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Background: Platelet function analysis utilizing platelet-rich plasma and optical density based aggregometry fails to identify patients at risk for uremia associated complications., Methods: We employed whole blood platelet aggregation analysis based on impedance as well as determination of ATP release from platelet granules detected by a chemiluminescence method. Ten chronic kidney disease (CKD) stage 4 or 5 predialysis patients underwent platelet evaluation. Our study aims to evaluate this platform in this patient population to determine if abnormalities could be detected., Results: Analysis revealed normal aggregation and ATP release to collagen, ADP, and high-dose ristocetin. ATP release had a low response to arachidonic acid (0.37 ± 0.26 nmoles, reference range: 0.6-1.4 nmoles). Platelet aggregation to low-dose ristocetin revealed an exaggerated response (20.9 ± 18.7 ohms, reference range: 0-5 ohms)., Conclusions: Whole blood platelet analysis detected platelet dysfunction which may be associated with bleeding and thrombotic risks in uremia. Diminished ATP release to arachidonic acid (an aspirin-like defect) in uremic patients may result in platelet associated bleeding. An increased aggregation response to low-dose ristocetin (a type IIb von Willebrand disease-like defect) is associated with thrombus formation. This platelet hyperreactivity may be associated with a thrombotic diathesis as seen in some uremic patients.

The elimination of substances between 10 and 50 kDa by conventional high-flux membranes is not satisfactory. We investigated in vivo the elimination of middle-sized uremic solutes by conventional polyflux (PF) and modified high-cut-off (HCO) membranes. All 12 patients underwent four treatments, two with the HCO dialyzer and two with the PF dialyzer, each in either a haemodialysis (HD) or haemodiafiltration (HDF) mode. The reduction ratio of urea, creatinine, β2-microglobulin (β2M), leptin, soluble TNF-RI, complement factor D, IL-6, sIL-6 receptor, advanced glycation end-products (AGEs) and albumin was determined. In addition, the amount removed was determined in the dialysate for β2M, complement factor D, AGEs and albumin. Treatment with HCO removed β2M, sTNF-RI, factor D, and high molecular AGE significantly better than conventional high-flux membranes. The albumin loss was higher when using HCO membranes. HCO membranes are a promising approach to improve removal of uremic toxins not affected by conventional high-flux membranes., (© 2013 S. Karger AG, Basel.)

Chronic hemodialysis (HD) patients are predisposed to several complications associated with pleural effusion. In addition, uremia can directly cause pleuritis. However, there are inadequate data about pathogenesis and natural course of uremic pleuritis. In this study, 76 chronic HD patients with pleural effusion admitted to the Respiratory Center of Masih Daneshvari Hospital, in Tehran, Iran between June 2005 and May 2011 were evaluated to figure out the etiology of their pleural disease. Among these patients, patients with uremic pleuritis were identified and studied. The rate of uremic pleuritis was 23.7%. Other frequent etiologies of pleural effusion were parapneumonic effusion (23.7%), cardiac failure (19.7%), tuberculosis (6.6%), volume overload, malignancy, and unknown. In patients with uremic pleuritis, dyspnea was the most common symptom, followed by cough, weight loss, anorexia, chest pain, and fever. Compared to patients with parapneumonic effusion, patients with uremic effusion had a significantly higher rate of dyspnea and lower rate of cough and fever. Pleural fluid analysis showed that these patients had a significantly lower pleural to serum lactic dehydrogenase ratio, total pleural leukocytes, and polymorphonuclear count compared to patients with parapneumonic effusion. Improvement was achieved in 94.1% of patients with uremic pleuritis by continuation of HD, chest tube insertion or pleural decortication; an outcome better than the previous reports. Despite the association with an exudative effusion, inflammatory pleural reactions in patients with uremic pleuritis may not be as severe as infection-induced effusions. Owing to the advancement in HD technology and other interventions, outcome of uremic pleuritis may be improved., (© 2012 The Authors. Hemodialysis International © 2012 International Society for Hemodialysis.)

Protein-bound uremic retention solutes, i.e. phenolic compounds, such as p-cresylsulfate, and indolic compounds, such as indoxyl sulfate, have been intensively studied in recent years and have been shown to be associated especially with cardiovascular toxicity and adverse outcomes in chronic kidney disease. In this review, we will focus on their toxicity and their removal by dialysis strategies, which is hampered due to their protein binding. Hemodiafiltration slightly improves the removal of protein-bound solutes as compared to hemodialysis, although the clinical benefit on outcomes still needs to be demonstrated. Removal by means of absorption and interference with intestinal generation or renal tubular excretion are interesting alternative strategies under investigation., (Copyright © 2013 S. Karger AG, Basel.)

Unlabelled: In adults, recurrent hemodialysis (HD)-induced cardiac injury results in ischemic myocardial dysfunction. Uremic children, like adults, share the full complement of uremia-related cardiovascular abnormalities but without significant atheromatous coronary artery disease. The aim of this study was, to assess the impact of HD on left ventricular (LV) myocardial function in children., Method: We assessed all single-center chronic HD patients (n = 15, range 1-17 years) excluding those with overt cardiac disease. Regional LV function and mechanical synchronicity was measured echographically by two-dimensional segmental longitudinal, circumferential and radial myocardial strain. All patients were assessed pre-dialysis and at the end of dialysis. In addition, we scanned age-matched controls at rest., Results: The peak longitudinal strain was lower in uremic patients compared with controls with a significant fall during HD (mean peak strain -19.9 controls, -17.9 pre-HD, -15.3 end of HD, p < 0.05). Radial strain was lower in uremic patients and increased during HD. Circumferential strain was preserved in uremic patients and fell during HD. Intrasegmental deformation synchronicity was progressively worse pre-dialysis and end of dialysis compared with controls. Intradialytic peak longitudinal strain reduction was significantly associated with systolic blood pressure and ultrafiltrate volume (p < 0.05)., Conclusion: Uremic children have impaired regional LV function, with a predisposition to longitudinal axis dysfunction and LV mechanical dyssynchrony, both of which are established markers of ischemic injury. This is further evidence for a characteristic cardiovascular phenotype in uremic patients that predisposes them to subclinical demand ischemia during dialysis., (Copyright © 2013 S. Karger AG, Basel.)

Protein-bound toxins are not efficiently removed by conventional hemodialysis techniques. In order to improve the removal of protein-bound toxins, we performed an in vitro study to evaluate the effects of dilution and pH change on the dissociation of protein-bound toxins from albumin. Human plasma harvested by therapeutic apheresis treatment was diluted with saline or isotonic NaHCO3 solution, and the amounts of the free fractions of indoxyl sulfate (IS) and homocysteine were determined. The results suggested that IS was dissociated easily from albumin by dilution and pH change; higher dilution was associated with more effective removal and a greater increase of the free fraction of IS. However, these methods did not facilitate dissociation of homocysteine from albumin. Effective removal of some protein-bound toxins may be achieved by applying dilution and pH change methods to blood purification techniques, such as pre-dilution on-line hemodiafiltration., (Copyright © 2013 S. Karger AG, Basel.)

Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.

Metabolic diseases such as hyperlipidemia and diabetes attenuate the cardioprotective effect of ischemic preconditioning. In the present study, we examined whether another metabolic disease, prolonged uremia, affects ischemia/reperfusion injury and cardioprotection by ischemic preconditioning. Uremia was induced by partial nephrectomy in male Wistar rats. The development of uremia was verified 29 wk after surgery. Transthoracic echocardiography was performed to monitor cardiac function. At week 30, hearts of nephrectomized and sham-operated rats were isolated and subjected to a 30-min coronary occlusion followed by 120 min reperfusion with or without preceding preconditioning induced by three intermittent cycles of brief ischemia and reperfusion. In nephrectomized rats, plasma uric acid, carbamide, and creatinine as well as urine protein levels were increased as compared with sham-operated controls. Systolic anterior and septal wall thicknesses were increased in nephrectomized rats, suggesting the development of a minimal cardiac hypertrophy. Ejection fraction was decreased and isovolumic relaxation time was shortened in nephrectomized rats demonstrating a mild systolic and diastolic dysfunction. Infarct size was not affected significantly by nephrectomy itself. Ischemic preconditioning significantly decreased infarct size from 24.8 ± 5.2% to 6.6 ± 1.3% in the sham-operated group and also in the uremic group from 35.4 ± 9.5% to 11.9 ± 3.1% of the area at risk. Plasma ANG II and nitrotyrosine were significantly increased in the uremic rats. We conclude that although prolonged experimental uremia leads to severe metabolic changes and the development of a mild myocardial dysfunction, the cardioprotective effect of ischemic preconditioning is still preserved.

Purpose of Review: Chronic kidney disease (CKD) is associated with oxidative stress and inflammation which contribute to progression of kidney disease and its numerous complications. Until recently, little attention had been paid to the role of the intestine and its microbial flora in the pathogenesis of CKD-associated inflammation. This article is intended to provide an over view of the impact of uremia on the structure and function of the gut and its microbial flora and their potential link to the associated systemic inflammation., Recent Findings: Recent studies conducted in the author's laboratories have demonstrated marked disintegration of the colonic epithelial barrier structure and significant alteration of the colonic bacterial flora in humans and animals with advanced CKD. The observed disruption of the intestinal epithelial barrier complex can play an important part in the development of systemic inflammation by enabling influx of endotoxin and other noxious luminal contents into the systemic circulation. Similarly via disruption of the normal symbiotic relationship and production, absorption and retention of noxious products, alteration of the microbial flora can contribute to systemic inflammation and uremic toxicity. In fact recent studies have documented the role of colonic bacteria as the primary source of several well known pro-inflammatory/pro-oxidant uremic toxins as well as many as-yet unidentified retained compounds., Summary: CKD results in disruption of the intestinal barrier structure and marked alteration of its microbial flora - events that play a major role in the pathogenesis of inflammation and uremic toxicity.

Objectives: What is the prognostic significance of achieving a systolic blood pressure of <140 mmHg?, Setting: Diabetic renal policlinic, university hospital of Lund, Sweden., Subjects: 118 type 2 diabetic patients with micro-macroalbuminuria were followed for four years (range 1-8 years). METHOD AND MAIN OUTCOME MEASURES: The prognostic significance of office, day- and nighttime measurements of blood pressure (BP) for development of cardiovascular complications was studied., Results: Forty-two percent (n=49) developed one or more of the following cardiovascular endpoints: 23% (n=27) death, 9% (n=10) stroke, 9% (n=11) myocardial infarction, 9% (n=11) heart failure, 31% (n=36) uremia and 17% (n=20) need for dialysis. Reaching the goal for day- and nighttime systolic BP (SBP) at baseline of <140 mmHg was associated with lower risk for developing uremia. Reaching the goal for nighttime SBP was associated with a decreased risk for developing myocardial infarction and need for dialysis treatment. None of these associations was found for office SBP. Patients not achieving the goal for nighttime systolic blood pressure of <140 mmHg had a 12.9 times higher risk of developing myocardial infarction and 3.9 times increased risk of uremia and 2.7 times increased risk for death than patients achieving the goal., Conclusion: Nighttime blood pressure had better prognostic significance for developing cardiovascular and renal complications than office and daytime blood pressure., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Ultrasound-guided cannulation of a large-bore catheter into the internal jugular vein was performed to provide temporary hemodialysis vascular access for uremia in a 65-yr-old woman with acute renal failure and sepsis superimposed on chronic renal failure. Despite the absence of any clinical evidence such as bleeding or hematoma during the procedure, a chest x-ray and computed tomographic angiogram of the neck showed that the catheter had inadvertently been inserted into the subclavian artery. Without immediately removing the catheter and applying manual external compression, the arterial misplacement of the hemodialysis catheter was successfully managed by open surgical repair. The present case suggests that attention needs to be paid to preventing iatrogenic arterial cannulation during central vein catheterization with a large-bore catheter and to the management of its potentially devastating complications, since central vein catheterization is frequently performed by nephrologists as a common clinical procedure to provide temporary hemodialysis vascular access.

Uremic pruritus remains one of the most frustrating and potentially disabling symptoms in patients with end-stage renal disease. It affects up to 90% of patients on dialysis. Several hypotheses have been postulated for the possible underlying etiology, but none is conclusive. Aside from kidney transplantation, which is the only definitive treatment, therapeutic approaches have largely been empirical, and no firm evidence-based treatments are available. The main goal of therapy remains to minimize the severity of pruritus and improve the quality of life especially among those who are not transplantation candidates or are waiting for surgery.

Functional deterioration of the peritoneal membrane in patients on peritoneal dialysis has been described as being the result of a combination of neoangiogenesis and fibrosis. Glucose, glucose degradation products, and the unphysiological pH of the dialysate solution contribute to these changes. Although newer solutions clearly perform better in terms of their biocompatibility in an in vitro setting and in animal models, the benefit of such solutions over older solutions in the clinical setting is so far unproven. The difficulties in showing a benefit of the newer, more biocompatible solutions in the clinical setting can be explained by the fact that other factors also affect the properties of the peritoneal membrane. These factors are often neglected in clinical studies, which results in unnoticed differences in case-mix and blurs the potential impact of the novel solutions. However, many of these factors are modifiable, and attention should be paid to them in clinical practice to maintain the integrity of the peritoneal membrane. This Review focuses on factors that potentially influence the integrity of the peritoneal membrane, other than those associated with the peritoneal dialysis fluid itself.

Recent studies of timing of dialysis initiation have challenged the recent trend to earlier initiation of therapy. The observed outcomes though are a consequence of the balance between the risks of advanced uremia versus the inherent dangers relating to dialysis therapy itself. Many of these risks are inherent in how dialysis treatment is currently carried out, and may indeed be amenable to mitigation, through refinement of clinical practice (and potentially modality choice). This article aims to lay out a discussion relating to patient outcomes being the composite result of this balance, pivoting on the vulnerability of a particular patient to these attendant risks.

Uremia describes the consequences of intoxication in chronic renal failure with substances that are renally cleared in healthy individuals. Acute uremia is a syndrome of gastrointestinal symptoms, pericarditis, pleuritis, and central nervous system alterations ending with coma. These symptoms can be resolved by renal replacement therapy. In addition, chronic uremia can result in damage of multiple organ systems, which continues to advance despite dialysis therapy. This is caused by retention of toxins that cannot be adequately removed due to insufficient treatment time or a molecular weight range hampering elimination. Uremic toxins can be generated by the energy or nucleic acid metabolism, they can be proteins or large molecules that are altered chemically by the uremic milieu. Chronic uremia can influence the majority of long-term complications of chronic renal failure: systemic microinflammation, cardiovascular disease, immunodeficiency, malnutrition, anemia, bone metabolism, and polyneuropathy. There are few therapeutic options other than kidney transplantation.

We present the case of a 61-year- old female patient in long-term hemodialysis who developed calcific uremic arteriolopathy (CUA) upon administration of the oral calcimimetic agent cinacalcet for treatment of secondary hyperparathyroidism. In May 2009, the baseline serum values were parathormone (PTH) 310 pg/ml, calcium 9.1 mg/dl and phosphorous 6.9 mg/dl. Necrotic wounds in the suprapubic fat tissue were successfully treated first, by correcting the calcium phosphorous product; second, through treatment with sodium thiosulfate and third, through intensive wound care with hyperbaric oxygen therapy and vacuum-assisted closure therapy, with no need for parathyroidectomy. Multiple factors have been described to play a role in the development of CUA. Based on the findings of this case, the treatment of CUA should be aimed at correcting different causes simultaneously.

Background: Vitamin D sterols may modulate vascular response to inflammation and vascular calcification (VC)., Methods: Rat aortic rings (RARs) and human vascular smooth muscle cells (HVSMCs) were treated in vitro with phosphate (P), tumour necrosis factor alpha (TNF-α), calcitriol (CTR) and paricalcitol (PCT). Rats having undergone subtotal nephrectomy (Nx) (n = 66) on a high-phosphorus diet were treated with Escherichia coli lipopolysacharide (LPS) (40-400 μg/kg/day) or LPS plus CTR (80 ng/kg/48 h) or LPS plus PCT (240 ng/kg/48 h) for 14 days., Results: In vitro, the addition of TNF-α to the medium increased the mineral content of RAR and HVSMC. Treatment with both vitamin D analogues decreased bone morphogenetic protein 2 but did not modify Runx-2. Calcification was prevented only by PCT. In vivo, treatment with LPS increased plasma levels of TNF-α, monocyte chemotactic protein-1 and interleukin-1alfa and induced calcification. The concomitant administration of LPS with either CTR or PCT led to a significant decrease in cytokine plasma levels and the decrease was more accentuated after treatment with PCT than with CTR. Rats treated with CTR showed an elevation in aortic Ca and marked Von Kossa staining; however, rats treated with PCT did not increase aortic Ca and did not show Von Kossa staining., Conclusion: Treatment with PCT resulted in more marked anti-inflammatory effect than treatment with CTR and, as opposed to CTR, PCT prevented VC.

Background: Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Parathyroid hyperplasia in uremic rats can be prevented by calcium-sensing receptor (CaSR) activation with the calcimimetic cinacalcet (Sensipar®/Mimpara®); however, it is unknown, how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT., Methods: We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT., Results: Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia. In rats with established sHPT, cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia. The cinacalcet-mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin-dependent kinase inhibitor p21. Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium., Conclusions: The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating CaSR activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH.

Posterior reversible encephalopathy syndrome (PRES) is characterized by acute onset of headache, nausea, focal neurological deficits or seizures along with radiological findings of white matter defects in the parietal and occipital lobes. Causes of PRES include uremia, hypertensive encephalopathy, eclampsia and immunosuppressive medications. Usually, the treatment of choice involves correcting the underlying abnormality. We describe an unusual case of recurrent PRES caused by uremia during a lupus flare in a patient with biopsy-proven Class IV Lupus Nephritis (LN) with vasculitis. PRES in systemic lupus erythematosis (SLE) is a rare clinical phenomenon and, when reported, it is associated with hypertensive encephalopathy. Our patient did not have hypertensive crisis, but had uremic encephalopathy. The patient's PRES-related symptoms resolved after initiation of hemodialysis. The temporal correlation of the correction of the uremia and the resolution of the symptoms of PRES show the etiology to be uremic encephalopathy, making this the first reported case of uremia-induced PRES in Class IV LN with vasculitis.

End-stage kidney disease (ESKD) is a major health problem associated with very high morbidity and mortality secondary to cardiovascular complications, especially in ESKD patients on dialysis. Therefore, exploring key mechanisms underlying cardiovascular alterations associated with ESKD may offer reasonable pharmacological targets that may benefit these patients. Imbalanced matrix metalloproteinases (MMP) activities have been implicated in many cardiovascular diseases, and growing evidence now indicates that excessive MMP activities contribute to cardiovascular complications in ESKD patients. However, there is no study on the effects of MMP inhibitors (MMPIs) in such patients. MMPIs may prevent against the vascular and cardiac changes associated with ESKD. In this MiniReview, we aimed at reviewing current evidence supporting the idea that pharmacological inhibition of imbalanced MMP activities in ESKD may decrease the morbidity and mortality associated with cardiovascular complications in ESKD patients. However, MMPs have variable effects during different phases of kidney disease, and therefore optimal timing for MMP inhibition during a disease process may vary significantly and is largely undetermined. While current research shows that MMPs play a role in the pathogenesis of the cardiovascular alterations found in ESKD patients, clinical studies are required to validate the idea of using MMPIs in ESKD., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

The expression of the renoprotective antiaging gene Klotho is decreased in uremia. Recent studies suggest that Klotho may be a tumor suppressor, and its expression may be repressed by DNA hypermethylation in cancer cells. Here we investigated the effects and possible mechanisms by which Klotho expression is regulated during uremia in uninephrectomized B-6 mice given the uremic toxins indoxyl sulfate or p-cresyl sulfate. Cultured human renal tubular HK2 cells treated with these toxins were used as an in vitro model. Injections of indoxyl sulfate or p-cresyl sulfate increased their serum concentrations, kidney fibrosis, CpG hypermethylation of the Klotho gene, and decreased Klotho expression in renal tubules of these mice. The expression of DNA methyltransferases 1, 3a, and 3b isoforms in HK2 cells treated with indoxyl sulfate or p-cresyl sulfate was significantly increased. Specific inhibition of DNA methyltransferase isoform 1 by 5-aza-2'-deoxycytidine caused demethylation of the Klotho gene and increased Klotho expression in vitro. Thus, inhibition of Klotho gene expression by uremic toxins correlates with gene hypermethylation, suggesting that epigenetic modification of specific genes by uremic toxins may be an important pathological mechanism of disease.

Introduction: In patients with chronic kidney disease (CKD) predisposition to bleeding is frequently seen due to disturbances in platelet adhesion and aggregation. Various tests have been utilized to evaluate the disturbance of hemostasis in end-stage renal disease patients. In this trial; we evaluated skin bleeding time in patients admitted to our hospital with uremic symptoms and having hemodialysis (HD) for the first time. We also examined the effects of HD and uremia on this test and investigated its effectiveness in predicting the hemorrhagic complications before implementation of invasive procedures in uremic patients., Material-Method: Twenty nine patients (13 men,16 women; mean age 59.7 ± 18.1) with CKD who presented with symptoms of uremia and treated with HD for the first time were enrolled in this trial. The skin bleeding time were measured before initiation of first hemodialysis and after the second hemodialysis session., Results: The skin bleeding time after the second dialysis was significantly shorter when compared to pre-dialysis values (p < 0.05). Correlation analysis between the skin bleeding time and urea, creatinine, hemoglobin, platelet, and bicarbonate showed no correlation., Conclusions: Skin bleeding time could reveal the uremic platelet dysfunction and beneficial effect of dialysis in the patients who presented with uremic symptoms and treated with HD for the first time. We suggest that skin bleeding time may be an appropriate test for the evaluation of hemostasis disturbance in uremic patients and prediction of the bleeding risk before invasive procedures.

Background: The present study was designed to investigate the possible association between infertility of male uremic patients and expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in their sperm., Methods: Semen was collected and analyzed. Serum levels of FSH, LH and testosterone were measured by radioimmunoassay. The sperm CFTR expressions of 21 uremic patients and 15 renal transplant patients were measured and compared with those of 32 healthy and 33 infertile men., Results: Only 9 ± 5.9% of sperm from uremic patients expressed CFTR, significantly less than those of the renal transplant patients (29 ± 14.3%, P< 0.001), the infertile men (42 ± 20.7%, P< 0.001) and the healthy men (51 ± 20.5%, P< 0.001). Furthermore, significantly fewer sperm from renal transplant patients expressed CFTR than those of the infertile men (P< 0.05) and the healthy men (P< 0.01). LH levels in uremic patients were significantly higher than in all other groups, whereas FSH levels in uremic patients were only significantly higher than in infertile and healthy men. There was no significant difference in testosterone level among the four categories., Conclusions: Sperm CFTR expression is depressed in uremic patients but recovers to some degree after renal transplant along with some improvement in fertility, indicating a 'reversible' change. These results suggest that the CFTR expression rate in sperm is correlated with the decline of uremic patients' fertility, and may be considered as a potential marker to assess the fertility of male uremic patients.

Background: The pattern of binding of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) comprise a conformational ACE fingerprint and is a sensitive marker of subtle protein conformational changes., Hypothesis: Toxic substances in the blood of patients with uremia due to End Stage Renal Disease (ESRD) can induce local conformational changes in the ACE protein globule and alter the efficacy of ACE inhibitors., Methodology/principal Findings: The recognition of ACE by 16 mAbs to the epitopes on the N and C domains of ACE was estimated using an immune-capture enzymatic plate precipitation assay. The precipitation pattern of blood ACE by a set of mAbs was substantially influenced by the presence of ACE inhibitors with the most dramatic local conformational change noted in the N-domain region recognized by mAb 1G12. The "short" ACE inhibitor enalaprilat (tripeptide analog) and "long" inhibitor teprotide (nonapeptide) produced strikingly different mAb 1G12 binding with enalaprilat strongly increasing mAb 1G12 binding and teprotide decreasing binding. Reduction in S-S bonds via glutathione and dithiothreitol treatment increased 1G12 binding to blood ACE in a manner comparable to enalaprilat. Some patients with uremia due to ESRD exhibited significantly increased mAb 1G12 binding to blood ACE and increased ACE activity towards angiotensin I accompanied by reduced ACE inhibition by inhibitory mAbs and ACE inhibitors., Conclusions/significance: The estimation of relative mAb 1G12 binding to blood ACE detects a subpopulation of ESRD patients with conformationally changed ACE, which activity is less suppressible by ACE inhibitors. This parameter may potentially serve as a biomarker for those patients who may need higher concentrations of ACE inhibitors upon anti-hypertensive therapy.

Background:  Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). Myocardial dysfunction may occur in patients with diabetes mellitus (DM) in the absence of coronary artery disease or left ventricular (LV) hypertrophy. Although tissue Doppler imaging (TDI) is a highly effective means of quantifying myocardial diastolic function, its differences in ESRD patients with diabetes and without diabetes remain unclear., Methods and Results:  A total of 101 ESRD patients on maintenance hemodialysis with normal LV systolic function were studied: 37 with type 2 DM and 64 without DM. Conventional echocardiography and TDI were performed to evaluate LV systolic and diastolic functions. The conventional LV systolic and diastolic echocardiographic parameters did not differ according to presence of DM, except for the left atrial size and volume index (P<0.001). The ESRD patients with DM, however, had significantly decreased mitral annular early diastolic peak velocity (e') and ratio of early to late diastolic mitral annular velocity (e'/a'; both P<0.02). Additionally, the group with DM had markedly higher estimated LV end-diastolic filling pressure (E/e'; P=0.011)., Conclusions:  ESRD patients with DM had advanced LV diastolic dysfunction on TDI. In ESRD patients with DM, diabetic cardiomyopathy associated with advanced LV diastolic dysfunction is observed.  (Circ J 2012; 76: 2380-2385).

Chitosan and alkalinizing agents can decrease morbidity and mortality in humans with chronic kidney disease (CKD). Whether this holds true in dog is not known. Objective of the study was to determine whether a commercial dietary supplement containing chitosan, phosphate binders, and alkalinizing agents (Renal), compared to placebo, reduces mortality rate due to uremic crises in dogs with spontaneous CKD, fed a renal diet (RD). A masked RCCT was performed including 31 azotemic dogs with spontaneous CKD. Dogs enrolled in the study were randomly allocated to receive RD plus placebo (group A; 15 dogs) or RD plus Renal (group B; 16 dogs). During a first 4-week period, all dogs were fed an RD and then randomized and clinically evaluated up to 44 weeks. The effects of dietary supplements on mortality rate due to uremic crises were assessed. At 44 weeks, compared to group A, dogs in group B had approximately 50% lower mortality rate due to uremic crises (P = 0.015). Dietary supplementation with chitosan, phosphate binders, and alkalinizing agents, along with an RD, is beneficial in reducing mortality rate in dogs with spontaneous CKD.

Aim: To investigate the correlation of the functional disequilibrium of regulatory T cells (Treg)/T-helper (Th17) cells with calcification and to explore the significance of their influence on the outcome of cardiovascular disease (CVD) in uremic patients after hemodialysis (HD)., Methods: Out of 66 uremia patients, 36 patients had CVD after HD (maintenance hemodialysis (MHD) group1) and 30 patients did not have CVD (MHD group2). Twenty healthy volunteers were selected as normal control group. Peripheral blood mononuclear cells were isolated and treated with recombinant human bone morphogenetic protein-2 (rhBMP-2). Treg and Th17 frequencies were measured by flow cytometry. Forkhead/winged helix transcription factor (Foxp3) and retinoic acid receptor-related orphan receptor-γt (ROR-γt) mRNA expressions were measured by real-time quantitative polymerase chain reaction. Levels of interleukin (IL)-10 and IL-17 were detected by enzyme-linked immunosorbent assay., Results: When compared with controls, rhBMP-2 upregulates Treg/Th17 functional disequilibrium in uremia patients, displaying higher Treg and Th17 frequencies, Foxp3 and ROR-γt expressions, and levels of cytokines (p < 0.05). These differences were also significant between MHD group1 and group2 (p < 0.05). It was also observed that Treg/Th17 functional disequilibrium was not only correlated with a calcification state but also consistent with the CVD., Conclusion: The Treg/Th17 cell function disequilibrium might act synergistically with calcification in the high incidence of CVD after HD.

Background: Chronic kidney disease (CKD) is associated with increased risk for cardiovascular diseases (CVD). We hypothesized that inadequate angiogenic response in uremic patients could result from dysfunction of bone marrow-derived stromal cells [mesenchymal stem cells (MSCs)]., Methods: We investigated whether MSCs are functionally competent in uremia induced by partial kidney ablation in C57Bl/6J mice., Results: Uremic MSCs showed decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1 and stromal cell-derived factor (SDF)-1α, increased cellular senescence, decreased proliferation, defects in migration in response to VEGF and SDF-1α and in vitro tube formation. Interestingly, the expression of fibroblast-specific protein-1 was higher in uremic MSCs. Uremia decreased hypoxia-inducible factor-1α, VEGF and VEGFR1 expression under hypoxia and Akt phosphorylation in both basal and VEGF-stimulated states. A diminished mitogenic effect on endothelial proliferation was observed in conditioned media from uremic MSCs. In addition, intravital microscopic analysis showed decreased angiogenesis in uremic MSCs., Conclusion: These results clearly demonstrate the functional incompetence in MSCs under uremic conditions and may significantly contribute to the disproportionately high risk for CVD in patients with CKD.

Human urotensin II (hUII) is a newly discovered substance that can dilate small blood vessels to decrease the blood pressure (BP). Our previous studies showed that some volume-overloaded patients on peritoneal dialysis can maintain normal BP (congestive heart failure excluded), suggesting that these patients have volume resistance capacity. This study is to investigate whether hUII plays an important role in this subgroup of patients on peritoneal dialysis. In this study, 105 patients on continuous ambulatory peritoneal dialysis were enrolled. Volume load was evaluated by the overhydration (OH) value obtained by bioimpedance analysis. OH < 2.0 kg was defined as normal volume (NV), and OH ≥ 2.0 kg as high volume (HV). Systolic blood pressure (SBP) <130 mmHg was defined as normotension (NT) and ≥130 mmHg as hypertension (HT). The patients were thus divided into four subgroups: (1) normotension with normal volume (NT-NV), (2) normotension with high volume (NT-HV), (3) normal volume with hypertension (HT-NV), and (4) high volume with hypertension (HT-HV). hUII was measured using radioimmunoassay method. hUII was significantly higher in normal SBP group than that in high SBP group (p < 0.05). hUII was higher in the NT-HV group compared with that in the HT-HV group (p < 0.05). Our study suggests that hUII may be involved in the pathogenesis of the volume resistance HT in peritoneal dialysis patients.

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.

Background: MicroRNAs (miRNAs) are important regulators of gene expression, which have roles in renal development and disease. They exist in biological fluids including blood and urine and may have signalling roles and potential as disease biomarkers., Methods: We measured the levels of miRNAs in patients with different stages of chronic kidney failure including those receiving maintenance haemodialysis treatment., Results: In patients with severe chronic renal failure, circulating levels of total and specific miRNAs are reduced in comparison to patients with mild renal impairment or normal renal function. A strong correlation exists between detected circulating miRNAs and estimated glomerular filtration rate, and less strong correlations with other features of chronic kidney disease, such as anaemia and hyperparathyroidism., Conclusion: These findings have important implications for the use of circulating miRNAs as biomarkers in individuals with renal impairment and for the pathogenesis of uraemia.

Purpose of Review: Inflammation is a major driving force of the uremic phenotype. This review provides an update on inflammatory biomarkers in chronic kidney disease and possible therapeutic approaches targeting the uremic inflammatory milieu., Recent Findings: Single and longitudinal changes of C-reactive protein provide important outcome prediction. The uremic phenotype, which includes persistent inflammation, oxidative stress and protein energy wasting, has recently been shown to overshadow the traditional risk profile. As several small randomized controlled trials have shown that various nutritional, nonspecific immunomodulatory and targeted anticytokine interventions may have anti-inflammatory potential, future randomized control trials are needed to explore whether interventions specifically targeting inflammation will improve the dismal prognosis in end-stage renal disease., Summary: Because circulating inflammatory markers predict outcomes in patients with end-stage renal disease, inflammation may be a logical future therapeutic target for nutritional and pharmacological interventions.

Background: Sexual function is altered in patients with type 1 diabetes (T1D) and end-stage renal disease (ESRD), thus affecting quality of life. The present study aimed to analyze sexual function in patients with T1D and ESRD (T1D+ESRD) who received a simultaneous kidney-pancreas (KP) or kidney-alone (KD) transplantation., Methods: Ten KP, 10 KD, 9 T1D+ESRD patients and 11 healthy control subjects were evaluated according to the following parameters: (1) medical/sexual history and physical examination; (2) International Index of Erectile Function; (3) Beck's inventory for depression; (4) assessment of hormonal profile; (5) quantitative sensory testing of both hand and penile sensory thresholds; and (6) hemodynamic penile assessment., Results: Controls and KP patients showed a higher rate of self-reported satisfactory erectile function as compared with KD and T1D+ESRD patients. Circulating androgens level resulted lower in both groups of transplanted patients and in patients with T1D+ESRD compared with healthy controls, albeit a relatively better profile was observed in KP. Both transplanted and T1D+ESRD patients showed peripheral hyposensitivity; however, healthy controls and KP showed better penile hemodynamic parameters compared with KD and T1D+ESRD., Conclusions: Our study demonstrates that sexual function, circulating sex steroids milieu, penile sensitivity, and hemodynamics are near-normalized for the most part in KP transplantation. Further studies are needed to assess the beneficial role and the overall impact of KP transplantation on sexual function in a long-term setting and a larger cohort of patients.

Background: The high rate of cardiovascular mortality in patients with end-stage renal disease (ESRD) is a significant barrier to improved life expectancy. Unique in this population is the marked development and aggressive worsening of vascular calcification (VC). Pyrophosphate (PPi), an endogenous molecule, appears to naturally inhibit soft tissue calcification, but may be depressed in chronic kidney disease (CKD) and ESRD. Although once thought to be a promising therapeutic, PPi's very short half-life in circulation curtailed earlier studies. We tested the possibility that a slow, continuous entry of PPi into the circulation and prevention of VC might be achieved by daily peritoneal dialysis (PD)., Methods: Pharmacokinetic studies were first carried out in rats with renal impairment resulting from a 5/6 nephrectomy. Efficacy studies were then performed in the apolipoprotein E gene knockout mouse model overlaid with CKD. PPi was delivered by means of a permanent peritoneal catheter in a solution simulating PD, but without the timed removal of spent dialysate. von Kossa's staining followed by semiquantitative morphological image processing, with separation of inside (intimal) and outside (presumed medial) lesions, was used to determine aortic root calcification., Results: In comparison to an intravenous bolus, delivery of PPi in a PD solution resulted in a slower, extended delivery over >4 h. Next, the efficacy studies showed that a 6-day/week PD-simulated administration of PPi resulted in a dose-dependent inhibition of aortic calcification in both intimal and medial lesions. A dose-response effect on total aortic calcification was also documented, with a full inhibition seen at the highest dose. A limited peritoneal catheter-related inflammation was observed, as expected, and included the placebo-treated control groups. This inflammatory response could have masked a lower level PPi-specific adverse effect, but none was observed., Conclusions: Our findings suggest potential for PPi, administered during PD, to prevent the development of VC and to potentially extend the life of ESRD patients.

Background: Uremic pruritus (UP) is still a common tormenting symptom among patients on hemodialysis (HD). The pathogenesis of UP is complex and not fully clarified. Some preliminary studies indicate that UP is a systemic inflammatory disease with a deranged balance of T helper (TH) cell differentiation toward TH1 predominance. The aim of this study was to further elucidate the potential contribution of TH1 cytokines to the pathogenesis of UP., Methods: In this study, 112 HD patients were screened for UP. After meeting the required criteria, 31 HD patients with UP were included in the study as case group and 30 age- and sex-matched HD patients without UP were enrolled as controls. The serum levels of interleukin (IL)-2 and interferon-γ (as TH1 cytokines), IL-4 (as a TH-2 cytokine), high-sensitive C-reactive protein (as an inflammatory marker), parathyroid hormone, calcium, phosphate, albumin and ferritin were measured in all patients. Moreover, blood variables including hemoglobin and mean corpuscular volume were also determined. The correlations of measured factors with UP severity were determined as well., Results: Except for the serum levels of IL-2, which were significantly higher in HD patients with itch versus those without it [0.544 ± 0.126 (U/mL) versus 0.318 ± 0.145 (U/mL); P < 0.0001], no statistically significant difference was observed in the levels of each of the above-mentioned factors between the two groups. Additionally, no correlation was detected between the levels of measured factors and UP severity., Conclusions: The results of our study, for the first time, point to the potential important role of IL-2 in UP and further support the notion of TH1 overactivity in its pathogenesis. Our study paves the way for further studies focusing on the contribution of IL-2 to the UP, such as the experimental use of anti-IL-2 receptor antibodies.

Oxidative response and inflammation constitute a major defense against infections, but if not properly regulated they could also lead to a number of deleterious effects. Patients affected by different stages of acute and chronic kidney disease, particularly patients on hemodialysis, present a marked activation of oxidative and inflammatory processes. This condition exposes these patients to an elevated risk of morbidity and mortality. This Review is up to date and it analyses the newest notions about pathophysiological mechanisms of oxidative stress and inflammation in patients with renal diseases, also considering the different strategies studied to counterbalance this high risk state., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate the effects of recombinant human endostatin (Endostar) on peritoneum angiogenesis in a model of dialysate exposure in rats., Methods: Forty male Sprague-Dawley rats were randomized to five groups: normal (group 1); uraemia (group 2); 4.25% peritoneal dialysate (PD) uraemic (group 3); uraemia + PD + recombinant human endostatin 10 mg/kg PD (group 4); and uraemia + PD + recombinant human endostatin 40 mg/kg PD (group 5). The uraemic rats model was established by 5/6 nephrectomy. Endostatin was administrated by s.c. injection every other day, over 28 days. After 28 days of PD fluid exposure, immunohistochemistry and reverse transcript polymerase chain reaction were used to detect protein and mRNA expressions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in each group. Microvessel density (MVD) was measured by immunohistochemistry., Results: Compared with group 1, the mRNA and protein expressions of VEGF and bFGF were significantly upregulated in groups 2 and 3 (P < 0.05). Compared with group 3, the mRNA and protein expressions of VEGF and bFGF were significantly downregulated in groups 4 and 5 (P < 0.05). Compared with group 4, the mRNA and protein expressions of VEGF and bFGF were significantly downregulated in group 5 (P < 0.05). Compared with group 1, MVD was significantly upregulated in groups 2 and 3 (P < 0.05). Compared with group 3, MVD was significantly downregulated in groups 4 and 5 (P < 0.05)., Conclusion: Endostar can effectively inhibit rat peritoneum neoangiogenesis and the effect was dose-dependent., (© 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.)

Tumoral calcinosis is an uncommon and severe complication of hemodialysis therapy. The most important pathogenic factor involved in uremic tumoral calcinosis is an increase in calcium-phosphorus product, not necessarily related to hyperparathyroidism. We report here a patient on hemodialysis who presented with increasing multifocal and uncommon sites of massive calcifications. The patient was examined, and a diagnosis of uremic tumor calcinosis was made. The patient was treated with the noncalcemic phosphate binder sevelamer, a strict diet, multiple hemodialysis sessions per week, and a low calcium dialysate, with improvement on biological findings a decrease in the volume of some tumors on his fingers and a global stable disease. Some nodes in hands and feet disappeared; in other sites, their diameter was reduced, and the largest nodule decreased from 5- to 2-cm diameter.

Purpose: The aim of this study was to evaluate cardiovascular remodeling after arteriovenous fistula (AVF) surgery and to characterize the effect of chronic kidney disease (CKD) in a rodent femoral AVF model., Methods: Sixteen rats (8 healthy; 8 CKD) underwent femoral AVF surgery; 4 animals served as controls. AVF and cardiac morphology as well as function were assessed during the fistula maturation process (until day 84 after surgery) using magnetic resonance imaging and histopathological analyses., Results: Histopathological analysis revealed that a glomerular and interstitial nephropathy caused CKD. In healthy and CKD animals, AVF surgery resulted in progressive downstream vein dilation and a subsequent cardiac adaptation. This vein dilation during maturation was less in CKD rats during the early postoperative course (day 21: p=0.0475) and similar thereafter until day 84. The dilation was accompanied by an aggravation of neointimal hyperplasia (NIH) and calcification in AVFs of CKD rats. The chronic volume overload resulted in both groups in a significantly increased end-diastolic volume (healthy rats: p=0.0087; CKD rats: p=0.0333). Simultaneously, cardiac output increased 195% in healthy and 244% in uremic rats, which was caused by both a significantly increased stroke volume and heart rate. The left ventricular mass rose in AVF animals and was increased at the end of the study period, indicating a distinct cardiac hypertrophy., Conclusion: Our rat model showed typical cardiovascular features of the AVF maturation process, which strongly resemble clinical findings in patients. Uremia caused inferior dilation in the early phase after surgery and an exacerbation of NIH. This model should help to identify the cellular and molecular mechanisms that contribute to AVF failure.

Critically ill animals may have preexisting renal disease or develop acute kidney injury as a consequence of their presenting complaint. Age, concurrent medical therapy, electrolyte and fluid imbalances, and exposure to potential nephrotoxicants are factors that predispose to acute kidney injury. Many risk factors are correctable or manageable, and these should be addressed whenever possible. Measurement of serum creatinine is insensitive for the detection of acute kidney injury, and clinicians should consider assessment of other parameters such as urine output, urinalysis, and urine chemistry results. A stepwise approach for management of acute kidney injury in small animal patients is outlined., (Copyright © 2011 Elsevier Inc. All rights reserved.)

End-stage renal disease (ESRD) causes oxidative stress, inflammation, low-density lipoprotein (LDL) oxidation, high-density lipoprotein (HDL) deficiency and accelerated atherosclerosis. Uptake of oxidized LDL by macrophages results in foam cell and plaque formation. HDL mitigates atherosclerosis via reverse cholesterol transport and inhibition of LDL oxidation. ESRD heightens LDL inflammatory activity and suppresses HDL anti-inflammatory activity. The effect of hemodialysis on the LDL and HDL inflammatory properties is unknown. By removing the potential pro-oxidant/proinflammatory uremic toxins, dialysis may attenuate LDL inflammatory and HDL anti-inflammatory properties. Conversely, exposure to dialyzer membrane and tubing and influx of impurities from dialysate can intensify LDL and HDL inflammatory activities. This study examined the effect of hemodialysis on LDL and HDL inflammatory activities. Plasma samples were obtained from 12 normal control and 26 ESRD patients before and after hemodialysis with (16 patients) or without (10 patients) heparinization. HDL and LDL were isolated and tested for monocyte chemotactic activity in cultured endothelial cells. ESRD patients had increased LDL chemotactic activity, reduced HDL anti-inflammatory activity, paraoxonase and glutathione peroxidase levels, and elevated plasma IL-6 before dialysis. Hemodialysis partially improved LDL inflammatory and HDL anti-inflammatory activities and enhanced patients' HDL ability to suppress their LDL inflammatory activity. The salutary effect on LDL inflammatory activity was significantly greater in patients dialyzed with than those without heparin. ESRD heightens LDL inflammatory and impairs HDL anti-inflammatory activities. Hemodialysis partially improves LDL and HDL inflammatory activities. The salutary effects of hemodialysis are in part mediated by heparin, which is known to possess lipolytic and antioxidant properties.

A total of 334 end-stage renal disease patients with moderate-to-severe uraemic xerosis were surveyed for quality of life assessment, using the generic Short-Form (SF-12) scale and the Dermatology Life Quality Index (DLQI). In parallel, the intensity of xerosis at four sites (the two lower legs, chest, forearm without arterio-venous shunt) was assessed, using a five-point lesional intensity score. Pruritus was auto-assessed by the patients, using a 100-mm visual analogue scale. Uraemic xerosis patients had a marked deterioration in the Physical Component Summary of SF-12 (mean ± SD: 34.92 ± 9.98) and DLQI (5.06 ± 4.73). Younger age (r = -0.20), xerosis intensity (r = 0.14), and the presence of pruritus (p < 0.0001) and its intensity (r = 0.50) were shown to be significant worsening factors of DLQI. Because a low, but significant, correlation between the intensity of xerosis and pruritus was also demonstrated (r = 0.18), the direct contribution of age, xerosis and pruritus on DLQI was analysed in a multiple linear regression model. Age and pruritus intensity, but not xerosis intensity, were found to be independent contributors to DLQI deterioration (p < 0.0005). On the other hand, uraemic xerosis without associated pruritus still resulted in DLQI alteration (3.24 ± 3.99). It was concluded that young age and intensity of uraemic pruritus compromise quality of life in uraemic xerosis patients. Some characteristics of uraemic xerosis other than xerosis intensity may also be involved in quality of life alteration.

Risk for amyloidosis in rheumatic diseases is associated with a long-lasting inflammation. To assess possible changes in the incidence of terminal uraemia due to amyloidosis associated with rheumatic diseases on a nationwide basis, we scrutinised the files of the Finnish Registry for Kidney Diseases for patients suffering from amyloidosis associated with rheumatoid arthritis (RA), ankylosing spondylitis (AS) or juvenile idiopathic arthritis (JIA) over the period 1995-2008. The registry has an estimated 97-99% coverage of all patients accepted for renal replacement therapy (RRT) in the country. Data on the consumption of antirheumatic drugs were collected from two sources: the Social Insurance Institution's Drug Reimbursement Register, and the Sales Register of the National Agency for Medicines from the above period. Altogether 264 cases were identified. Two hundred twenty-nine of them had RA, 15 AS and 20 JIA. When the total annual number of new admissions to RRT varied between 20 and 37 at the end of 1990s, it was under half of that from 2002 onwards. Over this period, the number of users of low-dose methotrexate (MTX) has increased 3.6-fold, the drug being the most frequently used disease modifying anti-rheumatic drug in Finland. The present nationwide series is the first to show that the incidence of end-stage renal disease due to amyloidosis associated with rheumatic diseases is decreasing. An obvious reason for this is intensive anti-rheumatic drug therapy.

Background and Objectives: Premature cardiovascular (CV) events, especially sudden cardiac death, are common in ESRD patients and associated with uremic cardiomyopathy. Identification of high-risk patients is difficult. Microvolt T-wave alternans (MTWA) is a noninvasive method of detecting variability in electrocardiogram (ECG) T-wave morphology and is a promising technique for identifying patients at high risk of ventricular tachyarrhythmias. MTWA results of ESRD and hypertensive left ventricular hypertrophy (LVH) patients were assessed to determine the prevalence of abnormal results and associations with uremic cardiomyopathy., Design, Setting, Participants, & Measurements: In this single-center observational study, 200 ESRD and 30 LVH patients underwent assessment including CV history, ECG, cardiac magnetic resonance imaging, and an MTWA exercise test. MTWA results were classified as "negative" or "abnormal" on the basis of previously published reports., Results: An abnormal MTWA result was more common in ESRD compared with LVH patients (57.5% versus 26.7%, respectively; P = 0.002). In ESRD patients, MTWA was significantly associated with uremic cardiomyopathy, clinical history of atherosclerosis (coronary, cerebral, peripheral) and diabetes mellitus, older age, and hemodialysis therapy. Independent associations with an abnormal MTWA result were older age, macrovascular disease, increased left ventricle (LV) mass, and LV dilation., Conclusions: Features of uremic cardiomyopathy are associated with an abnormal MTWA result.

Together with the development of peritoneal dialysis (PD), appropriate animal models play an important role in the investigation of physiological, pathophysiological and clinical aspects of PD. However, there is still not an ideal experimental PD animal model. In this study, 45 Sprague-Dawley rats were divided into three groups. Group 1 (n=15) was receiving daily peritoneal injection through the catheter connected to the abdominal cavity, using PD solution containing 3.86 % D-glucose. Group 2 (n=15) was receiving daily peritoneal injection of 0.9 % physiological saline through a catheter. Group 3 (n=15), which was subjected to sham operation, served as controls. Our results showed that WBC counts in peritoneal effluent of Group 1 were slightly higher than those of Group 2 and control group, respectively (p<0.05). However, there was no episode of infection in any group. In addition, there was no significant difference in neutrophils fractions among these three groups. Hematoxylin-eosin and Masson's trichrome staining demonstrated a dramatic increase in thickness of the mesothelium-to-muscle layer of peritoneum exposed to high glucose (Group 1) compared to Group 2 and controls (p<0.01). These data indicated that we established a novel rat model of PD with a modified catheter insertion method. This model is more practical, easy to operate, not too expensive and it will facilitate the investigate of long-term effects of PD.