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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 2  |  Page : 276-283
The role of theophylline in prevention of radiocontrast media-induced nephropathy


Department of Internal Medicine, Faculty of Medicine, Aleppo University Hospitals, Syrian Arab Republic

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Date of Web Publication9-Mar-2010
 

   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 2019 May 21];21:276-83. Available from: http://www.sjkdt.org/text.asp?2010/21/2/276/60194

   Introduction Top


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 Top


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 Top


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 Top


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 Top


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:

  1. Reduction of the incidence of contrast-induced nephropathy,
  2. Prevention of an increase of mean serum creatinine level, and
  3. 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.

 
   References Top

1.Hue SH, Bushinsky DA, Wish JB, et al. Hos­pital acquired renal insufficiency: a prospec­tive study. Am J Med 1983;74:743-8.  Back to cited text no. 1      
2.Lautin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-associated renal dysfunction: Incidence and risk factors. AJR Am J Roentgenol 1991;157(1):49-58.  Back to cited text no. 2      
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4.Schweiger MJ, Chambers CE. Prevention of contrast induced nephropathy: Recommenda­tions for the high risk patient undergoing cardiovascular procedures. Catheter Cardiovasc Interven 2007;69:135-40 .  Back to cited text no. 4      
5.Rudnick MR, Aaron K, Stainly G. Contrast­induced nephropathy: How it develops, how to prevent it. Clevland Clin J Med 2006;73(1):75­-87.  Back to cited text no. 5      
6.Pflueger A, Larson TS, Nath KA, King BF, Gross JM, Knox FG. Role of adenosine in contrast media-induced acute renal failure in diabetes mellitus. Mayo Clin Proc 2000;75: 1275-83.  Back to cited text no. 6  [PUBMED]    
7.Rudnick MR, Berns JS, Cohen RM, Goldfarb S. Contrast media-associated nephrotoxicity. Semin Nephrol 1997;17:15-26.  Back to cited text no. 7  [PUBMED]    
8.Heyman SN, Brezis M, Epstein FH, Spokes K, Silva P, Rosen S. Early renal medullary hypoxic injury from radiocontrast and indomethacin. Kidney Int 1991;40:632-42.  Back to cited text no. 8  [PUBMED]    
9.Eisenberg RL, Bank WO, Hedgeock MS. Renal failure after major angiography. Am J Med 1980;68:43-6.  Back to cited text no. 9      
10.Teruel JL, Marcen R, Herrero JA, et al. An easy easy and effective procedure to prevent radio­contrast agent nephrotoxicity in high-risk pa­tients. Nephron 1989;51:282.  Back to cited text no. 10  [PUBMED]    
11.Solomon RC, Werner C, Mann D, et al. Effects of saline, mannitol and furosemide on acute decreases in renal function induced by radio­contrast agents. N Engl J Med 1994;331:1416-­20.  Back to cited text no. 11      
12.Weisberg LS, Kurnik PB, Kurnik BR. Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 1994;45: 259-65.  Back to cited text no. 12  [PUBMED]    
13.Kapoor A, Sinha N, Sharma RK, et al. Use of dopamine in prevention of contrast induced acute renal failure: A randomized study. Int J Cardiol 1996;53:233-6.  Back to cited text no. 13  [PUBMED]    
14.Hall KA, Wong RW, Hunter CC, et al. Contrast induced nephrotoxicity: The effects of vaso­dilator therapy. J Surg Res 1992;53:317-20.  Back to cited text no. 14      
15.Abizaid AS, Clark CE, Mintz GS, et al. Effects of dopamine and aminophylline on contrast induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency. Am J Cardiol 1999;83:260-3.  Back to cited text no. 15  [PUBMED]    
16.Kurnick BR, Allgren RL, Genter FC, et al. Pros­pective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephro­pathy. Am J Kidney Dis 1998;31:674-80.  Back to cited text no. 16      
17.Neumayer HH, Junge W, Kufner A, Wenning A. Prevention of radiocontrast-media-induced nephrotoxicity by the calcium-channel blocker nitrendipine: A prospective randomized clini­cal trial. Nephrol Dial Transplant 1989;4:103-0­6.  Back to cited text no. 17      
18.Khoury Z, Schlicht JR, Como J, et al. The effect of prophylactic nifedipine on renal function in patients administered contrast media. Pharmaco­therapy 1995;15:59-65.  Back to cited text no. 18      
19.Katholi RE, Taylor GJ, McCann WP. Nephro­toxicity from contrast media: Attenuation with theophylline. Radiology 1995;195:17-22.  Back to cited text no. 19      
20.Huber W, Ilgmann K, Page M, et al. Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: Controlled, randomized, double-blinded study. Radiology 2002;223(3):772-9.  Back to cited text no. 20      
21.Huber W, Schipek C, Ilgmann K, et al. Effec­tiveness of theophylline prophylaxis of renal impairment after coronary angiography in pa­tients with chronic renal insufficiency. Am J Cardiol2003;91(10):1157-62.  Back to cited text no. 21      
22.Kapoor A, Kumar S. The role of theophylline in contrast-induced nephropathy: A case­control study. Nephrol Dial Transplant 2002; 17:1936-41.  Back to cited text no. 22      
23.Wolfgang H, Florian E. Prophylaxis of contrast material-induced nephropathy in patients in intensive care: Acetylcysteine, theophylline, or both? A randomized study. Radiology 2006; 239(3):793-804.  Back to cited text no. 23      
24.Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation Modifi­cation of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70.  Back to cited text no. 24  [PUBMED]    
25.Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast­induced nephropathy after percutaneous coro­nary intervention: Development and initial validation. J Am Coll Cardiol 2004;44:1393-9.  Back to cited text no. 25  [PUBMED]    
26.Erley CM, Duda SH, Schlepckow S, et al. Adenosine antagonist theophylline prevents the reduction of glomerular filtration rate after contrast media application. Kidney Int 1994; 45:1425-31.  Back to cited text no. 26  [PUBMED]    
27.Bagshaw SM, Ghali WA. Theophylline for prevention of contrast-induced nephropathy: A systematic review and metaanalysis. Arch Intern Med 2005;165(10):1087-93.  Back to cited text no. 27      

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

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]

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