High-Sensitivity C-Reactive Protein in Patients Undergoing Contrast Studies

Fundamentos: A utilização de agentes iodados em exames radiológicos pode causar nefropatia induzida por contraste (NIC) na presença de fatores de risco clássicos, como doença renal prévia e diabetes. Recentemente, níveis séricos elevados de proteína C-reativa ultrassensível (PCR-us) têm sido descritos como indicadores de maior risco de NIC. Independente da ocorrência de NIC, a PCR-us pode elevar-se após exames contrastados. Objetivo: Investigar o comportamento da PCR-us em pacientes submetidos à administração parenteral de agente de contraste iodado. Métodos: Estudo observacional, transversal, prospectivo, realizado no Hospital Universitário Antônio Pedro, de 2007 a 2014, envolvendo 51 pacientes, 30 homens e 21 mulheres, média de idade 60,19±20,0 anos, submetidos a exames com contraste de baixa osmolalidade (Iopamidol 612 mg/mL). Resultados: NIC ocorreu em 15 pacientes (29,4%). Não houve correlação entre a PCR-us aumentada e a ocorrência de NIC. O aumento percentual da PCR-us foi significativamente maior entre os pacientes submetidos ao cateterismo cardíaco (p=0,0044). O aumento médio da PCR-us nos pacientes submetidos ao cateterismo cardíaco e naqueles submetidos à administração do contraste iodado por veia periférica foi 100,3% e 13,8%, respectivamente. Conclusão: Os achados sugerem que o aumento da PCR-us após cateterismo cardíaco não pode ser atribuído ao agente de contraste iodado.


Introduction
The use of iodinated contrast is increasingly common.About 80 million/year diagnostic or therapeutic interventions are held with radiological contrast worldwide 1 .In the United States, the number of coronary percutaneous invasive procedures increased by more than 300% in the last two decades 2 .A serious complication from the use of these agents is the contrast-induced nephropathy (CIN) [3][4][5] .
CIN is the third iatrogenic cause of acute renal failure in hospitalized patients and is associated with high mortality rate 3,[6][7][8][9] .Its incidence is variable and depends on the presence of risk factors, the type and quantity of contrast agent used, sensitivity, and the method employed for the diagnosis of renal involvement 10,11 .
Vacuolation of epithelial cells of the renal proximal tubules follows the intravascular administration of iodinated contrast and the structural changes are reversible after a few days of its administration.It seems to be no correlation between the degree of vacuolization in the tubular cells and the intensity of functional renal damage 12,13 .In prospective studies, the incidence of CIN ranged from 12-27%, but may reach more than 60% in patients with diabetic nephropathy with creatinine >3 mg/dL 12 .
Advanced age, heart failure, hypovolemia, renal failure, chronic liver disease, hyperuricemia, female sex and high contrast doses are often identified as risk factors for CIN and require a critical assessment of the risks and benefits for contrast-enhanced studies.When tests using contrast media are indispensable, protective measures should be used 10,[14][15][16] .
High serum levels of high-sensitivity C-reactive protein (hs-CRP) have been recently related to increased risk of CIN.hs-CRP is a protein of the acute phase and may also increase during chronic inflammatory processes 1,17-19 .
Gao et al. 14 demonstrated that the level of pre-procedure hs-CRP was a strong independent predictor for the risk of CIN in patients undergoing coronary angioplasty.Similar results were found by Jian-Wei et al. 7 , especially in those patients whose baseline hs-CRP was >6.50 mg/L, which is also strongly associated with higher in-hospital mortality.Liu et al. 6 noted that post-procedure hs-CRP is a useful independent predictor of CIN and was also significantly associated with in-hospital mortality in patients undergoing primary percutaneous coronary intervention.
Increased levels of hs-CRP after administration of iodinated contrast medium in cardiac catheterization procedures, regardless of the presence of CIN, was reported by Carraro-Eduardo et al. 20 In an attempt to elucidate whether this increased hs-CRP had been caused by non-ionic iodinated contrast medium or by cardiac catheterization, patients submitted to administration of iodinated contrast by peripheral vein were compared with those undergoing catheterization.

Methods
Observational  evaluated immediately before and 48 hours after administration of iodinated contrast.
Contrast-induced nephropathy was considered when there was relative increase of 25% or absolute increase of 0.5 mg/dL at baseline serum creatinine within 48 hours of exposure to iodinated contrast in the absence of an alternative cause 3 .
Statistical analysis was performed using the software S-Plus 8.0.To compare numeric data, Mann-Whitney test was used.In this study, p values <0.05 were considered statistically significant.

Results
Based on the nonparametric Wilcoxon-Mann-Whitney test, there was a statistically significant difference between the volumes of contrasts applied to patients from the hemodynamics and tomography groups (U=78.500;W=268.500;p-value=0.004).
The patients in the HG group received greater amounts of contrast than the TG group (Figure 1).CIN occurred in 15 (29.4%) patients, 9 from the TG.There was no correlation between higher levels of hs-CRP and the occurrence of CIN.

Discussion
In this study, although the CIN occurred in 29.4% of patients, high levels of pre-procedure hs-CRP or hs-CRP increase after administration of iodinated contrast showed no correlation with renal injury.
In a study involving 165 patients undergoing primary percutaneous coronary intervention after myocardial infarction with ST-segment elevation, the incidence of CIN was significantly higher among patients with high hs-CRP 16 .Similar results were found in a retrospective study with 1452 patients 7 .This study involved a smaller number of patients with lower severity profile and lower medium levels of hs-CRP, which may explain this discrepancy in the results.
CIN is a serious adverse event from the use of nonionic iodinated contrast medium in cardiac catheterizations and is associated with increased morbidity and mortality 3,[6][7][8][9] .Its pathophysiology is complex, involving direct cytotoxicity, oxidative stress and intrarenal hemodynamic changes 4 .The participation of inflammatory components in the genesis of CIN is not totally clear yet 4 .
The percentage increase in hs-CRP was significantly higher in the HG group (p=0.0044)(Table 2).Average increase in the HG group was 100.3%, while in the TG group, the increase was 13.8%.
A previous study had found that hs-CRP, an acute phase reactant in inflammatory processes, was significantly increased in patients undergoing cardiac catheterization, regardless of the occurrence of CIN 20 .
There was a sevenfold increase of hs-CRP in the HG group than in the TG group.The average pre-procedure hs-CRP was not significantly different in both groups (p=0.5782).As the two groups were comparable and all patients underwent the same iodinated contrast agent, increased hs-CRP levels observed in patients undergoing catheterization seems to be a consequence of catheterization.While no patient has received any iodinated contrast agent levels exceeding 150 mL, average volumes of Iopamidol were significantly higher in the HG group and this may be a limitation of this study.
The association between high hs-CRP and increased risk of acute kidney injury after iodinated contrast administration has been demonstrated by different authors 7,16 .However, some studies demonstrate that hs-CRP increases routinely after iodinated contrast administration via cardiac catheterization and that this increase is a result of the contrast agent.Although a limitation in this study is that the average volume of contrast used in tests with arterial catheterization has been slightly larger than the one used in tests with administration of nonionic iodinated contrast via peripheral vein, it is a pioneer and is of clinical importance, since hs-CRP is an acute phase protein produced in the liver in response to tissue damage induced by various stimuli such as trauma, inflammation, infections and malignancies.
hs-CRP, more recently described, is able to detect much lower concentrations of hs-CRP (0.03 mg/L detection limit).Its importance was clearly demonstrated in JUPITER 21,22 , involving 18,000 participants.In this study, statins reduced infarction and strokes in patients without heart disease or hypercholesterolemia, but with changes in the serum levels of hs-CRP 21,22 .Not knowing that hs-CRP levels increase in invasive procedures such as cardiac catheterization may lead to misdiagnosis and inappropriate management.

Conclusion
The results strongly suggest that the increase in hs-CRP observed after hemodynamic tests is not due to the contrast medium, but to the invasive cardiac catheterization procedure.

Potential Conflicts of Interest
This study has no relevant conflicts of interest.

Sources of Funding
This study had no external funding sources.

Academic Association
This study is not associated with any graduate programs.

Figure 1
Figure 1 Distribution of contrast volumes of patients undergoing computed tomography and on hemodynamic test.

Table 1 Baseline characteristics of the study population
HS -hemodynamic study; CT -computed tomography; Crcreatinine; hs-CRP -high-sensitivity C-reactive protein; *values expressed as mean±standard deviation

Table 2 Biochemical profile after contrast test
HS -hemodynamic study; CT -computed tomography; Crcreatinine; hs-CRP -high-sensitivity C-reactive protein; *values expressed as mean±standard deviation