Introduction and Aims: Patients with chronic kidney disaeses (CKD) suffer from accelered vascular calcification (VC) and vitamin K defficiency.The vitamin K-dependent matrix Gla protein (MGP) is one of the most powerful inhibitors of VC.This prospective randomized intervention study assessed the impact of vitamin K2 supplementation on levels of the inactive form of MGP desphospho-uncarboxylated MGP (dp-ucMGP) in non-dialyzed 3 -5 stages CKD patients.Methods: Common carotid intima media thickness (CCA-IMT), coronary artery calcification score (CACS), serum mineral parameters, matrix Gla protein (MGP), desphospho-uncarboxylated MGP (dp-ucMGP), osteocalcin (OC) were measured at baseline and after 270±12 days of supplementation of 90 μg of vitamin K2 (menaquinone-7, MK-7) with 10 μg cholecalciferol (K+D group) or 10 μg vitamin D (group D) in 42 non-dialyzed CKD patients.Results: During the treatment period no significant changes of eGFR in both groups were observed.The significantly lower increase of CCA-IMT during the intervention period was noticed in group K+D: from 0.95±0.2mm at the beginning to 1.01±0.3mm, p=0.003 at the end, and in D group: from 1.02±0.2mm to 1.16±0.3mm, p=0.003.The change of CACS was numerically less in vitamin K+D treated patients than in D group (ΔCACS: 63.1±108.5 A.u. vs 74.4±127.1,p=0.7; 16% and 15.8%, p=0.91, respectively).After nine months of MK-7 supplementation a significant decrease of dp-ucMGP was found 1077.1±507.7 pmol/L vs 961.5±506.7,p=0.02.This effect was not observed in D group: 793.9±400.3pmol/L vs 820.7±565.2,p=0.7 respectively.The serum level of dp-ucMGP positively correlated with serum creatinine r=0.4,p=0,02, negatively with eGFR r=-0,5, p=0.003 at the beginning and r=0.4,p=0.03; r=-0.6,p=0.0001, respectively at the end of the study in both group.The positive correlation of dp-ucMGP and PTH level was noticed in all examined patients at the beginning and at the end of the study: r=0.4,p=0.04; r=0.4,p=0.01 respectively.Similar correlations were noticed between dp-ucMGP and OC: r=0.47, p=0.005; r=0.5; p=0.004 respectively.Any correlation between dp-ucMGP and estimated vascular changes was not find.Conclusions: The main determinant of dp-ucMGP level is the kidney function.Circulating level of dp-ucMGP may be a marker of vascular vitamin K status in CKD patients.The mechanisms by which vitamin K2 may exert the protective effect on progression of vessels damage are still uncertain, but may be connected with the impact of MK-7 on calcification's regulators, including the impact on the MGP carboxylation process.

Urotensin II (UTN), a cyclic vasoactive peptide expressed in multiple organs, had higher plasma levels that was previously shown to predict longer survival in dialysis patients. We sought to determine if this association exists in earlier stages of chronic kidney disease (CKD) by studying a cohort of 122 incident clinically stable pre-dialysis patients. Linear models were used to determine associations of UTN with baseline characteristics such as renal function and traditional and nontraditional cardiovascular risk factors. We used Cox regression analysis to model time-to-death as a function of UTN and the same variables for adjustment including a time-varying covariate that indicated progression to end-stage renal disease. No correlation was found between baseline glomerular filtration rate and plasma UTN. In adjusted analysis, UTN correlated directly with serum albumin and, inversely, with history of previous coronary events. During a mean follow-up of 41 months, 43 patients died - 29 from cardiovascular events. After adjusting for potential confounding factors, increased UTN predicted lower risk of death from all-cause and cardiovascular causes. In patients with moderate-to-severe CKD, plasma UTN was found to be an inverse predictor of overall and cardiovascular mortality.

In multiple regression the effect of an input (independent) variable on a continuous output (dependent or response) variable can be adjusted for the effect of confounding and modifying variables. This adjustment is useful to obtain either an unbiased estimate of the true association between an exposure and an outcome or to predict the outcome for given inputs after removing the influence of other factors. These factors are defined as confounders if they are associated with the exposure and are independent risk factors for the outcome, without being intermediates on the biological pathway between exposure and outcome. An interaction between exposure and another independent variable is present when the exposure-disease relationship varies across different values of this variable. Multivariable regression modeling removes the association between the confounder and the outcome eliminating the necessary condition for confounding. An interaction term can be also incorporated into the model to quantify any potential modifying effect.

General linear models can be considered the paradigm of all models used in clinical epidemiology. In these models, the independent variables combine in linear fashion to predict the values of the variable response. Since no model predicts the variable response perfectly, an error term is incorporated into the model to acknowledge what remains to be explained after getting a fit to the data. When this error term is normally distributed with constant variance, the linear models are reasonably appropriate to describe the input/output relationship of interest.

The Lombardy Registry of Dialysis and Transplantation (RLDT) since 1983 has collected data concerning patients affected by end-stage renal disease (ESRD) on renal replacement therapy (RRT) in Lombardy, a region of Northern Italy with 9 million inhabitants. This report illustrates the main features of ESRD patients on RRT: there were 6589 patients undergoing treatment at 31 December 2003, with a prevalence rate of 727 pmp. Patient numbers regularly increased by 4.5%/yr for the last 5 yrs. This phenomenon is probably due to the high incidence rate (172 pmp) of ESRD patients in Lombardy during these years related to a relatively stable mortality rate (15.2%). The increasing incidence is probably correlated to the population's characteristics: higher rates (189-223 pmp) were observed in certain provinces (Cremona, Lodi and Pavia) with a larger elderly population (people >65 yrs = >20%, people <65 yrs = <16%). Of dialysis modalities, 85% of prevalent patients were on hemodialysis (HD), 55% in hospital, and 30% in limited care units. The number of patients treated by peritoneal dialysis (PD) was stable during the last years, but showed a slow percentage decline (15% during 2003) since 1999. However, PD remains the first dialysis modality for 21.4% of new patients, with a wide variability among renal units. Regarding HD, highly efficient techniques (on-line hemodiafiltration (HDF)) represented 19.2%, with a significant increase (1.8%) compared to 2002. During 2003, the number of dialysis units in Lombardy was stable; there was only an increase in facility beds in limited care units in order to treat the increasing numbers of uremic patients.

Vascular calcifications are more frequent in dialysis patients than in the general population or in patients with cardiovascular disease (CVD) and normal renal function. The reasons for this high incidence are multiple; they include traditional factors such as hypertension, diabetes, dyslipidemia, and specific factors such as sodium overload, hyperomocysteinemia, chronic inflammation and oxidative stress, as well as mineral metabolism disturbances. Specifically, hyperphosphatemia and the elevated calcium (Ca) x phosphate product have been associated with an increased risk for the development of vascular calcification and death. Treatment with Ca salts can induce hypercalcemia, increased Ca x phosphate product and Ca overload. Sevelamer substitution for Ca salts has been documented to attenuate the progression of coronary artery and aortic calcification. A possible mechanism explaining this observation could be ongoing Ca loading related to oral Ca ingestion. Treatment with Ca salts could induce Ca overload, particularly in patients dialyzed against a high dialysate Ca (>1.5 mmol/L) solution, which is known to determine a positive dialysis balance. Conversely, an overall negative Ca balance can result from low Ca dialysate use (1.25 mmol/L) when the patients do not receive Ca supplements or vitamin D metabolites. Maintaining normal Ca and phosphate balances remains a primary goal in the management of dialysis patients. Control of hyperphopshataemia should be achieved either using Ca and aluminum-free phosphate binders, such as sevelamer, or Ca salts, alone or in combination, provided that a daily oral elemental Ca intake of 1.5 g is not exceeded.

Background. Arteriovenous fistulae survive longer than grafts and catheters. However, their short term outcomes may not be as good. We sought to determine whether fistulae created in patients referred to a nephrologist less than 3 months before dialysis start show higher risk of unsuccessful use and early failure.Methods. All patients receiving a new vascular access over a six-year period at three centres were enrolled. Logistic and Cox's regression techniques were used to model late referral on successful utilization for < 6 consecutive HD-sessions and time to failure within the first month from access creation, adjusting for demographics, comorbidities and surgical strategies.Results. Among the 535 subjects enrolled, 513 received a fistula. Without considering revisions, 119 fistulae (23.2%) were not successfully used and 61 (11.9%) failed early. Independent predictors of unsuccessful utilization were late referral (Odds Ratio 2.15 [95% Confidence Interval 1.23, 3.75]), vascular diseases (1.86 [1.16, 2.97]), absence of treated hypertension (2.07 [1.17, 3.68]), and heart failure limited to late referrals (10.74 [4, 28.82]). Late referral (Hazard Ratio 1.72 [1.05, 2.81]), absence of treated hypertension (1.80 [1.02, 3.18]) and heart failure (2.34 [1.34, 4.08]) also predicted primary early failure.Conclusions. Late patient referral and presence of cardiovascular diseases, particularly heart failure, are potentially modifiable risk factors for short-term outcomes improvement of hemodialysis fistulae.

High plasma asymmetrical dimethylarginine (ADMA) signals endothelial dysfunction and atherosclerosis in the general population and predicts mortality in ESRD. The relationship among plasma levels of ADMA, renal function, and the risk for progression to ESRD (halving GFR or dialysis start) and death in an incident cohort of 131 patients with chronic kidney disease was investigated. Cox's competing risk regression was used to model double-failure times (progression to ESRD and death) as a function of ADMA. Covariates that were considered for adjustment included clinical characteristics, baseline GFR (Modification of Diet in Renal Disease equation 7 formula), proteinuria, traditional cardiovascular risk factors, serum C-reactive protein, homocysteine, and concomitant therapies. Mean age at enrollment was 71 +/- 11 yr, and 24% of patients had diabetes. Baseline GFR ranged from 8 to 77 ml/min per 1.73 m2 (average 31 +/- 15 ml/min per 1.73 m2). ADMA was inversely related to GFR, ranking as the third predicting factor (partial r = -0.22, P = 0.01), after hemoglobin and urinary protein, in a general linear model that included multiple correlates of GFR. After a mean follow-up of 27 mo (range 3.4 to 36), 29 patients progressed to ESRD and 31 died. ADMA (hazard ratio per 0.1 muM/L 1.203; 95% confidence interval 1.071 to 1.350) predicted event occurrence independent of other potential confounders, including GFR, proteinuria, hemoglobin, and homocysteine. In patients with mild to advanced chronic kidney disease, plasma ADMA is inversely related to GFR and represents a strong and independent risk marker for progression to ESRD and mortality. These novel findings further expand the implications of previous observations in ESRD patients and generate hypotheses on the role of ADMA in progressive chronic nephropathies.

BACKGROUND:Many studies suggest a major prevalence of atherosclerotic renovascular disease (ARVD), caused by mono or bilateral renal artery stenosis (RAS). Unfortunately, there is no definite therapy to cure this disease to date; therefore, ARVD is burdened by important clinical complications with high social and economic costs. The last few years have seen important advancements in both medical therapy and in interventional radiology (for example, percutaneous transluminal renal artery stenting (PTRS)). All of them could affect, in some way, the natural history of ARVD, but to date the optimal strategy has not been established. METHODS:The protocol of a prospective, multicenter, randomized trial "Nephropathy Ischemic Therapy (NITER)" is presented. It enrolls patients with stable renal failure (glomerular filtration rate (GFR) >or=30 ml/min) and hypertension, and hemodynamically significant atherosclerotic ostial RAS (>or=70%) diagnosed by duplex Doppler (DD) ultrasonography and confirmed by magnetic resonance angiography (MRA). This study aims to evaluate whether medical therapy plus interventional PTRS is superior to medical therapy alone according to the following combined primary endpoint: death or dialysis initiation or reduction by >20% in estimated GFR after 0.5, 1, and 2 yrs of follow-up and an extended follow-up until the 4th year. Medical therapy means drugs to control hypertension, improve dyslipidemia and optimize platelet anti-aggregant therapy. The sample size is estimated in 50 patients per group to achieve a statistical significance of 0.05 in case of a reduction by 50% in the combined endpoints.

Most clinical research can be simplified as an investigation of an input/output relationship. The inputs are called explanatory (independent) variables or predictors and are thought to be related to the outcome, or response (independent) variable. This relationship is usually complicated by other factors related to both the input and the output (presence of confounding) and can vary according to the levels of the other variables (presence of interaction). This input/output relationship is usually described by statistical models that include a fit part and a residual component or difference between the data and the fit. The most popular models are the general linear models, which can be considered the paradigm of all models used in multi-variable analyzes.

BACKGROUND:Darbepoetin alpha is a novel erythropoiesis stimulating protein with unique properties as compared to recombinant human erythropoietin (rHuEPO), including a three-fold longer elimination half-life that allows for less frequent dosing. This study was aimed at testing the efficacy and safety of darbepoetin alpha in a large number of chronic dialysis patients switched from rHuEPO.METHODS:Nine hundred and fifty dialysis patients in stable treatment with rHuEPO were switched to darbepoetin alpha. Patients receiving rHuEPO 2 or 3 times weekly were switched to once weekly darbepoetin alpha and those receiving rHuEPO once weekly were switched to once every other week darbepoetin alpha. Patients received darbepoetin alpha by the same route of administration (SC or IV) as the one used for rHuEPO. The unit doses of darbepoetin alpha (10-150 microg) were titrated to maintain haemoglobin concentration within -1.0 and +1.5 g/dL of the individual mean baseline haemoglobin levels and between 10 and 13 g/dL for 24 weeks.RESULTS:The mean change in haemoglobin from baseline to the evaluation period (weeks 21-24) was statistically but not clinically significant [-0.10 g/dL (95% CI: -0.18, -0.02]. In general, the geometric mean weekly dose of study drug from screening/baseline to evaluation period remained substantially unmodified [(from 26.10 micro g/wk to 25.90 microg/wk; percentage change -0.40% (95% CI: -3.78, 3.10)]. Overall, darbepoetin alpha was well tolerated.CONCLUSIONS:The treatment of anaemia of a large dialysis patient population with unit dosing of darbepoetin alpha is effective and safe in maintaining target haemoglobin concentration at reduced dose frequency.

Vascular calcifications are more frequent in dialysis patients than in the general population or in patients with cardiovascular disease and normal renal function. The reasons for this high incidence are multiple. They include traditional factors such as hypertension, diabetes, dyslipidaemia, and specific factors such as sodium overload, hyperomocysteinaemia, chronic inflammation, oxidative stress as well as disturbance of mineral metabolism. Specifically, hyperphosphataemia and the elevated calcium (Ca) x phosphate product have been associated with an increased risk for development of vascular calcification and death. Even though a causal relationship between the use of Ca- containing phosphate binders and the development of vascular calcifications has not been documented, treatment with Ca salts can induce hypercalcaemia, increased Ca x phosphate product, and Ca overload. A net intestinal Ca absorption of 180-500 mg has been documented in uraemic patients after a meal containing 1200 mg of Ca. Thus, treatment with Ca salts may induce Ca overload when a patient is dialyszed against a high dialysate Ca (> 1.5 mmol/L) solution, which is known to determine a positive dialysis balance. On the contrary, an overall negative Ca balance can result from the use of a low Ca dialysate (1.25 mmol/L) when the patients do not receive Ca supplements or vitamin D metabolites. Maintaining a normal Ca and phosphate balance remains one of the primary goals in the management of dialysis patients. Control of hyperphopshataemia should be obtained using either Ca and aluminium- free phosphate binders, such as sevelamer, or Ca salts, while avoiding a daily oral elemental Ca intake > 1.5 g.

Background. This two country case control study of incident dialysis patients evaluates the outcomes of patients exposed to formalized multi-disciplinary clinic (MDC) programmes vs standard nephrologist care.Methods. Patients commencing dialysis in two centres (Vancouver, Canada and Cremona, Italy) were evaluated at and after dialysis start, as a function of MDC exposure vs nephrologist care alone. Only chronic kidney disease patients, with longer than 3 months of exposure to nephrology care, who had not previously received kidney replacement therapy were included. Study outcomes included laboratory parameters and survival. The MDC was similar in both countries and average exposure was 6-8 h per patient-year, as compared to 2-4 h for standard care. All patients had equal access to resources prior to dialysis and with respect to dialysis start, as all had been referred to the same local nephrology practices.Results. During the evaluation period 288 patients commenced dialysis after receiving more than 3 months nephrology care prior to dialysis. There were no major demographic differences between the cohorts. Mean duration of nephrology care prior to dialysis was 42 months, and dialysis was initiated at similar low glomerular filtration rate (GFR), though statistically significantly different (7.0 and 8.4 ml/min/m(2), P=0.001). The MDC patients had higher haemoglobin (102 vs 90 g/l, P < 0.0001), albumin (37.0 vs 34.8 g/l, P=0.002) and calcium levels (2.29 vs 2.16 mmol/l, P<0.0001) at dialysis start. Survival was significantly better in the MDC group demonstrated by Kaplan-Meier analysis (P=0.01). Cox proportional hazards analysis demonstrated standard nephrology clinic vs MDC attendance was a statistically significant independent predictor of death (hazards ratio = 2.17, 95 % confidence interval 1.11-4.28) after adjusting for other variables known to impact outcomes.Conclusions. This analysis of outcomes in two different countries suggests that despite equal and long exposure to nephrology care prior to dialysis, there appears to be an association of survival advantage for those patients exposed to formalized clinic care in addition to standard nephrologist follow-up. While other known predictors of survival such as adequacy of dialysis and severity of illness measures were not included in the model, those parameters require time on dialysis to be accumulated. Thus, the data do suggest that knowledge of patient status at the time of dialysis start is important. Further research is needed to determine which specific components of care both prior to dialysis and after its commencement are most important with respect to outcomes.

Autologous arteriovenous fistulas (AVF) have the best 5-yr patency and the lowest complication rate among hemodialysis vascular accesses. However, maturation requirements to optimize survival are unknown. A longitudinal cohort study was conducted to ascertain risk factors for failure, maturation time, and survival of the first AVF. All patients who initiated hemodialysis between January 1, 1997, and December 31, 2002, in three centers were included in this study. Analysis was restricted to patients who received an AVF. Cox regression was used to estimate the association between predictors of interest and primary and secondary AVF survival. Of the 535 patients enrolled (mean age, 66.5 yr; 57.8% male; 26.7% diabetic), 513 (96%) received an AVF. Patients who initiated with catheters (47%) cannulated their AVF earlier (median maturation period, 0.78 versus 1.80 mo; P < 0.001). Median primary and secondary survivals were longer than 50 and 72 mo, respectively. After adjustment for confounding factors, cardiovascular disease (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.26 to 2.67), utilization earlier than 1 mo after placement (HR, 1.94; 95% CI, 1.34 to 2.82), and referral within 3 mo of dialysis start (HR, 1.55; 95% CI, 1.04 to 2.32) were associated with a reduction in primary AVF survival. Presence of cardiovascular disease (HR, 2.21; 95% CI, 1.38 to 3.55), maturation time <15 d (HR, 2.12; 95% CI, 1.20 to 3.73), and presence of catheters at hemodialysis initiation (HR, 1.79; 95% CI, 1.13 to 2.84) were associated with lower secondary AVF survival. It is concluded that cardiovascular disease, late referral, temporary catheters, and early cannulation are associated with impaired AVF survival. It is recommended that AVF be allowed to mature at least 1 mo before cannulation.

Optimization of hemodialysis treatment parameters and the characteristics of the dialyzer are crucial for short- and long-term outcome of end stage renal disease patients. The new high-flux membrane Helixone® in the dialyzer of the FX series (Fresenius Medical Care, Germany) has interesting features, such as the relationship of membrane thickness and capillary diameter which increases middle molecule elimination by convection, as well as higher capillary packing and microondulation to improve the dialysate flow and distribution. Blood flow, dialysate flow and surface area are the main determinants of the performance of a dialyzer, however the impact of each parameter on small and middle molecule clearance in high flux dialysis has not been well explored. In order to find the best treatment condition for the new dialyzer series, we evaluated urea, creatinine, phosphate clearances and reduction rate of ß2-microglobulin in ten stable patients treated with different blood flows (effective Qb 280 and 360 ml/min), dialysate flow (Qd 300 or 500 ml/min) and dialyzer surfaces (1.4 and 2.2 m2, FX60 or FX100). KoA and Kt/V were also calculated. Blood flow, dialysate flow and surface area demonstrated a significant and independent effect on clearance of urea, creatinine and phosphate, as well as on Kt/V. Small solute clearance was stable over the treatment. In contrast to small solutes, reduction rate of ß2-microglobulin was related to increasing dialyzer surface only. The new dialyzer design of the FX series proves highly effective due to improved dialysate distribution and reduced diffusive resistance as shown by the small solute clearance. A high reduction rate of ß2-microglobulin is favored by improved fiber geometry and pore size distribution. These findings have potential long-term benefits for the patient