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| Year : 2010 | Volume
: 21
| Issue : 2 | Page : 276-283 |
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| The role of theophylline in prevention of radiocontrast media-induced nephropathy |
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Mahmoud Malhis, Sami Al-Bitar, Khair Al-Deen Zaiat
Department of Internal Medicine, Faculty of Medicine, Aleppo University Hospitals, Syrian Arab Republic
Click here for correspondence address and email
| Date of Web Publication | 9-Mar-2010 |
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 Abstract | | |
Contrast media induced nephropathy (CIN) results in significant morbidity and mortality. We therefore investigated whether theophylline (adenosine antagonist) reduces the incidence of contrast media induced nephropathy. Two hundred and eighty patients were randomly assigned to prophylactic administration of hydration with sodium bicarbonate plus theophylline (either orally or intravenously) (n=128) or hydration with sodium bicarbonate only (n=152). Blood Urea, creatinine, and glomerular filtration rate (MDRD) were measured before and after administration of contrast media. Both groups were similar in clinical characteristics and amount of contrast used. Theophylline prophylaxis significantly reduced the incidence of CIN (1.6% vs 7.9%; P= 0.015). Compared to low-risk patients, Theophylline prophylaxis significantly reduced the incidence of CIN in moderate and high-risk patients (0% vs 8.8%; P= 0.022 and 9.1% vs 42.1%; P= 0.014 respectively). In conclusion, prophylactic administration of theophylline reduces the incidence of CIN in moderate and high-risk patients for CIN.
How to cite this article:
Malhis M, Al-Bitar S, Al-Deen Zaiat K. The role of theophylline in prevention of radiocontrast media-induced nephropathy. Saudi J Kidney Dis Transpl 2010;21:276-83 |
How to cite this URL:
Malhis M, Al-Bitar S, Al-Deen Zaiat K. The role of theophylline in prevention of radiocontrast media-induced nephropathy. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2022 Aug 9];21:276-83. Available from: https://www.sjkdt.org/text.asp?2010/21/2/276/60194 |
| Introduction | |  |
Nephrotoxicity due to the administration of radiocontrast agents is a common and preventable cause of acute renal failure (ARF). Contrast-induced nephropathy (CIN) is the third leading cause of ARF in hospitalized patients. [1] The incidence of CIN varies from 0 to 50% depending on the definition of CIN used and the risk profile of the patient population included in the study. [2] CIN is defined as an increase in serum creatinine of at least 0.5 mg/dL in patients with a baseline serum creatinine less than 2 mg/dL or an increase of 25% in baseline SCr with a baseline serum creatinine more than or equal to 2 mg/dL at 48 h after administration of contrast media. [3],[4] CIN appears to be the result of a synergistic combination of direct tubular epithelial cell toxicity and alterations in renal hemo-dynamics with renal medullary ischemia. [5] Although the mediators of these changes are still not very clearly defined, alterations in the metabolism of prostaglandins, nitric oxide, endothelin, and adenosine may play a role. [6],[7],[8]
Various preventive strategies have been employed to reduce the incidence of CIN. [9],[10],[11],[12],[13],[14],[15],[16],[17],[18] These include administration of intravenous fluids, [9],[10] frusemide, [11] mannitol, [11],[12] low-dose dopamine, [13], [14,[15] atrial natriuretic peptide (ANP) [16] and calcium-channel blockers. [17],[18] However, the results of most studies are conflicting and only hydration is still the main preventive strategy so far.
Since adenosine may have a role in the pathogenesis of CIN, an adenosine antagonist (theophylline) has been investigated as a means of reducing the risk of CIN. [19],[20],[21],[22],[23] The purpose of this prospective study was to determine whether alterations in renal function after administration of radiocontrast agents can be prevented by theophylline.
| Materials and Methods | | |
We prospectively studied 280 patients, aged 14-79 years, who were referred to Aleppo University Hospitals for radiographic imaging with contrast medium (coronary angiography, percutaneous coronary angioplasty, CT scan, angiography, Intra venous pyelography). 57 patients had a serum creatinine ≥ 1.5 mg/dL. Exclusion criteria included (i) acute renal failure, (ii) maintenance dialysis, (iii) a history of acute myocardial infarction, (iv) left ventricular ejection fraction (EF) ≤ 25%, (v) allergy to contrast media, (vi) pregnancy, (vii) contraindications for theophylline use such as untreated high-grade arrhythmia or history of seizure, and (viii) the use of acetylcysteine. Prior to radiographic imaging, all patients had tests to measure serum Na+, K+, blood urea, creatinine. Glomerular filtration rate (GFR) was calculated using MDRD equation (Modification of Diet in Renal Disease). [24] The patients were randomized into two groups: control group (n= 152), who received hydration with sodium bicarbonate only, and theophylline group (n= 128), who received hydration with sodium bicarbonate plus theophylline (either orally; 200 mg b.d. starting 24 h before radiography and continuing for 48 h thereafter or intravenously; 200 mg theophylline as a short infusion 30 minutes before radiography and continuing with 200 mg b.d of oral theophylline for 48 h thereafter). All patients received 1-2 L of intravenous bicarbonate solution (150 meq/L) for 12 h after the procedure, hydration was performed according to clinical examination findings, radiographic evidence of pulmonary edema in patient with heart failure. Radiography was performed using Low-osmolar nonionic contrast agents (Iohexol, Iopamidol) or isoosmolar nonionic contrast agent (iodixanol). All laboratory tests were repeated 48h after radiography.
Case definition
CIN was defined as mentioned above.
CIN risk score was calculated in each patient. Patients were categorized into four groups according to the risk score for CIN: low risk (scores ≤ 5), moderate risk (scores 6-10), high risk (scores 11-15) and very high risk (scores ≥16) [Table 1],[Table 2]. [25]
Modification of Diet in Renal Disease equation:
GFR (mL/min/1.73m 2 ) = 186 × (Scr) -1.154 × (Age) -0.203 ×(0.742 if Female) × (1.210 if Black)
Follow-Up and Endpoints
Follow-up data were obtained from the hospital's databases, the patient's medical record, and interview. The primary end point was the incidence of contrast-induced nephropathy and the secondary end point was the need for hemodialysis.
| Statistical Analysis | | |
Student's t-test and Chi-Square tests were used to calculate the significance of the results. A P-value <0.05 was taken as significant. All data are expressed as means ± SD. Relative risk was performed for predictors of CIN. SPSS 12.0 was used for the statistical analysis.
| Results | | |
Patients receiving theophylline and control subjects were comparable with regard to risk factors for contrast-induced nephropathy [Table 3], such as mean serum creatinine level before contrast medium administration (1.38 mg/dL ± 0.79 vs 1.21 mg/dL ± 0.48, respectively), glomerular filtration rate (66 ± 26 vs 71 ± 27, respectively) amount of contrast medium (137 mL ± 76 vs 144 mL ± 78, respectively), diabetes prevalence (31.3% vs 33.6%, respectively) and heart failure prevalence (22.7% vs 19.7%, respectively), P> 0.05.
Incidence of and Predictive Factors for contrast-induced nephropathy
Of the 280 patients, 14 (5%) fulfilled the criteria for CIN. These patients with CIN [Table 4]; 6 (42.9%) were men, with mean age 58.64 ± 8.96 years, mean weight 79.29 ± 9.9 kg, and mean hemoglobin 11.37 ± 1.9 g/dL. 9 (64.3%) of them had a serum creatinine concentration before imaging ≥ 1.5 mg/dL [Figure 1],[Figure 2], more than 70% were diabetics, had heart failure, and were using diuretics. The mean amount of contrast media was196.4 ± 116.8 in patients with CIN.
Patients who developed CIN had higher mean Risk Score (12.00 ± 2.9) compared to those who did not develop CIN (4.55 ± 3.9) [Table 4].[Table 5] reveals the relative risk for each risk factor which has been calculated in the control group.
Analysis of the incidence of CIN according to risk score demonstrated significant trend for predicting CIN as the risk score increased (P< 0.001) [Table 6],[Figure 3].
Role of theophylline
Following administration of contrast medium, compared to baseline, there were no significant changes in serum creatinine concentrations 48 hours in the theophylline group; however mean GFR increased significantly [Table 7].
In contrast, the controls had an increase in serum creatinine and fall in GFR [Figure 4],[Table 7] P= 0.01 after radiography.
Incidence of CIN
Only two patients in the theophylline group (1.6%) fulfilled the criteria for CIN, compared to twelve (7.9%) in the control group (P= 0.015) [Table 8].
Three patients (one from the theophylline group and two from the control group) suffered from oliguria, two of the three patients responded to hydration and diuretics and one (from the theophylline group) required dialysis due to pulmonary edema.
According to CIN risk score, in low-risk patients theophylline prophylaxis nonsignificantly reduced the incidence of CIN (0% vs 1.0%; P= 0.339). In moderate and high-risk patients, theophylline prophylaxis significantly reduced the incidence of CIN (0% vs 8.8%; P= 0.022 and 9.1% vs 42.1%; P= 0.014) respectively, [Table 8].
| Discussion | | |
Our study shows that theophylline significantly reduces the incidence of CIN compared to hydration alone. Intravenous administration of contrast continues to be an important and often preventable cause of hospital-acquired ARF. Almost all patients have a peak in serum creatinine by 3-5 days and majority revert to normal renal function, and dialysis is rarely required, only one of our patient required dialysis. CIN may result from a synergistic combination of direct tubular epithelial-cell toxicity and renal tubular ischemia. [5]
Role of adenosine
Adenosine has been shown to reduce renal blood flow and glomerular perfusion pressure by means of A1-receptor-mediated renal afferent arteriolar vasoconstriction and A2-receptormediated efferent arteriolar vasodilatation. The administration of contrast in human subjects is known to be associated with the production of endogenous intrarenal adenosine. The vasoconstrictive and potentially deleterious effects of adenosine on renal blood flow can be significantly reduced with adenosine antagonists (e.g. theophylline). [5]
In addition to our results, several clinical studies [19],[20],[21],[22],[23] have shown a benefit of theophylline prophylaxis.
The efficacy of theophylline in reduction of CIN in our study was demonstrated in three ways:
- Reduction of the incidence of contrast-induced nephropathy,
- Prevention of an increase of mean serum creatinine level, and
- Prevention of a decrease glomerular filtration rate.
We also stratified our patients according to different risk factors, [Table 1] and[Table 2]. This scoring has been validated before by Mehran et al who developed a simple risk score for CIN after PCI. Data were obtained from 5,571 patients in a prospective interventional cardiology database who underwent PCI and had documented pre- and post-procedural SCr data. [25] We applied the same risk scores in our patients since these are the commonly encountered and well recognized risk factors. [10],[11],[12],[13],[14],[25]
Both, theophylline and control groups were comparable with regard to risk factors at base line. Overall the changes in serum creatinine, GFR and incidence of CIN was significantly less compared to control group, P<0.05. These changes occurred 48 hours after the contrast medium injection.
Patients in moderate and high risk score category, theophylline prophylaxis reduced the incidence of CIN (P= 0.014).
Role of theophylline in other studies:
Erley et al [26] studied the role of intravenous theophylline (5 mg/kg) and found that, compared with placebo, it prevented the fall in creatinine, inulin, and para-aminohippurate clearances. However, their cohort included only 15% of diabetics, and there were no significant changes in renal function in any of the patients they studied. In a study comparing saline hydration, saline hydration plus dopamine, and saline hydration plus intravenous aminophylline infusion, Abizaid et al [15] reported that neither dopamine nor aminophylline reduced the incidence of CIN when compared with saline hydration alone. Data for oral theophylline in the prevention of CIN is scant and contradictory. Katholi et al [19] studied the effect of 2.88 mg/kg oral theophylline (every 12 h, four doses) compared with placebo in the prevention of CIN. They reported that although serum creatinine did not change significantly, theophylline completely prevented the fall in creatinine clearance within 24h of non-ionic contrast use and almost half after ionic contrast. Kapoor et al studied 70 diabetics, half of the patients received oral theophylline, for development of CIN with high-osmolar contrast media. 11 (31%) of the control group and only one in the theophylline group developed CIN, P= 0.0004. They documented the true changes by measuring GFR by measuring the blood levels of 99mTc DTPA. Our study confirms their finding. Kapoor et al had included all type II diabetics in their study, nevertheless 70% of our patients were also diabetics. A recent systematic review and meta-analysis [27] also found evidence supporting the use of theophylline for the prevention of CIN, though promising, still remains inconclusive.
In conclusion, prophylactic administration of theophylline reduces the incidence of CIN in moderate and high-risk patients.
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Correspondence Address:
Khair Al-Deen Zaiat
Department of Internal Medicine Faculty of Medicine, Aleppo University Aleppo, Syrian Arab Republic
 Source of Support: None, Conflict of Interest: None  | Check |
PMID: 20228513 
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8] |
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