\u003c/p\u003e \u003cp\u003eIn addition, potential confounding factors, including medication use, nutritional status, and residual renal function, could not be fully controlled and may have influenced circulating Maresin-1 levels. Despite these limitations, this study provides the first clinical evidence of stage-dependent alterations in Maresin-1 in pediatric CKD, supporting its potential role as both a biomarker and a mechanistically relevant mediator of disease progression.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eAKI\u003c/strong\u003e: Acute kidney injury\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eANOVA\u003c/strong\u003e: Analysis of variance\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCAKUT\u003c/strong\u003e: Congenital anomalies of the kidney and urinary tract\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCKD\u003c/strong\u003e: Chronic kidney disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRF\u003c/strong\u003e: Chronic renal failure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDHA\u003c/strong\u003e: Docosahexaenoic acid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eECM\u003c/strong\u003e: Extracellular matrix\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eeGFR\u003c/strong\u003e: Estimated glomerular filtration rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eELISA\u003c/strong\u003e: Enzyme-linked immunosorbent assay\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eESRD\u003c/strong\u003e: End-stage renal disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGFR\u003c/strong\u003e: Glomerular filtration rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHD\u003c/strong\u003e: Hemodialysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ehsCRP\u003c/strong\u003e: High-sensitivity C-reactive protein\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIL\u003c/strong\u003e: Interleukin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIL-1\u0026beta;\u003c/strong\u003e: Interleukin-1 beta\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIL-6\u003c/strong\u003e: Interleukin-6\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLOX\u003c/strong\u003e: Lipoxygenase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaR1\u003c/strong\u003e: Maresin 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMAPK\u003c/strong\u003e: Mitogen-activated protein kinase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMCP-1\u003c/strong\u003e: Monocyte chemoattractant protein-1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNLRP3\u003c/strong\u003e: NOD-like receptor family pyrin domain-containing 3\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNF-\u0026kappa;B\u003c/strong\u003e: Nuclear factor kappa-light-chain-enhancer of activated B cells\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNSAIDs\u003c/strong\u003e: Non-steroidal anti-inflammatory drugs\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNrf2\u003c/strong\u003e: Nuclear factor erythroid 2\u0026ndash;related factor 2\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD\u003c/strong\u003e: Peritoneal dialysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePEW\u003c/strong\u003e: Protein\u0026ndash;energy wasting\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eROS\u003c/strong\u003e: Reactive oxygen species\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSMAD\u003c/strong\u003e: Mothers against decapentaplegic homolog (SMAD2/3 signaling pathway)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSPM\u003c/strong\u003e: Specialized pro-resolving mediator\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTGF-\u0026beta;\u003c/strong\u003e: Transforming growth factor-beta\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, investigation, visualization, project administration and writing: Muhammet Akig Guler; writing - review \u0026amp; editing: Halil Keskin (Both Muhammet Akig Guler and Halil Keskin contributed equally to this work as co-first authors); methodology and investigation: Muhammet Celik and Zafer Bayraktutan; software and validation, data curation, conceptualization, supervision: Hamza Halici, Emir Enis Yurdgulu and Yusuf Anil Ay; funding acquisition: All authors. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive any financial support for the research, authorship, or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw datasets analyzed in this study are available from the corresponding author upon reasonable request and with permission from the institutional review board.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective, controlled, cross-sectional study was conducted in accordance with the Declaration of Helsinki and approved by the Local Ethics Committee of Atat\u0026uuml;rk University Faculty of Medicine (Approval No: B.30.2.ATA.0.01.00/639). Written informed consent to participate was obtained from the parents or legal guardians of all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest relevant to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWise PH. The Future Pediatrician: The Challenge of Chronic Illness. J Pediatr. 2007;151(5). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpeds.2007.08.013\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2007.08.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJain S, Dewey RS. 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Shock. 2015;44(5). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/SHK.0000000000000446\u003c/span\u003e\u003cspan address=\"10.1097/SHK.0000000000000446\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Maresin 1, Chronic renal failure, Pediatric nephrology","lastPublishedDoi":"10.21203/rs.3.rs-8333931/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8333931/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eChronic renal failure (CRF) in children is characterized by persistent inflammation and oxidative stress, contributing to progressive loss of renal function and multisystem involvement. Maresin 1 (MaR1), a specialized pro-resolving lipid mediator derived from docosahexaenoic acid (DHA), plays a role in the resolution of inflammation and tissue repair. However, its circulating concentrations in pediatric CRF have not been examined. This study aimed to determine serum MaR1 levels across CRF stages in children and to assess its potential relevance as a biomarker reflecting disease severity.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eChildren were categorized as healthy controls or assigned to CRF stages 1\u0026ndash;5 according to estimated glomerular filtration rate (eGFR). Serum MaR1 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Group comparisons were performed using one-way ANOVA with Tukey\u0026rsquo;s post-hoc test (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSerum MaR1 levels differed significantly among the six groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Compared with healthy controls (\u0026asymp;\u0026thinsp;110\u0026thinsp;\u0026plusmn;\u0026thinsp;15 pg/mL), levels were substantially reduced in CRF stages 1\u0026ndash;3 (25\u0026ndash;70 pg/mL). In contrast, MaR1 concentrations increased in advanced stages, with marked elevations in stage 4 (\u0026asymp;\u0026thinsp;200\u0026thinsp;\u0026plusmn;\u0026thinsp;20 pg/mL) and stage 5 (\u0026asymp;\u0026thinsp;300\u0026thinsp;\u0026plusmn;\u0026thinsp;30 pg/mL).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSerum MaR1 concentrations show a stage-dependent, biphasic pattern in pediatric CRF, with suppression in early disease and elevation in advanced stages. These findings suggest that MaR1 may reflect underlying inflammatory dynamics in CRF and could merit further investigation as a potential biomarker and therapeutic target.\u003c/p\u003e","manuscriptTitle":"Stage-dependent rise of maresin 1 in pediatric chronic renal failure: Toward a novel diagnostic and therapeutic target","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 07:12:49","doi":"10.21203/rs.3.rs-8333931/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-01-16T08:14:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"168199035670662053565136563106859601965","date":"2026-01-08T12:16:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-08T10:43:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-05T10:00:50+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-15T08:16:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-15T06:04:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-12-15T05:58:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"61bc5cfa-99d8-4151-a429-a450a55325ce","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T07:12:49+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 07:12:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8333931","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8333931","identity":"rs-8333931","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}