Stefano Stuard

Serum Levels of Soluble Adhesion Molecules in Chronic Renal Failure and Dialysis Patients

Besides cell-bound adhesion molecules, which are of fundamental importance to a large number of physiological and pathological processes, soluble forms of adhesion molecules have been detected in the circulating blood in recent years. Circulating soluble adhesion molecules appear to be biologically active, and raised levels have been reported in a variety of disorders. In the present study, we used ELISA to measure the serum levels of four soluble adhesion molecules in 23 undialyzed patients with chronic renal failure (CRF), 13 patients on continuous ambulatory peritoneal dialysis (CAPD), 17 on chronic hemodialysis (HD) and 18 healthy controls having a similar mean and distribution of ages. The investigated soluble (s) molecules included intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), sE-selectin and sP-selectin. sICAM-1 was found to be elevated in patients with CRF (p < 0.05), on CAPD (p < 0.02) and HD (p < 0.0001) compared with the controls but levels did not differ between the three patient groups. The higher sVCAM-1 values found in CRF (p < 0.02), CAPD (p < 0.05) and HD (p < 0.0001) as compared to controls again failed to differentiate the three groups of patients. Soluble E-selectin was also raised in the three groups (p < 0.0001) with no difference between them. Increased sP-selectin was found in CRF (p < 0.05), CAPD (p < 0.02) and in HD patients (p < 0.0001) compared to controls, and levels in HD were significantly higher (p < 0.02) than in CRF patients. Predialysis serum molecule levels did not differ between HD patients treated with cuprophan or with polyacrylonitrile dialyzers. HD sessions with both dialyzers had no effect on sICAM-1, while a decrease (p < 0.02) in sP-selectin was found after dialysis with cuprophan. In undialyzed patients with CRF, regression analysis showed a strong linear correlation between serum creatinine and serum levels of each soluble molecule. These results demonstrate that serum levels of soluble adhesion molecules ICAM-1, VCAM-1, E-selectin and P-selectin are elevated in both undialyzed patients with CRF and patients on CAPD or HD. The elevated serum levels of these proteins probably reflect inadequate clearance as well as enhanced synthesis/release.

Neutrophil Reactive Oxygen Species Production during Hemodialysis: Role of Activated Platelet Adhesion to Neutrophils through P-Selectin

Platelet interaction with leukocytes can occur to a significant degree during hemodialysis, but it remains to be determined what pathophysiological consequences stem from the intradialytic formation of platelet-leukocyte coaggregates. By the use of flow cytometry techniques, this study was set out to analyze intradialytic platelet-neutrophil coaggregate formation and neutrophil hydrogen peroxide production from 10 end-stage renal disease patients each dialyzed with cuprophane and polyacrylonitrile membranes. Platelet-neutrophil coaggregates increased during dialysis with cuprophane, whereas no changes occurred with polyacrylonitrile membranes. Dialysis with cuprophane, unlike that with polyacrylonitrile, also resulted in a significant increase in neutrophil hydrogen peroxide production 10 min after dialysis initiation which persisted at significantly higher levels than predialysis values through the first 20 min. We found that the increased hydrogen peroxide production by neutrophils essentially occurred in concomitance with neutrophil-platelet coaggregation. Intracellular fluorescence representing hydrogen peroxide formation significantly increased through the first 20 min of cuprophane dialysis in neutrophils aggregated to platelets. By contrast, no change occurred in neutrophils not aggregated to platelets. Neutrophils which had formed aggregates with platelets produced higher hydrogen peroxide levels, as assessed by significantly higher fluorescence values, than non-aggregate-forming neutrophils at all time points tested. The phenomenon was duplicated in vitro when ADP-activated normal platelets were incubated with neutrophil cells but was largely inhibited when ADP-activated platelets were treated with anti-P-selectin antibody before incubation with neutrophils. These results strongly suggest that platelet-neutrophil aggregates occurring during hemodialysis, representing cell-cell interactions with pathophysiological effects, may serve as a new parameter to assess biocompatibility.

Chronic Fluid Overload and Mortality in ESRD

Sustained fluid overload (FO) is considered a major cause of hypertension, heart failure, and mortality in patients with ESRD on maintenance hemodialysis. However, there has not been a cohort study investigating the relationship between chronic exposure to FO and mortality in this population. We studied the relationship of baseline and cumulative FO exposure over 1 year with mortality in 39,566 patients with incident ESRD in a large dialysis network in 26 countries using whole-body bioimpedance spectroscopy to assess fluid status. Analyses were applied across three discrete systolic BP (syst-BP) categories (<130, 130-160, and >160 mmHg), with nonoverhydrated patients with syst-BP=130-160 mmHg as the reference category; >200,000 FO measurements were performed over follow-up. Baseline FO value predicted excess risk of mortality across syst-BP categories (<130 mmHg: hazard ratio [HR], 1.51; 95% confidence interval [95% CI], 1.38 to 1.65; 130-160 mmHg: HR, 1.25; 95% CI, 1.16 to 1.36; >160 mmHg: HR, 1.30; 95% CI, 1.19 to 1.42; all P<0.001). However, cumulative 1-year FO exposure predicted a higher death risk (P<0.001) across all syst-BP categories (<130 mmHg: HR, 1.94; 95% CI, 1.68 to 2.23; 130-160 mmHg: HR, 1.51; 95% CI, 1.35 to 1.69; >160 mmHg: HR, 1.62; 95% CI, 1.39 to 1.90). In conclusion, chronic exposure to FO in ESRD is a strong risk factor for death across discrete BP categories. Whether treatment policies that account for fluid status monitoring are preferable to policies that account solely for predialysis BP measurements remains to be tested in a clinical trial.

Delivering Quality of Care while Managing the Interests of All Stakeholders

National healthcare systems worldwide face growing challenges to reconcile interests of patients for high-quality medical care and of payers for sustainable and affordable funding. Advances in the provision of renal replacement therapy can only be made by developing and implementing appropriate sophisticated and state-of-the-art business models that include reimbursement schemes for comprehensive care packages. Such business models must succeed in integrating and reconciling the interests of all stakeholders. NephroCare as dialysis provider has adopted and tailored recognized management techniques, i.e. Balanced Scorecard and Kaizen, to achieve these goals. Success of the complete business model package is tangible – strategies initiated to improve treatment quality even at the cost of providers have been translated into win-win scenarios for the complete stakeholder community. Room for improvement exists: the possibility to extend the portfolio of service offerings within the comprehensive care frame, as well as the challenge for achieving a balance between the stability of targets while keeping these up to date concerning new insights.

An international observational study suggests that artificial intelligence for clinical decision support optimizes anemia management in hemodialysis patients

Managing anemia in hemodialysis patients can be challenging because of competing therapeutic targets and individual variability. Because therapy recommendations provided by a decision support system can benefit both patients and doctors, we evaluated the impact of an artificial intelligence decision support system, the Anemia Control Model (ACM), on anemia outcomes. Based on patient profiles, the ACM was built to recommend suitable erythropoietic-stimulating agent doses. Our retrospective study consisted of a 12-month control phase (standard anemia care), followed by a 12-month observation phase (ACM-guided care) encompassing 752 patients undergoing hemodialysis therapy in 3 NephroCare clinics located in separate countries. The percentage of hemoglobin values on target, the median darbepoetin dose, and individual hemoglobin fluctuation (estimated from the intrapatient hemoglobin standard deviation) were deemed primary outcomes. In the observation phase, median darbepoetin consumption significantly decreased from 0.63 to 0.46 μg/kg/month, whereas on-target hemoglobin values significantly increased from 70.6% to 76.6%, reaching 83.2% when the ACM suggestions were implemented. Moreover, ACM introduction led to a significant decrease in hemoglobin fluctuation (intrapatient standard deviation decreased from 0.95 g/dl to 0.83 g/dl). Thus, ACM support helped improve anemia outcomes of hemodialysis patients, minimizing erythropoietic-stimulating agent use with the potential to reduce the cost of treatment.

Modifiable factors associated with achievement of high-volume post-dilution hemodiafiltration: results from an international study.

Background The aim was to investigate factors associated with the successful achievement of ≥21 l/session of substitution fluid volume in patients on post-dilution hemodiafiltration. Methods 3315 patients treated in 6 European countries with the Fresenius 5008 CorDiax machine including the AutoSub Plus feature were considered. Variables that showed a relationship with convection volume were entered in a multivariable logistic regression model. Results Mean blood flow was 379 ± 68 ml/min. Median substitution volume was 24.7 L (IQR 22.0–27.4 L). Mean filtration fraction was 28.3 ± 4.1%. 81.5% of sessions qualified as high-volume HDF (substitution volumes ≥21 L). Higher age, dialyzer surface area, blood flow and treatment time were positively associated with the achievement of ≥21 L substitution volume; higher body mass index, male gender, higher hematocrit, graft or catheter vs. fistula, and start of week vs. mid-week were negatively associated. Conclusions Dialysis center policy in terms of blood flow, treatment time, filter size, and perhaps even hemoglobin targets plays a key role in achieving high-volume HDF. All of these are modifiable factors that can help in prescribing an optimal combination of dialyzer size, achievable blood flows, and treatment times.

Hemodiafiltration Reduces All-Cause and Cardiovascular Mortality in Incident Hemodialysis Patients: A Propensity-Matched Cohort Study

Background: The majority of studies suggesting that online hemodiafiltration reduces the risk of mortality compared to hemodialysis (HD) have been performed in dialysis-prevalent populations. In this report, we conducted an epidemiologic study of mortality in incident dialysis patients, comparing post-dilution online hemodiafiltration and high-flux HD, with propensity score matching (PSM) used to correct indication bias. Methods: Our study cohort comprised 3,075 incident dialysis patients treated in 64 Spanish Fresenius Medical Care clinics between January 2009 and December 2012. The primary outcome of this study was to investigate the impact of the type of renal replacement on all-cause mortality. An analysis of cardiovascular mortality was defined as the secondary outcome. To achieve these objectives, patients were followed until December 2016. Patients were categorized as high-flux HD patients if they underwent this treatment exclusively. If >90% of their treatment was with online hemodiafiltration, then the patient was grouped to that modality. Results: After PSM, a total of 1,012 patients were matched. Compared with patients on high-flux HD, those on online hemodiafiltration received a median replacement volume of 23.45 (interquartile range 21.27–25.51) L/session and manifested 24 and 33% reductions in all-cause and cardiovascular mortality (all-cause mortality hazards ratio [HR] 0.76, 95% CI 0.62–0.94 [p = 0.01]; and cardiovascular mortality HR 0.67, 95% CI 0.50–0.90 [p = 0.008]). Conclusions: This study shows that post-dilution online hemodiafiltration reduces all-cause and cardiovascular mortality compared to high-flux HD in an incident HD population.

Performance of a Predictive Model for Long-Term Hemoglobin Response to Darbepoetin and Iron Administration in a Large Cohort of Hemodialysis Patients

Anemia management, based on erythropoiesis stimulating agents (ESA) and iron supplementation, has become an increasingly challenging problem in hemodialysis patients. Maintaining hemodialysis patients within narrow hemoglobin targets, preventing cycling outside target, and reducing ESA dosing to prevent adverse outcomes requires considerable attention from caregivers. Anticipation of the long-term response (i.e. at 3 months) to the ESA/iron therapy would be of fundamental importance for planning a successful treatment strategy. To this end, we developed a predictive model designed to support decision-making regarding anemia management in hemodialysis (HD) patients treated in center. An Artificial Neural Network (ANN) algorithm for predicting hemoglobin concentrations three months into the future was developed and evaluated in a retrospective study on a sample population of 1558 HD patients treated with intravenous (IV) darbepoetin alfa, and IV iron (sucrose or gluconate). Model inputs were the last 90 days of patients’ medical history and the subsequent 90 days of darbepoetin/iron prescription. Our model was able to predict individual variation of hemoglobin concentration 3 months in the future with a Mean Absolute Error (MAE) of 0.75 g/dL. Error analysis showed a narrow Gaussian distribution centered in 0 g/dL; a root cause analysis identified intercurrent and/or unpredictable events associated with hospitalization, blood transfusion, and laboratory error or misreported hemoglobin values as the main reasons for large discrepancy between predicted versus observed hemoglobin values. Our ANN predictive model offers a simple and reliable tool applicable in daily clinical practice for predicting the long-term response to ESA/iron therapy of HD patients.

Atrial fibrillation in dialysis patients: time to abandon warfarin?

Atrial fibrillation (AF) is a frequent clinical complication in dialysis patients, and warfarin therapy represents the most common approach for reducing the risk of stroke in this population. However, current evidence based on observational studies, offer conflicting results, whereas no randomized controlled trials have been carried out so far. Additionally, many clinicians are wary of the possible role of warfarin as vascular calcification inducer and its potential to increase the high risk of bleeding among patients on dialysis. Ideally the most promising therapy would be based on direct inhibitors of factor Ila or Xa; however, at the moment, none of these drugs can be safely prescribed in dialysis patients, because of their potentially dangerous accumulation, and the lack of sufficient experience with apixaban or rivaroxaban, two drugs showing a favorable pharmacokinetic profile in end-stage renal disease. Hence, the use of vitamin K inhibitors is currently the only pharmacological option for stroke prevention in dialysis patients with atrial fibrillation, leaving the clinicians in a management conundrum. This review discusses the trade-offs implicated in warfarin use for this population, the promises of newly developed drugs, the role of dialysis as atrial fibrillation trigger, as well as potential non-pharmacological management options suitable in selected clinical situations.

Calcium Acetate/Magnesium Carbonate and Cardiovascular Risk Factors in Chronic Hemodialysis Patients

Background/Aim: Calcium acetate/magnesium carbonate (CaMg) is a recent phosphate binder that has been shown to have protective cardiovascular (CV) effects in animal models. The aim of this study was to evaluate the relationship between CaMg therapy and CV risk markers like pulse pressure (PP), left ventricular mass index (LVMI) and valvular calcifications compared to sevelamer or no phosphate binder (NPB) therapy in chronic hemodialysis (HD) patients. Methods: We performed a 48-month prospective study in 138 HD patients under hemodiafiltration with a dialysate Mg concentration of 0.5 mmol/l. Patients underwent treatment with CaMg or sevelamer for at least 36 months or NPB therapy. Demographic, clinical, biochemical and echocardiographic parameters were evaluated at baseline and after a 48-month period. Results: At the end of the study, patients who had taken CaMg showed a significant reduction in PP (p < 0.001), LVMI (p = 0.003), aortic (p = 0.004) and mitral valve calcifications (p = 0.03) compared with NPB patients. Patients under CaMg showed a significant reduction of PP (p < 0.001), LVMI (p = 0.01) and aortic valve calcifications (p = 0.02) compared to sevelamer patients. In a multivariable analysis, CaMg therapy was negatively associated with progression of LVMI (p = 0.02) and aortic valve calcifications (p = 0.01). Patients under CaMg showed higher serum Mg levels (0.93 ± 0.14 mmol/l) compared to patients under sevelamer (0.87 ± 0.13) or NPB patients (0.82 ± 0.12; p < 0.001). Conclusions: In prevalent HD patients, the use of CaMg over 48 months was associated with a reduction of PP and LVMI and with a stabilization of aortic valve calcifications. These protective and promising results of this new phosphate binder need to be confirmed in randomized controlled studies.