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Response of angiopoietin-like proteins 3 and 4 to haemodialysis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
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2014 (English)In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 37, no 1, 13-20 p.Article in journal (Refereed) Published
Abstract [en]

Background/Aim: Patients on chronic hemodialysis (cHD) have decreased activity of lipoprotein lipase (LPL). Angiopoietin-like proteins (ANGPTL) 3 and 4 have been shown to inactivate LPL. The aim of this study was to investigate the levels of the ANGPTLs in plasma of cHD-patients and to evaluate if cHD may alter these levels. Material and methods: Baseline data were collected from cHD patients (n = 23), and controls (n = 23) and samples were analyzed from 17 patients during low-flux or high-flux HD, and from ultrafiltrate (n = 5). The levels of ANGPTL3 and 4, LPL and triglycerides were studied in a cross-over design on cHD with local citrate compared to tinzaparin as anticoagulant. Results: The level of ANGPTL3 was higher than ANGPTL4 in patients and controls (p<0.01); the ANGPTL3 was 2.0 and ANGPTL4 was 3.3-fold higher in cHD versus controls. The levels of ANGPTL4 increased during cHD. After 180 min of HD the values had decreased again. When the dialysis was performed with high-flux filter, the mean level of ANGPTL4 at 180 min was below the value observed before cHD (p = 0.003). There was immunoreaction for ANGPTL4 in UFs when using high-flux, but not with low-flux, filter. ANGPTL3 was not detectable in UF. On cHD with citrate, no LPL activity was released into the blood. Conclusions: ANGPTL3 and ANGPTL4 were increased in HD patients. Anticoagulation with tinzaparin during cHD causes release of ANGPTL4 from tissues into blood. cHD using high-flux filters, to some extent, removed ANGPTL4. With citrate the levels of ANGPTL4 decreased.

Place, publisher, year, edition, pages
2014. Vol. 37, no 1, 13-20 p.
Keyword [en]
Hemodialysis, Lipoprotein lipase, Metabolism, Tinzaparin, Dialyzer, Citrate
National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-62722DOI: 10.5301/ijao.5000252ISI: 000338513800002OAI: oai:DiVA.org:umu-62722DiVA: diva2:577668
Available from: 2012-12-17 Created: 2012-12-15 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Lipoprotein lipase activity is reduced in dialysis patients. Studies on possible causal factors.
Open this publication in new window or tab >>Lipoprotein lipase activity is reduced in dialysis patients. Studies on possible causal factors.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular disease is a major cause of mortality and morbidity in patients on chronic haemodialysis (HD). One main contributing factor is renal dyslipidaemia, characterized by an impaired catabolism of triglyceride (TG)-rich lipoproteins with accumulation of atherogenic remnant particles. The enzyme lipoprotein lipase (LPL) is a key molecule in the lipolysis of TG-rich lipoproteins into free fatty acids. The activity of LPL is reduced in HD-patients. This study was performed to elucidate various conditions and factors that may have an impact on LPL-related lipid metabolism.

I. The functional pool of LPL is located at the vascular surface. The enzyme is released by heparin and low molecular weight heparins (LMWH) into the circulating blood and extracted and degraded by the liver. Heparin and LMWH are used for anticoagulation during HD to avoid clotting in the extracorporeal devices. This raises a concern that the LPL system may become exhausted by repeated administration of LMWH in patients on HD. In a randomized cross over designed study twenty patients on chronic HD were switched from a primed infusion of heparin to a single bolus of LMWH (tinzaparin).  The LPL activity in blood was higher on HD with LMWH at 40 minutes but lower at 180 minutes compared to HD with heparin. These values did not change during the 6-month study period. With heparin a significant TG reduction was found at 40 minutes and a significantly higher TG value at 180 and 210 minutes than at start. TG was higher during the HD-session with tinzaparin than with heparin. Our data demonstrate that repeated HD with heparin or with LMWH does not exhaust the LPL-system in the long term but does disturb the LPL system and TG metabolism during every HD session.

II. In this study HD patients were compared with patients on peritoneal dialysis (PD) in a case control fashion. PD patients showed the same reaction of the LPL system to LMWH as HD patients. This confirmed that both HD and PD patients had the same, reduced, heparin-releasable LPL pool. The main difference was that in PD patients the TG continued to be cleared effectively even at 180 minutes after the bolus of LMWH injection. This may be due to a slower removal of the released LPL by the liver in PD patients. 

III. In recent years, citrate (Citrasate) in the dialysate has been used in Sweden as a local anticoagulant for chronic HD. We performed a randomized cross over study that included 23 patients (16 men and 7 women) to investigate if citrate in the dialysate is safe and efficient enough as anticoagulant. The study showed that citrate anticoagulation eliminated the need of heparin or LMWH as anticoagulation for HD in half of the patients. However, individual optimization of doses of anticoagulants used together with citrate have to be made.

IV. Recently angiopoietin-like proteins, ANGPTL3 and 4 have emerged as important modulators of lipid metabolism as potent inhibitors of LPL. Twenty-three patients on chronic HD and 23 healthy persons were included as case and controls to investigate the levels of these proteins in plasma of HD-patients and to evaluate if HD may alter these levels. The data showed that plasma levels of ANGPTL3 and 4 were increased in patients with kidney disease compared to controls. This may lead to inactivation of LPL. High flux-HD, but not low flux-HD, reduced the levels of ANGPTL4, while the levels of ANGPTL3 were not significantly influenced.  On HD with local citrate as anticoagulant, no LPL activity was released into plasma during dialysis in contrast to the massive release of LPL with heparin (LMWH). Citrate HD was not associated with a significant drop in plasma TG at 40 minutes, while both HD with citrate and heparin resulted in significantly increased TG levels at 180 minutes compared to the start values.

Conclusions:  Citrate as a local anticoagulant during haemodialysis eliminates the need of heparin or LMWH in about half of the HD patients. Citrate does not induce release of LPL from its endothelial binding sites. We have shown that although HD with heparin causes release of the endothelial pool of LPL during each dialysis session, the basal pool is similarly low in PD patients that do not receive heparin. This indicates that the LPL pool is lowered as a consequence of the uraemia, per se. One explanation could be the increased levels of ANGPTL3 and 4. HD with high flux filters can temporarily lower the levels of ANGPTL4. Further studies are, however, needed to understand why LPL activity is low in patients with kidney disease.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 62 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1540
Keyword
Haemodialysis, lipoprotein lipase, ANGPTL3, ANGPTL4, citrate dialysate, dialyzer.
National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-62733 (URN)978-91-7459-541-3 (ISBN)
Public defence
2013-01-24, Sal E04, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-01-03 Created: 2012-12-16 Last updated: 2017-01-27Bibliographically approved

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Mahmood, DanaNilsson, SolveigOlivecrona, GunillaStegmayr, Bernd

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