Abstract: BACKGROUND: Treatment decisions made by patients with chronic kidney disease are crucial in the renal transplantation process. These decisions are influenced, amongst other factors, by attitudes towards different treatment options, which are modulated by knowledge and perceptions about the disease and its treatment and many other subjective factors. Here we study the attitude of dialysis patients to renal transplantation and the association of sociodemographic characteristics, patient perceptions and experiences with this attitude. METHODS: In a cross-sectional study, all patients from eight dialysis units in Budapest, Hungary, who were on haemodialysis for at least 3 months were approached to complete a self-administered questionnaire. Data collected from 459 patients younger than 70 years were analysed in this manuscript. RESULTS: Mean age of the study population was 53 +/- 12 years, 54% were male and the prevalence of diabetes was 22%. Patients with positive attitude to renal transplantation were younger (51 +/- 11 versus 58 +/- 11 years), better educated, more likely to be employed (11% versus 4%) and had prior transplantation (15% versus 7%)(P < 0.05 for all). In a multivariate model, negative patient perceptions about transplantation, negative expectations about health outcomes after transplantation and the presence of fears about the transplant surgery were associated, in addition to increasing age, with unwillingness to consider transplantation. CONCLUSIONS: Negative attitudes to renal transplantation are associated with potentially modifiable factors. Based on this we suggest that it would be necessary to develop standardized, comprehensible patient information systems and personalized decision support to facilitate modality selection and to enable patients to make fully informed treatment decisions.

Abstract: Kidney transplantation provides the best outcome for patients with end-stage renal failure both in terms of morbidity and mortality and health-related quality of life (QoL). Health-related QoL has become recognized as an important outcome measure in patients with different chronic medical conditions, including chronic kidney disease (CKD). There are several factors in kidney-transplanted patients which have a negative impact on QoL in these patients. Sleep disorders, such as insomnia, sleep apnea syndrome (SAS), and restless legs syndrome (RLS), are common in kidney-transplanted patients and clearly belong to this group of factors, although there is only limited published data available about the association between sleep problems and QoL in this patient population. The prevalence of both insomnia and RLS is reduced in kidney-transplanted patients compared to dialysis patients, and it is similar to the prevalence observed in the general population. The prevalence of sleep apnea, however, is very high, around 30%. The association between the presence of these sleep disorders and impaired QoL has been relatively well documented in dialysis patients, but there is only scarce published information about this association in the kidney transplant population. In this paper, we will summarize data from the literature describing the impact of sleep problems, which are potentially treatable, on QoL in kidney-transplanted patients. We suggest that the appropriate diagnosis and management of sleep disorders may improve QoL in kidney-transplanted patients.

Abstract: Obstructive sleep apnea is the most frequent sleep disorder. The prevalence of sleep apnea in the general population is 2-4% and the main characteristic of the disease is the intermittent cessation or substantial reduction of airflow during sleep, caused by complete, or near complete upper airway obstruction. Decreased airflow is followed by oxygen desaturation and intermittent arousals. The clinical presentation of the disorder is complex. Loud snoring with breathing pauses and daytime sleepiness should raise the suspicion of sleep apnea, but we have to consider this disease if the patient has therapy resistant hypertension, heart failure, arrhythmias, stroke, depression or memory problems. Family physicians have an important role in recognizing sleep apnea. High risk patients can easily be identified by the main symptoms and using the Berlin sleep apnea questionnaire. These patients should be referred to a sleep laboratory for polysomnographic assessment and, if necessary, for further treatment.

Abstract: Macula densa (MD) cells express the Na(+)/H(+) exchanger (NHE) isoform NHE2 at the apical membrane, which may play an important role in tubular salt sensing through the regulation of cell volume and intracellular pH. These studies aimed to determine whether NHE2 participates in the MD control of renin synthesis. Renal renin content and activity and elements of the MD signaling pathway were analyzed using wild-type (NHE2(+/+)) and NHE2 knockout (NHE2(-/-)) mice. Immunofluorescence studies indicated that NHE2(-/-) mice lack NHE3 at the MD apical membrane, so the other apical NHE isoform has not compensated for the lack of NHE2. Importantly, the number of renin-expressing cells in the afferent arteriole in NHE2(-/-) mice was increased approximately 2.5-fold using renin immunohistochemistry. Western blotting confirmed approximately 20% higher renal cortical renin content in NHE2(-/-) mice compared with wild type. No-salt diet for 1 wk significantly increased renin content and activity in NHE2(+/+) mice, but the response was blunted in NHE2(-/-) mice. Renal tissue renin activity and plasma renin concentration were elevated three- and twofold, respectively, in NHE2(-/-) mice compared with wild type. NHE2(-/-) mice also exhibited a significantly increased renal cortical cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase (mPGES) expression, indicating MD-specific mechanisms responsible for the increased renin content. Significant and chronic activation of ERK1/2 was observed in MD cells of NHE2(-/-) kidneys. Removal of salt or addition of NHE inhibitors to cultured mouse MD-derived (MMDD1) cells caused a time-dependent activation of ERK1/2. In conclusion, the NHE2 isoform appears to be important in the MD feedback control of renin secretion, and the signaling pathway likely involves MD cell shrinkage and activation of ERK1/2, COX-2, and mPGES, all well-established elements of the MD-PGE(2)-renin release pathway.

Abstract: We investigated the mechanism whereby cell contact injury stimulates the alpha-smooth muscle actin (SMA) promoter, a key process for epithelial-mesenchymal transition (EMT) during organ fibrosis. Contact disruption by low-Ca(2+) medium (LCM) activated Rac, PAK and p38 MAPK, and triggered the nuclear accumulation of myocardin-related transcription factor (MRTF), an inducer of the SMA promoter. Dominant negative (DN) Rac, DN-PAK, DN-p38, or the p38 inhibitor SB203580 suppressed the LCM-induced nuclear accumulation of MRTF and the activation of the SMA promoter. These studies define novel pathway(s) involving Rac, PAK, and p38 in the regulation of MRTF and the contact-dependent induction of EMT.

Abstract: Chronic kidney disease (CKD) is frequently associated with other chronic medical conditions. Adjusting for potential confounding factors that are associated with the outcome of interest is important both in clinical research and in everyday clinical practice. Comorbidity is such an important co-variable that it is reported to predict different outcomes in patients with ESRD. Health related quality of life (HRQoL) has increasingly been recognized as an important aspect of health care delivery, measure of effectiveness and patient experience, in chronic medical conditions. The progressively older ESRD patient population of industrialized countries is significantly debilitated by the burden of disease and also by the intrusiveness of renal replacement therapies. For these patients simply prolonging life is not enough. Little information has been published about the association of comorbidity and HRQoL. The aim of this review is to summarize the significance of comorbidity in patients with ESRD, with a special focus on the complex relationship between comorbidity and HRQoL. Several frequently used instruments will be described and the current literature, that compared the relative utility and accuracy of these tools, will be reviewed. Finally, the impact of selected medical conditions on HRQoL of patients with end-stage renal disease will be demonstrated.

Abstract: We examined the prevalence of diabetes in a large, Hungarian, nationally representative adult population sample. The overall prevalence of diabetes was 6.2% (95% CI: 5.7-6.6). Increasing age and body mass index (BMI), male gender, physical inactivity, lower self-reported financial status, hypertension and non-smoking were independently associated with diabetes.

Abstract: STUDY OBJECTIVES: We assessed the prevalence of self-reported snoring in the Hungarian population and established whether different types of snoring are associated with cardiovascular disorders and increased health-care utilization. DESIGN: Cross-sectional study. Door-to-door survey. SETTING: Nationally representative population in Hungary. PARTICIPANTS: Interviews were carried out in the homes of 12,643 persons. We used the Hungarian National Population Register as the sampling frame and implemented a clustered, stratified sampling procedure. The study population represented 0.16% of the population over the age of 18 years according to age, sex, and 150 subregions of the country. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Thirty-seven percent of men and 21% of women reported loud snoring with breathing pauses. Hypertension, myocardial infarction, and stroke were reported by 26%, 3%, and 4% of the respondents, respectively. There was a significant increase in the prevalence of hypertension, myocardial infarction, and stroke in quiet and loud snorers, as compared with nonsnorers. Multivariate analysis showed an association between loud snoring and hypertension (odds ratio [OR]: 1.40, 95% confidence interval [CI]: 1.24-1.58), myocardial infarction (OR: 1.34, CI: 1.04-1.73), and stroke (OR: 1.67, CI: 1.32-2.11) after statistical adjustment for age, sex, body mass index, diabetes, level of education, smoking, and alcohol consumption. Loud snoring was also associated with measures of health-care use in both sexes. CONCLUSIONS: Snoring is frequent in the Hungarian adult population, and loud snoring with breathing pauses, in contrast with quiet snoring, is associated with an increased risk of cardiovascular disease and increased health-care utilization.

Abstract: BACKGROUND: Transforming growth factor-beta (TGFbeta)-induced epithelial-myofibroblast transdifferentiation is a central mechanism contributing to the pathogenesis of progressive tubulo-interstitial fibrosis. We wanted to dissect the role of extracellular signal-regulated protein kinase (ERK1,2), p38 mitogen-activated protein kinase (p38 MAPK) and the receptor-regulated Smad proteins in the regulation of alpha-smooth muscle cell actin (alphaSMA) expression, a hallmark of myofibroblast formation, induced by TGFbeta in renal proximal tubular cells. METHODS: Activation of signalling molecules was assessed by western blotting using phospho-specific antibodies. To specifically interfere with signalling cascades, porcine proximal tubular cells (LLC-PK/AT1) were infected with recombinant replication-deficient adenoviruses. In other experiments, specific kinase inhibitors were used. The alphaSMA synthesis was assessed by western blotting or immunofluorescent staining of cellular alphaSMA. To assess the regulation of the alphaSMA promoter, tubular cells were transiently transfected with a 785 bp alphaSMA promoter-luciferase reporter construct and vectors interfering with the Smad pathway. RESULTS: Blocking ERK1,2 activation with PD98059 or p38 MAPK with SB 203580 potently inhibited the TGFbeta-induced alphaSMA synthesis in renal tubular cells. Adenoviral expression of dominant negative (DN) p38beta but not of p38alpha potently inhibited alphaSMA expression. Furthermore, adenoviral expression of DN MKK6b but not of DN MKK3b caused a substantial inhibition of the TGFbeta effect, confirming the role of p38beta in the regulation of TGFbeta-induced alphaSMA expression. Finally, inhibiting the Smad pathway with adenovirally delivered Smad7 and DN Smad3 also blocked TGFbeta-induced alphaSMA synthesis. CONCLUSION: TGFbeta-induced alphaSMA expression is regulated by the coordinated activation of a complex system of parallel MAPK and Smad signalling pathways in renal proximal tubular cells during epithelial-mesenchymal transdifferentiation.

Abstract: Epithelial-mesenchymal-myofibroblast transition (EMT), a key feature in organ fibrosis, is regulated by the state of intercellular contacts. Our recent studies have shown that an initial injury of cell-cell junctions is a prerequisite for transforming growth factor-beta1 (TGF-beta1)-induced transdifferentiation of kidney tubular cells into alpha-smooth muscle actin (SMA)-expressing myofibroblasts. Here we analyzed the underlying contact-dependent mechanisms. Ca(2+) removal-induced disruption of intercellular junctions provoked Rho/Rho kinase (ROK)-mediated myosin light chain (MLC) phosphorylation and Rho/ROK-dependent SMA promoter activation. Importantly, myosin-based contractility itself played a causal role, because the myosin ATPase inhibitor blebbistatin or a nonphosphorylatable, dominant negative MLC (DN-MLC) abolished the contact disruption-triggered SMA promoter activation, eliminated the synergy between contact injury and TGF-beta1, and suppressed SMA expression. To explore the responsible mechanisms, we investigated the localization of the main SMA-inducing transcription factors, serum response factor (SRF), and its coactivator myocardin-related transcription factor (MRTF). Contact injury enhanced nuclear accumulation of SRF and MRTF. These processes were inhibited by DN-Rho or DN-MLC. TGF-beta1 strongly facilitated nuclear accumulation of MRTF in cells with reduced contacts but not in intact epithelia. DN-myocardin abrogated the Ca(2+)-removal- +/- TGF-beta1-induced promoter activation. These studies define a new mechanism whereby cell contacts regulate epithelial-myofibroblast transition via Rho-ROK-phospho-MLC-dependent nuclear accumulation of MRTF.

Abstract: Although anemia is a known risk factor of mortality in several patient populations, no prospective study to date has demonstrated association between anemia and mortality in kidney-transplanted patients. In our prospective cohort study (TransQol-HU Study), we tested the hypothesis that anemia is associated with mortality and graft failure (return to dialysis) in transplanted patients. Data from 938 transplanted patients, followed at a single outpatient transplant center, were analyzed. Sociodemographic parameters, laboratory data, medical history and information on comorbidity were collected at baseline. Data on 4-year outcome (graft failure, mortality or combination of both) were collected prospectively from the patients' charts. Both mortality and graft failure rate during the 4-year follow-up was significantly higher in patients who were anemic at baseline (for anemic vs nonanemic patients, respectively: mortality 18% vs. 10%; p < 0.001; graft failure 17% vs 6%; p < 0.001). In multivariate Cox proportional hazard models the presence of anemia significantly predicted mortality (HR = 1.690; 95% CI: 1.115-2.560) and also graft failure (HR = 2.465; 95% CI: 1.485-4.090) after adjustment for several covariables. Anemia, which is a treatable complication, is significantly and independently associated with mortality and graft failure in kidney-transplanted patients.

Abstract: BACKGROUND: Previous studies showed an association between the presence of restless legs syndrome (RLS) and mortality in patients on dialysis therapy. An association between RLS and cardiovascular risk also was reported in the general population. However, no prospective study to date assessed the association between the presence of RLS and mortality in kidney transplant recipients. In a prospective cohort study (Transplantation and Quality of Life-Hungary Study), we tested the hypothesis that the presence of RLS predicts mortality in transplant recipients. STUDY DESIGN: Prospective cohort study was performed. SETTINGS & PARTICIPANTS: 804 kidney transplant recipients followed up at a single outpatient transplant center were enrolled in the study. Sociodemographic parameters, laboratory data, and medical history were collected at baseline. Data for 4-year outcomes were collected prospectively from patient charts. PREDICTOR: Presence of RLS assessed using the RLS Questionnaire. OUTCOME & MEASUREMENTS: We defined 3 primary outcomes: mortality with functioning graft, return to dialysis therapy, and the combined outcome of these 2. RESULTS: Mean age was 49 +/- 13 years, estimated glomerular filtration rate was 49 +/- 19 mL/min/1.73 m(2), and median time after transplantation was 54 months. During the 4 years, 97 patients died and 63 patients returned to dialysis therapy. Mortality at 4 years was significantly greater in patients who had RLS at baseline: univariate hazard ratio for the presence of RLS was 2.53 (95% confidence interval, 1.31 to 4.87). In multivariate Cox proportional hazard analysis, the presence of RLS significantly predicted mortality (hazard ratio, 2.02; 95% confidence interval, 1.03 to 3.95) after adjustment for several covariables. LIMITATIONS: The RLS Questionnaire was not validated in transplant recipients. We lacked information for key variables, including HLA mismatch, panel reactive antibodies, cold ischemic time, acute rejection episodes, viral infections, smoking status, and dyslipidemia. CONCLUSIONS: RLS, a potentially treatable disease, is a significant risk factor for mortality in kidney transplant recipients.

Abstract: OBJECTIVE: Restless legs syndrome (RLS) is associated with insomnia and impaired quality of life (QoL) in patients on maintenance dialysis; however, no information has been published on the association of RLS and QoL in kidney-transplanted patients. In a cross-sectional study, we analyzed the complex relationship between RLS, insomnia, and health-related QoL in kidney-transplanted patients. METHODS: In a cross-sectional survey at a single transplant center, 1067 patients were invited to participate. Complete data set was available from 785 kidney-transplanted patients. The RLS Questionnaire and the Athens Insomnia Scale were used to assess the prevalence of RLS and insomnia, respectively. QoL was measured using the Kidney Disease QoL-SF Questionnaire. RESULTS: Patients with RLS were three times more likely to have insomnia than patients without RLS (29% vs. 9%, P=.001), and the presence of RLS was a significant and independent predictor of insomnia in multivariate analysis. The presence of RLS was independently associated with impaired health-related QoL along several QoL domains after statistical adjustment for clinical and sociodemographic covariables. Importantly, this association remained significant even after adjusting for insomnia for some QoL domains. CONCLUSION: RLS is associated with poor sleep, increased odds for insomnia, and impaired QoL in kidney-transplanted patients. Our results suggest that both sleep-related and sleep-independent factors may contribute to the association of RLS and QoL.

Abstract:

Abstract: BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) is much more prevalent in patients on dialysis than in the general population. Our aim was to assess for the first time the prevalence of patients with a high risk for OSAS and its clinical correlates in a large sample of kidney transplanted patients. We also wanted to compare the prevalence of the disorder between waitlisted dialysis patients (WL) and kidney transplanted patients (Tx). METHODS: One thousand sixty-seven kidney transplanted patients were asked to participate in a cross-sectional survey ('TransQoL-HU Study'). Socio-demographic data, history of renal disease, medication, comorbidity and laboratory parameters were collected at enrolment. Patients completed a battery of self-administered questionnaires including the Berlin Sleep Apnoea Questionnaire to assess risk status of OSAS. RESULTS: The final analyses included 841 Tx and 175 WL patients. The prevalence of high risk for OSAS was similar in the transplanted group vs WL patients (27% vs 33%). In multivariate logistic regression analysis male gender, older age, lower educational status, worse kidney function, use of hypnotic drugs and comorbidity were independent predictors for high risk of OSAS in kidney transplanted patients. CONCLUSIONS: High risk for sleep apnoea is highly prevalent in the kidney transplanted population. In addition to the well-known risk factors of OSAS (male gender, obesity, use of hypnotic drugs, comorbidity), impaired kidney function was also independently associated with high risk for OSAS.

Abstract: Epithelial-mesenchymal transition (EMT) plays an important role in embryogenesis and organ formation. Over the last 10-15 years it has been established that EMT is a significant mechanism of tumor progression and metastasis formation and also of progressive tissue fibrosis in the kidney, liver and lung. EMT seen in these diverse physiological and pathophysiological contexts shares a number of stages and modules, but also carries distinct, context specific characteristics. EMT in tissue fibrosis is a form of reverse embryogenesis, when highly specialized epithelial cells in the specific organs will respond to injury with loosing their epithelial characteristics and functions and regaining characteristics of the cells from which they originated. EMT in the context of tissue fibrosis can be induced by different forms of injury or a set of humoral factors. The process is regulated by a complex balance of humoral and microenvironmental stimuli, in which cell-cell contacts and interaction of the transitioning cell with the extracellular matrix components is very important. Intense research in this exciting field yielded good understanding of many of the details of this fascinating process, although numerous questions still await proper answers. There is indication that understanding of the molecular mechanisms underlying "fibrotic" EMT may lead to the design of specific and effective therapeutic measures for progressive tissue fibrosis.

Abstract: BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) regulates normal extracellular matrix (ECM) metabolism and it is a key regulator of the fibrotic process. Both angiotensin II (Ang II) and angiotensin IV (Ang IV) have been reported to stimulate PAI-1 expression. It is not known how PAI-1 expression is regulated by the renin-angiotensin system (RAS) in renal tubular cells. METHODS: To dissect signaling mechanisms contributing to the up-regulation of the PAI-1 promoter, porcine proximal tubular cells stably expressing the rabbit AT1 receptor (LLC-PK/AT1) were transiently transfected with a luciferase reporter construct containing the PAI-1 promoter. Promoter activation was assessed by measuring luciferase activity from cell lysates. RESULTS: Ang II dose-dependently stimulated the transcriptional activity of the PAI-1 promoter in renal proximal tubular cells whereas Ang IV had no consistent effect on the promoter activity. Neither inhibition of the Extracellular Signal Regulated Kinase (ERK) cascade nor inhibition of the c-Jun-N-terminal Kinase (JNK) pathway did reduce the stimulation of the PAI-1 promoter by Ang II. However, genistein, a tyrosine kinase inhibitor blocked the effect of Ang II. CONCLUSION: Ang II but not Ang IV activates the PAI-1 promoter in renal proximal tubular cells and this effect is mediated by tyrosine kinases.

Abstract: Restless legs syndrome (RLS) is characterised by an urge to move the legs, uncomfortable sensations in the legs and worsening of these symptoms during rest with at least temporary relief brought on by activity. RLS occurs in 3-15% of the general population and in 10-30% of patients on maintenance dialysis. RLS may lead to severe sleep onset or maintenance insomnia, and greatly impaired quality of life. Current recommendations suggest dopaminergic therapy (levodopa or dopamine receptor agonists: pramipexol, ropinirole, pergolide or cabergoline) as the first-line treatment for RLS. This group of medications is effective in reducing RLS symptoms in the general population; limited information is available on the effect of these drugs in patients with renal failure. However, it must be noted that most published studies in uraemic patients had short treatment periods and insufficient statistical power because of small sample size. Frequent adverse effects of levodopa, seen mainly with continuous use, may limit its use significantly. Rebound and augmentation, problems relatively frequently seen with levodopa, seem to be less prevalent with the use of dopamine receptor agonists, although properly designed comparative trials are still needed to address this question. Alternative treatment options for RLS are gabapentin, benzodiazepines and opioids. For all of these medications, there are only very limited data available on their effectiveness and safety profile in patients on maintenance dialysis. Referral to a specialist for RLS management should be considered for patients with refractory RLS.

Abstract: OBJECTIVE: The aim of this study was to determine the basic psychometric properties, reliability, and validity of the Kidney Disease Quality of Life-Short Form (KDQOL-SF) questionnaire in kidney transplant patients. METHODS: The reliability and validity of the instrument were determined in 418 kidney transplant patients followed in a single outpatient transplant centre. RESULTS: Internal consistency of all the Medical Outcome Study Short Form 36 (SF-36) domains was very good, and the Cronbach's alpha value was above .70 for all but three of the disease-specific subscales. We found significant, moderate to strong negative correlations between most of the KDQOL-SF domains and the Center for Epidemiologic Studies-Depression (CES-D) scores. Finally, substantial differences in KDQOL-SF scores were seen between groups of transplanted patients who were expected to be clinically different, supporting the discriminant validity of the KDQOL-SF instrument. CONCLUSION: We propose that the KDQOL-SF is a reliable and valid tool and most of its subscales can be used to assess health-related quality of life (HRQOL) in kidney transplant patients and to compare HRQOL between different end stage renal disease (ESRD) patient populations.

Abstract: Sleep complaints are very common in patients with end-stage renal disease (ESRD) and contribute to their impaired quality of life. Both obstructive and central sleep apnea syndromes are reported more often in patients on dialysis than in the general population. Impaired daytime functioning, sleepiness, and fatigue, as well as cognitive problems, are well known in patients with sleep apnea. Increasing evidence supports the pathophysiological role of sleep apnea in cardiovascular disorders, which are the leading cause of death in ESRD patients. Uremic factors may be involved in the pathogenesis of sleep apnea in this patient population and optimal dialysis may reduce disease severity. Furthermore, treatment with continuous positive airway pressure may improve quality of life and may help to manage hypertension in these patients. Secondary restless legs syndrome is highly prevalent in patients on maintenance dialysis. The pathophysiology of the disorder may also involve uremia-related factors, iron deficiency, and anemia, but genetic and lifestyle factors might also play a role. The treatment of restless legs syndrome involves various pharmacologic approaches and might be challenging in severe cases. In this article we review the diagnosis and treatment of sleep apnea and restless legs syndrome, with a focus on dialysis patients. We also briefly review current data regarding sleep problems after transplantation, since these studies may indirectly shed light on the possible pathophysiological role of uremia or dialysis in the etiology of sleep disorders. Considering the importance of sleep disorders, more awareness among professionals involved in the care of patients on dialysis is necessary. Appropriate management of sleep disorders could improve the quality of life and possibly even impact upon survival of renal patients.

Abstract: Sleep-related breathing disorders are prevalent in the general population and are associated with a wide range of cardiovascular diseases. Obstructive sleep apnea is the most common form of sleep-related breathing disorders and is characterized by repetitive episodes of partial or complete upper airway obstruction, followed by oxygen-desaturation and arousals. These apneic events disrupt normal sleep and lead to various acute and chronic cardiovascular consequences. The current standard treatment with nasal continuous positive airway pressure eliminates apneas, improves sleep fragmentation and prevents consequent hemodynamic changes during sleep. Every patient with hypertension, obesity or heart disease should be asked routinely about symptoms of sleep apnea and referred for a sleep study if necessary.

Abstract: Obstructive sleep apnea is an increasingly common disorder and it is a novel cardiovascular disease risk factor. Repetitive apneas and hypopneas during sleep are accompanied by hypoxia, increased sympathetic activity and frequent arousals. Sleep apnea has clearly been demonstrated to be an independent risk factor for development of hypertension and it has also been implicated in the pathogenesis of atherosclerosis, congestive heart failure, pulmonary hypertension, cardiac arrhythmias and stroke. Several studies showed that obstructive sleep apnea is associated with an increased risk of cardiovascular morbidity and mortality. However, a number of trials that assessed the effect of continuous positive airway pressure treatment have shown a reduction in blood pressure, decrease in cardiac arrhythmias, improvement in left ventricular function and reduction in incidence and mortality of cardiovascular diseases. Despite the available effective therapy the majority of individuals with obstructive sleep apnea and cardiovascular disease remains underdiagnosed and untreated.

Abstract: BACKGROUND: Recent studies confirmed that sleep disorders have a significant impact on various aspects of health in patients at different stages of chronic kidney disease. At the same time, there is an almost complete lack of information on the prevalence and correlates of insomnia in kidney transplant recipients. METHODS: In a cross-sectional study, the Athens Insomnia Scale was used to assess the prevalence of insomnia in a large sample of kidney transplant recipients compared with wait-listed dialysis patients and also a matched group obtained from a nationally representative sample of the Hungarian population. RESULTS: The prevalence of insomnia was 15% in wait-listed patients, whereas it was only 8% in transplant recipients (P < 0.001), which, in turn, was not different from the prevalence of this sleep problem in the sample of the general population (8%). Prevalences of insomnia in the transplant group were 5%, 7%, and 14% for the groups with glomerular filtration rates (GFRs) greater than 60 mL/min (> 1.00 mL/s), 30 to 60 mL/min (0.50 to 1.00 mL/s), and less than 30 mL/min (< 0.5 mL/s), respectively (P < 0.01). However, estimated GFR was no longer associated significantly with insomnia in the transplant population after statistical adjustment for several covariates. In a multivariate model, insomnia was significantly and independently associated with treatment modality (transplantation versus wait listing), as well as the presence of depression, restless legs syndrome, and high risk for obstructive sleep apnea syndrome, and with self-reported comorbidity. CONCLUSION: The prevalence of insomnia was substantially less in the transplant group than in wait-listed dialysis patients and similar to that observed in the general population. Because this condition potentially is treatable, attention should be directed to the appropriate diagnosis and management of insomnia in the kidney transplant recipient population.

Abstract: Sleep-related complaints affect 50-80% of patients on dialysis. Sleep disorders impair quality of life significantly. Increasing evidence suggests that sleep disruption has a profound impact both on an individual and on a societal level. The etiology of sleep disorders is often multifactorial: biologic, social, and psychological factors play a role. This is especially true for insomnia, which is the most common sleep disorder in different populations, including patients on dialysis. Biochemical and metabolic changes, lifestyle factors, depression, anxiety, and other underlying sleep disorders can all have an effect on the development and persistence of sleep disruption, leading to chronic insomnia. Insomnia is defined as difficulty initiating or maintaining sleep, or having nonrestorative sleep. It is also associated with daytime consequences, such as sleepiness and fatigue, and impaired daytime functioning. In most cases, the diagnosis of insomnia is based on the patient's history, but in some patients objective assessment of sleep pattern may be necessary. Optimally the treatment of insomnia involves the combination of both pharmacologic and nonpharmacologic approaches. In some cases acute insomnia resolves spontaneously, but if left untreated, it may lead to chronic sleep problems. The treatment of chronic insomnia is often challenging. There are only a few studies specifically addressing the management of this sleep disorder in patients with chronic renal disease. Considering the polypharmacy and altered metabolism in this patient population, treatment trials are clearly needed. This article reviews the diagnosis of sleep disorders with a focus on insomnia in patients on dialysis.

Abstract: OBJECTIVES: The objectives of this study were to compare the factor structure and to assess the reliability of the Hungarian version of the Illness Intrusiveness Rating Scale (IIRS), testing internal validity and employing simultaneous confirmatory factor analysis (SCFA) in two large samples of North American versus Hungarian patients with end-stage renal disease (ESRD). METHODS: Translation was conducted according to current recommendations. Following pilot testing, 365 maintenance haemodialysis patients completed the scale. Hungarian data were compared with IIRS data from North American ESRD patients undergoing maintenance hemodialysis to evaluate item bias (Group x Item ANOVA). RESULTS: Confirmatory factor analyses indicated a good fit between the previously hypothesized three-factor model ("relationships and personal development", "intimacy", and "instrumental" life domains) of the original English version and the Hungarian translation. Although statistically significant (P<.05), the effect size for the Groups x Items interaction was not substantial. Internal consistency was very good (Cronbach's alpha=.80) for the total score, and, although somewhat lower than ideal, it was still in the acceptable range for the subscales (.64-.67). These numbers are similar to values reported for the original English version. Test-retest reliability was also acceptable. CONCLUSION: The Hungarian translation of the IIRS has the same three-dimensional factor structure as the original English-language version does. Furthermore, it is sufficiently reliable for research applications. These features satisfy important requirements of cultural equivalence.

Abstract: BACKGROUND: There is an almost complete lack of information on the epidemiology of sleep disorders in kidney-transplanted patients. In this report the authors assess the prevalence and clinical correlates of restless legs syndrome (RLS) in kidney-transplanted (Tx) patients. They also analyze the impact of declining renal function on this condition in the Tx population. Finally, the prevalence of RLS was compared between waitlisted dialysis patients (WL), and the Tx group. METHODS: In a cross-sectional study enrolling 992 patients (816 Tx and 176 WL), the presence of RLS was assessed using the Restless Legs Syndrome Questionnaire. Clinical and sociodemographic data were collected from the patients' medical records. RESULTS: In transplanted patients, the prevalence of RLS was 4.8%. RLS was associated strongly with declining renal function. In groups formed on the basis of estimated glomerular filtration rate (eGFR), the prevalence of RLS was 1.8%, 5.1%, 6.5%, and 23.5% in patients with eGFR greater than 60 mL/min/1.73 m 2 ; eGFR 30 to 59 mL/min/1.73 m 2 ; eGFR 15 to 29 mL/min/1.73 m 2 ; and eGFR less than 15 mL/min/1.73 m 2 , respectively (P < 0.001). There was also a significant association between RLS and lower serum hemoglobin, higher number of self-reported comorbid conditions, and higher prevalence of iron deficiency. RLS was significantly less frequent in patients taking steroids than in patients not taking this medication (4% versus 9%, P < 0.05). In multivariate analysis, not taking steroids, eGFR, self-reported comorbidity, and iron deficiency were significant and independent predictors of RLS. Dialysis treatment was associated with increased odds for RLS (odds ratio 2.2; 95% confidence interval 1.11 to 4.35; P < 0.05) even after adjusting for serum hemoglobin and comorbidity. CONCLUSION: The prevalence of RLS is significantly lower in Tx patients than in patients on maintenance dialysis. Declining renal function is associated with increasing prevalence of the condition.

Abstract: BACKGROUND: In a cross-sectional study, we analysed the complex relationship between restless legs syndrome (RLS), insomnia and specific insomnia symptoms and health-related quality of life (QoL) in patients on maintenance dialysis. METHODS: Data were obtained from 333 patients on chronic maintenance dialysis. To assess the prevalence of RLS, we used the RLS Questionnaire (RLSQ). The Athens Insomnia Scale (AIS) was used to assess insomnia and QoL was measured with the Kidney Disease Quality-of-Life Questionnaire. RESULTS: The prevalence of RLS was 14%. The number of comorbid conditions was significantly higher in patients with vs without RLS (median: three vs two; P<0.05). RLS patients were twice as likely to have significant insomnia as patients without RLS (35% vs 16%; P<0.05). Furthermore, RLS was associated with impaired overall sleep quality (median AIS score: 8 vs 4; P<0.01) and poorer QoL. RLS was a significant and independent predictor of several of the QoL domains after statistical adjustment for clinical and socio-demographic covariables. Importantly, this association remained significant even after adjusting for sleep quality. CONCLUSIONS: RLS is associated with poor sleep, increased odds for insomnia and impaired QoL in patients on maintenance dialysis. Based on the present results, we suggest that both sleep-related and sleep-independent factors may confer the effect of RLS on QoL.

Abstract: BACKGROUND: Although a known cardiovascular risk factor, anemia in the renal transplant recipients has only recently been receiving an increasing attention. METHODS: In a cross-sectional study, data was obtained from 959 patients followed at a single outpatient transplant clinic. Based on the guideline of the American Society of Transplantation, anemia was defined as hemoglobin (Hb) < or =130 g/L in males and < or =120 g/L in females. RESULTS: About one-third (34%) of the patients were anemic. The prevalence of anemia was comparable in males and females. Serum Hb concentration was significantly correlated with the estimated glomerular filtration rate (eGFR) (abbreviated modification of diet in renal disease formula) (r = 0.266, p < 0.001), serum transferrin (r = 0.268, p < 0.001) and serum albumin (r = 0.196, p < 0.001). None of the immunosuppressive medications or the use of angiotensin converting enzyme inhibitors was associated with a higher likelihood of anemia. In multivariate analysis the eGFR, serum albumin and serum transferrin, potential markers of nutritional status and/or chronic inflammation, and also iron deficiency were independently and significantly associated with anemia. Erythropoietin was administered only to 63 (19%) anemic patients. CONCLUSIONS: Post-transplant anemia is a prevalent and under-treated condition. Based on our results we suggest that, besides other factors, protein/energy malnutrition and/or chronic inflammation may be independently associated with anemia. Further studies are needed to determine whether the presence of anemia and its treatment will have an impact on long-term outcomes of this population.

Abstract: AIMS: An increasing amount of evidence suggests that 25-hydroxy vitamin D3 (25(OH)D3) may contribute to the bone health of patients with chronic kidney disease (CKD). The underlying vitamin D status of these patients, however, has often been neglected. In a cross-sectional study we assessed the association between vitamin D status and parathyroid function, bone turnover, bone mass and structure in patients on maintenance hemodialysis. METHODS: 69 patients on maintenance hemodialysis were assessed by bone densitometry (DEXA) and quantitative bone ultrasound (QUS). Serum 25-hydroxy vitamin D3 levels, serum markers of bone turnover and clinical data were tabulated. RESULTS: A high prevalence of potentially significant vitamin D3 deficiency was found in this patient group: 59% of the patients had a 25(OH)D3 level below 20 nmol/l. There was a significant negative correlation between serum 25(OH)D3 levels and serum intact parathyroid hormone (iPTH) (r = -0.231, p < 0.05), and this association remained significant after controlling for potential covariables. Furthermore, we show here that serum 25(OH)D3 concentration is positively correlated with bone mineral density (BMD) measured at the radius (r = 0.424, p < 0.01). Finally, we show for the first time that 25(OH)D3 levels are significantly and independently correlated with broadband ultrasound attenuation (beta = 0.262, p < 0.05) measured with calcaneal quantitative bone ultrasound (QUS) in patients with chronic renal failure. CONCLUSION: Vitamin D3 deficiency may contribute to the impaired bone health of patients on maintenance dialysis.

Abstract: OBJECTIVES: Epidemiological data describing the prevalence of sleep complaints in Hungary and its region are lacking; furthermore, limited information is available on health care use by individuals with sleep complaints. We assessed the prevalence of sleep complaints, insomnia in particular, in a nationally representative sample of the Hungarian population and assessed health care utilization by insomniacs. METHODS: Cross-sectional study, enrolling a nationally representative sample (N=12,643) of the adult Hungarian population. A battery of questionnaires was administered during a home interview. The Athens Insomnia Scale (AIS), additional questions on sleep behavior, as well as questions on current medical therapy for somatic and mental disorders were included in the battery of questionnaires administered. Psychosocial and demographic characteristics were also tabulated. RESULTS: Forty-seven percent of the sample reported at least one complaint related to sleep. Based on the AIS we report a 9% prevalence of insomnia in the total sample. Sleep deprivation was highly prevalent in the younger and middle-aged groups. The frequency of sleep problems increased with age. Individuals diagnosed with insomnia reported more frequent utilization of health services, including sick leave, emergency visits and hospitalization, than those without insomnia. CONCLUSION: Sleep complaints and sleep deprivation are frequent problems in the Hungarian population and are associated with increased health care utilization. The prevalence of insomnia in our sample was similar to what has been previously reported from other countries. The high prevalence of sleep-deprived individuals warrants further attention. Interventions that effectively improve insomnia may also reduce health care utilization by the affected individuals.

Abstract: Injury of the tubular epithelium and TGF-beta1-induced conversion of epithelial cells to alpha-smooth muscle actin (SMA)-expressing myofibroblasts are key features of kidney fibrosis. Since injury damages intercellular junctions and promotes fibrosis, we hypothesized that cell contacts are critical regulators of TGF-beta 1-triggered epithelial-to-mesenchymal transition (EMT). Here we show that TGF-beta 1 was unable to induce EMT in intact confluent monolayers, but three different models of injury-induced loss of epithelial integrity (subconfluence, wounding, and contact disassembly by Ca(2+)-removal) restored its EMT-inducing effect. This manifested in loss of E-cadherin, increased fibronectin production and SMA expression. TGF-beta 1 or contact disassembly alone only modestly stimulated the SMA promoter in confluent layers, but together exhibited strong synergy. Since beta-catenin is a component of intact adherens junctions, but when liberated from destabilized contacts may act as a transcriptional co-activator, we investigated its role in TGF-beta 1-provoked EMT. Contact disassembly alone induced degradation of E-cadherin and beta-catenin, but TGF-beta1 selectively rescued beta-catenin and stimulated the beta-catenin-driven reporter TopFLASH. Moreover, chelation of free beta-catenin with the N-cadherin cytoplasmic tail suppressed the TGF-beta1 plus contact disassembly-induced SMA promoter activation and protein expression. These results suggest a beta-catenin-dependent two-hit mechanism in which both an initial epithelial injury and TGF-beta 1 are required for EMT.

Abstract: BACKGROUND: Angiotensin II (Ang II) down-regulates renin expression in juxtaglomerular cells, however, recent experimental evidence obtained in transgenic mice suggested that Ang II may "paradoxically" increase transcriptional activity of the proximal renin promoter. METHODS: To dissect signalling mechanisms contributing to the up-regulation of the proximal renin promoter by Ang II, porcine proximal tubular cells stably expressing the rabbit AT(1) receptor (LLC-PK/AT(1)) were transiently transfected with a luciferase reporter construct containing the 582 bp long piece of the human renin promoter. Activation of mitogen-activated protein kinases (MAPK) was detected by western blotting using phospho-MAPK-specific antibodies. RESULTS: Ang II dose-dependently stimulated the transcriptional activity of the human renin promoter (10(-7) M Ang II: 3.50+/-1.25-fold stimulation). In these cells Ang II activated both extracellular signal-regulated kinase (ERK) and the c-Jun-N-terminal kinase (JNK). Inhibition of the ERK cascade did not reduce the stimulation of the renin promoter by Ang II, however, two expression vectors designed to inhibit the JNK pathway, the dominant negative JNK and the Jun-kinase interacting peptide inhibited the fold stimulation induced by Ang II (2.75+/-0.69 vs 1.6+/-0.23 and 1.8+/-0.34, respectively; P<0.01). Furthermore, genistein, a tyrosine kinase inhibitor, blocked the effect of Ang II both on the JNK and the promoter activation. CONCLUSION: Ang II may have a stimulatory effect on the proximal renin promoter in proximal tubular cells and this effect is mediated by tyrosine kinases and the JNK cascade.

Abstract: BACKGROUND: The prevalence of sleep problems (insomnia, restless legs syndrome, periodic limb movements in sleep and sleep apnoea) has been shown to be high in patients with end-stage renal disease (ESRD) and might contribute to impaired quality of life in this population. METHODS: In a cross-sectional study using self-administered questionnaires, we examined the prevalence of sleep disorders and assessed their effect on different aspects of health-related quality of life in a sample of Hungarian patients on maintenance dialysis. RESULTS: Our data confirm that sleep problems are frequent in patients with ESRD; 65% of the patients reported symptoms of at least one specific sleep disorder; insomnia was the most common sleep complaint with 49%, the prevalence of sleep apnoea was 32% and the prevalence of restless legs syndrome was 15%. Co-morbidity, assessed by the End-Stage Renal Disease Severity Index, was shown to be an independent predictor of sleep disorders. Patients with sleep disorders reported higher illness intrusiveness and worse self-perceived health than those without sleep problems. The presence of sleep disorders was an independent predictor of illness intrusiveness, an important determinant of health-related quality of life. CONCLUSION: Sleep disorders are important determinants of illness intrusiveness and health-related quality of life in patients with ESRD. Sleep problems may be treated successfully; therefore, more attention should be paid to assessing these problems in this patient population.

Abstract: Over the past ten-fifteen years there has been a continuous increase in the interest in quality of life research. There is a huge increase in the number of clinical trials applying quality of life as an outcome measure and also in the number of studies where assessment of quality of life is the main focus of the research. During the last decades the resources of health care has increasingly been directed towards the care of chronically ill patients. In these conditions several symptoms persist or may even worsen even with effective therapy. This provides an explanation why quality of life has become an important and useful outcome measure complementing the traditional "hard outcomes" such as morbidity and mortality. Assessment of quality of life is also an important component of cost-effectiveness studies and health-technology assessment. Recently, the overall quality of quality of life research has improved significantly. In the early days, several instruments were used without any rigorous methodological assessment of the instrument itself. At present there are a number of meticulously developed and well documented instruments available with their reliability and validity evaluated with psychometric methods in different patient's populations. When one wants to use one of these measures in a different cultural environment or in a different language one faces several difficulties and a rigorous methodology needs to be followed when translating and validating quality of life tools. In this review the authors discuss the significance of quality of life assessments and list some practical issues concerning the methodology of quality of life studies. Finally they provide a short description of the most commonly used instruments and will give a reference of the scales available in Hungarian.

Abstract: BACKGROUND: Female sex hormones may influence the progression of renal diseases. We therefore evaluated the effects of estradiol on the development of glomerulosclerosis in a remnant kidney model. METHODS: Ovariectomized or intact female Wistar rats underwent 5/6 nephrectomy. Ovariectomized animals were treated with vehicle, 17beta-estradiol alone or in combination with progesterone, intact rats received vehicle only. Twenty-four weeks after renal ablation, histological as well as molecular analysis were performed. RESULTS: Vehicle-treated ovariectomized animals developed severe proteinuria and glomerulosclerosis as compared with vehicle-treated intact rats. In addition, renal mRNA levels of platelet-derived growth factor-A chain (PDGF-A) were increased. Estradiol replacement reduced proteinuria, which was paralleled by a diminished glomerular injury and reduced transforming growth factor-beta1 (TGF-beta1) and PDGF-A mRNA expression. In animals that received combined hormone treatment there were no significant differences in proteinuria, creatinine clearance, renal histopathology and growth factor mRNA levels compared with those measured in vehicle-treated ovariectomized rats. Serum cholesterol and triglyceride levels were comparable between all groups during the whole follow-up period. CONCLUSIONS: The data suggest that estrogens protect against the development of glomerulosclerosis in the rat remnant kidney model.

Abstract: It has been recently recognized that angiotensin II (Ang II), in addition to its role in the regulation of the salt-fluid homeostasis is also a growth factor and contributes to the regulation of cellular hypertrophy or proliferation and extracellular matrix (ECM) formation. This article gives an overview on the role of mitogen activated protein kinase (MAPK) cascades in transducing the growth factor-like effects of Ang II.

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Abstract: New research suggests that, during tubulointerstitial fibrosis, alpha-smooth muscle actin (SMA)-expressing mesenchymal cells might derive from the tubular epithelium via epithelial-mesenchymal transition (EMT). Although transforming growth factor-beta(1) (TGF-beta(1)) plays a key role in EMT, the underlying cellular mechanisms are not well understood. Here we characterized TGF-beta(1)-induced EMT in LLC-PK(1) cells and examined the role of the small GTPase Rho and its effector, Rho kinase, (ROK) in the ensuing cytoskeletal remodeling and SMA expression. TGF-beta(1) treatment caused delocalization and downregulation of cell contact proteins (ZO-1, E-cadherin, beta-catenin), cytoskeleton reorganization (stress fiber assembly, myosin light chain phosphorylation), and robust SMA synthesis. TGF-beta(1) induced a biphasic Rho activation. Stress fiber assembly was prevented by the Rho-inhibiting C3 transferase and by dominant negative (DN) ROK. The SMA promoter was activated strongly by constitutively active Rho but not ROK. Accordingly, TGF-beta(1)-induced SMA promoter activation was potently abrogated by two Rho-inhibiting constructs, C3 transferase and p190RhoGAP, but not by DN-ROK. Truncation analysis showed that the first CC(A/T)richGG (CArG B) serum response factor-binding cis element is essential for the Rho responsiveness of the SMA promoter. Thus Rho plays a dual role in TGF-beta(1)-induced EMT of renal epithelial cells. It is indispensable both for cytoskeleton remodeling and for the activation of the SMA promoter. The cytoskeletal effects are mediated via the Rho/ROK pathway, whereas the transcriptional effects are partially ROK independent.

Abstract: Transforming growth factor-beta (TGF-beta) is a bimodal regulator of cellular growth. The cellular effects of TGF-beta depend on the intensity of signals emanating from TGF-beta receptors. Low levels of receptor activity are sufficient to stimulate cell proliferation, while higher degrees of receptor activation are associated with growth inhibition. To study the mechanisms of these effects, a tetracycline-inducible expression system was used to overexpress type II TGF-beta receptors in NIH 3T3 fibroblasts. Overexpressed type II TGF-beta receptors suppressed fibroblast proliferation elicited by TGF-beta1, fibroblast growth factor (FGF) or platelet-derived growth factor (PDGF). Accompanying these anti-proliferative effects, increases in extracellular-signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activity were detected. Furthermore, PDGF alpha-, but not PDGF beta-receptor protein levels were reduced by type II TGF-beta receptor overexpression. In conclusion, our system is an excellent tool to study the molecular mechanisms of growth inhibition by TGF-beta in fibroblasts. Activation of JNK and ERK, or modulation of PDGF receptor expression may be involved in this process.

Abstract: To study the role of extracellular-signal-regulated kinase (ERK) cascade and the small GTP-ase proteins in the activation of the c-fos promoter by angiotensin II (AII), transient transfection experiments were performed in CHO cells stably expressing the rat AT(1A) receptor. In this system AII activated ERK in 1 min and also increased the transcriptional activity of the c-fos promoter-luciferase reporter gene construct. The activation of the promoter proved to be dependent on the Ras-Raf-ERK cascade as cotransfection of expression vectors known to specifically inhibit this cascade blocked the effect of AII. Dominant-negative p21Rac1 mutant partially blocked the activation of the c-fos promoter by AII. However, activation of the c-fos promoter was independent of protein kinase C (PKC) as bisindolylmaleimide I, a specific PKC inhibitor did not block the effect of AII. These results suggest that AII activates the transcription of the c-fos through the Ras-Raf-ERK cascade. Furthermore, p21Rac1 is involved in the modulation of the c-fos promoter by AII.

Abstract: beta-galactosidase reporter plasmids containing different viral or minimal promoters are commonly used to correct variable transfection efficiencies in transient transfection experiments. The transcriptional activity of these promoters is thought to be stable under most circumstances. To determine if expression of beta-galactosidase from the commonly used beta-galactosidase plasmids remains stable upon stimulation of the cells with agonists we performed transient transfection experiments. CHO cells stably expressing the rat AT(1A) receptor were transfected with RSVbeta- or CMVbeta- or pTKbeta plasmids alone or together with a reporter construct in which luciferase transcription is driven by the c-fos promoter. Luciferase and/or beta-galactosidase activity was measured from the lysate of cells treated with angiotensin II or serum. We found that agonists increased the transcriptional activity of the different beta-galactosidase plasmids. The effect of angiotensin II and serum was different on the different promoters. Finally, cotransfection of other plasmids also modulated beta-galactosidase activity. These agonist induced variations of beta-galactosidase activity may influence the analysis and interpretation of the results in a systematic manner. Consequently we conclude that the use of a second reporter system to control for transfection efficiency in certain types of experiments may lead to a systematic error and is questionable as a general procedure.

Abstract: The renin-angiotensin system plays a pivotal role in the regulation of fluid, electrolyte metabolism and blood pressure. Molecular cloning and pharmacological studies have defined two major classes of Angiotensin II (Ang II) receptors, designated AT1 and AT2. Recently, it has been well recognized that Ang II, beside its classical physiological actions, is a profibrogenic peptide and displays characteristics of a growth factor. The emerging picture suggests that angiotensin receptor subtypes exert opposing features in many aspects of their biological function, most importantly in cellular growth and proliferation. Accordingly, the proliferative and/or growth-promoting effects of Ang II are thought to be mediated by AT1 receptor, whereas the AT2 receptor subtype may have growth-inhibitory properties. The novel finding that Ang II is able to induce apoptosis by AT2 receptors in diverse cell types is of great scientific interest, as recent studies revealed a role for apoptosis as a deliberate form of cell death in the pathogenesis of various cardiovascular diseases such as heart failure and vascular remodeling. Furthermore apoptotic cell death might occur during the development of progressive glomerulosclerosis. It is tempting to speculate that autocrine-paracrine vasoactive substances such as Ang II might regulate these apoptotic processes during pathogenic conditions.

Abstract: OBJECTIVE: To determine whether hormone replacement therapy can reverse established renal microvascular damage in type 2 diabetes and hypertension. DESIGN: Prospective, single centre clinical trial. SETTING: Outpatient clinics. PARTICIPANTS: Sixteen diabetic and hypertensive postmenopausal women (age 47-57 years) METHODS: Administration of a cyclic combination of oestradiol and norgestrel orally for 3.5 monthly cycles. RESULTS: Comparing the baseline values, mean (SD) 24-hour urine protein excretion was reduced from 0.452 g (0039) to 0.370 g (0.047) (P < 0.01) and creatinine clearance was increased from 1.68 mL/sec (0.11) to 1.77 mL/sec (0.08) (P < 0.05). Fasting plasma glucose also improved from 6.92 mmol/L (0.47) to 6.51 mmol/L (0.28) (P < 0.05), as did serum total cholesterol from 7.26 mmol/L (0.28) to 6.65 mmol/L (0.14) (P < 0.05). Blood pressure did not change significantly. Univariate linear regression analysis showed no significant correlation between the individual changes in blood pressure, fasting plasma glucose or serum cholesterol and the individual changes in proteinuria or creatinine clearance. CONCLUSIONS: This study shows that hormone replacement therapy may reduce proteinuria, and even improve creatinine clearance, in diabetic and hypertensive postmenopausal women. These effects are additive to nephroprotective therapy, and the mechanisms appear unrelated to conventional risk factors for vascular complications, such as high blood pressure, elevated plasma glucose or serum cholesterol.

Abstract: Renal bone disease results in significant morbidity in patients with end-stage renal failure. Renal osteodystrophy is a mixture of different conditions with different pathogenetic factors involved. Most recently a new form of renal bone disease, adynamic bone disease, has emerged as the most frequent finding on bone biopsy of patients on dialysis therapy. The etiology of this new entity is not fully understood, but relatively low levels of intact serum parathyroid hormone are frequently associated with this disorder and may play an important role in its pathogenesis.

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Abstract: We compared the efficacy and the long-term effects of nocturnal hemodialysis (NHD) versus conventional hemodialysis (CHD) in controlling serum phosphate levels in patients with end-stage renal disease (ESRD). Patients underwent thrice weekly CHD and were subsequently switched to NHD six nights weekly. In the "acute" study serum and dialysate phosphate were measured during and after dialysis, and the total dialysate was collected to calculate mass solute removal. Although pre-dialysis (1.7 +/- 0.6 vs. 1.5 +/- 0.8 mM) serum phosphate levels were similar in CHD and NHD, respectively, post-dialysis levels were slightly lower with CHD (0.7 +/- 0.2 vs. 0.8 +/- 0.2 mM, P < 0.05). The measured phosphate removed per session of CHD or NHD was comparable, 25.3 +/- 7.5 versus 26.9 +/- 9.8 mumol/session, respectively. On the other hand, the cumulative weekly phosphate removal was significantly higher with NHD as compared to CHD, 75.8 +/- 22.5 versus 161.6 +/- 59.0 mumol/week (P < 0.01). In the "chronic" study serum phosphate levels were measured monthly for five months on CHD and for five months after the patients were switched to NHD. Dietary phosphate intake and the dosage of phosphate binders were tabulated. Serum phosphate levels fell during NHD: 2.1 +/- 0.5 mM at the beginning of the study and 1.3 +/- 0.2 mM five months after being switched to NHD (P < 0.001). At the same time dietary phosphate intake increased by 50%. By the fourth month of NHD therapy none of the patients was taking any phosphate binders. In conclusion, NHD is more effective in controlling serum phosphate levels than CHD, allowing patients to discontinue their phosphate binders completely and to ingest a more liberal diet.

Abstract: In the past several years significant attention has been directed to the study of adynamic bone disease in uremic patients. Several reports have provided additional information about the prevalence of adynamic bone disease in different countries. It has now become clear that the pathogenesis of adynamic bone disease cannot be ascribed to one single aetiological factor, but rather to a host of complex factors. From recently published papers we have learned about the mechanism of downregulation of the parathyroid hormone/parathyroid hormone-related peptide receptor on osteoblast-like cells, which may be a very important step in the pathogenesis of adynamic bone disease. A provocative hypothesis attempts to link the widespread use of erythropoietin to the emergence of adynamic bone disease-lacking excessive aluminium accumulation. It appears from some studies that bone-specific alkaline phosphatase might become a valuable tool in differentiating high turnover from low/normal turnover bone disease; however, further studies are needed to establish the role of this marker in the diagnosis of adynamic bone disease. Several papers discussed the pros and cons of lowering the calcium concentration of the dialysate in order to prevent adynamic bone disease. The results of these studies help us to understand the pathogenesis and the clinical relevance of this lesion in attempts to provide better care for our patients.

Abstract: Smad proteins have recently been identified as mediators of transcriptional activation by members of the transforming growth factor-beta superfamily. To determine if Smads might also be involved in inducing gene transcription in response to other agonists, expression vectors for dominant-negative Smad proteins were constructed. These plasmids were transiently cotransfected with luciferase reporter genes and the effects of various agonists on reporter gene activity evaluated in NIH 3T3 cells. Dominant-negative Smad3, but not other dominant-negative Smads, reduced stimulation of the plasminogen activator inhibitor-1 (PAI-1) and other gene promoters by phorbol ester, cAMP, and platelet-derived growth factor. Activation of the PAI-1 promoter by TGF-beta or prostaglandin F2 alpha, and transactivation by c-Jun or JunB were not inhibited by dominant-negative Smad3, supporting the specificity of this mutant. These results suggest that Smad3, like CREB-binding protein (CBP), may participate in transcriptional activation by multiple agonists.

Abstract: The kinases and regulatory proteins that convey signals initiated by transforming growth factor-beta (TGF-beta) to the nucleus are poorly characterized. To study the role of the extracellular signal-regulated kinase (ERK) pathway in this process, we transiently transfected NIH 3T3 fibroblasts with TGF-beta-responsive luciferase reporter genes and expression vectors designed to interrupt this kinase cascade. Mitogen-activated protein (MAP) kinase phosphatase-1 and a dominant negative MAP/ERK kinase 1 mutant reduced stimulation of plasminogen activator inhibitor-1 (PAI-1) promoter activity by TGF-beta1 from 11.5- to 4-fold and 4.9-fold, respectively. Similar results were observed with the type I collagen promoters. TGF-beta1 increased ERK1 activity 4.5-fold at 5 min and 3. 1-fold at 3 h, while Jun kinase and p38 activity were not affected. Cotransfection of a dominant negative mutant of the small G protein, Rac, but not dominant negative Ras, Cdc42, or Rho mutants, reduced the effects of TGF-beta1 on the PAI-1 promoter by approximately half. In support of a role for Rac in signaling by TGF-beta, GTP binding to Rac was increased 3.7-fold following exposure of NIH 3T3 cells to TGF-beta1 for 3 min. These findings indicate that TGF-beta1 modulates gene expression partly through ERK and Rac in NIH 3T3 cells.

Abstract: A non-hydrolysable GTP analogue enhanced the formation of [3H]inositol polyphosphates in permeabilized adrenal glomerulosa cells. Pertussis toxin, which ADP-ribosylated Ni, failed to influence angiotensin-induced formation of 3H-labelled inositol phosphates and the incorporation of [32F]phosphate into phosphatidylinositol and phosphatidic acid. These results show that Ni is present and a G-protein activates phospholipase C also in glomerulosa cells, however, it is not Ni which couples angiotensin receptors to the enzyme.