Assessing the Limits in Kidney Transplantation: Use of Extremely Elderly Donors and Outcomes in Elderly Recipients.

BACKGROUND: Patient survival with end-stage renal disease is longer after kidney transplantation (KT) compared with those remaining on dialysis. Nevertheless, this remains uncertain when receiving a kidney from a donor ≥80 years old. METHODS: In a longitudinal mortality study in the Catalan Renal Registry including 2585 patients ≥60 years old on dialysis and placed on the KT waiting list, 1084 received a first KT from a deceased donor aged 60 to 79 years and 128 from a deceased donor ≥80 years. We calculated adjusted risk of graft loss by means of competing-risks regression, considering patient death with functioning graft as a competing event. To assess patient survival benefit from KT, we calculated the adjusted risk of death by nonproportional hazard analysis, taking the fact of being transplanted as a time-dependent effect. Considering all KT ≥60 (n = 1212), we assessed whether the benefit of KT varied per different recipient characteristics by calculating the interaction effect between all potential mortality risk factors and the treatment group. RESULTS: Compared with kidneys from donors 60 to 79 years old, graft survival was significantly lower for kidneys from donors aged ≥80 years (subhazard ratio = 1.55; 95% confidence interval, 1.00-2.38; P = 0.048). In comparison with those who remained on dialysis, adjusted risk of death 12 months after transplantation in recipients with a kidney from donors ≥80 years was 0.54 (95% confidence interval, 0.38-0.77; P < 0.0001). CONCLUSIONS: Despite KT from octogenarian deceased donors being associated with reduced graft survival, recipients had lower mortality rates than those remaining on dialysis, even if the kidney came from an extremely aged donor.

A paired survival analysis comparing hemodialysis and kidney transplantation from deceased elderly donors older than 65 years.

BACKGROUND: Kidney transplantation from deceased donors aged 65 years or older is associated with suboptimal patient and graft survival. In large registries, survival is longer after kidney transplantation than when remaining on dialysis. However, whether recipients of these old grafts survive longer than their dialysis counterparts is unknown. METHODS: We retrospectively assessed the outcomes of 5,230 recipients of first deceased donor grafts transplanted during the period of 1990 to 2010 in Catalonia, 915 of whom received grafts from donors 65 years or older. In a match-pair analysis, we aimed to pair each of 915 eligible cases with one control (1:1 ratio). Each pair had the same characteristics at the time of entering dialysis program: age, sex, primary renal disease, period of dialysis onset, and cardiovascular comorbidities. We found 823 pairs. RESULTS: Patient survival of 823 recipients of elderly donors was significantly higher than that of their 823 matched dialysis waitlisted nontransplanted partners (91.6%, 74.5%, and 55.5% vs. 88.8%, 44.2%, and 18.1%, respectively at 1, 5, and 10 years; P<0.001). The probability of death after the first year was similar (8.1% transplant vs 10.3% dialysis; P=0.137); however, analyzing the whole period, the adjusted proportional risk of death was 2.66 (95% confidence interval, 2.21-3.20) times higher for patients remaining on dialysis than for transplanted patients (P<0.001). CONCLUSION: Our study demonstrates that despite the fact that kidney transplantation from elderly deceased donors is associated with reduced graft and patient survival, their paired counterpart patients remaining on dialysis have a risk of death 2.66 times higher.

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.

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/10(5) 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.

[Angiotensin converting enzyme 2 and its emerging role in the regulation of the renin angiotensin system]. / Enzima conversiva de la angiotensina 2 y su papel emergente en la regulación del sistema renina-angiotensina.

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.

Enzima conversiva de la angiotensina 2 y su papel emergente en la regulación del sistema renina-angiotensina / Angiotensin converting enzyme 2 and its emerging role in the regulation of the renin angiotensin system

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 deuna 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 ECAencargada de la degradación de la angiotensina II a angiotensina 1-7, ofrece una nueva línea de estudio en el SRAA. La presente revisión 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 laadministración 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 blockerdecreases 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 offernew 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 geneand also mice treated with pharmacological ACE2 inhibitors. These results suggest that ACE2 might be a new therapeutic target within the RAS

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/10(5) 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 x 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.

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

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. METHODS: We analyzed 403 patients who received one or more renal grafts between 1979 and 2000: group A = patients who had stroke (n = 19); group B = those who did not (n = 384). Medical records and pertinent data were compiled. The risk of stroke was studied using univariate and multivariate Cox regression models. RESULTS: prevalence of stroke in RTR was 7.97% at 10 yr. Time elapsed between renal transplantation (RT) and stroke: 49.3 months. Possible risk factors based on the univariate analyses were: diabetic nephropathy (DN) (p < 0.001) and autosomal-dominant-polycystic-kidney-disease (p = 0.049) as original nephropathies, peripheral vascular disease (PVD) (p < 0.001), diabetes mellitus prior to RT (p = 0.005), age older than 40 yr (p = 0.037) and hypertension (p = 0.049). Other analysed risk factors such as gender, renal function, cytomegalovirus infection, hyperlipidemia, hyperuricemia, erythrocytosis or hypertensive donor failed to show any significant predictive value for stroke in these patients. When multivariate analyses were carried out, we found that DN (OR = 4.8; p = 0.010), PVD (OR = 8.2; p < 0.001) and age > 40 yr (OR = 3.3; p = 0.019) were predictive risk factors for stroke. For group A, hypertension was present in all patients, 68.4% had hyperlipidemia and 42.1% reported previous stroke. Cerebral hemorrhage occurred in seven of 19 (36.84%) of the stroke patients, but no subarachnoid hemorrhage occurred in them. Seven of 12 ischemic strokes were atherotrombotic. Considering all strokes, basal ganglia was the predominant localization. The outcome was poor, as nearly half of the patients died in the 3 months following stroke. CONCLUSIONS: Prevalence of stroke in our RTR population was 7.97%. Cerebral hemorrhage appears to be more prevalent in RTR than in general population. More than that, the cerebral hemorrhage rate we found is higher than that reported elsewhere in RTR. The main predictors of stroke were DN, PVD and age. No patient with interstitial nephropathy suffered stroke. Mortality is high in RTR with stroke.