Treprostinil, a prostacyclin analog, ameliorates renal ischemia–reperfusion injury: preclinical studies in a rat model of acute kidney injury

Graphical Abstract Background Renal ischemia–reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in vivo. Methods Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1–168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18–24 h before ischemia. Results Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil. Conclusions This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo.

Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

Objective: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. Conclusions: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

Should we use the oral selective IP receptor agonist selexipag off-label in children with pulmonary arterial hypertension?

We discuss the currently available data on the use of the prostacyclin mimetic selexipag in children and adolescents with pulmonary arterial hypertension (PAH). Future indications may include transitioning from intravenous prostacyclin/prostacyclin analog to oral selexipag, and vice versa, or adding selexipag as a third oral PAH-targeted agent in children not responding well to dual PAH therapy.

Treatment of Bone Marrow Edema of the Foot and Ankle With the Prostacyclin Analog Iloprost

Background: Bone marrow edema (BME) of the foot and ankle is challenging to treat. One approach is intravenous Iloprost treatment, which is a vasoactive prostacyclin analog. The aim of this study was to evaluate the early and intermediate outcome of intravenous Iloprost therapy on BME of the foot and ankle and to analyze the influence of its etiology and Association Research Circulation Osseous (ARCO) stage on the outcome. Methods: This was a retrospective study with prospective follow-up. All patients treated by intravenous Iloprost for BME of the foot and ankle (ARCO I-III) at a single orthopedic reference center were included. Demographics, medical history, and MRIs were assessed prior to treatment (t0). MRIs were used to assess the BMEs’ etiology (idiopathic/ischemic/metabolic, mechanical/degenerative, traumatic) and severity (ARCO). Complications as well as changes in pain, treatment, and MRI were evaluated after 3 months (t1). The following patient-rated outcome measures (PROMs) were assessed prospectively (t2): 12-Item Short Form Health Survey (SF-12), Visual Analog Scale Foot and Ankle (VAS FA), and the Foot Function Index (FFI) (also at t0). The descriptive outcomes and the influence of the etiology and ARCO on the outcome parameters were evaluated. Out of 70 eligible patients, 42 patients (60%; 47 ± 15 years; 30% female) with a mean follow-up of 28 ± 19 months were included. Results: Twelve patients reported minor complications during Iloprost therapy. At t1, pain decreased significantly in 56%, and the amount of BME decreased in 83% of patients. Both parameters correlated moderately (r = −0.463, P = .015). The PROMs at t2 revealed moderate results. The overall FFI improved from 59 ± 21 to 30 ± 22 ( P < .001), the overall VAS FA was 68 ± 20, the SF-12 Physical Component Summary 42 ± 12 and Mental Component Summary 50 ± 9. Subgroup analysis revealed no significant influence of the etiology or ARCO stage on any outcome measure. Conclusion: Iloprost therapy for BME of the foot and ankle resulted in a 60% pain and 80% edema decrease after 3 months. After 2 years, patient-rated outcome measures showed residual impairment. Neither the etiology nor ARCO stage significantly influenced the outcome. Level of Evidence: Level III, comparative study.