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Brazilian Journal of Nephrology

Print version ISSN 0101-2800

J. Bras. Nefrol. vol.37 no.1 São Paulo Jan./Mar. 2015

http://dx.doi.org/10.5935/0101-2800.20150005 

Original Articles

Contrast-induced nephropathy after computed tomography

Nefropatia induzida por contraste após tomografia computadorizada

Luciano da Silva Selistre1  2 

Vandréa Carla de Souza1  3 

Laurence Dubourg4 

Mário Bernardes Wagner2  3 

João Rubião Hoefel Filho2 

David Saitovitch2 

1University of Caxias do Sul

2Pontifical Catholic University of Rio Grande do Sul

3Federal University of Rio Grande do Sul

4Civilian Hospital of Lyon

ABSTRACT

Introduction:

Contrast induced nephropathy is the third most prevalent preventable cause of acute kidney injury in hospitalized patients. It defined as an absolute increase in serum creatinine ≥ 0.5 mg/dL and relative ≥ 25% increase.

Objective:

We studied the risk factors to intravenous injection contrast nephropathy after computed tomography.

Methods:

We studied 400 patients prospectively.

Results:

The incidence of contrast induced nephropathy, with an absolute or a relative increase were 4.0% and 13.9%, respectively. Diabetes and cardiac failure were independent risk factors for CIN a relative increase de serum creatinine (O.R.: 3.5 [95% CI: 1.92-6.36], p < 0.01, 2.61 [95% CI: 1.14-6.03%], p < 0.05, respectively).

Conclusions:

We showed association between uses of intravenous injection contrast after computed tomography with acute injury renal, notably with diabetes and heart failure.

Key words: contrast media; risk factors; tomography

Introduction

Contrast-induced nephropathy (CIN) is an important cause of acute kidney injury (AKI) in hospitalized patients. There are several risk factors associated with CIN after arterial infusion: high doses of iodine; diabetes mellitus (DM); old-age, chronic renal failure (CKD); female gender, heart failure (HF), association with nephrotoxic drugs, etc.1-6

CIN pathogenesis is related to direct toxic effect of contrast medium on the tubular epithelial cells and results from direct hemodynamic disturbances in renal blood flow. Renal tubules are less prone to injury when isosmotic contrast medium is used as compared to low-osmolality contrast media. Intravascular contrast administration effects on renal blood flow were biphasic. The initial vasodilatation turns into the longest lasting phase of reduced renal blood flow, consequent to vasoconstriction and hypoxia. Moreover, there is a release of endogenous factors such as endothelin, adenosine, free radicals, Ca2+ ions, and the glomerular filtration rate issue.6,7

However, the CIN incidence in computed tomography (CT) is quite complex. The use of intravenous contrast to enhance imaging has increased substantially in recent years. Studies have described a CIN incidence between 5 and 13% in outpatients after venous contrast injection to enhance CT scan images. These studies are limited by their retrospective design and patient selection bias.3,5,8,9

This study evaluated CIN incidence in hospitalized patients after CT scan with intravenous contrast injection, its relation with classic risk factors (DM, HF, old age, etc.) and contrast volume with variations in serum creatinine (SCr) levels.

Methods

Study population

Our cohort study allocated 400 hospitalized patients from a single center (Hospital São Lucas PUCRS) between January 01, 2007 and March 31, 2008. All patients underwent CT scan with hyperosmolar intravenous contrast (59.285 g, meglumine 15.1 g/100 mL, iodine content of 300 mg/mL, osmolality of 1650 mOsm/kg H2O, Telebrix 30 Laboratory Guebert).

Inclusion criteria for this study were: age over 18 years and hospitalization.

Exclusions criteria were: drugs that can interfere with the SCr assay (e.g.: cephalosporins, barbiturates, chemotherapeutic agents) and its secretion (e.g.: trimethoprim, cimetidine).

All patients signed consent forms. The local ethics committee approved this study.

Study execution

SCr values were obtained from a kinetic colorimetric compensated Jaffe technique (Roche Modular, Meylan; compensation according to manufacturer's recommendations). We evaluated the assay method's inaccuracy (intra-assay coefficient was 0.7%; interassay coefficients were 4.0% at low SCr (0.51 - 0.71 mg/dL) and 1.5% at high SCr concentrations (6.5 mg/dL), respectively. SCr was tested before and 48 hours after intravenous contrast injection.

To estimate GFR (eGFR), we used the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula:6

We did not divide our sample into CKD groups according to the KIDGO criteria because of the small number of patients with eGFR < 60 mL/min/1.73 m2.

Potential risk factors for CIN were considered based on the concepts and terminology from the American College of Radiology (ACR):5 DM, neoplasia, HF, CKD, female gender, low mean arterial blood pressure upon examination (MBP < 80 mmHg), CKD (eGFR < 60 mL/min/1.73 m2), old-age (≥ 65 years), obesity (BMI ≥ 30 kg/m2), anemia (Hematocrit < 36%). We defined CIN prophylaxis as the use of parenteral hydration with saline solution at a dose of 1 mL/kg/h 6 hours prior to the procedure, and continued up to 12 hours after it.

Outcomes

The primary outcomes was CIN incidence and association with risk factors. Secondary outcome was SCr variation vis-à-vis contrast volume per 1.73 m2 of BSA.

Statistical analysis

Our data was submitted to double entry, checking for inconsistencies.

We used backward stepwise linear and multivariable logistic regression, comparing the new variable to those previously reported. A p value < 0.05 was considered statistically significant. The analyses were performed using R for Windows, version 3.1.1 (R-Cran project) with the MASS package for Windows.

Results

Baseline clinical characteristics

The baseline clinical characteristics of those 400 patients are show on the Table 1. Upon inclusion in the cohort, the participants' mean ages were 59.2 ± 14.8 years. Elderly patients and male gender accounted for 40.2% and 50.4% respectively, with Caucasian predominance at 80.5%. Mean BMI was 24.36 ± 1.74 kg/m2, with underweight and obesity prevalences of 14.8% and 13.6%, respectively.

Table 1 Demographic data set 

Characteristics Patients (N = 400)
Age (years) 59.2 ± 14.8
Old-aged 161 (40.25%)
Female gender 198 (49.50%)
Ethnicity  
White 323 (80.75%)
Afro-Brazilian 77 (19.25%)
Body Mass Surface (m2) 1.74 ± 0.21
Body Mass Index (kg/m2) 24.36 ± 1.74
Obesity 59 (14.75%)
SCr (mg/dL) 0.96 ± 0.38
eGFR < 60 mL/min/1.73 m2 78 (19.50%)
Diabetes 73 (18.25%)
Heart Failure 30 (7.50%)
Neoplasia 249 (62.25%)
MBP < 80 mmHg 60 (15%)
Hematocrit < 36% 200 (50%)
Contrast Volume mL/1.73 m2 142.2 ± 37.7
Metformin 25 (6.25%)
Prophylaxis 97 (24.25%)

eGFR: Estimated glomerular filtration rate; SCr: Serum creatinine; MBP: Mean arterial blood pressure.

Most intravenous contrast-enhanced CT examinations were associated with malignancies (n = 249, 62.25%) in the chest, and chest-abdomen (n = 289, 72.25%). See details on Table 2. Mean contrast volume was of 142.2 ± 37.7 mL/1.73 m2 of BSA.

Table 2 Type of computerized tomography and volume contrast 

Localization N Median volume contrast per 1.73 m2 [IQR]*
Cranial 31(7.75%) 64.0 [54.5; 120.0]
Abdomen 64 (16%) 152.0 [105.5; 198.5]
Thorax 162 (40.5%) 156.0 [49.5; 229.5]
Thoracoabdominal 127 (31.75%) 198.5 [134.5; 249.0]
Others 16 (4%) 132.0 [30.0; 254.0]

Of the entire sample, 25 patients (6.25%) took metformin on the contrast injection day. Only 97 (24.25%) patients received intravenous hydration (Table 1).

We found an increase in baseline SCr of 25% in 61 (15.25%) patients and an absolute increase of 0.5 mg/dL in only 15 (3.75%) patients in our sample (Table 3).

Table 3 Incidence of contrast nephropathy and markers of renal injury 

Outcome
Creatinine (mg/dL)  
Baseline 0.9 ± 0.38
48 hours 1.0 ± 0.47
eGFR (mL/min/1.73 m2)  
Baseline 93.43 ± 14.8
48 hours 91.95 ± 14.7
Occurrence of CIN  
SCr increases ≥ 25% 61 (15.75%)
SCr increases ≥ 0.5 mg/dL 15 (3.75%)

eGFR: Estimated glomerular filtration rate; SCr: Serum creatinine; MBP: Mean arterial blood pressure.

Procedures and variation in renal function

Multivariable logistic regression

After using intravenous contrast for CT, we found an association between absolute increase in SCr ≥ 0.5 mg/dL (Table 4) and ≥ 25% (Table 5) and the following factors: old age, DM, female gender, obesity, HF, CKD, neoplasia and anemia.

Table 4 Risk factors to contrast nephropathy (SCr increases ≥ 0.5 mg/dl) 

Risk factors OR 95% CI P
Old-age 6.3 1.8 to 22.5 < 0.01
Diabetes 10.2 3.4 to 31.0 < 0.01
Female gender 0.9 0.3 to 2.5 0.8
Obesity 1.4 0.4 to 5.5 0.5
Heart failure 13.8 4.5 to 42.0 < 0.01
eGFR < 60 mL/ min/1.73 m2 3.9 1.3 to 11.0 < 0.05
Neoplasia 0.4 0.1 to 1.1 0.6
MBP < 80 mmHg 0.4 0.0 to 2.0 0.4
Hematocrit < 36% 0.6 0.2 to 1.9 0.4

SCr: Serum creatinine; eGFR: Estimated glomerular filtration rate; MBP: Mean arterial blood pressure; CI: Confidence interval; OR: Odds ratio.

Table 5 Risk factors to contrast nephropathy (SCr increases ≥ 25%) 

Risk factors OR 95% CI P
Old-age 1.0 0.6 to 1.8 0.9
Diabetes 3.5 1.9 to 6.4 < 0.01
Female gender 1.5 0.8 to 2.6 0.1
Obesity 1.7 0.8 to 3.3 0.1
Heart failure 2.6 1.1 to 5.9 < 0.05
eGFR < 60 mL/min/1.73 m2 0.5 0.2 to 1.0 0.1
Neoplasia 0.8 0.4 to 1.3 0.3
MBP < 80 mmHg 0.3 0.0 to 1.2 0.2
Hematocrit < 36% 0.8 0.5 to 1.4 0.5

SCr: Serum creatinine; eGFR: Estimated glomerular filtration rate; MBP: Mean arterial blood pressure; CI: Confidence interval; OR: Odds ratio.

Multivariate analysis revealed a relationship between an absolute increase in SCr ≥ 0.5 mg/dL and DM (O.R.: 10.22 [95% CI: 3.37-30.92], p < 0.01); old-age (OR 6.27 [95% CI: 1.74-22.57], p < 0.05) and HF (3.9 [95% CI: 1.36-11.00], p < 0.01) (Table 4).

The relative variation (Table 5) of SCr was associated with diabetes (O.R.: 3.5 [95% CI: 1.92-6.36], p < 0.01) and HF (OR 2.61 [95% CI: 1.14-6.03%], p < 0.05). However, it was not significant vis-à-vis old age and CKD (Table 5).

Regardless of reports in the medical literature, we did not find associations between female gender, obesity, neoplasia, MBP < 80 mmHg, anemia and CIN (Tables 4 and 5).

Multivariate analysis regression model and the impact on renal function fluctuation

Table 6 depicts the impact of contrast volume in relation to SCr increase. In the entire sample there was no difference in SCr after 116 mL of venous contrast injection per 1.73 m2 of BSA (model Ϋ1). However, DM and HF had a significant increase of 22% and 23% (p < 0.01) per 112 and 114 mL of intravenously injected contrast agent per 1.73 m2 of BSA, respectively (model Ϋ2 and Ϋ3). Patients with eGFR < 60 mL/min/1.73 m2 and the elderly in the sample did not show significant variation vis-à-vis contrast agent dose (model Ϋ4 and Ϋ5).

Table 6 Impact on SCr variation (percentage per 100 ml/1.73 m2 of contrast) 

Risk factors Model P
Entire population Ϋ1 = 116X + 0.07 0.3
Diabetes Ϋ2 = 112X + 0.22 < 0.01
Heart Failure Ϋ3 = 114X + 0.23 < 0.01
eGFR < 60 mL/min/1.73 m2 Ϋ4 = 118X + 0.01 0.8
Old-age Ϋ5 = 116X + 0.09 0.2

SCr: Serum creatinine; eGFR: Estimated glomerular filtration rate.

Discussion

CIN-related papers have been published since the 50's, notably after arterial contrast injection started. However, only a handful of studies have investigated CIN with intravenous contrast injection for CT.1-5,10 These studies described similar risk factors for patients undergoing CT and angiographic exams. Nyman et al.10 reported a CIN incidence of 6.4% after CT and higher CIN incidences in patients with impaired GFR.

Our results show CIN incidence after CT of 3.75 and 15.75%, with CIN defined as the absolute or relative increase of SCr, respectively. Thomsen et al.11 described that these two definitions of CIN are not interchangeable, because SCr is not an adequate marker for CIN. Thus, > 50% of renal function must be lost before an elevation in SCr is detected. In addition, SCr does not accurately depict GFR until a steady state has been reached, which may require several days12 - this could explain the different CIN incidence found in our study. The Acute Kidney Injury Network (AKIN) suggested two separate CIN endpoints using both absolute and relative SCr alterations.6 Their proposed diagnostic criteria for AKI include an absolute increase in the SCr level of ≥ 0.3 mg/dL. However, calculations by Waikar & Bonventre13 showed that increases in SCr of 0.3 mg/dL are only significant when they occur within 24 h; and 0.5 mg/dL at 48 h after CT may be a more appropriate cut-off point. Moreover, the medical literature is based on the concepts and terminology from the American College of Radiology (ACR) in reference to CIN studies, this report will do the same.5 However, we recognize that the clinical effects of slightly different definitions of CIN and AKI have yet to be clarified.6

Our results confirmed significantly classical risk factors to CIN after CT as being: CKD, DM and HF. Mehran et al.14 showed an incidence of 8.8% and 5.2%, after arterial injection in patients with CKD and DM, respectively. In patients with CKD, HF and the elderly, SCr rises more steeply when hemodynamic changes occur or contrast is administered.4,7

Our study demonstrated a statistically significant association, although low, between contrast medium volume and CIN, notably in DM and HF. It is opposite to the findings reported by other publications.8,10,15-17 Nyman et al.10 suggested a dose in grams of iodine numerically equal to the eGFR value in mL/min during percutaneous coronary intervention. These authors described a CIN frequency of 12% at an iodine dose (in grams)/GFR ratio of 1.1. Our study demonstrated the risk of GFR reduction by checking SCr, especially among patients with diabetes, CKD and HF.

Other relevant information from our data was: lowest prescription of preventive hydration before TC (27.75%) and higher intake of biguanide (metformin) on the contrast injection day (6.25%). The European Guidelines to CIN described that 75% of CIN studies reported some form of hydration as a prevention approach.18 They recommended expansion volume before contrast with saline or bicarbonate solution. Biguanide (metformin) has the possibility of worsening CIN, with an associated increased risk of lactic acidosis. However, there are no direct studies on the subject.18 Prevention guidelines are based on the expert consensus about metformin pharmacokinetics and CIN pathophysiology.4,6,18 In this study, we did not find any association between CIN and the use of metformin or lack of expansion volume (data not shown in the study).

The main strength of the meta-analysis is the large number of patients included (n = 400), resulting in an estimate of the CIN incidence after contrast-enhanced CT. Moreover, we have chosen a logistic model by default for all analyses to cope statistically with patient heterogeneity, resulting in a conservative incidence estimate compared to a fixed effects model.

The limitations of our study are mainly the facts that it was carried out in a single center and the impossibility of monitoring these patients to determine other possible outcomes such as death or dialysis.

Conclusion

Despite the difficulties due to the variability of this population, this study is one of the few prospective publications that have shown the use of intravenous contrast after CT as a variation factor associated with acute kidney injury. This condition is stronger in patients with diabetes and heart failure.

References

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Received: April 08, 2014; Accepted: December 04, 2014

Correspondência para: Luciano da Silva Selistre, Pontifical Catholic University of Rio Grande do Sul, Rua Adelino Roldo, nº 310, Caxias do Sul, RS, Brazil. CEP: 95052-020, Tel: 55 54 9122-4798. Fax: 55 54 32022540. E-mail: selistre71@gmail.com

Conflicting interests

The authors declare that they have no conflicting interests.

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