KDIGO Clinical Practice Guideline for Acute Kidney Injury
Theophylline: Recommendations and Rationale

Theophylline and fenoldopam in prevention of CI-AKI

Theophylline

• 4.4.4: We suggest not using theophylline to prevent CI-AKI. (2C)

Rationale

A rationale for the prophylactic use of adenosine antagonists in patients undergoing radiocontrast procedures was

Figure 16 | NAC and bicarbonate vs. NAC for risk of CI-AKI. Reprinted from Brown, JR, Block CA, Malenka DJ et al. Sodium bicarbonate plus N-acetylcysteine prophylaxis: a meta-analysis. JACC Cardiovasc Interv 2009; 2: 1116–1124,⁵⁰³ copyright 2009, with permission from American College of Cardiology Foundation; accessed http://interventions.onlinejacc.org/cgi/content/full/2/11/1116

suggested by results showing increased serum levels and urinary excretion of adenosine occurring after intravascular administration of contrast media.⁵⁰⁵ The efficacy of theophylline in preventing CI-AKI has been addressed by a systematic review and meta-analysis in 2005 (nine RCTs, 585 patients),⁵⁰⁶ and another meta-analysis in 2008 (six RCTs, 629 patients).⁴³² Both meta-analyses indicated a nonsignificant trend toward a renoprotective effect of theophylline prophylaxis. The incidence of CI-AKI tended to be lower (Bagshaw: OR 0.4, CI 0.14–1.16, P = 0.09; Kelly: OR 0.49, CI 0.23–1.06, P = 0.14), SCr concentrations 48 hours after intervention were significantly lower (-0.17 mg/dl; 95% CI -0.2 to -0.06 mg/dl [-15.0 µmol/l, CI -17.7 to -5.30 µmol/l]; P = 0.002) with theophylline compared to control therapies. However, the overall benefit was small and findings were inconsistent across studies. The benefit attributable to the use of theophylline tended to be less marked in patients receiving iso-osmolar, nonionic contrast media, and in patients undergoing a predefined saline protocol.

Neither meta-analysis included a RCT published in 2006 in 150 contrast-media examinations in 91 patients, in which the renoprotective effects of theophylline, NAC, and the combination of both were directly compared.⁵⁰⁷ All patients had at least one risk factor for developing CI-AKI, and received more than 100 ml of low-osmolar radiocontrast agent. The incidence of CI-AKI was significantly lower with theophylline as compared to NAC pretreatment (2% vs. 12%; P = 0.045), and did not differ between theophylline monotherapy and the combination treatment. The renoprotective superiority of theophylline, which was given as a single i.v. 200 mg dose 30 minutes prior to the procedure, was even more significant in patients with pre-existing renal damage as indicated by an SCr > 1.5 mg/dl ( > 133 µmol/l) (P = 0.008). Moreover, a recent study⁵⁰⁸ randomized 217 patients with eGFR between 30 and 60 ml/min who were undergoing coronary angiography to one of three prophylactic treatments: i.v. isotonic saline (1 ml/kg/h for 12 hours before and after contrast media (group 1, n = 72); isotonic saline as in group 1 together with NAC (600 mg p.o. twice daily the preceding day and the day of angiography (group 2, n = 73); or isotonic saline and NAC as in group 2 together with 200 mg theophylline orally twice daily for the preceding day and the day of angiography (group 3, n = 72). The incidence of CI-AKI (0.5 mg/dl or 44.2 µmol/l SCr increase within 48 hours of intravascular contrast-media injection) was 6.9% in group 1, 9.6% in group 2, and 0% in group 3 (P < 0.03), suggesting a beneficial effect of adding theophylline to a standard regimen in the prevention of CI-AKI. Notably, at least in this study, NAC administration had no additive protective effect compared to isotonic saline alone.

A very recent study⁵⁰⁹ randomly assigned patients to prophylactic administration of saline with sodium bicarbonate plus theophylline (either orally or i.v.) or sodium bicarbonate only. Theophylline plus bicarbonate prophylaxis significantly reduced the incidence of CI-AKI (1.6% vs. 7.9%; P = 0.015) compared to bicarbonate alone. Theophylline was administered either orally (200 mg b.i.d. starting the day before the contrast administration and continuing for 24 hours thereafter) or i.v. 200 mg in a short infusion before contrast administration and continuing orally at 200 mg b.i.d. for 48 hours. Theophylline prophylaxis significantly reduced the incidence of CI-AKI in moderate and high-risk patients (0% vs. 8.8%; P = 0.022 and 9.1% vs. 42.1%; P = 0.014, respectively). This study did not mention sideeffects of theophylline.

Although these data suggest that preinterventional theophylline administration might be helpful in patients at increased risk for CI-AKI, the possibility of cardiovascular side-effects and the interactions with numerous drugs associated with theophylline^510,511 should be recognized (Suppl Tables 26 and 27). As can be noted from the evidence profile tables, the evidence is low and the balance of benefits vs. harm is uncertain. In view of the low evidence and the uncertain balance of benefits vs. harm, the Work Group does not support the use of theophylline for prevention of CI-AKI.