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Lipoprotein lipase in hemodialysis patients and healthy controls: effects of heparin
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mortality from cardiovascular disease in patients on chronic hemodialysis (HD) is 10 to 20 times greater than in the general population. One major risk factor is renal dyslipidemia, characterised by an impaired catabolism of triglyceride (TG)-rich lipoproteins with accumulation of atherogenic remnant particles. A contributing factor may be derangement of the lipoprotein lipase (LPL) system, the major lipase in the catabolism of TG-rich lipoproteins. The functional pool of LPL is located at vascular surfaces, and is released by heparin into the circulating blood and extracted and degraded by the liver. Unfractionated heparin (UFH) is commonly used during dialysis to avoid clotting in the extracorporeal devices, but is increasingly replaced by various low molecular weight heparin (LMWH) preparations. Plasma LPL activity is usually lower after injection of LMWH which is therefore said to release less LPL and cause less disturbance of lipoprotein metabolism than UFH. However, animal studies have revealed that LMWH is as efficient as UFH in releasing LPL but is less efficient in retarding hepatic uptake. The aim of this study was to explore the effects of UFH and a LMWH (dalteparin) on LPL activity and TG concentrations in HD-patients compared with healthy controls, matched for age and gender. A disturbed LPL system might contribute to an impaired lipoprotein metabolism, and hence, an aggravated cardiovascular condition.

An 8-hour primed infusion of UFH to controls gave rise to an initial peak of LPL activity within 30 minutes. The activity then dropped by almost 80% over the next two hours and levelled off to a plateau that corresponded to 15% of the peak level. When UFH was infused to HD-patients the curve for LPL activity resembled that for controls, but was reduced by 50% during the peak, while the plateau activities were comparable. The interpretation was that the functional pool, represented by the initial peak, was impaired in HD-patients, while the production of lipase molecules, reflected by the plateau, was only marginally reduced. During the peak of LPL activity TG decreased in both groups, but less in HD-patients, as was expected from the lower circulating lipase activity. During the plateau phase with low lipase activity, TG increased towards and beyond baseline values.

When dalteparin was infused, the same pattern of plasma LPL activity was observed, although remarkably reduced. In controls the peak was only 30% and the subsequent plateau 40% compared with the activities during the UFH infusion. A bolus of UFH given when the LPL activity had levelled off to a plateau brought out about the same amount of activity, regardless of whether dalteparin or UFH had been infused. The conclusion was that both heparin preparations had reduced endothelial LPL to a similar extent, but that dalteparin less efficiently retarded the hepatic uptake of the enzyme. As a consequence to this, TG tended to reach higher levels after the dalteparin infusion. The LPL activities were further reduced in HD-patients during infusion with dalteparin, the peak was only 27% and the plateau 35% compared with the activities when UFH was infused. There was no decrease in TG, but rather a continuous increase, suggesting a profound depletion of functional LPL.

In another study in HD-patients, two anticoagulation regimes based on present clinical practice were compared, and the doses were adjusted to the respective manufacturers recommendation. UFH was administered as a primed infusion, whereas dalteparin was given only as a single bolus pre-dialysis, not followed by an infusion. The results were in line with those in the experimental studies and indicate that also in the clinical setting LMWH interferes with the LPL system as least as much as an infusion of UFH does, and temporarily impairs lipolysis of TG. This interference might, in consequence, contribute to an aggravated cardiovascular condition in HD-patients.

Place, publisher, year, edition, pages
2004. , 65 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 921
Keyword [en]
dalteparin, dialysis, lipoprotein metabolism, LMWH, LPL, triglycerides, UFH, uremia
Research subject
Medical and Physiological Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-340ISBN: 91-7305-742-8 (print)OAI: oai:DiVA.org:umu-340DiVA: diva2:143161
Public defence
2004-11-12, E04, 6E, 13:00
Opponent
Available from: 2004-10-27 Created: 2004-10-27 Last updated: 2010-08-11Bibliographically approved
List of papers
1. Lipoprotein lipase during continuous heparin infusion: Tissue stores become partially depleted
Open this publication in new window or tab >>Lipoprotein lipase during continuous heparin infusion: Tissue stores become partially depleted
2001 (English)In: Journal of Laboratory and Clinical Medicine, ISSN 0022-2143, E-ISSN 1532-6543, Vol. 138, no 3, 206-213 p.Article in journal (Refereed) Published
Abstract [en]

Lipoprotein lipase (LPL) and hepatic lipase (HL) are located at vascular surfaces in extrahepatic tissues and in the liver, respectively. Heparin displaces the enzymes into the circulating blood. Animal studies have shown that the liver takes up and degrades LPL. To explore whether heparin leads to a depletion of tissue stores, we followed the lipase activities in plasma during an 8-hour primed infusion of heparin in 10 healthy subjects. After an initial peak, the HL activity decreased slowly after a time curve similar to that for activated partial thromboplastin time. The time curve for LPL was different. After the initial peak, the activity dropped by almost 80%, from 30 to 120 minutes, and then leveled off to a plateau that corresponded to about 15% of the peak level. A second bolus of heparin was given to 4 subjects after 4 hours. The plasma LPL activity increased, but only to about 35% of the original peak level. We conclude that when heparin releases LPL into plasma, the lipase becomes liable to be taken up and degraded by the liver. After less than 1 hour, the stores of LPL have been exhausted, and recruitment of lipase into plasma depends on a slow but stable delivery of newly synthesized molecules.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-4168 (URN)10.1067/mlc.2001.117666 (DOI)11528374 (PubMedID)
Available from: 2004-10-27 Created: 2004-10-27 Last updated: 2010-08-11Bibliographically approved
2. Lipoprotein lipase during heparin infusion: lower activity in hemodialysis patients
Open this publication in new window or tab >>Lipoprotein lipase during heparin infusion: lower activity in hemodialysis patients
2003 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, Vol. 63, no 1, 45-53 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: [corrected] Patients on hemodialysis often have a moderate hypertriglyceridemia in combination with low HDL cholesterol. A contributing factor may be a derangement of the lipoprotein lipase (LPL) system. During dialysis, with heparin as anticoagulant, the enzyme is released into the circulating blood. METHODS: We have followed LPL activity and triglycerides during ordinary heparin administration in nine hemodialysis patients and controls matched for age and gender. Blood samples were drawn before heparin administration and at 15, 30, 60, 120, 180 and 240 min. RESULTS: LPL activity peaked at 15 or 30 min and then decreased to a plateau that was only 20%, of the peak. The activity was reduced in the patients by about 50% during the peak, and about 20% during the following plateau. During the peak of lipase activity the triglycerides decreased in both groups, but the change was less pronounced in patients, as was expected from the lower circulating lipase activity. During the plateau phase with low lipase activity, the triglycerides increased towards baseline values. CONCLUSIONS: During hemodialysis with heparin, there is a peak in LPL activity as well as a reduction in triglycerides during the first hour. Thereafter LPL activity decreases towards a plateau, while triglycerides increase towards baseline. The peak activity of LPL in the patients was only half that in controls, while the plateau was comparable. The data indicate that during and following each dialysis there is a period when LPL activity becomes depleted to a level that is limiting for normal lipoprotein metabolism.

Keyword
Cholesterol, dialysis, lipase turnover, post-heparin plasma, triglycerides, uremia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-4169 (URN)12729069 (PubMedID)
Available from: 2004-10-27 Created: 2004-10-27 Last updated: 2010-08-11Bibliographically approved
3. 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
Open this publication in new window or tab >>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
2003 (English)In: Journal of Laboratory and Clinical Medicine, ISSN 0022-2143, E-ISSN 1532-6543, Vol. 142, no 2, 90-99 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
APTT, activated partial thromboplastin time, AUC, area under the curve, BMI, body-mass index, HDL, high-density lipoprotein, HL, hepatic lipase, LDL, low-density lipoprotein, LML, low molecular weight, LPL, lipoprotein lipase, TG, triglyceride
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-4170 (URN)10.1016/S0022-2143(03)00059-3 (DOI)12960955 (PubMedID)
Available from: 2004-10-27 Created: 2004-10-27 Last updated: 2010-08-11Bibliographically approved
4. Lipoprotein lipase in hemodialysis patients: indications that low molecular weight heparin depletes functional stores, despite low plasma levels of the enzyme.
Open this publication in new window or tab >>Lipoprotein lipase in hemodialysis patients: indications that low molecular weight heparin depletes functional stores, despite low plasma levels of the enzyme.
2004 (English)In: BMC Nephrology, ISSN 1471-2369, Vol. 5, no 1, 17- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Lipoprotein lipase (LPL) has a central role in the catabolism of triglyceride-rich lipoproteins. The enzyme is anchored to the vascular endothelium through interaction with heparan sulphate proteoglycans and is displaced from this interaction by heparin. When heparin is infused, there is a peak of LPL activity accompanied by a reduction in triglycerides (TG) during the first hour, followed by a decrease in LPL activity to a stable plateau during the remaining session while TG increase towards and beyond baseline. This suggests that tissue stores of LPL become depleted. It has been argued that low molecular weight (LMW) heparins cause less disturbance of the LPL system than conventional heparin does. METHODS: We have followed LPL activity and TG during a dialysis-session with a LMW heparin (dalteparin) using the same patients and regime as in a previous study with conventional heparin, i.e. a primed infusion. RESULTS: The shape of the curve for LPL activity resembled that during the earlier dialyses with conventional heparin, but the values were lower during dialysis with dalteparin. The area under the curve for LPL activity during the peak period (0-180 minutes) was only 27% and for the plateau period (180-240 minutes) it was only 36% of that observed with conventional heparin (p < 0.01). These remarkably low plasma LPL activities prompted us to re-analyze LPL activity and to measure LPL mass in frozen samples from our earlier studies. There was excellent correlation between the new and old values which rules out the possibility of assay variations as a confounding factor. TG increased from 2.14 mmol/L before, to 2.59 mmol/L after the dialysis (p < 0.01). From 30 minutes on, the TG values were significantly higher after dalteparin compared to conventional heparin (p < 0.05). CONCLUSION: These results indicate that LMW heparins disturb the LPL system as much or more than conventional heparin does.

Keyword
Aged, Area Under Curve, Dalteparin/*pharmacology, Heparin/pharmacology, Humans, Kidney Diseases/*therapy, Lipoprotein Lipase/drug effects/*metabolism, Reference Values, Renal Dialysis, Triglycerides/metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-13118 (URN)10.1186/1471-2369-5-17 (DOI)15527497 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2010-08-11Bibliographically approved
5. A single bolus of a low molecular weight heparin to patients on haemodialysis depletes lipoprotein lipase stores and retards triglyceride clearing.
Open this publication in new window or tab >>A single bolus of a low molecular weight heparin to patients on haemodialysis depletes lipoprotein lipase stores and retards triglyceride clearing.
Show others...
2005 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 20, no 6, 1172-1179 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Low molecular weight heparins (LMWH) are increasingly used during haemodialysis (HD) to prevent clotting in the extracorporeal devices. It has been suggested that LMWH release endothelial-bound lipoprotein lipase (LPL) less efficiently than unfractionated heparin (UFH) does and thereby cause less disturbance of lipid metabolism. Evidence from in vitro studies and from animal experiments indicate, however, that both types of heparin preparations have the same ability to release endothelial LPL, but LMWH are less effective in preventing uptake and degradation of LPL in the liver. Model studies in humans indicate that LMWH cause as much depletion of LPL stores and impaired lipolysis of triglyceride (TG)-rich lipoproteins as UFH does. METHODS: Two anticoagulant regimes based on present clinical practice were compared in nine HD patients. UFH was administered as a primed infusion, whereas the LMWH (dalteparin) was given only as a single bolus pre-dialysis. Blood was sampled regularly for LPL activity and TG. RESULTS: LPL activity in blood was significantly lower during the dialysis with dalteparin. To explore the remaining activity at the endothelium, a bolus of UFH was given after 3 h of dialysis. The bolus brought out about the same amount of LPL, regardless of whether UFH or dalteparin had been used during dialysis. The increase in TG was significantly higher during dialysis with dalteparin. CONCLUSIONS: This study indicates that a single bolus of dalteparin pre-dialysis interferes with the LPL system as much as, or more than an infusion of UFH does.

Keyword
Adult, Aged, Aged; 80 and over, Anticoagulants/administration & dosage/*pharmacology, Dalteparin/administration & dosage/*pharmacology, Female, Heparin/pharmacology, Humans, Lipoprotein Lipase/*blood, Male, Middle Aged, Renal Dialysis, Triglycerides/blood
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-14831 (URN)10.1093/ndt/gfh774 (DOI)15797889 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2010-08-11Bibliographically approved

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