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Background: Factors predictive of renal outcome were investigated in 219 cases of biopsy-proven Henoch-Schönlein purpura nephritis (HSPN); 83 children and 136 adults enrolled in a national study were followed up for up to 27 years (median, 4.5 years)., Methods: The criterion for defining disease progression was time elapsed until doubling of baseline creatinine level and until dialysis therapy. Age, sex, data at onset (renal function, proteinuria, hematuria, hypertension, and crescents), and data during follow-up (proteinuria and therapy) were tested as covariates., Results: Multivariate Cox regression analysis indicated the following parameters as independent prognostic predictors: age (adults versus children, relative risk, 3.57; 95% confidence interval, 1.18 to 10.79; P = 0.024 for creatinine level doubling; relative risk, 14.89; 95% confidence interval, 1.72 to 129.07; P = 0.014 for dialysis therapy), sex (females versus males, relative risk, 5.71; 95% confidence interval, 1.67 to 19.55; P = 0.006 for creatinine level doubling; relative risk, 26.03; 95% confidence interval, 2.64 to 256.73; P = 0.005 for dialysis therapy), and mean proteinuria during follow-up (for each 1 g/d of protein increase, relative risk, 1.77; 95% confidence interval, 1.35 to 2.32; P < 0.001 for creatinine level doubling; relative risk, 1.73; 95% confidence interval, 1.18 to 2.52; P = 0.005 for dialysis therapy). Information for mean proteinuria levels during follow-up increased the sensitivity at logistic regression to 62.5%, with dialysis therapy as the end point. No data detected at diagnosis, including renal function impairment, proteinuria, hypertension, and crescentic nephritis (involving > 50% of glomeruli in only 2.6%), were significantly related to functional decline at multivariate Cox., Conclusion: This analysis indicates that, even more than when decreased renal function, severe proteinuria, hypertension, or crescents are present at onset, the risk for progression of HSPN (greater in adults and females) was associated with increasing mean proteinuria levels during follow-up.

Background: Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation., Methods: In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders., Results: Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22)., Conclusions: Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.

Heart failure is a prominent problem of public health, requiring innovating methods of health services organization. Nevertheless, data are still not available on prevalence, hospitalization rate, adherence to Guidelines and social costs in the general Italian population. The necessity to identifying patients with heart failure derives from the efficacy of new therapeutic interventions in reducing morbidity and mortality. In this study we aimed to identify, in a subset of the Eastern Veneto population, patients with heart failure through a pharmacologic-epidemiologic survey. The study was divided in 5 phases: (1) identification of patients on furosemide in the year 2000 in the ASL 10 of Eastern Veneto general population, through an analysis of a specific pharmaceutic service database; (2) definition of the actual prevalence of heart failure in a casual sample of these patients, through data base belonging to general practitioners, cardiologists, or others. Diagnosis was based on the following criteria: (a) previous diagnosis of heart failure; (b) previous hospitalization for heart failure; (c) clinical evidence, with echocardiographic control in unclear cases; (3) survey of hospitalizations; (4) evaluation of adhesion to guidelines, through both databases and questionnaires; (5) analysis of the social costs of the disease, with a retrospective "bottom up" approach. From a total population of 198,000 subjects, we identified 4502 patients on furosemide. In a casual sample of 10,661 subjects we defined a prevalence of heart failure in Eastern Veneto of 1.1%, that increased to 7.1% in octagenarians. The prescription of life saving drugs was satisfactory, while rather poor was the indication to echocardiography and to cardiologic consultation. Hospitalization rate for DRG 127 was low: 2.1/1000 inhabitants/year in the general population and 12.5 /1000 inhabitants/year in patients >70 years of age. Yearly mortality was 10.3%. Social costs were elevated (15.394 Euros/patient/year), due to a relevant sanitary component (hospital 53%, drugs 28%) and particularly a to an indirect cost component. In conclusion, the assumption of furosemide lends itself as a good marker for identifying patients with heart failure. Patient identification is simple, cheap and cost-efficient, and can be easily reproduced in other regional areas.

A new method of polymer classification is described involving dynamic mechanical analysis of polymer properties as temperature is changed. The method is based on the chemometric analysis of the damping factor (tan delta) as a function of temperature. In this study four polymer groups, namely, polypropylene, low density polyethylene, polystyrene and acrylonitrile-butadiene-styrene, each characterised by different grades, were studied. The aim is to distinguish polymer groups from each other. The polymers were studied over a temperature range of -50 degrees C until the minimum stiffness was reached, tan delta values were recorded approximately every 1.5 degrees . Principal components analysis was performed to visualise groupings and also for feature reduction prior to classification and clustering. Several clustering and classification methods were compared including k-means clustering, hierarchical cluster analysis, linear discriminant analysis, k-nearest neighbours, and class distances using both Euclidean and Mahalanobis measures. It is demonstrated that thermal analysis together with chemometrics provides excellent discrimination, representing a new approach for characterisation of polymers.

Background: On-line determination of ionic dialysance (ID) has been used to measure the clearance of small solutes like urea. However, attempts to determine the in vivo relationship between ID and urea clearance have led to discordant findings. The aim of this study was to determine the relationship between the mean values of repeated instantaneous determinations of ID throughout a dialysis session ((m)ID), obtained using a single-step inlet dialysate conductivity profile, and the mean values of urea clearance corrected for access recirculation (K(eu1)), total recirculation (access plus cardiopulmonary recirculation, K(eu2)), and the entire postdialysis urea rebound (K(wb))., Methods: Eighty-two anuric patients on chronic thrice-weekly hemodialysis were studied using an Integra machine equipped with the Diascan module for the automatic determination of ID. The mean values of repeated ID measurements made at 30-minute intervals were compared with K(eu1) (available for only 31 patients), K(eu2), and K(wb)., Results: The results in all 82 patients were: (m)ID = 176 +/- 23 mL/min; K(eu2) = 181 +/- 25 mL/min; K(wb) = 159 +/- 22 mL/min. The mean (m)ID/K(wb) and (m)ID/K(eu2) ratios were, respectively, 1.11 +/- 0.06 and 0.98 +/- 0.06. The results in the 31 patients for whom K(eu1) values were available were: (m)ID = 179 +/- 24 mL/min and K(eu1) = 200 +/- 27 mL/min; the mean (m)ID/K(eu1) ratio was 0.90 +/- 0.05., Conclusion: The mean value of repeated ID determinations obtained using a single-step conductivity profile underestimates urea clearance corrected for access recirculation, and may be considered an adequate estimate of urea clearance corrected for total recirculation.

Background: Loss of ultrafiltration (UF) of peritoneal membrane is one of the most important causes of peritoneal dialysis failure. UF is determined by osmotic forces acting mainly across small pores (UFSP) and ultrasmall pores or free water transport. At present, only semiquantitative estimates or complicated computer simulations are available to assess free water transport. The aim of this study was to assess free water transport during a 3.86% peritoneal equilibration test lasting 1 hour. In this condition, sodium transport is mainly due to convection, allowing the estimate of ultrafiltration of small pores and then of free water transport (total UF - UFSP)., Methods: In 52 peritoneal dialysis patients we performed a 3.86% peritoneal equilibration test (4 hours) and a 3.86% mini-peritoneal equilibration test (1 hour) and compared UF and small solute transports obtained with the two methods., Results: During the 3.86% mini-peritoneal equilibration test, UFSP and free water transport were 279 +/- 142 mL and 215 +/- 86 mL, respectively; free water transport well correlated to total UF during the 3.86% peritoneal equilibration test (r= 0.67). The groups of peritoneal transporters, categorized according to glucose dialysate ratio (D/D(0)) and to creatinine/plasma ratio (D/P(Creat)), were in good agreement for the two peritoneal equilibration tests (weighted kappa 0.62 and 0.61, respectively)., Conclusion: The 3.86% mini-peritoneal equilibration test is a simple and fast method to assess free water transport. It also gives information about total UF and small solute transports and it is in good agreement with the 3.86% peritoneal equilibration test.

Mathematical models are emerging as important tools in the study of microbiology. As an illustrative example, we present results from several models each generated to study the interaction of Mycobacterium tuberculosis and the immune system. Different mathematical models were formulated on the basis of assumptions regarding system-component interactions, enabling us to explore specific aspects at diverse biological scales (e.g. intracellular, cell-cell interactions, and cell population dynamics). In addition, we were able to examine both temporal and spatial aspects. At each scale, there were consistent themes that emerged as determinative in infection outcome. Factors we identified include both host and microbial characteristics. The use of the models lies in generating hypotheses that can then be tested experimentally. Here, we outline the primary host and bacterial factors that we have identified as key mechanisms that contribute to the success of M. tuberculosis as a human pathogen. Our goal is to stimulate experimentation and foster collaborations between theoretical and experimental scientists.

Detection and identification of impurities in pharmaceuticals is an essential task for determining the possible infringement of a patent. This article reports a multivariate analysis method to distinguish between tablets of the same substance on the basis of their origin, by characterizing route/process specific impurities via diagnostic ion chromatograms, using liquid chromatography/mass spectrometry (LC/MS). The approach is based on the formulation of a novel index that quantifies the similarity between LC/MS samples, named the component detection weighted index of analogy. The index estimates similarity by fully exploiting the two-dimensional nature of the data, where the relative contribution of chromatograms relates to their quality and noise level. Results show that well-defined clusters are formed according to the origin of tablets; a series of ions are identified as characterizing each class and can be used to predict the origin of unknown tablet samples. The method presented is designed for analysis of larger data sets and can be suitable for exploratory analysis where any a priori knowledge on the data is scarce or absent, hence requiring the acquisition of chromatograms in a broad m/z range.

Over the recent years, it has been clearly documented that hypertension and proteinuria are the major factors responsible for progression of chronic kidney disease (CKD). Therefore, a target BP of at least 130/80 mm Hg has been suggested in order to reduce the rate of progression and cardiovascular mortality. Some antihypertensive agents, such as ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and perhaps calcium channel blockers (CCBs), may also be capable of reducing CKD progression because they halt some of the pathogenetic mechanisms involved in renal damage, some of which is unrelated to reduction of proteinuria, per se. Although this specific effect seemed to be partially independent of blood pressure reduction, it remains controversial whether these drugs are really superior to other antihypertensive agents when blood pressure values recommended by guidelines are achieved. This issue is still a matter of debate because in published trials, target and achieved blood pressure values were constantly higher than those recommended today. Nevertheless, available findings seem to indicate that the renoprotective effect of these agents is at least partially independent of a better BP control. The only way to definitely solve this issue would be a new randomized trial. However, the clinical relevance of this trial is debatable, considering that we need all the drugs available to reach these recommended BP values.

Despite an increase in the use and average dose of recombinant human EPO (rh-EPO) over the last 15 years, a substantial percentage of patients still do not achieve hemoglobin targets recommended by international guidelines. The definition of rh-EPO resistance has been introduced to identify those patients in whom the target hemoglobin level is not attained despite a greater-than-usual dose of erythropoietin-stimulating agent (ESA). In recent years, increasing attention has been paid to the relationship between dialysis, increased inflammatory stimulus, malnutrition, and ESA response. About 35% to 65% of hemodialysis patients show signs of inflammation that could be a cause of anemia through the suppression of bone marrow erythropoiesis by a number of cytokines. A large proportion of chronic kidney disease patients also have protein-energy malnutrition and wasting; low serum albumin levels, together with other more specific nutritional markers, are predictors of rh-EPO response. A diminished nutritional state could then be a feature of patients who are resistant to ESA treatment, with malnutrition probably being a consequence of a chronic inflammatory state. Starting from the hypothesis that anemia, partially attributable to a reduced response to ESA, could be the link among malnutrition, inflammation, and the poor outcome of chronic kidney disease patients, we designed a multicenter observational study, the Malnutrition-Inflammation-Resistance-Treatment Outcome Study (MIRTOS), aimed at evaluating the impact and possible causes of resistance to ESA in a large sample of hemodialysis patients. We hope the results of MIRTOS will represent a step forward toward a better understanding of the factors influencing the response to ESA in hemodialysis patients.

Modern methods of high-throughput molecular biology render it possible to generate time series of metabolite concentrations and the expression of genes and proteins in vivo. These time profiles contain valuable information about the structure and dynamics of the underlying biological system. This information is implicit and its extraction is a challenging but ultimately very rewarding task for the mathematical modeler. Using a well-suited modeling framework, such as Biochemical Systems Theory (BST), it is possible to formulate the extraction of information as an inverse problem that in principle may be solved with a genetic algorithm or nonlinear regression. However, two types of issues associated with this inverse problem make the extraction task difficult. One type pertains to the algorithmic difficulties encountered in nonlinear regressions with moderate and large systems. The other type is of an entirely different nature. It is a consequence of assumptions that are often taken for granted in the design and analysis of mathematical models of biological systems and that need to be revisited in the context of inverse analyses. The article describes the extraction process and some of its challenges and proposes partial solutions.

Two-dimensional light-scattering patterns from aggregates have undergone feature extraction followed by multivariate statistical analysis. The aggregates are comprised of primary particles of varying shape and size. Morphological descriptors (features) were extracted by a nonlinear filtering algorithm (spectrum enhancement) and then processed by principal component analysis and discriminant function analysis. The analysis was performed on two data sets, one in which the aggregates had a fixed primary particle size but varied in overall dimension and another in which the aggregate size was fixed but the primary particle size varied. Classification of the samples was performed adequately, providing some distinction among the limited classes that were analyzed.

Background: An adequate estimation of urea distribution volume (V) in hemodialysis patients is useful to monitor protein nutrition. Direct dialysis quantification (DDQ) is the gold standard for determining V, but it is impractical for routine use because it requires equilibrated postdialysis plasma water urea concentration. The single pool variable volume urea kinetic model (SPVV-UKM), recommended as a standard by Kidney Disease Outcomes Quality Initiative (K/DOQI), does not need a delayed postdialysis blood sample but it requires a correct estimate of dialyser urea clearance., Methods: Ionic dialysance (ID) may accurately estimate dialyzer urea clearance corrected for total recirculation. Using ID as input to SPVV-UKM, correct V values are expected when end-dialysis plasma water urea concentrations are determined in the end-of-session blood sample taken with the blood pump speed reduced to 50 mL/min for two minutes (U(pwt2')). The aim of this study was to determine whether the V values determined by means of SPVV-UKM, ID, and U(pwt2') (V(ID)) are similar to those determined by the "gold standard" DDQ method (V(DDQ)). Eighty-two anuric hemodialysis patients were studied., Results: V(DDQ) was 26.3 +/- 5.2 L; V(ID) was 26.5 +/- 4.8 L. The (V(ID)-V(DDQ)) difference was 0.2 +/- 1.6 L, which is not statistically significant (P= 0.242). Anthropometric volume (V(A)) calculated using Watson equations was 33.6 +/- 6.0 L. The (V(A)-V(DDQ)) difference was 7.3 +/- 3.3 L, which is statistically significant (P < 0.001)., Conclusion: Anthropometric-based V values overestimate urea distribution volume calculated by DDQ and SPVV-UKM. ID allows adequate V values to be determined, and circumvents the problem of delayed postdialysis blood samples.

Background: Sodium removal (NaR) may have a major impact on the survival of peritoneal dialysis patients. The dialysate/plasma sodium concentration ratio (D/P(Na)) is an indirect index of transcellular water transport by aquaporin channels, and thus of ultrafiltration. Sodium concentration can be assessed by means of flame photometry (F), and direct (D-ISE) or indirect ion-selective electrodes (I-ISE), but these methods have different properties. I-ISE is being used increasingly in clinical laboratories. The aim of this study was to evaluate NaR and D/P(Na) using the three different measurement methods., Methods: We performed peritoneal equilibration tests (PETs) in 44 peritoneal dialysis patients and calculated the NaR. We also calculated D/P(Na) during the test; plasma and dialysate sodium concentrations were measured by F, D-ISE and I-ISE., Results: NaR was lower (P<0.001) with D-ISE (69+/-29 mmol) than with F (81+/-29 mmol) or I-ISE (79+/-28 mmol). D/P(Na) was also lower at baseline (0.92+/-0.02 vs 0.95+/-0.02 and 0.95+/-0.02; P<0.001), after 60 min (0.87+/-0.03 vs 0.90+/-0.03 and 0.90+/-0.03; P<0.001) and at the end of PET (0.88+/-0.04 vs 0.92+/-0.04 and 0.92+/-0.04; P<0.001) when measured by D-ISE in comparison with F and I-ISE, respectively., Conclusions: NaR and D/P(Na) were lower when measured by the D-ISE method compared with the F and I-ISE methods. NaR and D/P(Na) were similar when measured by F or I-ISE. I-ISE can be used reliably in the evaluation of NaR and D/P(Na) in everyday clinical practice of peritoneal dialysis.

Mycobacterium tuberculosis (Mtb) is an extraordinarily successful human pathogen, one of the major causes of death by infectious disease worldwide. A key issue for the study of tuberculosis is to understand why individuals infected with Mtb experience different clinical outcomes. To better understand the dynamics of Mtb infection and immunity, we coupled nonhuman primate experiments with a mathematical model we previously developed that qualitatively and quantitatively captures important processes of cellular priming and activation. These processes occur between the lung and the nearest draining lymph node where the key cells mediating this process are the dendritic cells (DC). The nonhuman primate experiments consist of bacteria and cell numbers from tissues of 17 adult cynomolgus macaques (Macaca fascicularis) that were infected with Mtb strain Erdman ( approximately 25 CFU/animal via bronchoscope). The main result of this work is that delays in either DC migration to the draining lymph node or T cell trafficking to the site of infection can alter the outcome of Mtb infection, defining progression to primary disease or latent infection and reactivated tuberculosis. Our results also support the idea that the development of a new generation of treatment against Mtb should optimally elicit a fast DC turnover at the site of infection, as well as strong activation of DCs for maximal Ag presentation and production of key cytokines. This will induce the most protective T cell response.

A key issue for the study of tuberculosis is to understand why individuals infected with Mycobacterium tuberculosis (Mtb) experience different clinical outcomes. To better understand the dynamics of Mtb infection and immunity, we have previously developed a temporal mathematical model that qualitatively and quantitatively characterizes the cellular and cytokine control network during infection. In this work we extend that model to a two compartmental model to capture the important processes of cellular activation and priming that occur between the lung and the nearest draining lymph node. We are able to reproduce typical disease progression scenarios including primary infection, latency or clearance. Then we use the model to predict key processes determining these different disease trajectories (i.e. identify bifurcation parameters), suggesting directions for further basic science study and potential new treatment strategies.

In toxicology, hazardous substances detected in organisms may often lead to different pathological conditions depending on the type of exposure and level of dosage; hence, further analysis on this can suggest the best cure. Urine profiling may serve the purpose because samples typically contain hundreds of compounds representing an effective metabolic fingerprint. This paper proposes a pattern recognition procedure for determining the type of cadmium dosage, acute or chronic, administrated to laboratory rats, where urinary profiles are detected using capillary electrophoresis. The procedure is based on the composition of a sample data matrix consisting of areas of common peaks, with appropriate pre-processing aimed at reducing the lack of reproducibility and enhancing the potential contribution of low-level metabolites in discrimination. The matrix is then used for pattern recognition including principal components analysis, cluster analysis, discriminant analysis and support vector machines. Attention is particularly focussed on the last of these techniques, because of its novelty and some attractive features such as its suitability to work with datasets that are small and/or have low samples/variable ratios. The type of cadmium administration is detected as a relevant feature that contributes to the structure of the sample matrix, and samples are classified according to the class membership, with discriminant analysis and support vector machines performing complementarily on a training and on a test set.

Proteinuria plays a causal role in the progression of IgA nephropathy (IgAN). A previous controlled trial showed that steroids are effective in reducing proteinuria and preserving renal function in patients with IgAN. The objective of this study was to evaluate the long-term effectiveness of steroids in IgAN, examine the trend of proteinuria during follow-up (starting from the hypothesis that the degree of reduction in proteinuria may influence IgAN outcome), and evaluate how histologic scores can influence steroid response. A secondary analysis of a multicenter, randomized, controlled trial of 86 adult IgAN patients who were receiving supportive therapy or intravenous methylprednisolone plus oral prednisone for 6 mo was conducted. Ten-year renal survival was significantly better in the steroid than in the control group (97% versus 53%; log rank test P = 0.0003). In the 72 patients who did not reach the end point (doubling in baseline serum creatinine), median proteinuria significantly decreased (1.9 g/24 h at baseline, 1.1 g/24 h after 6 mo, and 0.6 g/24 h after a median of 7 yr). In the 14 progressive patients, proteinuria increased from a median of 1.7 g/24 h at baseline to 2.0 g/24 h after 6 mo and 3.3 g/24 h after a median of 5 yr. Steroids were effective in every histologic class. Cox multivariate regression analyses showed that, in addition to steroids, a low baseline histologic score, a reduction in proteinuria after 6 mo, and no increase in proteinuria during follow-up all were independent predictors of a beneficial outcome. Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN. The histologic picture and proteinuria during early and late follow-up improve the prediction of outcome, but considerable variability remains outside the model.

In this work we re-examine an existing model of gastric acid secretion. The model is a 2-compartment model of the human stomach accounting for regions where relevant cells (D, G, ECL and parietal cells) and proteins and acid they secrete (somatostatin, gastrin, histamine, and gastric acid, respectively) are found. These proteins compose a positive and negative feedback system that controls the secretion of gastric acid by parietal cells. The original model consists of 18 ordinary differential equations and yields a stable 3-period limit cycle solution. We modify the existing model by introducing a delay into the system and assuming that the cell populations are in steady state over a short-time window (<300 h) and are able to reduce the system to an 8-equation delay differential equation model. In addition to demonstrating congruency between the two models, we also show that a similar stability is only reproducible when the delay in gastrin transport is approximately 30 min. This suggests that gastric acid secretion homeostasis likely depends strongly on the delay in gastrin transport from the antrum to the corpus.

Background: Cardiovascular instability still affects a large percentage of uraemic patients undergoing extracorporeal substitutive treatments. Post-dilution haemofiltration has been reported to be a method for improving cardiovascular stability; however, the limited removal of small molecular weight solutes together with the need for high blood flow from the fistula greatly restrict the use of this treatment. To increase the solute clearances and to partially resolve the necessity for high blood flow, the replacement solution, in a quantity about double that used in post-dilution mode, can be administered in pre-dilution mode. A high vascular stability has also been observed for pre-dilution haemofiltration. Since the lower morbidity may be due to less sodium removal when compared with haemodialysis, it would be important to characterize the sodium transport in this kind of treatment., Methods: Nine patients underwent nine pre-dilution haemofiltration treatments (one for each patient) with on-line prepared substitution fluid., Results: As mean values, total (NaF(pw)) and ionized (NaE(pw)) plasma water sodium concentrations increased from 149.4 +/- 2.8 mEq/l to 151.1 +/- 2.4 mEq/l, and from 143.1 +/- 2.8 to 144.5 +/- 1.2 mEq/l, respectively, during the treatment, suggesting a hypotonic concentration of net ultrafiltrate. Plotting the difference between final and initial ionized plasma water concentrations (fNaE(pw) - iNaE(pw)) against the difference between initial plasma water values and ionized sodium concentration in the reinfusate (iNaE(pw) - NaE(R)), a significant negative correlation was found, with the regression line that intercepts the abscissa at the (iNaE(pw) - NaE(R)) value of 8.8 mEq/l; this means that to avoid changes in NaE(pw) in our patients, the NaE(R) should be lower than the iNaE(pw) by this amount. This is quite different from the theoretical value of approximately 4 mEq/l necessary to avoid changes in NaE(pw) during haemodialysis. The ratio between the total sodium concentration in the ultrafiltrate (NaF(uf)) and NaF(pw) (alpha) at the post-reinfusion site was 0.96 and decreased to 0.94 when NaF(pw) values at the pre-reinfusion site were considered. This last value is quite close to the theoretical alpha value of post-dilution haemofiltration., Conclusion: As for post-dilution haemofiltration, less sodium removal, compared with haemodialysis, can partly explain the improved cardiovascular stability during pre-dilution haemofiltration.

The concept of dialysis adequacy has to be widened to include medium size and large molecule removal in addition to urea kinetics. The HEMO study found a non-significant trend toward a beneficial effect on mortality of high-flux dialysis compared with low-flux dialysis. In that study, the beneficial effect of convection could have been attenuated by the fact that 'internal filtration' in high-flux haemodialysis (HD) is lower than that expected by convection in haemofiltration (HF) or haemodiafiltration (HDF). To explore the putative beneficial effect of convection, this Italian multicentre study was planned, comparing on-line convective treatments (HF and HDF) with standard, low-flux HD. The enrolled patients will be evaluated prospectively on their usual treatment for 2 months (baseline period) and subsequently randomized to continue either with low-flux HD (50%) or to start on-line convective treatment (50%), HF or HDF according to a 1:1 ratio. The primary end point of the study will be cardiovascular stability and blood pressure control. As secondary aims of the study, the impact on symptoms, morbidity and mortality will be assessed. Feasibility and patient compliance during HF and HDF treatments will also be evaluated. The experimental phase of the study, of at least 2 years, is divided into a 3-month adaptation period and a subsequent evaluation period. A recruitment period of 1 year is planned. The study design has adequate power to detect an absolute reduction of 3% hypotensive episodes with the experimental convective treatments compared with standard low-flux HD.

Introduction: Every week, haemodialysis patients are exposed to approximately 400 l of water used for the production of dialysis fluids which, albeit with the interposition of a semi-permeable artificial membrane, come into direct contact with the bloodstream. It is therefore clearly important to know and monitor the chemical and microbiological purity of dialysis water., Methods: In this review, we analyse the sources of chemical and microbiological water contamination, and the problems involved in water purification systems and modalities. We also analyse the compliance of dialysis units with the microbiological standards established by the most widely accepted guidelines relating to the quality of dialysis fluids., Results: The risk of chemical contamination is due mainly to the primary pollution of municipal water, whereas the most important microbiological problem is the control of bacterial growth in the water treatment and distribution system. Dialysis water treatment implies various levels of pre-treatment, a final purification module (which, in many cases, is reverse osmosis: RO) and a hydraulic circuit for the distribution of the purified water. RO-based treatment systems produce water of optimal chemical and microbial quality, and so dialysis units need to concentrate on maintaining this quality level in the long term by means of effective maintenance and disinfection strategies. The most widely accepted standards for water purity are those recommended by the Association for the Advancement of Medical Instrumentation and the European Pharmacopea, which respectively allow bacterial growth of <200 and <100 c.f.u./ml, and an endotoxin concentration of <2 and <0.25 IU/ml. However, a number of multicentre studies have reported that 7-35% of water samples have bacterial growth of >200 c.f.u./ml, and up to 44% have endotoxin levels of >5 IU/ml., Conclusions: The results of multicentre studies indicate that the microbial quality of dialysis fluids is still a too often neglected problem, particularly as there is evidence of a possible relationship between dialysis fluid contamination and long-term morbidity. The time has now come to take advantage of innovations in water treatment processes and improvements in dialysis machines in order to modify clinical practices and start improvement processes aimed at decreasing the risk of microbial contamination to the minimum, as it has already been successfully done in the case of chemical contamination.

Over recent years, a target blood pressure of 125/75 mm Hg has been sought in order to reduce the rate of chronic renal disease (CKD) progression and cardiovascular mortality. Some antihypertensive agents, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and calcium channel blockers also may be capable of reducing CKD progression because they halt some of the pathogenetic mechanisms involved in renal damage. The possibility that combination treatments with ACE inhibitors and calcium-channel blockers may confer additive or even synergistic renoprotective effects other than blood pressure control is not only fascinating, but also particularly important because multidrug antihypertensive regimens are required to obtain adequate blood pressure in the majority of patients with CKD. This combination may provide better blood pressure control, appears to be better tolerated with fewer side effects than either drug alone, and may exert a greater renoprotective effect in patients at risk for renal failure than either an ACE inhibitors or a calcium channel blocker. However, the current available data are too few to confirm this hypothesis. Cardiovascular disease accounts for more than 50% of the deaths of hemodialysis patients. Thus, care must be taken to prevent and treat the cardiovascular risk factors optimally from the early phase of CKD, and for this reason effective antihypertensive therapy is the most important treatment, not only in order to delay CKD progression, but also to reduce the burden of cardiovascular disease. In this perspective combination therapy with ACE inhibitors and calcium channel blockers can give further advantages.

Background: The aim of this multicenter prospective study was to investigate the role of relative blood volume (RBV) reduction on intradialytic hypotension., Methods: One hundred twenty-three patients on chronic hemodialysis therapy were considered a priori normotensive (reference group A), intradialytic hypotension prone (group B), and hypertensive (group C). RBV was continuously monitored, and diastolic and systolic blood pressure (SBP) and heart rate (HR) were measured at 20-minute intervals during three dialysis sessions., Results: Intradialytic RBV reduction was -13.8% +/- 7.0% and similar in the three groups (P = 0.841). SBP and RBV decreased during dialysis, with a sharp initial decrease (in the first 20 minutes for SBP and the first 40 minutes for RBV), followed by a slower decrease. The lying bradycardic response before dialysis was less in group B than group A (a decrease of 3 +/- 7 versus 9 +/- 9 beats/min; P < 0.001). When symptomatic hypotension occurred, RBV reduction was not significantly different from that recorded at the same time during hypotension-free sessions (-13.9% +/- 6.4% versus -12.7% +/- 5.2%; P = 0.149). Group, baseline plasma-dialysate sodium gradient, RBV line irregularity, and early RBV and HR reduction during dialysis influenced the relative risk for symptomatic hypotension with a sensitivity of 80% versus 30% for RBV alone., Conclusion: We found no difference in reduction in RBV in the three groups and no critical RBV level for the appearance of symptomatic hypotension. With variables easily available within 40 minutes of dialysis, RBV monitoring increases the prediction of symptomatic hypotension., (Copyright 2002 by the National Kidney Foundation, Inc.)

Some antihypertensive agents may be capable of reducing chronic renal insufficiency (CRI) progression because they halt some of the pathogenic mechanisms involved in renal damage. Although this effect seems to be partially independent of BP reduction, it is still unclear whether these drugs are really superior to other antihypertensive agents when the BP values recommended by the present guidelines are actually achieved. This is particularly true when considering that, in published trials, target and achieved BP values were constantly higher than those nowadays recommended. Furthermore, in the majority of these studies, patients treated with ACE-inhibitors (ACE-I) or Angiotensin II receptor antagonists (ATIIRA) achieved lower BP values than those in control groups and BP values during 24 h were not recorded. Anyway, taking into account the role of baseline and follow-up BP values, the treatment effect remained significant in almost all of the multivariate models. These findings suggest that the renoprotective effect of these agents (ACE-I, ATIIRA) is partially independent of better BP control. However, caution should be paid in attributing true biologic renoprotective properties to drugs just on the basis of statistical adjustments of BP values, although robustly performed, without being aware of what those BP values actually reflect.

The transcription factor thyroid transcription factor-1 (TTF-1) is a homeodomain-containing protein that belongs to the NK2 family of genes involved in organogenesis. TTF-1 is required for normal development of the forebrain, lung, and thyroid. In a search for factors that regulate TTF-1 transcriptional activity, we isolated three genes (T:G mismatch-specific thymine DNA glycosylase (TDG), homeodomain-interacting protein kinase 2 (HIPK2), and Ajuba), whose products can interact with TTF-1 in yeast and in mammalian cells. TDG is an enzyme involved in base excision repair. In the present paper, we show that TDG acts as a strong repressor of TTF-1 transcriptional activity in a dose-dependent manner, while HIPK2 and Ajuba display no effect on TTF-1 activity, at least under the tested conditions. TDG-mediated inhibition occurs specifically on TTF-1-responsive promoters in thyroid and non thyroid cells. TDG associates with TTF-1 in mammalian cells through the TTF-1 carboxyl-terminal activation domain and is independent of the homeodomain. These findings reveal a previously unsuspected role for the repair enzyme TDG as a transcriptional repressor and open new routes toward the understanding of the regulation of TTF-1 transcriptional activity.

Previous studies from our laboratory have shown that Ca2+ and Mg2+ absorption in the mouse cortical thick ascending limb of Henle's loop (cTAL) is a passive, paracellular process driven by the transepithelial voltage. The passive permeability of the epithelium is enhanced by peptide hormones. The present study investigated whether divalent cation absorption in the cTAL is influenced by cell maturation and/or gender. For this purpose, mouse cTAL segments were microdissected from kidneys of female and male animals aged 4 and 8 weeks. The microdissected tubules were perfused in vitro at a luminal flow rate of 1.5 to 2.5 nl/min. Transepithelial Na+, Cl-, Ca2+ and Mg2+ net fluxes (JX, pmol.min-1.mm-1) were measured using electron microprobe analysis, and the transepithelial potential difference (PDte) was measured continuously. No differences were found in the PDte, JNa and JCl of the various animal groups but the transepithelial Ca2+ and Mg2+ transport capacity of the cTAL was higher in adults (8 weeks) than in young animals (4 weeks). Furthermore, irrespective of age, transepithelial Ca2+ net absorption was greater in male than in female animals. In contrast, the NaCl transport was maximal at 4 weeks in both genders. We conclude therefore that transepithelial divalent cation absorption in the mouse cTAL is an inductive process influenced by cell maturation and gender. The molecular basis of these inductions remains to be elucidated.