Effects of Aminophylline on Renal Function and Urine Volume of AKI Patient

Early Phase 1

• Conditions: Acute Kidney Injury
• Interventions: Drug: aminophylline; Drug: normal saline; Drug: frusemide

• Registration Number: NCT02983422
• Lead Sponsor: Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Brief Summary

This study evaluates the effects of aminophylline on serum creatinine and urine volume of AKI Patient.Half of participants will receive aminophylline and furosemide in combination,while the other half will receive only furosemide.

Detailed Description

Acute kidney injury (AKI) is a sudden perturbation of kidney function that is frequently associated with high morbidity and mortality rates . A diagnostic time limit of 48 hours was recently introduced to ensure early diagnosis, management and prevention of progression to irreversible renal function loss . Furthermore, early AKI biomarkers that can ensure prompt diagnosis have been identified. When these biomarkers become widely available to clinical practice, informed therapeutic interventions capable of aborting disease progression, morbidity and mortality multiplication can be applied . In the injured kidney, adenosine is released endogenously from the macula densa causing vasoconstriction of the renal afferent arterioles via the adenosine A1receptor as well as vasodilatation of the renal efferent arterioles via the adenosine A2 receptor; thereby reducing the renal blood flow and glomerular perfusion pressure leading to ischemic kidney injury . One measure that has been tried with the objective of achieving better AKI outcome is the use of aminophylline (an ethylenediamine coupled theophylline) . Aminophylline is converted to theophylline in the human body, which in turn vasodilates the renal afferent arterioles through competitive inhibition of adenosine on the adenosine A1 receptor.

Aminophylline and theophylline, methylxanthine nonselective adenosine receptor antagonists, have been effective in the management of AKI in certain clinical scenarios including heart failure, calcineurin inhibitor toxicity, and perinatal asphyxia. In the kidney, adenosine constricts the afferent arteriole and decreases glomerular blood flow; adenosine receptor blockade mitigates this vasoconstriction. Aminophylline also inhibits phosphodiesterase at higher concentrations, which leads to increased urine output.

Eligible subjects included all patients more than 18 years old with acute kidney injury in ICU. To ensure the safest oversight for the duration of the study drug infusion, the investigators only approached patients for consent if participants' ICU stay would likely be at least 72 hours . Patients were recruited in the preoperative clinic or in the inpatient ward/ICU; the nature of the consent process for this interventional drug trial necessitated that all procedures were elective or scheduled. Because aminophylline has been associated with tachycardia and seizures at high serum levels, and its metabolism may be affected by liver or thyroid dysfunction and sepsis, the investigators selected the following exclusion criteria: history of tachyarrhythmias, seizures, coagulopathy (international normalized ratio \> 1.5 while not taking warfarin),or hypothyroidism. Study investigators or research nurses recruited participants; written, informed consent was signed by each patient or guardian.

The treatment group received aminophylline 5 mg/kg IV load over 30 minutes, followed by 0.5 mg/kg IV every hour, for 72 hours .The control group received placebo bolus followed by IV infusions of normal saline (0.9%) every hour (matched by volume and appearance to the treatment group), for 72 hours.

Study Timeline

• Study First Submitted: 2016-11-26
• Status Verified: 2016-12
• Study Start: 2016-12
• Study First Submitted QC: 2016-12-02
• Last Update Submitted: 2016-12-02
• Study First Posted: 2016-12-06
• Last Update Posted: 2016-12-06
• Primary Completion: 2017-06
• Study Completion: 2017-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Patients with acute injury (AKI) with no lack of circulating volume (central venous pressure >8cmH2O)

Exclusion Criteria

• Patients with chronic kidney disease
• Patients with acute renal injury caused by insufficient circulating volume
• Patients who do not cooperate with the use of the drug therapy
• Patients who do not cooperate with the relevant examination

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group frusemide	normal saline	Use frusemide with Syringe pumps,maximum dose to 15mg/h，with placebo bolus followed by IV infusions of normal saline (0.9%) every hour (matched by volume and appearance to the treatment group)
Group aminophylline	frusemide	To increase the dose of frusemide until 15mg/h with Syringe pumps. If the urine doesn't reach 1ml/kg/h,then combined with Aminophylline(loading dose of 5mg/kg，and maintenance dose of 0.5mg/kg)
Group aminophylline	aminophylline	To increase the dose of frusemide until 15mg/h with Syringe pumps. If the urine doesn't reach 1ml/kg/h,then combined with Aminophylline(loading dose of 5mg/kg，and maintenance dose of 0.5mg/kg)
Group frusemide	frusemide	Use frusemide with Syringe pumps,maximum dose to 15mg/h，with placebo bolus followed by IV infusions of normal saline (0.9%) every hour (matched by volume and appearance to the treatment group)

Primary Outcome Measures

Name	Time	Method
urine volume	Change from urine volume at 2 weeks
Serum cystatin-C	Change from Serum cystatin-C at 2 weeks
Urine β_2-microglobulin	Change from Urine β_2-microglobulin at 2 weeks
serum creatinine	Change from serum creatinine at 2 weeks

Secondary Outcome Measures

Name	Time	Method
dose of norepinephrine	Change from dose of norepinephrine at 2 weeks
blood pressure	Change from baseline systolic blood pressure at 2 weeks
central venous pressure	Change from central venous pressure at 2 weeks