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1.  Reasons for the lack of salutary effects of cholesterol lowering interventions in ESRD populations 
Blood purification  2013;35(1-3):31-36.
Cardiovascular disease (CVD) is the main cause of premature death in patients with chronic kidney disease (CKD). The underlying mechanisms of CVD in patients with mild to moderate CKD are different from those with end-stage renal disease (ESRD). While serum cholesterol is frequently elevated and contributes to atherosclerosis in many CKD patients particularly those with nephrotic proteinuria, it is usually normal, even subnormal in most ESRD patients receiving hemodialysis. CVD in the ESRD population is primarily driven by oxidative stress, inflammation, accumulation of the oxidation-prone intermediate density lipoproteins (IDL), chylomicron remnants and small dense LDL particles as well as HDL deficiency and dysfunction, hypertension, vascular calcification, and arrhythmias. Only a minority of hemodialysis patients have hypercholesterolemia which is most likely due to genetic or unrelated factors. In addition due to peritoneal losses of proteins which simulate nephrotic syndrome, peritoneal dialysis patients often exhibit hypercholesterolemia. Clearly when present, hypercholesterolemia contributes to CVD in CKD and ESRD population and justifies cholesterol lowering therapy. However the majority of ESRD patients and a subpopulation of CKD patients with minimal proteinuria have normal or subnormal serum cholesterol levels and do not benefit from and can be potentially harmed by statin therapy. In fact the lack of efficacy of statins in hemodialysis patients has been demonstrated in several randomized clinical trials. This review is intended to provide an overview of the mechanisms responsible for the failure of statins to reduce cardiovascular morbidity and mortality in most ESRD patients and to advocate the adoption of individualized care principal in the management of dyslipidemia in this population.
doi:10.1159/000345176
PMCID: PMC3595172  PMID: 23343544
Statins; lipid disorders; cardiovascular disease; progression of kidney disease; hemodialysis; nephrotic syndrome
2.  Daily Ultrafiltration Results in Improved Blood Pressure Control and More Efficient Removal of Small Molecules during Hemodialysis 
Blood purification  2013;34(0):325-331.
Background
Although prior studies have shown that frequent hemodialysis (HD) can lead to improved control of dry weight (DW) in ESRD patients, there are no clinical studies examining whether this can improve blood pressure control and can also shorten the dialysis time needed to achieve satisfactory removal of small molecules. Several models of wearable dialysis systems are now under various stages of development. These devices present the possibility of hemodialyzing patients to their dry weights. We have built a prototype of a wearable ultrafiltration (UF) device (WUD) that can provide daily UF. Apart from better fluid control, we hypothesize that separating HD from UF will result in better blood pressure control and adequate weekly small molecule removal could be achieved with a decreased duration of dialysis We tested the hypothesis by in current hemodialysis patients using conventional dialysis equipment.
Methods
Thirteen patients were selected from a large urban hemodialysis center. The experimental period consisted of 4 weeks of daily UF (4 days/week of UF alone and 2 days/week of HD with UF). The duration of the HD sessions was increased by 15 to 30 minutes to maintain weekly standard Kt/V>2.0. The patients were then returned to their conventional 3 days/week of HD with UF and studied for 4 weeks. The pre-dialysis BPs Interdialytic weight gains, and Kt/V results of the experimental and return periods were compared to those of the 3 month control period. No changes were made in antihypertensive or other medication during the study.
Results
During the experimental period, mean arterial pressure decreased from 110 mmHg to 95mmHg (P<0.001), systolic BP from 158mmHg to 136mmHg (P<0.001) while interdialytic weight gains were reduced from 3.25 liters to 1.21 liters (p<0.0001). During the experimental period, weekly standard Kt/V of 2.16 was achieved in 8.24 hours/week of HD, as compared to 11.14 hours/week.
Conclusions
Volume control with daily UF results in improved BP control and, by separating the UF function from HD, adequate weekly standard Kt/V>2 can be achieved with twice weekly HD.
doi:10.1159/000345334
PMCID: PMC3727139  PMID: 23306592
Daily Ultrafiltration; Hemodialysis; Hypertension
3.  Cell-Based Strategies for the Treatment of Kidney Dysfunction: A Review 
Blood purification  2012;34(2):10.1159/000341649.
Conventional treatment of acute and chronic renal diseases has focused on solute removal. Novel strategies aim to treat the multifactorial disease states of acute kidney injury and chronic kidney disease by mitigating inflammation. Cell-based technologies for the treatment of kidney dysfunction fall under two broad categories: cell therapy and cell processing. Cell therapy utilizes cells that are isolated, cultured outside of the body, and reintroduced as therapy, leveraging beneficial metabolic and synthetic functions. For example, renal tubule cells have been used to provide gluconeogenesis, ammoniagenesis, metabolism of glutathione, catabolism of important peptide hormones, growth factors, and cytokines critical to multiorgan homeostasis and immunomodulation to treat renal dysfunction. Cell processing focuses on altering the characteristics of cell populations inside the body to provide therapy. The Selective Cytopheretic Device (SCD), is an example of this novel therapeutic strategy that aims to modulate the innate immune response during organ dysfunction, additional organ injury, by binding and deactivating leukocytes. In this review, both cell-therapy and cell-processing approaches will be discussed in the context of acute kidney injury and chronic renal disease.
doi:10.1159/000341649
PMCID: PMC3836365  PMID: 23095410
stem cell; renal assist device; renal replacement; acute kidney injury; end stage renal disease; cell-based; deice-based; tissue engineering; review
4.  Longitudinal Hemodiafilter Performance in Modeled Continuous Renal Replacement Therapy 
Blood Purification  2011;32(2):82-88.
Background/Aims
With advanced anticoagulation, many institutions operate continuous renal replacement therapy (CRRT) circuits longer than manufacturers’ recommendations. This extended use may change hemodiafilter performance and clearance properties. However, hemodiafilter performance over time has not been assessed. We investigated solute clearance over time in modeled CRRT.
Methods
In vitro continuous hemofiltration (CH) and continuous hemodialysis (CD) were operated for 48 h using AN69 polyacrylonitrile, cellulose triacetate, F70 polysulfone, and Optiflux F160NR polysulfone hemodiafilters with citrated bovine blood. Urea, creatinine, gentamicin, vancomycin, and albumin clearances were assessed in CH (ultrafiltration rates = 1 and 3 l/h). Clearances of urea, creatinine, gentamicin, and albumin, were assessed in CD with dialysate flow rate of 2 l/h.
Results
Solute CH clearances were significantly higher at 3 l/h. Only creatinine and gentamicin clearances were affected by time. Creatinine CD clearance significantly declined at 48 h for all hemodiafilters, especially polysulfone hemodiafilters.
Conclusions
CRRT duration affects solute transmembrane clearance. Clinicians should consider hemodiafilter age when assessing hemodialysis dose or drug clearance.
doi:10.1159/000324191
PMCID: PMC3064935  PMID: 21372565
Clearance; Continuous renal replacement therapy; Hemodialysis; Hemofiltration
5.  Motivational Interviewing to Engage Patients in Chronic Kidney Disease Management 
Blood Purification  2011;31(1-3):77-81.
Patients with chronic kidney disease (CKD) must manage numerous medical treatments and lifestyle changes that strain their treatment adherence. An important strategy to improve adherence is to activate the patients’ motivation to manage their CKD. This article describes an approach for enhancing patients’ motivation for change, called motivational interviewing (MI), a treatment that is increasingly being used in health care settings to counsel patients with chronic diseases. Its basic principles, techniques, empirical support, published applications for improving CKD patients’ self-management, and how to learn MI are presented. Research is needed to determine the efficacy and mechanisms of MI for CKD treatment as well as the development of innovative ways to deliver it to patients and train busy health care practitioners in the approach.
doi:10.1159/000321835
PMCID: PMC3202953  PMID: 21228571
Behavior change; Chronic kidney disease; Motivational interviewing; Self-management
6.  The Path to Wearable Ultrafiltration and Dialysis Devices 
Blood Purification  2011;31(1-3):92-95.
Wearable blood processing devices offer an attractive solution to problems inherent in clinic-based, intermittent end-stage renal disease therapies. What is involved in transitioning even a part of the current clinic-based population to ambulatory therapy has not been clearly enumerated. This paper addresses what a first-generation wearable device might accomplish, how issues of safety will need to be addressed, and what will make the device attractive to, and manageable by, the patient. Medical, technological, and economic issues are identified.
doi:10.1159/000321846
PMCID: PMC3202954  PMID: 21228574
Wearable devices; Ultrafiltration; Dialysis; Anticoagulation; Blood access
7.  Design and Rationale of Health-Related Quality of Life and Patient-Reported Outcomes Assessment in the Frequent Hemodialysis Network Trials 
Blood Purification  2011;31(1-3):151-158.
Background
End-stage renal disease patients experience significant impairments in health-related quality of life (HRQOL). Testing various strategies to improve patient HRQOL in multicenter clinical trials, such as the Frequent Hemodialysis Network (FHN) trials is vitally important. Aims: Theaim of this paper is to describe the design and conduct of HRQOL and patient-reported outcomes (PRO) assessment in the FHN trials.
Methods
In the FHN trials, HRQOL was examined as a multidimensional concept, and the SF-36 RAND Physical Health Composite score was one of the co-primary outcomes. The instruments completed to assess HRQOL included the Medical Outcomes Study Short Form SF-36, Health Utilities Index 3, Sleep Problems Index, Beck Depression Inventory and feeling thermometer. These instruments have been shown to have high reliability, validity and responsiveness to change in the end-stage renal disease population. Additional items evaluating PRO including sexual function, time to recovery after dialysis and patients’ self-perceived burden to caregiver were also assessed. All questionnaires were administered by trained interviewers using computer-assisted telephone interviewing to ensure blinding and minimizing selection bias. Interim analysis reveals that these instruments can be used to collect a comprehensive set of HRQOL measures with minimal patient burden.
Conclusions
Accurate measurement of HRQOL and PRO can help us test whether hemodialysis interventions improve the health and well-being of this compromised patient population. We have shown that a comprehensive set of HRQOL measures can be centrally collected through telephone interviews in a blinded fashion, in a way that is well tolerated with minimum respondent burden.
doi:10.1159/000321855
PMCID: PMC3202955  PMID: 21228584
Health-related quality of life; Frequent Hemodialysis Network; End-stage renal disease
8.  Mechanical Ventilation and the Kidney 
Blood Purification  2009;29(1):52-68.
Acute lung injury (ALI) and acute kidney injury (AKI) are complications often encountered in the setting of critical illness. Both forms of end-organ injury commonly occur in similar settings of systemic inflammatory response syndrome, shock, and evolving multiple organ dysfunction. Recent elucidation of the pathobiology of critical illness has led to a more basic mechanistic understanding of the complex interplay between injured organs in patients with multiple organ dysfunction syndrome; this has been aptly called ‘the slippery slope of critical illness’ [Kidney Int Suppl 1998;66:S25–S33]. Distant organ effects of apparently isolated injuries to the lungs, gut, and kidneys have all been discovered in recent years. In this article, we will review the harmful bidirectional interaction between ALI and AKI, which appears to be a common clinical syndrome with routine clinical implications. We will review the current understanding of lung-kidney interactions from both perspectives, including the renal effects of ALI and mechanical ventilation, and the pulmonary sequelae of AKI. In this review of the emerging evidence of deleterious bidirectional organ cross talk between lung and kidney, we will focus on the role of ventilator-induced kidney injury in the pathogenesis of AKI in patients with ALI.
doi:10.1159/000259585
PMCID: PMC2914396  PMID: 19923815
Acute kidney injury; Critical care nephrology; Acute lung injury; Mechanical ventilation; Cytokines
9.  Endothelial Progenitor Cells and Endothelial Vesicles – What Is the Significance for Patients with Chronic Kidney Disease? 
Blood Purification  2010;29(2):158-162.
Endothelial progenitor cells are cells derived from the bone marrow that circulate in the bloodstream and can exhibit phenotypic characteristics of endothelial cells. They are thought to be involved in postnatal vasculogenesis and to potentially help repair injured endothelium. Circulating endothelial cells are mature endothelial cells in the circulation, and endothelial vesicles or microparticles are thought to be derived from the membranes of endothelial cells as a result of injury or activation. Recent research has focused on using these markers of endothelial injury and repair to assess the state of endothelial health. These efforts have been hampered by lack of uniformity in methodology and terminology. Recent developments in flow cytometry techniques have allowed better characterization and definition of these cells. We review the common techniques used to identify and isolate these cells, clinical studies in patients with chronic kidney disease (CKD) where they serve as markers of endothelial health and predictors of outcome, and possible mechanisms of progenitor cell dysfunction in CKD.
doi:10.1159/000245643
PMCID: PMC2914407  PMID: 20093822
Endothelial progenitor cells; Bone-marrow-derived progenitor cells; Circulating endothelial cells; Endothelial microvesicles; Chronic kidney disease
10.  Etanercept Clearance during an in vitro Model of Continuous Venovenous Hemofiltration 
Blood Purification  2009;28(4):348-353.
Background/Aims
Etanercept is a tumor necrosis factor-α antagonist used in inflammation-mediated conditions. Continuous venovenous hemofiltration (CVVH) has also been used in patients with inflammatory conditions. This study evaluated etanercept clearance using an in vitro CVVH model.
Methods
Etanercept clearance was assessed in vitro in bovine blood at 1–3 mg/l final serum concentration, and urea control at 750 mg/l. CVVH was performed using polyacrylonitrile, polysulfone, and polymethylmethacrylate filters at 3 l/h ultrafiltrate and 200 ml/min blood flow rates. Transmembrane clearance was estimated using sieving coefficient calculations, and adsorptive removal rate was approximated using a mass balance calculation.
Results
Urea sieving coefficient remained constant (1.04 ± 0.01). Ultrafiltrate etanercept concentrations were undetectable (sieving coefficient < 0.02) and transmembrane and adsorptive clearances were negligible.
Conclusion
Etanercept is not cleared appreciably by transmembrane or adsorptive mechanisms in CVVH using polyacrylonitrile, polysulfone, or polymethylmethacrylate hemofilters.
doi:10.1159/000232936
PMCID: PMC2914439  PMID: 19729904
Etanercept; Continuous renal replacement therapy; Hemofiltration
11.  Kidney-Lung Crosstalk in the Critically Ill Patient 
Blood Purification  2009;28(2):75-83.
Despite advances in renal replacement therapy, the mortality of acute kidney injury (AKI) has remained high, especially when associated with distant organ dysfunction such as acute lung injury (ALI). Mortality rates for combined AKI/ALI reach 80% in critically ill patients. While the clinical presentation of AKI-associated ALI is characterized by increased pulmonary edema, a defining feature of the syndrome, the AKI-induced lung effects extend beyond simple volume overload. Furthermore, ALI and associated mechanical ventilation frequently lead to a decline in renal hemodynamics, structure and function. New experimental data have emerged in recent years focusing on the interactive effects of kidney and lung dysfunction, and these studies have highlighted the pathophysiological importance of proinflammatory and proapoptotic pathways as well as the complex nature of interorgan crosstalk. This review will examine our current understanding of the deleterious kidney-lung crosstalk in the critically ill.
doi:10.1159/000218087
PMCID: PMC2914422  PMID: 19439927
Acute kidney injury; Ischemia/reperfusion; Acute lung injury; Apoptosis
12.  Assessment of Body Composition in Dialysis Patients by Arm Bioimpedance Compared to MRI and 40K Measurements 
Blood Purification  2009;27(4):330-337.
This study used multi-frequency bioimpedance spectroscopy (BIS) of the arm and whole body to estimate muscle mass (MM) and subcutaneous adipose tissue (SAT) in 31 hemodialysis (HD) patients comparing these results with magnetic resonance imaging (MRI) and body potassium (40K) as gold standards. Total body and arm MM (MMMRI) and SAT (SATMRI) were measured by MRI. All measurements were made before dialysis treatment. Regression models with the arm (aBIS) and whole body (wBIS) resistances were established. Correlations between gold standards and the BIS model were high for the arm SAT (r2 = 0.93, standard error of estimate (SEE) = 3.6 kg), and whole body SAT (r2 = 0.92, SEE = 3.5 kg), and for arm MM (r2 = 0.84, SEE = 2.28 kg) and whole body MM (r2 = 0.86, SEE = 2.28 kg). Total body MM and SAT can be accurately predicted by arm BIS models with advantages of convenience and portability, and it should be useful to assess nutritional status in HD patients.
doi:10.1159/000207200
PMCID: PMC2822666  PMID: 19270452
Segmental bioimpedance; Magnetic resonance imaging; Skeletal muscle mass; Subcutaneous adipose tissue
13.  Role of Vasopressin and Vasopressin Receptor Antagonists in Type I Cardiorenal Syndrome 
Blood Purification  2009;27(1):28-32.
The pathogenesis of cardiac failure involves activation of the neurohumoral axis including stimulation of the sympathetic nervous system, the renin-angiotensin-aldosterone, and nonosmotic vasopressin systems. While these responses are critical in maintaining arterial pressure, they are associated with renal vasoconstriction, as well as sodium and water retention. In advanced circumstances, renal dysfunction and hyponatremia occur with cardiac failure. Even a modest rise in serum creatinine related to diminished renal function in heart failure patients is associated with increased risk for cardiovascular morbidity and mortality. Similarly, increased thirst and the nonosmotic stimulation of vasopressin in advanced cardiac failure leads to hyponatremia, which is also a major risk factor for mortality. Currently, V2 vasopressin receptor antagonists have been shown to correct hyponatremia in cardiac failure. One such agent, conivaptan, also is a V1 receptor antagonist which could theoretically benefit heart failure patients by decreasing cardiac afterload and remodeling. The effect of V2 receptor antagonists to correct hyponatremia in heart failure patients appears to be quite safe. However, to date no effect on mortality has been demonstrated.
doi:10.1159/000167005
PMCID: PMC2733524  PMID: 19169014
Hyponatremia; Antidiuretic hormone; Heart failure; Kidney function
14.  Role of Vasopressin and Vasopressin Receptor Antagonists in Type I Cardiorenal Syndrome 
Blood purification  2009;27(1):28-32.
The pathogenesis of cardiac failure involves activation of the neurohumoral axis including stimulation of the sympathetic nervous system, the renin-angiotensin-aldosterone, and nonosmotic vasopressin systems. While these responses are critical in maintaining arterial pressure, they are associated with renal vasoconstriction, as well as sodium and water retention. In advanced circumstances, renal dysfunction and hyponatremia occur with cardiac failure. Even a modest rise in serum creatinine related to diminished renal function in heart failure patients is associated with increased risk for cardiovascular morbidity and mortality. Similarly, increased thirst and the nonosmotic stimulation of vasopressin in advanced cardiac failure leads to hyponatremia, which is also a major risk factor for mortality. Currently, V2 vasopressin receptor antagonists have been shown to correct hyponatremia in cardiac failure. One such agent, conivaptan, also is a V1 receptor antagonist which could theoretically benefit heart failure patients by decreasing cardiac afterload and remodeling. The effect of V2 receptor antagonists to correct hyponatremia in heart failure patients appears to be quite safe. However, to date no effect on mortality has been demonstrated.
doi:10.1159/000167005
PMCID: PMC2733524  PMID: 19169014
Hyponatremia; Antidiuretic hormone; Heart failure; Kidney function
15.  Importance of Whole-Body Bioimpedance Spectroscopy for the Management of Fluid Balance 
Blood Purification  2009;27(1):75-80.
Introduction
Achieving normohydration remains a non-trivial issue in haemodialysis therapy. Preventing the deleterious effects of fluid overload and dehydration is difficult to achieve. Objective and clinically applicable methods for the determination of a target representing normohydration are needed.
Methods
Whole-body bioimpedance spectroscopy (50 frequencies, 5–1,000 kHz) in combination with a physiologic tissue model can provide an objective target for normohydration based on the concept of excess extracellular volume. We review the efficacy of this approach in a number of recent clinical applications. The accuracy to determine fluid volumes (e.g. extracellular water), body composition (e.g. fat mass) and fluid overload was evaluated in more than 1,000 healthy individuals and patients against available gold standard reference methods (e.g. bromide, deuterium, dual-energy X-ray absorptiometry, air displacement plethysmography, clinical assessment).
Results
The comparison with gold standard methods showed excellent accordance [e.g. R2 (total body water) = 0.88; median ± SD (total body water) = −0.17 ± 2.7 litres]. Agreement with high-quality clinical assessment of fluid status was demonstrated in several hundred patients (median ± SD = −0.23 ± 1.5 litres). The association between ultrafiltration volume and change in fluid overload was reflected well by the method (median ± SD = 0.015 ± 0.8 litres). The predictive value of fluid overload on mortality underlines forcefully the clinical relevance of the normohydration target, being secondary only to the presence of diabetes. The objective normohydration target could be achieved in prevalent haemodialysis patients leading to an improvement in hypertension and reduction of adverse events.
Conclusion
Whole-body bioimpedance spectroscopy in combination with a physiologic tissue model provides for the first time an objective and relevant target for clinical dry weight assessment.
doi:10.1159/000167013
PMCID: PMC2813803  PMID: 19169022
Fluid overload; Bioimpedance spectroscopy; Normohydration target; Haemodialysis
16.  Direct Hemoperfusion with a Cytokine-Adsorbing Device for the Treatment of Persistent or Severe Hypercytokinemia: A Pilot Study 
Blood Purification  2007;25(5-6):446-453.
Background/Aims
Cytokine overproduction has been noted during the aggravation of clinical conditions. Countermeasures to control hypercytokinemia are therefore important in critical care. We investigated the clinical efficacy of hemoadsorption therapy using a new cytokine-adsorbing device in critically ill patients with persistent or severe hypercytokinemia.
Methods
Direct hemoperfusion using the CYT-860, a cytokine-adsorber column (CYT-860-DHP), was performed in critically ill patients with hypercytokinemia. To evaluate the efficacy of CYT-860-DHP, changes in pathological and clinical parameters were examined.
Results
Seven patients with hypercytokinemia and a SOFA score of ≥5 underwent CYT-860-DHP treatment. Four patients survived 28 days after CYT-860-DHP treatment. Significant decreases in blood levels of cytokines were observed. PaO2/FIO2 improved significantly.
Conclusion
The possibility that CYT-860-DHP treatment can reduce blood cytokine levels and thereby improve the general condition of patients was suggested. These findings warrant the initiation of a prospective randomized trial to evaluate the clinical efficacy of CYT-860-DHP treatment.
doi:10.1159/000111568
PMCID: PMC2813796  PMID: 18037813
Hypercytokinemia; Cytokine-adsorbing device; Rapid cytokine assay

Results 1-16 (16)