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Lipoprotein lipase activity is reduced in dialysis patients. Studies on possible causal factors.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
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 [en]
Haemodialysis, lipoprotein lipase, ANGPTL3, ANGPTL4, citrate dialysate, dialyzer.
National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-62733ISBN: 978-91-7459-541-3 (print)OAI: oai:DiVA.org:umu-62733DiVA: diva2:577727
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
List of papers
1. Lipoprotein lipase responds similarly to tinzaparin as to conventional heparin during hemodialysis
Open this publication in new window or tab >>Lipoprotein lipase responds similarly to tinzaparin as to conventional heparin during hemodialysis
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2010 (English)In: BMC Nephrology, ISSN 1471-2369, E-ISSN 1471-2369, Vol. 11, 33Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
London: BioMed Central, 2010
National Category
Urology and Nephrology
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-40810 (URN)10.1186/1471-2369-11-33 (DOI)000208334900001 ()21129229 (PubMedID)
Available from: 2011-03-10 Created: 2011-03-10 Last updated: 2017-12-11Bibliographically approved
2. Post-heparin lipoprotein lipase activity is similar in patients on peritoneal dialysis compared to patients on haemodialysis
Open this publication in new window or tab >>Post-heparin lipoprotein lipase activity is similar in patients on peritoneal dialysis compared to patients on haemodialysis
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Lipoprotein lipase (LPL) activity is known to be reduced in patients with chronic kidney disease (CKD). Heparin, given as a bolus at start of the haemodialysis(1), induces a release of LPL from its binding sites at endothelial surfaces of capillaries to blood. It is not clear if the levels of endothelial LPL between dialysis sessions remains lowered in patients on HD due to the necessary frequent heparinizations. The aim of this study was to see if the pool of heparin-releasable LPL activity differed between patients on HD compared to those on PD that do not need anticoagulation during dialysis.

The study included 16 patients each on chronic PD or HD.  All patients received a bolus of low molecular weight heparin (tinzaparin 75 units/kg) intravenously to estimate the endothelial pool of LPL. Blood samples were drawn for analysis of LPL activity and triglycerides (TG) before and 40 and 180 minutes after the tinzaparin bolus.

Results: The increase in median LPL activity at 40 min after tinzaparin was similar in PD and HD patients. At 180 minutes a slightly higher median level of LPL activity was noted in the PD patients (6.1 mU/mL (n=6) versus 3.4 mU/mL (n=16), p=0.005). The TG concentration in plasma at 40 min was reduced relatively more in the PD patients than in the HD patients. At 180 min TG had returned to start levels in HD patients while they were still below the start level in PD patients.

Conclusion: Post-heparin LPL activity is similar in PD as in HD patients. This indicates that the endothelial LPL pool is not exhausted by repeated loss during each HD session.

Keyword
Peritoneal dialysis, haemodialysis, lipoprotein lipase, triglyceride, tinzaparin, anticoagulation.
National Category
Urology and Nephrology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-62720 (URN)
Available from: 2012-12-17 Created: 2012-12-15 Last updated: 2017-01-30Bibliographically approved
3. A significant proportion of patients treated with citrate containing dialysate need additional anticoagulation
Open this publication in new window or tab >>A significant proportion of patients treated with citrate containing dialysate need additional anticoagulation
2013 (English)In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 36, no 1, 1-6 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wichtig Editore Srl, 2013
Keyword
Hemodialysis, Dialysate, Citrate, Citrasate®, Tinzaparin, Anticoagulation
National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-62721 (URN)10.5301/ijao.5000172 (DOI)
Available from: 2012-12-17 Created: 2012-12-15 Last updated: 2017-12-06Bibliographically approved
4. Response of angiopoietin-like proteins 3 and 4 to haemodialysis
Open this publication in new window or tab >>Response of angiopoietin-like proteins 3 and 4 to haemodialysis
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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.

Keyword
Hemodialysis, Lipoprotein lipase, Metabolism, Tinzaparin, Dialyzer, Citrate
National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-62722 (URN)10.5301/ijao.5000252 (DOI)000338513800002 ()
Available from: 2012-12-17 Created: 2012-12-15 Last updated: 2017-12-06Bibliographically approved

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