Impaired monocyte cytokine production in critically ill patients with acute renal failure

BACKGROUND: Plasma levels of pro- and anti-inflammatory cytokines are predictive of mortality in patients with acute renal failure (ARF). Anti-inflammatory strategies are postulated to be beneficial in treatment. However, there are few studies simultaneously examining monocyte cytokine production and plasma cytokine levels in patients with ARF. METHODS: Study populations consisted of 20 critically ill patients with ARF, 19 critically ill patients without ARF (CRIT ILL), 28 healthy subjects (HS), 19 patients with chronic kidney disease (CKD), and 15 patients with end-stage renal disease (ESRD). Monocyte intracellular content of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-alpha (TNF-alpha) was determined by flow cytometry in whole blood. Plasma interleukin 6 and TNF-alpha concentrations were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: At baseline, there were no differences in intracellular monocyte cytokine levels between groups. After lipopolysaccaride stimulation, monocyte production of IL-1beta, TNF-alpha, and IL-6 in ARF patients was reduced by 41%, 84%, and 45%, respectively, compared to healthy subjects (P < 0.01 in each case), and similarly reduced compared to CKD and ESRD patients, and were similar to CRIT ILL patients. Plasma IL-6 levels were significantly higher in ARF patients than healthy subjects, CKD, and ESRD patients (all P < 0.001). CONCLUSION: Critically ill patients with acute renal failure have impaired monocyte cytokine production and elevated plasma cytokine levels in a pattern that closely resembles critically ill patients without ARF, and that is dissimilar to CKD and ESRD patients.     

The Impact of Arteriovenous Fistulae on the Myocardium: The Impact of Creation and Ligation in the Transplant Era

Cardiac hypertrophy is a relatively common complication seen in patients with advanced chronic kidney disease (CKD) and end‐stage renal disease (ESRD). Moreover, cardiac hypertrophy is even more frequently seen in patients with ESRD who have an arteriovenous (AV) access. There has been substantial evidence pertaining to the effects of AV access creation on the heart structure and function. Similarly, there is increasing evidence on the effects of AV access closure, flow reduction, transplantation, and immunosuppressive medication on both endpoints. In this review, we present the evidence available in the literature on these topics and open the dialog for further research in this interesting field.     

Angiotensin converting enzyme-independent angiotensin ii production by chymase is up-regulated in the ischemic kidney in renovascular hypertension

BACKGROUND: Tissue angiotensin II (ANG II) levels are elevated in both kidneys in renovascular hypertension (RVH). It has been demonstrated previously that intrarenal ANG II is augmented by an angiotensin converting enzyme (ACE) dependent mechanism in the non-ischemic kidney, but the role of ACE-independent production of ANG II in the kidney by the enzyme chymase is unknown. This study tested the hypothesis that intrarenal chymase activity is up-regulated in RVH. METHODS: A two-kidney, one-clip (2K1C) rat model was used to induce RVH (n = 6 rats/group). Regulation of intrarenal chymase activity by plasma ANG II was investigated using an ANG II-infusion model. At sacrifice 14 days post-operatively, steady-state ANG II levels in plasma and kidney were quantified by radioimmunoassay. ANG II production was quantified in kidney homogenates by incubating at 37 degrees C for 60 min with enzyme substrate (200 microm ANG I) alone or substrate containing the chymase inhibitor chymostatin. ANG II was separated and quantitated by HPLC. Chymase activity was defined as the fraction of ANG II production inhibited by Chymostatin. RESULTS: 2K1C and ANG II-infused rats developed significant hypertension, compared to control rats (P = 0.0001 and P = 0.001, respectively). Chymase-dependent ANG II production was increased in the ischemic kidney, but not the non-ischemic kidney, of 2K1C rats compared to control animals (*P < 0.05). Intrarenal chymase activity was unchanged by ANG II infusion (P = NS). CONCLUSIONS: Chymase activity is up-regulated in the ischemic kidney of 2K1C rats. Plasma ANG II does not appear to regulate intrarenal chymase activity, suggesting that ischemia per se up-regulates chymase activity in the kidney. ACE-independent ANG II production by chymase may provide a mechanism for augmenting intrarenal ANG II in the ischemic kidney in RVH.     

Cytokines in chronic kidney disease: potential link of MCP-1 and dyslipidemia in glomerular diseases

Background

Many studies have indicated a role for cytokines in chronic kidney disease (CKD). The aim of this study was to evaluate plasma and urinary levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), transforming growth factor-beta1 (TGF-β1), and interleukin-8 (IL-8/CXCL8) in pediatric patients with CKD stages 2–4.

Methods

Cytokines were measured in 37 healthy controls and in 42 CKD patients by enzyme-linked immunoassay. Patients were divided into groups according to CKD etiology: glomerular disease (group 1, n?=?11) and congenital anomalies of the kidney and urinary tract (group 2, n?=?31). Urinary cytokine measurements were standardized for creatinine.

Results

Plasma and urinary levels of MCP-1/CCL2 were significantly higher in both CKD groups compared to the control group. Between the two CKD groups, only urinary MCP-1/CCL2 levels were significantly different, with MCP-1/CCL2 levels higher in group 1 patients. Plasma and urinary levels of IL-8/CXCL8 and TGF-β1 were undetectable in the control group but comparable between the two CKD groups. In group 1 patients, urinary MCP-1/CCL2 levels were negatively correlated to serum albumin levels and positively correlated to the levels of total cholesterol and triglycerides. In group 2 patients, urinary levels of IL-8/CXCL8 were negatively correlated with the estimated glomerular filtration rate and positively correlated with body mass index.

Conclusions

Differences in cytokine profiles may be related to CKD etiology and other disease-associated alterations.     

Effect of chymase inhibition on the arteriovenous fistula stenosis in dogs

It was hypothesized that chymase may participate in hemodialysis vascular access dysfunction, as chymase has been known to be an effective enzyme in the conversion of angiotensin I (Ang I) to Ang II and in the latent TGF-beta1 to the active form. An arteriovenous (AV) fistula was created between the brachial artery and vein in dogs. In the AV anastomosis, when the walls of the venous and arterial sides were compared, the eccentric neointimal formation was most evident in the venous wall. Compared with the venous side downstream of the AV anastomosis, a severe neointimal hyperplasia was found in the venous side upstream of the AV anastomosis (intima/media, 153 +/- 25%). The chymase- and TGF-beta-positive mast cells were markedly accumulated in the proliferous neointima and media. In association with the reduction of chymase expression, a marked decrease in Ang II-, AT(1) receptor-, and TGF-beta-positive areas was achieved by NK3201 (a chymase inhibitor) treatment, and the neointima formation (intima/media: region A, 53 +/- 9%, P < 0.001; region B, 54 +/- 14%, P < 0.001) was also significantly suppressed in this group. Although lisinopril treatment also provided some beneficial effects with regard to the prevention of neointimal formation, the degree was less than that seen with chymase inhibition. These findings indicate that mast cell-derived chymase plays an essential role in the pathogenesis of the AV fistula access failure and that chymase inhibition may be a therapeutic target for the treatment of hemodialysis vascular access dysfunction in clinic settings.     

Pulmonary hypertension in hemodialysis patients: an unrecognized threat

Pulmonary hypertension (PH) is a progressive, fatal pulmonary circulatory disease that accompanies many conditions (including left to right side shunt) with compensatory elevated cardiac output. PH also complicates chronic hemodialysis (HD) therapy immediately after the creation of an arteriovenous (AV) access, even before starting HD therapy. It tends to regress after temporary AV access closure and after successful kidney transplantation. Affected patients have significantly higher cardiac output. This syndrome is associated with a statistically significant survival disadvantage. The laboratory hallmark of this syndrome is reduced basal and stimulatory nitric oxide (NO) levels. It appears that patients with end-stage renal disease (ESRD) acquire endothelial dysfunction that reduces the ability of their pulmonary vessels to accommodate the AV access-mediated elevated cardiac output, exacerbating the PH. Doppler echocardiographic screening of ESRD patients scheduled for HD therapy for the occurrence of PH is indicated. Early diagnosis enables timely intervention, currently limited to changing dialysis modality or referring for kidney transplantation.     

A comparison of quality of sleep between patients with chronic kidney disease not on hemodialysis and end-stage renal disease on hemodialysis in a developing country

Few studies have compared quality of sleep between pre-dialysis chronic kidney disease (pre-dialysis CKD) patients and end-stage renal disease patients on dialysis (ESRD) and have found inconsistent results. Objective of this study is to compare quality of sleep between patients with pre-dialysis CKD and ESRD in a developing country. This study was conducted in an out-patient department and hemodialysis unit of a tertiary care facility. Patients included had either pre-dialysis CKD or ESRD. Assessment of quality of sleep was done using Pittsburgh sleep quality index (PSQI). A total of 152 patients were included in the study. Out of these patients, 79 (52%) had ESRD and 73 (48%) had pre-dialysis CKD. Median PSQI score was 6 (IQR 3–8.8). Poor sleep quality (PSQI ≥5) was present in 100 (65.8%) patients. Only hemoglobin (β?=??0.39, p?β?=?0.56, p?β?=?0.22, p?r?=??0.34, p value .80) in pre-dialysis CKD patients. Poor sleep quality is common in patients with CKD including hemodialysis patients in a developing country, which is independent of kidney function in non-dialysis patients. There is no difference in quality of sleep between pre-dialysis CKD and ESRD patients.     

Plasma and urinary levels of cytokines in patients with idiopathic hypercalciuria

Background

Recent studies suggest that cytokines modulate bone turnover. Idiopathic hypercalciuria (IH) seems to be associated with bone mineral loss. Therefore, the aim of this study was to assess cytokines involved in bone turnover in patients with IH.

Methods

Plasma and spot-urine levels of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), transforming growth factor β1 (TGF-β1), and monocyte chemoattractant protein (MCP-1) were measured in 70 children and adolescents with IH and in 37 healthy controls. Patients with IH were subdivided according to their calciuria at the time of sample collection: ≥4 mg/kg/day (persistent IH, n=27) and below 4 mg/kg/day (controlled IH, n=43). Cytokines were determined by enzyme-linked immunoassay.

Results

Plasma and urinary concentrations of IL-1β, IL-6, IL-8, and TNF-α were undetectable in all groups. No differences were found between controlled and persistent hypercalciuria for plasma and urinary levels of MCP-1 and TGF-β1. On the other hand, MCP-1 levels were significantly higher in both subgroups of IH in comparison to healthy controls. Furthermore, urinary MCP-1 levels of IH patients correlated positively with bone mineral content (p=0.013).

Conclusion

Although cytokine measurements did not allow the differentiation between persistent and controlled IH, our findings suggest that MCP-1 might play a role in patients with IH.

     

慢性肾脏病患者血清1,25（OH）2D水平与蛋白尿及尿炎症细胞因子相关性研究

目的：探讨慢性肾脏病（CKD）1～4期患者血清1,25（OH）2D水平与蛋白尿、尿炎症细胞因子的关系。方法：对我科115例CKD1～4期患者及20例健康对照者进行血清1,25（OH）2D、血CRP,尿TGF-β1、MCP-1、TNF、IL-6,24h尿蛋白定量检测;分析血清1,25（OH）2D水平与以上指标相关性。结果：（1）CKD组患者血清1,25（OH）2D水平低于对照组（P〈0.05）;血CRP,尿MCP-1、TGF-β1、IL-6、TNF水平,24h尿蛋白定量高于对照组（P〈0.05）。（2）与GFR≥60ml·min^-1·1.73m^-2患者比较：GFR〈44ml·min^-1·1.73m^-2患者CRP,尿MCP-1、TGF-β1、IL-6、TNF水平、24h尿蛋白定量升高（P〈0.05）;血清1,25（OH）2D水平降低（P〈0.05）;而GFR45～59ml·min^-1·1.73m^-2患者与GFR≥60ml·min^-1·1.73m^-2患者比较,两组间差异无统计学意义（P〉0.05）;（3）单因素相关分析显示CKD患者血清1,25（OH）2D与年龄（r=-0.442）、收缩压（r=-0.464）、舒张压（r=-0.399）、GFR（r=0.902）、Scr（r=-0.430）、PTH（r=-0.341）、UA（r=0.237）、24h尿蛋白定量（r=-0.372）及尿TGF-β1（r=-0.894）、MCP-1（r=-0867）、TNF（r=-0.899）、IL-6（r=-0.934）水平相关（P〈0.05）。多元回归分析显示血清1,25（OH）2D与GFR呈正相关;与24h尿蛋白定量,尿MCP-1、IL-6,血Scr、PTH呈负相关。结论：CKD1～4期患者存在1,25（OH）2D水平降低,并与蛋白尿及尿炎症细胞因子水平密切相关。     

The odontogenic-related microinflammation in patients with chronic kidney disease

Objectives: This study estimated plasma levels of interleukin IL-1β, IL-6, tumour necrosis factor-α (TNF-α), interferon-γ (INF-γ) in chronic kidney disease (CKD) patients with a single odontogenic pathology. Material and methods: Forty-nine selected adult CKD patients with single odontogenic pathology based on clinical and X-ray examination: patients after proper root canal treatment, without periapical lesions (n?=?12), with pulp necrosis (n?=?7), with asymptomatic periapical lesions (n?=?22), with periodontal disease (n?=?8), and 14 with healthy teeth were enrolled. Patients with coexisting different dental pathologies and the evidence of other infection were excluded. In all patients plasma concentrations of CRP, IL-1β, IL-6, TNF-α, and INF-γ were measured. Results: Patients with periodontitis were characterized by increased concentrations of IL-6 and TNF-α. Those with pulp necrosis had significantly more frequently serum CRP level over 2?mg/L and presented significantly elevated IL-6, but decreased TNF-α concentration than in the subjects with healthy teeth. In patients with periapical lesions and patients after root canal therapy, the concentrations of cytokines did not indicate for the systemic inflammation. Conclusions: Periodontitis and pulp necrosis are important sources of systemic microinflammation in CKD patients. Plasma concentrations of IL-6 and TNF-α appear to be more sensitive markers of odontogenic inflammation in CKD patients than CRP.     

Attenuating effects of chymase inhibitor on pericardial adhesion following cardiac surgery

OBJECTIVE: Chymase, a serine protease, is released from mast cells, which is closely associated with adhesion formation. Chymase activates transforming growth factor-beta1 (TGF-beta1), which promotes tissue fibrosis. Recently we have found that chymase may play an important role in adhesion formation in hamsters. Accordingly, this study was designed to confirm that a chymase inhibitor prevents postoperative cardiac adhesions in large animals. METHODS: In 14 dogs, the epicardium was abraded 200 times with gauze and the mid-portion of the left anterior descending coronary artery (LAD) was exposed with No. 15 blade. Either chymase inhibitor (CI group, n = 7) or placebo (P group, n = 7) was sprayed into the pericardial cavity, then the pericardium was closed. Cardiac chymase activity, the level of TGF-beta1 in the pericardial fluid, the density of epicardial mast cells, the adhesion area between the heart and the pericardium, and the presence of adhesion between the mid-LAD and the pericardium were evaluated 1 and 2 months after surgery. Five nonsurgical dogs were used as a control for cardiac chymase activity. RESULTS: Cardiac chymase activity and TGF-beta1 level were lower in CI group than in P group (53.7 +/- 35.0 vs. 93.4 +/- 20.4 microU/mg protein, p = 0.01, 3.2 +/- 0.9 vs. 4.3 +/- 1.1 microg/mL, p = 0.06, respectively). In CI group, the density of mast cells (19 +/- 5 vs. 32 +/- 8 cells/cm, p < 0.01), the adhesion area (2.2 +/- 0.8 vs. 7.5 +/- 1.5 cm2, p < 0.01), and adhesions between the heart and the mid-LAD (0% vs. 57%) were all reduced. CONCLUSION: Chymase inhibitor suppresses cardiac chymase activity and reduces the TGF-beta1 level, resulting in a reduction of cardiac adhesion in a large animal.     

Cardiovascular Implantable Electronic Device Leads in CKD and ESRD Patients: Review and Recommendations for Practice

Cardiovascular implantable electronic devices (CIEDs) are frequently utilized for management of cardiac dysrhythmias in patients with chronic kidney disease or end‐stage renal disease receiving hemodialysis. The survival benefit from use of implantable cardioverter defibrillators in patients with CKD or ESRD is not as clear as in the general population, particularly when used for primary prevention of sudden cardiac death. Transvenous CIED leads are associated with central vein stenosis resulting in significant adverse consequences for existing or future arteriovenous access. Venous hypertension from CIED lead‐related central vein stenosis is a challenging clinical problem and may require repeated percutaneous interventions, replacement of the CIED, or creation of alternative arteriovenous access. Infections associated with transvenous CIED leads are more frequent and associated with worse outcomes in patients with renal disease. Epicardial CIED leads or other nontransvenous devices may reduce complications of both central venous stenosis and endovascular infection in these vulnerable patients. Consensus recommendations are offered for avoidance and management of complications arising from the use of CIEDs and arteriovenous hemodialysis access.     

The association of hepatitis C infection with the onset of CKD and progression into ESRD

Hepatitis C virus (HCV) infection is not only an important cause of chronic liver disease, but extrahepatic manifestations are common and include chronic kidney disease (CKD). HCV is classically associated with cryoglobulinemic glomerulonephritis in the context of mixed cryoglobulinemia syndrome, but other glomerular diseases also occur and may be significantly under‐recognized. HCV may cause glomerular disease by immune complex deposition; however, other potential mechanisms by which HCV promotes CKD include a direct cytopathic effect of the virus on renal tissue, and by its association with accelerated atherosclerosis, insulin resistance, and chronic inflammation. Epidemiologic studies show HCV infection confers an increased risk of incident CKD and accelerates progression of CKD to end‐stage renal disease (ESRD) in the general population, as well as subpopulations including diabetic patients, those coinfected with human immunodeficiency virus (HIV), and kidney transplant recipients. Patients with CKD and HCV infection experience inferior clinical outcomes, including poorer quality of life and an increased risk of mortality. Treatment with interferon‐based regimens is associated with decreased risk of incident CKD and ESRD, though prior studies are limited by the small number of patients with HCV and CKD who underwent treatment. With the advent of new, well‐tolerated direct‐acting antiviral combinations that are not cleared by the kidneys, it is possible to treat all genotypes of HCV infection in patients with CKD and ESRD. More data on the effect of direct‐acting antivirals on CKD incidence and progression are necessary. However, there is every expectation that with improved access to HCV treatment, the burden of CKD in patients with HCV could significantly decline.     

Tailoring the initial vascular access for dialysis patients

BACKGROUND: Creating a functioning initial arteriovenous (AV) access for aging and diabetic end-stage renal disease (ESRD) hemodialysis patients has been a challenge. METHODS: This study describes 748 consecutive primary AV access creations and their primary (unassisted) and secondary (assisted) access survival at a single center. Twenty-four percent of the patients had diabetes as their cause of ESRD and the average age was 59.6 years. No patient receiving an initial AV access required synthetic graft material. All received an AV fistula. Three types of fistulae were created and their distribution varied significantly for diabetic and non-diabetic patients (respective percentages): forearm AV fistula (24%, 62%), perforating vein fistula (PVF) at the elbow (48%, 21%) and non-PVF at the elbow (29%, 17%). RESULTS: Results of access survival for age groups <65 and 65+ years, male and female, diabetic and non-diabetic subgroups ranged from 51 to 75% for unassisted and from 75 to 96% for assisted two year access survival. PVF appeared to be advantageous over non-PVF access at the elbow. First intervention for peripheral steal syndrome was required at a rate of 7 and 0.6 per 100 patient-years at risk for diabetic and non-diabetic patients, respectively. The thrombosis rates per patient year of 0.03 for non-diabetics and 0.07 for diabetics are superior to previously published results for AV fistulae or for a combined AV fistula-AV graft approach. CONCLUSIONS: Potential explanations for these excellent results among elderly and diabetic patients include preoperative evaluation, exclusive use of native vessels, a variable surgical approach including PVF, and the experience of a single operator.     

氯沙坦含药血清对肾小管上皮-间充质转分化的抑制作用

目的:肾小管上皮细胞-间充质转分化(epithelial-to-mesenchymal transition,EMT)是肾小管间质纤维化(tubulointerstitial fibrosis,TIF)的关键发病机制,而肾小管间质纤维化是慢性肾脏病进展为终末期肾病(end-stage renal dis-ease,ESRD)的重要共同通路。血管紧张素ⅡAT1受体阻断剂氯沙坦对于延缓慢性肾脏病进展有一定的作用,但其能否抑制肾小管上皮细胞-间充质转分化继而抑制肾间质纤维化尚不清楚。本实验通过体外TGF-β1诱导HK-2细胞向间充质细胞转分化,观察氯沙坦对肾小管上皮细胞-间充质转分化的抑制作用及其可能机制。方法:在体外使用TGF-β1诱导HK-2细胞表型改变并给予氯沙坦大鼠含药血清干预。氯沙坦大鼠含药血清按照既定的操作程序获取。HK-2细胞行E-cadher-in,Vimentin,β-catenin和ZEB1免疫荧光染色及Western blot分析。结果:TGF-β1诱导肾小管上皮细胞HK-2转化为间充质细胞,细胞形态由卵圆形变为长梭形,上皮标志物E-cadherin表达下调,间充质标志物Vimentin表达上调,上皮细胞-间充质转分化相关分子β-catenin在胞浆、胞核的积聚增多以及ZEB1表达增强;氯沙坦大鼠含药血清能够部分抑制TGF-β1诱导的HK-2转化为间充质表型,并维持HK-2细胞的上皮表型,抑制E-cadherin的表达下调和Vimentin的表达上调;同时抑制β-catenin在胞浆、胞核的积聚以及ZEB1的表达。结论:研究结果提示氯沙坦可抑制体外的肾小管上皮细胞-间充质转分化,其机制可能与氯沙坦抑制β-catenin/ZEB1通路有关。     

Peripheral tissue release of interleukin-6 in patients with chronic kidney diseases: effects of end-stage renal disease and microinflammatory state

To examine if uremia influences muscle interleukin-6 (IL-6) metabolism we studied the exchange of IL-6 across the forearm in 16 patients with chronic kidney disease (CKD) (stages 3 and 4), in 15 hemodialysis (HD)-treated end-stage renal disease (ESRD) patients (n=15), and in six healthy controls. In addition, we performed an analysis of both IL-6 protein and IL-6 mRNA expression in muscle of CKD (stage 4) patients showing evidence of inflammation and in controls. A release of IL-6 from the forearm was observed in patients with elevated IL-6 plasma levels. Arterial IL-6 was directly related to released IL-6 (r=0.69; P<0.004) in HD patients. Both IL-6 protein and IL-6 mRNA expression were increased in muscle of inflamed CKD patients vs controls (P<0.05). Although muscle net protein balance was similar in all patients, it was significantly more negative in HD patients with high than in those with low IL-6 plasma levels (P<0.05). In addition, net protein balance was related to the forearm release of IL-6 in HD patients only (r=0.47; P<0.038). These data demonstrate that IL-6 expression is upregulated in muscle, and that muscle tissue, by releasing this cytokine, may contribute to the inflammatory response in HD patients. The release of IL-6 from peripheral tissues is associated with an increase in muscle protein loss in HD patients, suggesting that muscle release of IL-6 is linked to protein catabolism in these patients. The release of IL-6 from peripheral tissues may act as a signal for the inflammatory response and contribute to functional dysregulation in uremia.     

CKD Accelerates Development of Neointimal Hyperplasia in Arteriovenous Fistulas

Arteriovenous (AV) access failure resulting from venous neointimal hyperplasia is a major cause of morbidity in patients with ESRD. To understand the role of chronic kidney disease (CKD) in the development of neointimal hyperplasia, we created AV fistulae (common carotid artery to jugular vein in an end-to-side anastomosis) in mice with or without CKD (renal ablation or sham operation). At 2 and 3 wk after operation, neointimal hyperplasia at the site of the AV anastomosis increased 2-fold in animals with CKD compared with controls, but cellular proliferation in the neointimal hyperplastic lesions did not significantly differ between the groups, suggesting that the enhanced neointimal hyperplasia in the setting of CKD may be secondary to a migratory phenotype of vascular smooth muscle cells (VSMC). In ex vivo migration assays, aortic VSMC harvested from mice with CKD migrated significantly greater than VSMC harvested from control mice. Moreover, animals with CKD had higher serum levels of osteopontin, which stimulates VSMC migration. When we treated animals with bone morphogenic protein-7, which promotes VSMC differentiation, before creation of the AV anastomosis, the effect of CKD on the development of neointimal hyperplasia was eliminated. In summary, CKD accelerates development of neointimal hyperplasia at the anastomotic site of an AV fistula, and administration of bone morphogenic protein-7 neutralizes this effect.Arteriovenous (AV) access dysfunction such as stenosis and thrombosis constitute a major cause of morbidity for patients on chronic hemodialysis for end-stage kidney disease.¹ While AV fistulae constructed with native vessels are the best vascular access available owing to a lower incidence of stenosis, thrombosis, and infection compared with vascular grafts or central venous catheters, its failure rate up to 66% at 2 yr² remains unacceptably high as hemodialysis access related hospitalizations are on the rise and its cost are well over one billion dollars per annum in the United States alone.³The cause of failure is predominantly secondary to the occlusive neointimal hyperplastic (NH) lesion formation at the anastomosis and/or the outflow veins followed by in situ thrombosis.^4–7 Unlike restenosis seen with preocclusive atherosclerotic arteries after angioplasty and stenting, neointimal (new intimal) hyperplasia is seen at the anastomosis involving an artery or a synthetic graft (e.g., expanded polytetrafluoroethylene, or ePTFE, or Dacron) and a vein in the upper extremities. Although these blood vessels are predisposed to calcification, pre-existing NH, and needle stick injury, they are usually free of atherosclerotic plaque. Therefore, directional migration of vascular smooth muscle cells (VSMCs) into the luminal surface is critical to the anastomotic NH lesion formation.^8,9Several animal models with native or synthetic graft accesses have been used to gain insight into the pathologic mechanisms of NH lesion development.^10,11 However, these studies lacked the critical component of chronic kidney disease (CKD), and whether CKD plays a role in NH lesion formation remains unknown. CKD has been implicated in the development of atherosclerosis along with a host of other deranged factors such as hemodynamic forces, inflammatory mediators, platelet activation, coagulation cascade, and metabolic factors.^12,13 In this study, we used a murine model of CKD modified from Gagnon and Gallimore,¹⁴ to assess the effect of CKD on NH formation after AV fistula creation.     

Vascular access in elderly patients with end-stage renal disease

During the last few years, the number of elderly patients with end-stage renal disease (ESRD) has been increasing worldwide. Establishment of a viable vascular access is of primary importance in these patients. This review discusses the advantages and disadvantages of the available vascular access modalities [namely arteriovenous (AV) fistulae, AV grafts, and central venous catheters (CVCs)] in elderly ESRD patients. AV fistulae seem to be superior when compared with other vascular access alternatives with respect to patency, morbidity and mortality rates. On the other hand, due to the age-related advanced atherosclerosis in the elderly, higher failure rates for AV fistulae in this age group have been described. Two controversial issues, namely the higher infection and thrombosis rates in elderly ESRD patients, are also discussed. Current evidence suggests that old age should not comprise a drawback when selecting the appropriate vascular access modality (AV fistula, AV graft or CVC) for the performance of hemodialysis. The possible vascular access options in elderly ESRD patients should not be different from younger individuals.     

Attenuation of adhesion formation after cardiac surgery with a chymase inhibitor in a hamster model

OBJECTIVE: Chymase is one of the inflammatory mediators and is released from mast cells, which are closely associated with adhesion formation. Chymase also activates transforming growth factor beta1, which promotes tissue fibrosis. However, the role of chymase in cardiac adhesion formation has not yet been elucidated. We have assessed whether a specific chymase inhibitor, Suc-Val-Pro-Phe(p) (OPh)(2), prevents postoperative cardiac adhesions in hamsters. METHODS: In 66 hamsters the epicardium was abraded, and then either chymase inhibitor or placebo was injected into the left thoracic cavity, leaving the pericardium open. Cardiac chymase activity, the level of transforming growth factor beta1 in the pleural fluid, and the density of epicardial mast cells were measured 3 days postoperatively. The degree of adhesion formation was evaluated macroscopically and histologically 2 weeks postoperatively by using a grading score ranging from 0 (no adhesions) to 4 (severe adhesions). RESULTS: The cardiac chymase activity and level of transforming growth factor beta1 were lower in the chymase inhibitor-treated group compared with in the placebo-treated group (45.8 +/- 18.7 vs 79.7 +/- 13.7 microU/mg protein [P <.025] and 15.6 +/- 6.5 vs 33.2 +/- 9.8 microg/mL [P <.01], respectively). The density of mast cells was higher in the placebo-treated group, and there was suppression to 60% of this value in the chymase inhibitor-treated group. The adhesion scores were lower in the chymase inhibitor-treated group compared with in the placebo-treated group (1.3 +/- 1.3 vs 3.0 +/- 1.1, P <.01). CONCLUSION: Use of a chymase inhibitor suppresses not only cardiac chymase activity but also the level of transforming growth factor beta1, and this results in a reduction in postoperative cardiac adhesion.     

Chronic kidney disease: a European perspective

There is an exponential growth worldwide of patients with end-stage renal disease (ESRD). Prevalences, outcomes, and underlying causes of ESRD are relatively well documented through different organizations. It is, however, clear that a large part of the bad outcome of ESRD patients is due to deficient follow-up during the earlier chronic kidney disease (CKD) stages. Data on CKD, prevalence of the different stages, and the evolution to ESRD are rather scant, and available data are conflictive. This is at least partly due to the lack of an international standard for measurement of renal function. In addition, there is compiling evidence that presence of proteinuria, even with a normal renal function, predisposes to ESRD. Most authors now prefer the term "kidney injury" rather than "kidney failure" to indicate people at risk for evolution to ESRD or for complications of CKD. Detection of these patients at risk is important to implement measures to slow down progression of CKD and avoid secondary complications. As it is clear that most of these CKD patients die before they reach ESRD, it might be that by taking the necessary preventive measures, the number of ESRD patients might still further increase exponentially.