sildenafil-citrate and Acute-Kidney-Injury

We have detailed several of the urological manifestations of vascular disease. With the aging of the North American population, urologists will encounter the urological complications of vascular disease with ever-increasing frequency.

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Captopril; Clinical Trials as Topic; Humans; Hypertension, Renovascular; Impotence, Vasculogenic; Male; Piperazines; Prosthesis Implantation; Purines; Radioisotope Renography; Sildenafil Citrate; Stents; Sulfones; Vasodilator Agents

This study assessed whether i.v. sildenafil citrate prevented acute kidney injury in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass.. In a double-blind RCT, adults at increased risk of acute kidney injury undergoing cardiac surgery in a single UK tertiary centre were randomised to receive sildenafil citrate 12.5 mg kg. The analysis population comprised eligible randomised patients that underwent valve surgery or combined coronary artery bypass graft and valve surgery, with cardiopulmonary bypass, between May 2015 and June 2018. There were 60 subjects in the sildenafil group and 69 in the placebo control group. The difference between groups in creatinine concentration was not statistically significant (MD: 0.88 μmol L. These results do not support the use of i.v. sildenafil citrate for kidney protection in adult cardiac surgery.. ISRCTN18386427.

Topics: Acute Kidney Injury; Administration, Intravenous; Aged; Aged, 80 and over; Cardiac Surgical Procedures; Double-Blind Method; Female; Glucose; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Sildenafil Citrate; United Kingdom

Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio. We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil.. Thirty-six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC. Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery.

Topics: Acute Kidney Injury; Administration, Intravenous; Aged; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Sildenafil Citrate

To perform a randomized control trial (RCT) assessing the effect of phosphodiesterase 5 inhibitor (PDE5i) used prior to hilar clamping during robot assisted partial nephrectomy (RAPN) for renoprotection.. We performed an institutional review board approved, placebo controlled, double blinded RCT evaluating a single 100 mg oral dose of sildenafil immediately prior to RAPN. Primary end point was accrual, participation and retention of patients with secondary endpoints assessing post-operative renal functional outcomes and safety. Exclusion criteria included history of coronary artery disease, solitary kidney, suspected benign pathology, PDE5i intolerance or pregnant females.. Of 40 eligible consecutive patients undergoing RPN between 9/2013 and 12/2014, 30 (75%) were randomized to treatment and there was 100% participation and retention. The groups were well matched for all measured comorbidities. Intraoperative outcomes including warm ischemia time (median 15 vs. 16.5 min, P = 0.29) were similar. Change in eGFR demonstrated similar decrease between sildenafil versus placebo at 1 day (-8% vs. -10%, P = 0.53), 2 days (-9% vs. -9%, P = 0.77), and 1 month (-4% vs. -6%, P = 0.31) following RAPN. Intermediate follow up (median 183 days) demonstrated similar results (-8% vs. -1%, P = 0.16) between the two cohorts. Safety profiles were similar between the two cohorts without any adverse reactions to the sildenafil.. Successful retention of patients was achieved in this RCT. The secondary outcome of renoprotection was not identified. J. Surg. Oncol. 2016;114:785-788. © 2016 2016 Wiley Periodicals, Inc.

Topics: Acute Kidney Injury; Administration, Oral; Adult; Aged; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Hemostasis, Surgical; Humans; Laparoscopy; Male; Middle Aged; Nephrectomy; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Preoperative Care; Prospective Studies; Protective Agents; Reperfusion Injury; Robotic Surgical Procedures; Sildenafil Citrate; Treatment Outcome

Diclofenac, one of the most commonly used non-steroidal anti-inflammatory drugs, leads to severe adverse effects on the kidneys. The aim of the present study was to investigate the potential pretreatment effect of phosphodiesterase (1, 3 & 5) inhibitors on diclofenac-induced acute renal failure in rats. Rats orally received pentoxifylline (100 mg/kg), vinpocetine (20 mg/kg), cilostazol (50 mg/kg), or sildenafil (5 mg/kg) once per day for 6 consecutive days. Diclofenac (15 mg/kg) was injected on day-4, -5 and -6 in all groups except normal control group. The used phosphodiesterase inhibitors significantly reduced the diclofenac-induced elevation in the serum levels of blood urea nitrogen, creatinine and cystatin C. Moreover, the renal tissue contents of tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB as well as the protein expression of toll-like receptor (TLR) 4 and high mobility group box (HMGB) 1 were markedly reduced by the used phosphodiesterase inhibitors, as compared to the diclofenac control. This was reflected on the marked improvement in histopathological changes induced by diclofenac. Sildenafil showed the best protection regarding TNF-α and NF-κB, while cilostazol showed the best results regarding TLR4, HMGB1 and histopathological examination. This study revealed the good protective effect of these phosphodiesterase inhibitors against diclofenac-induced acute renal failure.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cilostazol; Creatinine; Diclofenac; Kidney; Male; NF-kappa B; Pentoxifylline; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Rats; Rats, Wistar; Sildenafil Citrate; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Vinca Alkaloids

Sildenafil is a phosphodiesterase inhibitor used clinically for treating erectile dysfunction. Few studies suggest sildenafil to be a renoprotective agent. The present study investigated the involvement of peroxisome proliferator-activated receptor γ (PPAR-γ) in sildenafil-mediated protection against ischemia-reperfusion-induced acute kidney injury (AKI) in rats.. The rats were subjected to ischemia-reperfusion injury (IRI) with 40 min of bilateral renal ischemia followed by reperfusion for 24 h. The renal damage was assessed by measuring creatinine clearance, blood urea nitrogen, plasma uric acid, electrolytes, and microproteinuria in rats. The thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels were measured to assess oxidative stress in renal tissues. The hematoxylin-eosin staining was carried out to demonstrate histopathologic changes in renal tissues. Sildenafil (0.5 and 1.0 mg/kg, intraperitoneal) was administered 1 h before subjecting the rats to renal IRI. In a separate group, bisphenol A diglycidyl ether (30 mg/kg, intraperitoneal), a PPAR-γ receptor antagonist, was given before sildenafil administration followed by IRI.. The ischemia-reperfusion demonstrated marked AKI with significant changes in serum and urinary parameters, enhanced oxidative stress, and histopathologic changes in renal tissues. The administration of sildenafil demonstrated significant protection against ischemia-reperfusion-induced AKI. The prior treatment with bisphenol A diglycidyl ether abolished sildenafil-mediated renal protection, thereby confirming involvement of PPAR-γ agonism in the sildenafil-mediated renoprotective effect.. It is concluded that sildenafil protects against ischemia-reperfusion-induced AKI through PPAR-γ agonism in rats.

Topics: Acute Kidney Injury; Animals; Benzhydryl Compounds; Drug Evaluation, Preclinical; Epoxy Compounds; Kidney; Kidney Function Tests; Male; Oxidative Stress; Phosphodiesterase 5 Inhibitors; PPAR gamma; Proteinuria; Random Allocation; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate

Contrast-induced acute kidney injury (CIAKI) is one of the commonest complications associated with contrast media (CM). Although the exact etiology of CIAKI remains unclear, one hypothesis involves vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIAKI. In this study we evaluated the protective effects of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil citrate, in a rabbit model of CIAKI. New Zealand white rabbits were used due to their susceptibility to CIAKI. To evaluate the effects of sildenafil, the drug was administered before CM infusion and repeatedly throughout the remainder of the experiment (6 mg/kg, p.o.). Animals were sacrificed after 48 hours and kidneys were prepared for histological evaluation. Intravenous administration of CM produced marked kidney injury. Serum creatinine concentrations were elevated within two hours of the infusion and remained elevated for the duration of the experiment. Histological evaluation of the kidneys revealed significant tubular necrosis. The effects of the CM were dose dependent. Treatment with sildenafil was associated with lesser degree of histological injury, attenuation in markers of acute kidney injury (48 hour creatinine 1.54±0.21 versus 4.42±1.31 mg/dl, p<0.05) and reduction in electrolyte derangement (percent change in serum K+ at 48 hours 2.55±3.80% versus 15.53±4.47%, p<0.05; serum Na+ at 48 hours -0.14±0.26% versus -1.97±1.29%, p = 0.20). The results suggest a possible role for PDE5 inhibitors in the treatment of CIAKI and warrant further evaluation to determine the exact mechanism of protection.

Topics: Acute Kidney Injury; Animals; Contrast Media; Creatinine; Disease Models, Animal; Glomerular Filtration Rate; Kidney; Male; Phosphodiesterase 5 Inhibitors; Rabbits; Sildenafil Citrate; Urological Agents

Recent studies demonstrate that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function after AKI may be key to the recovery of renal function. Mitochondrial function can be restored through the generation of new, functional mitochondria in a process called mitochondrial biogenesis (MB). Despite its potential therapeutic significance, very few pharmacological agents have been identified to induce MB. To examine the efficacy of phosphodiesterase (PDE) inhibitors (PDE3: cAMP and cGMP activity; and PDE4: cAMP activity) in stimulating MB, primary cultures of renal proximal tubular cells (RPTCs) were treated with a panel of inhibitors for 24 hours. PDE3, but not PDE4, inhibitors increased the FCCP-uncoupled oxygen consumption rate (OCR), a marker of MB. Exposure of RPTCs to the PDE3 inhibitors, cilostamide and trequinsin, for 24 hours increased peroxisome proliferator-activated receptor γ coactivator-1α, and multiple mitochondrial electron transport chain genes. Cilostamide and trequinsin also increased mRNA expression of mitochondrial genes and mitochondrial DNA copy number in mice renal cortex. Consistent with these experiments, 8-Br-cGMP increased FCCP-uncoupled OCR and mitochondrial gene expression, whereas 8-Br-cAMP had no effect. The cGMP-specific PDE5 inhibitor sildenafil also induced MB in RPTCs and in vivo in mouse renal cortex. Treatment of mice with sildenafil after folic acid-induced AKI promoted restoration of MB and renal recovery. These data provide strong evidence that specific PDE inhibitors that increase cGMP are inducers of MB in vitro and in vivo, and suggest their potential efficacy in AKI and other diseases characterized by mitochondrial dysfunction and suppressed MB.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Acute Kidney Injury; Adenosine Triphosphate; Animals; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Enzyme-Linked Immunosorbent Assay; Female; Folic Acid; Gene Expression; Hematinics; Kidney Cortex; Male; Mice; Mice, Inbred C57BL; Mitochondria; Oxygen Consumption; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 4 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Rabbits; Real-Time Polymerase Chain Reaction; Sildenafil Citrate; Sulfones; Uncoupling Agents

Acute kidney injury after cardiac surgery is common, has no effective treatments, and is associated with adverse outcomes. The aim of this study was to determine whether administration of the phosphodiesterase-5 inhibitor sildenafil citrate (SDF) would prevent the development of post-cardiopulmonary bypass (CPB) acute kidney injury in swine.. Adult pigs (n = 8 per group) were randomized to undergo sham procedure, CPB, or CPB plus administration of SDF, with recovery and reassessment at 24 hours.. Cardiopulmonary bypass resulted in a significant reduction in creatinine clearance relative to sham pigs (mean difference CPB versus sham, -47.9 mL/min; 95% confidence interval [CI]: -93.7 to -2.2; p = 0.039). This was prevented by the administration of SDF during CPB (mean difference CPB+SDF versus CPB, +55.6 mL/min; 95% CI: +6.5 to +104.7; p = 0.024). Cardiopulmonary bypass also resulted in a significant rise in the urinary biomarker interleukin-18 compared with sham procedures (mean difference 209.3 pg/mL; 95% CI: 120.6 to 298.1; p < 0.001) that was prevented by SDF administration. Post-CPB kidney injury was associated with vascular endothelial injury and dysfunction, reduced nitric oxide bioavailability, medullary hypoxia, cortical adenosine triphosphate depletion, inflammation, and evidence of proximal tubule epithelial cell stress manifest as phenotypic change. Administration of SDF to CPB pigs preserved nitric oxide bioavailability and prevented endothelial dysfunction, regional hypoxia, inflammation, and tubular changes.. In this model, phosphodiesterase-5 inhibition using SDF prevented post-CPB acute kidney injury by the preservation of nitric oxide bioavailability, and warrants evaluation as a renoprotective agent in clinical trials.

Topics: Acute Kidney Injury; Animals; Biomarkers; Cardiopulmonary Bypass; Female; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine

Topics: Acute Kidney Injury; Animals; Cardiopulmonary Bypass; Female; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Acute Kidney Injury; Adult; Humans; Male; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors

Topics: Acute Kidney Injury; Administration, Oral; Female; Humans; Infant; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors