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

BACKGROUND: Metabolic syndrome (MetS) and chronic kidney disease (CKD) are commonly associated with cardiovascular disease (CVD) and in these patients Mg concentration is usually decreased. This study evaluated 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.

The Role of Disturbed Mg Homeostasis in Chronic Kidney Disease Comorbidities.

Some of the critical mechanisms that mediate chronic kidney disease (CKD) progression are associated with vascular calcifications, disbalance of mineral metabolism, increased oxidative and metabolic stress, inflammation, coagulation abnormalities, endothelial dysfunction, or accumulation of uremic toxins. Also, it is widely accepted that pathologies with a strong influence in CKD progression are diabetes, hypertension, and cardiovascular disease (CVD). A disbalance in magnesium (Mg) homeostasis, more specifically hypomagnesemia, is associated with the development and progression of the comorbidities mentioned above, and some mechanisms might explain why low serum Mg is associated with negative clinical outcomes such as major adverse cardiovascular and renal events. Furthermore, it is likely that hypomagnesemia causes the release of inflammatory cytokines and C-reactive protein and promotes insulin resistance. Animal models have shown that Mg supplementation reverses vascular calcifications; thus, clinicians have focused on the potential benefits that Mg supplementation may have in humans. Recent evidence suggests that Mg reduces coronary artery calcifications and facilitates peripheral vasodilation. Mg may reduce vascular calcification by direct inhibition of the Wnt/ß-catenin signaling pathway. Furthermore, Mg deficiency worsens kidney injury induced by an increased tubular load of phosphate. One important consequence of excessive tubular load of phosphate is the reduction of renal tubule expression of α-Klotho in moderate CKD. Low Mg levels worsen the reduction of Klotho induced by the tubular load of phosphate. Evidence to support clinical translation is yet insufficient, and more clinical studies are required to claim enough evidence for decision-making in daily practice. Meanwhile, it seems reasonable to prevent and treat Mg deficiency. This review aims to summarize the current understanding of Mg homeostasis, the potential mechanisms that may mediate the effect of Mg deficiency on CKD progression, CVD, and mortality.

Hemodiafiltration with ultrafiltrate regeneration reduces free light chains without albumin loss in multiple myeloma patients.

BACKGROUND: Acute kidney injury (AKI) occurs in 12-20% of multiple myeloma (MM) patients. Several studies have shown a reduction of free light chains (FLC) using hemodialysis with High-Cut-Off membranes. However, this technique entails albumin loss. Hemodiafiltration with ultrafiltrate regeneration is a technique that includes a process of adsorption. The aim of this study was to evaluate the effectiveness of hemodiafiltration with ultrafiltrate regeneration in reducing FLC levels without causing albumin loss. METHODS: This is an observational study (2012 to 2018) including nine patients with MM (5 kappa, 4 lambda) and AKI. All patients were treated with chemotherapy and hemodiafiltration with ultrafiltrate regeneration. Blood Samples (pre and post-dialysis) and ultrafiltrate were collected pre and post-resin at 5 min after initiation of the session and 5 min before the end of the procedure. RESULTS: The serum levels of kappa and lambda were reduced by a 57.6 ± 10% and 33.5 ± 25% respectively. Serum albumin concentration remained unchanged after the procedure. In the ultrafiltrate, the mean FLC reduction ratio shortly after initiation of the dialysis procedure was: 99.2 and 97.06% for kappa and lambda respectively, and only 0.7% for albumin; and at the end of the session the percent reduction was: 63.7 and 33.62% for kappa and lambda respectively, and 0.015% for albumin. Patients clinical outcome was: 33.3% recovered renal function, 22.2% died during the first year and 44.4% required maintenance dialysis. CONCLUSIONS: Hemodiafiltration with ultrafiltrate regeneration reduces FLC levels without producing a significant loss of albumin; and, FLC removal is maintained throughout the session. Therefore, hemodiafiltration with ultrafiltrate regeneration may be considered an effective adjunctive therapy in patients with MM.

Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration.

Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) in vitro and in vivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells in vitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.

FGF23, Biomarker or Target?

Fibroblast growth factor 23 (FGF23) plays a key role in the complex network between the bones and other organs. Initially, it was thought that FGF23 exclusively regulated phosphate and vitamin D metabolism; however, recent research has demonstrated that an excess of FGF23 has other effects that may be detrimental in some cases. The understanding of the signaling pathways through which FGF23 acts in different organs is crucial to develop strategies aiming to prevent the negative effects associated with high FGF23 levels. FGF23 has been described to have effects on the heart, promoting left ventricular hypertrophy (LVH); the liver, leading to production of inflammatory cytokines; the bones, inhibiting mineralization; and the bone marrow, by reducing the production of erythropoietin (EPO). The identification of FGF23 receptors will play a remarkable role in future research since its selective blockade might reduce the adverse effects of FGF23. Patients with chronic kidney disease (CKD) have very high levels of FGF23 and may be the population suffering from the most adverse FGF23-related effects. The general population, as well as kidney transplant recipients, may also be affected by high FGF23. Whether the association between FGF23 and clinical events is causal or casual remains controversial. The hypothesis that FGF23 could be considered a therapeutic target is gaining relevance and may become a promising field of investigation in the future.

Increased Phosphaturia Accelerates The Decline in Renal Function: A Search for Mechanisms.

In chronic kidney disease (CKD), high serum phosphate concentration is associated with cardiovascular disease and deterioration in renal function. In early CKD, the serum phosphate concentration is normal due to increased fractional excretion of phosphate. Our premise was that high phosphate intake even in patients with early CKD would result in an excessive load of phosphate causing tubular injury and accelerating renal function deterioration. In CKD 2-3 patients, we evaluated whether increased phosphaturia accelerates CKD progression. To have a uniform group of patients with early CKD, 95 patients with metabolic syndrome without overt proteinuria were followed for 2.7 ± 1.6 years. The median decline in eGFR was 0.50 ml/min/1.73 m2/year. Patients with a more rapid decrease in eGFR had greater phosphaturia. Moreover, the rate of decrease in eGFR inversely correlated with the degree of phosphaturia. Additionally, phosphaturia independently predicted renal function deterioration. In heminephrectomized rats, a high phosphate diet increased phosphaturia resulting in renal tubular damage associated with inflammation, oxidative stress and low klotho expression. Moreover, in rats with hyperphosphatemia and metabolic syndrome antioxidant treatment resulted in attenuation of renal lesions. In HEK-293 cells, high phosphate promoted oxidative stress while melatonin administration reduced ROS generation. Our findings suggest that phosphate loading in early CKD, results in renal damage and a more rapid decrease in renal function due to renal tubular injury.

Phosphate control in reducing FGF23 levels in hemodialysis patients.

BACKGROUND: In hemodialysis patients, high levels of Fibroblast Growth Factor 23 (FGF23) predict mortality. Our study was designed to test whether the control of serum phosphate is associated with a reduction in serum FGF23 levels. Additionally other variables with a potential effect on FGF23 levels were evaluated. MATERIAL AND METHODS: The effect of sustained (40-weeks) control of serum phosphate on FGF23 levels (intact and c-terminal) was evaluated in 21 stable hemodialysis patients that were not receiving calcimimetics or active vitamin D. Patients received non-calcium phosphate binders to maintain serum phosphate below 4.5 mg/dl. In an additional analysis, values of intact-FGF23 (iFGF23) and c-terminal FGF23 (cFGF23) from 150 hemodialysis patients were correlated with parameters of mineral metabolism and inflammation. Linear mixed models and linear regression were performed to evaluate longitudinal trajectories of variables and the association between FGF23 and the other variables examined. RESULTS: During the 40-week treatment, 12 of 21 patients achieved the target of serum phosphate <4.5 mg/dl. In these 12 patients, iFGF23 decreased to less than half whereas cFGF23 did not reduce significantly. In patients with serum phosphate >4.5 mg, iFGF23 and cFGF23 increased two and four-fold respectively as compared with baseline. Furthermore, changes in serum phosphate correlated with changes in C-reactive protein (hs-CRP). In our 150 hemodialysis patients, those in the higher tertile of serum phosphate also showed increased hs-CRP, iPTH, iFGF23 and cFGF23. Multiple regression analysis revealed that iFGF23 levels directly correlated with both serum phosphate and calcium, whereas cFGF23 correlated with serum phosphate and hs-CRP but not with calcium. CONCLUSIONS: The control of serum phosphate reduced iFGF23. This reduction was also associated with a decreased in inflammatory parameters. Considering the entire cohort of hemodialysis patients, iFGF23 levels correlated directly with serum phosphate levels and also correlated inversely with serum calcium concentration. The levels of cFGF23 were closely related to serum phosphate and parameters of inflammation.

Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats.

Although magnesium has been shown to prevent vascular calcification in vitro, controlled in vivo studies in uremic animal models are limited. To determine whether dietary magnesium supplementation protects against the development of vascular calcification, 5/6 nephrectomized Wistar rats were fed diets with different magnesium content increasing from 0.1 to 1.1%. In one study we analyzed bone specimens from rats fed 0.1%, 0.3%, and 0.6% magnesium diets, and in another study we evaluated the effect of intraperitoneal magnesium on vascular calcification in 5/6 nephrectomized rats. The effects of magnesium on established vascular calcification were also evaluated in uremic rats fed on diets with either normal (0.1%) or moderately increased magnesium (0.6%) content. The increase in dietary magnesium resulted in a marked reduction in vascular calcification, together with improved mineral metabolism and renal function. Moderately elevated dietary magnesium (0.3%), but not high dietary magnesium (0.6%), improved bone homeostasis as compared to basal dietary magnesium (0.1%). Results of our study also suggested that the protective effect of magnesium on vascular calcification was not limited to its action as an intestinal phosphate binder since magnesium administered intraperitoneally also decreased vascular calcification. Oral magnesium supplementation also reduced blood pressure in uremic rats, and in vitro medium magnesium decreased BMP-2 and p65-NF-κB in TNF-α-treated human umbilical vein endothelial cells. Finally, in uremic rats with established vascular calcification, increasing dietary magnesium from 0.1% magnesium to 0.6% reduced the mortality rate from 52% to 28%, which was associated with reduced vascular calcification. Thus, increasing dietary magnesium reduced both vascular calcification and mortality in uremic rats.

Estudio prospectivo de las complicaciones asociadas a la biopsia percutánea en riñón nativo: experiencia en un centro / Prospective study of the complications associated with percutaneous renal biopsy of native kidneys: experience in a centre

Introducción: La biopsia renal percutánea (BRP) es una exploración invasiva fundamental para el estudio de enfermedades renales que lleva asociada una apreciable morbilidad. Estudios retrospectivos han mostrado que el 10-20 % de los casos presentan complicaciones menores y el 1,2-6,6 % complicaciones consideradas mayores. Sin embargo, este aspecto no ha sido examinado prospectivamente. Objetivo: El objetivo del estudio fue evaluar prospectivamente las complicaciones asociadas a la BRP en el riñón nativo. Métodos: Estudio prospectivo desde enero de 2009 hasta mayo de 2013 de las BRP realizadas por nefrólogos en riñón nativo bajo control ecográfico. Se analizaron variables clínicas y analíticas. Definimos complicación menor como la caída de la hemoglobina (Hb) de más de 1 g/dl y complicación mayor la necesidad de transfusión o técnica invasiva. Resultados: En este período se han realizado 241 BRP. La edad media de los pacientes fue de 49 años (± 17), la mayoría eran varones (56 %) y el 58,1 % padecían hipertensión arterial. Se realizaron dos punciones en el 51 %. Se observaron complicaciones menores en 46 pacientes (19,1 %) y mayores en 9 pacientes (3,7 %). En el análisis univariante, la Hb pre-BRP fue 10,3 g/dl (± 1,3) en aquellos que desarrollaron complicaciones mayores y 12,3 g/dl (± 2,2) en los demás (p = 0,003); en el análisis multivariante: OR 0,51, IC 95 %(0,2-0,9), p < 0,05. Conclusiones: La BRP es un procedimiento no exento de riesgos, ya que las complicaciones menores se presentaron en el 19,1 % y las mayores en el 3,7 % de los casos. La Hb pre-BRP es un factor de riesgo independiente para el desarrollo de complicaciones mayores (AU)

Background: Percutaneous renal biopsy (PRB) is a key invasive technique in the study of kidney disease and it is associated with considerable morbidity. Retrospective studies have shown minor complications in 10%-20% and major complications in 1.2%-6.6% of cases. However, this aspect has not been studied prospectively. Objective: The aim of our study was to prospectively assess complications related to PRB in the native kidney. Methods: From January 2009 to May 2013, we prospectively analysed PRB performed by nephrologists in native kidneys under ultrasound guidance. We analysed clinical and laboratory variables. We defined minor complications as the decrease in haemoglobin (Hb) of more than 1g/dL and major complications as the need for a transfusion or invasive technique. Results: 241 PRB were performed over this period. The mean patient age was 49 years (±17), the majority (56%) were male and 58.1% had high blood pressure. In 51% of cases, we carried out 2 punctures. There were minor complications in 46 patients (19.1%) and major complications in 9 patients (3.7%). In the univariate analysis, pre-PRB Hb was 10.3g/dL (±1.3) in patients with major complications and 12.3g/dL (±2.2) in the remaining patients (p=.003); in the multivariate analysis: OR 0.51, 95% CI (0.2-0.9),p<.05. Conclusions: PRB is a procedure that is not without risk, since minor complications occurred in 19.1% and major complications in 3.7% of cases. Pre-PRB Hb is an independent risk factor for the development of major complications (AU)

Prospective study of the complications associated with percutaneous renal biopsy of native kidneys: experience in a centre.

BACKGROUND: Percutaneous renal biopsy (PRB) is a key invasive technique in the study of kidney disease and it is associated with considerable morbidity. Retrospective studies have shown minor complications in 10%-20% and major complications in 1.2%-6.6% of cases. However, this aspect has not been studied prospectively. OBJECTIVE: The aim of our study was to prospectively assess complications related to PRB in the native kidney. METHODS: From January 2009 to May 2013, we prospectively analysed PRB performed by nephrologists in native kidneys under ultrasound guidance. We analysed clinical and laboratory variables. We defined minor complications as the decrease in haemoglobin (Hb) of more than 1g/dL and major complications as the need for a transfusion or invasive technique. RESULTS: 241 PRB were performed over this period. The mean patient age was 49 years (±17), the majority (56%) were male and 58.1% had high blood pressure. In 51% of cases, we carried out 2 punctures. There were minor complications in 46 patients (19.1%) and major complications in 9 patients (3.7%). In the univariate analysis, pre-PRB Hb was 10.3g/dL (±1.3) in patients with major complications and 12.3g/dL (±2.2) in the remaining patients (p=.003); in the multivariate analysis: OR 0.51, 95% CI (0.2-0.9), p<.05. CONCLUSIONS: PRB is a procedure that is not without risk, since minor complications occurred in 19.1% and major complications in 3.7% of cases. Pre-PRB Hb is an independent risk factor for the development of major complications.

Eficacia de la hemodiafiltración con regeneración del ultrafiltrado en la reducción de cadenas ligeras en mieloma múltiple con insuficiencia renal / Effectiveness of haemodiafiltration with ultrafiltrate regeneration in the reduction of light chains in multiple myeloma with renal failure

El fracaso renal agudo en el mieloma múltiple (MM) ocurre en un 12-20 % y es un factor de mal pronóstico para la supervivencia del paciente. Estudios recientes muestran que la diálisis con membrana "High-Cut-Off" (HCO) depura eficazmente las cadenas ligeras libres (CLL), aunque con gran pérdida de albúmina. Otras técnicas basadas en la adsorción, como la hemodiafiltración con regeneración del ultrafiltrado mediante adsorción en resina (HFR SUPRA), no han sido estudiadas. Se presentan tres casos de MM, dependientes de hemodiálisis desde el diagnóstico: dos son IgG kappa y uno IgA lambda. Los tres recibieron quimioterapia y HFR SUPRA. El objetivo del estudio fue evaluar la eficacia de la HFR SUPRA en la reducción de CLL, así como su efecto sobre la albúmina. Se obtuvieron muestras sanguíneas pre y posdiálisis y muestras de ultrafiltrado (UF) pre y posresina a los 5 minutos de empezar la sesión y 5 minutos antes de finalizar. La tasa de reducción media por sesión de CLL en sangre en los tres pacientes fue del 53 % y del 63 % (kappa) y del 38 % (lambda). En el UF la tasa de reducción media de CLL fue cercana al 99 %, tanto al inicio como al final de la diálisis, sin eliminación de albúmina. Con los resultados obtenidos podemos concluir que con esta técnica se consigue una reducción eficaz de las CLL, que se mantiene durante toda la sesión, sin que se produzca saturación de la resina y sin pérdida de albúmina. Por tanto, la HFR SUPRA es eficaz como tratamiento coadyuvante del MM (AU)

Acute kidney failure in multiple myeloma (MM) occurs in 12%-20% of patients and is a poor prognostic factor for patient survival. Recent studies have shown that dialysis with a High-Cut-Off membrane (HCO) removes free light chains (FLC) effectively although with significant albumin loss. Other adsorption-based techniques, such as haemodiafiltration with ultrafiltrate regeneration by adsorption in resin (SUPRA-HFR), have not been studied. We present three cases of MM, all haemodialysis-dependent since diagnosis. Two cases were IgG kappa and one was IgA lambda. All patients were treated with chemotherapy and SUPRA-HFR. The aim of this study was to evaluate the effectiveness of SUPRA-HFR in the reduction of FLC and its effect on albumin. We collected blood samples pre- and post-dialysis, and ultrafiltrate (UF) samples pre- and post-resin 5 minutes into the session and 5 minutes from the end. The mean reduction rate of FLC in blood per session in the three patients was 53% and 63% (kappa) and 38% (lambda). In the UF, the mean FLC reduction rate was close to 99%, both at the start and at the end of dialysis, without the removal of albumin. With the results obtained we can conclude that this technique achieves an effective reduction of FLC, which is maintained throughout the session, without resin saturation and without albumin loss. Therefore, SUPRA-HFR is effective as an adjunctive therapy for MM (AU)

Eficacia de la hemodiafiltración con regeneración del ultrafiltrado en la insuficiencia renal por mieloma múltiple / Effectiveness of haemodiafiltration with ultrafiltrate regeneration in renal failure due to multiple myeloma

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