Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy

BACKGROUND: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4). METHODOLOGY/PRINCIPAL FINDINGS: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin. CONCLUSIONS/SIGNIFICANCE: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment

Urinary Vitamin D Binding Protein and KIM-1 Are Potent New Biomarkers of Major Adverse Renal Events in Patients Undergoing Coronary Angiography

Background Vitamin-D-binding protein (VDBP) is a low molecular weight protein that is filtered through the glomerulus as a 25-(OH) vitamin D 3/VDBP complex. In the normal kidney VDBP is reabsorbed and catabolized by proximal tubule epithelial cells reducing the urinary excretion to trace amounts. Acute tubular injury is expected to result in urinary VDBP loss. The purpose of our study was to explore the potential role of urinary VDBP as a biomarker of an acute renal damage. Method We included 314 patients with diabetes mellitus or mild renal impairment undergoing coronary angiography and collected blood and urine before and 24 hours after the CM application. Patients were followed for 90 days for the composite endpoint major adverse renal events (MARE: need for dialysis, doubling of serum creatinine after 90 days, unplanned emergency rehospitalization or death). Results Increased urine VDBP concentration 24 hours after contrast media exposure was predictive for dialysis need (no dialysis: 113.06 ± 299.61ng/ml, n = 303; need for dialysis: 613.07 ± 700.45 ng/ml, n = 11, Mean ± SD, p<0.001), death (no death during follow-up: 121.41 ± 324.45 ng/ml, n = 306; death during follow-up: 522.01 ± 521.86 ng/ml, n = 8; Mean ± SD, p<0.003) and MARE (no MARE: 112.08 ± 302.00ng/ml, n = 298; MARE: 506.16 ± 624.61 ng/ml, n = 16, Mean ± SD, p<0.001) during the follow-up of 90 days after contrast media exposure. Correction of urine VDBP concentrations for creatinine excretion confirmed its predictive value and was consistent with increased levels of urinary Kidney Injury Molecule-1 (KIM-1) and baseline plasma creatinine in patients with above mentioned complications. The impact of urinary VDBP and KIM-1 on MARE was independent of known CIN risk factors such as anemia, preexisting renal failure, preexisting heart failure, and diabetes. Conclusions Urinary VDBP is a promising novel biomarker of major contrast induced nephropathy-associated events 90 days after contrast media exposure

Bedeutung von 20-Hydroxyeikosatetraen Säure bei experimentellen akuten Nierenschaden

20-Hydroxyeicosatetraenoic acid (20-HETE) can aggravate ischemia-reperfusion injury because of its vasoconstrictive und proinflammatory effects. Hypothesis: In this study we have shown that the inhibition of 20-HETE synthesis or blocking of 20-HETE action reduced acute ischemia-reperfusion (IR) injury of the kidney. Methods and Results: Ex vivo experiments have shown that IR stimulates 20-HETE release in isolated perfused kidneys. This effect can be reduced by treatment of the kidneys with HET0016 - inhibitor of Cytochrom P450 (CYP)-dependent 20-HETE-synthesis. Angiotensin II and phenylephrine cause concentration-dependent increase of perfusion-pressure in ex vivo perfused kidneys. Treatment with HET0016 decreases this effect in physiologic concentrations of Angiotensin II and Phenylephrin. Uninephrectomized male Lewis Rats were exposed to 45 min of warm ischemia by clamping the left renal vessels. 5 min prior to ischemia the animals received an injection of N-hydroxy-N'-(4-butyl-2methylphenyl) formamidine (HET0016; 20-HETE synthesis-inhibitor), 20-Hydroxyeicosa-6(Z),15(Z)-dienoic acid (20HEDE; 20-HETE-antagonist) or vehicle (DMSO) into the kidney artery. Kidneys were harvested 2 days after reperfusion. Treatment with HET0016 or 20HEDE significantly reduced renal dysfunction (serum creatinine, creatinine clearance and serum urea). Beside that, treatment with HET0016 and 20HEDE prior to iscemia significantly attenuated acute tubular injury, apoptosis and inflammatory infiltration of the renal tissue. IR-induced increase in fractional sodium-excretion in urine as a compensatory protective injury- respond was not influenced by both 20-HETE-inhibitors. Conclusions: Our data could offer a therapeutic perspective in IR-induced acute kidney injury after surgery with temporary occlusion of renal arterial blood, for example during partial nephrectomy, and after kidney transplantation. However, further studies are required to define the therapeutic window for 20-HETE antagonists or agonists.20-Hydroxyeicosatetraenoische Säure (20-HETE) kann den Ischämie-Reperfusion (IR)-Schaden durch die vasokonstriktorischen und proinflammatorischen Effekte verschlimmern. Hypothese: In der vorliegenden Arbeit sollte gezeigt werden, dass die Synthesehemmung oder Blockade der Wirkung von 20-HETE den IR- induzierten akuten Nierenschaden verringert. Methoden und Ergebnisse: Ex vivo Versuche an isoliert perfundierten Nieren zeigten, dass IR die 20-HETE Freisetzung verstärkt. Dies konnte durch Vorbehandlung mit HET0016 - einem Inhibitor der Cytochrom P450 (CYP)-abhängigen 20-HETE-Synthese – reduziert werden. Angiotensin II und Phenylephrin führten zu einer Konzentrations- abhängigen Steigerung des Perfusionsdruckes in ex vivo perfundierten Nieren. Behandlung mit HET0016 antagonisierte diesen Effekt bei physiologischen Konzentrationen von Angiotensin II und Phenylephrin. Uninephrektomierte männliche Lewis Ratten wurden für 45 Minuten einer warmen Ischämie durch Abklemmen der linken Nierengefäße unterzogen. Die Tiere erhielten 5 Minuten vor der Ischämie N-hydroxy-N'-(4-butyl-2methylphenyl) Formamidin (HET0016; 20-HETE Syntheseinhibitor), 20-Hydroxyeicosa-6(Z),15(Z)-diensäure (20HEDE; 20 -HETE-Antagonist) oder Vehikel (DMSO) durch die Nierenarterie infundiert. Die Organe wurden 2 Tage nach Reperfusion entnommen. Vorbehandlung mit HET0016 oder 20HEDE reduzierten die renale Dysfunktion signifikant (Serum-Kreatinin, Kreatininclearance und Serum-Harnstoff). Außerdem verringerte die Vorbehandlung mit HET0016 und 20HEDE deutlich den akuten Tubulusschaden, die Apoptose der Tubuluszellen und die inflammatorische Infiltration im Vergleich zur Vehikel-Gabe. Nach Schädigung durch IR kam es zu einer Reduktion der Natrium-Ausscheidung im Urin und Steigerung der fraktionellen Natriumexkretion. Dies wurde von beiden 20-HETE-Inhibitoren nicht signifikant beeinflusst. Zusammenfassung: Unsere Ergebnisse konnten zeigen, dass der Arachidonsäuremetabolit 20-HETE - ein potenter Vasokonstriktor – bei der Pathogenese des IR-induzierten akuten Nierenschadens beteiligt ist. Die Blockade von 20-HETE vor der renalen Ischämie wirkte renoprotektiv

Development and validation of a macroarray system - MutaCHIP ARTERO - for the detection of genetic variants involved in the pathogenesis of atherosclerosis

BACKGROUND: ardiovascular diseases are the leading cause of death in developed countries. The underlying mechanism is often atherosclerotic remodeling of blood vessels in organs such as heart, kidney, brain, and large arteries in case of peripheral arterial disease. Beside environmental and behavioral factors such as smoking or lack of physical activity, genetic variants in genes involved in lipid metabolism, blood pressure regulation, oxidative stress, and coagulation play a prominent role in the pathogenesis of atherosclerosis. METHODS: Thus, we developed and validated for clinical use and research a macroarray system for the simultaneous detection of key genetic variants in genes involved in lipid metabolism, blood pressure regulation, oxidative stress, and coagulation. RESULTS: When compared with standard PCR technologies to determine all these genetic variants in parallel, the macroarray system (MutaCHIP ARTERO) was as accurate but faster, cheaper, and easier to handle compared to classical real time PCR based technologies. CONCLUSIONS: MutaCHIP ARTERO is a gene chip for diagnostics of a complex genetic panel involved in the pathogenesis of atherosclerosis. This method is as sensitive and precise as real time PCR and is able to replicate real time PCR data previously validated in evaluation studies

A hybrid open and endovascular repair for treatment of bovine aortic arch aneurysm accompanied by aneurysm of patent ductus arteriosus with deployment of amplatzer duct occluder

A rare case of bovine aortic arch aneurysm accompanied by patent ductus Botalli aneurysm was treated using an off-pump hybrid procedure including supraaortic debranching combined with aortic stent grafting and oversewing of pulmonary artery end of the aneurysm. Postoperative computed tomography angiography showed persistent perfusion of the ductus Botalli aneurysm from pulmonary artery, which was successfully closed with an Amplatzer duct occluder. Twenty-two months of follow-up showed good general state of the patient's health status. This less invasive procedure is an alternative to aortic replacement under circulatory arrest and may be the only salvage option for patients in poor general condition

Targeting the epithelial cells in fibrosis: a new concept for an old disease

Fibrosis, which affects millions of individuals worldwide, is a leading cause of organ failure. For 40 years myofibroblasts have been recognized to be the key cellular players in fibrosis. Currently, several pharmaceutical targets are under investigation that may contribute to the activation of myofibroblasts. Recent preclinical and clinical evidence suggests that other components in the fibrotic microenvironment can trigger myofibroblast activation, providing new targets for pharmaceutical intervention. Epithelial cells may represent the most promising cellular phenotype that could be exploited in the design of new anti-fibrotic medicines through their paracrine action on myofibroblasts. The present review briefly highlights this hypothesis and discusses some interesting related pharmacological targets

Treatment of isolated ascending aortic aneurysm by off-pump epiaortic wrapping is safe and durable

OBJECTIVES: Isolated ascending aortic aneurysm (iAA) is usually treated by open graft repair requiring sternotomy, cardiopulmonary bypass (CPB) and cardioplegia. This approach carries significant mortality in older patients or those presenting with comorbidities. We report an original series of patients presenting with iAA and treated with epiaortic wrapping by using a synthetic mesh. This less invasive aortic repair technique allows reducing the aortic diameter to a predefined value and is performed without CPB. METHODS: Data from patients presenting with an iAA and treated with the wrapping technique (WT) by polypropylene/polyester mesh from November 2006 to July 2015 were collected. The end-points that were analysed included maximal aortic transverse diameter, perioperative mortality and morbidity, survival, freedom from reinterventions and aortic valve function during follow-up. The maximal aneurysm transverse diameter was analysed based on contrast-enhanced computed tomography (CTA) or magnetic resonance (MR) performed preoperatively, and during the follow-up. RESULTS: The off-pump WT was used in 33 cases with no perioperative mortality. The median radiological follow-up was 33.47 (range: 1-106) months. Overall, the WT achieved a 30% diameter reduction. The mean preoperative and postoperative ascending aortic transverse diameter was 5.5 cm [standard deviation (SD): 0.6] and 3.7 cm (SD: 0.30), respectively (P = 0.001). In addition, CTA or MR follow-up showed stable diameters at the level of the aortic root and the distal ascending aorta. No death occurred during the follow-up. At 5 years, the estimated freedom rate from reinterventions of the aortic root and ascending aorta was 94%. CONCLUSIONS: This series shows that the WT with a polypropylene/polyester mesh allows safe off-pump treatment of patients with iAA. Mid- and long-term results are promising. This technique could be an attractive alternative, especially for patients unfit for aortic surgery with CPB and cardioplegia

Head-to-Head Comparison of Oxidative Stress Biomarkers for All-Cause Mortality in Hemodialysis Patients

Oxidative stress (OS) presents even in the early chronic kidney disease (CKD) stage and is exacerbated in patients with end-stage renal disease (ESRD) undergoing maintenance hemodialysis (MHD). There is still a debate over the association between oxidative stress and mortality. Our study aims to compare head-to-head the prognostic value of different oxidative markers for all-cause mortality in hemodialysis (HD) patients. We thus enrolled 347 patients on HD in this prospective study. Four OS biomarkers were measured (carbonyl proteins, myeloperoxidase (MPO), advanced oxidation protein products (AOPPs), and oxidized low-density lipoprotein (ox-LDL)). During the 60-month follow-up period, 9 patients have been lost to follow-up and 168 (48.4%) patients died. Concerning the oxidative stress (ox-stress) byproducts, carbonyl proteins were lower in survivors (105.40 ng/mL (IQR 81.30–147.85) versus 129.65 ng/mL (IQR 93.20–180.33); p p = 0.0014). However, there are no significant differences in MPO, AOPP, and ox-LDL between the two groups. Kaplan–Meier survival analysis indicated that patients in the higher carbonyl proteins concentration (>117.85 ng/mL group) had a significantly lower survival rate (log-rank test, p < 0.001). Univariate Cox regression analysis showed a positive correlation between carbonyl proteins and all-cause mortality in the higher and lower halves. Even after adjustment for conventional risk factors, it remained a statistically significant predictor of an increased risk of death in MHD. Univariate Cox regression analysis of MPO showed that continuous MPO and Log MPO were significantly associated with all-cause mortality, except for binary MPO (divided according to the median of MPO). Multivariate Cox analysis for MPO showed that the mortality prediction remains significant after adjusting for multiple factors. In conclusion, not all ox-stress biomarkers predict all-cause mortality in HD patients to a similar extent. In the present study, carbonyl proteins and MPO are independent predictors of all-cause mortality in HD patients, whereas AOPPs and oxLDL are clearly not associated with all-cause mortality in HD patients

Renal fibrosis and proteomics: current knowledge and still key open questions for proteomic investigation

Renal tubulo-interstitial fibrosis is a non-specific process, representing the final common pathway for all kidney diseases, irrespective of their initial cause, histological injury, or etiology, leading to gradual expansion of the fibrotic mass which destroys the normal structure of the tissue and results in organ dysfunction and, ultimately, in end-stage organ failure. Proteomic studies of the fibrotic pathophysiological mechanisms have been performed in cell cultures, animal models and human tissues, addressing some of the key issues. This article will review proteomic contribution to the raising current knowledge on renal fibrosis biology and also mention seminal open questions to which proteomic techniques and proteomists could fruitfully contribute

Mid-term results of zone 0 thoracic endovascular aneurysm repair after ascending aorta wrapping and supra-aortic debranching in high-risk patients

OBJECTIVES: Surgical repair of aneurysmal disease involving the ascending aorta, aortic arch and eventually the descending aorta is generally associated with significant morbidity and mortality. A less invasive approach with the ascending wrapping technique (WT), supra-aortic vessel debranching (SADB) and thoracic endovascular aneurysm repair (TEVAR) in zone 0 was developed to reduce the associated risk in these patients. METHODS: During a 10-year period, consecutive patients treated by the ascending WT, SADB and TEVAR in zone 0 were included. All patients were considered at high risk for conventional surgery. Measured outcomes included perioperative deaths and morbidity, maximal aortic transverse diameter (TD) and its postoperative evolution, endoleak, survival, freedom from cardiovascular reinterventions, SADB freedom from occlusion and aortic valve function during follow-up. Median follow-up was 37.4 [mean = 34; range, 0-65; standard deviation (SD) = 20] months. RESULTS: Twenty-six cases were included with a mean age of 71.88 (r = 56-87; SD = 8) years. A mean of 2.9 supra-aortic vessels (75) per patient was debranched from the ascending aorta. The mean time interval from WT/SADB and TEVAR was 29 (r = 0-204; SD = 48) days. TEVAR was associated with chimney and/or periscope grafts in 6 (23%) patients, and extra-anatomical supra-aortic bypasses were performed in 6 (23%) patients. Perioperative mortality was 7.7% (2/26). Neurological events were registered in 3 (11.5%) cases, and a reintervention was required in 3 (11.5%) cases. After the WT, the ascending diameter remained stable during the follow-up period in all cases. At mean follow-up, significant shrinkage of the arch/descending aorta diameter was observed. A type I/III endoleak occurred in 3 cases. At 5 years, the rates of survival, freedom from cardiovascular reinterventions and SADB freedom from occlusion were 71.7, 82.3 and 96%, respectively. CONCLUSIONS: The use of the ascending WT, SADB and TEVAR in selected patients with complex thoracic aorta disease is safe and shows promising mid-term results at 3 years. The combination of these techniques could represent an alternative to the standard open surgical repair, especially in older patients or in patients unfit for cardiopulmonary bypass