Phosphorus restriction prevents rapamycin-induced kidney damage in rats.

INTRODUCTION: There are conflicting reports about the effect or rapamycin on the kidneys. Rapamycin is known to promote phosphaturia that may be associated to renal injury. METHODS: Detailed histopathological studies were performed on the kidneys of rats with normal (Control) and reduced (Nx) renal mass that were treated with rapamycin (1.3 mg/kg for 22 days) or placebo. The effect of rapamycin was also evaluated in Control and Nx rats fed different amounts of phosphorus: 0.6% P (NP), 1.2% P (HP) and 0.2% P (LP). Quantitative scores of kidney lesions were obtained for: interstitial nephritis (IN), tubular damage (TD), and nephrocalcinosis (NC). RESULTS: When compared with placebo, rapamycin administration to Nx rats resulted in significant increases in IN (4.17±0.74 vs 1.51±0.53 %) and TD (14.45±1.51 vs 8.61±1.83 %). Rapamycin also increased NC both in Control (0.86±0.23 vs 0.14±0.06 %) and Nx (0.86±0.32 vs 0.15±0.14 %) rats. In Control rats receiving rapamycin, feeding HP aggravated IN (3.25±0.48 %), TD (22.47±4.56 %) and NC (3.66±0.75 %) while feeding LP prevented development of any renal lesions. In Nx rats treated with rapamycin, HP intake also increased IN (8.95±1.94 %), TD (26.86±3.95 %) and NC (2.77±0.60 %) whereas feeding LP reduced all lesions to lower levels than in rats fed NP. Rapamycin treatment increased fractional excretion of P (FEP) and an excellent correlation between scores for renal lesions and FEP was found. CONCLUSION: Rapamycin has deleterious effects on kidney pathology causing lesions that are located mainly at tubular and tubulo-interstitial level. Rapamycin-induced kidney damage is more evident in rats that already have decreased renal function and seems to be related to the phosphaturic effect of the drug. Dietary P restriction prevents kidney damage in rats treated with rapamycin.

Pyridoxal-5'-phosphate: A cost-effective treatment candidate for hypertensive patients?

OBJECTIVES: Because angiotensin (Ang) II is an essential vasoconstrictive peptide, we analyzed the impact of its post-translational modification to pyruvamide-Ang II (Ang P) by pyridoxal-5'-phosphate (PLP) on blood pressure. PLP is a less expensive vitamin B6 derivative and, therefore, could be a cost-effective drug against hypertension. METHODS: Effect of Ang P on calcium ion entry into vascular smooth muscle cells (VSMCs) was analyzed. Binding affinity of Ang P to angiotensin II type 1 receptor (AT1R) was measured. Vasoconstrictive effect of Ang P was investigated using the bioassay of isolated perfused rat kidneys. Spontaneously hypertensive rats (SHR) were administered PLP. Additionally, Wistar Kyoto rats (WKY) received Ang II and PLP. Blood pressure was measured time-dependently. RESULTS: Ang II, incubated with PLP, was post-translationally modified to Ang P. Calcium ion entry in VSMCs was significantly lower with Ang P compared to Ang II. Binding affinity of Ang P to AT1R was lower compared to Ang II. Perfusion pressure of isolated perfused rat kidneys increased less by Ang P than by Ang II. Blood pressure of SHR treated with PLP decreased significantly. Blood pressure of WKY rats treated with Ang II was increased to hypertensive values, whereas blood pressure of WKY rats cotreated with Ang II and PLP was not. CONCLUSION: PLP induces a post-translational modification of Ang II decreasing blood pressure in rats. Assuming that increased PLP intake in the form of vitamin B6 might reduce blood pressure in hypertensive patients, PLP might be a cost-effective drug against hypertension.

Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency.

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.

Cognitive Impairment Related to Chronic Kidney Disease Is Associated with a Decreased Abundance of Membrane-Bound Klotho in the Cerebral Cortex.

Cognitive impairment (CI) is a complication of chronic kidney disease (CKD) that is frequently observed among patients. The aim of this study was to evaluate the potential crosstalk between changes in cognitive function and the levels of Klotho in the brain cortex in an experimental model of CKD. To induce renal damage, Wistar rats received a diet containing 0.25% adenine for six weeks, while the control group was fed a standard diet. The animals underwent different tests for the assessment of cognitive function. At sacrifice, changes in the parameters of mineral metabolism and the expression of Klotho in the kidney and frontal cortex were evaluated. The animals with CKD exhibited impaired behavior in the cognitive tests in comparison with the rats with normal renal function. At sacrifice, CKD-associated mineral disorder was confirmed by the presence of the expected disturbances in the plasma phosphorus, PTH, and both intact and c-terminal FGF23, along with a reduced abundance of renal Klotho. Interestingly, a marked and significant decrease in Klotho was observed in the cerebral cortex of the animals with renal dysfunction. In sum, the loss in cerebral Klotho observed in experimental CKD may contribute to the cognitive dysfunction frequently observed among patients. Although further studies are required, Klotho might have a relevant role in the development of CKD-associated CI and represent a potential target in the management of this complication.

Osteoporosis management in patients with chronic kidney disease (ERCOS Study): A challenge in nephrological care.

Fracture risk assessment in patients with chronic kidney disease (CKD) has been included in the CKD-MBD ("Chronic Kidney Disease-Mineral and Bone Disorders") complex in international and national nephrology guidelines, suggesting for the first time the assessment of bone mineral density (BMD) if the results can influence therapeutic decision-making. However, there is very little information on actual clinical practice in this population. The main objective of the ERCOS (ERC-Osteoporosis) study is to describe the profile of patients with CKD G3-5D with osteoporosis (OP) and/or fragility fractures treated in specialized nephrology, rheumatology and internal medicine clinics in Spain. Fifteen centers participated and 162 patients (mostly women [71.2%] postmenopausal [98.3%]) with a median age of 77 years were included. Mean estimated glomerular filtration rate (eGFR) was 36 mL/min/1.73 m2 and 38% of the included patients were on dialysis. We highlight the high frequency of prevalent fragility fractures [37.7%), mainly vertebral (52.5%) and hip (24.6%)], the disproportionate history of patients with glomerular disease compared to purely nephrological series (corticosteroids) and undertreatment for fracture prevention, especially in nephrology consultations. This study is an immediate call to action with the dissemination of the new, more proactive, clinical guidelines, and underlines the need to standardize a coordinated and multidisciplinary care/therapeutic approach to these patients in an efficient way to avoid current discrepancies and therapeutic nihilism.

Compact, portable, automatic sample changer stick for cryostats and closed-cycle refrigerators.

Beamlines are facilities that produce and deliver highly focused and intense beams of radiation, typically x rays, synchrotron radiation, or neutrons, for scientific research purposes. Millions of dollars are spent annually to maintain and operate these scientific beamlines, oftentimes running continuously between cycles. To reduce human intervention and improve productivity, mechanical sample changers are often commissioned for use. Designing sample changers is difficult because mechanical parts can be bulky, expensive, and challenging to design for instruments with low volume access, high radiation, and cryogenic environments. We present a portable and inexpensive sample changer stick that can hold and manipulate up to four samples, specifically designed for use with cryogenic closed-cycle refrigerators. The sample changer stick enables rapid and efficient exchange of samples without manual intervention, and is compatible with standard sample mounts such as vanadium cans. The sample changer stick includes a motorized rotation and lancing mechanism, which enables the precise positioning of each sample in the neutron beam, while ensuring compatibility with the operating temperatures and vacuum conditions required for closed-cycle refrigerators. The design has been successfully tested at the VISION beamline at the Spallation Neutron Source. The mechanical action and software controls are detailed. The sample changer stick is a valuable tool for scientists working with cryogenic closed-cycle refrigerators.

Rapamycin downregulates α-klotho in the kidneys of female rats with normal and reduced renal function.

Both mTOR and α-klotho play a role in the pathophysiology of renal disease, influence mineral metabolism and participate in the aging process. The influence of mTOR inhibition by rapamycin on renal α-klotho expression is unknown. Rats with normal (controls) and reduced (Nx) renal function were treated with rapamycin, 1.3 mg/kg/day, for 22 days. The experiments were conducted with rats fed 0.6% P diet (NP) and 0.2% P diet (LP). Treatment with rapamycin promoted phosphaturia in control and Nx rats fed NP and LP. A decrease in FGF23 was identified in controls after treatment with rapamycin. In rats fed NP, rapamycin decreased mRNA α-klotho/GADPH ratio both in controls, 0.6±0.1 vs 1.1±0.1, p = 0.001, and Nx, 0.3±0.1 vs 0.7±0.1, p = 0.01. At the protein level, a significant reduction in α-klotho was evidenced after treatment with rapamycin both by Western Blot: 0.6±0.1 vs 1.0±0.1, p = 0.01, in controls, 0.7±0.1 vs 1.1±0.1, p = 0.02, in Nx; and by immunohistochemistry staining. Renal α-klotho was inversely correlated with urinary P excretion (r = -0.525, p = 0.0002). The decrease in α-klotho after treatment with rapamycin was also observed in rats fed LP. In conclusion, rapamycin increases phosphaturia and down-regulates α-klotho expression in rats with normal and decreased renal function. These effects can be observed in animals ingesting normal and low P diet.

Uremic Toxins Induce THP-1 Monocyte Endothelial Adhesion and Migration through Specific miRNA Expression.

Atherosclerosis is initiated by the activation of endothelial cells that allows monocyte adhesion and transmigration through the vascular wall. The accumulation of uremic toxins such as indoxyl sulphate (IS) and p-cresol (PC) has been associated with atherosclerosis. Currently, miRNAs play a crucial role in the regulation of monocyte activation, adhesion, and trans-endothelial migration. The aim of the present study is to evaluate the effect of IS and PC on monocyte adhesion and migration processes in monocytes co-cultured with endothelial cells as well as to determine the underlying mechanisms. The incubation of HUVECs and THP-1 cells with both IS and PC toxins resulted in an increased migratory capacity of THP-1 cells. Furthermore, the exposure of THP-1 cells to both uremic toxins resulted in the upregulation of BMP-2 and miRNAs-126-3p, -146b-5p, and -223-3p, as well as the activation of nuclear factor kappa B (NF-κB) and a decrease in its inhibitor IĸB. Uremic toxins, such as IS and PC, enhance the migratory and adhesion capacity of THP-1 cells to the vascular endothelium. These toxins, particularly PC, contribute significantly to uremia-associated vascular disease by increasing in THP-1 cells the expression of BMP-2, NF-κB, and key miRNAs associated with the development of atherosclerotic vascular diseases.

Time-Dependent Changes of Klotho and FGF-23 Levels after Kidney Transplantation: Role of Cold Ischemia Time, Renal Function and Graft Inflammation.

We investigated the evolution of serum klotho (s-Kl) and FGF-23 during the first two years post-kidney transplantation (KT), considering the cold ischemia time (CIT), glomerular filtration rate (GFR) and graft subclinical inflammation (SCI). We undertook a prospective, cohort, multicenter study of consecutive patients between April 2018 and January 2021 (with follow-up at 24 months). Subgroups were analyzed according to the median CIT (<14 vs. ≥14 h), the median GFR (≤40 vs. >40 mL/min/1.73 m2) and the presence of SCI at month 3. A total of 147 patients were included. s-Kl and fibroblast growth factor-23 (FGF-23) levels were measured at baseline and at months 3, 12 and 24. Graft biopsies (n = 96) were performed at month 3. All patients had low s-Kl levels at month 3. Patients with CIT < 14 h exhibited a significant increase in s-Kl at month 24. In patients with CIT ≥ 14 h, s-Kl at month 3 fell and lower s-Kl levels were seen at month 24. Patients with a GFR > 40 had a lesser decrease in s-Kl at month 3. FGF-23 fell significantly at months 3 and 12 in both GFR groups, a reduction maintained during follow-up. There were significant inter-group differences in s-Kl from months 3 to 24. CIT, GFR at 3 months and SCI were significantly associated with s-KI at month 3. A reduction in s-Kl at month 3 post-KT could be explained by longer CIT and delayed graft function as well as by impaired graft function. Early SCI may regulate s-Kl increase post-KT.

Clinical Characteristics and Management of Patients with Secondary Hyperparathyroidism Undergoing Hemodialysis: A Feasibility Analysis of Electronic Health Records Using Natural Language Processing.

Introduction: This study aimed to assess the feasibility of applying natural language processing (NLP) to analyze real-world data (RWD) and resolve clinical problems in patients with secondary hyperparathyroidism and chronic kidney disease undergoing hemodialysis (SHPT/CKD-HD). The primary objective was to evaluate how well the guideline-recommended analytical goals are achieved in a Spanish cohort of SHPT/CKD-HD patients based on RWD. Methods: Unstructured data in the electronic health records (EHRs) from 8 hospitals were retrospectively analyzed using the EHRead® technology, based on NLP and machine learning. Variables extracted from EHRs included demographics, CKD-related clinical characteristics, comorbidities and complications, mineral and bone disorder parameter levels, and treatments at baseline, 6-month, and 12-month follow-up. Results: A total of 623 prevalent SHPT/CKD-HD patients were identified; of those, 282 fulfilled the inclusion criteria. They were predominantly elderly males with cardiovascular comorbidities, and the first cause of CKD was diabetic nephropathy. Diagnosis of SHPT was associated with an improvement in median values for PTH, calcium, and phosphate. However, the percentage of patients with normal PTH ranges remained stable during the study period (52.8-60.4%), while the percentage of patients with within-target range serum calcium or phosphate values showed an increasing trend (43.2-60% and 38.8-50%). At baseline, 74.1% of patients were using SHPT-related medication, including at least one vitamin D or analog (63.1%), phosphate binders (46.8%), and/or calcimimetics (9.6%). Conclusions: This study represents the first attempt to use clinical NLP to analyze SHPT/CKD-HD patients based on unstructured clinical data. This methodology is useful to address clinical problems based on RWD and identified a high rate of out-of-range mineral-bone analytical values in patients with HPT/CKD-HD and an increasing trend of out-of-range values for serum calcium and phosphate.

The Nutrient Rich Food Price Index: a nutrition-relevant adaptation of the Laspeyres price index to track the cost of affordable nutrient density.

Background: The Laspeyres price index is the ratio of the current cost of a market basket of commodities or food groups relative to base period prices. Objective: To develop a nutrition-relevant version of the Laspeyres price index, using market baskets based on tertiles of the nutrient rich food (NRF9.3) nutrient density metric. Methods: Nutrient composition data for 151 foods from the 2012 Mexico national health and nutrition survey (ENSANUT) were merged with food prices and price indices from the national institute of geography and statistics (INEGI). Nutrient Rich Food Index (NRF9.3) was the measure of nutrient density. May 2012 was the base period. Nutrient rich food price index (NRFPI) values were calculated for each tertile of NRF nutrient density scores for each month between June 2011 and March 2022. Results: The market basket of foods in the top tertile of NRF nutrient density scores cost more per 100 kcal and had higher NRFPI values compared to foods in the bottom tertile. Higher NRF9.3 scores were correlated with greater monthly inflation. The NRFPI for foods in the top tertile of NRF9.3 scores was marked by seasonal price spikes, and greater volatility compared to foods in the bottom tertile. Conclusion: The present adaptation of the Laspeyres Index used market baskets defined by nutrient density tertiles instead of commodity groups. This approach allows for easier tracking of the cost of nutrient dense foods and healthful diets across geographic regions and over time. Applied to Mexico food prices prior to and during the Covid-19 pandemic, the NRFPI was sensitive to time trends, seasonality, and price fluctuations. The new tool may be useful in monitoring the rising cost of healthy foods worldwide.

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

BACKGROUND: In chronic kidney disease (CKD) patients, increased levels of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality. The relationship between FGF23 and heart hypertrophy has been documented, however, it is not known whether FGF23 has an effect on vasculature. Vascular smooth muscle cells VSMCs may exhibit different phenotypes; our hypothesis is that FGF23 favours a switch from a contractile to synthetic phenotype that may cause vascular dysfunction. Our objective was to determine whether FGF23 may directly control a change in VSMC phenotype. METHODS: This study includes in vitro, in vivo and ex vivo experiments and evaluation of patients with CKD stages 2-3 studying a relationship between FGF23 and vascular dysfunction. RESULTS: In vitro studies show that high levels of FGF23, by acting on its specific receptor FGFR1 and Erk1/2, causes a change in the phenotype of VSMCs from contractile to synthetic. This change is mediated by a downregulation of miR-221/222, which augments the expression of MAP3K2 and PAK1. miR-221/222 transfections recovered the contractile phenotype of VSMCs. Infusion of recombinant FGF23 to rats increased vascular wall thickness, with VSMCs showing a synthetic phenotype with a reduction of miR-221 expression. Ex-vivo studies on aortic rings demonstrate also that high FGF23 increases arterial stiffening. In CKD 2-3 patients, elevation of FGF23 was associated with increased pulse wave velocity and reduced plasma levels of miR-221/222. CONCLUSION: In VSMCs, high levels of FGF23, through the downregulation of miR-221/222, causes a change to a synthetic phenotype. This change in VSMCs increases arterial stiffening and impairs vascular function, which might ultimately worsen cardiovascular disease.

Affordable Nutrient Density in Brazil: Nutrient Profiling in Relation to Food Cost and NOVA Category Assignments.

Affordable nutrient density is provided by low-cost and nutrient-rich foods. We explored nutrient density, cost, and NOVA category assignments within and across food groups in Brazil. The nutrient density of the foods (n = 591) was assessed using the Nutrient Rich Food Index (NRF9.3) based on protein, fiber, vitamin A (RAE), vitamin C, vitamin E (mg), Ca, Fe, K and Mg; and NRF6.3 score for priority nutrients: Ca, Fe, Zn, vitamin A, vitamin B12, and folate. Nutrients to limit (LIM) were saturated fat, added sugar, and sodium. Affordability was defined as the ratio of energy and/or nutrient density of foods and retail price per 100 kcal. Foods were classified as minimally processed (n = 106), processed (n = 188), ultra-processed (n = 286), and culinary ingredients (n = 11). Nutrient density was positively linked to per 100 kcal food cost. Ultra-processed foods (UPF) contained more energy, fat, sugar, and salt and had lower NRF scores compared to minimally processed (MPF) foods. UPF was also less expensive than MPF foods. Nutrient-rich foods below the median per 100 kcal costs included MPF foods, but also processed foods (PF) and UPF. Affordable nutrient-rich foods can be found in the different categories of the NOVA classification.

Características clínicas de los pacientes con accidente cerebrovascular de tipo isquémico admitidos durante el periodo de ventana terapéutica en el Servicio de Urgencias del Hospital de Clínicas / Clinical characteristics of patients with ischemic stroke admitted during the therapeutic window period in the Emergency Department of the Hospital de Clinicas

Introducción: Las enfermedades cardiovasculares son la primera causa de muerte. El accidente cerebrovascular isquémico es un problema de salud pública. Objetivos: Determinar las características clínicas de los pacientes con accidente cerebrovascular de tipo isquémico admitidos durante el periodo de ventana terapéutica en el Servicio de Urgencias del Hospital de Clínicas en el periodo 2018 - 2020. Materiales y métodos: Estudio observacional, descriptivo, retrospectivo, transversal. Los sujetos fueron los pacientes de sexo masculino y femenino, mayores de 18 años admitidos en la Unidad de Ictus del Servicio de Urgencias del Hospital de Clínicas en el periodo de ventana terapéutica comprendido entre junio del año 2018 y septiembre del año 2020. Resultados: Se incluyó en el estudio 512 pacientes. La media de edad fue 65 ± 12,1 años. El sexo más frecuente fue el masculino con (58,7%) y la mayoría proceden del Departamento Central (61,3%). Los factores de riesgo más frecuentes fueron la hipertensión arterial (83,3%), el sobrepeso (34,7%) y la diabetes mellitus tipo 2 (27,3%). Presentaron infarto moderado (41,8%) y la trombólisis fue realizada en el (16%) de los pacientes. Conclusión: Los pacientes que presentaron accidente cerebrovascular de tipo isquémico admitidos en el periodo de ventana terapéutica fueron en su mayoría del sexo masculino, edad media de 65 años, los factores de riesgo cardiovasculares más frecuentes fueron la hipertensión arterial, el sobrepeso y la diabetes mellitus tipo 2, el infarto moderado fue la más frecuente y escasa cantidad recibieron trombólisis.

Introduction: Cardiovascular diseases are the leading cause of death. Ischemic stroke is a public health problem. Objectives: To determine the clinical characteristics of patients with ischemic stroke admitted during the therapeutic window period in the Emergency Department of the Hospital de Clínicas in the period 2018 - 2020. Materials and methods: Observational, descriptive, retrospective, cross-sectional study. The subjects were male and female patients, over 18 years of age admitted to the Stroke Unit of the Emergency Service of the Hospital de Clínicas in the therapeutic window period between June 2018 and September 2020. Results: Included 512 patients in the study. The mean age was 65 ± 12,1 years. The most frequent sex was male with (58.7%), most of them come from the central department (61.3%). The most frequent risk factors were arterial hypertension (83.3%), overweight (34.7%) and type 2 diabetes mellitus (27.3%). They presented moderate infarction (41,8%). Thrombolysis was performed in (16%) of the patients. Conclusion: The patients who presented ischemic stroke admitted in the therapeutic window period were mostly male, mean age 65 years, the most frequent cardiovascular risk factors were arterial hypertension, overweight and mellitus diabetes type 2, moderate infarction was the most frequent and few received thrombolysis.

Oral Acid Load Down-Regulates Fibroblast Growth Factor 23.

Increased dietary acid load has a negative impact on health, particularly when renal function is compromised. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that is elevated during renal failure. The relationship between metabolic acidosis and FGF23 remains unclear. To investigate the effect of dietary acid load on circulating levels of FGF23, rats with normal renal function and with a graded reduction in renal mass (1/2 Nx and 5/6 Nx) received oral NH4Cl for 1 month. Acid intake resulted in a consistent decrease of plasma FGF23 concentrations in all study groups when compared with their non-acidotic control: 239.3 ± 13.5 vs. 295.0 ± 15.8 pg/mL (intact), 346.4 ± 19.7 vs. 522.6 ± 29.3 pg/mL (1/2 Nx) and 988.0 ± 125.5 vs. 2549.4 ± 469.7 pg/mL (5/6 Nx). Acidosis also decreased plasma PTH in all groups, 96.5 ± 22.3 vs. 107.3 ± 19.1 pg/mL, 113.1 ± 17.3 vs. 185.8 ± 22.2 pg/mL and 504.9 ± 75.7 vs. 1255.4 ± 181.1 pg/mL. FGF23 showed a strong positive correlation with PTH (r = 0.877, p < 0.0001) and further studies demonstrated that acidosis did not influence plasma FGF23 concentrations in parathyroidectomized rats, 190.0 ± 31.6 vs. 215 ± 25.6 pg/mL. In conclusion, plasma concentrations of FGF23 are consistently decreased in rats with metabolic acidosis secondary to increased acid intake, both in animals with intact renal function and with decreased renal function. The in vivo effect of metabolic acidosis on FGF23 appears to be related to the simultaneous decrease in PTH.

Chitosan-collagen-hydroxyapatite membranes for tissue engineering.

Tissue engineering is growing in developing new technologies focused on providing effective solutions to degenerative pathologies that affect different types of connective tissues. The search for biocompatible, bioactive, biodegradable, and multifunctional materials has grown significantly in recent years. Chitosan, calcium phosphates collagen, and their combination as composite materials fulfill the required properties and could result in biostimulation for tissue regeneration. In the present work, the chitosan/collagen/hydroxyapatite membranes were prepared with different concentrations of collagen and hydroxyapatite. Cell adhesion was evaluated by MTS assay for two in vitro models. Additionally, cytotoxicity of the different membranes employing hemolysis of erythrocytes isolated from human blood was carried out. The structure of the membranes was analyzed by X-rays diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and thermal stability properties by thermogravimetric methods (TGA). The highest cell adhesion after 48 h was obtained for chitosan membranes with the highest hydroxyapatite and collagen content. All composite membranes showed good cell adhesion and low cytotoxicity, suggesting that these materials have a significant potential to be used as biomaterials for tissue engineering. Graphical abstract.

An Expert Perspective on Phosphate Dysregulation With a Focus on Chronic Hypophosphatemia.

Because of their rarity, diseases characterized by chronic hypophosphatemia can be underrecognized and suboptimally managed, resulting in poor clinical outcomes. Moreover, serum phosphate may not be measured routinely in primary care practice. Authors participated in several working sessions to advance the understanding of phosphate homeostasis and the causes, consequences, and clinical implications of chronic hypophosphatemia. Phosphate levels are regulated from birth to adulthood. Dysregulation of phosphate homeostasis can result in hypophosphatemia, which becomes chronic if phosphate levels cannot be normalized. Chronic hypophosphatemia may be underrecognized as serum phosphate measurement is not always part of routine analysis in the primary care setting and results might be misinterpreted, for instance, due to age-specific differences not being accounted for and circadian variations. Clinical consequences of chronic hypophosphatemia involve disordered endocrine regulation, affect multiple organ systems, and vary depending on patient age and the underlying disorder. Signs and symptoms of chronic hypophosphatemic diseases that manifest during childhood or adolescence persist into adulthood if the disease is inadequately managed, resulting in an accumulation of clinical deficits and a progressive, debilitating impact on quality of life. Early identification and diagnosis of patients with chronic hypophosphatemia is crucial, and clinical management should be started as soon as possible to maximize the likelihood of improving health outcomes. Furthermore, in the absence of a universally accepted description for "chronic hypophosphatemia," a definition is proposed here that aims to raise awareness of these diseases, facilitate diagnosis, and guide optimal phosphate management strategies by improving monitoring and assessment of patient response to treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Complicaciones de la nefrolitotomía percutánea como tratamiento de la litiasis renal coraliforme

RESUMEN Introducción: La nefrolitotomía percutánea es la primera opción terapéutica para la litiasis renal coraliforme. Objetivo: Caracterizar a los pacientes con complicaciones de la nefrolitotomía percutánea para el tratamiento de la litiasis renal coraliforme. Método: Se estudió una serie de 191 pacientes, operados mediante nefrolitotomía percutánea. Variables estudiadas: tipo de litiasis coraliforme, posición para la técnica, condición de libre de litiasis después de la operación, presencia de complicaciones, momento, tipo y grado según clasificación de Clavien-Dindo. Se hallaron frecuencias absolutas, relativas y se utilizó el test de ji cuadrado para determinar asociación entre variables. Resultados: El 86,9 % tenía menos de 60 años, 67,0 % eran masculinos, 61,7 % presentaba comorbilidades. La litiasis coraliforme era parcial o total (30,3 % y 46,5 %, respectivamente). En 60,2 % afectaba el riñón izquierdo; 58,1 % se operaron en supino y 70,2 % quedaron libre de litiasis con la nefrolitotomía percutánea monoterapéutica. Ocurrieron complicaciones en 19,9 %; 16,2 % fueron postoperatorias, 14,1 % infecciosas, 7,8 % Clavien-Dindo I y 5,2 % IIIb. El tipo de litiasis y la posición de la nefrolitotomía percutánea no se asociaron con las complicaciones (p> 0,05). El grado de la complicación no se relacionó con el tipo de litiasis (p> 0,05). Conclusiones: Las complicaciones postoperatorias más frecuentes son las relacionadas con la infección y el sangrado; predominan ligeramente en los pacientes con litiasis coraliformes parcial, total y en los operados en supino; el grado Clavien-Dindo de las complicaciones, es mayor en las litiasis coraliformes más complejas.

ABSTRACT Introduction: Percutaneous nephrolithotomy is the first therapeutic option for staghorn kidney stones. Objective: To characterize patients with complications of percutaneous nephrolithotomy for the treatment of staghorn renal lithiasis. Method: A series of 191 patients, operated by percutaneous nephrolithotomy, was studied. Variables studied: type of staghorn lithiasis, position for the technique, stone-free condition after the operation, presence of complications, time, type and grade according to the Clavien-Dindo classification. Absolute and relative frequencies were found and the chi-square test was used to determine the association between variables. Results: 86.9 % were less than 60 years old, 67,0 % were male, 61,7 % had comorbidities. The staghorn lithiasis was partial or total (30,3 % and 46,5 %, respectively). In 60,2 % it affected the left kidney; 58.1 % underwent supine surgery and 70,2 % were stone free with monotherapeutic percutaneous nephrolithotomy. Complications occurred in 19,9 %; 16,2 % were postoperative, 14,1 % infectious, 7,8 % Clavien-Dindo I, and 5,2 % IIIb. The type of lithiasis and the position of the percutaneous nephrolithotomy were not associated with complications (p> 0,05). The degree of complication was not related to the type of lithiasis (p> 0,05). Conclusions: The most frequent postoperative complications are those related to infection and bleeding; they slightly predominate in patients with partial and total staghorn stones and in those operated on in the supine position; the Clavien-Dindo grade of complications is higher in the more complex staghorn stones.

Predicting mortality in hemodialysis patients using machine learning analysis.

BACKGROUND: Besides the classic logistic regression analysis, non-parametric methods based on machine learning techniques such as random forest are presently used to generate predictive models. The aim of this study was to evaluate random forest mortality prediction models in haemodialysis patients. METHODS: Data were acquired from incident haemodialysis patients between 1995 and 2015. Prediction of mortality at 6 months, 1 year and 2 years of haemodialysis was calculated using random forest and the accuracy was compared with logistic regression. Baseline data were constructed with the information obtained during the initial period of regular haemodialysis. Aiming to increase accuracy concerning baseline information of each patient, the period of time used to collect data was set at 30, 60 and 90 days after the first haemodialysis session. RESULTS: There were 1571 incident haemodialysis patients included. The mean age was 62.3 years and the average Charlson comorbidity index was 5.99. The mortality prediction models obtained by random forest appear to be adequate in terms of accuracy [area under the curve (AUC) 0.68-0.73] and superior to logistic regression models (ΔAUC 0.007-0.046). Results indicate that both random forest and logistic regression develop mortality prediction models using different variables. CONCLUSIONS: Random forest is an adequate method, and superior to logistic regression, to generate mortality prediction models in haemodialysis patients.