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Kidney International, Vol. 42 (1992), pp. 1247—1252
Severe defect in clearing postprandial chylomicron remnants in dialysis patients
MOSHE WEINTRAUB, AMIRA BURSTEIN, TOBY RA8sIN, MEIR LIR0N, YEHUDA RINGEL, SHALTIEL CABILI, MIRIAM BLUM, GARY PEER, and ADRIAN IAINA
Departments of Nephrology and Internal Medicine H, Tel Aviv Medical Center, Tel Aviv, Israel
Severe defect in clearing postprandial chylomicron remnants in dialysis focused on the nature and significance of lipid abnormalities in patients. Lipid abnormalities have been suggested as a major cause ofpatients with renal disease [11—14]. the accelerated atherosclerosis and the high incidence of coronary heart disease in chronic renal failure patients. In the present work the The lipid abnormalities in chronic renal failure are hypertri- postprandial lipoprotein metabolism was studied in chronic dialysis glyceridemic (hyper TG), high VLDL levels, triglyceride en- patients with or without fasting hypertriglyceridemia using the vitamin richment of LDL and HDL, and reduced HDL cholesterol [4, A loading test. This method investigates specifically postprandial lipo- protein metabolism. The determination of vitamin A ester level retinyl 15—17]. However, the degree of hypertriglyceridemic reported palmitate (RP) differentiates the circulating plasma chylomicron and in chronic renal failure (CRF) is only moderate, and according chylomicron remnant fractions from the endogenous VLDL and IDL. to epidemiologic surveys of normal populations such hyper TG Subjects with normal renal function with or without fasting hypertn- would lead to only a marginal increase in the risk of coronary glyceridemia served as control groups. Dialysis patients have signifi- cantly higher level of chylomicron remnants for a more prolongedheart disease [18]. It is therefore possible that other lipoproteins period of time than controls, irrespective of their fasting triglyceride with greater atherogenic potential than VLDL are found in levels. The area below retinyl palmitate chylomicron remnants curve these patients and are responsible for the accelerated athero- was 26308 12422sg/liter' hr in the normolipidemic dialysis patients, sclerosis. Chylomicron remnants, intestinal-derived lipopro- significantly higher than (6393 2098tgIliter' hr; P <0.0001)in the normolipidemic controls. The retinyl palmitate chylomicron remnants teins and VLDL remnants (IDL) are known to be very athero- curve of the hypertriglyceridemic dialysis patients was 21021 4560 genic lipid particles causing premature peripheral vascular gIliter' hr, which was higher than 12969 2215pg/liter' hr (P
1247 1248 Weiniraub el a!: Chylo,nkron remnants in dialysis end-stage renal failure dialysis patients with or without fastingbrought to a volume of 5 ml with saline. Alliquotes of superna- hyperlipidemia. tant and infranatant (0.5 ml) were wrapped in foil and assayed for retinyl ester. Additional aliquots were assayed for triglyc- Methods eride concentration. This procedure appears to separate a Patients predominantly chylomicron population from a predominantly chylomicron remnant population [31, 321. Twenty-one chronic renal failure adult patients on regular dialysis and 24 subjects with normal renal function participated Retiny! ester determination in the study. Retinyl palmitate was determined in total plasma (TP), GroupI.Fifteen subjects (7 females and 8 males) with noplasma chylomicron fraction (CM) and plasma chylomicron renal disease and normal renal function, and normal fastingremnants fraction (CMR). The assays were carried out in plasma lipids. subdued light with HPLC grade solvents. Retinyl acetate was Group 2.Ninehypertriglyceridemic patients (3 females and 6added to the samples as an internal standard. The samples were males) with normal renal function. then mixed with ethanol 4 ml, hexane 5 ml and water 4 ml with Group 3. Thirteen patients (5femalesand 8 males) withvortexing between each addition. Two phases were formed and end-stage renal failure. Seven were on maintenance hemodial-4 ml of the upper (hexane) phase was removed and evaporated ysis (HD) at least three months, for three times four hours perunder nitrogen [33]. The residue was dissolved in a small week, and six on continuous ambulatory peritoneal dialysisvolume of benzene, and an aliquote was injected into an HPLC (CAPD), who had been at least three months free from perito-5 sm ODS-l8 radial compression column. One hundred percent nitis. All these patients had normal fasting triglyceride levels. methanol was used as a mobile phase at a flow rate of 2 ml/min. Group4.Eight patients (3 females and 5 males) with CRF The effluent was monitored at 340 nm and the peak of retinyl with high fasting TG levels (4 on hemodialysis and 4 on CAPD).palmitate (RP) was identified by comparison to the retention None of the patients had liver disease, hypothyroidism, diabe-time of purified standard (Sigma Chemical Co., St. Louis, tes mellitus, or nephrotic syndrome. The criteria for normal Missouri, USA). In agreement with previous reports [301 it was lipids were fasting total cholesterol <240 mgldl and plasmafound that 75 to 80% of total plasma retinyl esters were triglycerides <180 mg/dl. The criteria for hypertriglyceridemiaaccounted for by retinyl palmitate. In addition the distribution was plasma TG >280 mg/dl. of retinyl esters remained constant throughout the study. Sixteen of the dialysis patients had documented myocardial infarction in their medical history. Lipid and lipoprotein determinations Vitamin A fat loading test Cholesterol and triglycerides were measured enzymatically using the reagents cholesterol 236991 and triglycerides 126012 The test Was performed as recently described [31]. After an(Boehringer Mannheim, Inc., Indianopolis, Indiana, USA). overnight 12 hour fast, subjects were given a fatty meal plusHDL cholesterol was determined after precipitation of plasma 60000 U of aqueous vitamin A/rn2 body surface. The fatty mealwith dextran sulfate-magnesium. contained 50 g of fat/m2 body surface, consisting of 65% calories as fat, 20% as carbohydrate and 15% as protein. It Statistical analysis contained 600 mg cholesterol/l000 calories, and the P/S ratio Data are presented as mean SD, using the unpaired Stu- was 0.3. This was given as a milkshake, scrambled eggs, breaddent's t-test with Bonferroni's correction to compare control and cheese, and was consumed in 10 minutes. and chronic renal failure groups within the categories of nor- The vitamin A was added to the milkshake. After the meal,molipidemic or hypertriglyceridemic groups. the subjects fasted for 10 hours, but drinking water was allowed The amounts of retinyl palmitate in total plasma, plasma as desired. Blood samples were drawn before the meal andchylomicron fraction and plasma chylomicron remnant fraction every hour after the meal. All subjects tolerated the meal well,were quantified by the ratio method [34] using retinyl acetate as without diarrhea or other symptoms of intestinal dysfunction. a reference [31]. Two way analysis of variance with repeated measurements Laboratory determinations was used to assess significant differences between groups. (The The blood samples were drawn in sodium EDTA containingStatview MAC II program was used for statistical analysis). test tubes and were immediately centrifuged at 1500 g for 15 minutes. One ml of plasma was stored wrapped in foil at —20°C Results for total plasma retinyl ester assay. Another sample of 0.5 ml The fasting plasma lipids and lipoprotein levels in the studied was stored at 4°C for triglyceride determinations. Another 2.5groups are given in Table 1. Both normal and high fasting ml of plasma was transferred into a 1/2 x 2 inch cellulose nitratetriglyceridemic dialysis groups had significantly lower mean tube and overlayered with 2,5mlsodium chloride solution (d =HDL-cholesterol than the normal controls. Total plasma, 1.006g/ml). Tubes were subjected to preparative ultracentri-plasma chylomicron fraction and plasma chylomicron remnant fugation for 1.6 x 106 g mm with a rotor (SW-55; Beckmanfraction, retinyl palmitate concentration after vitamin A fat Instruments, Inc., Fullerton, California, USA) to float chylo-loading test are given in Figure 1, and Table 2. micron particles of Sf >1,000 [311. The chylomicron containing supernatant (chylomicron frac- Controlsubjectsvith normal renal function tion), was removed and brought to a total volume of 5 ml with Normolipidemic subjects. Total plasma retinyl palmitate was saline. The infranatant (chylomicron remnant fraction) wasdetectable one hour after the Vit A fat meal, increased rapidly Weintraub el a!: C/zvloinicron remnants in dialysis 1249
Table 1. Fastingplasma lipids and lipoproteins, age, sex and body surface area (BSA) in the studied groups
Sex BSA Plasma lipids and lipoproteins mg/d! Group Age F M m TC TG LDL-C HDL-C Normolipidemic 58 8 7 1.75 210 l0l 144 soa controls (N =15) (5) (0.12) (22) (21) (12) (5.2) HyperTG 59 6 3 1.77 259 528a 135 33 controls (N =9) (Il) (0.14) (34) (lOS) (14) (3) Normolipidemic 63 8 5 1.75 200 157 133 36 CRF (N =13) (10) (0.11) (33) (31) (30) (6) HyperTG 58 5 3 1.81 223 346 141 35 CRF (N =8) (9) (0.12) (26) (41) (24) (4.2) Numbers are mean (SD). a P < 0.05 vs. the respective chronic renal failure group (unpaired I-test) between one and four hours, remained high until six hours,endemic patients with normal kidney function. In addition the declined rapidly between six and 10 hours to reach about 25%ofdialysis patients had a severe defect in the clearance of the peak levels, the plasma chylomicron and plasma chylomicronchylomicron remnants. The peak plasma chylomicron remnant remnant fractions appeared to behave differently. The plasmafraction was twofold higher than the normal kidney function chylomicron fraction RP levels closely paralleled those of totalhyperlipidemic patients. plasma RP. The plasma chylomicron remnant fraction RP levels The chylomicron/chylomicron remnant ratio was 3 in the were lower than chylomicron RP levels, increasing to peakhypertriglyceride normal kidney function group and 1.2 in the levels between three and six hours, remaining unchanged untilrespective dialysis group. In normolipidemic normal kidney eight hours and then slowly decreased. At nine to ten hoursfunction patients this ratio is 2.1. their concentration exceeded the chylomicron RP concentra- tions. Total plasma triglyceride after Vitamin A fat loading test Hyperlipide,nic subjects. Plasma, chylomicron and chylomi- cron remnants RP concentrations were abnormal compared The results of each group of subjects are given in Figure 2 and Table 2. with the normolipidemic control persons. The RP of the two In the two hypertriglyceridemic groups there was a severe lipoprotein fractions were several-fold higher then in the normal defect in the triglyceride clearance after the fatty meal. In the group. The most impressive differences were found in the total plasma and plasma chylomicron fraction RP peak levels andhypertriglyceridemic normal kidney function subjects, peak levels and areas below triglyceride curves were 896 151 mg/dl areas below RP curves, demonstrating a high accumulation and and 8442 a very slow disappearence of chylomicron RP. 1092 mg/dl hr, respectively. In the hypertriglycer- idemic patients on dialysis the peak levels and area under the Chronic renal failure dialysis patients curve were 767 174 rng/dl and 4708 764 mgldl 'hr. In the normolipidemic dialysis patients the triglyceride peak Normolipidemic patients. Both hemodialysis and continuouslevels and the area under triglyceride curves were only slightly ambulatory peritoneal dialysis patients had similar responses to hr the Vit A fat loading test and were taken as a group. increased, 35588 mg/dl and 2116 546 mgldl ' compared with 246 76 mg/dl and 1516 The normolipidemic dialysis patients had a twofold higher 374 mg/dl hr, respectively, in total plasma RP peak level compared with the respectivethe normolipidemic control persons. control group, 88343042 pg/liter and 4206 1923 pg/liter, P < 0.0003. The RP peak appeared at six hours and declined Discussion slowly to 60% of its peak at 10 hours. The degree of hypertriglycenidemia in patients with chronic The very high total plasma RP levels were caused mainly byrenal failure on dialysis does not correlate well with the the accumulation of RP in the plasma chylomicron remnantsincreased risk of coronary heart disease [181. Some studies have fraction. suggested that accumulation of other lipids or lipoproteins, The RP in the chylomicron remnants fraction had a peakincluding circulating chylomicron remnants may play a role in mean value of 4942 1984 zg/liter significantly higher then inthe increased development of atherosclerosis in these patients the normal kidney function normolipidemic group 1420 630 [21—251. jig/liter, P < 0.0023. Chylomicrons are synthesized in the intestine following fat The plasma chylomicron remnants fraction peak was found atingestion. They contain APO B-48, APO A-I, APO A-IV. After six hours and remained almost unchanged at 10 hours. secretion they acquire C apolipoproteins and APO E, trans- The mean value of the area under the chylomicron remnantsferred from HDL. After hydrolysis by lipoprotein lipase, these RP curves was 26308 12422 /.Lg/liter/hr, fourfold higher than inparticles are referred to as chylomicron remnants. The particles the normal renal function normolipidemic controls 6393 2098are then taken up by the hepatic APO E receptors (exogenous g!liter/hr, P < 0.0003. pathway). The VLDL with its main protein APO B-l00 assem- bled in the endoplasmatic reticulum of hepatocytes once in the Hyperlipidemic dialysis patients circulation are hydrolyzed to remnant particles IDL and to The dialysis patients with high fasting triglycerides hadLDL particles and cleared by LDL receptors (endogenous abnormal chylomicron clearance as found in the hypertriglyc-pathway). 1250 Weintraubet a!: Chylomicron remnants in dialysis
A Control groups
10000 Normolipidemic 10000 Hypertriglyceridemic
8000 8000
6000 6000
4000 4000
2000 2000
0 0 0 1 2 3 4 5 6 7 89 10 0 1 2 3 4 56 78 9 10
0. BCRF groups
10000 10000 Hypertriglyceridemic
8000 8000
6000 6000
4000 4000
2000 2000
0 (1 0 1 2 3 4 5 6 7 89 10 0 1 2 3 4 56 78 9 10 Time, hours Time, hours Fig. 1. Retinyl pal,nitate (RP) concentration curves in chronic renal failure (CRF) patients and control groups. Total plasma (•----•), chylomicronfraction (O----O)andchylomicron remnant fraction (Y----V). RP concentrations were determined for CRF patients with normal fasting lipids (N =13),and with hypertriglyceridemia (N =8)and in individuals with normal renal function with normal fasting lipids (N =15) and with hypertriglyceridemia (N =9).For each group the levels at each time point were averaged. Two way analysis of variance with repeated measurements between groups: for total plasma RP, F value =17.315, P <0.0001,for RP chylomicron fraction, F value =13.593,P <0.0001, for RP chylomicron remnants fraction, F value =23.38,P <0.0001.
The Vit A fat loading test differentiates between the chylo-mulation of these lipid particles in the circulation. Thus the microns and chylomicron remnants from VLDL and IDLarterial wall of these patients on dialysis might be exposed to despite their similar physical and chemical properties. It alsohigh postaprandial circulating chylomicron remnants during follows the metabolic steps of these lipoproteins, and thus islong periods of time. This metabolic defect occurs in both able to detect possible defects in both lipolysis or chylomicronnormolipidemic and hyperlipidemic dialysis patients. More- remnant liver uptake [31, 32]. over, the chronic renal failure patients with fasting hypertri- The present findings demonstrate a severe defect in postpran-glyceridemia have the same defect in the hydrolysis as persons dial lipoprotein metabolism in chronic renal failure patients.with hypertriglyceridemia and normal renal function. This is The main metabolic defect is not in the lipolysis step. This isevidenced by the accumulation of plasma chylomicron fraction evidenced by only a slight accumulation of plasma chylomicronand the postprandial total plasma triglycerides curves. A posi- fractions. Furthermore, the lipolysis, as shown by the postpran-tive correlation exists between the postprandial plasma chylo- dial triglyceride curves in normolipidemic dialysis patients,micron fraction curves and the plasma fasting triglycerides [31]. were similar to those in the normolipidemic nonrenal failureThis reflects competition between the absorbed exogenous fat group. and the triglyceride's endogenous origin [35].Asimilar defect in The main defect that causes the accumulation of the post-postprandial lipoprotein metabolism as in the normolipidemic prandial lipoproteins in these patients was the chylomicrondialysis patients occurs in type III hyperlipidemia. In this remnant uptake by the liver. This results in a threefold accu-condition the removal of chylomicron remnants is not normal, Weintraub et a!: Chylomicron remnants in dialysis 1251
Table 2. Plasma triglyceride (TO), retinyl palmitate (RP), peak levels 1200 and area under the curves in the total plasma (TP), chylomicron fraction (CM), chylomicron remnant fraction (CMR) in 1000 normolipidemic and hypertriglyceridemic (Hyper TO) patients with chronic renal failure (CRF) and with normal kidney function - 800 Normolipidemic Hyper TG 0 Control CRF Control CRF i— 600 (N = (N = (N = (N = Groups 15) 13) 9) 8) 400 Peak levels Plasma TG 246 355 896 767k 200 mg/dl (76) (88) (151) (174) RP pg/liter TP 4206 8834 9023 8610 0 (1923) (3042) (1232) (1612) 0 12 34 5 6 78 9 10 CM 3118 4505 6907 568l (1421) (1794) (1297) (1587) Time, hours CMR 1420 4942k 2373 4987k (630) (1984) (452) (1414) Fig. 2. Triglyceride concentration (TG) curves in chronic renal failure (CRF) patients and control groups. Total plasma triglyceride concen- Area under the curves trations were determined for CRF patients with normal fasting lipids 1516 2ll6 8442 4708k PlasmaTg (• •) (N=13),and with hypertriglyceridemia (V----V)(N =8)and mg/d1 hr (374) (546) (1509) (764) forindividuals with normal renalfunction with normal fasting lipids RP pg/liter hr (O----O)(N=15)and with hypertriglyceridemia (L1----LJ) (N=9).For TP 21202 49566 61159 48570 each group the levels at each time point were averaged. Two way (6947) (22401) (11243) (8022) analysis of variance with repeated measurements between groups: F 14815 CM 23257 47613 2769l value =147.8,P< 0.0001. (5755) (11791) (11212) (7378) CMR 6393 26308k 12696 2l02l (2098) (12422) (2215) (4560)
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