title: Inhaled nitric oxide therapy and risk of renal dysfunction: a systematic review and meta-analysis of randomized trials.
abstract: BACKGROUND
  Inhaled nitric oxide (iNO) is an important therapy for acute respiratory distress syndrome (ARDS), pulmonary hypertension and pediatric hypoxemic respiratory failure. Safety concerns regarding iNO and renal dysfunction have been reported; however, there are currently no systematic reviews on this issue. Our objective was to evaluate published randomized controlled trials (RCTs) to ascertain the risk of renal dysfunction associated with iNO therapy in patients with and without ARDS.
  
  
  METHODS
  A systematic review of databases was performed to identify RCTs which compared iNO with controls up to September 2014. Effect estimates for risk ratio (RR) of acute kidney injury (AKI) were pooled using a random-effects model.
  
  
  RESULTS
  Ten RCTs involving 1363 participants were included. Inhaled nitric oxide significantly increased the risk of AKI compared with controls (RR, 1.4, 95%CI, 1.06 to 1.83, p = 0.02). In the stratified analysis, a high cumulative-dose of iNO significantly increased the risk of AKI (RR, 1.52, 95%CI, 1.14 to 2.02, p = 0.004), whereas medium and low cumulative-doses did not (RR, 0.64, 95%CI, 0.23 to 1.81 and RR, 0.56, 95%CI, 0.11 to 2.86 respectively). In subgroup analysis by study population, an increased risk of AKI was observed in patients with ARDS (RR, 1.55, 95%CI, 1.15 to 2.09, p = 0.005) but not in those without (RR, 0.90, 95%CI, 0.49 to 1.67, p = 0.75).
  
  
  CONCLUSIONS
  The available data show that iNO therapy may increase the risk of renal dysfunction, especially with prolonged use and in patients with ARDS. The risk in pediatric population is unknown owing to limited data. We suggest monitoring renal function during iNO therapy, and that future trials of iNO should evaluate renal safety.
authors.affiliation: Institute of Epidemiology and Preventive Medicine, National Taiwan University, No.17 Xu-Zhou Road, Taipei, 10020, Taiwan. syruan@ntu.edu.tw.|Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. syruan@ntu.edu.tw.
authors.forename: Sheng-Yuan
authors.initials: SY
authors.lastname: Ruan
authors.affiliation: Institute of Epidemiology and Preventive Medicine, National Taiwan University, No.17 Xu-Zhou Road, Taipei, 10020, Taiwan. taomin.huang@gmail.com.
authors.forename: Tao-Min
authors.initials: TM
authors.lastname: Huang
authors.affiliation: Institute of Epidemiology and Preventive Medicine, National Taiwan University, No.17 Xu-Zhou Road, Taipei, 10020, Taiwan. honyenwu@ntu.edu.tw.|Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan. honyenwu@ntu.edu.tw.
authors.forename: Hon-Yen
authors.initials: HY
authors.lastname: Wu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. hdwu@ntuh.gov.tw.
authors.forename: Huey-Dong
authors.initials: HD
authors.lastname: Wu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. jefferycjyu@ntu.edu.tw.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Institute of Epidemiology and Preventive Medicine, National Taiwan University, No.17 Xu-Zhou Road, Taipei, 10020, Taiwan. mslai@ntu.edu.tw.
authors.forename: Mei-Shu
authors.initials: MS
authors.lastname: Lai
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000280:Administration, Inhalation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia / Q000188:drug therapy*; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*
chemical_list: D009569:Nitric Oxide