Josep Lloveras

Stroke in renal transplant recipients: epidemiology, predictive risk factors and outcome

Abstract: Background:  Cerebrovascular and cardiovascular diseases are the most important causes of increased morbidity and mortality in patients with end‐stage renal disease. Stroke has been widely reported in chronic dialysis patients, but there is scarce information about stroke in renal transplant recipients (RTR), although cerebrovascular events are the most common and potentially life‐threatening neurological complications in them. Our aim is to analyze the prevalence, risk factors, etiopathogenia, clinical aspects and outcome of stroke in RTR.

Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan

Angiotensin-converting enzyme (ACE)2 is a carboxypeptidase that degrades angiotensin II and other peptides. In the kidney, ACE2 localization within the glomerulus and tubules is cell specific. This study was aimed to investigate the localization of ACE2 within the renal vasculature. We also studied the effect of the administration of a specific angiotensin II type 1 receptor blocker, telmisartan, on ACE2 expression in the renal vasculature. ACE2 and ACE were localized in renal arterioles using confocal microscopy and specific cell markers. Quantitative measurements of ACE2 and ACE mRNA were estimated in kidney arterioles isolated by laser capture microdissection using real-time PCR. In kidney arterioles, ACE was localized in the endothelial layer, whereas ACE2 was localized in the tunica media. In mice treated with telmisartan (2 mg.kg(-1).day(-1)) for 2 wk, ACE2 expression was increased by immunostaining, whereas ACE expression was decreased. This was reflected in a decrease in the ACE/ACE2 ratio compared with vehicle-treated controls (0.53 +/- 0.14 vs. 7.59 +/- 2.72, P = 0.027, respectively). In kidney arterioles isolated by laser capture microdissection, the ACE/ACE2 mRNA ratio was also decreased compared with control mice (1.21 +/- 0.31 vs. 4.63 +/- 0.86, P = 0.044, respectively). In conclusion, in kidney arterioles ACE2 is preferentially localized in the tunica media, and its expression is increased after administration of the angiotensin II type 1 receptor blocker, telmisartan. Amplification of ACE2 in the renal vasculature may contribute to the therapeutic action of telmisartan by increasing angiotensin II degradation.

Circulating endothelial progenitor cells after kidney transplantation

Circulating endothelial progenitor cells (EPCs) promote vascular repair and maintain integrity of the endothelial monolayer. Reduced EPCs number has been associated with endothelial dysfunction in various cardiovascular diseases. Cardiovascular disease risk is higher in renal transplant patients (RT) than the general population. We studied EPCs number and proliferation in RT, and examined the association with other cardiovascular risk factors such as reduced glomerular filtration rate (GFR) and LDL cholesterol. EPCs concentration was determined in 94 RT and 39 control subjects (C) by flow cytometry. EPCs proliferation was also studied after 7 days in culture. EPCs concentration was significantly reduced in RT versus C (median 33.5 [5–177] vs. 53 [9–257] EPCs/105 PMN cells, p = 0.006). EPCs proliferation was also reduced in RT versus C (mean ± SD; 372.7 ± 229.3 vs. 539.8 ± 291.3 EPCs × field, p = 0.003). In multiple regression analysis, GFR, HDL, LDL and body weight were independent predictors of EPCs concentration in RT (r2= 0.25, p < 0.001). EPCs number is reduced in RT, particularly in patients with reduced GFR. Moreover, EPCs from RT studied in vitro, showed reduced proliferation, which is a sign of functional impairment. These alterations may be involved in increased cardiovascular risk of RT.

Putative endothelial progenitor cells are associated with flow‐mediated dilation in refractory hypertensives

Background. Hypertension has been related to endothelial dysfunction. Patients with refractory hypertension (RH) have a reduced number of endothelial progenitor cells (EPCs). Aim. To evaluate if blood EPC levels relate to endothelium‐dependent vasodilation (ED‐VD) in RH. Methods. We analyzed 29 RH confirmed by 24‐h ambulatory blood pressure monitoring and assessed complete clinical and laboratory evaluation. EPCs were isolated from peripheral mononuclear cells (MNC) by flow cytometry. ED‐VD was determined measuring flow‐mediated dilation (FMD) by venous occlusion plethysmography. Results. Circulating EPCs/105 MNC (median [Q1–Q3]): 23.0 [4.5–53.8]. FMD (median [Q1–Q3]): 211.7 [79.5–365.8]%. Significant correlations with log‐FMD: EPCs (r = 0.469; p = 0.018) and homocysteine (r = −0.414; p = 0.045). There was no collinearity between EPCs and homocysteine. FMD did not correlate with age, gender, office BP, 24‐h systolic blood pressure or 24‐h diastolic blood pressure, laboratory parameters, C‐reactive‐protein, left ventricular‐mass index, dyslipidaemia, smoking habit and statin or angiotensin system blockers treatment. Multiple linear regression analysis showed that after age‐adjustment, EPC (p = 0.027) and homocysteine (p = 0.004) were the only variables that predicted FMD (R = 0.740). After dividing patients according to EPC number, patients in the lower tertile showed a significantly reduced FMD compared with those in the group of the two upper tertiles of EPC: log‐FMD (mean±SD): 4.7±0.9 vs 5.6±0.8, respectively (p = 0.031). Conclusions. ED‐VD independently correlates with circulating EPCs in RH. Homocysteine is also an independent predictor of lower FMD in such patients.

Enzima conversiva de la angiotensina 2 y su papel emergente en la regulación del sistema renina-angiotensina

El sistema renina-angiotensina-aldosterona (SRAA) es un importante regulador de la función cardiovascular y renal. Su bloqueo mediante los inhibidores de la enzima conversiva de la angiotensina (ECA) y/o los antagonistas del receptor de la angiotensina II se acompaña de una reducción de los valores de presión arterial, reducción del riesgo cardiovascular y enlentecimiento de la progresión de la insuficiencia renal. El descubrimiento de la ECA2, una enzima homóloga de la ECA encargada de la degradación de la angiotensina II a angiotensina 1-7, ofrece una nueva línea de estudio en el SRAA. La presente revision expone la importancia de la ECA2 en diferentes órganos: el corazón, el pulmón y el riñón. A su vez, se detalla la importancia de dicha enzima mediante los diversos estudios realizados en modelos genéticamente manipulados con deleción del gen de la ECA2 y mediante la administración de un inhibidor de la ECA2. Los resultados de dichos estudios apuntan a un papel emergente de la ECA2 como una nueva diana terapéutica del SRAA. The renin-angiotensin system (RAS) plays a key role in the regulation of cardiovascular and renal function. Thus, RAS blockade with an angiotensin- converting enzyme (ACE) and/or angiotensin receptor blocker decreases blood pressure, cardiovascular events, and delays the progression of kidney disease. The discovery of ACE2, a homologue of ACE, capable of degrading angiotensin II to angiotensin 1-7, may offer new insights into the RAS. In this review we discuss the possible protective role of ACE2 in different organs, namely heart, lungs and kidneys. The role of this enzyme is inferred from recent studies performed using genetically manipulated mice that lack the ACE2 gene and also mice treated with pharmacological ACE2 inhibitors. These results suggest that ACE2 might be a new therapeutic target within the RAS.