Predictive and Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Diabetic Nephropathy: Protocol for a Systematic Review and Meta-Analysis

Background A growing body of research has implicated systemic inflammation in the pathogenesis of diabetic nephropathy (DN), with the neutrophil-to-lymphocyte ratio (NLR) emerging as a potential biomarker. However, individual studies and previous evidence syntheses have reported substantial heterogeneity in patient populations, DN definitions, renal function measures, and NLR thresholds, limiting the comparability and interpretation of findings. The extent to which these clinical and methodological differences contribute to variability in the association between NLR and DN remains insufficiently characterized. Objective This systematic review aims to quantify the association between NLR and DN across measures of disease presence, severity, and prognosis and to investigate potential sources of between-study heterogeneity through prespecified subgroup, sensitivity, and meta-regression analyses. Methods The protocol was designed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive literature search of the MEDLINE (Ovid), Embase, the CENTRAL, and Scopus databases was conducted from inception to February 28, 2025. Eligible studies included adults (aged >18 years) with type 2 diabetes mellitus (T2DM) and evaluated the predictive or prognostic value of NLR in relation to DN, using validated measures of DN including albuminuria, estimated glomerular filtration rate (eGFR), glomerular filtration rate (GFR), or serum creatinine. Randomized and nonrandomized interventional studies and observational studies were eligible, with no language restrictions. Two reviewers independently screened studies and extracted data on NLR levels and relevant effect estimates. The methodological quality of observational studies was assessed using the Newcastle-Ottawa Scale. Meta-analyses were performed in RStudio (version 4.5.1) using standardized mean differences or odds ratios, as appropriate, with 95% CIs. Random-effects models were used, and subgroup, sensitivity, and meta-regression analyses were performed to explore potential sources of heterogeneity. Results The study was initiated on August 31, 2024, and the protocol was first submitted to PROSPERO (CRD42025641025) on February 6, 2025. The literature search identified 1927 records, of which 805 (41.8%) duplicate records were removed. Following title and abstract screening, 123/1,222 (11%) full-text reports were assessed for eligibility, with 45/123 (36.6%) studies included in the qualitative synthesis and 40/45 in the quantitative synthesis. Screening of search results against the inclusion criteria was completed in March 2025. Data extraction was conducted from March 2025 to May 2025, followed by risk-of-bias and quality assessment from May 2025 to July 2025 and data analysis from July 2025 to October 2025. The completed systematic review and meta-analysis was submitted for publication on May 30, 2026. Conclusions This systematic review sought to synthesize the available evidence on the association between NLR and DN occurrence, severity, and prognosis in T2DM, examining its potential as a biomarker and the sources of variability across studies. If the anticipated associations are supported, NLR may warrant evaluation within risk-stratification models for T2DM.