Hiperparatiroidismo secundario y cambios de FGF23 en pacientes en hemodiálisis

La enfermedad renal crónica (ERC) está aumentando en todo el mundo y se ha convertido en una de las principales causas de morbilidad y mortalidad. En este contexto, las alteraciones del metabolismo óseo mineral, incluido el factor de crecimiento fibroblástico 23 (FGF23), desempeñan un papel fundamental en el hiperparatiroidismo secundario y en el desarrollo de calcificaciones vasculares. Los niveles séricos de FGF23 están extremadamente altos en los pacientes en hemodiálisis (HD) y se asocian a una un alto mayor mortalidad. Consecuentemente, los pacientes en HD muestran un alto riesgo de muerte. Aunque inicialmente se pensó, que FGF23 regulaba exclusivamente el metabolismo del fosfato y la vitamina D, investigaciones recientes han demostrado que FGF23 es crucial en la compleja red de comunicaciones entre el hueso y otros órganos. Además, un exceso de FGF23 tiene efectos descubiertos recientemente “no clásicos” que pueden ser en ocasiones son perjudiciales. Por lo tanto, es de gran importancia identificar los factores que pueden intervenir en la regulación del FGF23 en pacientes en diálisis. Para abordar este problema, se han diseñado cuatro estudios diferentes. Primero, se han estudiado las variables con un efecto potencial en los niveles de FGF23. En segundo lugar, se evalúa el aclaramiento de FGF23 durante la diálisis. En tercer lugar, se han determinado los factores asociados con los cambios agudos en FGF23. Cuarto, realizamos un estudio longitudinal para probar si las modificaciones de fosfato sérico fueron capaces de producir cambios significativos en los niveles de FGF23. Hemos encontrado que 1) los pacientes en hemodiálisis, con hiperfosfatemia, mostraron aumento de hs-CRP, PTH, iFGF23 y cFGF23. El análisis de regresión múltiple reveló que los niveles de iFGF23 se correlacionaban directamente tanto con el fosfato sérico como con el calcio, mientras que el cFGF23 se correlacionaba con el fosfato sérico y la PCR-hs, pero no con el calcio. Los niveles de cFGF23 estaban estrechamente relacionados con el fosfato sérico y con los parámetros de inflamación; 2) El iFGF23 y el cFGF23 disminuyeron durante la diálisis. Sin embargo, mientras que el cFGF23 mostró una tendencia hacia una reducción progresiva durante la sesión de hemodiálisis, el iFGF23 solo disminuyó al final de la sesión de hemodiálisis; 3) La reducción de iFGF23 se asoció con cambios de calcio. No se observó correlación entre los cambios agudos en fosfato, PTH y FGF23; 4) el control del fosfato sérico se asoció a una reducción del 60% en los niveles circulantes de iFGF23 mientras que no se observaron cambios en los niveles séricos de cFGF23. Los pacientes, que no lograron el control de fosfato, mostraron un aumento de dos veces en iFGF23 y un aumento de cuatro veces en cFGF23. Es importante hacer notar que los cambios de fosfato se correlacionaron con los cambios en la proteína C reactiva (hs-CRP). En síntesis, el fosfato sérico, el calcio y la inflamación son los tres factores más importantes asociados con el aumento de FGF23. De forma aguda, tanto el iFGF23 como el cFGF23 se reducen a lo largo de una sesión de diálisis. Sin embargo, es probable, que los cambios en el calcio sérico sean los responsables de las modificaciones agudas en iFGF23. Finalmente, el control de fosfato sérico redujo el iFGF23 que también se asoció con una disminución de los parámetros inflamatorios

Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease

Fibroblast Growth Factor 23 (FGF23) and Klotho play an essential role in the regulation of mineral metabolism, and both are altered as a consequence of renal failure. FGF23 increases to augment phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This effect of FGF23 requires the presence of Klotho in the renal tubules. However, Klotho expression is reduced as soon as renal function is starting to fail to generate a state of FGF23 resistance. Changes in these proteins directly affect to other mineral metabolism parameters; they may affect renal function and can produce damage in other organs such as bone, heart, or vessels. Some of the mechanisms responsible for the changes in FGF23 and Klotho levels are related to modifications in the Wnt signaling. This review examines the link between FGF23/Klotho and Wnt/β-catenin in different organs: kidney, heart, and bone. Activation of the canonical Wnt signaling produces changes in FGF23 and Klotho and vice versa; therefore, this pathway emerges as a potential therapeutic target that may help to prevent CKD-associated complications

Pancreatic autoantibodies and CD14+CD16+ monocytes subset are associated with the impairment of ß-cell function after simultaneous pancreas-kidney transplantation

Pancreatic autoantibodies (AAb) has been associated with a worse pancreas graft survival after simultaneous pancreas-kidney transplantation (SPK). However, due to the variable time for AAb to become positive and the lack of early biomarkers suggesting such autoimmune activation, the mechanisms leading ß-cell destruction remain uncertain. The present study aimed to evaluate the association between post-transplant AAb and the functional impairment of the pancreatic ß-cell and also the association of such AAb with inflammation after SPK. In a longitudinal study, we analyzed the impact of post-transplant glutamic acid decarboxylase (GAD-65) and the insulinoma-associated autoantigen 2 (IA-2) AAb on pancreas graft function. Serum Hb1Ac and C-peptide (C-pep) were longitudinally compared between a group with positive posttransplant AAb (AAb+; n = 40) and another matched group with negative AAb (AAb-; n = 40) until the fifth year following seroconversion. In the cross-sectional analysis, we further evaluated the systemic signatures of inflammation by measuring pro-inflammatory CD14+CD16+ monocytes by flow-cytometry and interleukin 17-A serum levels in 38 SPK recipients and ten healthy controls. In the longitudinal study, patients with AAb+ showed higher levels of Hb1Ac (p<0.001) and lower C-pep levels (p<0.001) compared to those who remained AAb- throughout the follow-up. In the cross-sectional study, AAb+ patients showed a higher percentage of CD14+CD16+ monocytes compared with those with AAb- and the healthy controls (6.70±4.19% versus 4.0±1.84% and 3.44±0.93%; p = 0.026 and 0.009 respectively). Also, CD14+CD16+ monocytes correlated with Hb1Ac and C-pep serum levels. Multivariate logistic regression showed that posttransplant AAb+ was independently associated with a higher percentage of pro-inflammatory monocytes (adjusted-OR 1.59, 95%CI 1.05–2.40, p = 0.027). The group of patients with positive AAb also showed higher levels of IL17A as compared with the other groups (either healthy control or the negative AAb subjects). In conclusion, pancreatic AAb+ after SPK were not only associated with higher Hb1Ac and lower c-peptide serum levels but also with an increased percentage of CD14+CD16+ monocytes and higher levels of circulating IL17-A

Dietary Mg Supplementation Decreases Oxidative Stress, Inflammation, and Vascular Dysfunction in an Experimental Model of Metabolic Syndrome with Renal Failure

whether a dietary Mg supplementation might attenuate vascular dysfunction through the modulation of oxidative stress and inflammation in concurrent MetS and CKD. Methods: A rat model of MetS (Zucker strain) with CKD (5/6 nephrectomy, Nx) was used. Nephrectomized animals were fed a normal 0.1%Mg (MetS+Nx+Mg0.1%) or a supplemented 0.6%Mg (MetS+Nx+Mg0.6%) diet; Sham-operated rats with MetS receiving 0.1%Mg were used as controls. Results: As compared to controls, the MetS+Nx-Mg0.1% group showed a significant increase in oxidative stress and inflammation biomarkers (lipid peroxidation and aortic interleukin-1b and -6 expression) and Endothelin-1 levels, a decrease in nitric oxide and a worsening in uremia and MetS associated pathology as hypertension, and abnormal glucose and lipid profile. Moreover, proteomic evaluation revealed changes mainly related to lipid metabolism and CVD markers. By contrast, in the MetS+Nx+Mg0.6% group, these parameters remained largely similar to controls. Conclusion: In concurrent MetS and CKD, dietary Mg supplementation reduced inflammation and oxidative stress and improved vascular function

Pretransplant CMV-Specific T-Cell Immunity But Not Dose of Antithymocyte Globulin Is Associated With Recovery of Specific Immunity After Kidney Transplantation

Background: This is a prospective, multicenter, observational study in cytomegalovirus (CMV)-seropositive kidney transplant recipients with pretransplant CMV-specific cell-mediated immunity (CMV-CMI) receiving antithymocyte globulin (ATG). We aimed to investigate posttransplant CMV-CMI over time and the impact of the dose-dependent ATG. Methods: CMV-CMI was assessed at days +30, +45, +60, and +90 after transplantation with the QuantiFERON-CMV assay. A reactive result (interferon-? [IFN-?] ? 0.2 IU/mL) indicated a positive CMV-CMI. Results: A total of 78 positive CMV-CMI patients were enrolled in the study, of which 59.5% had a positive CMV-CMI at day +30 and 82.7% at day +90. Multivariate logistic regression analysis showed that ATG dose was not associated with positive CMV-CMI at any point. However, pretransplant IFN-? level (>12 IU/mL vs ?12 IU/mL) was associated with positive CMV-CMI at day +30 (odds ratio, 12.9; 95% confidence interval, 3.1-53.3; P < .001). In addition, all the patients who did not recover CMV-CMI at day +90 had a pretransplant IFN-? level ?12 IU/mL. Conclusions: More than half of CMV-seropositive kidney transplant recipients receiving ATG recover (or maintain) CMV-CMI by the first month after transplantation. The pretransplant IFN-? level, but not the ATG dose, shows a strong association with the kinetics of this recovery.This work was supported by the Fundación Progreso y Salud, Consejería de Salud y Familias, Junta de Andalucía (grant number PI-0294-2014); Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (grant number CP 18/00073 to M. F. R.); Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia e Innovación, Spanish Network for Research in Infectious Diseases (grant numbers REIPI RD16/0016/0002, RD16/0016/0003, RD16/0016/0007, RD16/0016/0008, RD16/0016/0009 and RD16/0016/0012); cofinanced by European Development Regional Fund “A way to achieve Europe,” Operative Program Intelligent Growth 2014- 2020; Spanish Network for Research in Renal Diseases (grant numbers RD16/0009/0006, RD16/0009/0008, RD16/0009/0013, RD16/0009/0014, RD16/0009/0019, RD16/0009/0034); Centro de Investigación Biomédica en Red Enfermedades Respiratorias (grant number CB06/06/0058); and Spanish Group for the Study of Infection in Transplantation and the Immunocompromised Host of the Spanish Society of Infectious Diseases and Clinical Microbiolog

Supplemental Material The direct effect of fibroblast growth factor 23 on vascular smooth muscle cell phenotype and function

3 pages. -- Figure S1. Supplemental Material. Effects of anti-miR-221 and miR-222. -- Figure S1. Supplemental Material: A) Anti-miR-221 and B) anti-miR-222 transfection for 48 h decreased not significantly the expression of miR-221 and miR-222 in VSMC. -- Figure S2. Supplemental Material. Recombinant Klotho administration did not modify the expression of contractile markers of VSMC. -- Figure S3. Histological quantifications in thoracic aortas of rats of synthetic markers of VSMC.Peer reviewe

The direct effect of fibroblast growth factor 23 on vascular smooth muscle cell phenotype and function

[Background] In chronic kidney disease (CKD) patients, increased levels of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality. The relationship between FGF23 and heart hypertrophy has been documented, however, it is not known whether FGF23 has an effect on vasculature. Vascular smooth muscle cells VSMCs may exhibit different phenotypes; our hypothesis is that FGF23 favours a switch from a contractile to synthetic phenotype that may cause vascular dysfunction. Our objective was to determine whether FGF23 may directly control a change in VSMC phenotype.[Methods] This study includes in vitro, in vivo and ex vivo experiments and evaluation of patients with CKD stages 2–3 studying a relationship between FGF23 and vascular dysfunction.[Results] In vitro studies show that high levels of FGF23, by acting on its specific receptor FGFR1 and Erk1/2, causes a change in the phenotype of VSMCs from contractile to synthetic. This change is mediated by a downregulation of miR-221/222, which augments the expression of MAP3K2 and PAK1. miR-221/222 transfections recovered the contractile phenotype of VSMCs. Infusion of recombinant FGF23 to rats increased vascular wall thickness, with VSMCs showing a synthetic phenotype with a reduction of miR-221 expression. Ex-vivo studies on aortic rings demonstrate also that high FGF23 increases arterial stiffening. In CKD 2–3 patients, elevation of FGF23 was associated with increased pulse wave velocity and reduced plasma levels of miR-221/222.[Conclusion] In VSMCs, high levels of FGF23, through the downregulation of miR-221/222, causes a change to a synthetic phenotype. This change in VSMCs increases arterial stiffening and impairs vascular function, which might ultimately worsen cardiovascular disease.This work was supported by a Spanish government grant from the Programa Nacional I+D+I 2013–2016 and Instituto de Salud Carlos III (ISCIII) grants PI18/0138 and PI21/0654 co-financing from European Funds (FEDER), Consejería de Salud (grants PI-0136 and PI-0169-2020) from the Junta de Andalucía, Framework Programme 7 Syskid UE grant FP7-241544, and EUTOX and REDinREN from the ISCIII. N.V. and J.M.D.-T. were supported by Consejería de Economía, Innovación, Ciencia y Empleo (grant CVI-7925) from the Junta de Andalucía. Y.A. and J.R.M.-C. are senior researchers supported by the Nicolás Monardes Programme, Consejería de Salud-Servicio Andaluz de Salud (Junta de Andalucía).Peer reviewe

Control of hyperparathyroidism with the intravenous calcimimetic etelcalcetide in dialysis patients adherent and non-adherent to oral calcimimetics

Background. In dialysis patients, non-adherence to oral cinacalcet adds complexity to the control of secondary hyperparathyroidism. The present study aims to evaluate the use of intravenous calcimimetic, etelcalcetide, in the control of secondary hyperparathyroidism in patients adherent and non-adherent to oral calcimimetics. Method. The Simplified Medication Adherence Questionnaire was used to identify non-adherence. Almost half of the patients were non-adherent to the treatment with cinacalcet. Twenty-five patients (15 non-adherent) were switched from cinacalcet to etelcalcetide and were followed-up monthly for 8 months. Results. Cinacalcet was discontinued for 1 week before the initiation of etelcalcetide. After this period, the serum PTH levels increased by2-fold in adherent patients, whereas it did not change in non-adherent patients suggesting that they were not taking the medication. Etelcalcetide progressively reduced serum parathyroid hormone (PTH) (mean 6 standard deviation) from 818 6 395 to 367 6 289 pg/mL (P< 0.001) in non-adherents, and from 496 6 172 to 228 6 111 pg/mL (P< 0.01) in adherent patients with a mean dose of 7.0 6 2.3 and 5.1 6 1.2 mg in non-adherent and in adherent patients, respectively. Etelcalcetide increased the percentage of patients with PTH on target from 28% to 58%. Patients with serum calcium <8.4 mg/dL increased from 8% to 40%, although they remained asymptomatic. The percent of patients with serum phosphate on target increased from 40% to 65%. Conclusion. The lack of adherence to cinacalcet is a possible cause of the apparent lack of response to oral calcimimetic.The use of etelcalcetide ensures compliance and control of secondary hyperparathyroidism in both non-adherent and adherent patients.M.V.P.-R.d.M. is the recipient of a research contract sup ported by the Rio Hortega Programme from the National Institute of Health Carlos III.Ye

Impact of Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibody C1q-Binding Ability on Kidney Allograft Outcome

The consolidation of single antigen beads (SAB-panIgG) assay in the detection of preformed anti-human leukocyte antigen (HLA) antibodies has improved transplantation success. However, its high sensitivity has limited the allograft allocation for sensitized patients, increasing their waiting time. A modification of the standard SAB-panIgG assay allows the detection of that subset of antibodies capable of binding C1q (SAB-C1q assay). However, the clinical usefulness of SAB-C1q assay for determining the unacceptable mismatches is under discussion. We retrospectively analyzed the impact of preformed donor-specific anti-HLA antibodies (DSA) according to the C1q-binding ability on allograft outcome, examining 389 single-kidney transplanted patients from deceased donors. Recipients with preformed C1q-binding DSA showed the lowest allograft survival up to 7 years (40.7%) compared to patients with preformed non-C1q-binding DSA (73.4%; p = 0.001) and without DSA (79.1%; p

The value of ABPM and subclinical target organ damage parameters in diagnosis of resistant hypertension

Introduction: We aimed to assess the effectiveness of ambulatory blood pressure monitoring (ABPM) and subclinical target organ damage parameters for diagnosis of resistant hypertension (RH). Methods: We assessed demographic and anthropometric variables, the incidence of cardiovascular events and subclinical target organ damage (n = 112). We also studied the relationship between these variables and the ABPM results. Results: Of the 112 patients referred from primary care with a diagnosis of RH, 69 (61.6%) were confirmed by ABPM. We found statistically significant differences (p < 0.001) between patients with RH and pseudo-resistant hypertension in the appearance of subclinical target organ damage. A percentage of 84 of the patients had microalbuminuria: 66.25 ± 30.7 mg/dl); 44.9% had stage 3 chronic kidney disease: the average glomerular filtration was 59 ml/min/1.73 m2; and 56.5% had left ventricular hypertrophy on echocardiography. Fundoscopy revealed that 64% of the patients had hypertensive retinopathy. Three variables were associated with an increased HR risk: microalbuminuria, hypertensive retinopathy and left ventricular hypertrophy (OR 5.7, 6.2 and 11.2, respectively). Conclusions: This study shows that the systematic testing for target organ damage, particularly in terms of albuminuria, is a simple and inexpensive tool, with a high predictive value for RH (85%), which could be useful for prioritizing patients who need ABPM. Resumen: Introducción: El presente estudio tiene como objetivo destacar la importancia de la monitorización ambulatoria de la presión arterial (MAPA) y de los parámetros de lesión subclínica de órgano diana en el diagnóstico de hipertensión refractaria (HR). Métodos: Se estudiaron pacientes con diagnóstico de HR (n = 112). Se analizaron variables demográficas, antropométricas, riesgo cardiovascular y lesión subclínica de órgano diana y se relacionaron con la confirmación de HR a través de la MAPA. Resultados: Del total de 112 pacientes con el diagnóstico de HR derivados desde atención primaria se confirmaron mediante MAPA el 61,6% de los casos (n = 69). Se observaron diferencias estadísticamente significativas (p < 0,001) en la aparición de lesión subclínica de órgano diana en los hipertensos refractarios respecto a los pseudorrefractarios. Un 84% de los pacientes con HR presentaban microalbuminuria: 66,25 ± 30,7 mg/dl). El 44,9% tienen una enfermedad renal crónica estadio 3 con filtrado glomerular medio de 59 ml/min/1,73 m2. El 56,5% presentaba hallazgos ecocardiográficos de hipertrofia de ventrículo izquierdo. El examen de fondo de ojo reveló que un 64% de los pacientes presentaban retinopatía hipertensiva. Las 3 variables que se asociaron a mayor riesgo de HR fueron la presencia de microalbuminuria, retinopatía hipertensiva e hipertrofia de ventrículo izquierdo por ecocardiograma (OR 5,7, 6,2 y 11,2, respectivamente). Conclusiones: Nuestro estudio demuestra que la búsqueda sistemática de daño de órgano diana, especialmente en lo referente a albuminuria, es una herramienta sencilla y barata, con un valor predictivo de HR alto (85%). Podría ser de utilidad en circunstancias en las que es necesario priorizar la realización de MAPA. Keywords: Ambulatory blood pressure monitoring, Resistant hypertension, Subclinical target organ damage, Palabras clave: Monitorización ambulatoria de la presión arterial, Hipertensión refractaria, Lesión subclínica de órgano dian