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1.
BMC Emerg Med ; 21(1): 42, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33823795

RESUMEN

BACKGROUND: Recent studies have shown a decrease of admissions to accident and emergency (A&E) departments after the local outbreaks of COVID-19. However, differential trends of admission counts, for example according to diagnosis, are less well understood. This information is crucial to inform targeted intervention. Therefore, we aimed to compare admission counts in German A&E departments before and after 12th march in 2020 with 2019 according to demographic factors and diagnosis groups. METHODS: Routine data of all admissions between 02.12.2019-30.06.2020 and 01.12.2018-30.06.2019 was available from six hospitals in five cities from north-western, eastern, south-eastern, and south-western Germany. We defined 10 diagnosis groups using ICD-10 codes: mental disorders due to use of alcohol (MDA), acute myocardial infarction (AMI), stroke or transient ischemic attack (TIA), heart failure, pneumonia, chronic obstructive pulmonary disease (COPD), cholelithiasis or cholecystitis, back pain, fractures of the forearm, and fractures of the femur. We calculated rate ratios comparing different periods in 12.03.2020-30.06.2020 with 12.03.2019-30.06.2019. RESULTS: Forty-one thousand three hundred fifty-three cases were admitted between 12.03.2020-30.06.2020 and 51,030 cases between 12.03.2019-30.06.2019. Admission counts prior to 12.03. were equal in 2020 and 2019. In the period after 12.03., the decrease of admissions in 2020 compared to 2019 was largest between 26.03. and 08.04. (- 30%, 95% CI - 33% to - 27%). When analysing the entire period 12.03.-30.06., the decrease of admissions was heterogeneous among hospitals, and larger among people aged 0-17 years compared to older age groups. In the first 8 weeks after 12.03., admission counts of all diagnoses except femur fractures and pneumonia declined. Admissions with pneumonia increased in this early period. Between 07.05. and 30.6.2020, we noted that admissions with AMI (+ 13%, 95% CI - 3% to + 32%) and cholelithiasis or cholecystitis (+ 20%, 95% CI + 1% to + 44%) were higher than in 2019. CONCLUSIONS: Our results suggest differential trends of admission counts according to age, location, and diagnosis. An initial decrease of admissions with MDA, AMI, stroke or TIA, heart failure, COPD, cholelithiasis or cholecystitis, and back pain imply delays of emergency care in Germany. Finally, our study suggests a delayed increase of admissions with AMI and cholelithiasis or cholecystitis.


Asunto(s)
COVID-19/epidemiología , Servicio de Urgencia en Hospital/tendencias , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Preescolar , Alemania/epidemiología , Humanos , Lactante , Recién Nacido , Persona de Mediana Edad , Pandemias , Aceptación de la Atención de Salud , SARS-CoV-2 , Adulto Joven
2.
J Biol Chem ; 286(15): 12959-70, 2011 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-21321125

RESUMEN

Nephrin, the key molecule of the glomerular slit diaphragm, is expressed on the surface of podocytes and is critical in preventing albuminuria. In diabetes, hyperglycemia leads to the loss of surface expression of nephrin and causes albuminuria. Here, we report a mechanism that can explain this phenomenon: hyperglycemia directly enhances the rate of nephrin endocytosis via regulation of the ß-arrestin2-nephrin interaction by PKCα. We identified PKCα and protein interacting with c kinase-1 (PICK1) as nephrin-binding proteins. Hyperglycemia induced up-regulation of PKCα and led to the formation of a complex of nephrin, PKCα, PICK1, and ß-arrestin2 in vitro and in vivo. Binding of ß-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by PKCα. Further, cellular knockdown of PKCα and/or PICK1 attenuated the nephrin-ß-arrestin2 interaction and abrogated the amplifying effect of high blood glucose on nephrin endocytosis. In C57BL/6 mice, hyperglycemia over 24 h caused a significant increase in urinary albumin excretion, supporting the concept of the rapid impact of hyperglycemia on glomerular permselectivity. In summary, we have provided a molecular model of hyperglycemia-induced nephrin endocytosis and subsequent proteinuria and highlighted PKCα and PICK1 as promising therapeutic targets for diabetic nephropathy.


Asunto(s)
Arrestinas/metabolismo , Endocitosis , Hiperglucemia/metabolismo , Proteínas de la Membrana/metabolismo , Proteína Quinasa C-alfa/metabolismo , Albuminuria/genética , Albuminuria/metabolismo , Animales , Arrestinas/genética , Glucemia/genética , Glucemia/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Humanos , Hiperglucemia/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Modelos Biológicos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilación/genética , Proteína Quinasa C-alfa/genética , beta-Arrestinas
3.
Nephrol Dial Transplant ; 27(8): 3330-7, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22492827

RESUMEN

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.


Asunto(s)
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 Riesgo
4.
Sleep Breath ; 16(1): 123-33, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21213062

RESUMEN

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.


Asunto(s)
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 Tratamiento
5.
J Am Soc Nephrol ; 22(12): 2193-202, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22034640

RESUMEN

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.


Asunto(s)
Autofagia/fisiología , Podocitos/fisiología , Receptores de Superficie Celular/fisiología , Animales , Supervivencia Celular , Femenino , Ratones , Receptor de Prorenina
6.
J Mol Med (Berl) ; 100(5): 781-795, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35451598

RESUMEN

Chronic hyperglycemia, as in diabetes mellitus, may cause glomerular damage with microalbuminuria as an early sign. Noteworthy, even acute hyperglycemia can increase glomerular permeability before structural damage of the glomerular filter can be detected. Despite intensive research, specific antiproteinuric therapy is not available so far. Thus, a deeper understanding of the molecular mechanisms of albuminuria is desirable. P38 MAPK signaling is involved in the development of hyperglycemia-induced albuminuria. However, the mechanism of increased p38 MAPK activity leading to increased permeability and albuminuria remained unclear. Recently, we demonstrated that acute hyperglycemia triggers endocytosis of nephrin, the key molecule of the slit diaphragm, and induces albuminuria. Here, we identify p38 MAPK as a pivotal regulator of hyperglycemia-induced nephrin endocytosis. Activated p38 MAPK phosphorylates the nephrin c-terminus at serine 1146, facilitating the interaction of PKCα with nephrin. PKCα phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of ß-arrestin2 to nephrin. ß-arrestin2 triggers endocytosis of nephrin by coupling it to the endocytic machinery, leading to increased glomerular permeability. Pharmacological inhibition of p38 MAPK preserves nephrin surface expression and significantly attenuates albuminuria. KEY MESSAGES: Acute hyperglycemia triggers endocytosis of nephrin. Activated p38 MAPK phosphorylates the nephrin c-terminus at serine 1146, facilitating the interaction of PKCα with nephrin. PKCα phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of ß-arrestin2 to nephrin. ß-arrestin2 triggers endocytosis of nephrin by coupling it to the endocytic machinery, leading to a leaky glomerular filter. Pharmacological inhibition of p38 MAPK preserves nephrin surface expression and significantly attenuates albuminuria under hyperglycemic conditions.


Asunto(s)
Albuminuria , Hiperglucemia , Proteínas de la Membrana , Podocitos , Proteínas Quinasas p38 Activadas por Mitógenos , Albuminuria/tratamiento farmacológico , Albuminuria/enzimología , Albuminuria/metabolismo , Endocitosis , Humanos , Hiperglucemia/metabolismo , Proteínas de la Membrana/metabolismo , Podocitos/metabolismo , Proteína Quinasa C-alfa/metabolismo , Serina/metabolismo , Treonina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
7.
Nephrol Dial Transplant ; 26(3): 914-20, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20682605

RESUMEN

BACKGROUND: Impaired renal function has recently been reported in obstructive sleep apnoea (OSA). The underlying mechanisms, however, are not entirely understood. This study investigated the influence of mild-to-moderate OSA and its treatment on renal haemodynamics as assessed by the renal resistance index (RRI). METHODS: RRI has been measured by colour duplex ultrasound in 64 patients with newly diagnosed mild-to-moderate OSA and 61 controls without OSA at baseline and follow-up after 9.9 months. Treatment with continuous positive airway pressure was offered to all patients with OSA (apnoea/hypopnoea index ≥ 5/h). RESULTS: Increased values of RRI (≥ 1 SD [8.9%] above the age-adjusted normal value) were found in 41 out of 64 (64.0%) OSA patients when compared with 20 out of 61 (32.8%) controls (P < 0.001). The corresponding mean RRI was 70.50 ± 9.01 vs 66.51 ± 8.33 (P = 0.012). In multivariate analyses, the influence of OSA on RRI was independent from hypertension, diabetes mellitus, age and baseline renal function. At follow-up, RRI decreased only in patients with effective OSA treatment but remained unchanged in ineffectively treated OSA patients and controls. CONCLUSIONS: For the first time, this prospective controlled observational study demonstrates an impairment of renal haemodynamics in OSA as measured by an increased RRI. These changes of renal blood flow may identify OSA patients at high risk of declining renal function. Both parenchymal and vascular renal diseases are proposed as pathomechanisms for this association. An effective treatment of OSA resulted in a decreased RRI, suggesting an improvement in renal perfusion. Further studies are needed to elucidate the role of impaired renal haemodynamics in OSA.


Asunto(s)
Presión de las Vías Aéreas Positiva Contínua , Obstrucción de la Arteria Renal/etiología , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/prevención & control , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico
8.
Respiration ; 82(5): 409-17, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21311167

RESUMEN

BACKGROUND: Endothelial dysfunction has recently been demonstrated in obstructive sleep apnea (OSA), but the underlying mechanisms are not entirely understood. Oxidative stress is a typical feature of OSA. OBJECTIVES: We investigated the influence of oxidative stress and continuous positive airway pressure (CPAP) on microvascular endothelial function in OSA. METHODS: Endothelial function of forearm resistance vessels was assessed by strain gauge venous occlusion plethysmography after intra-arterial infusion of the endothelium-independent vasodilator sodium nitroprusside (1.6, 3.2, and 4.0 µg/min) and the endothelium-dependent vasodilator acetylcholine (Ach, 15, 30 and 40 µg/min) in patients with (n = 11) and without (n = 8) OSA (apnea-hypopnea index ≥15/h). These measurements have been repeated after local intra-arterial infusion of the antioxidant vitamin C (25 µg/min). Furthermore, 6 patients have been reevaluated after 6 months of OSA treatment. RESULTS: Patients with OSA demonstrated impaired endothelial function compared to those without OSA. Thus, related to baseline flow, the increase in forearm blood flow induced by Ach was blunted in patients with OSA (148.7 ± 29.7% in OSA vs. 233.6 ± 45.7% in controls, p = 0.001). This difference, however, was abolished by co-infusion of vitamin C. Endothelial function markedly improved following treatment in 5 of 6 OSA patients. CONCLUSIONS: This study strongly suggests that microvascular endothelial function is affected by OSA predominantly through increased oxidative stress, and treatment of OSA may improve endothelial function mainly by reducing oxidative stress. The role of oxidative stress-induced endothelial dysfunction as a potential promoter of atherosclerosis and an increased cardiovascular risk in patients with OSA should be investigated in further controlled studies.


Asunto(s)
Presión de las Vías Aéreas Positiva Contínua , Endotelio Vascular/fisiopatología , Estrés Oxidativo , Apnea Obstructiva del Sueño/fisiopatología , Vasodilatadores/uso terapéutico , Acetilcolina/administración & dosificación , Ácido Ascórbico/administración & dosificación , Aterosclerosis/fisiopatología , Velocidad del Flujo Sanguíneo , Capilares/fisiopatología , Femenino , Antebrazo/irrigación sanguínea , Humanos , Infusiones Intraarteriales , Masculino , Microcirculación , Persona de Mediana Edad , Nitroprusiato/administración & dosificación , Pletismografía , Polisomnografía , Estudios Prospectivos , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/terapia , Resistencia Vascular
9.
PLoS One ; 14(3): e0214048, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30925158

RESUMEN

This study evaluated the combined effect of recipient-to-donor weight and sex mismatch after deceased-donor renal transplantation in a German transplant cohort and the evolution of recipient-to-donor weight difference over a 13-year observation period. The association of absolute weight and sex difference with graft failure was explored in an outpatient cohort of deceased-donor transplant recipients who underwent kidney transplantation between 2000 and 2012. Graft failure was defined as repeated need for dialysis or death with a functioning graft. Recipient and donor sex pairings were classified as sex concordant (MDMR/FDFR) or discordant (MDFR/FDMR). These classes were further stratified into four groups according to recipient-to-donor weight mismatch ≥10 kg (recipient > donor) or <10 kg (recipient < donor). Multivariable Cox proportional hazards models were applied to evaluate the time to graft loss adjusting for donor, immunologic, surgical, organizational, and recipient predictors. Sex-concordant transplant pairings <10 kg weight difference served as the reference group. Among 826 transplant recipients, 154 developed graft failure (18.6%). Median graft survival time was 3.9 years; first quartile (0.2-1.2), second quartile (1.2-2.9), third quartile (2.9-5.8), and fourth quartile (5.8-12.4). After multivariable adjustment, the highest relative hazard for graft failure was observed for sex-discordant transplant pairings with a ≥10 kg weight difference between recipient and donor (compared to the reference group MDMR/FDFR with weight difference <10 kg, MDMR/FDFR with weight difference ≥10 kg, hazard ratio 1.86, 95% confidence interval 1.07-3.32-p = 0.029; MDFR/FDMR with weight difference <10 kg, hazard ratio 1.14, 95% confidence interval 0.78-1.68-p = 0.507, and MDFR/FDMR with weight difference ≥10 kg, hazard ratio 2.00, 95% confidence interval 1.15-3.48-p = 0.014). A recipient-to-donor weight mismatch of ≥10 kg was associated with an increased risk of graft loss or recipient death with a functioning graft. Concurrent sex discordance seemed to enhance this effect as indicated by an increase in the hazard ratio. We detected no significant tendency for increasing recipient-to-donor weight differences from 2000 to 2012.


Asunto(s)
Supervivencia de Injerto , Trasplante de Riñón , Adulto , Anciano , Peso Corporal , Estudios de Cohortes , Femenino , Alemania , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores Sexuales , Factores de Tiempo , Donantes de Tejidos
10.
J Vis Exp ; (143)2019 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-30735184

RESUMEN

Proteinuria results from the disruption of the glomerular filter that is composed of the fenestrated endothelium, glomerular basement membrane, and podocytes with their slit diaphragms. The delicate structure of the glomerular filter, especially the slit diaphragm, relies on the interplay of diverse cell surface proteins. Studying these cell surface proteins has so far been limited to in vitro studies or histologic analysis. Here, we present a murine in vivo biotinylation labeling method, which enables the study of glomerular cell surface proteins under physiologic and pathophysiologic conditions. This protocol contains information on how to perfuse mouse kidneys, isolate glomeruli, and perform endogenous immunoprecipitation of a protein of interest. Semi-quantitation of glomerular cell surface abundance is readily available with this novel method, and all proteins accessible to biotin perfusion and immunoprecipitation can be studied. In addition, isolation of glomeruli with or without biotinylation enables further analysis of glomerular RNA and protein as well as primary glomerular cell culture (i.e., primary podocyte cell culture).


Asunto(s)
Glomérulos Renales/metabolismo , Proteínas de la Membrana/metabolismo , Coloración y Etiquetado , Animales , Biotina/metabolismo , Ratones Endogámicos C57BL , Nefritis/metabolismo , Nefritis/patología , Perfusión , Podocitos/metabolismo
11.
Nephrol Dial Transplant ; 23(12): 4016-20, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18593741

RESUMEN

BACKGROUND: Vitamin D has emerged as an important survival factor in patients with chronic kidney disease. Non-activated vitamin D may also have beneficial effects on bone, cardiovascular and immune functions. Cholecalciferol is the prevalent non-activated vitamin D in Europe, but there is no valid prospective data available about its use in haemodialysis patients. Thus, we initiated a prospective study to evaluate dosing, safety and tolerability of cholecalciferol supplementation in haemodialysis patients. METHODS: The prospective study included 64 haemodialysis patients. During replenishment phase patients received 20 000 IU cholecalciferol/week for 9 months. In the open maintenance phase (15 months), patients were randomized to a treated group (20 000 IU cholecalciferol/month) and an untreated group, which did not receive cholecalciferol. RESULTS: Calcidiol [25(OH)D] deficiency (<37.5 nmol/l; <15 microg/l) was detected in 61/64 patients (95%). During the replenishment phase, calcidiol increased significantly from 16.65 +/- 9.6 to 79.48 +/- 27.15 nmol/l (6.66 +/- 3.84 microug/l to 31.79 +/- 10.86 microg/l) (P < 0.001). Recommended levels (>75 nmol/l; >30 microg/l; K/DOQI) were achieved in 57% of patients. Calcium increased from 2.28 +/- 0.17 to 2.37 +/- 0.19 mmol/l (9.1 +/- 0.69 mg/dl to 9.49 +/- 0.75 mg/dl) (P<0.01). Phosphorus, calcium-phosphorus product and parathyroid hormone showed no significant changes. Fifty-nine patients progressed to the maintenance phase. Analysis per protocol showed a significant drop of calcidiol in the treated [83.98 +/- 31.73 versus 78.5 +/- 38.75 nmol/l (33.59 +/- 12.69 versus 31.4 +/- 15.5 microg/l) (P < 0.001)] and untreated groups [86.35 +/- 40.75 versus 53.4 +/- 26.2 nmol/l (34.54 +/- 16.3 versus 21.36 +/- 10.48 microg/l) (P < 0.001)]. The comparison of the treated and the untreated groups showed no significant differences at the beginning of the maintenance phase: 83.98 +/- 31.73 versus 86.35 +/- 40.75 nmol/l (33.59 +/- 12.69 versus 34.54 +/- 16.3 microg/l). At the end they differed significantly: 78.5 +/- 38.75 versus 53.4 +/- 26.2 nmol/l (31.4 +/- 15.5 versus 21.36 +/- 10.48 microg/l) (P < 0.001). CONCLUSION: Vitamin D deficiency is present in a majority of haemodialysis patients. Supplementation with cholecalciferol is safe, well tolerated and reasonable to replenish vitamin D stores in haemodialysis patients. However, only 57% of patients achieved recommended calcidiol levels, thus favouring additional dose-finding studies.


Asunto(s)
Colecalciferol/administración & dosificación , Diálisis Renal , Deficiencia de Vitamina D/tratamiento farmacológico , Calcifediol/sangre , Colecalciferol/efectos adversos , Tolerancia a Medicamentos , Femenino , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Estudios Prospectivos , Diálisis Renal/efectos adversos , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/etiología
12.
Int Urol Nephrol ; 50(8): 1529-1534, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29946816

RESUMEN

PURPOSE: Pre-diabetes, a risk factor for post-transplant diabetes mellitus (PTDM), represents an early therapeutic target for prevention of PTDM. We evaluated glucose metabolism post-transplantation and the ability to predict pre-diabetes and PTDM from haemoglobin A1c (HbA1c) levels at 90 days, at 1 year, and at 3 years in long-term post-transplantation follow-up. METHODS: HbA1c levels were measured in 71 non-diabetic deceased-donor transplant recipients at four time points (during transplantation, 90-days post-transplantation, 1-year post-transplantion, and at the final post-transplantation follow-up visit 2.71 ± 1.26 years after transplantation). The predictive power of HbA1c levels at 90 days post-transplantation was determined by calculating the sensitivity, specificity, false-positive rates, and false-negative rates. A multivariate logistic regression analysis was performed to determine risk factors for pre-diabetes and PTDM at 1-year post-transplantation and at the last follow-up visit (2.71 ± 1.26 years after renal transplantation). RESULTS: HbA1c values ≥ 5.7% were seen in 79% of patients at 90 days post-transplant, in 83% at 1 year, and in 69% of patients on follow-up. HbA1c cut-off levels of < 5.7% or ≥ 5.7% showed the highest predictive sensitivity for pathological HbA1c levels (≥ 5.7%) at 1 year post-transplantation (0.83) and at last follow-up (0.86), whereas cut-off levels of < 6.2% or .≥ 6.2% showed the highest specificity (0.97 and 1.00, respectively). The HbA1c level at 90 days was a risk factor for disturbed glucose-metabolism at 1 year (p = 0.000) and at the final follow-up (p = 0.031). CONCLUSION: HbA1c levels at 90 days post-transplantation are predictive of disturbed glucose metabolism at 1 year and on long-term follow-up and may serve as predictive tools for early therapeutic interventions to prevent PTDM.


Asunto(s)
Glucemia/metabolismo , Hemoglobina Glucada/metabolismo , Trasplante de Riñón/efectos adversos , Estado Prediabético/sangre , Receptores de Trasplantes , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Prueba de Tolerancia a la Glucosa , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estado Prediabético/epidemiología , Estado Prediabético/etiología , Factores de Riesgo , Factores de Tiempo , Donantes de Tejidos
13.
Eur J Endocrinol ; 178(6): 605-611, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29636356

RESUMEN

OBJECTIVE: Primary aldosteronism (PA) is the most common endocrine form of arterial hypertension. The German Conn's Registry's purpose is to improve treatment outcomes of PA. We assessed whether key clinical, biochemical and epidemiological characteristics of newly diagnosed PA cases have changed over time, potentially indicating a different screening and referral practice in Germany evolving from 2008 to 2016. DESIGN: The German Conn's Registry is a multicenter database prospectively analyzing morbidity and long-term outcome of patients with PA. METHODS: Phenotypic changes between three year periods were calculated using Mann-Whitney U tests and Kruskal-Wallis tests for independent variables. RESULTS: Over three time periods from 2008 to 2016, we noted a relative decrease of unilateral PA cases (67 vs 43%). Significantly more females were diagnosed with PA (33 vs 43%). Median daily defined drug doses decreased (3.1 vs 2.0) in the presence of unchanged SBP (150 vs 150 mmHg), plasma aldosterone (199 vs 173 ng/L) and PRC (3.2 vs 3.2 U/L). Median ARR values decreased (70 vs 47 ng/U) and median potassium levels at diagnosis (3.5 vs 3.7 mmol/L) increased as the percentage of normokalemic patients (25 vs 41%), indicating milder forms of PA. CONCLUSIONS: Our results are in accordance with an increased screening intensity for PA. We identified a trend toward diagnosing milder forms, increasingly more females and less unilateral cases of PA.


Asunto(s)
Hiperaldosteronismo/fisiopatología , Hipertensión/fisiopatología , Sistema de Registros , Adulto , Aldosterona/metabolismo , Antihipertensivos/administración & dosificación , Presión Sanguínea , Femenino , Alemania/epidemiología , Humanos , Hiperaldosteronismo/tratamiento farmacológico , Hiperaldosteronismo/epidemiología , Hiperaldosteronismo/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Masculino , Persona de Mediana Edad , Polonia/epidemiología , Potasio/metabolismo , Estudios Prospectivos , Renina/metabolismo , Índice de Severidad de la Enfermedad , Distribución por Sexo
14.
Exp Clin Transplant ; 15(6): 620-626, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28332958

RESUMEN

OBJECTIVES: This study investigated the effect of prediabetes in long-term deceased-donor renal transplant recipients regarding graft survival, graft function, and evolution of new-onset diabetes after transplant compared with a control group of graft recipients with normal glucose tolerance test results. MATERIALS AND METHODS: This was a follow-up trial of 187 deceased-donor renal transplant recipients. Based on oral glucose tolerance test results, the cohort was divided into groups A and B, comprising individuals with normal glucose metabolism (n = 130, 69.9%) and individuals with prediabetes (n = 56, 30.1%). Data are shown as means ± standard errors. RESULTS: Both groups showed similar total transplant survival (116.8 ± 5.4 vs 114.5 ± 7.4 mo; P = .742) and transplant survival measured since oral glucose tolerance test (58.5 ± 1.4 vs 59.5 ± 1.9 mo; P = .990, Mantel-Cox P = .943). Univariate and multivariate Cox regression analyses showed no association of prediabetes with graft loss. Transplant function changes were similar between cohorts (-3 ± 1 vs -5 ± 2 mL/min/1.73 m2 body surface area, using the Chronic Kidney Disease Epidemiology Collaboration formula; P = .538). At 5-year follow-up, recipients with prediabetes had higher hemoglobin A1c than controls (5.99% ± 0.10% vs 5.67% ± 0.04%; P = .002). Prediabetes was associated with a 4.5-fold increased hazard of new-onset diabetes after transplant (P = .021). CONCLUSIONS: Prediabetes was associated with a 4.5-fold higher hazard ratio for new-onset diabetes after transplant but not with reduced graft function or survival.


Asunto(s)
Diabetes Mellitus/epidemiología , Supervivencia de Injerto , Trasplante de Riñón/efectos adversos , Estado Prediabético/epidemiología , Adulto , Aloinjertos , Biomarcadores/sangre , Glucemia/metabolismo , Distribución de Chi-Cuadrado , Diabetes Mellitus/sangre , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/mortalidad , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Humanos , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Trasplante de Riñón/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estado Prediabético/sangre , Estado Prediabético/diagnóstico , Estado Prediabético/mortalidad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
15.
PLoS One ; 12(6): e0179217, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28604827

RESUMEN

Injury of the glomerular filter causes proteinuria by disrupting the sensitive interplay of the glomerular protein network. To date, studies of the expression and trafficking of glomerular proteins have been mostly limited to in vitro or histologic studies. Here, we report a novel in vivo biotinylation assay that allows the quantification of surface expression of glomerular proteins in mice. Kidneys were perfused in situ with biotin before harvest. Afterwards glomeruli were isolated and lyzed. The protein of interest was separated by immunoprecipitation and the amount of surface-expressed protein was quantified by Western blot analysis with streptavidin staining. As proof-of-concept, we examined the presence of nephrin in the slit diaphragm in two well-established murine models of proteinuric kidney disease: nephrotoxic nephritis and adriamycin nephropathy. In proteinuric animals, significantly less nephrin was detected in the slit diaphragm. When proteinuria decreased once again during the course of disease, the amount of surface nephrin returned to the baseline. Our present results suggest that our assay is a valuable tool to study the glomerular filter in proteinuric kidney diseases. Note that the assay is not limited to proteins expressed in the slit diaphragm, and all surface proteins that are accessible to biotin perfusion and immunoprecipitation qualify for this analysis.


Asunto(s)
Enfermedades Renales/orina , Proteínas de la Membrana/orina , Proteinuria/orina , Albuminuria , Animales , Modelos Animales de Enfermedad , Expresión Génica , Enfermedades Renales/genética , Enfermedades Renales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Proteínas de la Membrana/genética , Ratones , Nefritis/genética , Nefritis/patología , Nefritis/orina , Proteinuria/genética , Proteinuria/patología , Factores de Tiempo
16.
Cardiovasc Res ; 66(2): 345-52, 2005 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-15820203

RESUMEN

OBJECTIVE: Hypertension is characterized by sympathetic overactivity. Neuropeptide Y (NPY) and ATP are cotransmitters of norepinephrine (NE) and regulate renovascular resistance. The present study analyzes sympathetic nonadrenergic neurotransmission in hypertensive (SH-SP) and normotensive (WKY) rats. In addition, adult and young hypertensive rats were compared to investigate the role of aging on sympathetic nonadrenergic cotransmission in hypertensive disease. METHODS: Pressor responses to renal nerve stimulations (RNS) and drugs were measured on isolated perfused kidneys of young (8-10 weeks) and adult (18-24 weeks) WKY, and SH-SP rats. RESULTS: RNS evoked contractions at 1 Hz were resistant to blockade by the alpha-adrenoceptor antagonist phentolamine (1 microM) but abolished by the P2 receptor blocker suramin (100 microM). Compared to adult WKY, RNS-induced pressor responses were unchanged in adult SH-SP and young WKY, but significantly greater in young SH-SP rats. The NPY-Y1 receptor antagonist BIBP3226 (1 microM) reduced phentolamine-resistant pressor responses in adult and young WKY, young SH-SP, but not in adult SH-SP rats. In contrast to WKY and young SH-SP rats, exogenously perfused NPY (0.1 microM) was unable to potentiate RNS-induced, phentolamine-resistant pressor responses in adult SH-SP rats. NE and the stable ATP analogue alpha,beta-mATP increased the perfusion pressor response more potently in adult SH-SP than in WKY rats. CONCLUSIONS: Neuronally released NPY plays a major role in potentiating RNS-induced nonadrenergic pressor responses in kidneys of WKY and young SH-SP rats. In adult SH-SP rats NPY fails to enhance these responses. In this hypertensive model ageing seems to be associated with a loss of a modulatory role of renal NPY Y1 receptors. Since pressor responses to NE and ATP are higher in SH-SP animals, functional NPY-Y1 receptor downregulation might be an adaptive mechanism.


Asunto(s)
Adenosina Trifosfato/farmacología , Envejecimiento/fisiología , Riñón/efectos de los fármacos , Neuropéptido Y/farmacología , Sistema Nervioso Simpático/fisiología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Riñón/metabolismo , Masculino , Norepinefrina/farmacología , Perfusión , ARN Mensajero/análisis , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/genética , Receptores Purinérgicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
17.
Dtsch Med Wochenschr ; 141(24): 1771-1776, 2016 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-27903028

RESUMEN

Patients with kidney disease have a significantly increased cardiovascular morbidity and mortality. Especially diabetics have an increased risk to develop renal insufficiency and cardiovascular events. Two recent studies show that the SGLT2 inhibitor Empagliflozin and the GLP1 agonist Liraglutid are able to lower the cardiovascular risk of type2 diabetics with renal insufficiency. Recent observations suggest that bradycardia and asystole are main triggers for sudden cardiac death in patients with chronic kidney disease. In line with these results registry data failed to confirm benefits of cardioverters/defibrillators in hemodialysis patients. Whether cardiac resynchronization therapy may slower pathomechanisms of cardiomyopathy in patients with chronic kidney disease still needs to be confirmed in prospective trials. Taken together implementation of device therapy in hemodialysis patients should integrate indications of current guidelines with individual patient risks and life expectancy. Everolimus-eluting stents have shown superior results compared to bare metal stents in terms of ischemia-driven target-lesion-revascularization in patients with chronic kidney disease in a prospective trial. These results were corroborated by registry data reporting survival benefit associated with the use of drug-eluting stents in patients with chronic renal disease.


Asunto(s)
Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Enfermedades Renales/mortalidad , Enfermedades Renales/terapia , Síndrome Cardiorrenal/mortalidad , Síndrome Cardiorrenal/prevención & control , Comorbilidad , Medicina Basada en la Evidencia , Alemania , Humanos , Prevalencia , Factores de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento
18.
Sci Rep ; 6: 39513, 2016 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-28004760

RESUMEN

Glomerular permeability and subsequent albuminuria are early clinical markers for glomerular injury in hypertensive nephropathy. Albuminuria predicts mortality and cardiovascular morbidity. AT1 receptor blockers protect from albuminuria, cardiovascular morbidity and mortality. A blood pressure independent, molecular mechanism for angiotensin II (Ang II) dependent albuminuria has long been postulated. Albuminuria results from a defective glomerular filter. Nephrin is a major structural component of the glomerular slit diaphragm and its endocytosis is mediated by ß-arrestin2. Ang II stimulation increases nephrin-ß-arrestin2 binding, nephrin endocytosis and glomerular permeability in mice. This Ang II effect is mediated by AT1-receptors. AT1-receptor mutants identified G-protein signaling to be essential for this Ang II effect. Gαq knockdown and phospholipase C inhibition block Ang II mediated enhanced nephrin endocytosis. Nephrin Y1217 is the critical residue controlling nephrin binding to ß-arrestin under Ang II stimulation. Nephrin Y1217 also mediates cytoskeletal anchoring to actin via nck2. Ang II stimulation decreases nephrin nck2 binding. We conclude that Ang II weakens the structural integrity of the slit diaphragm by increased nephrin endocytosis and decreased nephrin binding to nck2, which leads to increased glomerular permeability. This novel molecular mechanism of Ang II supports the use of AT1-receptor blockers to prevent albuminuria even in normotensives.


Asunto(s)
Angiotensina II/metabolismo , Endocitosis , Glomérulos Renales/metabolismo , Proteínas de la Membrana/metabolismo , beta-Arrestinas/metabolismo , Albuminuria/metabolismo , Animales , Biotinilación , Presión Sanguínea , Citoesqueleto/metabolismo , Femenino , Proteínas de Unión al GTP/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Mutación , Permeabilidad , Podocitos/citología , Unión Proteica , Transducción de Señal , Fosfolipasas de Tipo C/antagonistas & inhibidores , Fosfolipasas de Tipo C/metabolismo
19.
J Hypertens ; 23(9): 1691-8, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16093914

RESUMEN

OBJECTIVE: Angiotensin (Ang) II enhances renal sympathetic neurotransmission and stimulates nitric oxide (NO) release. The present study investigates whether Ang II-mediated modulation of sympathetic neurotransmission is dependent on NO production in the kidney. AT2 -/y receptor-deficient mice are used to identify the Ang II receptor subtype involved. METHODS: Mice kidneys were isolated and perfused with Krebs-Henseleit solution. Drugs were added to the perfusion solution in a cumulative manner. Release of endogenous noradrenaline (NA) was measured by high-performance liquid chromatography (HPLC). AT1 receptor expression was analysed by real-time polymerase chain reaction (PCR). RESULTS: Ang II (0.01-30 nmol/l) dose dependently increased pressor responses in kidneys of AT2 -/y mice and wild-type (AT2 +/y) mice. Maximal pressor responses and EC50 values for Ang II was greater in AT2 -/y than in AT2 +/y mice. L-NAME (N(omega)-nitro-L-arginine methyl ester; 0.3 mmol/l) enhanced Ang II-induced pressor responses in both strains. In AT2 -/y mice, Ang II-induced facilitation of NA release was more pronounced than in AT2 +/y mice. L-NAME reduced Ang II-mediated facilitation of NA release in both strains. This reduction was more potent in AT2 -/y mice. In kidneys of AT2 -/y mice the AT1 receptor expression was significantly upregulated. CONCLUSION: These results suggest that activation of AT1 receptors by Ang II releases NO in mouse kidney to modulate sympathetic neurotransmission. Since AT1 receptors are upregulated in AT2 -/y mice kidneys, NO-dependent effects were greater in these mice. Thus, NO seems to play an important modulatory role for renal sympathetic neurotransmission.


Asunto(s)
Angiotensina II/farmacología , Riñón/inervación , Óxido Nítrico/metabolismo , Receptor de Angiotensina Tipo 2/genética , Sistema Nervioso Simpático/efectos de los fármacos , Animales , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Epinefrina/análisis , Epinefrina/metabolismo , Riñón/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , NG-Nitroarginina Metil Éster/farmacología , Perfusión , Reacción en Cadena de la Polimerasa , Regulación hacia Arriba , Resistencia Vascular/efectos de los fármacos
20.
Br J Pharmacol ; 145(1): 66-74, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15711586

RESUMEN

Nucleotides like ATP and UTP act as potent extracellular signalling molecules. Released from sympathetic nerve endings as cotransmitters of noradrenaline or paracrine from nonexcitatory cells, they activate specific receptors (ion-gated P2X(1-7) and G-protein-coupled P2Y(1,2,4,6,11-15)). Which of these subtypes, however, are able to modulate vasoconstriction in the kidney is unclear. Wild-type- and P2Y4-receptor-deficient mice kidneys were isolated and perfused with Krebs-Henseleit solution. Pressor responses to renal nerve stimulations (RNS) and added drugs were recorded. Release of endogenous noradrenaline was measured by HPLC. RNS (1-15 Hz) induced a frequency-dependent increase in the perfusion pressor (14.2+/-5.1-67.3+/-6.9 mmHg) and noradrenaline release (1.4+/-0.3-24.2+/-3.4 ng g(-1) kidney). Pressor responses to RNS were not (1-2 Hz) or only partially (5-15 Hz) blocked by the alpha-adrenoceptor antagonist phentolamine (1 microM). Combination of phentolamine and the P2-receptor blocker PPADS (5 microM) prevented RNS-induced pressor responses. The P2X(1,3)-receptor selective antagonist NF279 (10 microM) reduced RNS-induced pressor responses in a frequency-dependent manner. Perfusion of ATP, ADP, UTP, UDP and alpha,beta-meATP concentration dependently increased perfusion pressor with the following rank order of potency alpha,beta-meATP>ADP approximately ATP approximately UDP > or = UTP. NF279 (10 microM) reduced alpha,beta-meATP- (0.1 microM) (21.7+/-3.9% of control) but not UTP- (0.3 microM) (102.6+/-15.3% of control) induced pressor responses. No differences in nucleotide-induced effects were detected among wild-type and P2Y4-receptor knockout mice. Continuous perfusion of alpha,beta-meATP (0.01 microM) potentiated UTP-, UDP- and ATP-gamma S-induced pressor responses. Neuronally and paracrine-released nucleotides evoked renal vasoconstriction by activation of P2X(1,3)- and P2Y6-like receptors in mice. Pretreatment with the P2X(1,3)-receptor agonist alpha,beta-meATP potentiated P2Y6-like receptor-mediated vasoconstrictions.


Asunto(s)
Riñón/irrigación sanguínea , Neurotransmisores/fisiología , Norepinefrina/fisiología , Nucleótidos/fisiología , Receptores Purinérgicos P2/fisiología , Vasoconstricción/fisiología , Animales , Relación Dosis-Respuesta a Droga , Riñón/inervación , Ratones , Ratones Endogámicos C57BL , Neurotransmisores/metabolismo , Nucleótidos/metabolismo , Receptores Purinérgicos P2/clasificación , Receptores Purinérgicos P2/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Vasoconstricción/efectos de los fármacos
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