Saudi Journal of Kidney Diseases and Transplantation

ORIGINAL ARTICLE
Year
: 2010  |  Volume : 21  |  Issue : 2  |  Page : 276--283

The role of theophylline in prevention of radiocontrast media-induced nephropathy


Mahmoud Malhis, Sami Al-Bitar, Khair Al-Deen Zaiat 
 Department of Internal Medicine, Faculty of Medicine, Aleppo University Hospitals, Syrian Arab Republic

Correspondence Address:
Khair Al-Deen Zaiat
Department of Internal Medicine Faculty of Medicine, Aleppo University Aleppo, Syrian Arab Republic

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;21:276-283


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 Jan 25 ];21:276-283
Available from: https://www.sjkdt.org/text.asp?2010/21/2/276/60194


Full Text

 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.

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 (PRole 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, andPrevention 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, PRole 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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