Redox Metabolism and Vascular Calcification in Chronic Kidney Disease.

Vascular calcification (VC) is a common complication in patients with chronic kidney disease which increases their mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some of the main redox regulators, such as catalase, the main scavenger of H2O2, remains unclear. In the present study, epigastric arteries of kidney transplant recipients, a rat model of VC, and an in vitro model of VC exhibiting catalase (Cts) overexpression were analysed. Pericalcified areas of human epigastric arteries had increased levels of catalase and cytoplasmic, rather than nuclear runt-related transcription factor 2 (RUNX2). In the rat model, advanced aortic VC concurred with lower levels of the H2O2-scavenger glutathione peroxidase 3 compared to controls. In an early model of calcification using vascular smooth muscle cells (VSMCs), Cts VSMCs showed the expected increase in total levels of RUNX2. However, Cts VMSCs also exhibited a lower percentage of the nucleus stained for RUNX2 in response to calcifying media. In this early model of VC, we did not observe a dysregulation of the mitochondrial redox state; instead, an increase in the general redox state was observed in the cytoplasm. These results highlight the complex role of antioxidant enzymes as catalase by regulation of RUNX2 subcellular location delaying the onset of VC.

Experimental Models to Study Diabetes Mellitus and Its Complications: Limitations and New Opportunities.

Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the pathophysiological and molecular mechanisms involved in its development are not fully clarified, and there is no treatment to cure DM. This review will focus on the features, advantages and limitations of some of the most used DM models in rats, such as the spontaneous models: Bio-Breeding Diabetes-Prone (BB-DP) and LEW.1AR1-iddm, as representative models of type 1 DM (DM-1); the Zucker diabetic fatty (ZDF) and Goto-kakizaki (GK) rats, as representative models of type 2 DM (DM-2); and other models induced by surgical, dietary and pharmacological-alloxan and streptozotocin-procedures. Given the variety of DM models in rats, as well as the non-uniformity in the protocols and the absence of all the manifestation of the long-term multifactorial complications of DM in humans, the researchers must choose the one that best suits the final objectives of the study. These circumstances, added to the fact that most of the experimental research in the literature is focused on the study of the early phase of DM, makes it necessary to develop long-term studies closer to DM in humans. In this review, a recently published rat DM model induced by streptozotocin injection with chronic exogenous administration of insulin to reduce hyperglycaemia has also been included in an attempt to mimic the chronic phase of DM in humans.

Effects of a Losartan-Antioxidant Hybrid (GGN1231) on Vascular and Cardiac Health in an Experimental Model of Chronic Renal Failure.

Drugs providing antihypertensive and protective cardiovascular actions are of clinical interest in controlling cardiovascular events and slowing the progression of kidney disease. We studied the effect of a hybrid compound, GGN1231 (derived from losartan in which a powerful antioxidant was attached), on the prevention of cardiovascular damage, cardiac hypertrophy, and fibrosis in a rat model of severe chronic renal failure (CRF). CRF by a 7/8 nephrectomy was carried out in male Wistar rats fed with a diet rich in phosphorous (0.9%) and normal calcium (0.6%) for a period of 12 weeks until sacrifice. In week 8, rats were randomized in five groups receiving different drugs including dihydrocaffeic acid as antioxidant (Aox), losartan (Los), dihydrocaffeic acid+losartan (Aox+Los) and GGN1231 as follows: Group 1 (CRF+vehicle group), Group 2 (CRF+Aox group), Group 3 (CRF+Los group), Group 4 (CRF+Aox+Los group), and Group 5 (CRF+GGN1231 group). Group 5, the CRF+GGN1231 group, displayed reduced proteinuria, aortic TNF-α, blood pressure, LV wall thickness, diameter of the cardiomyocytes, ATR1, cardiac TNF-α and fibrosis, cardiac collagen I, and TGF-ß1 expression. A non-significant 20% reduction in the mortality was also observed. This study showed the possible advantages of GGN1231, which could help in the management of cardiovascular and inflammatory processes. Further research is needed to confirm and even expand the positive aspects of this compound.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part I: non-small cell lung cancer and breast cancer

Oligometastatic disease (OMD) defines a cancer status that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While diagnostic imaging tools have considerably improved in recent years, unidentified micrometastases can still evade current detection techniques, allowing the disease to progress. The various OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of early disease control. In view of increasing OMD detection rates in current real-world clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies might translate into promising treatment options. This expert review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of non-small cell lung cancer and breast cancer (Part I), and prostate cancer and colorectal cancer (Part II), aiming to offer specialists a pragmatic framework to help improve patient management (AU)

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part II: prostate cancer and colorectal cancer

Oligometastatic disease (OMD) defines a status of cancer that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While imaging diagnostic tools have considerably improved in recent years, unidentified micrometastases can still escape from current detection techniques allowing disease to progress. The variety of OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of an early disease control. Based on increasing detection rates of OMD in the current real clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies may translate into promising treatment options. This experts’ review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of Non-Small Cell Lung Cancer and Breast Cancer (Part I), and Prostate Cancer and Colorectal Cancer (Part II), aiming to offer specialists a pragmatic framework that might contribute to the improved management of patients (AU)

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part II: prostate cancer and colorectal cancer.

Oligometastatic disease (OMD) defines a status of cancer that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While imaging diagnostic tools have considerably improved in recent years, unidentified micrometastases can still escape from current detection techniques allowing disease to progress. The variety of OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of an early disease control. Based on increasing detection rates of OMD in the current real clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies may translate into promising treatment options. This experts' review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of Non-Small Cell Lung Cancer and Breast Cancer (Part I), and Prostate Cancer and Colorectal Cancer (Part II), aiming to offer specialists a pragmatic framework that might contribute to the improved management of patients.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part I: non-small cell lung cancer and breast cancer.

Oligometastatic disease (OMD) defines a cancer status that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While diagnostic imaging tools have considerably improved in recent years, unidentified micrometastases can still evade current detection techniques, allowing the disease to progress. The various OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of early disease control. In view of increasing OMD detection rates in current real-world clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies might translate into promising treatment options. This expert review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of non-small cell lung cancer and breast cancer (Part I), and prostate cancer and colorectal cancer (Part II), aiming to offer specialists a pragmatic framework to help improve patient management.

The type of Setophaga ruficoronata (Kaup 1851) is a hybrid: implications for the taxonomy of Myioborus warblers (Passeriformes: Parulidae).

Hybridization, rapid diversification, and uncertainties surrounding type specimens add complexity to the already intricate taxonomy of high Andean Myioborus warblers of northern South America. In this study, we propose a reassessment of species boundaries within M. ornatus and M. melanocephalus, drawing on comparisons of name-bearing types. We also consider insights from a recent study of a hybrid zone in southern Colombia and northern Ecuador. We present three species delimitation alternatives that offer improved clarity compared to the current taxonomy, and discuss the rationale behind recognizing chrysops and bairdi as distinct species while redefining the species ornatus and melanocephalus, given the available evidence.

Útero bicorporeo - doble cérvix con embarazo gemelar en una sola cavidad uterina: reporte de caso / Bicorporeo uterus - double cervix with twin pregnancy in a single uterine cavity: case report

El embarazo gemelar en una de las cavidades uterinas del útero bicorpóreo es una rara presentación clínica. La viabilidad de este tipo de embarazo es de baja probabilidad, dado que esta malformación puede condicionar parto prematuro, placentación anormal, restricción del crecimiento fetal o progresión anormal del trabajo de parto. Se presenta un caso de un útero bicorpóreo con doble cérvix y una gestación gemelar en unas de las cavidades uterinas, con muerte fetal de uno de los fetos y parto pretérmino de 28 semanas del otro gemelo. Dada la rareza de la presentación se describen el caso y los hallazgos imagenológicos representativos.

Twin pregnancy in one of the uterine cavities of the bicoporous uterus is a rare clinical presentation. The viability of this type of pregnancy is unlikely since this malformation can lead to premature delivery, abnormal placentation, fetal growth restriction or abnormal progression of labor. We present a case of bicoporous uterus with double cervix with twin pregnancy in one of the uterine cavities, with stillbirth of one of the fetuses and preterm delivery of the other twin at 28 weeks. Given the rarity of the presentation, the case and representative imaging findings are described.

Evaluación de un modelo explicativo del riesgo suicida con base en factores familiares / Evaluation of an explanatory model of suicide risk based on family factors

Resumen El suicidio es una problemática de salud mental de alto impacto en la sociedad actual, tanto en el mundo como en Colombia. Dentro de las conceptualizaciones modernas como el modelo socioecológico de la prevención del suicidio, se ha reconocido que los factores familiares son determinantes muy importantes del riesgo y la protección. El presente estudio tuvo como propósito evaluar un modelo explicativo del riesgo por ideación suicida en adolescentes que involucre las dimensiones de socialización parental y la funcionalidad familiar percibida, así como establecer la influencia del estilo de socialización de padres y madres. Para tales objetivos, se desarrolló un estudio cuantitativo, de alcance explicativo y de corte transversal. A una muestra de 268 adolescentes de 12 a 16 años, el 51.9 % de sexo femenino y 48.1 % masculino, ubicados en la ciudad de Valledupar, Colombia, se aplicó la Escala de socialización parental en la adolescencia (ESPA-29), el APGAR Familiar y la Escala de Ideación Suicida BECK-HF. Mediante SPSS 25 y AMOS 25 se evaluaron cinco modelos explicativos diferentes. El modelo de mejores indicadores de bondad de ajuste (χ. = 22.2, p = .022, CMINDF = 2.023, CFI = .968, TLI = .919, NFI = .942, RMSEA = .061) establece una influencia de la aceptación/implicación de ambos padres sobre el funcionamiento familiar, lo que reduce el nivel de ideación suicida. En este último, también inciden directamente la edad y la coerción/imposición del padre. Como conclusión, se demuestra la importancia del funcionamiento familiar, de las conductas de apoyo y afecto de la dimensión aceptación/implicación, pues presentan un efecto protector ante el riesgo suicida. De igual manera, los datos ponen de relieve que las conductas de coerción/imposición del padre, mas no de la madre, fueron un factor de riesgo. Como limitante de este estudio se presenta la no inclusión de otros factores en el modelo que podrían influir en el riesgo suicida, por lo que se sugiere realizar investigaciones que tengan en cuenta estos otros factores a nivel social e intrapersonales, pero con evaluaciones desde el modelo explicativo, que poco se evidencia en la literatura científica.

Abstract Suicide is a high-impact mental health problem in today's society, both in the world and in Colombia: in fact, epidemiological data shows that there has been an upward trend in the suicide rate both in the country and in the city of Valledupar, which is the local context of interest. On the other hand, within modern conceptualizations such as the socio-ecological model of suicide prevention, it has been recognized that family factors are very important determinants of risk and protection. The different investigations reviewed as antecedents show congruently that family dysfunction as well as coercive paternal socialization behaviors are risk factors for suicide. Likewise, adequate family functionality and parental acceptance, and involvement behaviors are protective factors. Similarly, different studies have shown that older adolescents and females are at greater risk of suicidal behavior. The purpose of this study was to evaluate an explanatory model of the risk of suicidal ideation, which involved the dimensions of parental socialization and perceived family functionality, as well as to establish the influence of the parents' socialization style, based on the findings of previous studies. For this purpose, a quantitative, explanatory and cross-sectional study was developed. The ESPA-29, the APGAR and the BECK-HF Suicidal Ideation Scale were applied to a sample of 268 adolescents from the city of Valledupar, Colombia. A simple random sampling was used for the selection of participants within a neighborhood of the city of Valledupar. The sample consisted of 51.9 % female and 48.1 % male adolescents. The approval of the parents was obtained through an informed consent of the legal representative, as well as an informed consent for the adolescents, which complies with the characteristics requested by the Colegio Colombiano de Psicólogos. Using SPSS 25 and AMOS 25, five different explanatory models were evaluated, with a SEM modeling-Path Analysis. The model of best goodness of fit indicators (χ. = 22.2, p = .022, CMINDF = 2.023, CFI = .968, TLI = .919, NFI = .942, RMSEA = .061) establishes an influence of acceptance/involvement of both parents on family functioning, which reduces the level of suicidal ideation; age and coercion/imposition of the father also directly affect the latter. The data demonstrate the importance of family functioning and of supportive and affective behaviors of the acceptance/involvement dimension, since they present a protective effect against suicidal risk. In the same way, the data shows that the coercion/imposition behaviors of the father, but not the mother, were a risk factor. Although the father's authoritarian style did predict a greater risk of suicidal ideation, it was the indulgent style, and not the authoritative style, that presented the lowest risk. Although the measurements obtained by this research do not allow us to unambiguously explain why this difference occurs between the study's findings and what is suggested by the scientific literature regarding maternal and paternal styles of socialization in the face of suicide, there are possible determining factors for the results. The possibility is raised that, at a cultural level, beliefs about the maternal role in families in the Colombian Caribbean region, which arise from a formation of matrilocal families, influence the perception of greater acceptability of punishment by the mother towards their children. On the other hand, there is the lack of evidence of significant differences in terms of suicide risk according to sex. Some directions are suggested for future research, mainly to broaden the research spectrum on the role of the family in suicide prevention and to corroborate in the context of the Colombian Caribbean region the finding about the absence of effect of coercion/imposition behaviors carried out by the mother.

Vitamin D Treatment Prevents Uremia-Induced Reductions in Aortic microRNA-145 Attenuating Osteogenic Differentiation despite Hyperphosphatemia.

In chronic kidney disease, systemic inflammation and high serum phosphate (P) promote the de-differentiation of vascular smooth muscle cells (VSMC) to osteoblast-like cells, increasing the propensity for medial calcification and cardiovascular mortality. Vascular microRNA-145 (miR-145) content is essential to maintain VSMC contractile phenotype. Because vitamin D induces aortic miR-145, uremia and high serum P reduce it and miR-145 directly targets osteogenic osterix in osteoblasts, this study evaluated a potential causal link between vascular miR-145 reductions and osterix-driven osteogenic differentiation and its counter-regulation by vitamin D. Studies in aortic rings from normal rats and in the rat aortic VSMC line A7r5 exposed to calcifying conditions corroborated that miR-145 reductions were associated with decreases in contractile markers and increases in osteogenic differentiation and calcium (Ca) deposition. Furthermore, miR-145 silencing enhanced Ca deposition in A7r5 cells exposed to calcifying conditions, while miR-145 overexpression attenuated it, partly through increasing α-actin levels and reducing osterix-driven osteogenic differentiation. In mice, 14 weeks after the induction of renal mass reduction, both aortic miR-145 and α-actin mRNA decreased by 80% without significant elevations in osterix or Ca deposition. Vitamin D treatment from week 8 to 14 fully prevented the reductions in aortic miR-145 and attenuated by 50% the decreases in α-actin, despite uremia-induced hyperphosphatemia. In conclusion, vitamin D was able to prevent the reductions in aortic miR-145 and α-actin content induced by uremia, reducing the alterations in vascular contractility and osteogenic differentiation despite hyperphosphatemia.

Racial differences in early adolescent substance use: Child abuse types and family/peer substance use as predictors.

This study examined the associations among child abuse types, family/peer substance use, and adolescent substance use, as well as testing whether these associations vary by race. The sample was derived from the Longitudinal Studies of Child Abuse and Neglect (N = 562). Child sexual abuse, family substance use, and peer substance use were associated with a higher likelihood of adolescent substance use. Sexual abuse was more strongly associated with substance use in Black youth than in White youth. Conversely, greater peer substance use had a stronger association with substance use in White youth than in Black youth.

Community modeling reveals the importance of elevation and land cover in shaping migratory bird abundance in the Andes.

The tropical Andes are characterized by extreme topographic and climatic complexity, which has likely contributed to their outstanding current species diversity, composed of many range-restricted species. However, little is known about how the distribution and abundance of highly mobile organisms, like long-distance migratory birds, varies across different land covers, elevations, and climatic conditions within the Andes. We conducted 1,606 distance-sampling point counts across the Colombian Andes, spanning elevations from 253 to 3,708 m, a range of precipitation regimes and representative land covers. We then employed a novel application of a multispecies hierarchical modeling approach to evaluate how elevation, local land cover, aboveground woody biomass, cloud cover, precipitation, and seasonality in precipitation shape the abundance of the migratory land bird community in the Andes. We detected 1,824 individuals of 29 species of migratory land birds, six of which were considered incidental in our study region. We modeled the abundance of the remaining 23 species, while considering observer and time of day effects on detectability. We found that both elevation and land cover had an overriding influence on the abundance of migratory species across the Andes, with strong evidence for a mid-elevation peak in abundance, and species-specific responses to both variables. As a community, migratory birds had the highest mean abundance in shade coffee plantations, secondary forest, and mature forest. Aboveground woody biomass did not affect the abundance of all species as a group, but a few showed strong responses to this variable. Contrary to predictions of a positive correlation between abundance and precipitation, we found no evidence for community-level responses to precipitation, aside for a weak tendency for birds to select areas with intermediate levels of precipitation. This novel use of a multispecies model sheds new light on the mechanisms shaping the winter distribution of migratory birds and highlights the importance of elevation and land cover types over climatic variables in the context of the Colombian Andes.

Contribución de fósforo y PTH al desarrollo de hipertrofia y fibrosis cardíaca en un modelo experimental de insuficiencia renal crónica / Contribution of phosphorus and PTH to the development of cardiac hypertrophy and fibrosis in an experimental model of chronic renal failure

Antecedentes y objetivo: Mantener niveles adecuados de fósforo sérico en el paciente con enfermedad renal crónica es fundamental para su correcto manejo clínico. Sin embargo resulta difícil su control de forma aislada porque normalmente se asocian con aumentos séricos de hormona paratiroidea (PTH). En el presente estudio se analizaron los efectos de la hiperfosfatemia aislada, en presencia de PTH elevada y normal, sobre la inflamación, hipertrofia y fibrosis cardíaca en un modelo de insuficiencia renal experimental. Materiales y métodos: Se formaron cuatro grupos de ratas. A dos grupos se les realizó paratiroidectomía total (PTx). A las ratas con Ca < 7,5 mg/dL y PTH < 50 pg/mL se les realizó nefrectomía 7/8 (IRC) y se les colocó un pellet subcutáneo que libera PTH 1-34 (5 μg/kg/día). Un grupo recibió dieta con P normal (PN) (grupo IRC + PTx + rPTH + PN) y otro dieta con P alto (0,9% PA) (grupo IRC + PTx + rPTH + PA). Otros dos grupos que solo tenían IRC recibieron dieta PN (IRC + PN) y PA (IRC + PA). Se añadió también un grupo SHAM para nefrectomía y paratiroidectomía. Tras 14 semanas las ratas fueron sacrificadas. Resultados: Los grupos con dieta alta en fósforo (IRC + PA e IRC + PTx + rPTH + PA) tuvieron una reducción significativa del aclaramiento de creatinina y también del peso corporal, con un aumento del fósforo sérico independientemente de la paratiroidectomía, pero no así con los niveles séricos de calcio, FGF23 y de calcitriol que fueron 2-3 veces superiores en el grupo con hiperparatiroidismo secundario (IRC + PA). El diámetro de los cardiomiocitos fue superior en el grupo IRC + PA, mientras la paratiroidectomía (IRC + PTx + rPTH + PA) los redujo significativamente, a pesar de los elevados y similares valores de fósforo sérico. El TNF-α, Adam17 y la fibrosis cardíaca a nivel histológico y molecular mostraron un patrón similar con aumentos en el grupo con hiperparatiroidismo secundario severo (IRC + PA). (AU)

Background and objective: Adequate serum phosphorus levels in patients with chronic kidney disease is essential for their clinical management. However, the control of hyperphosphatemia is difficult because is normally associated with increases in serum PTH. In the present study, the effects of hyperphosphatemia, in the presence of elevated and normal PTH, on cardiac inflammation, hypertrophy and fibrosis in an experimental renal failure model were analyzed. Materials and methods: Four groups of rats were formed. Two groups underwent total parathyroidectomy (PTx). Rats with Ca < 7.5 mg/dL and PTH < 50 pg/mL underwent 7/8 nephrectomy (CRF) and a subcutaneous pellet was placed that releases PTH 1-34 (5 μg/kg/day). One group received a diet with normal P (NP) (CRF + PTx + rPTH + NP group) and another with a high P diet (0.9% HP) (CRF + PTx + rPTH + HP group). Other two groups that only had CRF received NP (CRF + NP) and HP (CRF + HP) diet. A SHAM group for nephrectomy and parathyroidectomy was also added. After 14 weeks the rats were sacrificed. Results: The groups with a diet high in phosphorus (CRF + H A and CRF + PTx + rPTH + HP) had a significant reduction in creatinine clearance and also in body weight with an increase in serum phosphorus regardless of parathyroidectomy, but not serum levels of calcium, FGF23 and calcitriol that were 2-3 times higher in the group with secondary hyperparathyroidism (CRF + HP). The diameter of the cardiomyocytes was greater in the CRF + HP group, while parathyroidectomy (CRF + PTx + rPTH + HP) significantly reduced them, despite the high and similar serum phosphorus values. TNF-α, Adam17 and cardiac fibrosis at the histological and molecular level showed a similar pattern with increases in the group with severe secondary hyperparathyroidism (CRF + HP). (AU)

Digest: Selection for staggered pollen release as a driver of heteranthery.

Why do some flowers have stamens of different shapes and sizes? Focusing on a group of Neotropical flowering plants, Dellinger et al. tackled this question and found that the evolution of heteranthery, contrary to the predominant view, is not strictly related to pollen-reward pollination and selection for division of labor between stamens. Moreover, they found support for the idea that selection for staggered pollen release might lead to heteranthery.

Contribution of phosphorus and PTH to the development of cardiac hypertrophy and fibrosis in an experimental model of chronic renal failure. / Contribución de fósforo y PTH al desarrollo de hipertrofia y fibrosis cardíaca en un modelo experimental de insuficiencia renal crónica.

BACKGROUND AND OBJECTIVE: Adequate serum phosphorus levels in patients with chronic kidney disease is essential for their clinical management. However, the control of hyperphosphatemia is difficult because is normally associated with increases in serum PTH. In the present study, the effects of hyperphosphatemia, in the presence of elevated and normal PTH, on cardiac inflammation, hypertrophy and fibrosis in an experimental renal failure model were analyzed. MATERIALS AND METHODS: Four groups of rats were formed. Two groups underwent total parathyroidectomy (PTx). Rats with Ca < 7.5 mg/dL and PTH < 50 pg/mL underwent 7/8 nephrectomy (CRF) and a subcutaneous pellet was placed that releases PTH 1-34 (5 µg/kg/day). One group received a diet with normal P (NP) (CRF + PTx + rPTH + NP group) and another with a high P diet (0.9% HP) (CRF + PTx + rPTH + HP group). Other two groups that only had CRF received NP (CRF + NP) and HP (CRF + HP) diet. A SHAM group for nephrectomy and parathyroidectomy was also added. After 14 weeks the rats were sacrificed. RESULTS: The groups with a diet high in phosphorus (CRF + H A and CRF + PTx + rPTH + HP) had a significant reduction in creatinine clearance and also in body weight with an increase in serum phosphorus regardless of parathyroidectomy, but not serum levels of calcium, FGF23 and calcitriol that were 2-3 times higher in the group with secondary hyperparathyroidism (CRF + HP). The diameter of the cardiomyocytes was greater in the CRF + HP group, while parathyroidectomy (CRF + PTx + rPTH + HP) significantly reduced them, despite the high and similar serum phosphorus values. TNF-α, Adam17 and cardiac fibrosis at the histological and molecular level showed a similar pattern with increases in the group with severe secondary hyperparathyroidism (CRF + HP). CONCLUSIONS: Hyperphosphatemia confirmed its importance in the genesis of secondary hyperparathyroidism, but also of kidney damage that was independent of PTH levels. However, inflammation, fibrosis, and cardiomyocyte growth were more closely related to PTH levels, since in the presence of similar severe hyperphosphatemia, parathyroidectomy reduced the values of inflammatory parameters, cardiac hypertrophy, and fibrosis.

Role of the RANK/RANKL/OPG and Wnt/ß-Catenin Systems in CKD Bone and Cardiovascular Disorders.

In the course of chronic kidney disease (CKD), alterations in the bone-vascular axis augment the risk of bone loss, fractures, vascular and soft tissue calcification, left ventricular hypertrophy, renal and myocardial fibrosis, which markedly increase morbidity and mortality rates. A major challenge to improve skeletal and cardiovascular outcomes in CKD patients requires a better understanding of the increasing complex interactions among the main modulators of the bone-vascular axis. Serum parathyroid hormone (PTH), phosphorus (P), calcium (Ca), fibroblast growth factor 23 (FGF23), calcidiol, calcitriol and Klotho are involved in this axis interact with RANK/RANKL/OPG system and the Wnt/ß-catenin pathway. The RANK/RANKL/OPG system controls bone remodeling by inducing osteoblast synthesis of RANKL and downregulating OPG production and it is also implicated in vascular calcification. The complexity of this system has recently increased due the discovery of LGR4, a novel RANKL receptor involved in bone formation, but possibly also in vascular calcification. The Wnt/ß-catenin pathway plays a key role in bone formation: when this pathway is activated, bone is formed, but when it is inhibited, bone formation is stopped. In the progression of CKD, a downregulation of the Wnt/ß-catenin pathway has been described which occurs mainly through the not coincident elevations of sclerostin, Dickkopf1 (Dkk1) and the secreted Frizzled Related Proteins (sFRPs). This review analyzes the interactions of PTH, P, Ca, FGF23, calcidiol, calcitriol and Klotho with the RANKL/RANKL/OPG system and the Wnt/ß-catenin, pathway and their implications in bone and cardiovascular disorders in CKD.

Effects of calcitriol and paricalcitol on renal fibrosis in CKD.

BACKGROUND: In chronic kidney disease, the activation of the renin-angiotensin-aldosterone system (RAAS) and renal inflammation stimulates renal fibrosis and the progression to end-stage renal disease. The low levels of vitamin D receptor (VDR) and its activators (VDRAs) contribute to worsen secondary hyperparathyroidism and renal fibrosis. METHODS: The 7/8 nephrectomy model of experimental chronic renal failure (CRF) was used to examine the anti-fibrotic effects of treatment with two VDRAs, paricalcitol and calcitriol, at equivalent doses (3/1 dose ratio) during 4 weeks. RESULTS: CRF increased the activation of the RAAS, renal inflammation and interstitial fibrosis. Paricalcitol treatment reduced renal collagen I and renal interstitial fibrosis by decreasing the activation of the RAAS through renal changes in renin, angiotensin receptor 1 (ATR1) and ATR2 mRNAs levels and renal inflammation by decreasing renal inflammatory leucocytes (CD45), a desintegrin and metaloproteinase mRNA, transforming growth factor beta mRNA and protein, and maintaining E-cadherin mRNA levels. Calcitriol showed similar trends without significant changes in most of these biomarkers. CONCLUSIONS: Paricalcitol effectively attenuated the renal interstitial fibrosis induced by CRF through a combination of inhibitory actions on the RAAS, inflammation and epithelial/mesenchymal transition.

Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences.

Fibrosis is a process characterized by an excessive accumulation of the extracellular matrix as a response to different types of tissue injuries, which leads to organ dysfunction. The process can be initiated by multiple and different stimuli and pathogenic factors which trigger the cascade of reparation converging in molecular signals responsible of initiating and driving fibrosis. Though fibrosis can play a defensive role, in several circumstances at a certain stage, it can progressively become an uncontrolled irreversible and self-maintained process, named pathological fibrosis. Several systems, molecules and responses involved in the pathogenesis of the pathological fibrosis of chronic kidney disease (CKD) will be discussed in this review, putting special attention on inflammation, renin-angiotensin system (RAS), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, microRNAs (miRs), and the vitamin D hormonal system. All of them are key factors of the core and regulatory pathways which drive fibrosis, having a great negative kidney and cardiac impact in CKD.