Predictive value of inflammatory prognostic index for contrast-induced nephropathy in patients undergoing coronary angiography and/or percutaneous coronary intervention

The purpose of this study was to investigate the relationship between Inflammatory Prognostic Index (IPI) levels and Contrast-Induced Nephropathy (CIN) risk and postoperative clinical outcomes in patients undergoing coronary angiography (CAG) and/or percutaneous coronary intervention (PCI). A total of 3,340 consecutive patients who underwent CAG and/or PCI between May 2017 and December 2022 were enrolled in this study. Based on their baseline IPI levels, patients were categorized into four groups. Clinical characteristics and postoperative outcomes were compared among these groups. In-hospital outcomes focused on CIN risk, repeated revascularization, major bleeding, and major adverse cardiovascular events (MACEs), while the long-term outcome examined the all-cause readmission rate. Quartile analysis found a significant link between IPI levels and CIN risk, notably in the highest quartile (P < 0.001). Even after adjusting for baseline factors, this association remained significant, with an adjusted Odds Ratio (aOR) of 2.33 (95%CI 1.50–3.64; P = 0.001). Notably, baseline IPI level emerged as an independent predictor of severe arrhythmia, with aOR of 0.50 (95%CI 0.35–0.69; P < 0.001), particularly driven by the highest quartile. Furthermore, a significant correlation between IPI and acute myocardial infarction was observed (P < 0.001), which remained significant post-adjustment. For patients undergoing CAG and/or PCI, baseline IPI levels can independently predict clinical prognosis. As a comprehensive inflammation indicator, IPI effectively identifies high-risk patients post-procedure. This study underscores IPI's potential to assist medical professionals in making more precise clinical decisions, ultimately reducing mortality and readmission rates linked to cardiovascular disease (CVD).


Study design and population
We collected retrospective data from 16,759 patients undergoing CAG and/or PCI at Fujian Medical University Union Hospital between May 2017 and December 2022.Exclusion criteria were age < 18, missing or limited serum creatinine data, on-pump coronary artery bypass grafting (CABG), contrast agent allergies, ongoing dialysis, and missing data or discharge status.3,340 patients were included for analysis.Inclusion/exclusion flowchart for the study groupis shown in Fig. 1.The study was approved by the hospital's Ethics Committee and followed the Declaration of Helsinki.

Data collection and clinical definition
We obtained baseline data from the Electronic Medical Records System of Fujian Medical University Union Hospital, which primarily comprised sociodemographic information, admission and discharge diagnoses, results of laboratory and imaging tests, medication details, procedural characteristics, and discharge outcomes.Laboratory tests were conducted at the Laboratory Center of Fujian Medical University Union Hospital.Venous blood samples were collected after a fasting period of over 8 h, with water deprivation during the final 3-4 h of the fast.
Hypertension, diabetes mellitus (DM) and stroke were defined using the 10th Revision Codes of the International Classification of Diseases (ICD-10) 15 .The guidelines for the prevention and treatment of dyslipidemia in Chinese adults (2016) 16 , were used to define the diagnosis of hyperlipemia.The diagnostic criteria of chronic kidney disease (CKD) were based on Guidelines for the Screening, Diagnosis and Prevention of Chronic kidney Disease in China (2017) 17 , estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m 2 and calculated with

Statistical analysis
In order to assess the impact of IPI levels on clinical outcomes in patients, we divided IPI into four groups based on quartiles.Enumeration data were expressed as numbers and percentage values (%), analyzed using the χ 2 test.When χ 2 test test conditions were not met, Fisher exact test was used, and values of P < 0.05 (two-sided) were considered significant.Shapiro-Wilk test was used to test the normality of continuous variables.Continuous variables were expressed as mean ± standard deviation (for normal distribution) and analyzed using ANOVA analysis, or as median and interquartile range (IQR) for non-normal distribution, the Mann-Whitney U test was used.First, univariate logistic regression analysis was used to determine the potential risk factors for in-hospital mortality (P < 0.05), and then multivariate logistic regression analysis was used to confirm that the previously significant variables were independent factors (P < 0.05).Multivariate Cox proportional hazard regression and Kaplan-Meier survival curve were used to evaluate all-cause readmission rate.All statistical analyses were performed using SPSS 26.0 software (https:// www.ibm.com/ produ cts/ spss-stati stics).The graph was drawn using GraphPad Prism 9.3.1 software (https:// www.graph pad.com/).

Ethics approval
Ethical Approval was obtained from the Fujian Medical University Union Hospital ethics committee (2023KY032) prior to data collection.

Informed consent
Informed consent was provided by all participants.
Patients in group 4 exhibited elevated preoperative creatinine levels (p < 0.001) and baseline urea nitrogen levels (p < 0.001).However, these patients also displayed a tendency toward reduced glomerular filtration rates (p < 0.001).Conversely, individuals with higher IPI levels tended to have elevated absolute neutrophil counts (p < 0.001) and white blood cell counts (WBC) (p < 0.001), but diminished absolute lymphocyte counts (p < 0.001).Moreover, the NLR was notably higher among subjects with IPI levels in the second and fourth quartiles (p < 0.001).Additionally, patients with IPI levels in the highest quartile exhibited decreased red blood cell count (RBC) levels (p < 0.001), concomitant with reductions in ALP (p < 0.001) and hemoglobin (Hb) levels (p < 0.001), while CRP (p < 0.001) and blood glucose (p < 0.001) levels increased.
Patients in group 4 had higher levels of preoperative creatinine (p < 0.001) and baseline urea nitrogen (p < 0.001), but these patients also tended to have lower glomerular filtration rate (p < 0.001).Individuals with higher IPI levels tended to have higher absolute neutrophil counts (p < 0.001) and white blood cell counts (WBC) (p < 0.001), but had lower absolute lymphocyte counts (p < 0.001).At the same time, NLR was higher in subjects with IPI levels in the second and fourth quartiles (p < 0.001).In addition, patients with IPI levels in the highest quartile had lower RBC levels (p < 0.001), accompanied by a decrease in ALP(p < 0.001), hemoglobin (Hb) (p < 0.001), while CRP (p < 0.001) and blood glucose (p < 0.001) levels increased.
In terms of medication, we observed that the use of diuretics increased in tandem with higher IPI levels.Conversely, the use of other medications such as calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor enkephalinase inhibitors (ACEI/ARB/ARNI),β-blockers, dual antiplatelet therapy (DAPT), and statins exhibited an inverse relationship with IPI levels (p < 0.001).Regarding surgical characteristics, it is noteworthy that patients in the highest quartile of IPI levels had the highest number of infarcted arteries (p < 0.001).Conversely, patients with IPI levels in the lowest quartile were more likely to receive hydration therapy (p < 0.001) and undergo repeat angiography within seven days (p < 0.001), with a greater amount of contrast agent used.Furthermore, there was a significant negative correlation between IPI levels and the likelihood of undergoing PCI (80.4 vs 65.7 vs 49.2 vs 38.2%, p < 0.001), indicating that patients with lower IPI levels were more inclined to undergo PCI.More detailed baseline information is provided in Table 1.

IPI as a predictor of CIN risk and clinical outcome
In the quartile analysis, the distribution of IPI levels was as follows: ≤ 0.11 (4.2%), 0.12-0.74(9.7%), 0.75-1.93(16.5%), and ≥ 1.94 (22.2%).These results reveal a strong positive correlation between high IPI levels and the risk of CIN.Even after adjusting for baseline confounders in model 2, this difference remained significant (p = 0.001).Notably, variables such as absolute neutrophil count, white blood cell count, absolute lymphocyte count, and hemoglobin were excluded from the model due to collinearity (variance inflation factor [VIF] > 5).Subgroup analysis indicated that male patients faced a 1.44 times higher risk of CIN compared to females.Moreover, PCI and DAPT were identified as protective factors against CIN (p < 0.05), while preoperative CKD, pulmonary infection, diuretic use, NYHA class III, and glomerular filtration rate emerged as independent risk factors (p < 0.05) (Fig. 2).
Furthermore, a significant positive correlation was observed between patients' IPI levels and all-cause inhospital mortality (0.2% vs 1.1% vs 1.3% vs 3.4%, p < 0.001), with the highest quartile driving this association.However, multivariate logistic regression analysis failed to confirm this relationship (adjusted odds ratio [aOR] 2.50; 95% CI 0.49-12.78;p = 0.348).Additionally, there were no significant differences in the incidence of repeated revascularization and major bleeding across different IPI levels (p > 0.05).These conclusions were further supported by adjusted results.
In addition, different baseline IPI levels were found to be independently associated with postoperative MACE, including arrhythmia and acute myocardial infarction (AMI), in patients undergoing CAG and/or PCI (p < 0.001).Specifically, the incidence of arrhythmia was highest among patients with baseline IPI levels in the highest quartile, although no significant difference was initially observed between the groups (3.2%, p > 0.05).However, subsequent multivariate analysis revealed significant differences between the groups (aOR 0.50; 95% CI 0.35-0.69;p < 0.001) (Fig. 3).Similarly, baseline IPI levels were independently associated with the risk of AMI in patients (p < 0.001), with this association further confirmed after adjusting for covariates (aOR 3.00; 95% CI 1.89-4.76;p < 0.001) (Fig. 4).Moreover, there was no significant difference observed between IPI levels and the risk of stroke (p > 0.05) (Table 2).
During the 1-year follow-up, 1095 out of 3340 patients were readmitted (32.8%).According to the results of univariate analysis, a higher baseline IPI level was associated with a lower rate of all-cause readmission (p < 0.001); however, multivariate analysis did not confirm this result.Kaplan-Meier curves for the all-cause readmission rate as shown below(Fig.5)(Table 2).

Discussion
This study is the first to examine the link between IPI levels and the risk of CIN and clinical outcomes in patients having CAG and/or PCI.Higher IPI levels were independently associated with increased CIN risk, and baseline IPI levels predicted severe arrhythmia and AMI.These findings suggest that IPI could be a useful prognostic marker in this patient population.
CIN is a complication that often arises in patients undergoing CAG and/or PCI, with notable morbidity and lethality 19 .Its development is likely associated with factors such as immunity, oxidative stress, and inflammatory responses 20 .While the exact pathophysiological mechanism remains uncertain, it is hypothesized to involve the cytotoxicity of contrast agents on renal tubules, leading to aggravated renal vasoconstriction, endothelial dysfunction, renal medulla ischemia, and hypoxia, ultimately resulting in renal tubular cell injury and death.Our analysis of 3340 patients undergoing CAG and/or PCI revealed a clear relationship between IPI levels and the risk of CIN.Particularly, patients in the highest quartile of IPI levels, indicative of more severe inflammatory responses, demonstrated a significantly elevated risk of CIN (p < 0.001).This association persisted even after adjusting for baseline confounders, consistent with prior studies 21 .Additionally, factors such as endothelial dysfunction, oxidative stress, and renal vasoconstriction have been identified as potential contributors to CIN 22 .Iodine contrast media (ICM) can induce activating transcription factor-2 (ATF2) to activate the oxidative stress system and make it participate in the inflammatory response.Moreover, ICM-induced renal parenchymal hypoxia can cause excessive release of reactive oxygen species (ROS), which directly leads to renal tubular and vascular endothelial dysfunction.Furthermore, subgroup analysis indicated that PCI treatment and preoperative use of DAPT were protective against CIN, whereas preoperative CKD and diuretic use increased the risk.These www.nature.com/scientificreports/findings are in line with existing research 23,24 , suggesting that PCI may improve renal hemodynamics, while diuretic use may exacerbate renal tubular toxicity 25 .Identifying high-risk individuals is crucial for implementing targeted interventions.
An increasing body of research suggests that inflammation plays a crucial role in the development and destabilization of atherosclerotic plaques, highlighting its significance in CAD [26][27][28] .Our study, focusing on patients undergoing CAG and/or PCI, revealed a notable association between baseline levels of the IPI and postoperative MACE, including AMI and severe arrhythmia (p < 0.05).Specifically, patients in the highest quartile of IPI demonstrated the highest incidence of AMI, a finding that remained significant even after adjusting for baseline confounders (p < 0.001).Subsequent subgroup analysis identified hyperlipidemia and the extent of coronary artery involvement as independent risk factors for AMI, while preoperative DAPT emerged as a protective factor, consistent with previous studies 21 .The severity of the inflammatory response, as reflected by IPI levels, correlates with the magnitude of AMI, which is closely linked to immune-inflammatory responses and oxidative stress 29 .The intensity of the inflammatory response during AMI affects infarct size and subsequent ventricular remodeling 30 , serving as an indicator of AMI severity to some extent.Interestingly, while initially no difference  in severe arrhythmia incidence was observed among patients with varying IPI levels (p > 0.05), this association became significant after adjustment (p < 0.001).Furthermore, subgroup analysis identified atrial fibrillation as an independent risk factor for severe arrhythmia in patients.However, existing research on the relationship between inflammation and arrhythmia risk presents conflicting conclusions 31,32 , likely due to variations in study  www.nature.com/scientificreports/populations and designs.Therefore, future studies with longer follow-up periods and larger, multicenter samples are needed to obtain more definitive evidence on the association between inflammatory factors and arrhythmias.Coronary stent implantation is the primary method for revascularization in patients with CHD 19 .In-stent restenosis (ISR) is a significant postoperative complication that has attracted considerable attention.The pathogenesis of ISR is complex, involving vascular endothelial cell injury and apoptosis 38,39 , excessive proliferation and migration of vascular smooth muscle cells (VSMC), in-stent intimal hyperplasia, in-stent thrombosis, and persistent vascular inflammation.At present, there are also studies have shown that radioactive exposure such as ultra-high dose rate FLASH irradiation (FLASH-IR)stimulates endothelial cell activation, causes inflammatory response activation and thrombophilia, and induces and accelerates vascular atherosclerosis, which can also lead to ISR [43][44][45]47,49 . Previus studies have reported that 17% to 32% of patients with stent implantation develop ISR, typically occurring 6 to 12 months after PCI 33 .However, existing research predominantly focuses on the long-term association between individual inflammatory factor levels and ISR, overlooking the exploration of the relationship between IPI levels and repeated revascularization.Our study findings indicate no significant association between IPI and repeated revascularization (p > 0.05). Ths contrasts with some prior research conclusions 34 , possibly due to population differences in inflammatory responses and the duration of inflammation persistence.Further investigations are necessary to clarify these inconsistencies and comprehensively understand the role of inflammation in ISR and repeated revascularization.
After nearly 1 year of follow-up in this study, a significant correlation was observed between IPI and the allcause readmission rate.However, after adjusting for covariates, Cox regression analysis did not provide further evidence to support this relationship (p > 0.05).The study findings indicated that the risk of all-cause readmission in male patients was 1.3 times higher than that in female patients (p > 0.05), consistent with findings from other studies 35 .This could be attributed to the higher mortality rate and incidence of adverse cardiac events among elderly male patients post-PCI compared to females 36 .Additionally, elderly male patients tend to have higher rates of smoking, drinking, and being overweight compared to females.Furthermore, research by domestic scholars has shown that elderly male patients exhibit lower compliance with chronic disease treatment and medication than elderly female patients 37 , leading to a higher risk of all-cause readmission in male patients.Additionally, we observed significantly lower all-cause readmission rates among patients who underwent PCI compared to those who did not (p < 0.001).This highlights the importance of focusing on patients who do not receive PCI treatment and ensuring timely PCI intervention based on the disease condition.

Limitations
Our study is subject to limitations.It is a single-center retrospective study, and there may be biases (such as selection bias) present.Therefore, future research should aim for greater perfection and stricter quality control in order to minimize potential sources of error.Future research should prioritize multicenter prospective studies for broader insights.Also, we lack long-term follow-up data, focusing mainly on short-term in-hospital prognosis.Moreover, The occurrence and development of CIN involve many factors.This study is limited to the comparison of basic data such as age, gender, course of disease and laboratory biochemical examination, the changes of pathology and related molecular mechanisms have not been discussed, further research is needed in the future.Lastly, IPI levels may change during hospitalization, so future studies should monitor them dynamically.Despite limitations, our study is the largest to date and the first to explore IPI levels' association with patient prognosis in coronary angiography and/or percutaneous coronary intervention.

Conclusion
This study is the first to investigate the IPI in patients undergoing CAG and/or PCI.We found that IPI is significantly associated with clinical prognosis, predicting the risk of CIN and postoperative outcomes independently.Its affordability and ease of use make it a valuable tool for early intervention strategies.Moving forward, more structured trials with increased participant involvement are needed to confirm our findings.

Figure 2 .
Figure 2. Predictors of CIN in patients undergoing CAG and/or PCI.Forest plot for the effects sizes of individual predictors of CIN in patients undergoing CAG and/or PCI.Abbreviations: CKD, chronic kidney disease; PCI, percutaneous coronary intervention; DAPT, dual antiplatelet therapy; GFR, glomeruar filtration rate; BMI, body mass index.

Figure 3 .
Figure 3. Predictors of acute severe arrhythmia in patients undergoing CAG and/or PCI.Forest plot for the effects sizes of individual predictors of severe arrhythmia in patients undergoing CAG and/or PCI.Abbreviations: ACEI or ARB or ARNI, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers or angiotensin receptor-neprilysin inhibitors; EF, ejection fraction.

Figure 4 .
Figure 4. Predictors of acute myocardial infarction in patients undergoing CAG and/or PCI.Forest plot for the effects sizes of individual predictors of acute myocardial infarction in patients undergoing CAG and/or PCI.Abbreviations: DAPT, dual antiplatelet therapy; CCB, Calcium Channel Blockers; GFR, glomeruar filtration rate; RBC, red blood cells; EF, ejection fraction; MI, myocardial infarction.

Table 1 .
Baseline characteristics in patients undergoing CAG and/or PCI.SBP systolic blood pressure, DBP diastolic blood pressure, BMI body mass index, LOS length of stay, EF ejection fraction, MI myocardial infarction, CVA cerebrovascular accident, PCI percutaneous coronary intervention, CABG coronary artery bypass graft surgery, DM diabetes mellitus, CKD chronic kidney disease, ACS acute coronary syndrome, AF atrial fibrillation, PAH pulmonary artery hypertension, HF heart failure, CCB Calcium Channel Blockers, ACEI or ARB or ARNI angiotensin-converting enzyme inhibitors or angiotensin receptor blockers or angiotensin receptor-neprilysin inhibitors, DAPT dual antiplatelet therapy, ALP albumin, Scr serum creatinine, NE neutrophils, WBC White blood cells, RBC red blood cells, TC total cholesterol, GFR glomeruar filtration rate, NLR neutrophil to lymphocyte ratio, Hs-CRP high-sensitivity C-reactive protein.

Table 2 .
The risk of CIN and clinical outcomes in patients undergoing CAG and/or PCI.CIN contrastinduced nephropathy, AMI acute myocardial infarction, MACE major adverse cardiovascular events.Model 1 was adjusted for age and sex.Model 2 was adjusted for Model 1 plus other risk factors.