KDIGO Clinical Practice Guideline for Acute Kidney Injury
Recommendations and Rationale

• 3.7.1: We suggest that a single dose of theophylline may be given in neonates with severe perinatal asphyxia, who are at high risk of AKI. (2B)

Rationale

AKI occurs in 60% of neonates suffering from perinatal asphyxia.²⁵⁷ Experimental studies indicated an important role of adenosine-mediated vasoconstriction in neonatal kidneys exposed to normocapnic hypoxemia.²⁵⁸ A potential renoprotective effect of theophylline in perinatal asphyxia has been assessed in three randomized, placebo-controlled clinical trials,^259–261 including a total of 171 term neonates. Theophylline was uniformly administered in the first hour of life as a single i.v. bolus at a dose of 5mg/kg^259,261 or 8mg/kg.²⁶⁰ The three studies all observed significantly higher GFR, higher urine output with more negative fluid balance, and lower urinary β2-microglobulin excretion, with theophylline as compared to placebo during the first 3–5 days of life. In each study, theophylline treatment was associated with a significantly reduced risk of severe renal dysfunction (17–25% vs. 55–60% in placebo group, RR 0.3–0.41). The beneficial effect was selective for kidney function, whereas the incidence of central nervous system, cardiac, pulmonary, and gastrointestinal complications was unaltered. Patient survival was not affected by treatment. In line with these studies in mature neonates, a similar improvement of GFR and urine output was observed during the first 2 days of life by administration of 1 mg/kg theophylline vs. placebo in 50 very preterm neonates with respiratory distress syndrome.²⁶² The further evolution of renal function was followed throughout the first year of life by Bhat et al.,²⁶⁰ who found equally normal glomerular and tubular function in both groups from 6 weeks of age onward. Hence, while theophylline clearly improves renal function in the first week of life in postasphyctic neonates, the overall benefit from this intervention in neonatal intensive care is less evident in view of the complete long-term recovery of renal function in the placebo-treated controls and the absence of an effect on patient survival.

In recent years, the advent of selective adenosine A1 receptor antagonists has prompted the conduct of some interesting clinical trials, which to date have focused on the prevention and treatment of cardiorenal syndrome. In a double-blind placebo-controlled trial of 63 patients with CHF, single doses of the adenosine A1 antagonist BG9719 had a marked stimulatory effect on diuresis and increased GFR.²⁶³ When coadministered with furosemide, BG9719 showed a synergistic diuretic effect and prevented the decrease in GFR associated with the loop diuretic.

Rolofylline, another adenosine A1 receptor antagonist, was tested in two double-blind placebo-controlled RCTs in patients with acute decompensated heart failure. In the first study, rolofylline or placebo was administered either concomitantly with furosemide for 3 days (146 patients), or as a single infusion in 35 diuretic resistant patients.²⁶⁴ In both substudies, rolofylline improved urine output and CrCl compared to placebo. The second trial involved 301 patients hospitalized for acute heart failure with renal impairment who received either placebo or one of three doses of rolofylline for 3 days.²⁶⁵ Rolofylline administration dosedependently attenuated the rise in SCr observed in the placebo group within 14 days, and tended to reduce 60-day mortality or readmission for cardiovascular or renal causes.

Three pivotal phase III trials in a total of 2500 patients were recently completed, aiming to corroborate the renoprotective effects of rolofylline in patients with cardiorenal syndrome, and to establish drug safety. The final results of the PROTECT trial have recently been published.²⁶⁶ Rolofylline, as compared to placebo, did not provide a benefit with respect to the three primary end-points: survival, heartfailure status, and changes in renal function. Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P = 0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P = 0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. Thus, rolofylline does not appear to be effective for treatment of cardiorenal AKI.