Circulating Lymphocyte Subsets Are Associated with Diabetic Kidney Disease and Overall Survival in Patients with Type 2 Diabetes.

Background: The immune mechanism of diabetic kidney disease (DKD) has not yet been fully elucidated. This study aimed to characterize circulating lymphocyte subsets in patients with type 2 diabetes mellitus (T2DM), with a particular focus on DKD-related immune alterations and prognosis. Methods: Circulating T cells, B cells and NK cells were identified by flow cytometry. The primary endpoint was all-cause mortality, and overall survival was defined as the time from enrollment to death from any cause or last follow-up. Associations between lymphocyte subsets, inflammatory indices and renal function parameters were analyzed. Cox regression was used to identify factors associated with overall survival in patients with DKD and in the whole T2DM cohort. A prognostic nomogram was developed in the whole T2DM cohort to estimate 1-, 2-, 3-, and 5-year overall survival (OS) probabilities. Model performance was evaluated using the concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Mendelian randomization (MR) was performed as a further exploratory analysis to assess whether immune-related traits were genetically associated with DKD susceptibility, with inverse variance weighting (IVW) as the primary analytical method. Results: In total, 74 T2DM patients were divided into DKD (stage 3-4 of chronic kidney disease) and non-DKD groups. Median follow-up duration was 34.6 months. DKD patients exhibited elevated levels of NK cells, the monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). In patients with DKD, higher PLR and serum creatinine (SCr) were associated with poorer overall survival, whereas CD4+CD25+ T cell frequency was not significant after adjustment. In the whole T2DM cohort, higher frequency of circulating CD4+CD25+ T cells were associated with improved survival (HR 0.920, 95% CI 0.858-0.986, p = 0.019), whereas elevated PLR and SCr were linked to poorer outcomes. The exploratory nomogram incorporating CD4+CD25+ T cells, PLR, and SCr, showed acceptable internal performance in this cohort. As a separate exploratory analysis, MR suggested that genetically proxied CD4 expression on activated CD4 regulatory T cells was associated with a lower risk of DKD. Conclusions: DKD was associated with higher mortality and elevated MLR-, NLR-, PLR-, and NK cell levels in patients with T2DM. In patients with DKD, PLR and SCr were associated with overall survival, supporting the prognostic relevance of systemic inflammation and renal dysfunction. Individual lymphocyte subsets were not independently associated with survival in the DKD cohort after adjustment, whereas CD4+CD25+ T cell frequency provided additional prognostic information in the whole extended T2DM cohort analysis. Further validation is warranted.