RESUMEN
Albuminuria is characterized by a disruption of the glomerular filtration barrier, which is composed of the fenestrated endothelium, the glomerular basement membrane, and the slit diaphragm. Nephrin is a major component of the slit diaphragm. Apart from hemodynamic effects, Ang II enhances albuminuria by ß-Arrestin2-mediated nephrin endocytosis. Blocking the AT1 receptor with candesartan and irbesartan reduces the Ang II-mediated nephrin-ß-Arrestin2 interaction. The inhibition of MAPK ERK 1/2 blocks Ang II-enhanced nephrin-ß-Arrestin2 binding. ERK 1/2 signaling, which follows AT1 receptor activation, is mediated by G-protein signaling, EGFR transactivation, and ß-Arrestin2 recruitment. A mutant AT1 receptor defective in EGFR transactivation and ß-Arrestin2 recruitment reduces the Ang II-mediated increase in nephrin ß-Arrestin2 binding. The mutation of ß-Arrestin2K11,K12, critical for AT1 receptor binding, completely abrogates the interaction with nephrin, independent of Ang II stimulation. ß-Arrestin2K11R,K12R does not influence nephrin cell surface expression. The data presented here deepen our molecular understanding of a blood-pressure-independent molecular mechanism of AT-1 receptor blockers (ARBs) in reducing albuminuria.
Asunto(s)
Angiotensina II , Endocitosis , Proteínas de la Membrana , Receptor de Angiotensina Tipo 1 , Endocitosis/efectos de los fármacos , Endocitosis/fisiología , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Angiotensina II/farmacología , Angiotensina II/metabolismo , Humanos , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 1/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Ratones , Albuminuria/metabolismo , Podocitos/metabolismo , Podocitos/efectos de los fármacos , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Compuestos de Bifenilo/farmacología , Irbesartán/farmacología , Células HEK293 , Arrestina beta 2/metabolismo , Arrestina beta 2/genética , Bencimidazoles , TetrazolesRESUMEN
(1) Background: Sympathetic overactivity is a major contributor to resistant hypertension (RH). According to animal studies, sympathetic overactivity increases immune responses, thereby aggravating hypertension and cardiovascular outcomes. Renal denervation (RDN) reduces sympathetic nerve activity in RH. Here, we investigate the effect of RDN on T-cell signatures in RH. (2) Methods: Systemic inflammation and T-cell subsets were analyzed in 17 healthy individuals and 30 patients with RH at baseline and 6 months after RDN. (3) Results: The patients with RH demonstrated higher levels of pro-inflammatory cytokines and higher frequencies of CD4+ effector memory (TEM), CD4+ effector memory residential (TEMRA) and CD8+ central memory (TCM) cells than the controls. After RDN, systolic automated office blood pressure (BP) decreased by -17.6 ± 18.9 mmHg. Greater BP reductions were associated with higher CD4+ TEM (r -0.421, p = 0.02) and CD8+ TCM (r -0.424, p = 0.02) frequencies at baseline. The RDN responders, that is, the patients with ≥10mmHg systolic BP reduction, showed reduced pro-inflammatory cytokine levels, whereas the non-responders had unchanged inflammatory activity and higher CD8+ TEMRA frequencies with increased cellular cytokine production. (4) Conclusions: The pro-inflammatory state of patients with RH is characterized by altered T-cell signatures, especially in non-responders. A detailed analysis of T cells might be useful in selecting patients for RDN.
Asunto(s)
Hipertensión , Hipotensión , Humanos , Simpatectomía , Resultado del Tratamiento , Linfocitos T , Riñón , Presión Sanguínea/fisiología , CitocinasRESUMEN
Kidney transplant recipients (KTRs) are extremely vulnerable to SARS-CoV-2 infection and show an impaired immune response to SARS-CoV-2 vaccination. We analyzed factors related to vaccination efficiency in KTRs. In a multicenter prospective observational study (NCT04743947), IgG antibodies levels against SARS-CoV-2 spike S1 subunit and their neutralization capacity after SARS-CoV-2 vaccination were analyzed in 225 KTRs and compared to 176 controls. After the vaccination, 56 (24.9%) KTRs became seropositive of whom 68% had neutralizing antibodies. This immune response was significantly lower compared to controls (239 [78-519] BAU/ml versus 1826 [560-3180] BAU/ml for KTRs and controls, p < .0001). The strongest predictor for an impaired response was mycophenolate mofetil (MMF) treatment. Multivariate regression analysis revealed that MMF-free regimen was highly associated with seroconversion (OR 13.25, 95% CI 3.22-54.6; p < .001). In contrast, other immunosuppressive drugs had no significant influence. 187 out of 225 KTRs were treated with MMF of whom 26 (13.9%) developed antibodies. 23 of these seropositive KTRs had a daily MMF dose ≤1 g. Furthermore, higher trough MMF concentrations correlated with lower antibody titers (R -0.354, p < .001) supporting a dose-dependent unfavorable effect of MMF. Our data indicate that MMF dose modification could lead to an improved immune response.
Asunto(s)
COVID-19 , Trasplante de Riñón , Anticuerpos Antivirales , Vacunas contra la COVID-19 , Humanos , Inmunidad , Trasplante de Riñón/efectos adversos , Ácido Micofenólico/uso terapéutico , SARS-CoV-2 , Receptores de Trasplantes , VacunaciónRESUMEN
BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.
Asunto(s)
Desnervación/métodos , Procedimientos Endovasculares/métodos , Hipertensión/terapia , Arteria Renal/inervación , Arteria Renal/cirugía , Procedimientos Quirúrgicos Ultrasónicos/métodos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Monitoreo Ambulatorio de la Presión Arterial , Bloqueadores de los Canales de Calcio/uso terapéutico , Resistencia a Medicamentos , Femenino , Humanos , Riñón/irrigación sanguínea , Masculino , Persona de Mediana Edad , Método Simple Ciego , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéuticoRESUMEN
Modification of vaccination strategies is necessary to improve the immune response to SARS-CoV-2 vaccination in kidney transplant recipients (KTRs). This multicenter observational study analyzed the effects of the third SARS-CoV-2 vaccination in previously seronegative KTRs with the focus on temporary mycophenolate mofetil (MMF) dose reduction within propensity matched KTRs. 56 out of 174 (32%) previously seronegative KTRs became seropositive after the third vaccination with only three KTRs developing neutralizing antibodies against the omicron variant. Multivariate logistic regression revealed that initial antibody levels, graft function, time after transplantation and MMF trough levels had an influence on seroconversion (P < .05). After controlling for confounders, the effect of MMF dose reduction before the third vaccination was calculated using propensity score matching. KTRs with a dose reduction of ≥33% showed a significant decrease in MMF trough levels to 1.8 (1.2-2.5) µg/ml and were more likely to seroconvert than matched controls (P = .02). Therefore, a MMF dose reduction of 33% or more before vaccination is a promising approach to improve success of SARS-CoV-2 vaccination in KTRs.
Asunto(s)
COVID-19 , Trasplante de Riñón , Humanos , Ácido Micofenólico/uso terapéutico , Vacunas contra la COVID-19 , Rechazo de Injerto , Inmunosupresores/uso terapéutico , Inmunosupresores/farmacología , SARS-CoV-2 , COVID-19/prevención & control , Receptores de Trasplantes , InmunidadRESUMEN
BACKGROUND: Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. METHODS: We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. RESULTS: Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. CONCLUSIONS: Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.
Asunto(s)
Hipertensión Renal/etiología , Hipertensión Renal/prevención & control , Nefritis/etiología , Nefritis/prevención & control , Receptores Adrenérgicos alfa 2/fisiología , Sistema Nervioso Simpático/fisiopatología , Transmisión Sináptica/fisiología , Angiotensina II , Animales , Modelos Animales de Enfermedad , Hipertensión Renal/fisiopatología , Ratones , Ratones Noqueados , Nefritis/fisiopatología , SimpatectomíaRESUMEN
Recently, an alternative renin-angiotensin system pathway has been described, which involves binding of angiotensin-(1-7) to its receptor Mas. The Mas axis may counterbalance angiotensin-II-mediated proinflammatory effects, likely by affecting macrophage function. Here we investigate the role of Mas in murine models of autoimmune neuroinflammation and atherosclerosis, which both involve macrophage-driven pathomechanisms. Mas signaling affected macrophage polarization, migration, and macrophage-mediated T-cell activation. Mas deficiency exacerbated the course of experimental autoimmune encephalomyelitis and increased macrophage infiltration as well as proinflammatory gene expression in the spleen and spinal cord. Furthermore, Mas deficiency promoted atherosclerosis by affecting macrophage infiltration and migration and led to increased oxidative stress as well as impaired endothelial function in ApoE-deficient mice. In summary, we identified the Mas axis as an important factor in macrophage function during inflammation of the central nervous and vascular system in vivo. Modulating the Mas axis may constitute an interesting therapeutic target in multiple sclerosis and/or atherosclerosis.
Asunto(s)
Aterosclerosis/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Macrófagos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Aterosclerosis/inmunología , Aterosclerosis/fisiopatología , Diferenciación Celular , Movimiento Celular , Proliferación Celular , Encefalomielitis Autoinmune Experimental/inmunología , Endotelio Vascular/fisiopatología , Femenino , Expresión Génica , Masculino , Ratones Endogámicos C57BL , Estrés Oxidativo , Proto-Oncogenes Mas , Médula Espinal/metabolismo , Bazo/metabolismo , Linfocitos T/fisiologíaRESUMEN
Changes in renal hemodynamics have a major impact on blood pressure (BP). Angiotensin (Ang) II has been shown to induce vascular dysfunction by interacting with phosphodiesterase (PDE)1 and PDE5. The predominant PDE isoform responsible for renal vascular dysfunction in hypertension is unknown. Here, we measured the effects of PDE5 (sildenafil) or PDE1 (vinpocetine) inhibition on renal blood flow (RBF), BP, and renal vascular function in normotensive and hypertensive mice. During acute short-term Ang II infusion, sildenafil decreased BP and increased RBF in C57BL/6 (WT) mice. In contrast, vinpocetine showed no effect on RBF and BP. Additionally, renal cGMP levels were significantly increased after acute sildenafil but not after vinpocetine infusion, indicating a predominant role of PDE5 in renal vasculature. Furthermore, chronic Ang II infusion (500 ng·kg-1·min-1) increased BP and led to impaired NO-dependent vasodilation in kidneys of WT mice. Additional treatment with sildenafil (100 mg·kg-1·day-1) attenuated Ang II-dependent hypertension and improved NO-mediated vasodilation. During chronic Ang II infusion, urinary nitrite excretion, a marker for renal NO generation, was increased in WT mice, whereas renal cGMP generation was decreased and restored after sildenafil treatment, suggesting a preserved cGMP signaling after PDE5 inhibition. To investigate the dependency of PDE5 effects on NO/cGMP signaling, we next analyzed eNOS-KO mice, a mouse model characterized by low vascular NO/cGMP levels. In eNOS-KO mice, chronic Ang II infusion increased BP but did not impair NO-mediated vasodilation. Moreover, sildenafil did not influence BP or vascular function in eNOS-KO mice. These results highlight PDE5 as a key regulator of renal hemodynamics in hypertension.
Asunto(s)
Angiotensina II , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertensión/prevención & control , Inhibidores de Fosfodiesterasa 5/farmacología , Arteria Renal/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Citrato de Sildenafil/farmacología , Vasodilatadores/farmacología , Animales , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipertensión/inducido químicamente , Hipertensión/enzimología , Hipertensión/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Arteria Renal/enzimología , Arteria Renal/fisiopatología , Vasodilatación/efectos de los fármacos , Alcaloides de la Vinca/farmacologíaRESUMEN
BACKGROUND: Mortality of critically-ill patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) in an intensive-care setting continues to remain high. There is still uncertainty as to which factors should guide clinical judgement. METHODS: A cohort of 155 patients admitted to an intensive-care unit and necessitating RRT due to AKI were retrospectively analyzed. Demographic and clinical parameters at the time of RRT initiation were retrieved. Multi- and univariate analyses were performed to determine the impact of different risk factors on mortality. RESULTS: The most common causes of AKI were sepsis (39.3%) and cardiac events (32%). The majority of patients were treated by continuous (67.3%), the others by intermittent RRT. After 30 days, 51.0% of patients survived. Nonsurvivors were older (73 vs. 69 years), had a higher APACHEE II score (30.1 ± 5.6 vs. 26.5 ± 7.1), and were more likely to be vasopressor dependent, mechanically ventilated, or treated by continuous RRT. Multivariate analysis revealed that higher age, higher APACHEE II score, and lower serum creatinine at baseline were independent predictors for mortality, whereas histories of diabetes mellitus, arterial hypertension, coronary heart disease, or stroke were not. CONCLUSION: Critically-ill patients with AKI requiring RRT continue to have a high mortality. Age and APACHE II score showed an impact on mortality whereas traditional cardiovascular risk factors did not. Higher BUN and creatinine levels do not have a negative impact on mortality. Our findings support the current practice that RRT initiation should primarily be guided by clinical decision.â©.
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Lesión Renal Aguda/mortalidad , Unidades de Cuidados Intensivos , Terapia de Reemplazo Renal , Lesión Renal Aguda/terapia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Hyperuricemia is very common in industrialized countries and known to promote vascular smooth muscle cell proliferation. Juvenile hyperuricemia is a hallmark of uromodulin-associated kidney disease characterized by progressive interstitial renal fibrosis leading to end-stage renal disease within decades. Here we describe a member of a Polish-German family with a history of familial background of chronic kidney disease, hyperuricemia, and gout. This patient had hypertension because of bilateral small renal arteries, hyperuricemia, and chronic kidney disease. Clinical and molecular studies were subsequently performed in 39 family members, which included a physical examination, Duplex ultrasound of the kidneys, laboratory tests for renal function, and urine analysis. In eight family members contrast-enhanced renal artery imaging by computed tomography-angiography or magnetic resonance imaging was conducted and showed that bilateral non-arteriosclerotic small caliber renal arteries were associated with hyperuricemia and chronic kidney disease. Of the 26 family members who underwent genotyping, 11 possessed the P236R mutation (c.707C>G) of the uromodulin gene. All family members with a small caliber renal artery carried the uromodulin P236R mutation. Statistical analysis showed a strong correlation between reduced renal artery lumen and decreased estimated glomerular filtration rate. Thus, bilateral small caliber renal arteries are a new clinical phenotype associated with an uromodulin mutation.
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Tasa de Filtración Glomerular , Gota/genética , Hiperuricemia/genética , Enfermedades Renales/genética , Arteria Renal/diagnóstico por imagen , Arteria Renal/patología , Uromodulina/genética , Adolescente , Adulto , Anciano , Angiografía , Niño , Enfermedad Crónica , Femenino , Genotipo , Gota/complicaciones , Gota/fisiopatología , Humanos , Hiperuricemia/complicaciones , Hiperuricemia/fisiopatología , Enfermedades Renales/complicaciones , Enfermedades Renales/fisiopatología , Fallo Renal Crónico/etiología , Túbulos Renales Distales/química , Masculino , Persona de Mediana Edad , Mutación , Tamaño de los Órganos , Linaje , Fenotipo , Ácido Úrico/sangre , Uromodulina/análisis , Adulto JovenRESUMEN
The aim of the study was to evaluate the possible contribution of non-endothelial eNOS to the regulation of blood pressure (BP). To accomplish this, a double transgenic strain expressing eNOS exclusively in the vascular endothelium (eNOS-Tg/KO) has been generated by endothelial-specific targeting of bovine eNOS in eNOS-deficient mice (eNOS-KO). Expression of eNOS was evaluated in aorta, myocardium, kidney, brain stem and skeletal muscle. Organ bath studies revealed a complete normalization of aortic reactivity to acetylcholine, phenylephrine and the NO-donors in eNOS-Tg/KO. Function of eNOS in resistance arteries was demonstrated by acute i.v. infusion of acetylcholine and the NOS-inhibitor L-NAME. Acetylcholine decreased mean arterial pressure in all strains but eNOS-KO responded significantly less sensitive as compared eNOS-Tg/KO and C57BL/6. Likewise, acute i.v. L-NAME application elevated mean arterial pressure in C57BL/6 and eNOS-Tg/KO, but not in eNOS-KO. In striking contrast to these findings, mean, systolic and diastolic BP in eNOS-Tg/KO remained significantly elevated and was similar to values of eNOS-KO. Chronic oral treatment with L-NAME increased BP to the level of eNOS-KO only in C57BL/6, but had no effect on hypertension in eNOS-KO and eNOS-Tg/KO. Taken together, functional reconstitution of eNOS in the vasculature of eNOS-KO not even partially lowered BP. These data suggest that the activity of eNOS expressed in non-vascular tissue might play a role in physiologic BP regulation.
Asunto(s)
Presión Sanguínea , Endotelio Vascular/fisiopatología , Hipertensión/genética , Hipertensión/fisiopatología , Óxido Nítrico Sintasa de Tipo III/genética , Animales , Bradicardia/complicaciones , Bovinos , Endotelio Vascular/metabolismo , Hipertensión/complicaciones , Hipertensión/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Óxido Nítrico Sintasa de Tipo III/metabolismoRESUMEN
BACKGROUND: Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension. METHODS AND RESULTS: A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±20.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 10 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/90; P for all <0.001), respectively. In patients with true treatment resistance there was a significant reduction with RDN in 24-hour SBP (-10.1/-10.2/-11.7 mm Hg, P<0.001), diastolic BP (-4.8/-4.9/-7.4 mm Hg, P<0.001), maximum SBP (-11.7/-10.0/-6.1 mm Hg, P<0.001) and minimum SBP (-6.0/-9.4/-13.1 mm Hg, P<0.001) at 3, 6, and 12 months, respectively. There was no effect on ambulatory BP monitoring in pseudoresistant patients, whereas office BP was reduced to a similar extent. RDN was equally effective in reducing BP in different subgroups of patients. Office SBP at baseline was the only independent correlate of BP response. CONCLUSIONS: RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial/tendencias , Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Hipertensión/cirugía , Riñón/inervación , Simpatectomía/tendencias , Anciano , Monitoreo Ambulatorio de la Presión Arterial/métodos , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Riñón/fisiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Simpatectomía/métodosRESUMEN
BACKGROUND: Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. METHODS: In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. RESULTS: The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P=0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients (0.7%) as compared with 3 patients (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P=0.02). CONCLUSIONS: Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.).
Asunto(s)
Albuminuria/prevención & control , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Imidazoles/uso terapéutico , Tetrazoles/uso terapéutico , Adolescente , Adulto , Anciano , Albuminuria/epidemiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Enfermedad Coronaria/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Tetrazoles/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by inhibitors such as matrix Gla protein (MGP), a protein activated in the presence of vitamin K. HD patients exhibit marked vitamin K deficiency, and supplementation with vitamin K reduces inactive MGP levels in these patients. The VitaVasK trial analyses whether vitamin K1 supplementation affects the progression of coronary and aortic calcification in HD patients. METHODS: VitaVasK is a prospective, randomized, parallel group, multicentre trial (EudraCT No.: 2010-021264-14) that will include 348 HD patients in an open-label, two-arm design. After baseline multi-slice computed tomography (MSCT) of the heart and thoracic aorta, patients with a coronary calcification volume score of at least 100 will be randomized to continue on standard care or to receive additional supplementation with 5 mg vitamin K1 orally thrice weekly. Treatment duration will be 18 months, and MSCT scans will be repeated after 12 and 18 months. Primary end points are the progression of thoracic aortic and coronary artery calcification (calculated as absolute changes in the volume scores at the 18-month MSCT versus the baseline MSCT). Secondary end points comprise changes in Agatston score, mitral and aortic valve calcification as well as major adverse cardiovascular events (MACE) and all-cause mortality. VitaVask also aims to record MACE and all-cause mortality in the follow-up period at 3 and 5 years after treatment initiation. This trial may lead to the identification of an inexpensive and safe treatment or prophylaxis of VC in HD patients.
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Antifibrinolíticos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Diálisis Renal , Calcificación Vascular/prevención & control , Vitamina K 1/uso terapéutico , Antifibrinolíticos/administración & dosificación , Proteínas de Unión al Calcio/fisiología , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Progresión de la Enfermedad , Proteínas de la Matriz Extracelular/fisiología , Humanos , Estudios Multicéntricos como Asunto , Selección de Paciente , Estudios Prospectivos , Tomografía Computarizada por Rayos X , Calcificación Vascular/fisiopatología , Vitamina K 1/administración & dosificación , Proteína Gla de la MatrizRESUMEN
Dialysis procedure rates in Germany were changed in 2002 from per-session to weekly flat rate payments, and quality assurance was introduced in 2009 with defined treatment targets for spKt/V, dialysis frequency, treatment time, and hemoglobin. In order to understand trends in treatment parameters before and after the introduction of these changes, we analyzed data from 407 to 618 prevalent patients each year (hemodialysis over 90 days) in 14-21 centers in cross-sections of the Dialysis Outcomes and Practice Patterns Study (phases 1-4, 1998-2011). Descriptive statistics were used to report differences over time in the four quality assurance parameters along with erythropoietin-stimulating agent (ESA) and intravenous iron doses. Time trends were analyzed using linear mixed models adjusted for patient demographics and comorbidities. The proportion of patients with short treatment times (less than 4 h) and low spKt/V (below 1.2) improved throughout the study and was lowest after implementation of quality assurance. Hemoglobin levels have increased since 1998 and remained consistent since 2005, with only 8-10% of patients below 10 g/dl. About 90% of patients were prescribed ESAs, with the dose declining since peaking in 2006. Intravenous iron use was highest in 2011. Hence, trends to improve quality metrics for hemodialysis have been established in Germany even after introduction of flat rate reimbursement. Thus, analysis of facility practice patterns is needed to maintain quality of care in a cost-containment environment.
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Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/terapia , Pautas de la Práctica en Medicina/tendencias , Garantía de la Calidad de Atención de Salud/tendencias , Mecanismo de Reembolso/tendencias , Diálisis Renal/economía , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Control de Costos , Relación Dosis-Respuesta a Droga , Eritropoyetina/uso terapéutico , Femenino , Alemania/epidemiología , Hemoglobinas/metabolismo , Humanos , Hierro/uso terapéutico , Fallo Renal Crónico/sangre , Modelos Lineales , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina/economía , Estudios Prospectivos , Garantía de la Calidad de Atención de Salud/economía , Mecanismo de Reembolso/economía , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND: The von Willebrand factor-directed nanobody caplacizumab has greatly changed the treatment of immune thrombotic thrombocytopenic purpura (iTTP) in recent years. Data from randomized controlled trials established efficacy and safety. OBJECTIVES: This study aims to address open questions regarding patient selection, tailoring of therapy duration, obstacles in prescribing caplacizumab in iTTP, effect on adjunct treatment, and outcomes in the real-world setting. METHODS: We report retrospective, observational cohorts of 113 iTTP episodes treated with caplacizumab and 119 historical control episodes treated without caplacizumab. We aggregated data from the caplacizumab phase II/III trials and real-world data from France, the United Kingdom, Germany, and Austria (846 episodes, 396 treated with caplacizumab, and 450 historical controls). RESULTS: Caplacizumab was efficacious in iTTP, independent of the timing of therapy initiation, but curtailed the time of active iTTP only when used in the first-line therapy within 72 hours after diagnosis and until at least partial ADAMTS13-activity remission. Aggregated data from multiple study populations showed that caplacizumab use resulted in significant absolute risk reduction of 2.87% for iTTP-related mortality (number needed to treat 35) and a relative risk reduction of 59%. CONCLUSION: Caplacizumab should be used in first line and until ADAMTS13-remission, lowers iTTP-related mortality and refractoriness, and decreases the number of daily plasma exchange and hospital stay. This trial is registered at www. CLINICALTRIALS: gov as #NCT04985318.
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Púrpura Trombocitopénica Idiopática , Púrpura Trombocitopénica Trombótica , Anticuerpos de Dominio Único , Trombosis , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Proteína ADAMTS13RESUMEN
BACKGROUND: Hypertension is associated with impaired glucose metabolism and insulin resistance. Chronic activation of the sympathetic nervous system may contribute to either condition. We investigated the effect of catheter-based renal sympathetic denervation on glucose metabolism and blood pressure control in patients with resistant hypertension. METHODS AND RESULTS: We enrolled 50 patients with therapy-resistant hypertension. Thirty-seven patients underwent bilateral catheter-based renal denervation, and 13 patients were assigned to a control group. Systolic and diastolic blood pressures, fasting glucose, insulin, C peptide, hemoglobin A(1c), calculated insulin sensitivity (homeostasis model assessment-insulin resistance), and glucose levels during oral glucose tolerance test were measured before and 1 and 3 months after treatment. Mean office blood pressure at baseline was 178/96±3/2 mm Hg. At 1 and 3 months, office blood pressure was reduced by -28/-10 mm Hg (P<0.001) and -32/-12 mm Hg (P<0.001), respectively, in the treatment group, without changes in concurrent antihypertensive treatment. Three months after renal denervation, fasting glucose was reduced from 118±3.4 to 108±3.8 mg/dL (P=0.039). Insulin levels were decreased from 20.8±3.0 to 9.3±2.5 µIU/mL (P=0.006) and C-peptide levels from 5.3±0.6 to 3.0±0.9 ng/mL (P=0.002). After 3 months, homeostasis model assessment-insulin resistance decreased from 6.0±0.9 to 2.4±0.8 (P=0.001). Additionally, mean 2-hour glucose levels during oral glucose tolerance test were reduced significantly by 27 mg/dL (P=0.012). There were no significant changes in blood pressure or metabolic markers in the control group. CONCLUSIONS: Renal denervation improves glucose metabolism and insulin sensitivity in addition to a significantly reducing blood pressure. However, this improvement appeared to be unrelated to changes in drug treatment. This novel procedure may therefore provide protection in patients with resistant hypertension and metabolic disorders at high cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00664638 and NCT00888433.
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Glucemia/metabolismo , Hipertensión Renal/metabolismo , Hipertensión Renal/cirugía , Riñón/inervación , Simpatectomía/métodos , Antihipertensivos/uso terapéutico , Presión Sanguínea/fisiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a Medicamentos , Femenino , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/metabolismo , Humanos , Hipertensión Renal/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Proyectos Piloto , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: After renal transplantation, patients are prone to develop impairments in glucose metabolism. In 2005, the American Diabetes Association published new guidelines on the diagnosis of pre-diabetes [plasma glucose levels from 100 to 125 mg/dL fasting or from 140 to 199 mg/dL 2 h after an oral glucose tolerance test (OGTT)]. This study sought to evaluate the prevalence and the potentially associated factors of pre-diabetes in a cohort of renal transplant patients on maintenance immunosuppressive medication. Furthermore, the diagnostic value of HbA1-c measurements in predicting pre-diabetes in transplant patients is undetermined. METHODS: Two hundred consecutive renal transplant patients of our outpatient transplant clinic were evaluated using a standard OGTT. On the day of testing, multiple factors presumably associated with pre-diabetes were assessed via a standardized questionnaire: daily steroid dosage, triglyceride levels, cholesterol levels, estimated glomerular filtration rate (eGFR) [abbreviated Modification of Diet in Renal Disease (MDRD) formula], systolic and diastolic blood pressure, pulse pressure, age, gender, body mass index (BMI), BMI <>30 and <>25, number of renal transplants, number of rejection episodes prior to testing, source of renal transplant, cause of renal failure and medications as related to the prescription of cyclosporine, tacrolimus, mycophenolate mophetil, angiotensin-converting enzyme inhibitors, AT1-blockers, statins, ß-blockers and thiazide diuretics. Patients diagnosed with pre-diabetes were compared to subjects with normal test results. Fishers exact test and the Wilcoxon rank-sum test were applied to compare the two study populations, whereas multivariate logistic regression was used to seek potential risk factors as related to other covariates. Risk ratios (RRs) to develop pre-diabetes were calculated for significant variables. RESULTS: Ten patients had results indicative of post-transplant diabetes whereas data sets of three other patients were incomplete and were thus not included in the analysis. From the remaining 187 patients, 130 (69.5%) displayed normal test results whereas 57 (30.5%) had results indicative of pre-diabetes. On multivariate regression analysis, patients with pre-diabetes were significantly older {55.3 ± 12.1 versus 47.7 ± 12.6 years, P = 0.0007, RRs per 5 years increase 1.28 [95% confidence interval (95% CI) 1.11-1.47]}, had more rejection episodes [0.26 ± 0.48 versus 0.12 ± 0.37, P = 0.0024, RRs per rejection episode 3.99 (95% CI 1.63-9.77)] and showed lower diastolic blood pressure readings [77 ± 10 mmHg versus 81 ± 10 mmHg, P = 0.0362, RR per 5 mmHg decrease 1.14 (95% CI 1.04-1.49)]. CONCLUSIONS: There is a high incidence of latent pre-diabetes among renal transplant recipients. Increasing age, rejection episodes and lower diastolic blood pressure proved to be associated with pre-diabetes. In contrast to post-transplant diabetes, tacrolimus use and HbA1-c levels were not prognostic of pre-diabetes.
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Trasplante de Riñón/efectos adversos , Estado Prediabético/etiología , Adulto , Factores de Edad , Glucemia/metabolismo , Estudios de Cohortes , Femenino , Alemania/epidemiología , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Rechazo de Injerto/etiología , Humanos , Hipotensión/etiología , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Trasplante de Riñón/fisiología , Masculino , Persona de Mediana Edad , Estado Prediabético/sangre , Estado Prediabético/epidemiología , Prevalencia , Pronóstico , Factores de RiesgoRESUMEN
PURPOSE: A close relationship between obstructive sleep apnea (OSA) and atherosclerosis has been reported, but it is still discussed controversially whether OSA affects vascular function and structure independently. Therefore, we prospectively investigated the independent impact of OSA and its treatment on arterial stiffness. METHODS: One hundred seventy-two patients with suspected OSA were prospectively enrolled in a non-randomized 6-month study to determine whether effective treatment (respiratory events sufficiently reduced and proven compliance) of OSA with continuous positive airway pressure (CPAP) would affect vascular function as measured by augmentation index (Aix) and pulse wave velocity (PWV). Additionally, using a nested case-control, we matched 45 pairs of patients with and without OSA for gender, age, and hypertension. RESULTS: Overall, OSA (n = 117) was associated with increased Aix (23.6 ± 13.5 vs. 8.9 ± 13.7, p < 0.001) and PWV (9.1 ± 1.6 vs. 7.8 ± 1.6 m/s, p < 0.001) as compared with that in controls without OSA (n = 55). Multivariable analysis and results from the nested case-control cohort showed that OSA was associated with increased Aix and PWV independently from hypertension, age, gender, body mass index, and antihypertensive medications. In 49 effectively treated OSA patients, Aix (baseline 22.0 ± 13.4, follow-up 20.1 ± 12.9, p < 0.01) and PWV (baseline 9.6 ± 1.5, follow-up 8.7 ± 1.4, p < 0.05) had improved. In contrast, ineffectively treated OSA patients (n = 39) showed no change in Aix and PWV. CONCLUSIONS: This prospective controlled study suggests that OSA is independently associated with increased arterial stiffness. Furthermore, treatment with CPAP significantly reduced arterial stiffness. These findings extend our understanding of the recently shown cardiovascular burden in OSA and help to explain why CPAP treatment proved to ameliorate cardiovascular outcome even in patients without preexisting cardiovascular disease.
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Aterosclerosis/fisiopatología , Aterosclerosis/terapia , Presión de las Vías Aéreas Positiva Contínua , Avance Mandibular/instrumentación , Ferulas Oclusales , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/terapia , Rigidez Vascular/fisiología , Adulto , Anciano , Presión Sanguínea/fisiología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/terapia , Femenino , Alemania , Humanos , Hipertensión/fisiopatología , Hipertensión/terapia , Masculino , Persona de Mediana Edad , Polisomnografía , Estudios Prospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
The prorenin receptor (PRR) is highly expressed in podocytes, but its role in the maintenance of podocyte function is unknown. Here we generated podocyte-specific PRR-knockout mice and found that these animals died between 2 to 3 wk after birth. Within 14 d, PRR-knockout mice developed nephrotic syndrome, albuminuria with podocyte foot-process fusion, and cytoskeletal changes. Podocyte-specific PRR deletion also led to disturbed processing of multivesicular bodies and enrichment of autophagosomal (LC3) and lysosomal (LAMP2) markers, indicating a functional block in autophagosome-lysosome fusion and an overload of the proteasomal protein-degradation machinery. In vitro, PRR knockdown and pharmacologic blockade of vacuolar H(+)-ATPases, which associate with the PRR, increased vesicular pH, led to accumulation of LC3-positive and LAMP2-positive vesicles and altered the cytoskeleton. Taken together, these results suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein-turnover machinery. Furthermore, PRR contributes to the control of lysosomal pH, which is important for podocyte survival and cytoskeletal integrity.