Dose–response analysis of systemic immune-inflammation index and risk of chronic kidney disease
Authors: Xiumei Zhao, Tianhong Wang, Leng Zhou
Journal: International Journal of Surgery (2023)

Dear Editor, Characterized by a gradual decline in kidney function, chronic kidney disease (CKD) has significant impacts on both patients and society, as it increases the risk of cardiovascular disease, hospitalization, and all-cause mortality. Previous studies acknowledged that low triiodothyronine had a significant impact on the prognosis of patients with CKD1. In addition, inflammation is thought to contribute to the development of kidney injury, which may ultimately result in chronic impairment of kidney function2. Therefore, the search for novel risk factors or biomarkers for CKD is receiving increasing attention and is expected to pave the way for new preventive strategies. The systemic immune-inflammation index (SII) is a novel index based on the lymphocyte, neutrophil, and platelet counts. Accumulating evidence demonstrates that the SII is a useful index reflecting the systemic immune and inflammatory status of the human body3. However, the relationship between CKD and SII remains uncertain and requires further investigation. To investigate the association between SII and CKD, we conducted a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) 2005–2018 data. After excluding the individuals aged less than 20 (N=31 122), this study included a total of 39 068 participants. SII is calculated by combining peripheral neutrophil (N), lymphocyte (L), and platelet (P) counts, expressed as P×N/L (109/l)3. In our study, we adopted a cutoff value of 330×109/l for all subsequent analyses, based on previous research conducted using NHANES data4. In this study, we adopted the estimated glomerular filtration rate (eGFR, ml/min/1.73 m2) and urinary albumin-to-creatinine ratio (ACR) as indicators to evaluate kidney function. Detailed process of data cleansing, definition of covariates and CKD, and statistical analyses can be found in the Supplemental Files (Supplemental Digital Content 1, https://links.lww.com/JS9/B570). The demographic characteristics and renal function status of participants were shown in Supplementary Table S1 (Supplemental Digital Content 1, https://links.lww.com/JS9/B570). There were 6815 (17.4%) individuals with CKD after eGFR and ACR estimates. The median and IQR of ACR (mg/g) and eGFR (ml/min/1.73 m2) were 7.3 (9.8) and 95.6 (32.4). The median of SII levels was 467.4 (IQR: 329.3). The association between SII levels and kidney function was presented in Figure 1. In the adjusted models, the increasing SII levels (per SD) were associated with higher odds of CKD (OR=1.18, 95% CI:1.15–1.22; Fig. 1A) and were linked with ACR increase (β value: 0.10, 95% CI: 0.09–0.11; Fig. 1B). Conversely, the growing SII levels (per SD) were negatively associated with eGFR (β value: −0.007, 95% CI: −0.018, −0.012; Fig. 1C). We then examined the exposure–response association of SII levels with kidney function by classifying the distribution of SII levels into quartiles. A significant trend was observed in increasing SII values and decreasing kidney function, as suggested by the monotonic increase in CKD and ACR risk (both Ptrend≤0.001). Meanwhile, a slight negative association between SII quartiles and eGFR was found (Ptrend=0.04).Figure 1: The association between SII and chronic kidney disease. (A–C) Depict the results of univariate and multivariable analyses of SII with CKD, ACR, and eGFR, respectively. (D–F) Show the restricted cubic splines associated with SII and CKD, ACR, and eGFR, respectively. The restricted cubic splines were adjusted as the full model. Crude model: without any covariate. Adjusted full model included covariates, comprising age, sex, body mass index, the ratio of family poverty, ethnicity, smoking status, alcohol use, cardiovascular disease, diabetes, and hypertension. ACR, albumin-to-creatinine ratio; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; SII, systemic immune-inflammation index; Q1–Q4: quartile 1 to quartile 4; SD, standard deviation.In the restricted cubic spline analysis, we found that the dose–response of continuous SII levels with CKD and ACR were linear (Fig. 1D, E, both Poverall<0.001), and the association between continuous SII levels and eGFR was non-linear (Fig. 1F, Pnon-linear<0.001). Stratified analyses were performed for continuous SII levels (per SD) and CKD onset (Fig. S1, Supplemental Digital Content 1, https://links.lww.com/JS9/B570). We found that the positive association was more pronounced in a former smoking group than the never and now-smoking group (P for interaction =0.03). In addition, the Mexican American group has a higher risk of CKD when the growing SII levels are tested, compared with the other four ethnicities (P for interaction =0.01). We cannot find an effect modification of SII levels with body mass index, the ratio of family income to poverty, alcohol use, cardiovascular disease, diabetes, hypertension, sex, and age group (P for interaction >0.05). CKD is a significant public health concern. Substantial evidence suggests that renal inflammation is a crucial factor in the onset and advancement of CKD. This study identified a linear dose–response relationship between continuous SII levels and both CKD and ACR and a non-linear association between continuous SII levels and eGFR. These findings indicate that the SII index can serve as an independent risk factor associated with CKD. These novel risk factors show a promising application for early identification and intervention of CKD, which may pave the way for new preventive strategies. However, further prospective and experimental research is necessary to validate these findings in a larger population. Ethics approval As all data is publicly accessible, institutional review board approval was not required. Consent Written informed consent was obtained from all the participants before attending this survey. Source of funding This work was supported by the Natural Science Foundation of China (No. 81700074). Author contribution X.Z.: conceptualization, data acquisition, and writing; T.W.: statistical analysis and writing; L.Z.: review, editing, and supervision. Conflicts of interest disclosure The authors declare no conflicts of interest. Research registration unique identifying number (UIN) Name of the registry: not applicable. Unique identifying number or registration ID: not applicable. Hyperlink to your specific registration (must be publicly accessible and will be checked): not applicable. Guarantor All authors. Data availability statement Data are available from the corresponding author if the justification for the requirement is justified. Provenance and peer review Not commissioned, externally peer-reviewed.