Uremic Stomatitis: A Latin American Case Series and Literature Review.

BACKGROUND: Uremic stomatitis is often unfamiliar to healthcare professionals. This study presents five cases of uremic stomatitis, providing a comprehensive analysis of their demographic distribution, clinicopathological features, and management strategies based on existing literature. METHODS: Data were collected from centers across Brazil, Argentina, Venezuela, and Mexico. Electronic searches were conducted in five databases supplemented by manual scrutiny and gray literature. RESULTS: The series consisted of three men and two women with a mean age of 40.2 years. Lesions mostly appeared as white plaques, particularly on the tongue (100%). The median blood urea level was 129 mg/dL. Histopathological analysis revealed epithelial changes, including acanthosis and parakeratosis, with ballooned keratinocytes in the suprabasal region. Oral lesions resolved subsequent to hemodialysis in three cases (75%). Thirty-seven studies comprising 52 cases of uremic stomatitis have been described hitherto. Most patients were male (65.4%) with a mean age of 43.6 years. Clinically, grayish-white plaques (37.3%) and ulcers/ulcerations (28.9%) were common, particularly on the tongue (30.9%). Hemodialysis was performed on 27 individuals. The resolution rate of oral lesions was 53.3%. CONCLUSION: Earlier recognition of uremic stomatitis, possibly associated with long-term uremia, holds the potential to improve outcomes for patients with undiagnosed chronic kidney disease.

Early inflammatory changes and CC chemokine ligand-8 upregulation in the heart contribute to uremic cardiomyopathy.

Uremic cardiomyopathy is a common complication in chronic kidney disease (CKD) patients, accounting for a high mortality rate. Several mechanisms have been proposed to link CKD and cardiac alterations; however, the early cardiac modifications that occur in CKD that may trigger cardiac remodeling and dysfunction remain largely unexplored. Here, in a mouse model of CKD induced by 5/6 nephrectomy, we first analyzed the early transcriptional and inflammatory changes that occur in the heart. Five days after 5/6 nephrectomy, RNA-sequencing showed the upregulation of 54 genes in the cardiac tissue of CKD mice and the enrichment of biological processes related to immune system processes. Increased cardiac infiltration of T-CD4+ lymphocytes, myeloid cells, and macrophages during early CKD was observed. Next, since CC chemokine ligand-8 (CCL8) was one of the most upregulated genes in the heart of mice with early CKD, we investigated the effect of acute and transient CCL8 inhibition on uremic cardiomyopathy severity. An increase in CCL8 protein levels was confirmed in the heart of early CKD mice. CCL8 inhibition attenuated the early infiltration of T-CD4+ lymphocytes and macrophages to the cardiac tissue, leading to a protection against chronic cardiac fibrotic remodeling, inflammation and cardiac dysfunction induced by CKD. Altogether, our data show the occurrence of transcriptional and inflammatory changes in the heart during the early phases of CKD and identify CCL8 as a key contributor to the early cardiac inflammatory state that triggers further cardiac remodeling and dysfunction in uremic cardiomyopathy.

Uremia and Inadequate Oxygen Supply Induce Eryptosis and Intracellular Hypoxia in Red Blood Cells.

BACKGROUND/AIMS: Chronic kidney disease is frequently accompanied by anemia, hypoxemia, and hypoxia. It has become clear that the impaired erythropoietin production and altered iron homeostasis are not the sole causes of renal anemia. Eryptosis is a process of red blood cells (RBC) death, like apoptosis of nucleated cells, characterized by Ca2+ influx and phosphatidylserine (PS) exposure to the outer RBC membrane leaflet. Eryptosis can be induced by uremic toxins and occurs before senescence, thus shortening RBC lifespan and aggravating renal anemia. We aimed to assess eryptosis and intracellular oxygen levels of RBC from hemodialysis patients (HD-RBC) and their response to hypoxia, uremia, and uremic toxins uptake inhibition. METHODS: Using flow cytometry, RBC from healthy individuals (CON-RBC) and HD-RBC were subjected to PS (Annexin-V), intracellular Ca2+ (Fluo-3/AM) and intracellular oxygen (Hypoxia Green) measurements, at baseline and after incubation with uremic serum and/or hypoxia (5% O2), with or without ketoprofen. Baseline levels of uremic toxins were quantified in serum and cytosol by high performance liquid chromatography. RESULTS: Here, we show that HD-RBC have less intracellular oxygen and that it is further decreased post-HD. Also, incubation in 5% O2 and uremia triggered eryptosis in vitro by exposing PS. Hypoxia itself increased the PS exposure in HD-RBC and CON-RBC, and the addition of uremic serum aggravated it. Furthermore, inhibition of the organic anion transporter 2 with ketoprofen reverted eryptosis and restored the levels of intracellular oxygen. Cytosolic levels of the uremic toxins pCS and IAA were decreased after dialysis. CONCLUSION: These findings suggest the participation of uremic toxins and hypoxia in the process of eryptosis and intracellular oxygenation.

Uremic endothelial-derived extracellular vesicles: Mechanisms of formation and their role in cell adhesion, cell migration, inflammation, and oxidative stress.

p-Cresyl sulfate (PCS), indoxyl sulfate (IS), and inorganic phosphate (Pi) are uremic toxins found in chronic kidney disease (CKD) that are closely related to endothelial extracellular vesicles (EVs) formation. The present study aimed to understand the role of EVs and their role in cell adhesion and migration, inflammation, and oxidative stress. Human endothelial cells were treated with PCS, IS, and Pi in pre-established uremic and kinetic recommendations. EVs were characterized using scanning electron microscopy, flow cytometry, and NanoSight assays. The concentrations of EVs were established using Alamar Blue and MTT assays. Cell adhesion to extracellular matrix proteins was analyzed using an adhesion assay. Inflammation and oxidative stress were assessed by vascular cell adhesion molecule-1 expression/monocyte migration and reactive oxygen species production, respectively. The capacity of EVs to stimulate endothelial cell migration was evaluated using a wound-healing assay. Our data showed that endothelial cells stimulated with uremic toxins can induce the formation of EVs of different sizes, quantities, and concentrations, depending on the uremic toxin used. Cell adhesion was significantly (P < 0.01) stimulated in cells exposed to PCS-induced extracellular vesicles (PCSEVs) and inorganic phosphate-induced extracellular vesicles (PiEVs). Cell migration was significantly (P < 0.05) stimulated by PCSEVs. VCAM-1 expression was evident in cells treated with PCSEVs and IS-induced extracellular vesicles (ISEVs). EVs are not able to stimulate monocyte migration or oxidative stress. In conclusion, EVs may be a biomarker of endothelial injury and the inflammatory process, playing an important role in cell-to-cell communication and pathophysiological processes, although more studies are needed to better understand the mechanisms of EVs in uremia.

How do Uremic Toxins Affect the Endothelium?

Uremic toxins can induce endothelial dysfunction in patients with chronic kidney disease (CKD). Indeed, the structure of the endothelial monolayer is damaged in CKD, and studies have shown that the uremic toxins contribute to the loss of cell-cell junctions, increasing permeability. Membrane proteins, such as transporters and receptors, can mediate the interaction between uremic toxins and endothelial cells. In these cells, uremic toxins induce oxidative stress and activation of signaling pathways, including the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways leads to overexpression of proinflammatory (e.g., monocyte chemoattractant protein-1, E-selectin) and prothrombotic (e.g., tissue factor) proteins. Uremic toxins also induce the formation of endothelial microparticles (EMPs), which can lead to the activation and dysfunction of other cells, and modulate the expression of microRNAs that have an important role in the regulation of cellular processes. The resulting endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases, such as atherosclerosis and thrombotic events. Therefore, uremic toxins as well as the pathways they modulated may be potential targets for therapies in order to improve treatment for patients with CKD.

Uremia and Hypoxia Independently Induce Eryptosis and Erythrocyte Redox Imbalance.

BACKGROUND/AIMS: Red blood cell (RBC) death could contribute to anemia in chronic kidney disease (CKD) patients. Recent observational research has suggested a relationship between RBC death (eryptosis) and hypoxemia in hemodialysis patients. Thus, we studied the isolated and joint effects of a uremic toxin (indoxyl sulfate; IS) and hypoxia on RBC biology. METHODS: We incubated RBC from healthy donors with IS at concentrations of 0.01mM, 0.09mM and 0.17mM under both normoxic (21% O2) and hypoxic (5% O2) conditions for 24 hours. Eryptosis was evaluated by RBC phosphatidylserine (PS) exposure, cell volume, and cytosolic calcium which were quantified by Annexin-V+, forward scatter, and Fluo-3AM+ binding, respectively. RBC redox balance was reported by reactive oxygen species (ROS) production and intracellular reduced glutathione (GSH). Analyses were performed by flow cytometry. RESULTS: Hypoxia induced a 2-fold ROS production compared to normoxia. PS exposure and cytosolic calcium increased, while cell volume decreased by hypoxia and likewise by IS. IS increased ROS production in a dose-dependent manner under conditions of both normoxia and hypoxia. The same conditions promoted a GSH decrease with IS intensifying the hypoxia-induced effects. CONCLUSION: In summary, our results indicate that the concurrent presence of hypoxia and uremia augments RBC death and may therefore, contribute to the genesis of anemia in CKD.

Uremic neuropathy: an overview of the current literature.

INTRODUCTION: Peripheral neuropathy is a disorder that affects the cell body, axon or myelin of motor or peripheral sensory neurons and occurs in 60-100% of patients who are submitted to dialysis due to chronic kidney disease. Uremic neuropathy (UN) is attributed to the accumulation of organic waste, evident in patients with reduced glomerular filtration rate. OBJECTIVES: This review aims to make clinical characteristics of uremic neuropathy evident enabling early diagnosis and treatment. METHODS: This is a literature review of articles published on PubMed over the last 10 years using "Uremic Neuropathy" as "Title/Abstract". RESULTS: A total of nine articles that met the inclusion criteria were included. UN is a distal symmetric sensorimotor polyneuropathy that occurs due to the accumulation of uremic toxins associated with an oxidative stress-related free radical activity. Hyperkalemia is thought to play an important role in its pathophysiology. Diagnosis depends on nerve conduction studies, and treatment includes dialysis or renal transplant. CONCLUSION: Clinical presentations of UN are broad and non-specific; nonetheless, it is important to detect early changes in order to avoid its progression. The earlier UN is diagnosed and treated, the more successful are the clinical outcomes.

Role of Organic Anion Transporters in the Uptake of Protein-Bound Uremic Toxins by Human Endothelial Cells and Monocyte Chemoattractant Protein-1 Expression.

Organic anion transporters (OATs) are involved in the uptake of uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS), which play a role in endothelial dysfunction in patients with chronic kidney diseases (CKD). In this study, we investigated the role of OAT1 and OAT3 in the uptake of PCS and IS into human endothelial cells. PCS was synthesized via p-cresol sulfation and characterized using analytical methods. The cells were treated with PCS and IS in the absence and presence of probenecid (Pb), an OAT inhibitor. Cell viability was assessed using the MTT assay. The absorbed toxins were analyzed using chromatography, OAT expression using immunocytochemistry and western blot, and monocyte chemoattractant protein-1 (MCP-1) expression using enzyme-linked immunosorbent assay. Cell viability decreased after toxin treatment in a dose-dependent manner. PCS and IS showed significant internalization after 60 min treatment, while no internalization was observed in the presence of Pb, suggesting that OATs are involved in the transport of both toxins. Immunocytochemistry and western blot demonstrated OAT1 and OAT3 expression in endothelial cells. MCP-1 expression increased after toxins treatment but decreased after Pb treatment. PCS and IS uptake were mediated by OATs, and OAT blockage could serve as a therapeutic strategy to inhibit MCP-1 expression.

Effect of 1,25-(OH)2D3 and lipopolysaccharide on mononuclear cell inflammation in type 2 diabetes mellitus and diabetic nephropathy uremia.

The prevention and treatment of type-2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), which are disorders with high incidence rates, is of primary importance. In this study, we analyzed the effect of 1,25-(OH)2D3 and lipopolysaccharide (LPS) in combination with interleukin (IL)-15 on the inflammatory immune response and expression of vitamin D receptor (VDR) in mononuclear cells of T2DM and DN uremia (DNU) patients. The human acute monocytic leukemia cell line THP-1 was treated with peripheral blood serum isolated from 30 healthy controls and T2DM and DNU patients each, cultured in the presence or absence of 1,25-(OH)2D3, and subsequently treated with LPS and IL-15. The VDR mRNA and protein expression in THP-1 cells was detected by real-time polymerase chain reaction and western blot (and immunofluorescence assay), respectively, and IL-6 and IL-10 concentrations in the culture supernatant were detected by enzyme-linked immunosorbent assay. LPS treatment induced a significant decrease in VDR mRNA expression in T2DM and DNU serum-treated THP-1 cells compared to the control cells (P < 0.05). The VDR protein expression in DNU serum-treated THP-1 cells was also significantly down-regulated (P < 0.05). LPS treatment induced IL-6 secretion in serum-treated THP-1 cells (P < 0.05), while 1,25-(OH)2D3 treatment inhibited IL-6 secretion to some extent. These findings suggested that LPS down-regulates the expression of VDR in mononuclear cells of T2DM and DNU patients and induces an imbalance in the pro-inflammatory and anti-inflammatory cytokine response, while 1,25-(OH)2D3 partially reversed the effect of LPS and protected patients with T2DM and DNU.

Uremic Toxicity-Induced Eryptosis and Monocyte Modulation: The Erythrophagocytosis as a Novel Pathway to Renal Anemia.

BACKGROUND: We tested the effect of uremia on red blood cell (RBC) eryptosis, CD14++/CD16+ monocytes and erythrophagocytosis. DESIGN: RBC and monocytes from chronic kidney disease (CKD) stages 3/4 (P-CKD3/4) or hemodialysis (HD) patients and healthy controls (HCs) cells incubated with sera pools from patients with CKD stages 2/3 (S-CKD2/3) or 4/5 (S-CKD4/5) were evaluated to assess eryptosis, monocyte phenotypes and reactive oxygen species (ROS) by cytometer. Erythrophagocytosis was evaluated by subsequent co-incubation of preincubated HC-monocytes and autologous-RBC. RESULTS: HC-eryptosis (1.3 ± 0.9%) was lower than in HD (4.3 ± 0.5%) and HC-RBC incubated with S-CKD4/5 (5.6 ± 1%). CD14++/CD16+ were augmented in P-CKD3/4 (34.6 ± 8%) and HC-monocytes incubated with S-CKD4/5 (26.4 ± 7%) than in HC (5.4 ± 1%). In these cells, ROS was increased (44.5 ± 9%; control 9.6 ± 2%) and inhibited by N-acetylcysteine (25 ± 13%). Erythrophagocytosis was increased in CD14++/CD16+ (60.8 ± 10%) than in CD14++/CD16- (15.5 ± 2%). CONCLUSIONS: Sera pools from CKD patients increase eryptosis and promote a proinflammatory monocyte phenotype. Both processes increased erythrophagocytosis, thereby suggesting a novel pathway for renal anemia.

Altered Renal Expression of Relevant Clinical Drug Transporters in Different Models of Acute Uremia in Rats. Role of Urea Levels.

BACKGROUND/AIMS: Organic anion transporter 1 (Oat1) and 3 (Oat3) are organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. We investigated the effects of acute uremia on the renal expression of Oat1 and Oat3 in three in vivo experimental models of acute kidney injury (AKI): induced by ischemia, by ureteral obstruction and by the administration of HgCl2. We also evaluated the influence of urea in the expression of these transporters in proximal tubular cells suspensions. METHODS: Membranes were isolated from kidneys of each experimental group and from cell suspensions incubated with different urea concentrations. Oat1 and Oat3 expressions were performed by immunoblotting. RESULTS: A good correlation between uremia and the renal protein expression of Oat1 and Oat3 was observed in vivo. Moreover, the incubation of isolated proximal tubular cells with different concentrations of urea decreases protein expression of Oat1 and Oat3 in plasma membranes in a dose-dependent manner. CONCLUSION: The more severe the renal failure, the more important is the decrease in protein expression of the transporters in renal membranes where they are functional. The in vitro study demonstrates that urea accounts, at least in part, for the decreased expression of Oat1 and Oat3 in proximal tubule plasma membranes.

A toxina urêmica ácido guanidinicoacético inibe o metabolismo oxidativo dos neutrófilos de cães / Uremic toxin guanidine acetic acid inhibits the oxidative metabolism of neutrophils in dogs

Among the uremic toxins proven to affect the neutrophil function in humans with chronic kidney disease(CKD), guanidine compounds stand out. To achieve a clearer understanding of the mechanisms thataffect the immunity of uremic patients, the hypothesis that guanidine acetic acid (GAA) contributesto the inhibition of oxidative metabolism and an increase in neutrophil apoptosis in healthy dogswas investigated in vitro. To this end, neutrophils isolated from ten healthy dogs were incubated inpure RPMI 1640 (control) and enriched with 5 mg/L of GAA. Capillary flow cytometry was usedto quantify superoxide production in neutrophils with the probe (hydroethidine), in the presenceand absence of phorbol-12-myristate-13-acetate (PMA), in order to assess oxidative metabolism.Apoptotic indices were quantified using the Annexin V-PE system, with and without the inductiveeffect of camptothecin. Neutrophils isolated and incubated in a GAA-enriched medium producedsmaller amounts of superoxide (p 0.001) when activated with PMA, however, this inhibition ofoxidative metabolism occurred without significantly altering their viability or rate of apoptosis. Thus, the results show guanidine compounds contribute to immunosuppression in dogs with CKD.(AU)

Dentre as toxinas urêmicas que comprovadamente afetam a função neutrofílica na doença renalcrônica (DRC) em humanos, destacam-se os compostos guanidínicos. A fim de melhor entenderos mecanismos que afetam a imunidade de pacientes urêmicos, no presente estudo foi investigadain vitro a hipótese de que o composto guanidínico ácido guanidinicoacético (AGA) contribui parainibição do metabolismo oxidativo, aumentando a apoptose dos neutrófilos de cães saudáveis. Paratal, neutrófilos isolados de dez cães saudáveis foram incubados em meio de cultura RPMI 1640puro (controle) e enriquecido com 5 mg/L de AGA. Utilizando-se citometria de fluxo capilar paraa avaliação do metabolismo oxidativo, quantificou-se a produção de superóxido dos neutrófilosempregando-se a sonda hidroetidina, com e sem a presença do estímulo com acetato miristato deforbol (PMA). O índice apoptótico foi quantificado utilizando-se o sistema Anexina V-PE, com e semo efeito indutor da camptotecina. Os neutrófilos isolados e incubados em meio enriquecido com AGA,quando ativados com PMA, produziram uma menor quantidade de superóxido (p 0,001), porém talinibição do metabolismo oxidativo ocorreu sem alterar significativamente a viabilidade e a taxa deapoptose. Assim, os resultados evidenciam que os compostos guanidínicos podem contribuir paraimunossupressão de cães com DRC.(AU)

A toxina urêmica ácido guanidinicoacético inibe o metabolismo oxidativo dos neutrófilos de cães / Uremic toxin guanidine acetic acid inhibits the oxidative metabolism of neutrophils in dogs

Among the uremic toxins proven to affect the neutrophil function in humans with chronic kidney disease(CKD), guanidine compounds stand out. To achieve a clearer understanding of the mechanisms thataffect the immunity of uremic patients, the hypothesis that guanidine acetic acid (GAA) contributesto the inhibition of oxidative metabolism and an increase in neutrophil apoptosis in healthy dogswas investigated in vitro. To this end, neutrophils isolated from ten healthy dogs were incubated inpure RPMI 1640 (control) and enriched with 5 mg/L of GAA. Capillary flow cytometry was usedto quantify superoxide production in neutrophils with the probe (hydroethidine), in the presenceand absence of phorbol-12-myristate-13-acetate (PMA), in order to assess oxidative metabolism.Apoptotic indices were quantified using the Annexin V-PE system, with and without the inductiveeffect of camptothecin. Neutrophils isolated and incubated in a GAA-enriched medium producedsmaller amounts of superoxide (p 0.001) when activated with PMA, however, this inhibition ofoxidative metabolism occurred without significantly altering their viability or rate of apoptosis. Thus, the results show guanidine compounds contribute to immunosuppression in dogs with CKD.

Dentre as toxinas urêmicas que comprovadamente afetam a função neutrofílica na doença renalcrônica (DRC) em humanos, destacam-se os compostos guanidínicos. A fim de melhor entenderos mecanismos que afetam a imunidade de pacientes urêmicos, no presente estudo foi investigadain vitro a hipótese de que o composto guanidínico ácido guanidinicoacético (AGA) contribui parainibição do metabolismo oxidativo, aumentando a apoptose dos neutrófilos de cães saudáveis. Paratal, neutrófilos isolados de dez cães saudáveis foram incubados em meio de cultura RPMI 1640puro (controle) e enriquecido com 5 mg/L de AGA. Utilizando-se citometria de fluxo capilar paraa avaliação do metabolismo oxidativo, quantificou-se a produção de superóxido dos neutrófilosempregando-se a sonda hidroetidina, com e sem a presença do estímulo com acetato miristato deforbol (PMA). O índice apoptótico foi quantificado utilizando-se o sistema Anexina V-PE, com e semo efeito indutor da camptotecina. Os neutrófilos isolados e incubados em meio enriquecido com AGA,quando ativados com PMA, produziram uma menor quantidade de superóxido (p 0,001), porém talinibição do metabolismo oxidativo ocorreu sem alterar significativamente a viabilidade e a taxa deapoptose. Assim, os resultados evidenciam que os compostos guanidínicos podem contribuir paraimunossupressão de cães com DRC.

Relationship among serum creatinine, serum gastrin, calcium-phosphorus product, and uremic gastropathy in cats with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) in cats is associated with gastrointestinal signs commonly attributed to uremic gastropathy. Consequently, patients often are treated with antacids and gastrointestinal protectants. This therapeutic regimen is based on documented gastric lesions in uremic humans and dogs, but the nature and incidence of uremic gastropathy in cats are unknown. HYPOTHESIS/OBJECTIVES: Evaluate uremic gastropathy in CKD cats to facilitate refinement of medical management for gastrointestinal signs. ANIMALS: Thirty-seven CKD cats; 12 nonazotemic cats METHODS: Stomachs were evaluated for the presence of classic uremic gastropathy lesions. Histopathologic lesions were compared with serum creatinine concentrations, calcium-phosphorus product (CPP), and serum gastrin concentrations. RESULTS: Gastric ulceration, edema, and vascular fibrinoid change were not observed. The most important gastric lesions in CKD cats were fibrosis and mineralization. Sixteen CKD cats (43%) had evidence of gastric fibrosis of varying severity and 14 CKD cats (38%) had gastric mineralization. CKD cats were more likely to have gastric fibrosis and mineralization than nonazotemic controls (P = .005 and P = .021, respectively). Only cats with moderate and severe azotemia had gastric mineralization. CPP was correlated with disease severity; severely azotemic CKD cats had significantly higher CPP when compared with nonazotemic controls, and to mildly and moderately azotemic cats (P < .05). Gastrin concentrations were significantly higher in CKD cats when compared with nonazotemic controls (P = .003), but increased concentrations were not associated with gastric ulceration. CONCLUSIONS AND CLINICAL IMPORTANCE: Uremic gastropathy in CKD cats differs from that described in other species and this difference should be considered when devising medical management.

Autogenous radiocephalic hemodialysis access in patients with small caliber cephalic veins after expansion with a Fogarty catheter.

Autogenous arteriovenous fistula (AVF) is the first choice for hemodialysis access in renal failure with uremia. However, AVF cannot be performed in some patients due to small and narrow veins in the forearm. In this study, a Fogarty catheter was used to establish autogenous radiocephalic hemodialysis access in patients with small caliber cephalic veins, and the patency rate and complications of this method were observed. Sixty-seven patients with uremia were divided into a treatment group (40 cases, caliber of cephalic veins<2.5 mm) and a control group (27 cases, caliber of cephalic veins≥2.5 mm). According to ultrasound results, the treatment group received AVF after expansion with a Fogarty catheter, and the control group received traditional AVF. The fistula patency rate and complications were observed during follow-up. All patients were followed up for an average period of 18 months (range=3-36 months). AVF was successfully used in 58 patients for hemodialysis, with primary access failure in 9 cases (5 cases in the treatment group and 4 cases in the control group) due to early thrombosis. The primary and secondary patency rates 12 months after surgery in the treatment group were 64 and 72%, respectively, and those in the control group were 60 and 76%, respectively. Patients with small caliber cephalic veins can be treated with radiocephalic fistula after the caliber of cephalic veins is expanded to more than 2.5 mm with a Fogarty catheter. The long-term patency rate awaits observation in a longer follow-up period.

Thalidomide suppresses inflammation in adenine-induced CKD with uraemia in mice.

BACKGROUND: Persistent systemic inflammation has been widely recognized in patients with chronic kidney disease (CKD), and is associated with increased risk of morbidity and mortality. Intervention therapies aiming for the blockade of inflammatory cytokines are considered attractive approaches for CKD patients with signs of chronic inflammation. In this context, thalidomide, due to its potent anti-inflammatory and immunomodulatory properties, may represent an alternative strategy of treatment. In the present study, we developed an experimental model of CKD with uraemia in mice, induced by a diet rich in adenine, which causes progressive renal dysfunction, resembling the human uraemic features. Inflammatory parameters were analysed in this model of CKD and the potential beneficial effects of thalidomide as an anti-inflammatory drug was also investigated. METHODS: C57/BL-6 mice were fed with an adenine-containing diet during a period of 6 weeks. Thirty mice were divided into three groups: Control group (animals receiving normal diet), ADE group (mice receiving adenine-containing diet) and ADE + TLD group (CKD mice receiving thalidomide, 30 mg/kg/day, by gavage). Besides biochemical and histopathological changes, local and systemic inflammatory parameters were also analysed, including expression of cytokines interleukin (IL)-1ß, tumour necrosis factor-α, IL-6, IL-4 and IL-10 in kidney samples by real-time RT-PCR and quantification of serum levels of cytokines. Finally, the electrophoretic mobility shift assay (EMSA) for NF-κB was also examined. RESULTS: Adenine-fed mice developed advanced CKD characterized by a marked increase in serum urea, creatinine, phosphorus and intact parathyroid hormone (iPTH) levels. In addition, histological changes of tubulointerstitial injury, characterized by deposition of crystals in the kidney, accompanied by tubular dilatation, degeneration of proximal tubular epithelium with loss of the brush border, inflammatory cellular infiltration, foreign-body granuloma formation and interstitial fibrosis were also evident. By immunohistochemistry, Mac-2- and α-SMA-positive cells were identified in the tubulointerstitial compartment. Treatment with thalidomide significantly reduced serum urea, creatinine, phosphorus and iPTH levels and protected against tubulointerstitial injury. Local and systemic inflammation in the mice model of adenine-induced CKD was confirmed by the findings of significantly high expression of cytokine mRNA levels and NF-κB activation in the kidney tissue as well as marked increased serum levels of inflammatory cytokines. Thalidomide treatment significantly reduced gene expression of these cytokines and the activation of the NF-κB in the renal tissue and the circulating levels of cytokines. CONCLUSIONS: Dietary adenine caused advanced CKD with uraemia in mice providing a useful experimental model to study molecular and morphological changes associated with this disease. The negative impact of inflammation in this CKD model was overcome by the marked anti-inflammatory effects of thalidomide, promoting renal protection.

Prevalência da síndrome das pernas inquietas em pacientes em terapias de hemodiálise em um centro na região sul de Santa Catarina – Brasil / Restless legs syndrome prevalence in patients in haemodialysis therapy in a reference service in south Santa Catarina – Brazil

Introdução: A síndrome das pernas inquietas (SPI) tem sido relacionada a diversas doenças, entre elas doença renal e anemia. Objetivo: Descrever a prevalência da síndrome das pernas inquietas (SPI) nos pacientes em terapia de hemodiálise na região da Associação dos Municípios da Região de Laguna, Santa Catarina, Sul do Brasil (AMUREL). Métodos: 117 indivíduos submetidos à terapia de hemodiálise na região da AMUREL foram entrevistados para se avaliar a presença, o tipo (primária ou secundária) e a gravidade da SPI, creatinina, ureia, ferro e ferritina séricos. Resultados: A prevalência de SPI foi de 30,8% (n=36). Dos portadores, 33,3% tiveram o diagnóstico de SPI primária e 66,7% (n=24) o de SPI secundária .Quanto à gravidade, 58,3% foram classificados como intermitente, 16,7% em persistente leve, 8,3% em persistente moderada e 16,7% em ersistente grave. A maior parte dos casos de SPI não tinha sido diagnosticada anteriormente. Não foi encontrada correlação com os parâmetros bioquímicos nem diferenças significativas entre os sexos. Conclusão: A síndrome das pernas inquietas é comum e pouco diagnosticada. Sua prevalência é considerável e aumenta substancialmente em indivíduos urêmicos. Não encontramos nenhuma evidência de que anemia por deficiência de ferro e ferritina, nem índices altos de ureia e creatinina séricos possam desempenhar um importante papel patogênico.

Introduction: Restless legs syndrome (RLS) has been related to several diseases, including renal disease and anaemia. Aim: To determine the prevalence of restless legs syndrome in patients under haemodialysis therapy in the region of the Association of Municipalities of the Region of Laguna (AMUREL), in the state of Santa Catarina, South Brazil. Methods: 117 patients undergoing haemodialysis in the AMUREL region were interviewed in order to evaluate the presence, type (primary or secondary), and severity of RLS, as well as their serum creatinine, urea, iron, and ferritin levels. Results: The prevalence of RLS was 30.8% (n=36). Among the affected individuals, 33.3% were diagnosed with primary RLS and 66.7% (n=24) with secondary RLS. Concerning severity, 58.3% were rated as intermittent, 16.7% as mildly persistent, 8.3% as moderately persistent, and 16.7% as severely persistent. Most of the cases of RLS had not been diagnosed before. No correlation of RLS was detected with the biochemical measures, nor differences between the sexes. Conclusion: Restless legs syndrome is common and underdiagnosed. Its prevalence is considerable and increases significantly in uraemic individuals. We failed to find any evidence that iron and ferritin deficiency anaemia, or high serum urea and creatinine, can play an important pathogenic role.

Phosphorus overload and PTH induce aortic expression of Runx2 in experimental uraemia.

BACKGROUND: Vascular calcification (VC) is commonly seen in patients with chronic kidney disease (CKD). Elevated levels of phosphate and parathormone (PTH) are considered nontraditional risk factors for VC. It has been shown that, in vitro, phosphate transforms vascular smooth muscle cells (VSMCs) into calcifying cells, evidenced by upregulated expression of runt-related transcription factor 2 (Runx2), whereas PTH is protective against VC. In addition, Runx2 has been detected in calcified arteries of CKD patients. However, the in vivo effect of phosphate and PTH on Runx2 expression remains unknown. METHODS: Wistar rats were submitted to parathyroidectomy, 5/6 nephrectomy (Nx) and continuous infusion of 1-34 rat PTH (at physiological or supraphysiological rates) or were sham-operated. Diets varied only in phosphate content, which was low (0.2%) or high (1.2%). Biochemical, histological, immunohistochemistry and immunofluorescence analyses were performed. RESULTS: Nephrectomized animals receiving high-PTH infusion presented VC, regardless of the phosphate intake level. However, phosphate overload and normal PTH infusion induced phenotypic changes in VSMCs, as evidenced by upregulated aortic expression of Runx2. High-PTH infusion promoted histological changes in the expression of osteoprotegerin and type I collagen in calcified arteries. CONCLUSIONS: Phosphate, by itself is a potential pathogenic factor for VC. It is of note that phosphate overload, even without VC, was associated with overexpression of Runx2 in VSMCs. The mineral imbalance often seen in patients with CKD should be corrected.

Characteristics and causes of immune dysfunction related to uremia and dialysis.

From the immunologic viewpoint, chronic kidney disease (CKD) is characterized by disorders of both the innate and adaptive systems, generating a complex and still not fully understood immune dysfunction. Markers of a chronically activated immune system are closely linked to several complications of CKD and represent powerful predictors for mortality in the CKD population. On the other hand, CKD patients respond poorly to vaccination and to challenges such as bacterial infection. Interestingly, the main causes of death in patients with CKD are cardiovascular and infectious diseases, both being pathologic processes closely linked to immune function. Therefore, accelerated tissue degeneration (as a consequence of chronic inflammation) and increased rate of sepsis (because of a poorly orchestrated immune response) represent the most important targets for interventions aiming to reduce mortality in CKD patients. Understanding the mechanisms behind the immune dysfunction that is peculiar to CKD generates a perspective to improve outcomes in this group of patients.