RESUMEN
α-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy.NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.
Asunto(s)
alfa-Globulinas , Riñón , Daño por Reperfusión , Animales , Daño por Reperfusión/patología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Daño por Reperfusión/tratamiento farmacológico , alfa-Globulinas/metabolismo , alfa-Globulinas/farmacología , Masculino , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Modelos Animales de Enfermedad , Tasa de Filtración Glomerular/efectos de los fármacos , Ratones Endogámicos C57BL , Humanos , Ratones , Hemo-Oxigenasa 1/metabolismo , Ratas , Ratas Sprague-Dawley , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Distribución TisularRESUMEN
BACKGROUND: Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes. METHODS: We measured cFGF23 on plasma samples from 388 patients with CKD 3-5 who had serial measurements of cFGF23, with a mean of 4.2 samples per individual. We used linear regression analysis to assess the annual rate of change in cFGF23 and assessed the relationship between time-varying cFGF23 and the outcomes in a cox-regression analysis. RESULTS: Across our population, median baseline eGFR was 32.3mls/min/1.73m2, median baseline cFGF23 was 162 relative units/ml (RU/ml) (IQR 101-244 RU/mL). Over 70 months (IQR 53-97) median follow-up, 76 (19.6%) patients progressed to RRT, 86 (22.2%) died, and 52 (13.4%) suffered a major non-fatal CV event. On multivariate analysis, longitudinal change in cFGF23 was significantly associated with risk for death and progression to RRT but not non-fatal cardiovascular events. CONCLUSION: In our study, increasing cFGF23 was significantly associated with risk for death and RRT.
Asunto(s)
Factor-23 de Crecimiento de Fibroblastos/sangre , Insuficiencia Renal Crónica/sangre , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/mortalidad , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function.
Asunto(s)
Albuminuria/tratamiento farmacológico , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Moléculas de Adhesión Celular/antagonistas & inhibidores , Nefropatías Diabéticas/tratamiento farmacológico , Modelos Biológicos , Compuestos Orgánicos/farmacocinética , Administración Oral , Albuminuria/sangre , Albuminuria/etiología , Amina Oxidasa (conteniendo Cobre)/sangre , Amina Oxidasa (conteniendo Cobre)/metabolismo , Disponibilidad Biológica , Variación Biológica Poblacional , Moléculas de Adhesión Celular/sangre , Moléculas de Adhesión Celular/metabolismo , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Simulación por Computador , Nefropatías Diabéticas/sangre , Relación Dosis-Respuesta a Droga , Femenino , Absorción Gastrointestinal , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Voluntarios Sanos , Humanos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Compuestos Orgánicos/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Eliminación Renal , Distribución TisularRESUMEN
Located within the brain's ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in Klothoflox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis.
Asunto(s)
Envejecimiento/inmunología , Encéfalo/inmunología , Plexo Coroideo/inmunología , Glucuronidasa/inmunología , Envejecimiento/genética , Animales , Femenino , Glucuronidasa/genética , Hipocampo/inmunología , Humanos , Proteínas Klotho , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunologíaRESUMEN
The vascular adhesion protein-1 (VAP-1) inhibitor ASP8232 reduces albuminuria in patients with type 2 diabetes and chronic kidney disease. A mechanism-based model was developed to quantify the effects of ASP8232 on renal markers from a placebo-controlled Phase 2 study in diabetic kidney disease with 12 weeks of ASP8232 treatment. The model incorporated the available pharmacokinetic, pharmacodynamic (plasma VAP-1 concentration and activity), serum and urine creatinine, serum cystatin C, albumin excretion rate, urinary albumin-to-creatinine ratio, and urine volume information in an integrated manner. Drug-independent time-varying changes and different drug effects could be quantified for these markers using the model. Through simulations, this model provided the opportunity to dissect the relationship and longitudinal association between the estimated glomerular filtration rate and albuminuria and to quantify the pharmacological effects of ASP8232. The developed drug-independent model may be useful as a starting point for other compounds affecting the same biomarkers in a similar time scale.
Asunto(s)
Albuminuria/tratamiento farmacológico , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Moléculas de Adhesión Celular/antagonistas & inhibidores , Nefropatías Diabéticas/tratamiento farmacológico , Modelos Biológicos , Compuestos Orgánicos/farmacología , Administración Oral , Anciano , Albuminuria/sangre , Albuminuria/etiología , Amina Oxidasa (conteniendo Cobre)/metabolismo , Biomarcadores/sangre , Biomarcadores/orina , Moléculas de Adhesión Celular/metabolismo , Ensayos Clínicos Fase II como Asunto , Simulación por Computador , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/orina , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Humanos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Compuestos Orgánicos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies for prevention and treatment of secondary hyperparathyroidism. Here we investigate the specific role of Klotho expressed in the parathyroid glands (PTGs) in mediating parathyroid hormone (PTH) and serum calcium homeostasis, as well as the potential interaction between calcium-sensing receptor (CaSR) and Klotho. We generated mouse strains with PTG-specific deletion of Klotho and CaSR and dual deletion of both genes. We show that ablating CaSR in the PTGs increases PTH synthesis, that Klotho has a pivotal role in suppressing PTH in the absence of CaSR, and that CaSR together with Klotho regulates PTH biosynthesis and PTG growth. We utilized the tdTomato gene in our mice to visualize and collect PTGs to reveal an inhibitory function of Klotho on PTG cell proliferation. Chronic hypocalcemia and ex vivo PTG culture demonstrated an independent role for Klotho in mediating PTH secretion. Moreover, we identify an interaction between PTG-expressed CaSR and Klotho. These findings reveal essential and interrelated functions for CaSR and Klotho during parathyroid hyperplasia.
Asunto(s)
Glucuronidasa/fisiología , Glándulas Paratiroides/metabolismo , Hormona Paratiroidea/biosíntesis , Receptores Acoplados a Proteínas G/fisiología , Animales , Huesos/patología , Calcio/metabolismo , Calcio de la Dieta/administración & dosificación , Femenino , Factor-23 de Crecimiento de Fibroblastos , Glucuronidasa/deficiencia , Glucuronidasa/genética , Homeostasis , Hipercalcemia/genética , Hipercalcemia/patología , Hiperparatiroidismo/genética , Hiperparatiroidismo/patología , Hiperplasia , Hipocalcemia/metabolismo , Hipofosfatemia/genética , Hipofosfatemia/patología , Inmunoprecipitación , Riñón/patología , Proteínas Klotho , Masculino , Ratones , Glándulas Paratiroides/patología , Hormona Paratiroidea/genética , Mapeo de Interacción de Proteínas , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores Sensibles al Calcio , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Phosphate homeostasis is primarily maintained in the renal proximal tubules, where the expression of sodium/phosphate cotransporters (Npt2a and Npt2c) is modified by the endocrine actions of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). However, the specific contribution of each regulatory pathway in the proximal tubules has not been fully elucidated in vivo. We have previously demonstrated that proximal tubule-specific deletion of the FGF23 coreceptor Klotho results in mild hyperphosphatemia with little to no change in serum levels of FGF23, 1,25(OH)2D3, and PTH. In the present study, we characterized mice in which the PTH receptor PTH1R was specifically deleted from the proximal tubules, either alone or in combination with Klotho ( PT-PTH1R-/- and PT-PTH1R/KL-/-, respectively). PT-PTH1R-/- mice showed significant increases in serum FGF23 and PTH levels, whereas serum phosphate levels were maintained in the normal range, and Npt2a and Npt2c expression in brush border membrane (BBM) did not change compared with control mice. In contrast, PT-PTH1R/KL-/- mice displayed hyperphosphatemia and an increased abundance of Npt2a and Npt2c in the renal BBM, along with increased circulating FGF23 levels. While serum calcium was normal, 1,25(OH)2D3 levels were significantly decreased, leading to extremely high levels of PTH. Collectively, mice with a deletion of PTH1R alone in proximal tubules results in only minor changes in phosphate regulation, whereas deletion of both PTH1R and Klotho leads to a severe disturbance, including hyperphosphatemia with increased sodium/phosphate cotransporter expression in BBM. These results suggest an important interplay between the PTH/PTH1R and FGF23/Klotho pathways to affect renal phosphate handling in the proximal tubules.
Asunto(s)
Factores de Crecimiento de Fibroblastos/sangre , Glucuronidasa/metabolismo , Hiperfosfatemia/sangre , Túbulos Renales Proximales/metabolismo , Hormona Paratiroidea/sangre , Fosfatos/sangre , Reabsorción Renal , Animales , Calcitriol/sangre , Calcio/sangre , Células Cultivadas , Factor-23 de Crecimiento de Fibroblastos , Predisposición Genética a la Enfermedad , Glucuronidasa/deficiencia , Glucuronidasa/genética , Hiperfosfatemia/genética , Hiperfosfatemia/fisiopatología , Túbulos Renales Proximales/fisiopatología , Proteínas Klotho , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Receptor de Hormona Paratiroídea Tipo 1/deficiencia , Receptor de Hormona Paratiroídea Tipo 1/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/metabolismo , Regulación hacia ArribaRESUMEN
Circulating levels of bone-derived fibroblast growth factor 23 (FGF23) increase early during acute and chronic kidney disease and are associated with adverse outcomes. Membrane-bound Klotho acts as a permissive coreceptor for FGF23, and its expression was recently found in osteoblasts/osteocytes. We hypothesized that Klotho in bone cells is part of an autocrine feedback loop that regulates FGF23 expression during renal failure. Thus, we induced renal failure in mice with targeted deletion of Klotho in long bones. Uremic wild-type (KLfl/fl ) and knockout (Prx1-Cre;KLfl/fl ) mice both responded with reduced body weight, kidney atrophy, hyperphosphatemia, and increased bone turnover. Importantly, long bones of Prx1-Cre;KLfl/fl mice but not their axial skeleton failed to increase FGF23 expression as observed in uremic KLfl/fl mice. Consequently, Prx1-Cre;KLfl/fl mice had significantly lower serum FGF23 and parathyroid hormone levels, and higher renal 1-α-hydroxylase expression, serum 1,25-dihydroxyvitamin D, and calcium levels than KLfl/fl mice. These results were confirmed in two independent models of renal failure, adenine diet induced and 5/6 nephrectomy. Moreover, FGF23-treated bone cells required Klotho to increase FGF23 mRNA and ERK phosphorylation. In summary, our novel findings show that Klotho in bone is crucial for inducing FGF23 production upon renal failure. We propose the presence of an autocrine feedback loop in which Klotho senses the need for FGF23.-Kaludjerovic, J., Komaba, H., Sato, T., Erben, R. G., Baron, R., Olauson, H., Larsson, T. E., Lanske, B. Klotho expression in long bones regulates FGF23 production during renal failure.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/metabolismo , Riñón/metabolismo , Insuficiencia Renal/metabolismo , Animales , Huesos/metabolismo , Calcitriol/metabolismo , Calcio/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Glucuronidasa/deficiencia , Proteínas Klotho , Ratones Noqueados , Osteoblastos/metabolismo , Hormona Paratiroidea/genética , Fosfatos/metabolismoRESUMEN
Osteocytes within the mineralized bone matrix control bone remodeling by regulating osteoblast and osteoclast activity. Osteocytes express the aging suppressor Klotho, but the functional role of this protein in skeletal homeostasis is unknown. Here we identify Klotho expression in osteocytes as a potent regulator of bone formation and bone mass. Targeted deletion of Klotho from osteocytes led to a striking increase in bone formation and bone volume coupled with enhanced osteoblast activity, in sharp contrast to what is observed in Klotho hypomorphic (kl/kl) mice. Conversely, overexpression of Klotho in cultured osteoblastic cells inhibited mineralization and osteogenic activity during osteocyte differentiation. Further, the induction of chronic kidney disease with high-turnover renal osteodystrophy led to downregulation of Klotho in bone cells. This appeared to offset the skeletal impact of osteocyte-targeted Klotho deletion. Thus, our findings establish a key role of osteocyte-expressed Klotho in regulating bone metabolism and indicate a new mechanism by which osteocytes control bone formation.
Asunto(s)
Envejecimiento/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Glucuronidasa/metabolismo , Osteocitos/metabolismo , Osteogénesis/fisiología , Animales , Densidad Ósea , Huesos/metabolismo , Huesos/patología , Diferenciación Celular , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/genética , Humanos , Inmunohistoquímica , Proteínas Klotho , Ratones , Ratones Noqueados , Osteoblastos/fisiología , Osteoclastos/fisiología , Cultivo Primario de Células , Transducción de SeñalRESUMEN
Klotho is a transmembrane protein expressed in the renal tubules where it acts as a permissive coreceptor for fibroblast growth factor 23 (FGF23). FGF23 signaling reduces the abundance of CYP27b1 and phosphate cotransporters NPT2a and NPT2c, leading to a decrease in 1,25(OH)2D3 synthesis and a rise in urinary phosphate excretion, respectively. Systemic or whole-nephron deletion of Klotho in mice results in renal FGF23 resistance characterized by high 1,25(OH)2D3 and phosphate levels and premature aging. Expression of Klotho is highest in the distal tubules, whereas 25OH vitamin D 1α hydroxylation and phosphate reabsorption predominantly occur in the proximal tubules. Currently, the segment-specific roles of Klotho in renal tubules are not fully understood. Here we have generated mice with Klotho specifically ablated from the proximal tubules using 3 different Cre mouse strains. All 3 models displayed impaired urinary phosphate excretion and increased abundance of NPT2a in the brush border membrane. Notably, hyperphosphatemia in knockout mice was mild or nonexistent under basal conditions but occurred upon high phosphate loading, indicating the presence of compensatory mechanisms. Effects on 1,25(OH)2D3 varied between mouse strains but were modest overall. Thus, Klotho expressed in the proximal tubules has a defined but limited role in renal phosphate handling in vivo.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/metabolismo , Túbulos Renales/fisiología , Fosfatos/metabolismo , Eliminación Renal , Envejecimiento Prematuro/metabolismo , Animales , Calcitriol/metabolismo , Femenino , Factor-23 de Crecimiento de Fibroblastos , Glucuronidasa/genética , Humanos , Hiperfosfatemia/sangre , Hiperfosfatemia/genética , Inmunohistoquímica , Túbulos Renales/citología , Proteínas Klotho , Ratones , Ratones Endogámicos C57BL , Fosfatos/orina , Cultivo Primario de Células , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/metabolismoRESUMEN
AIMS: The aim of this study was to evaluate the associations between bone histomorphometry and bone volume measured by dual-energy X-ray absorptiometry (DXA) in wait-listed dialysis patients. Further, the circulating markers of mineral metabolism and bone turnover were compared. MATERIAL AND METHODS: Bone biopsies were performed on 61 wait-listed dialysis patients. Plasma samples were obtained for indicators of mineral metabolism and bone turnover. Bone mineral density (BMD) was determined by DXA and bone histomorphometry was performed. RESULTS: Bone histomorphometry could be determined in 52 patients (72% men, 54% on hemodialysis and median dialysis vintage 18 months). Adynamic bone disease was present in 21% of patients and 4% had osteomalacia. High turnover bone disease (mixed uremic osteodystrophy and osteitis fibrosa) was observed in 48% of patients (17% and 31%, respectively). 10% of patients had normal bone histomorphometry while 17% had mild osteitis fibrosa. Mineralization defect was found in 33% of patients. There was a strong correlation between femoral neck (FN) T-score and histologically measured cancellous bone volume (p = 0.004), FN T-score having a good negative predictive value for low cancellous bone volume. Plasma osteocalcin levels were significantly higher in the high-turnover group and lower in the mineralization defect group (p = 0.014 and p = 0.02, respectively). CONCLUSIONS: Our study confirms the high frequency of abnormal bone histology in wait-listed dialysis patients. Low bone turnover was less common than previously reported. Noninvasive markers had a limited value for assessing bone histology, whereas femoral BMD reflected bone volume well.
Asunto(s)
Huesos/patología , Diálisis Renal , Absorciometría de Fotón , Adulto , Fosfatasa Alcalina/sangre , Biomarcadores/sangre , Biopsia/métodos , Densidad Ósea/fisiología , Enfermedades Óseas Metabólicas , Remodelación Ósea/fisiología , Huesos/metabolismo , Calcificación Fisiológica/fisiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Femenino , Fémur/patología , Humanos , Masculino , Persona de Mediana Edad , Minerales/metabolismo , Osteítis Fibrosa Quística/diagnóstico , Osteocalcina/sangre , Osteomalacia/diagnóstico , Hormona Paratiroidea/sangre , Listas de EsperaRESUMEN
AIM: Numerous biomarkers have been shown to associate with clinical endpoints in chronic kidney disease (CKD). There is limited evidence whether biomarkers improve risk prediction in relation to clinical outcomes. Our study investigates whether a small suite of key chronic kidney disease-mineral and bone disorder biomarkers could be used to enhance risk assessment in CKD. METHODS: Fetuin-A, fibroblast growth factor-23 and osteoprotegerin were measured on baseline plasma samples from 463 patients recruited to the Chronic Renal Insufficiency Standards Implementation Study. The biomarkers were analysed in relation to progression to end stage kidney disease, death and major cardiovascular events. RESULTS: Over a median follow up of 46 months (interquartile range 21-69), fibroblast growth factor-23 was associated with risk for renal replacement therapy (hazard ratio (HR) 1.35, P = 0.05, 95% confidence interval (CI) 1.001-1.820), cardiovascular events (HR 1.74 P < 0.001, 95% CI 1.303-1.305) and death (HR 1.4 P = 0.005, 95% CI 1.109-1.767). Osteoprotegerin was associated with risk for death (HR 1.06, P = 0.03, 95% CI 1.006-1.117). There was no clear association between Fetuin-A and any of the clinical endpoints. The addition of biomarkers to risk models led to marginal improvement in model discrimination and reclassification. CONCLUSION: Biomarkers are often associated with clinical endpoints, and we observed such associations in our study of patients with advanced CKD. However, the markers analysed in our study were of limited benefit in improving the prediction of these outcomes. Any extra information biomarkers may provide to improve risk prediction in clinical practice needs to be carefully balanced against the potential cost of these tools.
Asunto(s)
Factores de Crecimiento de Fibroblastos/sangre , Osteoprotegerina/sangre , Insuficiencia Renal Crónica/sangre , alfa-2-Glicoproteína-HS/análisis , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Progresión de la Enfermedad , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Curva ROC , Diálisis Renal , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/terapia , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
Klotho acts as a co-receptor for and dictates tissue specificity of circulating FGF23. FGF23 inhibits PTH secretion, and reduced Klotho abundance is considered a pathogenic factor in renal secondary hyperparathyroidism. To dissect the role of parathyroid gland resident Klotho in health and disease, we generated mice with a parathyroid-specific Klotho deletion (PTH-KL(-/-)). PTH-KL(-/-) mice had a normal gross phenotype and survival; normal serum PTH and calcium; unaltered expression of the PTH gene in parathyroid tissue; and preserved PTH response and sensitivity to acute changes in serum calcium. Their PTH response to intravenous FGF23 delivery or renal failure did not differ compared to their wild-type littermates despite disrupted FGF23-induced activation of the MAPK/ERK pathway. Importantly, calcineurin-NFAT signaling, defined by increased MCIP1 level and nuclear localization of NFATC2, was constitutively activated in PTH-KL(-/-) mice. Treatment with the calcineurin-inhibitor cyclosporine A abolished FGF23-mediated PTH suppression in PTH-KL(-/-) mice whereas wild-type mice remained responsive. Similar results were observed in thyro-parathyroid explants ex vivo. Collectively, we present genetic and functional evidence for a novel, Klotho-independent, calcineurin-mediated FGF23 signaling pathway in parathyroid glands that mediates suppression of PTH. The presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action.
Asunto(s)
Factores de Crecimiento de Fibroblastos/genética , Proteínas de la Membrana/genética , Hormona Paratiroidea/genética , Transducción de Señal/genética , Animales , Calcineurina/metabolismo , Inhibidores de la Calcineurina , Calcio/sangre , Ciclosporina/farmacología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Riñón/metabolismo , Proteínas Klotho , Proteínas de la Membrana/metabolismo , Ratones , Glándulas Paratiroides/metabolismo , Hormona Paratiroidea/sangre , Eliminación de Secuencia , Vitamina D/metabolismoRESUMEN
BACKGROUND/AIMS: Vitamin D deficiency and elevated serum fibroblast growth factor-23 (FGF23) levels are hallmark features and surrogate markers of adverse clinical outcomes in patients with chronic kidney disease (CKD). Convection of molecules over the dialysis membrane during online hemodiafiltration (ol-HDF) increases the removal of larger waste molecules compared with traditional high-flux hemodialysis (HD). The primary aim of this study was to explore the long-term impact of ol-HDF on serum 25(OH)D and FGF23. METHOD: An observational, prospective, noncomparator study including 35 patients who were switched from HD to ol-HDF. Serum 25(OH)D and FGF23 were measured at baseline (i.e., time of switch to ol-HDF) and at 6, 12, and 24 months. RESULTS: At follow-up time points, there was a significant reduction in serum 25(OH)D compared with baseline (p<0.0001) whereas FGF23 was unaltered (p>0.05). The decrease in 25(OH)D was more prominent in individuals with higher baseline 25(OH)D levels. CONCLUSION: Ol-HDF may lower systemic 25(OH)D levels by convective mechanisms although the clinical significance remains unknown. Further controlled studies are warranted to replicate these findings in larger patient cohorts.
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Hemodiafiltración , Fallo Renal Crónico/terapia , Vitamina D/análogos & derivados , Adulto , Anciano , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Vitamina D/sangreRESUMEN
The importance of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent community-based cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=-0.52 for estimated GFR, R=0.22 for urinary albumin-to-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P<0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P<0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.
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Albuminuria/sangre , Albuminuria/epidemiología , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/epidemiología , Anciano , Biomarcadores/sangre , Estudios Transversales , Femenino , Humanos , Modelos Lineales , Masculino , Prevalencia , Estudios Prospectivos , Factores de Riesgo , SolubilidadRESUMEN
Klotho was discovered as an antiaging gene, and α-Klotho (Klotho) is expressed in multiple tissues with a broad set of biologic functions. Membrane-bound Klotho binds fibroblast growth factor 23 (FGF23), but a soluble form of Klotho is also produced by alternative splicing or cleavage of the extracellular domain of the membrane-bound protein. The relative organ-specific contributions to the levels and effects of circulating Klotho remain unknown. We explored these issues by generating a novel mouse strain with Klotho deleted throughout the nephron (Six2-KL(-/-)). Klotho shedding from Six2-KL(-/-) kidney explants was undetectable and the serum Klotho level was reduced by approximately 80% in Six2-KL(-/-) mice compared with wild-type littermates. Six2-KL(-/-) mice exhibited severe growth retardation, kyphosis, and premature death, closely resembling the phenotype of systemic Klotho knockout mice. Notable biochemical changes included hyperphosphatemia, hypercalcemia, hyperaldosteronism, and elevated levels of 1,25-dihydroxyvitamin D and Fgf23, consistent with disrupted renal Fgf23 signaling. Kidney histology demonstrated interstitial fibrosis and nephrocalcinosis in addition to absent dimorphic tubules. A direct comparative analysis between Six2-KL(-/-) and systemic Klotho knockout mice supports extensive, yet indistinguishable, extrarenal organ manifestations. Thus, our data reveal the kidney as the principal contributor of circulating Klotho and Klotho-induced antiaging traits.
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Glucuronidasa/fisiología , Riñón/metabolismo , Envejecimiento/metabolismo , Animales , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Riñón/patología , Proteínas Klotho , Masculino , Ratones NoqueadosRESUMEN
BACKGROUND: We aimed to investigate the associations between circulating endostatin and the different aspects of renal dysfunction, namely, estimated (cystatin C) glomerular filtration rate (GFR) and urine albumin-creatinine ratio (ACR). METHODS: Two independent longitudinal community-based cohorts of elderly. ULSAM, n = 786 men; age 78 years; median GFR 74 ml/min/1.73 m(2); median ACR 0.80 mg/mmol); and PIVUS, n = 815; age 75 years; 51% women; median GFR; 67 ml/min/1.73 m(2); median ACR 1.39 mg/mmol. Cross-sectional associations between the endostatin levels and GFR as well as ACR, and longitudinal association between endostatin at baseline and incident CKD (defined as GFR <60 ml/min/1.73 m(2)) were assessed. RESULTS: In cross-sectional regression analyses adjusting for age, gender, inflammation, and cardiovascular risk factors, serum endostatin was negatively associated with GFR (ULSAM: B-coefficient per SD increase -0.51, 95% CI (-0.57, -0.45), p < 0.001; PIVUS -0.47, 95% CI (-0.54, -0.41), p < 0.001) and positively associated with ACR (ULSAM: B-coefficient per SD increase 0.24, 95% CI (0.15, 0.32), p < 0.001; PIVUS 0.13, 95% CI (0.06-0.20), p < 0.001) in both cohorts. Moreover, in longitudinal multivariable analyses, higher endostatin levels were associated with increased risk for incident CKD defined as GFR <60 ml/min/1.73 m(2) at re-investigations in both ULSAM (odds ratio per SD increase of endostatin 1.39 (95% CI 1.01-1.90) and PIVUS 1.68 (95% CI 1.36-2.07)). CONCLUSIONS: Higher circulating endostatin is associated with lower GFR and higher albuminuria and independently predicts incident CKD in elderly subjects. Further studies are warranted to investigate the underlying mechanisms linking endostatin to kidney pathology, and to evaluate the clinical relevance of our findings.
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Albuminuria/orina , Creatinina/orina , Endostatinas/sangre , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica/sangre , Anciano , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Incidencia , Estudios Longitudinales , Masculino , Pronóstico , Estudios Prospectivos , Insuficiencia Renal Crónica/epidemiología , Suecia/epidemiologíaRESUMEN
The concept of chronic kidney disease-mineral bone disorder (CKD-MBD) does not appear to fulfil the requirements for a syndrome at first glance, but its definition has brought some clear-cut benefits for clinicians and patients, including wider and more complex diagnostic and therapeutic approaches to the management of this challenging set of issues. Admittedly, not all components of CKD-MBD are present in all patients at all times, but these are highly interrelated, involving mineral and bone laboratory abnormalities, clinical and histological bone disease and finally, cardiovascular disease. The presence of typical biological bone ossification processes in an ectopic anatomical location in CKD has helped to define the existence of an unprecedented bone-vascular relationship, extending its interest even to other medical specialities. For now, we believe that CKD-MBD does not reach full criteria to be defined as a syndrome. However, this novel concept has clearly influenced current clinical guidelines. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF/KDOQI™) guidelines in 2003 for instance recommended that calcium-based phosphate binders should be avoided to treat hyperphosphataemia in the presence of cardiovascular calcifications. In 2009, the KDIGO and other guidelines reinforced and extended this recommendation by stating that it is reasonable to choose oral phosphate binder therapy by taking into consideration other components of CKD-MBD. Similarly, it is also considered reasonable to use information on vascular/valvular calcification to guide the management of CKD-MBD. Our current assumption as a working group 'CKD-MBD' is that CKD-MBD has the potential to be defined a true syndrome, such as a constellation of concurrent signs and symptoms that suggest a common underlying mechanism for these components as opposed to the term disease. The term 'syndrome' also implies that in any patient at risk due to the presence of one or a few components of the entire syndrome, the screening for additional components is highly recommended. However, it has not currently been demonstrated that there is an additive predictive value, which can be derived from identifying individual components. Despite all we have learned about this putative syndrome, we have been left with only a hypothetical framework about how to treat patients. So while we agree that the concept of CKD-MBD has influenced, and continues to influence, our current clinical hypotheses, definitive proof of a benefit of interventions in CKD-MBD is still lacking and a global-multiple therapeutic approach to treat simultaneously several components of CKD-MBD should be tested by well-designed new randomized controlled trials.
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Densidad Ósea , Enfermedades Óseas Metabólicas/patología , Calcinosis/patología , Hiperfosfatemia/patología , Insuficiencia Renal Crónica/patología , Enfermedades Óseas Metabólicas/metabolismo , Calcinosis/metabolismo , Humanos , Hiperfosfatemia/metabolismo , Insuficiencia Renal Crónica/metabolismo , SíndromeRESUMEN
Fibroblast growth factor-23 (FGF23), a regulator of mineral metabolism, has been linked to cardiovascular disease in chronic kidney disease. As community-based data of the longitudinal association between FGF23 and cardiovascular events are lacking, we investigated a possible relationship in 727 men of the Uppsala Longitudinal Study of Adult Men population-based cohort (mean age 77 years). During a median follow-up of 9.7 years, 110 participants died of cardiovascular causes. In Cox regression models adjusted for age and established cardiovascular risk factors, higher serum FGF23 was associated with a significantly increased risk for cardiovascular mortality (hazard ratio (HR) per increased s.d. of 1.36). This relationship remained significant, albeit attenuated, after adjustment for glomerular filtration rate (GFR) (HR 1.21). FGF23 was also associated with all-cause mortality, although the association was weaker than that with cardiovascular mortality, and it was nonsignificant in fully adjusted multivariate models. Spline analysis suggested a log-linear relationship between FGF23 and outcome. Participants with a combination of high FGF23 (>60 pg/ml), low GFR (<60 ml/min), and micro-/macro-albuminuria (albumin/creatinine ratio above 3 mg/ml) had an almost eightfold increased risk compared with participants without these abnormalities. Thus, a higher FGF23 level is associated with an increased cardiovascular mortality risk in the community. Clinical trials are needed to determine whether FGF23 is a modifiable risk factor.
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Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Factores de Crecimiento de Fibroblastos/sangre , Características de la Residencia , Anciano , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Estudios de Cohortes , Factor-23 de Crecimiento de Fibroblastos , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Análisis de Regresión , Factores de Riesgo , Tasa de Supervivencia , Suecia/epidemiologíaRESUMEN
PURPOSE OF REVIEW: The wealth of data regarding fibroblast growth factor-23 (FGF23) and Klotho in chronic kidney disease (CKD) has risen exponentially over the past decade. This review is an attempt to summarize pivotal aspects of previous research, provide an update of recent findings and define important areas for future investigation. RECENT FINDINGS: The phosphaturic hormone FGF23 increases dramatically as renal function declines. Identification of contributing stimuli to the rise in FGF23 is fundamental and recent evidence suggest a multifactorial cause which entails perturbed osteocyte function and renal mechanisms such as Klotho deficiency and, somewhat paradoxically, systemic Klotho excess. Circulating FGF23 predicts adverse outcomes, particularly cardiovascular disease, in CKD as well as in the general population. The concept of FGF23 merely as a biomarker and regulator of mineral metabolism is currently challenged by data linking FGF23 to pathological processes such as cardiac hypertrophy. Conversely, tissue level of the FGF23 coreceptor Klotho declines in early CKD and this deficiency is linked to accelerated ageing, cellular senescence, vascular calcification, oxidative stress and renal fibrosis. At present, methodological difficulties limit the utility of soluble Klotho measurements. Animal proof-of-concept studies have demonstrated beneficial effects of Klotho delivery in CKD, whereas anti-FGF23 therapy using neutralizing antibodies improved biochemical and bone parameters at the expense of increased vascular calcification and mortality. SUMMARY: Pathological alterations of FGF23-Klotho in CKD are implicated as clinical biomarkers and may provide novel therapeutic strategies to alleviate the cardiovascular risk and slow CKD progression.