RESUMO
Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to mark the transcription start sites of active genes. Here, we show that H3K4me3 domains that spread more broadly over genes in a given cell type preferentially mark genes that are essential for the identity and function of that cell type. Using the broadest H3K4me3 domains as a discovery tool in neural progenitor cells, we identify novel regulators of these cells. Machine learning models reveal that the broadest H3K4me3 domains represent a distinct entity, characterized by increased marks of elongation. The broadest H3K4me3 domains also have more paused polymerase at their promoters, suggesting a unique transcriptional output. Indeed, genes marked by the broadest H3K4me3 domains exhibit enhanced transcriptional consistency and [corrected] increased transcriptional levels, and perturbation of H3K4me3 breadth leads to changes in transcriptional consistency. Thus, H3K4me3 breadth contains information that could ensure transcriptional precision at key cell identity/function genes.
Assuntos
Células/metabolismo , Código das Histonas , Histonas/metabolismo , Transcrição Gênica , Animais , Inteligência Artificial , Genômica , Humanos , Lisina/metabolismo , Metilação , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , RNA Polimerase II/metabolismoRESUMO
According to current models of hematopoiesis, lymphoid-primed multi-potent progenitors (LMPPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)Flt3(hi)) and common myeloid progenitors (CMPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)CD41(hi)) establish an early branch point for separate lineage-commitment pathways from hematopoietic stem cells, with the notable exception that both pathways are proposed to generate all myeloid innate immune cell types through the same myeloid-restricted pre-granulocyte-macrophage progenitor (pre-GM) (Lin(-)Sca-1(-)c-Kit(+)CD41(-)FcγRII/III(-)CD150(-)CD105(-)). By single-cell transcriptome profiling of pre-GMs, we identified distinct myeloid differentiation pathways: a pathway expressing the gene encoding the transcription factor GATA-1 generated mast cells, eosinophils, megakaryocytes and erythroid cells, and a pathway lacking expression of that gene generated monocytes, neutrophils and lymphocytes. These results identify an early hematopoietic-lineage bifurcation that separates the myeloid lineages before their segregation from other hematopoietic-lineage potential.
Assuntos
Diferenciação Celular , Linhagem da Célula , Linfócitos/fisiologia , Células Mieloides/fisiologia , Células Progenitoras Mieloides/fisiologia , Animais , Antígenos CD/metabolismo , Células Cultivadas , Biologia Computacional , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Hematopoese , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Análise de Sequência de RNA , Análise de Célula Única , Análise Serial de Tecidos , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing1, but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing2,3. They are also the most widely used cell type for reprogramming to induced pluripotent stem (iPS) cells, a process that has implications for regenerative medicine and rejuvenation strategies4. Here we show that fibroblast cultures from old mice secrete inflammatory cytokines and exhibit increased variability in the efficiency of iPS cell reprogramming between mice. Variability between individuals is emerging as a feature of old age5-8, but the underlying mechanisms remain unknown. To identify drivers of this variability, we performed multi-omics profiling of fibroblast cultures from young and old mice that have different reprogramming efficiencies. This approach revealed that fibroblast cultures from old mice contain 'activated fibroblasts' that secrete inflammatory cytokines, and that the proportion of activated fibroblasts in a culture correlates with the reprogramming efficiency of that culture. Experiments in which conditioned medium was swapped between cultures showed that extrinsic factors secreted by activated fibroblasts underlie part of the variability between mice in reprogramming efficiency, and we have identified inflammatory cytokines, including TNF, as key contributors. Notably, old mice also exhibited variability in wound healing rate in vivo. Single-cell RNA-sequencing analysis identified distinct subpopulations of fibroblasts with different cytokine expression and signalling in the wounds of old mice with slow versus fast healing rates. Hence, a shift in fibroblast composition, and the ratio of inflammatory cytokines that they secrete, may drive the variability between mice in reprogramming in vitro and influence wound healing rate in vivo. This variability may reflect distinct stochastic ageing trajectories between individuals, and could help in developing personalized strategies to improve iPS cell generation and wound healing in elderly individuals.
Assuntos
Envelhecimento/metabolismo , Reprogramação Celular , Senescência Celular/fisiologia , Fibroblastos/metabolismo , Cicatrização , Animais , Linhagem Celular , Reprogramação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mediadores da Inflamação/metabolismo , Judeus/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Processos Estocásticos , Fatores de Tempo , Cicatrização/efeitos dos fármacosRESUMO
Combined heart-kidney transplantation (HKT) is a growing therapeutic strategy in patients with advanced heart failure (HF) and concomitant chronic kidney disease (CKD). Although patients with advanced HF and need for chronic haemodialysis have a clear indication for combined HKT, challenges to current practice lie in identifying those patients with severely depressed kidney function, which will not recover kidney function after restoration of appropriate haemodynamic conditions following heart transplantation (HT) alone. Because of the paucity of available organs, maximisation of kidney graft utility whilst minimising the operative risks associated with combined transplantation is mandatory. The benefits of HKT go beyond the mere restoration of kidney function. Data from registry analysis show that HKT improves overall survival in patients with CKD, as compared to heart transplant only, and it is associated with reduced incidence of heart allograft rejection, likely through the promotion of host immune tolerance mechanisms. In patients not requiring chronic dialysis, kidney-after-heart strategy may be explored, instead of combined HKT, in particular when the aetiology of CKD is unclear. This indeed allows for monitoring and gaging of indications for combined transplantation in the postoperative period. This approach however should be matched with priority listing for kidney transplantation given the high waitlist mortality in heart transplant recipients with associated CKD. The use of kidney machine perfusion may represent an additional tool to optimise the outcome of HKT, allowing more time to stabilise the patient after HT surgery.
Assuntos
Insuficiência Cardíaca , Transplante de Coração , Transplante de Rim , Insuficiência Renal Crônica , Humanos , Transplante de Rim/efeitos adversos , Seleção de Pacientes , Estudos Retrospectivos , Transplante de Coração/efeitos adversos , Insuficiência Cardíaca/cirurgia , Insuficiência Cardíaca/complicações , Rejeição de EnxertoRESUMO
BACKGROUND: Administrative healthcare databases are widespread and are often standardized with regard to their content and data coding, thus they can be used also as data sources for surveillance and epidemiological research. Chronic dialysis requires patients to frequently access hospital and clinic services, causing a heavy burden to healthcare providers. This also means that these patients are routinely tracked on administrative databases, yet very few case definitions for their identification are currently available. The aim of this study was to develop two algorithms derived from administrative data for identifying incident chronic dialysis patients and test their validity compared to the reference standard of the regional dialysis registry. METHODS: The algorithms are based on data retrieved from hospital discharge records (HDR) and ambulatory specialty visits (ASV) to identify incident chronic dialysis patients in an Italian region. Subjects are included if they have at least one event in the HDR or ASV databases based on the ICD9-CM dialysis-related diagnosis or procedure codes in the study period. Exclusion criteria comprise non-residents, prevalent cases, or patients undergoing temporary dialysis, and are evaluated only on ASV data by the first algorithm, on both ASV and HDR data by the second algorithm. We validated the algorithms against the Emilia-Romagna regional dialysis registry by searching for incident patients in 2014 and performed sensitivity analyses by modifying the criteria to define temporary dialysis. RESULTS: Algorithm 1 identified 680 patients and algorithm 2 identified 676 initiating dialysis in 2014, compared to 625 patients included in the regional dialysis registry. Sensitivity for the two algorithms was respectively 90.8 and 88.4%, positive predictive value 84.0 and 82.0%, and percentage agreement was 77.4 and 74.1%. CONCLUSIONS: Algorithms relying on retrieval of administrative records have high sensitivity and positive predictive value for the identification of incident chronic dialysis patients. Algorithm 1, which showed the higher accuracy and has a simpler case definition, can be used in place of regional dialysis registries when they are not present or sufficiently developed in a region, or to improve the accuracy and timeliness of existing registries.
Assuntos
Algoritmos , Diálise Renal , Bases de Dados Factuais , Feminino , Humanos , Classificação Internacional de Doenças , Itália/epidemiologiaRESUMO
BACKGROUND/AIMS: Many potentially toxic molecules accumulate in the blood during hepatic dysfunction. In clinical practice, it is very difficult to remove bilirubin, the most widely studied toxin, and particularly the unconjugated form, strongly albumin-bound. The aim of this in vitro study was to assess irreversible bilirubin adsorption as a protein-bound compound marker, using Cytosorb® (Cytosorbents Corp.), a new hemoadsorption device designed to remove cytokines. METHODS: We performed 4 in vitro experiments, dynamic and static, with different albumin-bilirubin solutions. RESULTS: All experiments showed the resin's ability to break the albumin-bilirubin complex (Experiment 1, 2), leading to efficient bilirubin removal for 24 h (Removal Rate: 90% Experiment 3) with minimal albumin loss. No sign of bilirubin release from the charged resin was detected (Experiment 4). CONCLUSION: Cytosorb® seems a promising artificial liver support, thanks to its ability to adsorb bilirubin and its proven ability to modulate the cytokines involved in hepatic dysfunction.
Assuntos
Bilirrubina/sangue , Falência Hepática/sangue , Falência Hepática/terapia , Desintoxicação por Sorção/instrumentação , Desintoxicação por Sorção/métodos , Humanos , Albumina Sérica HumanaRESUMO
BACKGROUND: A classification tree model (CT-PIRP) was developed in 2013 to predict the annual renal function decline of patients with chronic kidney disease (CKD) participating in the PIRP (Progetto Insufficienza Renale Progressiva) project, which involves thirteen Nephrology Hospital Units in Emilia-Romagna (Italy). This model identified seven subgroups with specific combinations of baseline characteristics that were associated with a differential estimated glomerular filtration rate (eGFR) annual decline, but the model's ability to predict mortality and renal replacement therapy (RRT) has not been established yet. METHODS: Survival analysis was used to determine whether CT-PIRP subgroups identified in the derivation cohort (n = 2265) had different mortality and RRT risks. Temporal validation was performed in a matched cohort (n = 2051) of subsequently enrolled PIRP patients, in which discrimination and calibration were assessed using Kaplan-Meier survival curves, Cox regression and Fine & Gray competing risk modeling. RESULTS: In both cohorts mortality risk was higher for subgroups 3 (proteinuric, low eGFR, high serum phosphate) and lower for subgroups 1 (proteinuric, high eGFR), 4 (non-proteinuric, younger, non-diabetic) and 5 (non-proteinuric, younger, diabetic). Risk of RRT was higher for subgroups 3 and 2 (proteinuric, low eGFR, low serum phosphate), while subgroups 1, 6 (non-proteinuric, old females) and 7 (non-proteinuric, old males) showed lower risk. Calibration was excellent for mortality in all subgroups while for RRT it was overall good except in subgroups 4 and 5. CONCLUSIONS: The CT-PIRP model is a temporally validated prediction tool for mortality and RRT, based on variables routinely collected, that could assist decision-making regarding the treatment of incident CKD patients. External validation in other CKD populations is needed to determine its generalizability.
Assuntos
Modelos Teóricos , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal/mortalidade , Terapia de Substituição Renal/tendências , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient.
Assuntos
Acidose Tubular Renal/genética , Proteína 1 de Troca de Ânion do Eritrócito/genética , Doenças Raras/genética , Insuficiência Renal Crônica/genética , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Perda Auditiva Neurossensorial/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Estudos Retrospectivos , Adulto JovemRESUMO
Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendants. The histone H3 lysine 4 trimethylation (H3K4me3) complex, composed of ASH-2, WDR-5 and the histone methyltransferase SET-2, regulates Caenorhabditis elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendants.
Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Epigênese Genética/genética , Padrões de Herança , Longevidade/genética , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cromatina/metabolismo , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas , Longevidade/fisiologia , Masculino , Metilação , Mutação/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linhagem , Proteína 2 de Ligação ao Retinoblastoma/genética , Proteína 2 de Ligação ao Retinoblastoma/metabolismoRESUMO
The transcription factors that control lineage specification of haematopoietic stem cells (HSCs) have been well described for the myeloid and lymphoid lineages, whereas transcriptional control of erythroid (E) and megakaryocytic (Mk) fate is less understood. We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment. FOG-1-deficient HSCs and preMegEs, the latter normally bipotent for the Mk and E lineages, underwent myeloid transcriptional reprogramming, and formed myeloid, but not erythroid and megakaryocytic cells in vitro. These results identify FOG-1 and GATA-1 as required for formation of bipotent Mk/E progenitors and their E-lineage commitment, respectively, and show that FOG-1 mediates transcriptional Mk/E programming of HSCs as well as their subsequent Mk/E-lineage commitment. Finally, C/EBPs and FOG-1 exhibited transcriptional cross-regulation in early myelo-erythroid progenitors making their functional antagonism a potential mechanism for separation of the myeloid and Mk/E lineages.
Assuntos
Eritropoese/genética , Fator de Transcrição GATA1/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Células Progenitoras de Megacariócitos e Eritrócitos/citologia , Proteínas Nucleares/fisiologia , Trombopoese/genética , Fatores de Transcrição/fisiologia , Animais , Células da Medula Óssea/citologia , Proteína beta Intensificadora de Ligação a CCAAT/deficiência , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/deficiência , Proteínas Estimuladoras de Ligação a CCAAT/genética , Linhagem da Célula , Células Cultivadas/citologia , Ensaio de Unidades Formadoras de Colônias , Células Precursoras Eritroides/citologia , Fator de Transcrição GATA1/genética , Células Progenitoras de Megacariócitos/citologia , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Transcrição GênicaRESUMO
BACKGROUND: In the USA, the increase in the prevalence of obesity in the general population has been accompanied by a marked increase in the prevalence and incidence of obesity in the dialysis population. However, secular trends of body mass index (BMI) have not been investigated in European renal registries. METHODS: We investigated the secular trend of BMI across 18 years (1994-2011) in two haemodialysis (HD) registries (Calabria in southern Italy and Emilia in northern Italy) on a total of 16 201 prevalent HD patients and in a series of 3559 incident HD patients. We compared trends in BMI for HD patients with those in the background general population of the same regions. RESULTS: The average BMI rose from 23.5 kg/m(2) in 1994 to 25.5 (+8.5%) in 2011 in the Calabria registry and from 23.7 in 1998 to 25.4 (+7.1%) in 2011 in the Emilia registry (P < 0.001). The proportion of obese patients (i.e. with BMI >30 kg/m(2)) rose from 6 to 14% in Calabria and from 6 to 16% in Emilia (P < 0.001). These patterns were fully confirmed in incident patients and were mirrored by a substantial decline in the prevalence of underweight-normal and underweight (P < 0.001) patients. Of note, the steepness of the increase in BMI in haemodialysis patients was 3.7 times more pronounced than that in the coeval, age- and sex-matched general population of Calabria and Emilia. CONCLUSIONS: In two regional haemodialysis registries in Italy a steady increase in overweight and obese patients is observed. These patterns are more pronounced than those found in the general population. If further confirmed in other European haemodialysis cohorts, these findings may have relevant public health implications.
Assuntos
Índice de Massa Corporal , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Diálise Renal/efeitos adversos , Idoso , Feminino , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Sobrepeso/etiologia , Prevalência , Sistema de RegistrosRESUMO
Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubular-interstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib-based therapy combined with high cut-off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL(-1) and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was 8 mL/min/1.73 m(2) . Serum free light chain (sFLC) median concentration was 6,040 mg L(-1) . Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3-year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI.
Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Rim/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/uso terapêutico , Diálise Renal/métodos , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Cadeias Leves de Imunoglobulina/sangue , Quimioterapia de Indução , Rim/imunologia , Rim/patologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/fisiopatologia , Indução de Remissão , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/fisiopatologia , Análise de SobrevidaRESUMO
Chronic inflammation is a complication of conventional hemodialysis that induces progressive cardiovascular damage. An apparently straightforward manipulation to treat this-removal of a large amount of uremic toxins by convection-has proven that the relationships between inflammation and convective techniques such as hemodiafiltration are more complicated than we currently understand. This Commentary addresses all the doubts and questions that lie behind the assertion that convection is the solution to the problem of inflammation in dialysis.
Assuntos
Hemodiafiltração/métodos , Inflamação/prevenção & controle , Diálise Renal/métodos , Feminino , Humanos , MasculinoRESUMO
Metabolism is influenced by age, food intake, and conditions such as diabetes and obesity. How do physiological or pathological metabolic changes influence stem cells, which are crucial for tissue homeostasis? This Commentary reviews recent evidence that stem cells have different metabolic demands than differentiated cells, and that the molecular mechanisms that control stem cell self-renewal and differentiation are functionally connected to the metabolic state of the cell and the surrounding stem cell niche. Furthermore, we present how energy-sensing signaling molecules and metabolism regulators are implicated in the regulation of stem cell self-renewal and differentiation. Finally, we discuss the emerging literature on the metabolism of induced pluripotent stem cells and how manipulating metabolic pathways might aid cellular reprogramming. Determining how energy metabolism regulates stem cell fate should shed light on the decline in tissue regeneration that occurs during aging and facilitate the development of therapies for degenerative or metabolic diseases.
Assuntos
Células-Tronco Adultas/metabolismo , Células-Tronco Embrionárias/metabolismo , Metabolismo Energético/fisiologia , Transdução de Sinais/fisiologia , Células-Tronco Adultas/citologia , Animais , Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/citologia , HumanosRESUMO
BACKGROUND: Central venous catheter (CVC) preparation for a haemodialysis (HD) session is a critical non-standardized manoeuvre. METHODS: We compared the procedure in use at our centre (C) versus the use of Haemocatch® (H), a device recently presented for the management of CVC, in 12 patients, with C during 7 dialysis sessions and H during the subsequent 7 sessions. RESULTS: Out of 75 HD sessions with C and 75 with H, both the number of connections and disconnections of the CVC via a syringe and the amount of blood wasted during the manoeuvres proved significantly lower with H (2.19 ± 0.59 for H vs. 4.23 ± 0.78 for C, p = 0.00093; 5.97 ± 2.77 ml for H vs. 14.57 ± 6.3 ml for C, p = 0.000078, respectively). CONCLUSIONS: The new device could improve the quality of care in the HD patients carrying a CVC: standardization of the procedure, reduced blood wasting and infection risk.
Assuntos
Cateterismo Venoso Central/métodos , Cateteres Venosos Centrais , Diálise Renal , Cateterismo Venoso Central/instrumentação , Humanos , Diálise Renal/métodosRESUMO
BACKGROUND & AIMS: Fractionated plasma separation and adsorption (FPSA) is an extracorporeal procedure that supports liver function by removing endogenous toxins that cause complications from acute-on-chronic liver failure (AOCLF). We performed a randomized trial to investigate survival of patients with AOCLF treated with FPSA. METHODS: Patients with AOCLF were randomly assigned to groups given a combination of FPSA and standard medical therapy (SMT) (FPSA group, n = 77) or only SMT (SMT group, n = 68). The Prometheus liver support system was used to provide 8 to 11 rounds of FPSA (minimum of 4 hours each) for 3 weeks. Primary end points were survival probabilities at days 28 and 90, irrespective of liver transplantation. RESULTS: Baseline clinical parameters and number of transplant patients were similar between study arms. Serum bilirubin level decreased significantly in the FPSA group but not in the SMT group. In an intention-to-treat analysis, the probabilities of survival on day 28 were 66% in the FPSA group and 63% in the SMT group (P = .70); on day 90, they were 47% and 38%, respectively (P = .35). Baseline factors independently associated with poor prognosis were high SOFA score, bleeding, female sex, spontaneous bacterial peritonitis, intermediate increases in serum creatinine concentration, and combination of alcoholic and viral etiology of liver disease. There were no differences between the 2 groups in the incidence of side effects. CONCLUSIONS: Among all patients with AOCLF, extracorporeal liver support with FPSA does not increase the probability of survival. Further studies are needed to assess whether therapy might be beneficial in specific subsets of patients.
Assuntos
Doença Hepática Terminal/terapia , Circulação Extracorpórea , Falência Hepática Aguda/terapia , Desintoxicação por Sorção , Adulto , Bilirrubina/sangue , Biomarcadores/sangue , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/mortalidade , Europa (Continente) , Circulação Extracorpórea/efeitos adversos , Circulação Extracorpórea/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Desintoxicação por Sorção/efeitos adversos , Desintoxicação por Sorção/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
Multiple myeloma (MM) is still one of the most common haematological diseases and is associated with a poor prognosis. It is frequently worsened by acute kidney failure that, in turn, aggravates the risk of death. In the past few years, the idea has made headway that the removal of free light chains (FLC) by means of extracorporeal blood purification systems may facilitate the recovery of renal function. Up to now, many different extracorporeal techniques have been put forward in FLC removal, such as plasma exchange, dialysis with super-flux filters, and adsorption by means of cartridge of resins. In this paper, we illustrate the use of polymethylmethacrylate (PMMA) dialysis membranes with a high adsorptive capacity (Toray BK-F; Toray Industries, Inc., Tokyo, Japan). We have evaluated light chain removal by means of an original dialysis procedure using a double-filter circuit made of PMMA working in sequential dialysis (DELETE system). The system provides satisfactory results in terms of FLC removal and, at the same time, ensures an adequate dialysis treatment (Kt/V >1.5) with significant reduction in urea, creatinine, and ß2-microglobulin. The dual PMMA filter system combines an acceptable cost/efficiency ratio when compared with other methods and constitutes a concrete prospect in FLC removal. Its preferential setting of use is in patients with MM or with monoclonal gammopathies, who are on chronic dialysis and maintain high circulating levels of FLC.
Assuntos
Hemodiafiltração/instrumentação , Hemodiafiltração/métodos , Cadeias Leves de Imunoglobulina/sangue , Mieloma Múltiplo , Polimetil Metacrilato , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Adsorção , Humanos , Mieloma Múltiplo/sangue , Mieloma Múltiplo/terapia , Paraproteinemias/sangue , Paraproteinemias/complicações , Paraproteinemias/terapia , Fatores de RiscoRESUMO
BACKGROUND: Since primary membranous nephropathy is a heterogeneous disease with variable outcomes and multiple possible therapeutic approaches, all 13 Nephrology Units of the Italian region Emilia Romagna decided to analyze their experience in the management of this challenging glomerular disease. METHODS: We retrospectively studied 205 consecutive adult patients affected by biopsy-proven primary membranous nephropathy, recruited from January 2010 through December 2017. The primary outcome was patient and renal survival. The secondary outcome was the rate of complete remission and partial remission of proteinuria. Relapse incidence, treatment patterns and adverse events were also assessed. RESULTS: Median (IQR) follow-up was 36 (24-60) months. Overall patient and renal survival were 87.4% after 5 years. At the end of follow-up, 83 patients (40%) had complete remission and 72 patients (35%) had partial remission. Among responders, less than a quarter (23%) relapsed. Most patients (83%) underwent immunosuppressive therapy within 6 months of biopsy. A cyclic regimen of corticosteroid and cytotoxic agents was the most commonly used treatment schedule (63%), followed by rituximab (28%). Multivariable analysis showed that the cyclic regimen significantly correlates with complete remission (odds ratio 0.26; 95% CI 0.08-0.79) when compared to rituximab (p < 0.05). CONCLUSIONS: In our large study, both short- and long-term outcomes were positive and consistent with those published in the literature. Our data suggest that the use of immunosuppressive therapy within the first 6 months after biopsy appears to be a winning strategy, and that the cyclic regimen also warrants a prominent role in primary membranous nephropathy treatment, since definitive proof of rituximab superiority is lacking.
RESUMO
Pontin is a highly conserved DNA helicase/ATPase which is a component of several macromolecular complexes with functions that include DNA repair, telomere maintenance and tumor suppression. While Pontin is known to be essential in yeast, fruit flies and frogs, its physiological role in mammalian organisms remains to be determined. We here find that Pontin is highly expressed in embryonic stem cells and hematopoietic tissues. Through germline inactivation of Ruvbl1, the gene encoding Pontin, we found it to be essential for early embryogenesis, as Ruvbl1 null embryos could not be recovered beyond the blastocyst stage where proliferation of the pluripotent inner cell mass was impaired. Conditional ablation of Ruvbl1 in hematopoietic tissues led to bone marrow failure. Competitive repopulation experiments showed that this included the loss of hematopoietic stem cells through apopotosis. Pontin is, therefore, essential for the function of both embryonic pluripotent cells and adult hematopoietic stem cells.