Hemodialysis patients have signs of a chronic thrombotic burden.

BACKGROUND: Cardiovascular diseases are the dominant cause of morbidity in hemodialysis (HD) patients. Unless sufficient anticoagulation is used during HD, clotting may appear. The objective was to investigate if levels of fibrin degradation products (D-dimer) were increased before and during HD. METHODS: The combined observational study included 20 patients performing a total of 60 hemodialysis divided into three sessions of low-flux dialysis. None of the patients suffered from any clinically evident thromboembolic event before or during the study. Median bolus anticoagulation (mainly tinzaparin) doses were 84 Units/kg bow. Blood samples were drawn before HD (predialysis), and at 30min and 180min during HD with focus on analyzing D-dimer levels and its relation to interdialytic weight gain (IDWG) and speed of fluid elimination by HD (UF-rate). RESULTS: Predialysis, D-dimer levels (mean 0.767 ±0.821, min 0.136mg/L) were above the upper reference value in 95% of the sessions. D-dimer levels were lowered at 30min (p<0.001) and returned to predialysis levels at 180min. Predialysis D-dimer correlated with NT-pro-BNP, Troponin T, IDWG and UF-rate. Multiple regression analysis revealed that the D-dimer levels were significantly related to IDWG and the UF-rate. CONCLUSIONS: D-dimer levels were elevated in a high proportion predialysis and during HD and related to the IDWG and the UF-rate. Awareness of D-dimer levels and future studies will help clarify if optimization of those variables, besides anticoagulation and biocompatibility measures, will eradicate the repeated subclinical thromboembolic events related to each HD; one reason that may explain organ damage and shortened life span of these patients.

Wearable and implantable artificial kidney devices for end-stage kidney disease treatment: Current status and review.

BACKGROUND: Chronic kidney disease (CKD) is a major cause of early death worldwide. By 2030, 14.5 million people will have end-stage kidney disease (ESKD, or CKD stage 5), yet only 5.4 million will receive kidney replacement therapy (KRT) due to economic, social, and political factors. Even for those who are offered KRT by various means of dialysis, the life expectancy remains far too low. OBSERVATION: Researchers from different fields of artificial organs collaborate to overcome the challenges of creating products such as Wearable and/or Implantable Artificial Kidneys capable of providing long-term effective physiologic kidney functions such as removal of uremic toxins, electrolyte homeostasis, and fluid regulation. A focus should be to develop easily accessible, safe, and inexpensive KRT options that enable a good quality of life and will also be available for patients in less-developed regions of the world. CONCLUSIONS: Hence, it is required to discuss some of the limits and burdens of transplantation and different techniques of dialysis, including those performed at home. Furthermore, hurdles must be considered and overcome to develop wearable and implantable artificial kidney devices that can help to improve the quality of life and life expectancy of patients with CKD.

Interdialytic weight gain of less than 2.5% seems to limit cardiac damage during hemodialysis.

AIMS: To investigate if a single low-flux HD induces a rise in cardiac biomarkers and if a change in clinical approach may limit such mechanism. MATERIAL AND METHODS: A total of 20 chronic HD patients each underwent three different study-dialyses. Dialyzers (low-flux polysulfone, 1.8 sqm) had been stored either dry or wet (Wet) and the blood level in the venous chamber kept low or high. Laboratory results were measured at baseline, 30 and 180 min, adjusted for the effect of fluid shift. Ultrasound measured microemboli signals (MES) within the return line. RESULTS: Hemodialysis raised cardiac biomarkers (p < 0.001): Pentraxin 3 (PTX) at 30 min (by 22%) and at 180 min PTX (53%), Pro-BNP (15%), and TnT (5%), similarly for all three HD modes. Baseline values of Pro-BNP correlated with TnT (rho = 0.38, p = 0.004) and PTX (rho = 0.52, p < 0.001). The changes from pre- to 180 min of HD (delta-) were related to baseline values (Pro-BNP: rho = 0.91, p < 0.001; TnT: rho = 0.41, p = 0.001; PTX: rho = 0.29, p = 0.027). Delta Pro-BNP (rho = 0.67, p < 0.001) and TnT (rho = 0.38, p = 0.004) correlated with inter-dialytic-weight-gain (IDWG). Biomarkers behaved similarly between the HD modes. The least negative impact was with an IDWG ⩽ 2.5%. Multiple regression analyses of the Wet-High mode does not exclude a relation between increased exposure of MES and factors such as release of Pro-BNP. CONCLUSION: Hemodialysis, independent of type of dialyzer storage, was associated with raised cardiac biomarkers, more profoundly in patients with higher pre-dialysis values and IDWG. A limitation in IDWG to <2.5% and prolonged ultrafiltration time may limit cardiac strain during HD, especially in patients with cardiovascular risk.

A surgical girdle postoperatively may prevent pain and tunnel infections of peritoneal dialysis patients.

AIM: When performing acute onset dialysis after insertion of catheters for peritoneal dialysis, pain exists and tunnel infections may develop. This study investigated whether patients benefit from the use of a surgical girdle and specific dressing postoperatively to prevent pain and tunnel infections. MATERIALS AND METHODS: In 85 consecutive patients, the development of tunnel infections was followed. The patients used a surgical girdle when they were in supine position from day 1 to day 3. The peritoneal dialysis catheter was fixed in a curvature avoiding stretch in the exit. A total of 53 patients participated in a retrospective questionnaire to evaluate abdominal pain within the first 3 days after surgery either with or without girdle. A visual analogue scale from 0 to 10 was used. RESULTS: In 23 patients, data on pain both with and without the girdle could be recorded. Pain was relieved more when using the girdle versus no girdle (median day 1 3.0 vs 4.0, p < 0.001, n = 30, Wilcoxon paired). The development of tunnel infections during the latest 7-year period (exposure period 1487 months) showed a total of three episodes (one every 495 months) of which one caused a subsequent peritonitis, while the other two resolved after antibiotic therapy. Peritonitis episodes appeared at a mean of 37-month interval. CONCLUSION: The use a surgical girdle for 3 days postoperatively and a fixation of the peritoneal dialysis catheter in a curved loop relieves the pain and results in few tunnel infections and subsequent episodes of peritonitis.

An in-vitro assay using human spermatozoa to detect toxicity of biologically active substances.

Identifying the key toxic players within an in-vivo toxic syndrome is crucial to develop targeted therapies. Here, we established a novel method that characterizes the effect of single substances by means of an ex-vivo incubation set-up. We found that primary human spermatozoa elicit a distinct motile response on a (uremic) toxic milieu. Specifically, this approach describes the influence of a bulk toxic environment (uremia) as well as single substances (uremic toxins) by real-time analyzing motile cellular behavior. We established the human spermatozoa-based toxicity testing (HSTT) for detecting single substance-induced toxicity to be used as a screening tool to identify in-vivo toxins. Further, we propose an application of the HSTT as a method of clinical use to evaluate toxin-removing interventions (hemodialysis).

Haemodialysis with Tinzaparin Versus Dialysate Citrate as Anticoagulation.

Anticoagulation with citrate-containing haemodialysate (cHD) is an alternative to tinzaparin haemodialysate (tHD). The study investigated whether cHD would differ when changed from tHD. The same 18 patients were their own controls followed up with cHD for 5 months. LDL-cholesterol decreased at the end of a cHD session (p = 0.01). Neutrophils (p = 0.013) and monocytes (p = 0.007) dropped more during a cHD session. During the follow-up period of cHD, approximately 50% needed additional tinzaparin. Before the cHD session could start, there was a lower total cholesterol at 2 weeks (p = 0.014) and LDL-cholesterol at 1 month (p = 0.011) versus an increase of LDL at 5 months (p = 0.02). Only patients without additional tinzaparin had a reduction of -C-reactive protein (CRP) at 2 months of cHD (p < 0.05) but not later. Solely cHD seems possible only in half of the patients. A greater reduction in granulocytes and monocytes during cHD indicates a more extensive blood membrane interaction, while CRP may be lower.

An evaluation of four modes of low-dose anticoagulation during intermittent haemodialysis.

INTRODUCTION: Intensive care participants that need dialysis frequently suffer from increased risk of bleeding. Standard intermittent haemodialysis (SHD) includes anticoagulation to avoid clotting of the dialysis system. The aim of this study was to clarify which of four different low-dose anticoagulant modes was preferable in reducing the exposure to i.v. unfractionated heparin (heparin) and maintaining patency of the dialysis circuit. METHODS: Twenty-three patients on SHD were included to perform haemodialysis with four modes of low-dose anticoagulation. For comparative analyses, patients served as their own control. Haemodialysis with a single bolus of tinzaparin at the start was compared to haemodialysis initiated without i.v. heparin but priming with (1) heparin in saline (H), (2) heparin and albumin in saline (HA), (3) heparin and albumin in combination with a citrate-containing dialysate (HAC), (4) saline and usinga heparin-coated filters (Evodial®). The priming fluid was discarded before dialysis started. Blood samples were collected at 0, 30 and 180 min during haemodialysis. Smaller bolus doses of heparin (500 Units/dose) were allowed during the modes to avoid interruption by clotting. FINDINGS: The mean activated partial thromboplastin (APTT) time as well as the doses of anticoagulation administered was highest with SHD and least with HAC and Evodial®. Mode H versus SHD had the highest rate of prematurely interrupted dialyses (33%, p = 0.008). The urea reduction rate was less with Evodial® vs. SHD (p < 0.01). One hypersensitivity reaction occurred with Evodial®. Changes in blood cell concentrations and triglycerides differed between the modes. DISCUSSION: If intermittent haemodialysis is necessary in patients at risk of bleeding, anticoagulation using HAC and Evodial® appeared most preferable with least administration of heparin, lowest APTT increase and lowest risk for prematurely clotted dialyzers in contrast to the least plausible H mode.

Sources of Mortality on Dialysis with an Emphasis on Microemboli.

Patients on chronic hemodialysis have a shortened survival compared to the general population. There are multiple sources of morbidity and mortality unique to the dialysis population that account for this. Reasons include the effects of blood membrane interactions, intradialytic hypotension, myocardial stunning, excessive interdialytic weight gain, high-flow arteriovenous fistulae, and impaired lipid break down by anticoagulation administered during HD. Another risk factor, not well appreciated, is the occurrence of microemboli of air (microbubbles) during HD. Such microemboli are not effectively removed by the venous air trap and the safety system provides no warning when these small microbubbles enter the venous bloodline of the extra corporeal circuit and then the venous circulation of the patient. Data indicate that the gas emboli are not fully adsorbed and become embedded by fibrin resulting in a combined clot that causes microemboli in the lung. In addition, these microbubbles (of the size of blood corpuscles) can pass the pulmonary circulation into the left heart and then into the general arterial circulation explaining their detection not only in the lungs but also in the brain and heart of patients. Risk factors for such microbubble appearance include the high blood pump speed associated with high-efficiency dialyses. This review will discuss these various issues in relation to the better outcome of patients in Japan and also how to reduce some of these risk factors.

Few Outflow Problems With a Self-locating Catheter for Peritoneal Dialysis: A Randomized Trial.

We developed a technique for direct start of peritoneal dialysis. Using a coiled or straight Tenckhoff catheter often results in obstruction of flow. A self-locating Wolfram catheter is on the market. It is not clarified if this results in a benefit.The primary aim of this study was to perform a randomized investigation to clarify if the use of a self-locating peritoneal dialysis (PD) catheter would result in different flow problems than a straight Tenckhoff catheter.A total of 61 insertions were made who were randomized and received either a straight Tenckhoff (n = 32) or a self-locating Wolfram catheter (n = 29). A previously described operation technique allowed immediate postoperative start of dialysis. Seven straight Tenckhoff catheters had to be changed into self-locating catheters, and none vice versa, due to flow problems (P = 0.011). An early leakage resulted in temporarily postponed PD in 4 patients. This study showed that using the present operation technique the self-locating PD-catheter causes fewer obstruction episodes than a straight Tenckhoff catheter. This facilitates immediate postoperative start of PD.

A significant proportion of patients treated with citrate containing dialysate need additional anticoagulation.

BACKGROUND: The blood membrane interaction induced during hemodialysis (HD) activates the coagulation system. To prevent clotting and to maintain dialyzer patency, an anticoagulant such as tinzaparin is used. To increase patency of the dialyzers and to reduce the risk of bleeding related to anticoagulation, citrate-containing dialysate has been introduced in Europe. 
 PURPOSE: The aim of this randomized, cross-over study was to investigate if citrate-containing dialysate was safe and efficient enough as the sole anticoagulation agent in chronic HD patients. 
 MATERIAL AND METHODS: In this clinical setting, 23 patients on chronic hemodialysis were randomized in a cross-over design using anticoagulation either by LMWH-tinzaparin or citrate (Cit) as dialysate (22 completed the study). The study included paired analyses of subjective patency, ionized calcium (iCa), urea reduction rate. 
During Cit-HD, the iCa was significantly more reduced with prolonged time. The lowest iCa measured was 0.96 mmol/l. The median iCa after 210 min of HD was 1.02 for Cit-Hd and 1.16 for standard tinzaparin-HD (p = 0.001). Patency of dialyzers was estimated as clear in 14%, stripes of clotted fibers in 36%, and a red filter in 32% of HD session. The addition of approximately 40% of the patients' usual dose of tinzaparin was given to 7 of the patients as a bolus. Four Cit-HD sessions had to be interrupted prematurely due to clotting. 
 CONCLUSION: A significant proportion of patients treated with citrate-containing dialysate need additional anticoagulation.

Lipoprotein lipase responds similarly to tinzaparin as to conventional heparin during hemodialysis.

BACKGROUND: Low molecular weight (LMW) heparins are used for anticoagulation during hemodialysis (HD). Studies in animals have shown that LMW-heparins release lipoprotein lipase (LPL) as efficiently as unfractionated (UF) heparin, but are less able to retard hepatic uptake of the lipase. This raises a concern that the LPL system may become exhausted by LMW-heparin in patients on HD. We have explored this in the setting of clinical HD. METHODS: Twenty patients on chronic hemodialysis were switched from a primed infusion of UF-heparin to a single bolus of tinzaparin. There were long term follow up of variables for the estimation of dialysis efficacy as well as of the LPL release during dialysis and the subsequent impact on the triglycerides. RESULTS: The LPL activity in blood was higher on tinzaparin at 40 but lower at 180 minutes during HD. These values did not change during the 6 month study period. There were significant correlations between the LPL activities in individual patients at the beginning and end of the 6 month study period and between the activities on UF-heparin and on tinzaparin, indicating that tissue LPL was not being exhausted. Triglycerides were higher during the HD-session with tinzaparin than UF-heparin. The plasma lipid/lipoprotein levels did not change during the 6 month study period, nor during a 2-year follow up after the switch from UF-heparin to tinzaparin. Urea reduction rate and Kt/V were reduced by 4 and 7% after 6 months with tinzaparin. CONCLUSION: Our data demonstrate that repeated HD with UF-heparin or tinzaparin does not exhaust the LPL-system.

The role of EUTox in uremic toxin research.

In this publication, we review the activities of the European Uremic Toxin Work Group (EUTox) in the field of uremic toxin research. Founded in 1999 under the umbrella of the European Society of Artificial Organs (ESAO), and active since 2000, this group focuses essentially on questions related to solute retention and removal during chronic kidney disease, and on the deleterious impact of those solutes on biological/biochemical systems. As of January 1, 2009, the group had met 28 times; it organized the third meeting, "Uremic Toxins in Cardiovascular Disease," which took place in October 2008 in Amiens, France. The current group is composed of 25 members belonging to 23 European research institutions. As of November 1, 2008, in total 69 papers had been published to which at least two different research groups belonging to EUTox have contributed in a collaborative effort. Of these, 40 papers were on original research and eight were specific EUTox reviews or position statements. A website (http://www.eutox.info) summarizes all relevant information concerning the work group. EUTox also developed an interactive uremic toxin database, where concentrations of known toxins are displayed, to be used by researchers in the field. In the future, EUTox intends to continue its focus on bench to bedside research with specific consideration of proteomics, metabonomics, secretomics, and genomics.

Cardiovascular conditions in hemodialysis patients may be worsened by extensive interdialytic weight gain.

The risk of death is increased for hemodialysis (HD) patients compared with age-matched healthy subjects, the main reason for this being cardiovascular conditions. This prospective study investigated whether the burden of interdialytic weight gain (IDWG) was of importance for cardiovascular end points and survival. A total of 97 HD patients were studied. The end points included death (reasons given), acute myocardial infarction, or coronary vascular intervention. The extent of ultrafiltration was measured at predefined follow-up points. The IDWG was calculated as ultrafiltration/body weight given in weight%. The burden of IDWG was analyzed. End points occurred in 77 (79%) of the patients during the 5-year study period. The extent of IDWG was higher in those with end points due to cardiovascular reasons (3.77 weight% vs. 3.19 P<0.001), cardiac reasons (P<0.001), congestive heart failure (P<0.01), aortic aneurysm, and intracerebral bleeding (P<0.024). To reduce the risk for cardiovascular events, it is important to avoid too extensive IDWG in HD patients.

Development of air micro bubbles in the venous outlet line: an in vitro analysis of various air traps used for hemodialysis.

Venous air traps were tested in vitro with respect to presence of micro bubbles. Three types of venous air traps were measured (Bioline, Bioline GmbH, Luckenwalde, Germany; Gambro, Gambro AB, Lund, Sweden; Fresenius M.C., Fresenius Medical Care AG & Co. KGaA, Bad Homburg, Germany). Measurements (n = 10) were taken for each air trap, fluid flow (50-600 mL/min), and fluid level (high/low). A 1.5-MHz ultrasound probe was used with an analysis device. The probe was mounted on the outlet line downstream of the venous air trap. A semisynthetic fluid was used to resemble blood viscosity. Occurrences of micro bubbles, without inducing an alarm of the dialysis device, were detected in almost all measurements. The amount of bubbles increased with increasing flow. There were more bubbles with low fluid level compared with high level. The Bioline tubing released the least bubbles in high fluid level. At low level, the Gambro tubing showed the least bubbles at flows 50-400 mL/min, and the Fresenius M.C. tubing showed the least bubbles at flows 400-600 mL/min. High fluid level in the air trap reduced generation of micro bubbles compared to low level, as did lower fluid flow versus high flow. The design of the air trap was also of importance.

A survey of blood purification techniques.

Apheresis may be performed with many different techniques. The basis for different therapeutic approaches lies in the pathophysiological processes present in the diseases that have to be treated. Over the years more sophisticated devices have been developed. The most frequent treatment is plasma exchange (plasmapheresis) using centrifugation or single filtration techniques. In addition cascade filtration and subsequent adsorption from plasma is done. Thereby removal is done by adsorption of molecules such as bilirubin, immunoglobulins (immunoadsorption), circulating immune complexes, various antibodies including those against blood types. Such adsorption technologies have also been developed to allow adsorption directly from a column perfused by whole blood (hemoperfusion). By combining various techniques, systems are available that allow bridging of patients with hepatic failure to transplantation (MARS, Prometheus). By adding e.g., hepatic cells to such systems, besides dialysis and adsorption, cells will help to degrade toxic molecules. Such bioreactors are in clinical use. Apheresis includes also the removal or retrieval of cells from blood for e.g., stemcell transplantation, polycythaemia or hemochromatosis. Removal of leukocytes from blood using leukocyte filters is indicated in inflammatory bowel diseases. By specifically irradiating lymphocytes and monocytes with UV light using the technique of extra corporeal photochemotherapy (ECTP) various immunological diseases are treated. On the other hand, various alternative techniques may be used for the same disorder. Thus for patients with high plasma LDL-cholesterol not responding to other lipid lowering strategic treatment, alternative therapy may be done either by cascade filtration, adsorption technology from plasma, heparin precipitation (HELP-system) or hemoperfusion. This article describes various techniques in clinical use.

Lower plasma levels of lipoprotein lipase after infusion of low molecular weight heparin than after administration of conventional heparin indicate more rapid catabolism of the enzyme.

The functional pool of lipoprotein lipase (LPL) is anchored to heparan sulfate at the vascular endothelium. Injection of heparin releases the enzyme into the circulating blood. Animal experiments have shown that the enzyme is then extracted and degraded by the liver. Low molecular weight (LMW) heparin preparations are widely used in the clinic and are supposed to release less LPL. In this study, we infused a LMW heparin into healthy volunteers for 8 hours. The peak of LPL activity was only about 30% and the subsequent plateau of LPL activity only about 40% compared with those seen with conventional heparin. When a bolus of heparin was given after 4 hours' infusion of LMW or conventional heparin, only relatively small, and similar, amounts of LPL entered plasma. This suggests that the difference between LMW and conventional heparin lay in the ability to retain LPL in the circulating blood, not in the ability to release the lipase. Triglycerides (TGs) decreased when the heparin infusion was started, as expected from the high circulating LPL activities. After 1 to 2 hours, TG levels increased again, and after 8 hours they were about twice as high as before the heparin infusion. This indicates that the amount of LPL available for lipoprotein metabolism had become critically low in relation to TG transport rates. This study indicates that LMW heparin compared with conventional heparin causes as much or more depletion of LPL and subsequent impairment of TG clearing.

Therapeutic apheresis in Sweden: update of epidemiology and adverse events.

The indications of apheresis have changed over time due to results from various studies as well as the innovation of new techniques and ideas. To get an overview of the indications used for apheresis by colleagues elsewhere, data from registries are valuable. In addition, registries can be used for detection of severe adverse events as well as extent of adverse events in various types of treatment. To have a basis for statistical calculations, apheresis units need to be very large or centralisation of data needs to be performed. Data from more than 20000 procedures show that in about 4.3% of occasions adverse events and other problems will develop. Interruption of the procedure was done in 1%, most frequently a plasma exchange. Technical problems can be expected more frequent when performing LDL apheresis and immunoadsorption. Severe adverse events needing medication or interruption of the treatment, such as hypotension and arrhythmia, will develop in about 1% of the procedures. Such an episode occurs more often in patients with TTP/HUS and Guillain-Barré syndrome than in hypercholesterolemia, hyperviscosity syndrome or septic shock/MODS. The non-severe adverse events have increased over time. The results will provide focus in analyses for the reduction of such adverse events.

Three purse-string sutures allow immediate start of peritoneal dialysis with a low incidence of leakage.

Peritoneal dialysis (PD) depends to a great extent on a well-functioning dialysis catheter. The number of patients choosing PD also depends on the possibility of starting dialysis with this technique without needing to use hemodialysis (HD) intermediate or in the beginning of the procedure. This review describes various insertion techniques focusing on a surgical insertion technique using purse-string sutures to fix the peritoneum around the catheter with the inner cuff of a Tenckhoff catheter invaginated between purse-string sutures of the peritoneal membrane and the inner rectus muscle fascia. A third purse-string suture is used to fix the catheter and to tighten the hole in the external rectus fascia. This technique enables immediate start of PD with only a limited risk for early and late leakage. Similar fixation sutures could be considered when inserting catheters, using other insertion modes, to tighten the hole and the position of the cuff and the catheter.

Plasma exchange as rescue therapy in multiple organ failure including acute renal failure.

OBJECTIVE: To describe the outcome of using a rescue therapy including plasma exchange given to patients with a progressive acute disseminated intravascular coagulation and multiple organ dysfunction syndrome. STUDY DESIGN: Retrospective study. SETTING: University and county hospital. PATIENTS: Included were 76 consecutive patients (41 men and 35 women) treated with plasma exchange as rescue therapy besides optimal conventional therapy during a progressive course of disseminated intravascular coagulation and multiple organ dysfunction syndrome, including acute renal failure. Of the 76 patients, 66% needed dialysis. The distribution was hemodialysis in 76%, continuous arteriovenous hemofiltration in 36%, continuous venovenous hemodialysis in 12%, and peritoneal dialysis in 24%. The median organ-failure score was 5 (range, 1-6). Seventy-two percent required mechanical ventilation; septic shock was present in 88%. The median septic shock score was 4 (range, 2-4). Nine patients had another reason than sepsis for the multiple organ dysfunction syndrome. INTERVENTION: Plasma exchange (centrifugation technique) was performed until disseminated intravascular coagulation was reversed (median, two times; range, 1-14). Besides antibiotics and fluid administration, most patients received heparin or low molecular weight heparin (77%), steroids (87%), and inotropes (88%). More than one vasoactive drug was used in 57% of the patients. MEASUREMENTS AND MAIN RESULTS: Eighty-two percent of the patients survived and could leave the hospital. The previously observed survival rates by others for this category of patients would be <20%, and thus, the outcome in this study is significantly better. CONCLUSION: Plasma exchange using plasma as replacement may, in addition to conventional intensive care, help to reverse severe progressive disseminated intravascular coagulation and multiple organ dysfunction syndrome and improve survival.