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- Mahmood, Dana, 1965-
(författare)
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Lipoprotein lipase activity is reduced in dialysis patients. Studies on possible causal factors.
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Holmberg, Benny, 1958-
(författare)
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Analysis of risk factors in patients with severe chronic kidney disease. The role of atorvastatin.
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aim: There had been no randomized end-point studies with statins for patients with severe renal failure. The purpose of this prospective, open, randomized, controlled study was to investigate whether atorvastatin (10 mg/day) would alter cardiovascular end-points and the overall mortality rate of patients with chronic kidney disease stage 4 or 5 (creatinine clearanceMaterial & Methods: This was an open, prospective, randomized study. A total of 143 patients were included: 73 were controls and 70 were prescribed 10 mg/day of atorvastatin. As efficacy variables, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride levels were determined at the start of the study and at 1, 3, 6, 12, 18, 24, 30 and 36 months. The primary end-points were all cause of mortality, non-lethal acute myocardial infarction, and coronary artery intervention. Various risk factors were studied. In the 97 patients on haemodialysis inter dialysis weight gain (IDWG) was calculated as ultrafiltration in kg/body weight in kg given in percentage of the weight. The burden of IDWG was analyzed.Results: In the atorvastatin group, total cholesterol and low-density lipoprotein cholesterol were significantly reduced, the latter by 35% at 1 month and then sustained. Atorvastatin was withdrawn in 23% of patients due to unacceptable side effects, most frequent complaints being gastrointestinal discomfort and headache. Primary end-points occurred in 74% of the subjects. There was no difference in cardiovascular endpoint and survival between the control and atorvastatin groups. The 5-year end-point-free survival rate from study entry was 20%. There was no evidence of more benefit of atorvastatin for patients with diabetes mellitus and chronic kidney disease versus the other patients; instead plasma fibrinogen increased. The IDWG was significantly larger in patients who suffered from end-points due to cardiovascular reasons, cardiac reasons, congestive heart failure, aortic aneurysm, and intracerebral bleeding.Conclusion: These data showed that in contrast to other patient groups, patients with severe chronic kidney disease 4 and 5, including those with diabetes mellitus, seem to have no benefit from 10mg/day of atorvastatin. Instead we found a high IDWG to be an important risk factor that should be prevented. There was no evident connection between atorvastatin medication and IDWG.
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| 3. |
- Ulf, Forsberg, 1968-
(författare)
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Presence of microemboli during haemodialysis and methods to reduce the exposure to microbubbles
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite chronic dialysis treatment, patients with end stage renal disease undergoing maintenance haemodialysis (HD) remain at a substantially increased risk of morbidity. Previous reports using Doppler ultrasound (DU) during HD have revealed microembolic signals (ME) in the venous circulation.In vitro studies confirm the emergence of microbubbles of air that may pass the security system of the HD circuit without triggering the alarm. The aim of this thesis was to elucidate the presence of ME during HD and examine methods that might reduce exposure to ME in vivo. The first study utilized DU to verify the presence of ME in 40 patients during standard HD. Investigation within 30 minutes after the start of HD and just before the end of session revealed the presence of ME in the venous blood line during both phases. The air trap did not alert for the presence of ME. This indicated that ME may pass into the patient during the entire HD run.Study 2 analyzed the presence of ME prior to start and during HD when measured at the AV-access and also carotid artery. A total of 54 patients were examined using DU as the investigative technique. ME increased significantly after start of HD in the AV-access, but also at the carotid artery site. These data indicated that ME can enter the body and even pass the lung barrier. The question arose if microbubbles of air are resorbed or may cause ischemic lesions in organs such as the brain.Study 3 examined whether the amount of ME detected in the AV-access would change by using either a high or a low blood level in the venous air trap/chamber. This was a prospective, randomized and double-blind study of 20 HD patients who were their own controls. After 30 min of standard HD, measurement of ME with DU was performed for two minutes. The chamber setting was changed and after another 30 minutes a new recording was carried out for two minutes. Data showed that setting a high blood level significantly reduced the extent of ME that entered the patient. The results also indicated that ME consisted mainly of microbubbles.In study 4, twenty patients were randomized in a cross-over setting of HD. Three options were used: a wet-stored dialyzer with high blood level (WH) and a dry-stored dialyzer using either a high (DH) or a low (DL) blood level in the venous chamber. The exposure of ME, detected by DU, was least when using mode WF, more with mode DH, and most with mode DL. There was a correlation between higher blood flow and more extensive exposure to ME.Study 5 was an autopsy study of a chronic HD patient with the aim of searching for microbubbles deposited in organs. Microbubbles of gas were verified in the vessels of the lungs, brain and heart. By using a fluorescent stain of anti-fibrinogen it was verified that the microbubbles were covered by clots that had to be preformed before death occurred. This indicated that air microbubbles are not completely absorbed and could result in embolic deposition in the organs of HD patients.In conclusion, these in vivo studies showed that ME pass the air trap without inducing an alarm and enter the venous blood line of the patient. The data confirmed the presence of ME in the AV-access and also in the carotid artery. Autopsy data of a deceased HD patient demonstrated the presence of microbubbles in the capillaries of the lungs, but also in the systemic circulation such as in the brain and the heart. A high blood level in the venous chamber and wet-stored dialyzer can reduce, but not eliminate the exposure to microbubbles for patients undergoing HD.
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