A recent human study sought to replicate previous success seen in animal models of reperfusion injury, reports Urology Times SUO internship program member Katie Murray, DO.
|Katie Murray, DO||UT|
Washington-Despite promising renoprotective results in renal ischemia reperfusion injury associated with partial nephrectomy with the use of phosphodiesterase-type-5 inhibitors in murine and rat models, the same beneficial effect was not seen in human patients, according to a recent study.
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In a randomized, double-blinded, placebo-controlled trial presented at the 2015 Society of Urologic Oncology annual meeting in Washington, patients were assigned to either receive oral sildenafil, 100 mg, or placebo immediately prior to robot-assisted laparoscopic partial nephrectomy. The primary endpoint of this study was accrual and retention of patients with secondary endpoints assessing renal functional outcomes following hilar clamping and safety of the medication. Patients were excluded from the trial if they had significant history of coronary artery disease, solitary kidney, suspected benign pathology, were pregnant, or had prior intolerance of PDE-5 inhibitor therapy.
This study was completed over a 15-month time frame. Thirty patients were randomized, and all of these patients remained on study and received treatment and had proper follow-up. Lead author Louis Spencer Krane, MD, from the National Cancer Institute in Bethesda, MD said this preliminary study taught him that randomized surgical trials are feasible but can be extremely cumbersome to perform. Despite the challenges of this randomized trial, the investigators were able to randomize and treat patients accordingly with 100% retention. According to the study design and objective, the study was positive in meeting the primary endpoint.
Randomization allowed for matched groups, with nearly half of both groups being male patients with a median age of 59 and 57 years of age in the sildenafil and placebo group, respectively. Baseline comorbid conditions including diabetes mellitus, hypertension, and chronic obstructive pulmonary disease were not different between the two groups. Tumor size was slightly smaller in the sildenafil group at a median of 2.3 cm (IQR 2.2, 3) and 3 cm (IQR 2.8, 4.1) in the placebo group (p=.045). Although size was slightly different, nephrometry scores were similar.
Intraoperative characteristics were similar between the groups, including estimated blood loss, warm ischemia time, use of intraoperative vasopressors, and amount of fluid administration. Serum creatinine values (mg/dL) and estimated glomerular filtration rate (GFR) were obtained on all patients preoperatively and at short term (1-to 2-day) follow-up. Of the 15 patients in each arm, eight in the sildenafil group and 11 in the placebo group had 1 to 3 months follow-up with laboratory values. Baseline serum creatinine and GFR were not different between the groups. The median percent change in GFR at 2 days post-op was decreased by 8% in both groups and decreased 4% and 6% in the sildenafil and placebo groups, respectively at 1 month post-op (p=.31). Of note, the median baseline GFR in patients in both groups was >80.
In conclusion, the authors were able to report feasibility of this trial but were unable to identify any role that sildenafil may have as a renoprotective agent in patients undergoing robot-assisted laparoscopic partial nephrectomy. Dr. Krane claimed that although the animal studies with sildenafil were promising, any future clinical trial powered to find a difference in GFR after robot-assisted partial nephrectomy would need to be extremely large in number. His institution does not have current plans to perform any of these studies in the near future.
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