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Urinary nitrate concentration as a marker for kidney transplant rejection.
Riddell, A, Kirkwood, J, Smallwood, M, Winyard, P, Knight, B, Romanczuk, L, Shore, A, Gilchrist, M
BMC nephrology. 2020;(1):441
Abstract
BACKGROUND Early identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and recipient. Current practice depends on detecting a creatinine rise. A biomarker to diagnose transplant rejection at an earlier time point than current practice, or to inform earlier decision making to biopsy, could be transformative. It has previously been shown that urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice. METHODS We conducted a prospective observational study, recruiting renal transplant participants over an 18-month period. We made no alterations to the patients' clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance. We assessed the urinary nitrate to creatinine ratio (uNCR) between patient groups: routine attendances, biopsy proven rejection, biopsy proven no rejection and other call backs. uNCR was examined over time for those with biopsy proven transplant rejection. These four groups were compared using an ANOVA test. RESULTS A total of 2656 samples were collected. uNCR during biopsy proven rejection, n = 15 (median 49 μmol/mmol, IQR 23-61) was not significantly different from that of routine samples, n = 164 (median 55 μmol/mmol, IQR 37-82) (p = 0.55), or biopsy proven no rejection, n = 12 (median 39 μmol/mmol, IQR 21-89) (P = 0.77). Overall uNCR was highly variable with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection. The total taking Tacrolimus was 204 patients, with no statistical difference between the uNCR of all those on Tacrolimus, against those not, p = 0.18. CONCLUSION The urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.
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Gender Differences in Long-Term Outcomes of Medical Therapy and Successful Percutaneous Coronary Intervention for Coronary Chronic Total Occlusions.
Guo, L, Lv, H, Zhong, L, Wu, J, Ding, H, Xu, J, Huang, R
Journal of interventional cardiology. 2019;:2017958
Abstract
BACKGROUND There is a paucity of information about the gender differences in clinical outcomes of successful percutaneous coronary intervention (PCI) compared with medical therapy (MT) in patients with coronary chronic total occlusions (CTOs). OBJECTIVES We aimed to investigate the impact of gender on long-term clinical outcomes associated with successful CTO-PCI versus MT in patients with CTOs. METHODS Between January 2007 and December 2016, a total of 1702 patients with ≥1 CTO were enrolled. After exclusion, 1294 patients with 1520 CTOs were analyzed and were divided into the female group (n = 304, 23.5%) and the male group (n = 990, 76.5%). The patients in the female or male group were assigned to a MT group or successful CTO-PCI group according to the treatment strategy. In the female group, they were divided into two groups: 177 patients in the MT group and 127 patients in the successful CTO-PCI group. In the male group, they were divided into two groups: 623 patients in the MT group and 367 patients in the successful CTO-PCI group. The primary outcome was cardiac death. The secondary outcome was major adverse cardiac event (MACE). RESULTS The median overall follow-up duration was 3.6 (IQR, 2.1-5.0) years, there were no significant differences between the MT and successful CTO-PCI groups with respect to the prevalence of cardiac death (MT vs. successful PCI: 6.8% vs. 3.9%, p=0.287) and MACE (20.9% vs. 21.3%, p=0.810) in female patients. In the male group, the occurrence of cardiac death (MT vs. successful PCI: 6.6% vs. 3.8%, p=0.066) was similar between the two groups. The MACE rate (30.0% vs. 18.5%, p < 0.001) was significantly higher in the MT group. Heart failure (hazard ratio 3.40, 95% confidence interval 1.23-9.40, p=0.018) was an independent predictor of cardiac death in female patients. CONCLUSIONS Successful CTO-PCI was not associated with reduced risk of cardiac death compared with medical therapy alone in both female and male patients. However, men have a significant reduction in MACE rate after successful CTO-PCI. Aggressive CTO-PCI should be considered carefully among female patients.
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The Effectiveness of Trimetazidine Treatment in Patients with Stable Angina Pectoris of Various Durations: Results from the CHOICE-2 Study.
Glezer, M, ,
Advances in therapy. 2018;(7):1103-1113
Abstract
INTRODUCTION Trimetazidine (TMZ) has been shown to reduce angina symptoms and to increase exercise capacity in randomized clinical trials, but more extensive data would be useful to assess its effects in real-world clinical practice and in patients with different durations of disease. METHODS CHOICE-2 was a Russian, multicenter, 6-month, open-label, prospective observational study that assessed the effect of adding TMZ modified release 35 mg bid to antianginal treatment in a real-world setting. The present analysis of CHOICE-2 results explored the effects of adding TMZ to background antianginal therapies with regard to the duration of stable angina. RESULTS A total of 741 patients with known durations of disease were divided into four groups according to stable angina pectoris (AP) duration, ranging from less than 1 year to more than 9 years. Addition of TMZ led to a significant decrease in the frequency of angina attacks and in the use of short-acting nitrates in all groups. In patients with recently diagnosed angina (AP duration < 1 year), the average number of angina attacks per week decreased significantly from 3.75 ± 4.63 to 0.67 ± 1.51 and in those with advanced disease (AP duration > 9 years) from 5.63 ± 5.24 to 1.32 ± 2.07. Angina-free walking distance also improved significantly. Addition of TMZ also improved patient well-being. Results were achieved rapidly (within 2 weeks), were maintained over 6 months, and were obtained in all patient groups regardless of angina duration. CONCLUSION TMZ added to other antianginal therapies proved to be effective for reducing angina attacks and short-acting nitrate use, increasing angina-free walking distance, and improving patient well-being in a real-life setting, irrespective of angina duration, including patients with recently diagnosed angina. This provides an opportunity for intensification of treatment early on in the disease process, with the aim of decreasing angina burden and improving patient quality of life. FUNDING Servier. TRIAL REGISTRATION ISRCTN identifier ISRCTN65209863. Plain language summary available for this article.
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Relationship Between Urinary Nitrate Excretion and Blood Pressure in the InChianti Cohort.
Smallwood, MJ, Ble, A, Melzer, D, Winyard, PG, Benjamin, N, Shore, AC, Gilchrist, M
American journal of hypertension. 2017;(7):707-712
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Abstract
BACKGROUND Inorganic nitrate from the oxidation of endogenously synthesized nitric oxide (NO) or consumed in the diet can be reduced to NO via a complex enterosalivary circulation pathway. The relationship between total nitrate exposure by measured urinary nitrate excretion and blood pressure in a large population sample has not been assessed previously. METHODS For this cross-sectional study, 24-hour urinary nitrate excretion was measured by spectrophotometry in the 919 participants from the InChianti cohort at baseline and blood pressure measured with a mercury sphygmomanometer. RESULTS After adjusting for age and sex only, diastolic blood pressure was 1.9 mm Hg lower in subjects with ≥2 mmol urinary nitrate excretion compared with those excreting <1 mmol nitrate in 24 hours: systolic blood pressure was 3.4 mm Hg (95% confidence interval (CI): -3.5 to -0.4) lower in subjects for the same comparison. Effect sizes in fully adjusted models (for age, sex, potassium intake, use of antihypertensive medications, diabetes, HS-CRP, or current smoking status) were marginally larger: systolic blood pressure in the ≥2 mmol urinary nitrate excretion group was 3.9 (CI: -7.1 to -0.7) mm Hg lower than in the comparison <1 mmol excretion group. CONCLUSIONS Modest differences in total nitrate exposure are associated with lower blood pressure. These differences are at least equivalent to those seen from substantial (100 mmol) reductions in sodium intake.
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Impaired flow-mediated dilation in hospitalized patients with community-acquired pneumonia.
Loffredo, L, Cangemi, R, Perri, L, Catasca, E, Calvieri, C, Carnevale, R, Nocella, C, Equitani, F, Ferro, D, Violi, F, et al
European journal of internal medicine. 2016;:74-80
Abstract
BACKGROUND Community-acquired pneumonia (CAP) is complicated by cardiovascular events as myocardial infarction and stroke but the underlying mechanism is still unclear. We hypothesized that endothelial dysfunction may be implicated and that endotoxemia may have a role. METHODS Fifty patients with CAP and 50 controls were enrolled. At admission and at discharge, flow-mediated dilation (FMD), serum levels of endotoxins and oxidative stress, as assessed by serum levels of nitrite/nitrate (NOx) and isoprostanes, were studied. RESULTS At admission, a significant difference between patients with CAP and controls was observed for FMD (2.1±0.3 vs 4.0±0.3%, p<0.001), serum endotoxins (157.8±7.6 vs 33.1±4.8pg/ml), serum isoprostanes (341±14 vs 286±10 pM, p=0.009) and NOx (24.3±1.1 vs 29.7±2.2μM). Simple linear correlation analysis showed that serum endotoxins significantly correlated with Pneumonia Severity Index score (Rs=0.386, p=0.006). Compared to baseline, at discharge CAP patients showed a significant increase of FMD and NOx (from 2.1±0.3 to 4.6±0.4%, p<0.001 and from 24.3±1.1 to 31.1±1.5μM, p<0.001, respectively) and a significant decrease of serum endotoxins and isoprostanes (from 157.8±7.6 to 55.5±2.3pg/ml, p<0.001, and from 341±14 to 312±14 pM, p<0.001, respectively). Conversely, no changes for FMD, NOx, serum endotoxins and isoprostanes were observed in controls between baseline and discharge. Changes of FMD significantly correlated with changes of serum endotoxins (Rs=-0.315; p=0.001). CONCLUSIONS The study provides the first evidence that CAP is characterized by impaired FMD with a mechanism potentially involving endotoxin production and oxidative stress.
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Concomitant nitrates enhance clopidogrel response during dual anti-platelet therapy.
Lee, DH, Kim, MH, Guo, LZ, De Jin, C, Cho, YR, Park, K, Park, JS, Park, TH, Serebruany, V
International journal of cardiology. 2016;:877-81
Abstract
BACKGROUND Despite advances in modern anti-platelet strategies, clopidogrel still remains the cornerstone of dual anti-platelet therapy (DAPT) in patients undergoing percutaneous coronary interventions (PCI). There is some inconclusive evidence that response after clopidogrel may be impacted by concomitant medications, potentially affecting clinical outcomes. Sustained released nitrates (SRN) are commonly used together with clopidogrel in post-PCI setting for mild vasodilatation and nitric oxide-induced platelet inhibition. METHODS We prospectively enrolled 458 patients (64.5 ± 9.6 years old, and 73.4% males) following PCI undergoing DAPT with clopidogrel and aspirin. Platelet reactivity was assessed by the VerifyNow™ P2Y12 assay at the maintenance outpatient setting. RESULTS Concomitant SRN (n=266) significantly (p=0.008) enhanced platelet inhibition after DAPT (251.6 ± 80.9PRU) when compared (232.1 ± 73.5PRU) to the SRN-free (n=192) patients. Multivariate logistic regression analysis with the cut-off value of 253 PRU for defining heightened platelet reactivity confirmed independent correlation of more potent platelet inhibition during DAPT and use of SRN (Relative risk=1.675; Odds ratio [1.059-2.648]; p=0.027). In contrast, statins, calcium-channel blockers, beta blockers, angiotensin receptor blockers, ACE-inhibitors, diuretics, and anti-diabetic agents did not significantly impact platelet inhibition following DAPT. CONCLUSION The synergic ability of SRN to enhance response during DAPT may have important clinical implications with regard to better cardiovascular protection, but extra bleeding risks, requiring further confirmation in a large randomized study.