IL-1β, TNF-α, TGF-β, and bFGF expression in bone biopsies before and after parathyroidectomy

IL-1β, TNF-α, TGF-β, and b FGF expression in bone biopsies before and after parathyroidectomy.BackgroundThere is growing evidence pointing to an involvement of cytokines and growth factors in renal osteodystrophy. In this study, the expression of interleukin-lβ (IL-1β), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and basic fibroblast growth factor (bFGF) in bone biopsies taken from uremic patients before and 1 year after parathyroidectomy (PTX) was evaluated. Biochemical features and histomorphometric outcome were also studied.MethodsIliac bone biopsies were taken before and 1 year after PTX in nine uremic patients with severe hyperparathyroidism (HPT). Immunohistochemical techniques were used to identify the expression of IL-1β, TNF-α, TGF-β, and bFGF in these bone samples.ResultsAt the time of the second bone biopsy, the mean serum total alkaline phosphatase activity was normal, whereas mean serum intact parathyroid hormone (iPTH) level was slightly above the upper limit of normal values. Histomorphometric analysis showed a decrease in resorption parameters and static bone formation parameters after PTX. Dynamically, mineral apposition rate (MAR) and mineralization surface (MS/BS) decreased significantly. There was a marked local expression of IL-1β, TNF-α, TGF-β, and bFGF in bone biopsies before PTX, particularly in fibrous tissue and resorption areas. One year after PTX, IL-1β decreased from 23.6 ± 7.5% to 9.9 ± 3.1%, TNF-α from 4.5 ± 1.5% to 0.7 ± 0.8%, TGF-β from 49.6 ± 9.8% to 15.2 ± 4.6%, and bFGF from 50.9 ± 12.7% to 12.9 ± 7.9% (P < 0.001). A significant correlation was documented between cytokines and growth factors expression in bone with iPTH levels before and after PTX (P < 0.05).ConclusionsBased on these results, we suggest that IL-1β, TNF-α, TGF-β, and bFGF are involved in bone remodeling regulation, acting as local effectors, possibly under the control of PTH

PDGF and TGF-β contribute to the natural course of human IgA glomerulonephritis

PDGF and TGF-β contribute to the natural course of human Ig-A glomerulonephritis. PDGF and TGF-β are known mediators of mesangial cell proliferation and matrix expansion. The presence of these regulatory factors was examined in 30 renal biopsies from patients with IgA glomerulonephritis (IgA-GN) at the mRNA and protein level. Normal renal tissue served as control. The mRNA expression of PDGF A/B chains, PDGF-βR and TGF-β1 was evaluated by means of RT/PCR with subsequent Southern blot hybridization and/or non-radiactive in situ hybridization. In addition, PDGF-AB/BB, PDGF-βR, TGF-β isoforms (β1, β1+2, β2+3), the small TGF-β1 latency associated peptide (TGF-β1 LAP) and the extracellular matrix proteins tenascin and decorin were analyzed by immunocytochemistry. The expression of growth factors was correlated with light microscopic and clinical features. Compared to normal control kidneys, an increased expression of PDGF-BB/PDGF-βR mRNAs and the corresponding proteins was observed in all biopsies with IgA-GN. Up-regulation was related to the degree of glomerular proliferation and the extent of fibrosing interstitial lesions. In contrast, there was a discordance between TGF-β1 mRNA and protein expression (evaluated by immunocytochemistry). In all biopsies, irrespective of the stage of the disease, abundant TGF-β1 transcripts were detected, whereas TGF-β1 immunoreactivity was expressed to a lesser degree and disclosed a more variable staining pattern. In patients with significant proliferative glomerular lesions and minor tubulointerstitial alterations, TGF-β1 positivity was confined to areas of glomerular proliferation, whereas in cases with more severe histology including sclerosing lesions TGF-β1 immunoreactivity was less prominent. The distribution and the intensity of TGF-β1 LAP staining commonly exceeded the positivity noted for TGF-β1, indicating only limited TGF-β1 activation. A decreased reactivity for tenascin accompanied the morphological features of glomerular sclerosis. The staining patterns and the fact that only very few inflammatory cells, particularly CD68 positive monocytes/macrophages, were detected in glomeruli confirm that predominantly resident glomerular cells (mesangial and endothelial cells) are the major source of up-regulated growth factor production in IgA-GN. Since the expression of PDGF-AB/BB paralleled the severity of proliferative glomerular changes, PDGF seems to represent a potential indicator of activity in this condition. It is suggested that an imbalance between PDGF and TGF-β (by restricted translation and/or activation) production contribute to the progressive nature of IgA-GN

Islet transplantation as a clinical tool: present state and future perspectives

O transplante de ilhotas é um procedimento em desenvolvimento, como alternativa para o tratamento do diabetes tipo 1 que está na fronteira entre o experimental e o clínico. É uma terapia celular na qual as células são implantadas em território diferente do fisiológico em que apenas determinado número incerto conseguirá se adaptar. Aperfeiçoar este processo para obter os mesmos resultados que no transplante de pâncreas, representa um desafio para o qual convergem contribuições da biologia celular, da imunologia e das técnicas de laboratório que se entrelaçam de maneira extremamente complexa. Este trabalho revisa a literatura expondo a evolução do procedimento, a sua metodologia atual e os resultados clínicos obtidos. As perspectivas futuras do transplante diante dos recentes avanços também são discutidas.Islet transplant is an innovative treatment for type 1 diabetic patients, which still lies between experimental and approved transplant therapy. Islet cells are seeded in a non-physiological territory where an uncertain fraction will be able to adapt and survive. Thus, the challenge lies in improving the whole procedure, employing the tools of cell biology, immunology and laboratory techniques, in order to reach the results obtained with whole organ transplant. This review describes the procedure, its progress to the present methodology and clinical results obtained. Future perspectives of islet transplantation in the light of recent biotechnological advances are also focused

Differential microRNA Profile in Operational Tolerance: A Potential Role in Favoring Cell Survival

Background: Operational tolerance (OT) is a state of graft functional stability that occurs after at least 1 year of immunosuppressant withdrawal. MicroRNAs (microRNA) are small non-coding RNAs that downregulate messenger RNA/protein expression of innumerous molecules and are critical for homeostasis. We investigated whether OT in kidney transplantation displays a differential microRNA profile, which would suggest that microRNAs participate in Operational Tolerance mechanisms, and may reveal potential molecular pathways.Methods: We first compared serum microRNA in OT (n = 8) with chronic rejection (CR) (n = 5) and healthy individuals (HI) (n = 5), using a 768-microRNA qPCR-panel. We used the Thermo Fisher Cloud computing platform to compare the levels of microRNAs in the OT group in relation to the other study groups. We performed validation experiments for miR-885-5p, by q-PCR, in a larger number of study subjects (OT = 8, CR = 12, HI = 12), as individual samples.Results: We detected a differential microRNA profile in OT vs. its opposing clinical outcome—CR—suggesting that microRNAs may integrate transplantation tolerance mechanisms. Some miRNAs were detected at higher levels in OT: miR-885-5p, miR-331-3p, miR-27a-5p vs. CR; others, we found at lower levels: miR-1233-3p, miR-572, miR-638, miR-1260a. Considering highly predicted/experimentally demonstrated targets of these miRNAs, bioinformatics analysis revealed that the granzyme B, and death receptor pathways are dominant, suggesting that cell death regulation integrates transplantation tolerance mechanisms. We confirmed higher miR-885-5p levels in OT vs. CR, and vs. HI, in a larger number of subjects.Conclusions: We propose that epigenetics mechanisms involving microRNAs may integrate human transplantation tolerance mechanisms, and regulate key members of the cell death/survival signaling. miR-885-5p could favor cell survival in OT by diminishing the levels of CRADD/RAIDD and CASP3. Nonetheless, given the nature of any complex phenomenon in humans, only cumulative data will help to determine whether this microRNA differential profile may be related to the cause or consequence of operational tolerance

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Preemptive-TIPS improves outcome in high-risk variceal bleeding : An observational study

Objective Patients admitted with acute variceal bleeding (AVB) and Child Pugh C score (CP\u2010C) or Child Pugh B plus active bleeding at endoscopy (CP\u2010B+AB) are at high risk for treatment failure, rebleeding and mortality. Preemptive TIPS (p\u2010TIPS) has been shown to improve survival in these patients but its use in clinical practice has been challenged and not routinely incorporated. The present study aimed to further validate the role of preemptive TIPS in a large number of high\u2010risk patients. Design Multicenter, international, observational study including 671 patients from 34 centers admitted for AVB and high\u2010risk of treatment failure. Patients were managed according to current guidelines and use of drugs and endoscopic therapy (D+E) or preemptive TIPS (p\u2010TIPS) was based on individual center policy. Results p\u2010TIPS in the setting of AVB is associated with a lower mortality in Child C patients compared to D+E (1 year mortality 22% vs 47% in D+E group; P=0.002). Mortality rate in CP\u2010B+AB patients was low and p\u2010TIPS did not improve it. In CP\u2010C and CP\u2010B +AB patients, p\u2010TIPS reduces treatment failure and rebleeding (1 year CIF\u2010probability of remaining free of the composite endpoint: 92% vs 74% in the D+E group; P=0.017), development of \u201cde novo\u201d or worsening of previous ascites without increasing rates of hepatic encephalopathy. Conclusion p\u2010TIPS must be the treatment of choice in CP\u2010C patients with AVB. Due to the strong benefit in preventing further bleeding and ascites, p\u2010TIPS could be a good treatment strategy for CP\u2010B+AB patients

Reimbursement of dialysis: a comparison within MERCOSUR

Los procedimientos de terapia de reemplazo renal exigen una gran volumen de recursos. Los cambios demográficos, el envejecimiento de la población y el aumento de la prevalencia de diabetes e hipertensión resultan&nbsp; en un aumento sustancial de la población con enfermedad renal en etapa terminal (ESRD). Además, el incremento en el número de nuevos casos ha ido acompañado de un incremento creciente de los costes de la Terapia de Reemplazo Renal debido al alto costo tecnológico requerido y la especialización del trabajo para realizar el tratamiento. Aunque la enfermedad renal crónica (ERC) está reconocida como un problema de salud pública mundial, cada país tiene su propia política de afrontamiento y modelo de reembolso. Este artículo examinó y comparó el reembolso de diálisis crónica en cuatro países miembros del Mercado Común del Sur (MERCOSUR), que incluye Argentina, Brasil, Paraguay y Uruguay. A partir de los análisis se pudo concluir que existen diferencias monetarias entre países en cuanto al reembolso por diálisis, pero que se atenúan al aplicar la normalización de los resultados obtenidos según el nivel de vida de cada país. En general, Brasil fue el país que mantuvo el reembolso más bajo entre los países por servicios de diálisis, y Argentina tiene un reembolso de procedimiento que incluye elementos específicos, como medicamentos, y no tiene ajustes de reembolso para diferentes grupos de pacientes o estrategias de tratamientos de diálisis no estandarizados. Los resultados obtenidos, al compararlos con la revisión de la literatura internacional que analiza los reembolsos gubernamentales por diferentes tipos de diálisis en todo el mundo, revelaron una menor tasa de reembolso en los países miembros del MERCOSUR en relación a los países de mayores ingresos.Os procedimentos de Terapia Renal Substitutiva demandam grande quantidade de recursos financeiros. Mudanças demográficas, envelhecimento da população e aumento da prevalência de diabetes e hipertensão sugerem aumento substancial na população com doença renal em estágio terminal (ESRD). Além disso, O aumento no número de novos casos tem sido acompanhado por um aumento crescente nos custos para a Terapia Renal Substitutiva devido à tecnologia de alto custo necessária e a especialização do trabalho para execução do tratamento. Apesar da doença renal crônica (DRC) ser reconhecida como um problema de saúde pública mundial, cada país possui sua própria política de enfrentamento e modelo de reembolso. Este artigo examinou e comparou o reembolso da diálise crônica em quatro países membros do Mercado Comum do Sul (MERCOSUL), que inclui Argentina, Brasil, Paraguai e Uruguai. A partir de análises, foi possível concluir que existem diferenças monetárias entre os países quanto ao reembolso para a diálise mas que são atenuadas quando aplicadas a normalização dos resultados obtidos em função do padrão de vida de cada país. Em geral, o Brasil foi o país que manteve o menor reembolso entre os países para serviços de diálise, e a Argentina tem um reembolso de procedimento que inclui elementos específicos, como medicamentos, e não possui ajustes de reembolso para grupos diferentes de pacientes nem estratégias de diálise não padronizadas.&nbsp; Os resultados obtidos, quando comparados com a revisão da literatura internacional que analisa reembolsos governamentais para diferentes modalidades de diálise em todo o mundo, revelaram menor taxa de reembolso nos países membros do MERCOSUL em relação aos países de maior renda.Medical support for chronic dialysis requires large amount of financial&nbsp;resources.&nbsp;Demographic shifts, aging of the population and increase of diabetes and hypertension prevalence&nbsp;suggest substantial rise in the end-stage renal disease (ESRD) population. In addition, this increase has been accompanied by increasing costs to the providers of treatment that holds a dominant position within dialysis market because of expensive technology&nbsp;required&nbsp;and intensity of labor in the delivery of the treatment.&nbsp;Despite chronic kidney disease (CKD) has been recognized as a worldwide public health problem, each country has&nbsp;its&nbsp;own&nbsp;public policy and its own&nbsp;reimbursement&nbsp;model. This paper&nbsp;has&nbsp;examined&nbsp;and compared reimbursement of chronic dialysis in four countries members of&nbsp;Common Market of the South (MERCOSUR),&nbsp;that includes Argentina, Brazil, Paraguay&nbsp;and&nbsp;Uruguay,&nbsp;and from analyzes it was possible to conclude that exist monetary differences among countries regarding reimbursement for dialysis that is attenuated when applied normalization of&nbsp;obtained results as a function of the living standard per country. In general, Brazil was the country that&nbsp;maintained the lowest reimbursement among countries&nbsp;to&nbsp;maintenance dialysis services&nbsp;but&nbsp;reimbursement package in Argentina include more specific elements and neither has reimbursement adjustments for specific patient groups nor nonstandard dialysis strategies. The obtained results, when compared with international literature review that compared government reimbursement for different dialysis strategy worldwide,&nbsp;reveals&nbsp;lower reimbursement rate in the countries member of MERCOSUR when it compared with&nbsp;high-income&nbsp;countries.&nbsp