Inflammatory Indicator and Hematological Indices in Contrast Induced Nephropathy among Patients Receiving Coronary Intervention: A Systematic Review and Meta-Analysis

Background: Strong indicators of inflammation, such as C-reactive protein (CRP), hypersensitive CRP (hs-CRP), and a series of hematological indices, including platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), hematocrit (HCT) and red blood cell distribution width (RDW), are regarded related with the incidence of contrast induced nephropathy (CIN) closely. Whereas, it remains unclear whether they can function as predictors of CIN onset. The objective of this meta-analysis was to determine the relationship between above indicators and CIN incidence among patients receiving coronary intervention. Methods: Clinical studies were retrieved from the electronic databases of PubMed, EMBASE, Google Scholar, Clinical Trials, and science direct from their inception to June 3rd, 2020. Meta-analysis was performed on pool eligible studies. Two reviewers screened all titles and abstracts and independently assessed all articles. Results: A total of 26 studies involving 29,454 patients were included in the metaanalysis. Pooled analysis results revealed that patients with higher CRP (odds ratio [OR]=1.06, 95% confidence interval [CI]: 1.01–1.12, P=0.02), hs-CRP (OR=1.03, 95% CI: 1.01–1.06, P=0.004), NLR (OR=1.11, 95% CI: 1.01–1.20, P=0.02), RDW (OR=1.35, 95% CI: 1.19–1.53, P<0.00001), and lower HCT (OR=0.94, 95% CI: 0.92– 0.97, P=0.0003) all exhibited significantly higher CIN rates, but there was no significant association between PLR and CIN risk (OR=1.12, 95% CI: 0.99–1.26, P=0.07). Conclusion: The meta-analysis reported here demonstrates that pre-angiography Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 16 June 2020 doi:10.20944/preprints202006.0199.v1


Introduction
Contrast-induced nephropathy (CIN) is an increasingly common cause of iatrogenic acute kidney injury (AKI), leading to the extension of hospitalization, increasement of the short-and long-term mortality, and accelerated progression of underlying chronic kidney disease.(1) Inflammation contribute to the pathogenesis of CIN in the setting of acute coronary syndrome (2) and diabetic kidney disease. Whereas, whether above inflammatory indicators and hematological indices before coronary intervention can function as predictors of CIN onset remains ambiguous. Therefore, the primary purpose of our study was to evaluate the predictive value of them for CIN using meta-analytical methodology.

Literature search strategy
To identify studies involving the association between inflammatory indicators (CRP/hs-CRP), a serious of hematological indices (PLR, NLR, HCT, RDW) and CIN incidence following coronary intervention, a literature search was conducted among 5 English databases (PubMed, EMBASE, Google Scholar, Clinical Trials, and science direct), from their inception to July 31, 2018. We checked these electronic databases using the following searching strategies: ("C-reactive protein" or "high sensitivity Creactive protein" or "CRP" or "hs-CRP" or "neutrophil to lymphocyte ratio" or "neutrophil/lymphocyte" or "NLR" or "platelet to lymphocyte ratio" or "platelet/lymphocyte" or "PLR" or "red blood cell distribution width" or "RDW" or "hematocrit" or "HCT") and ("contrast induced nephropathy" or "acute kidney injury").
Additionally, we performed a computerized search of abstracts. Finally, we screened the references in all relevant articles to identify additional articles that were not retrieved during the initial literature search.

Selection criteria
Our meta-analysis included all studies meeting the following criteria: the definition of CIN: serum creatinine change ≥ 25% or ≥ 44.2 mmol/l (0.5 mg/dL) within short time following coronary angiography and PCI if necessary, patients receiving carotid, peripheral artery angiography or transcatheter aortic valve implantation were excluded; all patients examined at least one of the above inflammatory indicators or hematological indices before coronary intervention; results were part of an original analysis and provided with odds ratio (ORs) and 95% confidence interval (CI) to present the risk of CIN; papers were published in English. We only selected the articles published in peer-reviewed journals and excluded reviews, letters, and meeting abstracts.

Quality assessment
Through independently screening of titles and abstracts by 2 reviewers, the initial relevance evaluation was implemented. The full text was obtained if either reviewer considered any titles or abstracts met the eligibility criteria. The quality and bias risk of the selected papers were critically appraised separately by 2 reviewers. Quality assessment was conducted for each of the eligible studies by using the validated Newcastle-Ottawa Quality Assessment Scale (NOS) to reflect the combined scores of selection, comparability and outcome description. (15) This scale is composed of 8 items that assess patient selection, study comparability, and outcome with scores ranging from 0 to 9. In our meta-analysis, studies with a score ＞6 were graded as high quality.(16) Eventual consensus governance resolved disagreements.

Data extraction
Information from each study was abstracted independently by 2 investigators using a standardized data extraction form, predesigned on the basis of the Cochrane Consumers and Communication Review Group data extraction template. Any disagreement over extracted data was resolved through discussion until the 2 investigators reached a consensus opinion. The primary endpoint was CIN onset. The following information was recorded for each publication: first author's name, publication year, country of origin, cohort design, patient status, numbers of patients, CIN definition, NOS score, detailed patient information including sex distribution, age, rate of hypertension, diabetes mellitus, multi-vessel disease, CIN, value of hemoglobin, left ventricular ejection fractions, estimated glomerular filtration rate, inflammatory indicators or hematological indices in individual studies. When key pieces of information were not present in articles, the corresponding author was contacted. The missing information was classified as "not applicable" when the whole dataset could not be obtained.

Statistical methods
Dichotomous results were summarized as pooled ORs and 95% CIs around the point estimates. ORs was abstracted or calculated to quantitatively evaluate the association between value of individual inflammatory indicators, hematological indices and the CIN incidence rate. The overall pooled effect was assessed using the z-statistic with a p-value＜0.05 representing statistical significance. Heterogeneity between the studies was assessed by x 2 statistics and expressed as an "I 2 " value. When I 2 ≥50% or the P-value for the I 2 statistic was<0.05, which indicated significant heterogeneity across the studies, the pooled estimate was calculated using a random effects model and if the data were contrary, a fixed effect model was adopted. All statistical analyses were carried out using RevMan 5.3 software. All analyses were based on previous published researches, thus no ethical approval or patient consent was required.

Search results
The search strategy yielded 1689 potentially relevant references in the electronic databases. We initially excluded 858 duplicated publications. Upon review of the remaining abstracts, we further removed 747 more articles for reasons of ineligibility.
According to the inclusion criteria established for the present study, an additional 58 articles were excluded. We thus finally selected 26 studies , which consisted of a cohort of 29,454 patients receiving coronary intervention (figure 1).
All of the 26 selected studies assessed the association analysis between preangiography CRP/hs-CRP, hematological indices and CIN, 13 of them contained the relationship between CIN and CRP/hs-CRP (19, 23, 24, 27, 28, 32, 34-36, 38, 39, 41, 43), while 5 of them reported NLR (25,36,38,39,42), 4 explored PLR (19,26,36,42), 5 RDW (29,30,40,41,44) and 7 HCT (17,18,21,31,33,37,40). The definition of CIN was almost consistent among the enrolled studies: serum creatinine change ≥ 25% or ≥ 44. A summary of the available information included in the present meta-analysis is provided in Table 1. NOS score was >6 in each selected study. Basic information and situation, medical history, severity of vascular disease, contrast volume and individual pre-angiographic value of inflammatory indicators or hematological indices were shown in Table 2.  figure 2f). No significant heterogeneity was found among RDW subgroup, so we performed a sensitivity analysis among other subgroups by recalculating ORs and I 2 with 1 study removed and all others included from the pooled estimate, we assessed the influence of each study on the overall estimate. Sensitivity analysis showed no substantial difference in I 2 and pooled ORs when any single study was excluded in most subgroups, which indicated that the conclusion was robust. When we performed a sensitivity analysis in HCT subgroup, we found a substantial difference in I 2 without change in pooled OR when the study of Nakamura(31) was excluded. The heterogeneity may come from the relatively smaller sample (n= 66), higher level of eGFR and higher incidence of CIN due to the wide range of definition time (2-5 days after procedure).
Then we performed subgroup analyses by design, study race (Xanthoderm vs. Caucasian), and whether ACS or non-ACS (Table 3). The country and publication year distribution of our included studies were showed in the figure 3.

Publication bias.
In the meta-analysis, funnel plots were generally asymmetrical. These results indicated that publication bias was significant across the included studies.

Discussion
To our knowledge, so far this is the first systemic review and meta-analysis to investigate the impact of several preprocedural inflammatory indicators and hematological indices on the occurrence of CIN in patients who received coronary intervention. The results from our study suggested that there was a significant link in STEMI patients (59).
Although we failed to get the accurate association between PLR and CIN incidence, a large-scale supported the potential possibility, they demonstrated that being in the PLR 4th quartile was significantly associated with an increased risk of developing CIN (OR 2.26, 95%CI 1.25-4.09, p<0.007), which was not included in our meta-analysis because the overall OR value was not available.(60) PLR >177.5 was found an independent predictive factor for CI-AKI. (61)  Potential publication bias represents a concern, since positive results are more likely to be reported than negative observations. Therefore, more detailed prospective data is needed for future analyses to determine efficient combination of above indicators for further improving the predictive efficiency in clinical practice.

Conclusion
In conclusion, our findings support the hypothesis that a serious of easily acquired inflammatory indicators (CRP, hs-CRP) and hematological indices (NLR, HCT, RDW) are associated with the increasing incidence of CIN, which could help develop algorithms to identify patients at increased risk for CIN who would then be subjected to increased preventive measures. Large-scale prospective studies will be required before we add some of them into novel risk scores.

a. competing interests
There are no competing interests in our study.

b. funding
The authors received no financial support for the research, authorship, and/or publication of this article.
c. data sharing statement No additional unpublished data are available