Reduced lipid concentrations during four years of dialysis with

Transcription

1 Kidney International, Vol. 4 (199/), pp Reduced lipid concentrations during four years of dialysis with low molecular weight heparin HEINZ JLJRGEN DEUBER and WALTER SCHULZ Institute of Nephro/ogv and Osteology. III Med. K/inik. Municipal Hospital of Bamherg. Bamherg, Germany Reduced lipid concentrations during four years of dialysis with low molecular weight heparin. Heparin is used as standard anticoagulant in the extracorporeal circuit of hemodialysis. Widespread use of this drug revealed several potentially adverse effects, such as release of lipoprotein lipase and hepatic lipase from the endothelial surface. Recently it was found that anticoagulatory potency and provocation of adverse effects are linked to different subfractions of heparin. A heparin subfraction of 4 to 6 Daltons rather specifically inhibits factor Xa and therefore has a very high antithronibotic potency. Its effects on release of lipases are minor. During a four year period five patients on maintenance hemodialysis were treated with this low molecular weight heparin (LMWH) subfraction. Additionally, another five patients successively received standard heparin, LMWH and again standard heparm. At all circumstances during treatment with LMWH there was a significant (.1 < P <.5) reduction both of cholesterol and triglyceride blood concentrations. LMWH is efficient in avoiding clotting in extracorporeal circuit during hemodialysis in doses of 17 to 95 U/kg (initial dose) and 7 to 2 U/kg/hr (continuous dose). Hemodialysis became applicable after the detection of heparm as an anticoagulant. Since then there have been millions of dialysis treatments. Some side effects of this therapy, such as serious hemorrhage [11, adverse effects on platelets [2, 31, allergies, and effects on lipolysis [4 6] that may induce raised serum lipid concentrations, became a problem in many patients who were on maintenance hemodialysis. Some years ago it was found that the antithrombotic and anticoagulatory potency of heparin, being a mixture of polysaccharides of different molecular weights (2, to 25, Daltons), is linked to subfractions with well-defined ranges of molecular weights. One of these low molecular weight heparin (LMWH) subfractions (4, to 6, Daltons) shows a very high affinity to antithrombin III, and therefore affects platelet function less than unfractionated standard heparin [7, 8J. Because of its relatively specific effect on antithrombin Ill with a minor influence on the activities of factors IX and XI [91, LMWH shows low activity in broadly based anticoagulant assays, such as PTT [4, 1, 11]. There are results of both in vitro and in vivo studies which indicate a beneficial effect of LMWH on lipid metabolism [5]. This study was planned to elucidate long-term LMWH effects Received for publication January 1, 1991 and in revised form April 15, 1991 Accepted for publication April 16, by the International Society of Nephrology on lipid metabolism in patients who are on maintenance hemodialysis. Methods Long-term study Included in this study were five patients with high cholesterol and triglyceride concentrations, aged 47 to 65 years (mean: 53 7 years). The mean body weight was 6 9 kg. All were on maintenance hemodialysis (3 x 4 hrs/week) at least 18 months prior to the start of this study, and received standard heparin in doses of 29 to 143 U/kg (initial dose) and 14 to 28 U/kg/hr (continuous dose). After start of this prospective, four year study, every month blood concentrations of cholesterol and triglycerides were determined. Occurrence of clotting of extracorporeal circuit was documented. All other dialysis patients in our unit were used as the control group. Intraindis'idual ssi'itchover Included in this study were five patients with high cholesterol and triglyceride concentrations, aged 2 to 67 years (mean: 5 18 years). The mean body weight was kg. All of them were on maintenance hemodialysis (3 x 4 hrs/week) at least 18 months prior to the start of this study, and received standard heparin in doses of 29 to 143 U/kg (initial dose) and 14 to 28 U/kg/hr (continuous dose). After the change from standard heparin to LMWH, triglyceride and cholesterol blood concentrations were controlled as in the long-term study. After a LMWH treatment period of 12 months, each patient was switched back to the prior dosage of standard heparin. During the following 12 months the same controls as during LMWH period were performed. In neither group were there additional therapeutic interventions that might interfere with lipid concentrations. No patient of the study group received any special advice on dietary behavior or lipid reducing drugs. All blood samples were taken directly before onset of dialysis therapy without advance notification of the patients. All dialysis sessions started four to six hours after last food intake. Laboratory methods All samples were examined in the same laboratory. Triglyceride concentrations were determined by measurement of glycerol after hydrolysis by lipase and esterase as described [12]. 496

2 W Fig. 1. Mean cholesterol concentrations during a.four year treatment with LMWH instead of standard heparin to avoid clotiin in extracorporeal circuit during hemodialysi (N 5). Symbol is: ( ) cholesterol. Cholesterol concentrations were determined by an enzymatic assay using esterase and oxidase, and measuring of hydrogenperoxide as described by Trinder l3]. Global coagulatory tests, such as coagulation time or determination of PTT, were done in each patient during the first four weeks of each therapeutic regimen. Paralleling these routine laboratory investigations, the specific antifactor Xa activity was determined in each of the blood samples collected for measuring global coagulatory potencies. For determination of specific anti-xa activity, a commercially available kit (Coatest, KabiVitrum, Germany) was used. Statistics The statistical evaluation of the data mainly was descriptive, by calculation of the mean and SEM. Values of cholesterol and triglyceride concentrations were compared during and at the end of periods of application of different kinds of heparin, that is, LMWH period versus run-in period, and in the case of switchover study, the second standard heparin period versus the run-in period, and second standard heparin period versus the LMWH period. For comparison of data, the Kruskal-Wallis test, and sign test of McNemar and test of Nemenyi were used. Decisions were made on the basis of a 5% significance level. Results Throughout the study period there was no significant clotting in the extracorporeal circuit in any patient independent of heparin or kind of dialyzer used. The doses of LMWH used in this study caused therapeutic levels of.4 to 1. U anti-xa/ml. These anti-xa levels did not cause any prolongation of PTT and only showed minor effects on coagulation time. There was a significant (P <.5) reduction of the mean cholesterol Concentrations throughout the study period of four years applying LMWH compared with the prior period where standard heparin was used (Fig. 1, Table 1). At the beginning of the LMWH pre-treatment period the mean cholesterol concentration was mg/dl. At the end of the study period the mean cholesterol concentration in serum of patients was mg/dl. Concomitantly there was a far more significant (P <.1) drop of serum triglyceride concentrations throughout the study period compared with pre-treatment triglyceride concentrations (Fig. 2, Table 2). At the beginning of the pre-treatment period there was a mean serum triglyceride concentration of Deuber and Schulz: Heparin in dialysis Il Table 1. Cholesterol concentrations during four years of LMWH treatment Cholesterol mgldl MeansEM [ ]L L LMWH was used instead of standard heparin to avoid clotting in the extracorporeal circuit during hemodialysis E Fig. 2. Mean triglyceride concentrations during a four year treatment with LMWH instead of standard heparin to avoid clotting in extracorporeal circuit during hemodialysis (N 5). Symbol is: (_s ) triglycerides. mg/dl. At the end of the four year study period there was a mean serum triglyceride concentration of mgldl. To exclude accidental trends in the development of serum

3 498 Deuber and Schulz: Heparin in dialysis Table 2. Triglyceride concentrations during a four year dialysis treatment with LMWH Triglycerides mgldl Mean SEM II ! ! I ! II ! III IS III LMWH was used instead of standard heparin to avoid clotting in the extracorporeal circuit during hemodialysis. concentrations of both cholesterol and of triglycerides throughout this long term, follow-up study applying LMWH to avoid clotting of the extracorporeal circuit, in a different group of patients a cross over study was performed with standard heparin and LMWH. This second group arbitrarily had marked higher cholesterol and slightly higher triglyceride concentrations than the first one. After a run-in period of 12 months, five patients were switched over from therapy with standard heparin to therapy with LMWH. After another 12 months they were switched back to the therapy with standard heparin. Immediately after onset of therapy with LMWH there was a decline of mean cholesterol concentration from mg/dl (start of therapy with LMWH) to mgldl (end of LMWH therapy). Directly after the second beginning of therapy with standard heparin there was a rapid increase in mean serum cholesterol concen- After 12 months of the second therapy with standard heparin the mean serum cholesterol concentration was higher than during the run-in period ( mgldl vs mgldl). The mean serum cholesterol concentration was signifi- 5), 5) C.) Fig. 3. Mean cholesterol concentrations during three periods of anticoagulation. Symbol is: (. ) cholesterol. During the first 12 months 5 patients received standard heparin therapy. At time all patients were switched over from standard heparin to LMWH and kept on this therapeutic regimen for another 12 months. Thereafter they were switched back to their prior doses of standard heparin and continued hemodialysis treatment. Table 3. Cholesterol concentrations during three periods of anticoagulation Cholesterol mgldl I Mean SEM ! ! During the first 12 months, patients received therapy with standard heparin. At time, all patients were switched from standard heparin to LMWH, and were maintained on this therapy for an additional 12 months. Then they were switched back to their prior doses of standard heparin and continued hemodialysis treatment. cantly (P <.5) lower at the end of treatment period with LMWH compared both with run-in period and end of the second standard heparin application (Fig. 3, Table 3). In this cross over trial the mean serum triglyceride concentration in principle showed the same course as mean serum cholesterol concentration. Directly after switching over from standard heparin to LMWH there was a decrease of serum triglyceride concentrations. This effect was reversed immediately after reapplication of standard heparin. During this second period of therapy with standard heparin, there was a significant (P <.5) rise of serum triglyceride concentrations that overshot the concentrations of the run-in period by approximately 1 mgldl in the

4 Deuber and Schulz: Heparin in dialysis a 3 i 2 >- ) Fig. 4. Mean triglyceride ( -) concentration during three periods of anticoagulation. During the first 12 months 5 patients received a therapy with standard heparin. At time all patients were switched over from standard heparin to LMWH and kept on this therapeutic regimen for another 12 months. Thereafter they were switched back to their prior doses of standard heparin and continued hemodialysis treatment with standard heparin. mean. The significantly (P <.5) lowest mean serum concentration of triglycerides was found at the end of treatment period with LMWH ( mg/dl) compared with both the end of the run-in period ( mg/dl) and the end of new application of standard heparin ( mg/dl; Fig. 4, Table 4). During the whole study period there were flo significant alterations in dry body weight of patients (68 12 kg during run-in period, kg during therapy with LMWH and kg during the second therapy with standard heparin) and in mean serum phosphate concentrations ( mg/dl vs mg/dl vs mg/dl). Discussion The doses of LMWH used in this study caused therapeutic levels of.4 to 1. U anti-xa!ml without clotting independently of the kind of dialyzer used. These anti-xa levels did not cause any prolongation of PTT and only showed minor effects on coagulation time. These results correspond with those of von Bonsdorff et al [41. The results of this prospective clinical trial strongly support the experimental findings that low molecular weight heparin (LMWH) dialysis is apt to reduce high cholesterol and triglyceride concentrations in serum of patients on maintenance hemodialysis. According to our results this effect seems to remain stable over a long time. As shown in prior publications of Bambauer et al [14], Deuber and Schulz [151, and Schrader, Valentin and Tönnis [61, there are significant reductions both of cholesterol and of triglycerides directly after the start of a low molecular weight heparin therapy during dialysis. All published studies concerning this question lack a long study period [5, 11, 14, 15]. This study was done to attempt to close this gap. An additional problem of most studies published so far [5, 6, 14, 15] is that there were no cross over designs. Therefore it could not be excluded that all effects observed during the application of low molecular weight heparin might be produced by chance, due to alterations in dietary behavior of patients or other intraindividual factors influencing metabolism of lipids in the long run. Food records were not planned in this study because it could not be expected to get reliable nutritional data during this long Table 4. Triglyceride concentrations during three periods of anticoagulation Triglycerides mgldl I Mean SEM I During the first 12 months, patients received therapy with standard heparin. At time, all patients were switched to LMWH therapy for the second 12 months. Then the patients were switched back to their prior doses of standard heparin, and continued hemodialysis treatment. study period, and because patients should not be focused on their eating behavior. This study design should avoid bias by not influencing the eating behavior of patients. As tentative controls of unchanged eating behavior there were data for dry body weights and phosphate concentrations in the blood. Even though both parameters cannot prove unchanged fat intake they are considered to make a marked change of diet unlikely, at least by clinical aspects. Additionally, in this trial a cross over design was included. This made patients switch over from standard heparin to low molecular weight heparin, and then after a period of 12 months, switch back to standard heparin. The treatment period with the second application of standard heparin also lasted 12 months. Therefore, there was plenty of time at both therapy conditions to examine lipid alterations that might be produced by timely trends in dietary behavior or metabolism in patients. It is not reasonable to argue that patients immediately changed fat intake when heparin was changed. At all circumstances tested there were significant drops of mean cholesterol and of mean lipid concentrations in patients during therapy with low molecular weight heparin compared with standard heparin. These reduced lipid concentrations lasted during the study period of four years. This finding is true regardless of the degree of cholesterol or triglyceride concentrations. In both parts of this study there were significant reductions of fat concentrations even though the subjects studied showed marked differences of cholesterol concentrations. This significant reduction both of cholesterol and of triglycerides might remove one of the risk factors for atherosclerosis in those patients who are on maintenance hemodialysis, and

5 5 Deuber and Schulz: Heparin in dialysis therefore prevent secondary complications such as stroke or coronary heart disease. The biochemical hypothesis for these findings is a minor influence of low molecular weight heparin on lipases compared to standard heparin [5, 6]. Whether this hypothesis is sufficient for the explanation of our findings that, after switching over from low molecular weight heparin to standard heparin, there seems to be an overshooting rise of lipid concentrations in patient serum yet remains unclear. Studies should be performed to elucidate these surprising results. Also studies are necessary to investigate long-term changes in lipoprotein patterns in dialysis patients, as our short-term controls during 18 months [15] suggest both a reduction of LDL and a rise of HDL. Reprint requests to Dr.med.Heinz Jbrgen Deuber, Institute of Nephrology and Osteology, III.Med.Klinik, Municipal Hospital of Bamberg, Buger Strasse 8, D-86 Bamberg, Germany. References 1. LEONARD CD, WElL E, SCRJBNER BH: Subdural haematomas in patients undergoing haemodialysis. Lancet 2:239 24, KELTON JC: Heparin-induced thrombocytopenia. Haemostasis 16: , REINER M, CHEUNG H: Fibrinogen, in Standard Methods of Clinical Chemistry, (vol 3) edited by SELIGSON D, New York, London, Academic Press, 1961, pp VON BONSDORFF M, STIEKEMA J, HARJANNE A, ALAPIESSA U: A new low molecular weight heparinoid Org 1172 as anticoagulant in hemodialysis. mt j Artif Organs 13, 2:13 18, NIKOLAY J, SCHULZ E, TRAUT, Ni-i H, BIESEL E. ZIELKE E: Zur Beeinfiussung erhohter Triglyzerid- und Cholesterinspiegel bei chronisch dialysepflichtigen Patienten durch Antikoagulation mit niedermolekularem Heparin. Nieren- und Hochdruckkrankheiten 19, 12: , SCI-IRADER J, VALENTIN R, TONNIS Hi: Low molecular weight heparin in hemodialysis and hemofiltration patients. Kidney mt 28: , ANDERSSON LO, BARROWCLIFFE TW, HOLMER E, JOHNSON EA, SIMs GEC: Anticoagulant properties of heparin fractionated by affinity chromatography on matrix bound antithrombin Ill and by gel filtration. Thromb Res 9: , JOHNSON EA, KIRKwD TBL, STIRLING Y: Four heparin preparations: Anti-Xa potentiating effect of heparin after subcutaneous injection. Throtnb Haemosiasis 35: , HOLMER E, LINDAHL U, BACHSTROM G: Anticoagulant activities and effects on platelets of a heparin fragment with high affinity for antithrombin. Thromb Res 18: , ANASTASSIADES E, IRELAND H, FLYNN A, LANE DA, CURTIS JR: A low molecular weight heparin (Kabi 2165, 'Fragmin") in repeated use for hemodialysis: Prevention of clotting and prolongation of the venous compression time in comparison with commercial unfractionated heparin. Nephrol Dial Transplant 5:l35 l4, CARTER Ci, KELTON JO, HIRSCH J,GENT M: Relationship between the antithrombotic and anticoagulant effects of low molecular weight heparin. Thromb Res 21: , WAHLEFELD AW: Triglycerides, determination after enzymatic hydrolysis, in Methods of Enzymatic Analysis (2nd ed., vol. 4), edited by BERGMEYER l-iv, Weinheim, Verlag Chemie, 1974, p TRINDER P: Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. (abstract) Ann C/in Biochem 6:24, BAMBAUER R, ROCKER S, WEBER U, KOHLER M: Comparison of low-molecular-weight heparin to standard heparin in hemodialysis. (abstract) Blood Purif 8 (2):95, DEUBER HJ, SCHULZ W: Wirkungen des in der Hamodialysebehandlung eingesetzten niedermolekularen Heparin auf das Blutbild und den Fettstoffwechsel nach 18 monatiger Therapie. Nieren- and Hochdruckkrankheiten 7: , 1988