RESUMEN
International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation.
RESUMEN
BACKGROUND AND OBJECTIVES: Studies analysing the association of albuminuria and prevalent frailty in community-dwelling very old adults are scarce and lack information on incident frailty. We investigated the association of kidney function decline and increase of albuminuria with frailty worsening or death in very old adults. DESIGN: Longitudinal analyses with biennial visits of the Berlin Initiative (cohort) Study and a frailty follow-up of 2.1 years. SETTING/SUBJECTS: 1,076 participants with a mean age of 84.3 (5.6) years of whom 54% were female. METHODS: Partial proportional odds models were used to assess the association of estimated glomerular filtration rate (eGFR) decline and/or albuminuria (albumin creatinine ratio, ACR) with frailty worsening or death. RESULTS: At frailty baseline, 1,076 participants with an eGFR of 50 (13) ml/min/1.73 m2, 48% being prefrail and 31% frail were included. After median 2.1 years, 960 (90%) participants had valid information on frailty transition: 187 (17.5%) worsened and 111 (10.3%) died. In the multivariable model, the odds of frailty worsening for participants with albuminuria in combination with eGFR <60 ml/min/1.73 m2 were elevated [OR (95% CI): 2.47 (1.41-4.31)] compared to participants without albuminuria and eGFR ≥60 ml/min/1.73 m2 as there was a rapid eGFR decline of ≥3 ml/min/1.73 m2 per year [1.55 (1.04-2.33)] and albuminuria trajectories six years prior [1.53 (1.11-2.10)] to frailty baseline. The odds of death for each exposure were even higher. CONCLUSIONS: In older adults, advanced stages of CKD and albuminuria alone were associated with 2-fold odds of frailty worsening independent of death.
Asunto(s)
Fragilidad , Insuficiencia Renal Crónica , Humanos , Femenino , Anciano , Anciano de 80 o más Años , Masculino , Albuminuria/diagnóstico , Albuminuria/complicaciones , Tasa de Filtración Glomerular , Estudios de Cohortes , Riñón , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/complicaciones , Creatinina , Factores de RiesgoRESUMEN
BACKGROUND: In older adults, epidemiological data on incidence rates (IR) of hospital-acquired acute kidney injury (AKI) are scarce. Also, little is known about trajectories of kidney function before hospitalization with AKI. METHODS: We used data from biennial face-to-face study visits from the prospective Berlin Initiative Study (BIS) including community-dwelling participants aged 70+ with repeat estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C. Primary outcome was first incident of hospital-acquired AKI assessed through linked insurance claims data. In a nested case-control study, kidney function decline prior to hospitalization with and without AKI was investigated using eGFR trajectories estimated with mixed-effects models adjusted for traditional cardiovascular comorbidities. RESULTS: Out of 2020 study participants (52.9% women; mean age 80.4 years) without prior AKI, 383 developed a first incident AKI, 1518 were hospitalized without AKI, and 119 were never hospitalized during a median follow-up of 8.8 years. IR per 1000 person years for hospital-acquired AKI was 26.8 (95% confidence interval (CI): 24.1-29.6); higher for men than women (33.9 (29.5-38.7) vs. 21.2 (18.1-24.6)). IR (CI) were lowest for persons aged 70-75 (13.1; 10.0-16.8) and highest for ≥ 90 years (54.6; 40.0-72.9). eGFR trajectories declined more steeply in men and women with AKI compared to men and women without AKI years before hospitalization. These differences in eGFR trajectories remained after adjustment for traditional comorbidities. CONCLUSION: AKI is a frequent in-hospital complication in individuals aged 70 + showing a striking increase of IR with age. eGFR decline was steeper in elderly patients with AKI compared to elderly patients without AKI years prior to hospitalization emphasising the need for long-term kidney function monitoring pre-admission to improve risk stratification.
Asunto(s)
Lesión Renal Aguda , Masculino , Anciano , Humanos , Femenino , Anciano de 80 o más Años , Tasa de Filtración Glomerular , Incidencia , Estudios Prospectivos , Estudios de Casos y Controles , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Hospitales , Factores de Riesgo , Creatinina , Estudios RetrospectivosRESUMEN
OBJECTIVE: Acute kidney injury (AKI) is a common complication after cardiac surgery (CS). Because a therapeutic regimen remains scarce, the early implementation of preventive strategies is crucial. The authors investigated risk factors and the typical clinical course of CS-associated AKI (CS-AKI) to derive strategies for perioperative clinical routines. DESIGN: Retrospective data analysis. SETTING: The data were collected from clinical routines in a maximum care university hospital. PARTICIPANTS: Patients. INTERVENTIONS: The authors retrospectively analyzed data from 538 patients who underwent CS. MEASUREMENTS AND MAIN RESULTS: The median age of the 466 patients included was 66.6 years; 65.7% were men. AKI occurred in 131 (28.1%) patients, mainly (89.0%) starting postoperatively within 72 hours p. Thirty-one (6.7%) patients showed Kidney Disease Improving Global Outcome AKI stage 3. AKI was significantly more frequent in patients with chronic kidney disease (p < 0.001), emergency admission (p < 0.001), heart failure (p < 0.001), and postoperative complications (p < 0.001). In a multivariate analysis, postoperative CS-AKI risk significantly decreased with each 1 or 10 mL/min preoperative glomerular filtration rate (GFR) (odds ratio, 0.962 and 0.677; 95% confidence interval, 0.947-0.977 and 0.577-0.793; p < 0.001 and p < 0.0001). Only in patients who developed Kidney Disease Improving Global Outcome AKI stage 3, an early postoperative trend to decreased GFR and increased creatinine levels was observed. CONCLUSIONS: Especially in patients with preexisting CKD and signs of CS-AKI occurring on the day of surgery, close monitoring of renal function should be performed for at least 72 hours after CS to detect an onset of AKI early and initiate renal protective strategies. Optimal preoperative fluid management might prevent postoperative AKI.
Asunto(s)
Lesión Renal Aguda , Procedimientos Quirúrgicos Cardíacos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Anciano , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Tasa de Filtración Glomerular , Humanos , Masculino , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
RATIONALE & OBJECTIVE: Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) are associated with cardiovascular events in the general population but their utility among older adults is unclear. We investigated the associations of eGFR and UACR with stroke, myocardial infarction (MI), and death among older adults. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: 1,581 participants (aged≥70 years) in the Berlin Initiative Study (BIS) without prior stroke or MI. EXPOSURES & PREDICTORS: Serum creatinine- and cystatin C-based eGFR, UACR categories, and measured GFR (n=436). OUTCOMES: Stroke, MI, and all-cause mortality. ANALYTICAL APPROACH: HRs and 95% CIs derived from multivariable-adjusted Cox proportional hazards models for association analyses. Net reclassification improvement (NRI) and C statistic differences comparing the predictive benefit of kidney measures with a traditional cardiovascular risk model. RESULTS: During a median follow-up of 8.2 years, 193 strokes, 125 MIs, and 531 deaths occurred. Independent of UACR, when GFR was estimated using the creatinine- and cystatin C-based BIS equation, eGFR of 45 to 59mL/min/1.73m2 (vs eGFR>60mL/min/1.73m2) was associated with stroke (HR, 2.23; 95% CI, 1.55-3.21) but not MI or all-cause mortality. For those with eGFR<45mL/min/1.73m2, the HRs were 1.99 (95% CI, 1.23-3.20) for stroke, 1.38 (95% CI, 0.81-2.36) for MI, and 1.57 (95% CI, 1.20-2.06) for mortality. Compared with UACR<30mg/g, UACR of 30 to 300mg/g was not associated with stroke (HR, 0.91; 95% CI, 0.63-1.33) but was associated with MI (HR, 1.65; 95% CI, 1.09-2.51) and all-cause mortality (HR, 1.63; 95% CI, 1.34-1.98). Prediction analysis for stroke showed significant positive NRI for eGFR calculated using the cystatin C-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the creatinine- and cystatin C-based BIS and Full Age Spectrum equations. UACR demonstrated significant positive NRIs for MI and mortality. LIMITATIONS: eGFR and UACR categorization based on single assessments; lack of cause-specific death data. CONCLUSIONS: eGFR of 45 to 59mL/min/1.73m2 without albuminuria was associated with stroke but not MI or all-cause mortality in older adults. In contrast, UACR of 30 to 300mg/g was associated with MI and all-cause mortality but not with stroke. Furthermore, cystatin C-based eGFR improved risk prediction for stroke in this cohort of older adults.
Asunto(s)
Albuminuria/epidemiología , Tasa de Filtración Glomerular , Mortalidad , Infarto del Miocardio/epidemiología , Insuficiencia Renal Crónica/epidemiología , Accidente Cerebrovascular/epidemiología , Anciano , Anciano de 80 o más Años , Causas de Muerte , Estudios de Cohortes , Creatinina/metabolismo , Cistatina C/metabolismo , Femenino , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Pruebas de Función Renal , Masculino , Modelos de Riesgos Proporcionales , Insuficiencia Renal Crónica/metabolismo , Factores de RiesgoRESUMEN
BACKGROUND: Statins achieve potent LDL lowering in the general population leading to a significant cardiovascular (CV) risk reduction. In renal transplant recipients (RTR) statins are included in treatment guidelines, however, conclusive evidence of improved cardiovascular outcomes has not been uniformly provided and concerns have been raised about simultaneous use of statins and the immunosuppressant cyclosporine. This study aimed to elucidate the effect of statins on a compound CV endpoint, comprised of ischaemic CV events and CV mortality in RTR, with subgroup analysis focussing on cyclosporine users. METHOD: 622 included RTR (follow-up 5.4 years) were matched based on propensity scores and dichotomized by statin use. Survival analysis was conducted. RESULTS: Cox regression showed that statin use was not significantly associated with the compound CV endpoint in a fully adjusted model (HR = 0.81, 95% CI = 0.53-1.24, P = .33). Subgroup analyses in RTR using cyclosporine revealed a strong positive association of statin use with the CV compound outcome in a fully adjusted model (HR = 6.60, 95% CI 1.75-24.9, P = .005). Furthermore, statin use was positively correlated with cyclosporine trough levels (correlation coefficient 0.11, P = .04). CONCLUSION: In conclusion, statin use does not significantly decrease incident CV events in an overall RTR cohort, but is independently associated with CV-specific mortality and events in cyclosporine using RTR, possibly due to a bilateral pharmacological interaction.
Asunto(s)
Angina de Pecho/epidemiología , Enfermedades Cardiovasculares/mortalidad , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Accidente Cerebrovascular Isquémico/epidemiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Infarto del Miocardio/epidemiología , Revascularización Miocárdica/estadística & datos numéricos , Adulto , Anciano , Angioplastia Coronaria con Balón/estadística & datos numéricos , Causas de Muerte , Estudios de Cohortes , Puente de Arteria Coronaria/estadística & datos numéricos , Femenino , Humanos , Terapia de Inmunosupresión , Incidencia , Masculino , Persona de Mediana EdadRESUMEN
In chronic kidney disease (CKD), hyperphosphatemia is a key factor promoting medial vascular calcification, a common complication associated with cardiovascular events and high mortality. Vascular calcification involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), but the complex signaling events inducing pro-calcific pathways are incompletely understood. The present study investigated the role of acid sphingomyelinase (ASM)/ceramide as regulator of VSMC calcification. In vitro, both, bacterial sphingomyelinase and phosphate increased ceramide levels in VSMCs. Bacterial sphingomyelinase as well as ceramide supplementation stimulated osteo-/chondrogenic transdifferentiation during control and high phosphate conditions and augmented phosphate-induced calcification of VSMCs. Silencing of serum- and glucocorticoid-inducible kinase 1 (SGK1) blunted the pro-calcific effects of bacterial sphingomyelinase or ceramide. Asm deficiency blunted vascular calcification in a cholecalciferol-overload mouse model and ex vivo isolated-perfused arteries. In addition, Asm deficiency suppressed phosphate-induced osteo-/chondrogenic signaling and calcification of cultured VSMCs. Treatment with the functional ASM inhibitors amitriptyline or fendiline strongly blunted pro-calcific signaling pathways in vitro and in vivo. In conclusion, ASM/ceramide is a critical upstream regulator of vascular calcification, at least partly, through SGK1-dependent signaling. Thus, ASM inhibition by repurposing functional ASM inhibitors to reduce the progression of vascular calcification during CKD warrants further study.
Asunto(s)
Transdiferenciación Celular , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Esfingomielina Fosfodiesterasa/farmacología , Calcificación Vascular/patología , Amitriptilina/farmacología , Animales , Células Cultivadas , Ceramidas/metabolismo , Condrogénesis/efectos de los fármacos , Fendilina/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Fosfatos/farmacologíaRESUMEN
BACKGROUND: treatment goals for blood pressure (BP) lowering in older patients with heart failure (HF) are unclear. OBJECTIVE: to assess whether BP control < 140/90 mmHg is associated with a decreased risk of mortality in older HF patients. DESIGN: population-based prospective cohort study. SETTING/SUBJECTS: participants of the Berlin Initiative Study, a prospective cohort of community-dwelling older adults launched in 2009. Clinical information was obtained in face-to-face interviews and linked to administrative healthcare data. METHODS: Cox proportional hazards models estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of cardiovascular death and all-cause mortality associated with normalised BP (systolic BP < 140 mmHg and diastolic BP < 90 mmHg) compared with non-normalised BP (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) in HF patients. The primary analysis considered only baseline BP ('time-fixed'); an additional analysis updated BP during follow-up ('time-dependent'). RESULTS: at baseline, 544 patients were diagnosed with HF and treated with antihypertensive drugs (mean age 82.8 years; 45.4% female). During a median follow-up of 7.5 years and compared with non-normalised BP, normalised BP was associated with similar risks of cardiovascular death (HR, 1.24; 95% CI, 0.84-1.85) and all-cause mortality (HR, 1.16; 95% CI, 0.89-1.51) in the time-fixed analysis but with increased risks of cardiovascular death (HR, 1.79; 95% CI, 1.23-2.61) and all-cause mortality (HR, 1.48; 95% CI, 1.15-1.90) in the time-dependent analysis. CONCLUSIONS: BP control < 140/90 mmHg was not associated with a decreased risk of mortality in older HF patients. The increased risk in the time-dependent analysis requires further corroboration.
Asunto(s)
Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Hipertensión , Anciano , Anciano de 80 o más Años , Presión Sanguínea , Estudios de Cohortes , Femenino , Insuficiencia Cardíaca/diagnóstico , Humanos , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Measuring glomerular filtration rate (GFR) using iohexol plasma clearance has been proposed as the preferred way for GFR determination. The extended multiple-sample protocol is based on fitting the full concentration-time decay-curve, and from the obtained fit-parameters, the area under the curve (AUC) and GFR (the injected dose divided by the AUC) were calculated. The goal of the current study is to evaluate the impact of different fitting procedures on the precision of GFR-results obtained from the full concentration-time curve, and compare these results with those obtained with simplified multiple-samples and single-sample protocols. METHODS: The concentration-time curves of 8 samples at times 30, 60, 90, 120, 150, 180, 240 and 300 min after bolus injection of iohexol of 570 adults, aged 70+, from the Berlin Initiative Study (BIS), were analysed. The fit-parameters for the two-compartment model (double-exponential decay curve), and from these, the AUC and GFR were obtained with 8 different fitting procedures. RESULTS: The two-compartmental non-linear least squares fitting procedure showed the best accuracy (541 out of 570 reported GFR-results were within 5% of the majority of the 8 fitting methods). The two-compartmental slope-intercept fitting procedure was not always applicable and the non-compartmental fitting procedures did not always allow to calculate the GFR. All correction formulas for the simplified late multiple-samples methods showed acceptable accuracy and precision with a preference for Ng's correction formula (Lin's CCC = 0.992, bias = 0.5 ± 2.5). Jacobsson's iterative method was the best one-sample method, with Lin's CCC = 0.983 and bias = - 0.6 ± 3.4. CONCLUSION: The fitting procedure has an important impact on the precision of the calculated AUC and GFR. The simplified late-sample protocols and one-sample methods did not suffer from fitting problems and showed acceptable equivalence when compared to the full compartment GFR-results. TRIAL REGISTRATION: The "Berlin Initiative Study" is officially registered with the German Register for Clinical Studies ("Deutschen Register Klinischer Studien"(DRKS)) under registration number DRKS00017058 , since April 12, 2019, and it is also visible on the WHO clinical trials registry platform (within the next 4 weeks after the registration date).
Asunto(s)
Medios de Contraste/farmacocinética , Tasa de Filtración Glomerular , Yohexol/farmacocinética , Área Bajo la Curva , Humanos , Riñón/metabolismo , Tasa de Depuración MetabólicaRESUMEN
BACKGROUND: Population mean GFR is lower in older age, but it is unknown whether healthy aging is associated with preserved rather than lower GFR in some individuals. METHODS: We investigated the cross-sectional association between measured GFR, age, and health in persons aged 50-97 years in the general population through a meta-analysis of iohexol clearance measurements in three large European population-based cohorts. We defined a healthy person as having no major chronic disease or risk factors for CKD and all others as unhealthy. We used a generalized additive model to study GFR distribution by age according to health status. RESULTS: There were 935 (22%) GFR measurements in persons who were healthy and 3274 (78%) in persons who were unhealthy. The mean GFR was lower in older age by -0.72 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], -0.96 to -0.48) for men who were healthy versus -1.03 ml/min per 1.73 m2 per year (95% CI, -1.25 to -0.80) for men who were unhealthy, and by -0.92 ml/min per 1.73 m2 per year (95% CI, -1.14 to -0.70) for women who were healthy versus -1.22 ml/min per 1.73 m2 per year (95% CI, -1.43 to -1.02) for women who were unhealthy. For healthy and unhealthy people of both sexes, both the 97.5th and 2.5th GFR percentiles exhibited a negative linear association with age. CONCLUSIONS: Healthy aging is associated with a higher mean GFR compared with unhealthy aging. However, both the mean and 97.5 percentiles of the GFR distribution are lower in older persons who are healthy than in middle-aged persons who are healthy. This suggests that healthy aging is not associated with preserved GFR in old age.
Asunto(s)
Envejecimiento/fisiología , Medios de Contraste/farmacocinética , Tasa de Filtración Glomerular , Estado de Salud , Yohexol/farmacocinética , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Alemania , Humanos , Islandia , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Noruega , Factores SexualesRESUMEN
RATIONALE & OBJECTIVE: Glomerular filtration rate (GFR) estimation based on creatinine or cystatin C level is currently the standard method for assessing GFR in epidemiologic research and clinical trials despite several important and well-known limitations. Plasma iohexol clearance has been proposed as an inexpensive method for measuring GFR that could replace estimated GFR in many research projects. However, lack of standardization for iohexol assays and the use of different protocols such as single- and multiple-sample methods could potentially hamper comparisons across studies. We compared iohexol assays and GFR measurement protocols in 3 population-based European cohorts. STUDY DESIGN: Cross-sectional investigation. SETTING & PARTICIPANTS: Participants in the Age, Gene/Environment Susceptibility-Kidney Study (AGES-Kidney; n=805), the Berlin Initiative Study (BIS, n=570), and the Renal Iohexol Clearance Survey Follow-up Study (RENIS-FU; n=1,324). TESTS COMPARED: High-performance liquid chromatography analyses of iohexol. Plasma iohexol clearance calculated using single- versus multiple-sample protocols. OUTCOMES: Measures of agreement between methods. RESULTS: Frozen samples from the 3 studies were obtained and iohexol concentrations were remeasured in the laboratory at the University Hospital of North Norway. Lin's concordance correlation coefficient ρ was>0.96 and Cb (accuracy) was>0.99 for remeasured versus original serum iohexol concentrations in all 3 cohorts, and Passing-Bablok regression did not find differences between measurements, except for a slope of 1.025 (95% CI, 1.006-1.046) for the log-transformed AGES-Kidney measurements. The multiple-sample iohexol clearance measurements in AGES-Kidney and BIS were compared with single-sample GFRs derived from the same iohexol measurements. Mean bias for multiple-sample relative to single-sample GFRs in AGES-Kidney and BIS were-0.25 and-0.15mL/min, and 99% and 97% of absolute differences were within 10% of the multiple-sample result, respectively. LIMITATIONS: Lack of comparison with an independent gold-standard method. CONCLUSIONS: Agreement between the iohexol assays and clearance protocols in the 3 investigated cohorts was substantial. Our findings indicate that plasma iohexol clearance measurements can be compared across these studies.
Asunto(s)
Envejecimiento/sangre , Medios de Contraste/metabolismo , Tasa de Filtración Glomerular/fisiología , Yohexol/metabolismo , Tasa de Depuración Metabólica/fisiología , Vigilancia de la Población , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Cohortes , Estudios Transversales , Femenino , Estudios de Seguimiento , Interacción Gen-Ambiente , Alemania/epidemiología , Humanos , Islandia/epidemiología , Pruebas de Función Renal/métodos , Masculino , Persona de Mediana Edad , Noruega/epidemiologíaRESUMEN
The investigation of vascular calcification and its underlying cellular and molecular pathways is of great interest in current research efforts. Therefore, suitable assays are needed to allow examination of the complex calcification process under controlled conditions. The current study describes a new ex vivo model of isolated-perfused rat aortic tissue with subsequent quantification and vessel staining to analyze the calcium content of the aortic wall. A rat aorta was perfused ex vivo with control and calcification media for 14 days, respectively. The calcification medium was luminally perfused and induced a significant increase in calcium deposition within the media of the vessel wall detected alongside the elastic laminae. Perfusion with control medium induced no calcification. In addition, the mRNA expression of the osteogenic marker bone morphogenetic protein 2 (BMP-2) increased in aortic tissue after perfusion, while SM22α as smooth muscle marker decreased. This newly developed ex vivo model of isolated-perfused rat aorta is suitable for vascular calcification studies testing inducers and inhibitors of vessel calcification and studying signaling pathways within calcification progression.
Asunto(s)
Aorta/metabolismo , Calcificación Vascular/etiología , Animales , Proteína Morfogenética Ósea 2/genética , Calcio/metabolismo , Masculino , Proteínas de Microfilamentos/análisis , Proteínas Musculares/análisis , Perfusión , Ratas , Ratas Wistar , Transducción de Señal/fisiologíaRESUMEN
Background Accurate assessment of kidney function is needed for a variety of clinical indications and for research. The measurement of the serum clearance of iohexol has emerged as a feasible method to reach this objective. We report the analytical validation and clinical application of a new high-performance liquid chromatography (HPLC) - tandem mass spectrometry (MS/MS) assay to quantify iohexol in human serum. Specificity was enhanced due to the use of method specific acceptance limits for relative ion (RI) intensities. Methods The internal standard ioversol was added to 50 µL serum prior to protein precipitation with methanol. Linear gradient elution was performed on a Waters Oasis® HLB column. Three transitions for both iohexol and ioversol were monitored allowing calculation of RIs. Measurements acquired during method validation were used as a training set to establish stricter acceptance criteria for RIs which were then tested retrospectively on clinical routine measurements (86 measurements) and on mathematically simulated interferences. Results The method was linear between 5.0 µg/mL (lower limit of quantification [LLOQ]) and 100.3 µg/mL iohexol. Intraday and interday imprecision were ≤2.6% and ≤3.2%, respectively. Bias was -1.6% to 1.5%. All validation criteria were met, including selectivity, recovery, extraction efficiency and matrix effects. Retrospectively acceptance limits for RIs could be narrowed to ±4 relative standard deviations of the corresponding RIs in the training set. The new limits resulted in an enhanced sensitivity for the simulated interferences. Conclusions Criteria for validation were met and the assay is now used in our clinical routine diagnostics and in research.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Precipitación Química , Cromatografía Líquida de Alta Presión/normas , Tasa de Filtración Glomerular , Humanos , Yohexol/análisis , Yohexol/aislamiento & purificación , Yohexol/normas , Pruebas de Función Renal/métodos , Límite de Detección , Estándares de Referencia , Reproducibilidad de los Resultados , Suero/química , Espectrometría de Masas en Tándem/normasRESUMEN
INTRODUCTION: End-stage renal disease (ESRD) is associated with exponentially elevated cardiovascular mortality. Arterial stiffness (AS) - usually expressed with pulse wave velocity (PWV) - is an established independent predictor of cardiovascular risk beyond the traditional risk factors. Higher PWV values are frequently observed in patients with ESRD. Due to the intrinsic physiologic relationship between PWV and prevailing arterial pressure, PWV can change without relevant changes in the arterial wall structure, and thus an individual pressure-independent expression of PWV is essential. METHODS: The study is a single-center observational study. Repeated measurements of blood pressure (BP) and pulse wave analysis were performed during each dialysis session of 1 week. Aortic PWV was then adjusted to 120 mm Hg central systolic BP (PWV120) based on individually determined relationship. PWV120 values were compared between single sessions. Calculation of the PWV120 was performed retrospectively. RESULTS: Fifty-four subjects were included, 61.1% of whom were male. The median age was 75.5 years, and median dialysis vintage was 33.1 months. Mean systolic/diastolic BP was 121.4/70.5 mm Hg, and the median heart rate was 64.6 beats/min. Mean PWV was 10.9 m/s, and mean PWV120 was 11.3 m/s. PWV120 did not change across single dialysis session during 1 week, while systolic, diastolic BP, PWV, and ultrafiltration volume differed significantly. DISCUSSION/CONCLUSIONS: Our data suggest that true AS does not change in the short-term course in dialysis patients. The observed changes in PWV are rather associated with BP change due to intrinsic pressure dependence. Our analytical approach represents a novel method for this purpose, which is easy in performance and also applicable for large interventional trials and clinical practice.
Asunto(s)
Diálisis/efectos adversos , Fallo Renal Crónico/complicaciones , Rigidez Vascular/fisiología , Anciano , Humanos , Fallo Renal Crónico/terapia , Pacientes Ambulatorios , Factores de TiempoRESUMEN
BACKGROUND: Older adults have the highest drug utilization due to multimorbidity. Although the number of people over age 70 is expected to double within the next decades, population-based data on their medication patterns are scarce especially in combination with polypharmacy and potentially inappropriate medication (PIM). Our objective was to analyse the frequency of polypharmacy, pattern of prescription (PD) and over-the-counter (OTC) drug usage, and PIMs according to age and gender in a population-based cohort of very old adults in Germany. METHODS: Cross-sectional baseline data of the Berlin Initiative Study, a prospective cohort study of community-dwelling adults aged ≥70 years with a standardized interview including demographics, lifestyle variables, co-morbidities, and medication assessment were analysed. Medication data were coded using the Anatomical Therapeutic Chemical (ATC) classification. Age- and sex-standardized descriptive analysis of polypharmacy (≥5 drugs, PD and OTC vs. PD only and regular and on demand drugs vs regular only), medication frequency and distribution, including PIMs, was performed by age (≥80) and gender. RESULTS: Of 2069 participants with an average age of 79.5 years, 97% (95%CI [96%;98%]) took at least one drug and on average 6.2 drugs (SD = 3.5) with about 40 to 66% fulfilling the criteria of polypharmacy depending on the definition. Regarding drug type more female participants took a combination of PD and OTC (male: 68%, 95%CI [65%;72%]); female: 78%, 95%CI [76%;80%]). Most frequently used were drugs for cardiovascular diseases (85%, 95%CI [83%;86%]). Medication frequency increased among participants aged ≥80 years, especially for cardiovascular drugs, antithrombotics, psychoanaleptics and dietary supplements. Among the top ten prescription drugs were mainly cardiovascular drugs including lipid-lowering agents (simvastatin), beta-blockers (metoprolol, bisoprolol) and ACE inhibitors (ramipril). The most common OTC drug was acetylsalicylic acid (35%; 95%CI [33%;37%])). Dose-independent PIM were identified for 15% of the participants. CONCLUSIONS: Polypharmacy was excessive in older adults, with not only PD but also OTC drugs contributing to the high point prevalence. The medication patterns reflected the treatment of chronic diseases in this age group. There was even an increase in medication frequency between below and above 80 years especially for drugs of cardiovascular diseases, antithrombotic medication, psychoanaleptics, and dietary supplements.
Asunto(s)
Vida Independiente , Polifarmacia , Lista de Medicamentos Potencialmente Inapropiados , Autoinforme , Anciano , Berlin , Estudios Transversales , Femenino , Alemania/epidemiología , Humanos , Prescripción Inadecuada , Masculino , Estudios ProspectivosRESUMEN
Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m2, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.
Asunto(s)
Insuficiencia Renal Crónica/diagnóstico , Factores de Edad , Humanos , PronósticoRESUMEN
AIMS: To assess whether blood pressure (BP) values below 140/90 mmHg during antihypertensive treatment are associated with a decreased risk of all-cause mortality in community-dwelling older adults. METHODS AND RESULTS: Within the Berlin Initiative Study, we assembled a cohort of patients ≥70 years treated with antihypertensive drugs at baseline (November 2009-June 2011). End of prospective follow-up was December 2016. Cox proportional hazards models yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality associated with normalized BP [systolic BP (SBP) <140 mmHg and diastolic BP (DBP) <90 mmHg] compared with non-normalized BP (SBP ≥140 mmHg or DBP ≥90 mmHg) overall and after stratification by age or previous cardiovascular events. Among 1628 patients (mean age 81 years) on antihypertensive drugs, 636 exhibited normalized BP. During 8853 person-years of follow-up, 469 patients died. Compared with non-normalized BP, normalized BP was associated with an increased risk of all-cause mortality (incidence rates: 60.3 vs. 48.5 per 1000/year; HR 1.26; 95% CI 1.04-1.54). Increased risks were observed in patients ≥80 years (102.2 vs. 77.5 per 1000/year; HR 1.40; 95% CI 1.12-1.74) and with previous cardiovascular events (98.3 vs. 63.6 per 1000/year; HR 1.61; 95% CI 1.14-2.27) but not in patients aged 70-79 years (22.6 vs. 22.7 per 1000/year; HR 0.83; 95% CI 0.54-1.27) or without previous cardiovascular events (45.2 vs. 44.4 per 1000/year; HR 1.16, 95% CI 0.90-1.48). CONCLUSION: Blood pressure values below 140/90 mmHg during antihypertensive treatment may be associated with an increased risk of mortality in octogenarians or elderly patients with previous cardiovascular events.
Asunto(s)
Determinación de la Presión Sanguínea/métodos , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antihipertensivos/uso terapéutico , Presión Sanguínea/fisiología , Enfermedades Cardiovasculares/mortalidad , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Alemania/epidemiología , Humanos , Hipertensión/epidemiología , Hipertensión/mortalidad , Vida Independiente , Masculino , Estudios ProspectivosRESUMEN
Calcification of the vessel wall contributes to high cardiovascular morbidity and mortality. Vascular calcification (VC) is a systemic disease with multifaceted contributing and inhibiting factors in an actively regulated process. The exact underlying mechanisms are not fully elucidated and reliable treatment options are lacking. Due to the complex pathophysiology, various research models exist evaluating different aspects of VC. This review aims to give an overview of the cell and animal models used so far to study the molecular processes of VC. Here, in vitro cell culture models of different origins, ex vivo settings using aortic tissue and various in vivo disease-induced animal models are summarized. They reflect different aspects and depict the (patho)physiologic mechanisms within the VC process.
Asunto(s)
Susceptibilidad a Enfermedades , Modelos Biológicos , Calcificación Vascular/etiología , Calcificación Vascular/metabolismo , Animales , Calcificación Fisiológica , Modelos Animales de Enfermedad , Humanos , Calcificación Vascular/patologíaRESUMEN
Vascular calcification and stiffening of the arterial wall is a systemic phenomenon that is associated with aging and it can be increased by several risk factors. The underlying mechanisms, especially the pathways of cellular senescence, are under current investigation. Easily manageable in vitro settings help to study the signaling pathways. The experimental setting presented here is based on an in vitro model using rat vascular smooth muscle cells and the detection of senescence and osteoblastic markers via immunofluorescence and RNAscope™. Co-staining of the senescence marker p21, the osteoblastic marker osteopontin, detection of senescence-associated heterochromatin foci, and senescence-associated ß-galactosidase is possible within one test approach requiring fewer cells. The protocol is a fast and reliable evaluation method for multiplexing of calcifying and senescence markers with fluorescence microscopy detection. The experimental setting enables analysis on single cell basis and allows detection of intra-individual variances of cultured cells.
Asunto(s)
Osteopontina/genética , Calcificación Vascular/genética , beta-Galactosidasa/genética , Quinasas p21 Activadas/genética , Envejecimiento/genética , Animales , Arterias/metabolismo , Biomarcadores/metabolismo , Senescencia Celular/genética , Humanos , Microscopía Fluorescente , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/ultraestructura , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/ultraestructura , Ratas , Transducción de Señal/genética , Quinasas p21 Activadas/metabolismoRESUMEN
BACKGROUND: Smoking remains the most important avoidable cause of global mortality. Even though the number of cigarette smokers declines in first world countries, the uses of alternative nicotine delivery products increase and may even surpass the sells of cigarettes. In this light, the explicit role of nicotine in the development of cardiovascular diseases should be elucidated. OBJECTIVES: This narrative review attempts to connect current literature about possible effects of nicotine on the environment of the vasculature to the pathogenesis of vascular calcification, focusing on the tunica media of the vessel wall. METHODS: For this review, papers found on Pubmed and Medline until December 2018 by searching for the keywords nicotine, vascular calcification, oxidative stress, osteoblastic transdifferentiation and matrix degradation were considered. RESULTS: Nicotine creates an environment that probably facilitates and maybe even induces osteogenic transdifferentiation of VSMC by inflammation, endothelial dysfunction and reactive oxygen species. This process is believed to be a key event in calcification of the tunica media of the vessel wall. Furthermore, nicotine could lead to the formation of nucleation sites for hydroxyapatite by facilitating matrix vesicles and extracellular matrix degradation. CONCLUSIONS: There is a growing body of evidence implicating that nicotine alone could impair vascular function and lead to vascular calcification. Further research is necessary to elucidate the explicit influence of nicotine on arteriosclerosis.