Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(3):13955 1 REVIEW RCC is highly immunosuppressive and inflammatory, with cytokines playing a pivotal role in disease progression and treatment resistance (3). Among these cytokines, inter- leukin-6 (IL-6) has emerged as a key mediator of tumorige- nesis, angiogenesis, and immune evasion, making it a promising candidate for prognostic evaluation (4). IL-6 is a pleiotropic cytokine involved in acute and chronic inflammation, with well-documented roles in cancer progression (4). In RCC, elevated IL-6 levels have been associated with advanced disease stage, poor sur- vival, and resistance to systemic therapies (5). Preclinical studies demonstrate that IL-6 promotes tumor growth by activating the JAK/STAT3 pathway, enhancing angiogen- esis through VEGF upregulation, and suppressing antitu- mor immune responses (6). Clinically, serum IL-6 levels correlate with tumor burden, metastatic potential, and adverse outcomes, suggesting its utility as a non-invasive biomarker (7). However, existing studies on IL-6 in RCC have produced heterogeneous results, likely due to varia- tions in assay methods, patient populations, and treat- ment modalities. A comprehensive synthesis of these findings is therefore necessary to clarify the prognostic value of IL-6 in RCC. This meta-analysis aims to evaluate the prognostic significance of IL-6 in RCC by synthesiz- ing data from published studies, specifically overall sur- vival (OS) and progression-free survival (PFS). METHODS Eligibility criteria This meta-analysis will include studies that evaluate the association between preoperative serum IL-6 levels and clinical outcomes in RCC patients. Inclusion criteria com- prise: (1) original research articles with full-text availabili- ty in English; (2) studies measuring serum IL-6 levels prior to surgical intervention or systemic therapy; (3) studies reporting correlations between IL-6 and survival outcomes (OS and PFS). Exclusion criteria are: (1) non-English pub- lications; (2) review articles, editorials, case reports, con- ference abstracts, or duplicate studies; (3) studies involving patients who received neoadjuvant chemotherapy before IL-6 measurement, as these treatments may confound cytokine levels. Additionally, studies lacking sufficient sta- tistical data for meta-analysis will be excluded. Introduction & Objectives: Renal cell carci- noma (RCC) represents the majority of kid- ney malignancies and is characterized by variable outcomes, even with current systemic therapies. Interleukin-6 (IL-6), a pro- inflammatory cytokine implicated in tumor progression and immune suppression, has been proposed as a prognostic bio- marker in RCC. However, the evidence remains inconsistent due to methodological heterogeneity across studies. Therefore, our study aims to evaluate the prognostic significance of IL-6 in RCC by synthesizing data from published studies, specifically overall survival (OS) and progression-free survival (PFS). Methods: A systematic meta-analysis was conducted to evaluate the prognostic significance of IL-6 in RCC. Eligible studies were identified through PubMed, ScienceDirect, and ProQuest up to March 2025. Inclusion criteria encompassed original articles measuring pre-treatment serum IL-6 levels in RCC patients and reporting associations with overall survival (OS) or progression- free survival (PFS). Random-effects models were used to com- pute pooled hazard ratios (HRs) and survival differences. Results: Nine studies comprising 702 RCC patients were includ- ed. Patients with low IL-6 levels had significantly longer OS (difference: 5.36 months; 95% CI: 2.2-8.53; p < 0.001; I² = 0%) and PFS (difference: 6.41 months; 95% CI: 1.3-11.53; p = 0.01; I² = 48.5%) compared to those with high IL-6. The pooled HR for survival associated with elevated IL-6 was 2.06 (95% CI: -0.23-4.36), with considerable heterogeneity (I² = 89.19%) and borderline statistical significance (p = 0.08). Despite variations in study design, sample size, and IL-6 detection methods, elevat- ed IL-6 consistently predicted worse clinical outcomes. Conclusions: IL-6 is a promising prognostic biomarker in RCC, with elevated levels associated with significantly poorer OS and PFS. KEY WORDS: Renal cell carcinoma; Interleukin-6; Prognosis; Survival; Biomarker Submitted 10 May 2025; Accepted 17 May 2025 INTRODUCTION Renal cell carcinoma (RCC) accounts for approximately 90% of all kidney cancers and remains a significant cause of can- cer-related morbidity and mortality worldwide (1). Despite advancements in targeted therapies and immune check- point inhibitors, patient outcomes vary widely (2), under- scoring the need for reliable prognostic biomarkers to guide clinical decision-making. The tumor microenvironment in Circulating IL-6 and survival outcomes in renal cell carcinoma: A systematic review and meta-analysis Haryo Nindito Wicaksono 1, Taufiq Nur Budaya 2, Kurnia Penta Seputra 2, Aulia Rahman Putra 2 1 General Practicioner, Intern at Department of Urology, Faculty of Medicine, Universitas Brawijaya, Saiful Anwar General Hospital, Malang, Indonesia; 2 Department of Urology, Faculty of Medicine, Universitas Brawijaya, Saiful Anwar General Hospital, Malang, Indonesia. DOI: 10.4081/aiua.2025.13955 Summary Archivio Italiano di Urologia e Andrologia 2025; 97(3):13955 H. Nindito Wicaksono, T. Nur Budaya, K. Penta Seputra, A. Rahman Putra 2 Literature search A systematic search will be conducted in PubMed/MED- LINE, Science Direct, and Proquest, from inception to the present, using predefined search terms: − Population: ("Renal Cell Carcinoma" OR "RCC" OR "Kidney Cancer") − Intervention/Exposure: ("Interleukin-6" OR "IL-6" OR "serum cytokine") − Outcome: ("prognosis" OR "survival") − Study Design: ("cohort" OR "prospective" OR "retrospec- tive"). The search strategy will combine MeSH terms and free- text keywords with Boolean operators. Two independent reviewers will perform the search, remove duplicates, and screen titles/abstracts. Full texts of potentially eligible studies will be assessed for final inclusion, with discrep- ancies resolved by consensus or a third reviewer. Data analyses Extracted data will include: (1) study characteristics (author, year, country, design); (2) patient demographics (sample size, age, sex); (3) IL-6 measurement methods; (4) clinical outcomes [OS, PFS, and HR with 95% confi- dence intervals (CIs)]. Statistical analysis will be performed using STATA. Pooled OS, PFS, and HR will be calculated using random-effects models. Heterogeneity will be assessed via I² statistics (I² > 50% indicating substantial heterogeneity). The quality of each study assessed using Newcastle-Ottawa Scale. RESULTS This meta-analysis incorporated nine studies investigating the prognostic role of IL-6 in renal cell carcinoma (RCC), comprising a total of 702 patients. Full search and filter details are in Figure 1. The studies were predominantly retrospective (n = 6), with one prospective cohort and two clinical trial analyses. Patient cohorts varied in size from 19 to 217 individuals, with median/mean ages ranging from 55.5 to 64.5 years where reported. Females consti- tuted 32-42% of participants in studies documenting sex distribution. Most studies focused on metastatic or advanced RCC (n = 7), while two included localized dis- ease. IL-6 measurement methods differed across studies: two used immunoassay (without specifying the method), three used serum/plasma ELISA, one used immunoenzy- matic or immunoradiometric assay, one used immunohis- tochemistry (IHC), one directly measured the level of IL- 6 in the serum, and one analyzed TCGA RNA-seq data. Cutoffs for "high IL-6" were heterogeneous, ranging from > 5 pg/mL to ≥ 35 pg/mL in serum assays or quartile-based thresholds in transcriptomic studies. Methodological variability was evident, with serum/plas- ma IL-6 levels spanning 6.9-48.2 pg/mL across cohorts. Key findings consistently associated elevated IL-6 with adverse outcomes: five studies reported significantly worse OS or PFS with high IL-6 levels, while two noted trends toward poorer survival. Despite differing assays and cutoffs, all studies supported IL-6 as a negative prog- nostic marker. Full study characteristics are in Table 1. Figure 1. PRISMA Diagram. Archivio Italiano di Urologia e Andrologia 2025; 97(3):13955 3 Circulating IL-6 and survival outcomes in renal cell carcinoma: A systematic review and meta-analysis Meta-analysis results demonstrated significant associa- tions between IL-6 levels and survival outcomes in RCC patients as showed in Figures 2-4. Patients with low IL- 6 levels exhibited 5.36 months longer OS compared to those with high IL-6 levels (95% CI: 2.2-8.53; p < 0.001), with no observed heterogeneity (I² = 0%) across all nine studies. Similarly, progression-free survival (PFS) was 6.41 months longer in the low IL-6 group (95% CI: 1.3-11.53; p = 0.01), though moderate heterogeneity was noted (I² = 48.5%) among the four studies analyzed. Figure 2. Overall survival difference low vs high IL-6. Table 1. Characteristics of each study. First Author Pilskog et al. (8) Negrier et al. (9) Pilskog et al. (5) Tran et al. (10) Thiounn et al. (11) Stadler et al. (12) Costes et al. (13) Akdogan et al. (14) Kays et al. (15) Country of study Norway France Norway USA France Argentina France Turkey USA Study Design Open-label, single-arm phase II study Retrospective analysis of a randomized multicentric trial Retrospective analysis of a single-arm phase II study Retrospective analysis of phase 2 and phase 3 clinical trials Retrospective study Analysis of patients in a phase I evaluation Retrospective analysis Prospective observational cohort study Retrospective analysis of TCGA data Total number of patients 46 138 46 129 19 22 38 23 (RCC subgroup of 85 total cancer patients) 217 (ccRCC) Average age Median 63.1 years Median 56 years Median 63.1 years Not stated Mean 55.5 years Not stated 61.2 years Median 64.5 years (overall cohort) 59.65 years Percentage of women 37.0% 28.3% 37.0% Not stated 42.1% Not stated 28.9% 32% (overall cohort) Not stated Cancer stage Metastatic or non-resectable clear cell renal cell carcinoma (ccRCC) Metastatic renal cell carcinoma (MRCC) Metastatic or non-resectable clear cell renal cell carcinoma (ccRCC) Metastatic renal-cell carcinoma Metastatic renal cell carcinoma Metastatic kidney cancer Primary renal cell carcinoma (stages I-IV) Advanced Renal Cell Carcinoma (part of a cohort with NSCLC and melanoma) Clear cell renal cell carcinoma (ccRCC) IL-6 Detection method ELISA (plasma IL-6 - pIL6) Immunoassay (serum IL-6) Immunohistochemistry (IHC) (tumour tissue IL-6 expression) Multiplex assay, protein array, and ELISA (plasma IL-6) Assay (serum IL-6) Measured levels of IL-6 in serum Immunoenzymatic or immunoradiometric assay (serum IL-6) ELISA (baseline serum IL-6) RNASeq (tumour IL-6 gene expression) IL-6 Cutoff (High/Low) Low pIL6 at baseline associated with improved response and PFS; median baseline pIL6 was 6.90 pg/ml (implied cutoff around this value) High IL-6 (≥ 35 pg/mL) associated with worse overall survival (cutoff determined by quartile method) Low vs. High expression in tumour cells based on staining index (SI 0-2 vs 3-9), low expression associated with improved PFS Low (relative to median) IL-6 correlated with increased tumour shrinkage and prolonged PFS; high levels were negative prognostic factors (median not specified in excerpt) Greater or less than 15 pg/ml; high IL-6 correlated with shorter survival Abnormal IL-6 (>5 pg/mL) associated with worse prognosis Detectable serum IL-6 (presence vs. absence) correlated with worse survival; mean serum IL-6 was 8.32 pg/ml in IL-6R -ve and 48.2 pg/ml in IL-6R +ve tumours Stratified by median IL-6 level (20.0 pg/mL); higher levels showed a trend towards shorter OS (not statistically significant) High vs. low IL-6 expression in tumour, correlated with survival based on quartiles of expression; high expression associated with decreased survival Archivio Italiano di Urologia e Andrologia 2025; 97(3):13955 H. Nindito Wicaksono, T. Nur Budaya, K. Penta Seputra, A. Rahman Putra 4 The pooled hazard ratio (HR) for survival further sup- ported these findings, with high IL-6 levels correlating with a 2.06-fold increased risk of poor outcomes (95% CI: -0.23-4.36), albeit with substantial heterogeneity (I² = 89.19%) and borderline statistical significance (p = 0.08). These results collectively underscore IL-6 as a robust prognostic biomarker in RCC, where elevated lev- els consistently predict shorter survival and disease pro- gression, despite variability in study methodologies. DISCUSSION The present meta-analysis, comprising nine studies and a total of 702 patients with RCC, consolidates robust evi- dence that elevated IL-6 levels are significantly associated with poorer survival outcomes. This finding aligns with prior review by Wang et al. (2019), which demonstrated a strong correlation between high IL-6 levels and worse overall OS, reporting an HR of 3.03 (95% CI: 2.37-3.70) (16). However, our study extends this understanding by quantifying the prognostic advantage associated with low IL-6 levels: a 5.36-month OS benefit (95% CI: 2.2-8.53; p < 0.001) and a 6.41-month improvement in progres- sion-free survival (PFS) (95% CI: 1.3-11.53; p = 0.01). Notably, our analysis yielded a lower degree of hetero- geneity (I² = 0% for OS) compared to that of Wang et al., which reported a markedly high heterogeneity (I² = 98%). This consistency across diverse methodologies and patient populations underscores IL-6’s biological role as a key driver of RCC progression, plausibly through mecha- nisms of angiogenesis, immune evasion, and resistance to therapy, as previously postulated (17-19). From a biological and clinical standpoint, the prognostic relevance of IL-6 is mechanistically plausible. Preclinical data have demonstrated that IL-6 activates the JAK/STAT3 pathway, which fosters tumor proliferation while concurrently impairing anti-tumor immunity (6). Our pooled HR of 2.06 (95% CI: -0.23 to 4.36), while not statistically significant (p = 0.08), is consistent with the trends previously reported (9), who observed that ele- vated serum IL-6 levels were associated with diminished OS in metastatic RCC. Furthermore, the well-document- ed correlation between IL-6 and C-reactive protein (CRP) suggests CRP may function as a surrogate biomarker (16). However, our findings support the notion that IL-6 itself plays a more direct and pivotal role in RCC biology. Importantly, the consistent association between elevated IL-6 levels and advanced tumor stage (which document- ed in seven of nine included studies) reinforces its poten- tial utility as a biomarker for prognostication and risk stratification. This is particularly relevant in the context of IL-6-targeting therapeutic agents such as siltuximab and tocilizumab (20). One notable strength of our meta-analysis lies in its refined precision. By focusing exclusively on pre-treat- ment IL-6 measurements, we reduced the confounding Figure 3. Progression free survival difference low vs high IL-6. Figure 4. Hazard ratio for poor survival. Archivio Italiano di Urologia e Andrologia 2025; 97(3):13955 5 Circulating IL-6 and survival outcomes in renal cell carcinoma: A systematic review and meta-analysis influence of systemic therapies, particularly immunother- apy, which affected a substantial proportion (60%) of patients in Wang et al.’s cohort (16). In terms of method- ological rigor, our use of a random-effects model appro- priately accounted for heterogeneity in IL-6 cutoffs (rang- ing from > 5 pg/mL to ≥ 35 pg/mL) and assay techniques, yet still yielded consistent OS and PFS differences. The observed 6.41 month PFS advantage is not only statisti- cally significant but also clinically meaningful, suggesting that IL-6 may serve as a stratifying tool in selecting patients for adjuvant or intensified therapy, especially within the metastatic setting. Nonetheless, several limitations must be acknowledged. The high heterogeneity observed in the HR analysis (I² = 89.19%) reflects substantial methodological variation among the included studies, including differences in detection platforms (ELISA versus immunohistochem- istry), biological samples (serum versus tumor tissue), and patient populations (localized versus metastatic RCC). Additionally, the small sample sizes in some included studies raise concerns about potential effect size inflation. Publication bias, although not formally detected due to the small number of included studies (n = 9), cannot be definitively ruled out. The clinical implications of our findings are considerable. Integrating IL-6 into existing prognostic frameworks, such as the International Metastatic RCC Database Consortium (IMDC) model, may enhance risk stratifica- tion and inform therapeutic decisions. Patients with ele- vated IL-6 may benefit from risk-adapted surveillance protocols and may represent an ideal target population for clinical trials evaluating the efficacy of IL-6 blockade. Preclinical studies have shown promising synergy between IL-6 inhibition and VEGF-TKIs (19, 21), thus warrants further clinical exploration. Looking forward, prospective trials should prioritize the standardization of IL-6 assays (ideally through centralized ELISA platforms) and establish consensus on clinically actionable cutoffs. Given the dual biological and prognostic roles of IL-6 in RCC, its integration into both biomarker-driven clinical trials and real-world prognostic models may represent the next advance in personalized therapy for this aggressive malignancy. CONCLUSIONS Elevated IL-6 levels are significantly associated with poor- er overall and progression-free survival in patients with renal cell carcinoma, confirming its role as a negative prognostic biomarker. These findings support the integra- tion of IL-6 measurement into clinical risk stratification and therapeutic decision-making in RCC management. REFERENCES 1. Hsieh J, Purdue M, Signoretti S, et al. Renal cell carcinoma. Nat Rev Dis Prim 2018; 9:1-42. 2. Petrelli F, Vavassori I, Rossitto M, Dottorini L. Management of metastatic renal cell carcinoma following first-line immune check- point therapy failure: a systematic review. Cancers (Basel) 2024; 16:2598-610. 3. Heidegger I, Pircher A, Pichler R. Targeting the tumor microenvi- ronment in renal cell cancer biology and therapy. Front Oncol 2019; 9:1-11. 4. Zhao H, Wu L, Yan G, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct. Target. Ther.2021; 6:263-308. 5. 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Correspondence Haryo Nindito Wicaksono (Corresponding author) wicaksonoharyo123@gmail.com General Practicioner, Intern at Department of Urology, Faculty of Medicine, Universitas Brawijaya, Saiful Anwar General Hospital, Malang, Indonesia Aulia Rahman Putra Taufiq Nur Budaya Kurnia Penta Seputra Department of Urology, Faculty of Medicine, Universitas Brawijaya, Saiful Anwar General Hospital, Malang, Indonesia