[World Kidney Day 2013 and the Italian experience since 2006]. / Giornata Mondiale del Rene 2013 e l'esperienza Italiana dal 2006 a oggi.

Renal disease is common, insidious and treatable. The prevalence of chronic kidney disease and its cumulative global costs are rapidly increasing. Since 2006 the World Kidney Day (WKD) has worked to raise awareness of the disease and the importance of its prevention within communities and institutions. Italian Nephrology, through the joint action of the Italian Society of Nephrology (SIN) and the Italian Kidney Foundation (FIR) has worked to convey the message during WKD celebrations,meeting the community directly in Italian town squares and high schools, where informative material was provided together with blood pressure and urine dip-stick testing. This year, the WKD was held on March 14th, and was preceded by an extensive program of information broadcast on TV and radio and published in newspapers and magazines. More than 100 nephrology units in 118 cities were either involved in at least one of the programs organized in Italian town squares, high schools and renal clinics, or provided other spontaneous initiatives. This paper describes the history of the Italian experience in the WKD from its beginning in 2006 until the present day.

A translational approach to micro-inflammation in end-stage renal disease: molecular effects of low levels of interleukin-6.

Inflammation plays a key role in the progression of cardiovascular disease, the leading cause of mortality in ESRD (end-stage renal disease). Over recent years, inflammation has been greatly reduced with treatment, but mortality remains high. The aim of the present study was to assess whether low (<2 pg/ml) circulating levels of IL-6 (interleukin-6) are necessary and sufficient to activate the transcription factor STAT3 (signal transducer and activator of transcription 3) in human hepatocytes, and if this micro-inflammatory state was associated with changes in gene expression of some acute-phase proteins involved in cardiovascular mortality in ESRD. Human hepatocytes were treated for 24 h in the presence and absence of serum fractions from ESRD patients and healthy subjects with different concentrations of IL-6. The specific role of the cytokine was also evaluated by cell experiments with serum containing blocked IL-6. Furthermore, a comparison of the effects of IL-6 from patient serum and rIL-6 (recombinant IL-6) at increasing concentrations was performed. Confocal microscopy and Western blotting demonstrated that STAT3 activation was associated with IL-6 cell-membrane-bound receptor overexpression only in hepatocytes cultured with 1.8 pg/ml serum IL-6. A linear activation of STAT3 and IL-6 receptor expression was also observed after incubation with rIL-6. Treatment of hepatocytes with 1.8 pg/ml serum IL-6 was also associated with a 31.6-fold up-regulation of hepcidin gene expression and a 8.9-fold down-regulation of fetuin-A gene expression. In conclusion, these results demonstrated that low (<2 pg/ml) circulating levels of IL-6, as present in non-inflamed ESRD patients, are sufficient to activate some inflammatory pathways and can differentially regulate hepcidin and fetuin-A gene expression.

The burden of amputation among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Hemodialysis patients are at increased risk of amputation, particularly those with diabetes. Limited data exist about the prevalence, incidence, risk factors for, and sequelae of amputation in hemodialysis patients. STUDY DESIGN: A prospective observational study of hemodialysis practices and outcomes. SETTING & PARTICIPANTS: Data from 29,838 patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) from 1996 to 2004 were analyzed. PREDICTOR/FACTOR: Demographic factors, comorbid conditions, laboratory values, years since end-stage renal disease onset, and currently prescribed medications at study enrollment. OUTCOME: Prior amputation at study enrollment by using logistic regression and amputation during follow-up by using Cox models. Amputation was ascertained from medical record review. RESULTS: There was a high prevalence (6%) and incidence (2.0 events/100 patient-years at risk) of amputation in hemodialysis patients; patients with diabetes had a more than 9 times greater incidence of new amputation. Wide variations among countries were observed in risk of amputation, with the lowest prevalence in Japan and the highest in Belgium, France, and Germany. Traditional cardiovascular risk factors, such as age, peripheral vascular disease, and smoking were predictive of amputation, as were such risk factors related to hemodialysis as altered mineral metabolism and years of hemodialysis therapy. In patients with diabetes, greater relative risks of amputation were observed in men, smokers, and those with other diabetic complications, anemia, and malnutrition. The relative risk of mortality after amputation was 1.54 (95% confidence interval, 1.41 to 1.68; P < 0.001) with a mean survival of 2.0 versus 3.8 years. LIMITATIONS: The database does not differentiate between types of amputations; some amputations may have concerned the upper limbs and could have been linked to ischemia related to vascular access. CONCLUSIONS: Amputation in hemodialysis patients is a very frequent event, particularly in patients with diabetes, and is associated with both traditional cardiovascular risk factors and factors linked to kidney failure treated by hemodialysis. Interventional trials are needed to reduce the burden of amputation.

Awareness of hypertension and proteinuria in randomly selected patients in 11 Italian cities. A 2005 report of the National Kidney Foundation of Italy.

Arterial hypertension and proteinuria are risk factors for chronic kidney disease. A mobile clinic was parked in a central plaza of 11 Italian cities to check blood pressure (BP), prescribe antihypertensive drugs, assess for proteinuria, and provide awareness about hypertension. Among 3757 patients, 56% were hypertensive, 37% were not diabetic nor proteinuric with BP >or=140/90 mm Hg, 17% were diabetic or proteinuric with BP >or=130/80 mm Hg, and 11% were on treatment with BP at target. Among 1204 treated patients, 400 (33%) had controlled BP. Among all 2114 hypertensive patients, only 1344 (64%) were aware of their hypertension. Awareness was greater among treated patients at target (99%). As many as 523 (14%) patients had proteinuria >or=30 mg/dL. The authors conclude that awareness of people walking in the street about their BP and proteinuria is insufficient. Mobile screening clinics may increase public awareness and detection of hypertension and proteinuria in the general community and detect patients at risk for chronic kidney disease.

Pulse pressure and presence of coronary artery calcification.

BACKGROUND: Coronary calcification (CAC) is found in early stages of CKD. Pulse pressure (PP) predicts CAC in dialysis patients. This study evaluates the accuracy of PP in predicting CAC in patients not yet on dialysis (CKD patients). METHODS: CKD patients (n = 388) underwent coronary calcium score (CAC score) and abdominal x-ray (n = 128) for estimating aorta calcification (AAC). Biochemistry and PP were measured every 3 and 6 months in patients with stage 4 to 5 and 2 to 3 CKD, respectively. The accuracy of PP and AAC was assessed by receiver operating characteristics analysis. RESULTS: PP correlated with CAC score in the whole cohort and in patients with stages 2 to 3 and stages 4 to 5 CKD. PP >60 mmHg predicted CAC score >0 (OR: 2.14; P < 0.001), > or =100 (OR: 2.92; P < 0.001), > or =400 (OR: 6.17; P < 0.001) after multivariable adjustment. Area under the curve (AUC) was 0.626 for CAC score >0, 0.676 for score >100, and 0.746 for score >400. PP >60 mmHg reduced the rate of event-free survival. AAC was found in 58% of patients and correlated with CAC score. AUC was 0.628 for CAC score >0, 0.652 for score >100, 0.831 for score >400. CONCLUSION: PP may identify CKD patients with subclinical CAC who need further evaluation. Accuracy of PP and AAC is nearly similar in predicting CAC. High PP indicates vessel wall alterations leading to adverse outcome.

Fetuin-A gene expression, synthesis and release in primary human hepatocytes cultured in a galactosylated membrane bioreactor.

This paper reports on human hepatocytes cultured in a galactosylated membrane bioreactor in order to explore the modulation of the effects of a pro-inflammatory cytokine, Interleukin-6 (IL-6) on the liver cells at molecular level. In particular the role of IL-6 on gene expression and production of a glycoprotein, fetuin-A produced by hepatocytes, was investigated by culturing hepatocytes in the membrane bioreactor, both in the absence and presence of IL-6 (300 pg/ml). IL-6 modulated the fetuin-A gene expression, synthesis and release by primary human hepatocytes cultured in the bioreactor. A 75% IL-6-induced reduction of fetuin-A concentration in the medium was associated with a 60% increase of C-reactive protein in the same samples. Real-time-PCR demonstrated an 8-fold IL-6-induced reduction of fetuin-A gene expression. These results demonstrate that the hepatocyte galactosylated membrane bioreactor is a valuable tool to study IL-6 effects and gave evidence, for the first time, that IL-6 down-regulates the gene expression and synthesis of fetuin-A by primary human hepatocytes. The human hepatocyte bioreactor behaves like the in vivo liver, reproducing the same hepatic acute-phase response that occurs during the inflammatory process.

A project to prevent renal diseases in the general population.

BACKGROUND: Early identification of subjects unaware of hypertension, diabetes and urinary abnormalities may prevent and/or reduce the onset and progression of kidney disease and ameliorate outcomes. In this study, the presence of hypertension, diabetes and urinary abnormalities was checked in subjects walking in a large square of Naples. METHODS: Data on age, habits and history of hypertension and/or diabetes were collected. Systolic and diastolic blood pressure were recorded. Protein, glucose, leukocytes and red blood cells were measured in urine. RESULTS: Participants numbered 698. Smoking (past or current smoking) was reported by 77%. Many of the participants with hypertension (35%) showed uncontrolled hypertension despite antihypertensive therapy. Hypertension was found for the first time in 154 subjects, and was confirmed in 28% of them afterwards; 23 participants (15% of hypertensive subjects) did not recheck blood pressure (BP) despite our summons. Proteinuria was found in 18% of new hypertensive participants. In 14 out of 17 diabetic participants without history of hypertension, hypertension was found for the first time and confirmed thereafter. Urinary abnormalities were present in more than one half of the participants, and were more prevalent in women and diabetics. Diabetics numbered 55 out of 698 subjects. In spite of therapy, glucosuria was present in almost one third of diabetics. Glucosuria was found in 6 participants with no history of diabetes (0.9% of all subjects). CONCLUSIONS: These data demonstrate that (a) many persons with hypertension are not aware of it; (b) control of hypertension is inadequate in most treated hypertensive patients and even worse in diabetics; (c) urinary abnormalities are frequently present in otherwise healthy subjects; (d) projects with the aim of raising awareness of hypertension, urinary abnormalities and diabetes in out-clinic subjects should be supported; (e) the use of a transportable clinic parked in residential areas of cities appears a suitable way for promoting evaluation of BP and urine test in subjects unaware of disease.

Progression of coronary artery calcification in predialysis patients.

BACKGROUND: In patients on dialysis coronary artery calcification (CAC) rapidly proceeds due to impaired mineral metabolism and/or exogenous calcium load. Progression has not been assessed in patients with chronic kidney disease not yet requiring dialysis (CKD patients). In this study, rate and determinants of CAC progression have been evaluated in CKD patients who are exposed to minor derangement of mineral metabolism and calcium load. METHODS: Consecutive patients were enrolled. Exclusion criteria were: symptomatic coronary disease, arrhythmia, myocardial infarction, and diabetes. Serum calcium, phosphorus, parathyroid hormone, homocysteine, C-reactive protein, triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol were serially measured. Fetuin-A was assessed at entry into the study. CAC progression was detected by measuring total calcium score (TCS) with computed tomography. Initial and final scans were obtained. Predictive factors of progression were investigated. RESULTS: Fifty-three patients had CKD (stage 3-5 CKD; K-DOQI classification) not yet requiring dialysis, and 60 patients had normal renal function (NRF patients). Follow-up lasted 24 +/- 4.2 months (mean +/- SE). Patients with CAC were older with lower serum fetuin-A. TCS increased from 73 +/- 17 to 80 +/- 20 (mean +/- SE; p = NS) in NRF patients, and from 384 +/- 116 to 602 +/- 140 (mean +/- SE; p < 0.01) in CKD patients. Serum phosphorus [OR = 1.97 (1.14-3.41, 95% CI); p = 0.015] was the only variable that was associated with CAC progression. Cardiovascular events occurred in CKD patients with CAC. CONCLUSION: CAC progression was prominent in CKD patients and correlated with serum phosphorus. Fatal and nonfatal cardiovascular events were more frequent in CKD patients. Studies are required to ascertain whether the attainment of serum phosphorus concentration lower than that suggested by current guidelines may reduce CAC progression and ultimately mortality.

Matrix GLA protein gene polymorphisms: clinical correlates and cardiovascular mortality in chronic kidney disease patients.

BACKGROUND: Increased vascular calcification plays an important role in the pathogenesis of cardiovascular events in chronic kidney disease (CKD) patients. It is the result of an active ossification process counteracted by 'protective' proteins, such as matrix GLA protein (MGP). Polymorphisms of MGP have been identified. METHODS: The aim of this study was to define the distribution of two MGP polymorphisms (-7, -138) in 99 hemodialysis (HD) patients, in 26 patients with CKD stage 3 and in 135 age- and sex-matched healthy controls. Patients were followed up for 12 months to record any cardiovascular deaths. The cause of death was determined by medical doctors, considering the medical history of each patient. The primers were designed with Primer Express software. RESULTS: MGP -138TT homozygotes were more frequent in the HD group versus controls (p = 0.0004). Additionally, the frequency of the T allele was significantly higher in the HD group (p = 0.0006). The frequency of the A allele of MGP-7 was significantly higher both in the HD group (p = 0.033) and in the CKD group (p = 0.0017) versus controls. MGP-7 GG homozygotes were significantly less common in the CKD group than in controls (p = 0.037). Combination -138TT -7AA was significantly more frequent in both CKD patients (p = 0.001) and in HD patients (p = 0.029) than in controls. Seventeen out of 99 HD patients experienced fatal cardiovascular events. Sixteen (94.1%) were -138TT homozygotes and either -7AA homozygotes or -7GA heterozygotes. CONCLUSION: This study suggests that CKD and HD patients have a different distribution of MGP gene polymorphism as compared with the normal population. Altered MGP gene polymorphism may be a negative prognostic factor for the progression to end-stage renal disease and for cardiovascular events in CKD patients.

Coronary artery calcification in patients with CRF not undergoing dialysis.

BACKGROUND: Coronary artery calcification (CAC) correlates with the extent of coronary atherosclerosis and, consequently, with an increased risk for cardiovascular events. CAC is more frequent in uremic patients than in the general population. Nearly all data about CAC relate to patients on dialysis therapy. This study evaluates the prevalence and extent of CAC in patients with chronic renal failure (CRF) not yet on dialysis therapy. METHODS: Consecutive outpatients with CRF not on dialysis therapy were enrolled and compared with controls (ie, healthy volunteers and patients with essential hypertension with normal renal function). Patients and controls were asymptomatic and had no previous history of myocardial infarction, coronary bypass surgery, or angioplasty. Patients with diabetes were excluded. Clinical characteristics, biochemical test results (included homocysteinemia and C-reactive protein level), and serum concentrations of calcium, phosphorus, and intact parathyroid hormone (iPTH) were evaluated in patients and controls. CACs were searched for and scored by means of spiral computed tomography (CT). To assess the CAC progression rate, spiral CT was repeated in some patients. RESULTS: Eighty-five patients and 55 controls were studied. Patients were aged 52 +/- 13 years and had a CRF duration of 6.3 +/- 5.6 years, glomerular filtration rate of 33.0 +/- 16.0 mL/min (0.55 +/- 0.27 mL/s), serum calcium level of 9.5 +/- 0.5 mg/dL (2.37 +/- 0.12 mmol/L), serum phosphorus level of 4.1 +/- 0.9 mg/dL (1.32 +/- 0.29 mmol/L), and serum iPTH level of 143 +/- 121 pg/mL (ng/L). CAC was found in 40% of patients and 13% of controls; calcification scores were 422 +/- 634 in patients and 43.9 +/- 33 in controls. Only age ( P < 0.001) was a predictor of CAC. In patients with a repeated score performed (after a mean of 7.9 months), calcification scores increased (from 383 +/- 627 to 682 +/- 890) in 8 of 10 patients. CONCLUSION: CAC is already present in the early phase of CRF; the prevalence is greater in patients with CRF than in controls, but less than that reported in dialysis patients. Serum concentrations of calcium, phosphorus, iPTH, and inflammation markers do not predict the appearance or progression of CAC.

Screening for depression in hemodialysis patients: associations with diagnosis, treatment, and outcomes in the DOPPS.

BACKGROUND: Depressive symptoms and depression are the most frequent psychologic problems reported by hemodialysis patients. We assessed the prevalence of depressive symptoms and physician-diagnosed depression, their variations by country, and associations with treatment by antidepressants among hemodialysis patients. We also assessed whether depressive symptoms were independently associated with mortality, hospitalization, and dialysis withdrawal. METHODS: The sample was represented by 9382 hemodialysis patients randomly selected from dialysis centers of 12 countries enrolled in the Dialysis Outcomes and Practice Patterns Study (DOPPS II). Depressive symptoms were assessed by the short version of the Center for Epidemiological Studies Depression Screening Index (CES-D), using > or =10 CES-D score as the cut-off value. RESULTS: Overall prevalence of physician-diagnosed depression was 13.9%, and percentage of CES-D score > or =10 43.0%. While the smallest prevalence of physician-diagnosed depression was observed in Japan (2.0%) and France (10.6%), the percentage of CES-D score > or =10 in these counties was similar to the whole sample. Patients on antidepressants also varied by country, 34.9% and 17.3% among those with physician-diagnosed depression and CES-D scores > or =10, respectively. In Cox models adjusted for several comorbidities, CES-D scores > or =10 were associated with significantly higher relative risks (RR) of death (RR = 1.42; 95% CI = 1.29 to 1.57), hospitalization (RR = 1.12; 95% CI = 1.03 to 1.22), and dialysis withdrawal (RR = 1.55; 95% CI = 1.29 to 1.85). CONCLUSION: The data suggest that depression is underdiagnosed and undertreated among hemodialysis patients. CES-D can help identify hemodialysis patients who are at higher risk of death and hospitalization. Interventions should target these patients with the goal to improve survival and reduce hospitalizations.

The role of interleukin-6 and of its soluble receptors in the biocompatibility of dialysis treatment.

Proinflammatory cytokines, in addition to their role in host defence, may be considered mediators of disease; a reduction of cytokine synthesis or effects is, therefore, becoming a target of many diseases. IL-6 is a pro-inflammatory cytokine that may play a role in several clinical problems related to dialysis treatment. An enhanced spontaneous production of IL-6 by Peripheral Blood Mononuclear Cells (PBMC) harvested from ESRD patients dialyzed with a poor biocompatible membrane has been first demonstrated by our group. These results were also obtained in patients undergoing continuous peritoneal dialysis, in absence of peritonitis. We have also demonstrated that IL-6 release was inversely correlated with serum albumin changes. Biological activities of IL-6 may be modulated by two soluble circulating receptors, namely sIL-6R and sgp130. sIL-6R may enhance the inflammatory effects of IL-6 and is, therefore, an "agonistically" acting molecule. We have recently studied sIL-6R production in ESRD patients dialyzed with different membranes; the conclusion was that poor biocompatible membranes, via the sIL-6R, might further increase the inflammatory effects of IL-6. On the contrary, sgp130 can efficiently bind the IL-6/sIL-6R complex with "antagonistic" effects. We have evaluated plasma levels of sgp130 in 18 ESRD patients regularly dialyzed with hemophan membranes (HE) and in 15 patients dialyzed with more biocompatible synthetic membranes (BIO). Our results demonstrate that plasma levels of sgp130 in HE are 33% higher than in both healthy controls and BIO. Circulating levels of sgp130 were correlated positively with C-reactive protein (r: 0.338, p<0.05) and negatively with serum albumin (r: -0.334, p<0.05). These results suggest that higher circulating levels of sgp130 are likely associated with higher IL-6 levels. These higher amounts are probably insufficient to control the activity of IL-6 and may be considered only as a marker of PBMC activation.

Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a prospective, observational study based on data collected from nationally representative samples of haemodialysis facilities. The burden of anaemia in haemodialysis patients is substantial, leading to considerable morbidity, mortality and reduced quality of life. This study examines anaemia management and outcomes based on data from five European countries participating in the DOPPS: France, Germany, Italy, Spain and the UK. METHODS: Baseline data on demographics, co-morbidities and anaemia management in 4591 haemodialysis patients from 101 nephrology facilities were collected in 1998-2000. Using multivariate Cox survival analyses to adjust for patient characteristics, relationships between haemoglobin concentration at study entry and rates of mortality and hospitalization were evaluated. RESULTS: For a year 2000 sample of prevalent patients on haemodialysis >180 days, mean haemoglobin concentration was 11.0 g/dl; 53% had a haemoglobin concentration > or = 11 g/dl [1998-1999 = 44% (P < 0.05)]. In 2000, 84% of prevalent patients were prescribed recombinant human erythropoietin (rHuEpo). Higher haemoglobin concentrations were associated with decreased relative risk (RR) for mortality (RR = 0.95 for every 1 g/dl higher haemoglobin, P = 0.03) and hospitalization (RR = 0.96, P = 0.02). Patients with haemoglobin <10 g/dl were 29% more likely to be hospitalized than patients with haemoglobin 11-12 g/dl (P < 0.001). CONCLUSION: Even after adjustment, lower haemoglobin concentrations were associated with higher morbidity and mortality in European haemodialysis patients. A trend to increased haemoglobin concentrations was observed following publication of the European Best Practice Guidelines (EBPG) on anaemia management for chronic kidney disease patients, but efforts must continue to achieve EBPG goals.

Insomnia in maintenance haemodialysis patients.

BACKGROUND: Studies in the last 15 years have shown a high prevalence of sleep disorders in maintenance haemodialysis (HD) patients. METHODS: To investigate whether the new technical and therapeutic advances of the last decade have had a positive impact on sleep disturbances in HD patients: 694 patients (384 males, 310 females) were surveyed using a specific questionnaire; their clinical, lifestyle and dialysis data were also recorded. RESULTS: Forty-five per cent of patients (n=311; 156 males, 155 females) complained of insomnia, defined either by delayed sleep onset and/or night-time waking, and were included in the insomnia group; the remainder were used as controls (control group). There was a significantly higher risk of insomnia in patients with >12 months on dialysis, in patients dialysed in the morning (P<0.003), and in patients with higher parathyroid hormone (PTH) levels (P<0.05). Body mass index, body weight gain and blood pressure did not differ between the groups, and neither did the dialysis parameters. Creatinine and urea plasma levels were higher in the control group vs the insomnia group (P<0.001), but there was no difference in haemoglobin concentrations or use of erythropoietin, calcitriol and antihypertensive drugs. Cigarette smoking, caffeine or alcohol intake were comparable in the two groups. The most frequently recorded sleep disorders were night-time waking (92%), trouble falling asleep (67%) and early morning waking (62%). Restless leg symptoms were described in 52% of patients with insomnia. CONCLUSIONS: The prevalence of insomnia in HD patients is still very high; elderly patients, and those with longer time on dialysis and high levels of PTH are at major risk of insomnia, whereas type of dialysis, haemoglobin levels and behavioural factors do not seem to play a critical role in determining this sleep disorder.