Prog. Lipid Res. Vol. 30, No. 2/3, pp. 275-279, 1991 Printed in Great Britain. All fights reserved
0163-7827/91/$0.00+ 0.50 C) 1991 Pergamon Press pie
ABNORMALITIES OF LIPOPROTEIN COMPOSITION IN RENAL INSUFFICIENCY PER-OLA ATTMAN*t a n d PETAR ALAUI~VIC~
Department of Nephrology, University of G6teborg, S-41345 G~teborg, Sweden ~Lipoprotein and Atherosclerosis Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, U.S.A.
I. II. Ill. IV. V. VI.
CONTENTS ABBREVIATIONS INTRODUCTION LwiD AND APOLIPOPROTEINC O ~ I T I O N LIPOPROa'mNCOMPOSrnON LIPID METABOLISMAND ITS RELATION TO RENAL FUNCTION CLINICALSIGNIFICANCEOF RENAL DYSLIPOPROTEINEMIA CONCLUSION ACKNOWLEDGEMENTS REFERENCES
275 275 275 276 277 278 278 279 279
ABBREVIATIONS VLDL--very low density lipoproteins
IDL--intermediate density lipoproteins LDL--Iow density lipoproteins HDL--high density lipoprotein TG--triglycerides
GFR--glomerular filtration rate Apo---apolipoprotein LP--lipoprotein LPL--lipoprotein lipas¢
HTGL--hepatic triglyceride lipase I. I N T R O D U C T I O N
Chronic renal insufficiency is frequently accompanied by altered lipid transport proThe plasma concentrations of triglycerides (TG) and cholesterol are usually within the normal range in early renal insufficiency when the glomerular filtration rate (GFR) is reduced to 50-20 ml/min) In advanced renal insufficiency--uremia--when GFR is reduced to below 20 ml/min, patients may frequently develop a moderate hypertriglyceridemia) -1°'~3~5'33The hypertriglyceridemia often persists during subsequent dialysis. However, a significant number of patients with advanced renal failure may still have normal plasma TG concentrations. Plasma cholesterol levels are often within the normal range even in advanced renal failure, a-1°'~3,25.33These findings indicate that the underlying abnormality of lipid transport in renal insufficiency is mainly confined to the metabolism of TG or TG-rich lipoproteins. c e s s e s . 4'7"1s
II. L I P I D A N D A P O L I P O P R O T E I N
COMPOSITION
The TG increase in advanced renal insufficiency is detected mainly in very low density (VLDL) and in intermediate density lipoproteins (IDL), but may also be found in low density (LDL) and high density lipoproteins (HDL).t°'25'32'33Furthermore, despite unaltered plasma cholesterol levels, there is an increase in both unesterified cholesterol and cholesteryl esters in VLDL and IDL but not in LDL. However, the concentrations of HDL-cholesterol are significantly decreased, affecting equally HDL2- and HDL3-cholesterol levels both in the early renal insufficiency and in advanced renal failure) -~°'~3'25'32'33 *Address for correspondence: Department of Nephrology, University of 06teborg, Sahlgrenska sjukhuset, S-41345, G6teborg, Sweden. 275
276
P. O. ATrMA~ and P. ALxuvowc TABLE 1. Lipid and Apolipoprotein Mass of Lipoprotein Density Classes in Patients with Renal Insufficiency* Lipid mass Patients
VLDL
IDL
LDL
CRF I (n = 12)
32.6t (19.2)
31.6 (19.6)
CRF II (n = 12)
92.0 (86.4)
Controls~ (n = 13)
28.7 (19.4)
Apolipoprotein mass HDL VLDL (mg/100 dl)
IDL
LDL
HDL
108.6 (33.3)
46.9 (27.8)
5.7 (4.3)
10.8 (5.9)
75.3 (20.5)
125.3 (20.3)
51.1 (29.8)
145.4 (42.5)
53.5 (19.9)
18.5 (17.3)
20.4 (14.5)
89.0 (27.8)
95.1 (37.2)
25.3 (25.9)
124.6 (40.2)
62.4 (24.9)
4.8 (2.9)
5.3 (3.5)
75.4 (22.9)
168.7 (49.6)
*Patients with renal insufficiency (CRF) arc separated into two groups according to renal function (glomerular filtration rate, GFR). CRF I -- GFR > 15 ml/min; CRF II -- GFR ~< 15 ml/min. Lipid mass is the sum of triglyceride and cholesterol concentrations in each density class. Apolipoprotein mass is the sum of ApoB, ApoC-II, ApoC-III and ApoE concentrations in VLDL and IDL, and of ApoA-I, ApoA-II, ApoB, ApoC-II, ApoC-III and ApoE concentrations in LDL and HDL. tMean (S.D.). :~Controls arc healthy, asymptomatic and normolipidemic subjects.
The dyslipoproteinemia is reflected primarily in an altered apolipoprotein profile of plasma and lipoprotein fractions? .s-~°,25 It is characterized by reduced concentrations of apolipoproteins A-I and A-II, normal or slightly increased levels of ApoB and ApoC-I, increased levels of ApoC-II and normal or even reduced levels of ApoE. The most characteristic abnormality is a significant increase in plasma levels of ApoC-III. s.9,25 Although the ApoC-III levels are usually well correlated with the TG levels, increased concentrations of ApoC-III are also frequently found in normotriglyceridemic patients. A reduced ApoA-I/ApoC-III ratio appears to be the hallmark of renal disease characterizing both the early renal insufficiency and patients with advanced renal failure, irrespective of whether the TG concentrations are increased or not. s,9,25 When present, the increased concentrations of ApoB are found in VLDL and IDL, whereas the levels of ApoB in LDL are normal. 1°There is a shift in the distribution of ApoC and ApoE from HDL to TG-rich lipoproteins in VLDL, IDL and LDL.I° This redistribution is reflected in the characteristically reduced ratio of ApoC-III in heparin supernate to ApoC-III in heparin precipitate (ApoC-III-ratio) found in both hypertriglyceridemic and normotriglyceridemic uremic patients. 9 In addition, apolipoproteins of intestinal origin such as ApoA-IV and ApoB-48 have been identified in VLDL and LDL or uremic patients. 6,32 The redistribution of lipids and apolipoproteins is more prominent in advanced renal failure but can also be detected in the early renal insufficiency (Table 1). m°'25In advanced renal failure, the lipid and apolipoprotein mass is increased more than 3-fold in VLDL, 2- to 3-fold in IDL but is often normal in LDL. In HDL, the lipid and apolipoprotein mass is reduced by 40-45% of its normal concentration. In the early renal insufficiency, there is a 2-fold increase in the apolipoprotein mass in IDL and a 25-30% decrease in the lipid mass of HDL. As a result of a proportionally greater increase in ApoC-III concentrations, the ratio of ApoC-III to ApoE is significantly increased in lipoproteins of lower density classes both in the advanced renal failure and in the early renal insufficiency?° Despite decreased levels of ApoA-I and ApoA-II, their ratio is normal or slightly reduced.! ° Patients on hemodialysis have a distribution of lipids and apolipoproteins similar to that of patients with advanced renal insufficiency in the predialytic stage, s,~°,~3,33 III. L I P O P R O T E I N C O M P O S I T I O N
The results of lipid and apolipoprotein determinations in patients with renal insufficiency show that the dyslipoproteinemia is more frequently reflected in the altered distribution and concentration of apolipoproteins than lipids. The distribution of apolipoproteins and
Lipoprotein abnormafities in renal insufficiency
277
lipids indicates an increase in the ApoB-containing lipoproteins of lower density classes on one hand and a decrease in the ApoA-containing lipoproteins in HDL on the other. Preliminary results on the fractionation of apolipoprotein-defined lipoprotein families by sequential immunoprecipitation3 have shown that, in patients with advanced renal insufficiency both before and during hemodialysis, increased concentrations of ApoBcontaining lipoproteins are due to elevated levels of triglyceride-rich lipoprotein B:C (LP-B:C) and lipoprotein B:C:E (LP-B:C:E). There is no change in the concentration of cholesteryl ester-rich lipoprotein B (LP-B), a major lipoprotein family in the LDL density region characterized by ApoB as the sole protein constituent. Patients before dialysis have a 5-fold increase in the concentration of LP-B :C particles and a less pronounced increase in the concentration of LP-B: C: E particles. However, in hemodialysis patients, there is a nearly 3-fold increase in the concentration of LP-B: C: E with little change in that of LP-B:C. The reason for this difference between patients before and during dialysis is not known. The increased concentrations of LP-B: C: E particles may also be due to increased levels of LP-A-II: B: C: D: E (LP-A-II: B complex) particles coprecipitated with anti-ApoE serum during the sequential immunoprecipitation of ApoB-containing lipoproteins. 2,3 The ApoB-containing lipoprotein particles seem to be distributed throughout the entire lower density spectrum with an increase of LP-B: C and LP-B: C: E in VLDL, IDL and LDL, and an increase of LP-B in VLDL and IDL. These findings show that the dyslipoproteinemia of renal failure is characterized by increased accumulation of intact and partially delipidized TG-rich ApoB-containing lipoproteins including LP-B:C, LP-B: C: E and LP-A-II: B complex. IV. L I P I D M E T A B O L I S M A N D ITS R E L A T I O N TO R E N A L F U N C T I O N
The accumulation of intact or partially delipidized TG-rich lipoprotcin families of intestinal and hepatic origin with abnormal lipid and apolipoprotein composition suggests that reduced catabolism and clearance of these lipoproteins may be one of the main underlying defects of lipoprotein transport in renal insufficiency?'7'~8This interpretation is supported by findings that patients with renal failure have reduced clearance of exogenous lipid emulsions and radiolabeled TG 11'2°'~4'4~-43as well as increased postabsorptiv¢ plasma concentrations of retinyl esters transported by intestinal lipoproteins." Individual variations in TG production may further modulate the triglyceridemic response to the reduced catabolism. 1~-2°,42The observed alterations in the HDL composition may be due, at least partially, to this catabolic defect. The impaired catabolism may be attributed to a number of underlying factors that are still only partially identified. A significant factor seems to be the impaired activity of tissue and plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). A low activity of LPL repeatedly detected in renal f a i l u r e 12,17'21'26'2sc a n also be identified during the earlier stages of renal insufficiencye8 resulting in decreased conversion of VLDL to IDL and LDL. It may be due, in addition to reduced enzyme concentrations, to the presence of still unidentified inhibitors of LPL in uremic plasma e~ or reduced insulin-mediated activation caused by insulin resistance or relative insulin deficiency,m,4°It has been suggested that secondary hyperparathyroidism may be a significant factor contributing to the reduced insulin-mediated stimulation of LPL in patients with renal failure.~ The reduced activity of HTGL may result in further delay of lipoprotein transport because of impaired catabolism and/or uptake of remnant lipoproteins. 5'3~'36Although the precise mechanisms of reduced lipolytic activities have not been identified, treatment of chronic renal failure with drugs that promote lipolysis, such as fibrates, may significantly improve the LPL and HTGL activities and results in reduced concentrations of TG and VLDL and increased concentrations of HDL. ~6~ It has been suggested that the reduced activity of lecithin:cholesterol acyltransferase may be, at least partially, responsible for a decreased transfer of apolipoproteins C and E between HDL and VLDL and IDL as well as reduced catabolism of TG-rich lipoproteins. 29 The compositional abnormalities of TG-rich lipoproteins may render them less suitable as substrates for lipolysis and receptor mediated
278
P.O. ATT~IANand P. ALAUPOVlC
uptake. Studies from our laboratory have shown that uremic VLDL contain a TG-rich lipoprotein family, the LP-A-II: B complex, which displays a low reactivity towards human milk LPL. 2"3 The reduced uptake of uremic LDL by fibroblasts may be related, at least in part, to the altered composition of LDL particles, u The increased APOC-III/APOE ratio in TG-rich lipoproteins could impair their recognition by lipoprotein receptors and prolong their residence time in the circulation. The altered composition of VLDL and LDL has also been incriminated as an important factor inhibiting the transfer of cholesteryl esters from HDL to these lipoprotein density classes in hemodialysis patients. 22 In contrast to the progress made in characterizing compositional abnormalities of lipoproteins that accumulate in renal insufficiency, much less is known about the pathophysiological relationships between the progressive impairment of renal function and the abnormalities of lipid transport. The findings of characteristic, albeit subtle, changes in patients with only moderate reduction of renal function suggest that factors other than uremic toxicity may be of significant importance. Whether these changes are directly related to the metabolic functions o f renal parenchyma or secondary events, such as alterations of insulin effects, remains to be established. It has been suggested that certain apolipoproteins may be synthesized or metabolized by the kidney15,23and that, even in the terminal renal failure in dialysis, the kidney parenchyma could contribute to the metabolism of TG-rich lipoproteins as shown by Robert e t al. 3s in bilaterally nephrectomized patients. V. CLINICAL SIGNIFICANCE OF RENAL DYSLIPOPROTEINEMIA The clinical significance of renal dyslipoproteinemia has not been fully clarified. Vascular disease is a frequent complication of chronic renal failure, and the possible atherogenic potential of uremic dyslipoproteinemia has not emerged as a significant risk factor for vascular disease in dialysis patients when compared to hypertension.37'39In view of recent findings that TG-rich ApoB-containing lipoproteins may be associated with a more rapid development of atherosclerosis in nonrenal patients 14 and the well known atherogenic properties of remnant lipoproteins, as exemplified in type III hyperlipoproteinemia, it is possible that, in certain patients, the uremic dyslipoproteinemia may contribute to the development of atberosclerotic vascular disease during the progression of renal insufficiency and be manifested by increased cardiovascular morbidity during dialysis. Although, generally, there is no increase in the concentration of atherogenic LDL fraction, the uremic dyslipoproteinemia is characterized by a significant elevation of the remnant IDL fraction and a marked reduction of the anti-atherogenic APOA-I and ApoA-II-containing HDL fraction. Furthermore it has recently been reported that increased concentrations of lipoprotein(a) are frequently found in patients with renal failure, which could constitute an additional risk factor for atherosclerosis in these patients. 35 It has also been suggested recently that the characteristic development of glemerulosclerosis leading to destruction of glomerular function and progressive renal failure is an atberomatoid process resembling that of atherosclerosis in other segments of the vascular system. 27 In experimental renal disease, the development of this deleterious lesion is significantly promoted by hyperlipidemia and retarded by lipid lowering measures.27Thus, the dyslipoproteinemia caused by the renal disease could possibly contribute to the progression of the glomerular and tubular lesions and further deterioration of renal function. 3° VI. CONCLUSION Renal insufficiency is accompanied by characteristic abnormalities of lipoprotein composition primarily related to the altered metabolism of triglyceride-rich lipoproteins and reflected in abnormal apolipoprotein rather than lipid profiles in the plasma. The pathophysiological background is complex and the clinical significance of the dyslipoproteinernia remains to be clarified.
Lipoprotein abnormalities in renal insufficiency
279
Acknowledgements--Some of the studies reviewed in this paper have been supported by the Swedish Medical Research Council (Project B 88/90-19X08312) and the resources of the Oklahoma Medical Research Foundation. We thank Mrs Ann Stenman and Mrs Margo French for the secretarial and editorial assistance.
(Received 2 8 M a y 1991) REFERENCES
1. AKMAL,M., ~ , S. E., SOLIMAN,A. R. and MASm~Y,S. G. Kidney Int. 37, 854-858 (1990). 2. ALAUI~VlC,P., KNIGHT-GIBSON,C., WANG,C.-S., DOWNS,D., KOKEN,E., BREWER,H. B., JR and GREGG,R. E. J. Lipid Res. 32, 9-19 (1991). 3. ALAUt~VIC, P., TAVELLA,M., BARD, J. M., WANG, C. S., ATTMAN,P..-O., KOREN, E., CORDER, C., KN[GHT-GmSON,C. and DOWNS,D. Adv. Exp. Med. Biol. 243, 289-297 (1988). 4. API~L, G. Kidney Int. 39, 169-193 (1991). 5. APPLEBAUM-BOWDEN,D., CK)LDBERG,A. P., HAZZA~, W. R., StmsJg~, D. J., BRUNZELL,J. D., HUTTU~N, J. K., NIKIGL~,E. A. and EHNHOLM,C. MetQ~ol~m ~J~ 917--924 (1979). 6. ATGER,V., BEYNE,P., FROMmnmZ,K., ROULLET,J. B. and DR01W~,T. Ann. Biol. Clin. 47, 497-501 (1989). 7. ATTMAN,P.-O. and ALAUVOVIC,P. Kidney Int. 39 (Suppl. 31) (1991). 8. ATTMAN,P.-O. and ALAUPOVIC,P. Nephron 57, 401-410 (1991). 9. ArrMAN,P.-O., ALAUPOWC,P. and GUSTmSON,A. Kidney Int. 32, 368-375 (1987). 10. ATTMAN,P.-O., ALAUPOVXC,P., K~oHT-GmSON,C. and TAWLLA,M. Am. J. Kidney Dis. 14, 432 (Abstr.) (1989). I1. Aal'MAN,P.-O. and GUSTAFSON,A. Fur. J. Ciin. Invest. 9, 285-291 (1979). 12. ATT~N, P.-O., GUSTM~ON,A., ALAUPOWC,P. and WANG,C.-S. Am. J. Nephroi. 4, 92-98 (1984). 13. BAGDADE,J. K., CASARETTO,A. and ALmmS, J. J. J. Lab. Clin. Med. 87, 37-48 (1976). 14. BLANKENHORN,D. H., ALAUPOWC,P., WICKHAM,E., CI-nN,H. A. and Azlm, S. T. Circulation 81, 470--476 (1990). 15. BLUE,M.-L., WILLIAMS,D. L. ZUCKER,S., KHAN,S. A. and BLUM,C. B. Proc. Natl. Acad. Sci. U.S.A. 80, 283-287 (1983). 16. CHAN,M. K. Metabolism 38, 939-945 (1989). 17. CH~, M. K., PERSAUO,J., VARGI-n~,Z. and Moogtm~, J. F. Kidney Int. 25, 812-818 (1984). 18. CHAN,M. K., VARGHF,~S,Z. and MOOmtEAD,J. F. Kidney Int. 19, 625-637 (1981). 19. C-MAN,M. K., VARGHESE,Z., PERSALro,J., BAILLOD,R. A. and MOOm4EAD,J. F. Clin. Nephrol. 17, 183-190 (1982). 20. CHAN,P. C. K., PERSAUD,J., VARGHE~,Z., KINGSTONE,D., BAILLOD,R. A. and Moom~s~, J. F. Cl/n. Nephrol. 31, 88-95 (1989). 21. CRAW~'OitO,G. A., MAHONY,J. F. and STEWART,J. H. Clin. Sci. 60, 73-80 (1981). 22. DIEPLINGER,H., SCHOENFELD,P. V. and FIELDING,C. J. J. Clin. Invest. 77, 1071-1083 (1986). 23. GLASS,C. K., PITTMAN,R. C., KELLER,G. A. and STEINBERG,D. J. Biol. Chem. 2,q8, 7161-7167 (1983). 24. G-ON~N,G., GOLDSERG,A. P., HARTER,H. R. and SCHOm~LD,G. Metabolism 34, 10-14 (1985). 25. GROTZMACHER,P., M~Z, W., PESCHKE,B., GROSS,W. and SCHO~I~, W. Nephrnn .~0, 103-111 (1988). 26. HUTTUNEN,J. K., PASTERNACK,A., VgNTTINEN,T., EHNHOLM,C. and NIKKIL~,E. Acta Med. Scand. 204, 211-218 (1978). 27. KEAr,m, W. F., KASlSKE,B. L. and O'DOm~'F.L,M. P. Am. J. Nephroi. 8, 261-271 (1988). 28. McCosH, E. J., SOLANGI,K., RIVERS,J. M. and GOODMAN,A. Am. J. Clin. Nutr. 28, 1036-1043 (1975). 29. McLEOD,R., Rimw, C. E. and FROHLICH,J. Kidney Int. 2.~, 683--688 (1984). 30. MOORtm~, J. F., EL-NAHAS,M., CHAN,M. K. and VARGHIGSE,Z. Lancet If, 1309-1312 (1982). 31. MORDASINI,R., FREY,F., FLURY,W., KLOSI~G. and GRI~'EN,H. N. Engi. J. Med. 297, 1362-1366 (1977). 32. NESTEL,P. J., FUME,N. H. and TAN, M. H. N. Engl. Y. Med. 307, 329-333 (1982). 33. NORBECK,H. E. and CARLSON,L. A. Acta Med. Scand. 209, 489-503 (1981). 34. NORBECK,H. E. and ROss~R, S. Acta Med. Scand. 211, 69-74 (1982). 35. PARSY,D., DRACON,M., CACHERA,C., PAm~, J.-H., VAmtOUTm,G., TAQtmT,A. and FRUCHART,J.-F. Nephrol. Dial. Transplant 3, 51-56 (1988). 36. PASTERNACK,A., V,~rl'TINEN,T., SOLAKIVI,T., KUU$1,T. and KORTE,T. Clm. Nephrol. 27, 163-168 (1987). 37. RITZ,E., AUOUSXaN,J., BOMM~,J., GNmSO,A. and HAmmeOSCH,W. Kidney Int. Suppl. 17, $84-$87 (1985). 38. ROeERT,D., JEANMONOD,R., FAV~, H., FRUCH~T,J.-F., S ~ G C m R , E. and Rinse, W. Metabolism 38, 514-521 (1989). 39. ROSTAND,S. G., KIRK,K. A. and RUTSKY,E. A. Kidney Int. 22, 304-308 (1982). 40. ROULLET,J. B., LACOUR,B., YVERT,J. P. and DRO~g2, T. Am. J. Physiol. 7,$0, E373-E376 (1986). 41. RUSSEL,G. J., DAVmS,T. G. and WALLS,J. Ciin. Nephroi. 13, 282-286 (1980). 42. SANFELIPPO,M. L., SV4ENSON,R. S. and REAWN,G. M. Kidney Int. 11, 54--61 (1977). 43. SAWIE,E., GmSON,J. C., CRAWFORD,G. A., S~ONS,L. A. and M~dtONV,J. F. Kidney Int. 18, 771-782 (1980). 44. WILSON,D. E., CHAN,I.-F., CHEUNG,A. K., DUTZ,W. and Bucm, K. N. Atherosclerosis 37, 189-197 (1985).
0163-7827/91/$0.00+ 0.50 C) 1991 Pergamon Press pie
ABNORMALITIES OF LIPOPROTEIN COMPOSITION IN RENAL INSUFFICIENCY PER-OLA ATTMAN*t a n d PETAR ALAUI~VIC~
Department of Nephrology, University of G6teborg, S-41345 G~teborg, Sweden ~Lipoprotein and Atherosclerosis Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, U.S.A.
I. II. Ill. IV. V. VI.
CONTENTS ABBREVIATIONS INTRODUCTION LwiD AND APOLIPOPROTEINC O ~ I T I O N LIPOPROa'mNCOMPOSrnON LIPID METABOLISMAND ITS RELATION TO RENAL FUNCTION CLINICALSIGNIFICANCEOF RENAL DYSLIPOPROTEINEMIA CONCLUSION ACKNOWLEDGEMENTS REFERENCES
275 275 275 276 277 278 278 279 279
ABBREVIATIONS VLDL--very low density lipoproteins
IDL--intermediate density lipoproteins LDL--Iow density lipoproteins HDL--high density lipoprotein TG--triglycerides
GFR--glomerular filtration rate Apo---apolipoprotein LP--lipoprotein LPL--lipoprotein lipas¢
HTGL--hepatic triglyceride lipase I. I N T R O D U C T I O N
Chronic renal insufficiency is frequently accompanied by altered lipid transport proThe plasma concentrations of triglycerides (TG) and cholesterol are usually within the normal range in early renal insufficiency when the glomerular filtration rate (GFR) is reduced to 50-20 ml/min) In advanced renal insufficiency--uremia--when GFR is reduced to below 20 ml/min, patients may frequently develop a moderate hypertriglyceridemia) -1°'~3~5'33The hypertriglyceridemia often persists during subsequent dialysis. However, a significant number of patients with advanced renal failure may still have normal plasma TG concentrations. Plasma cholesterol levels are often within the normal range even in advanced renal failure, a-1°'~3,25.33These findings indicate that the underlying abnormality of lipid transport in renal insufficiency is mainly confined to the metabolism of TG or TG-rich lipoproteins. c e s s e s . 4'7"1s
II. L I P I D A N D A P O L I P O P R O T E I N
COMPOSITION
The TG increase in advanced renal insufficiency is detected mainly in very low density (VLDL) and in intermediate density lipoproteins (IDL), but may also be found in low density (LDL) and high density lipoproteins (HDL).t°'25'32'33Furthermore, despite unaltered plasma cholesterol levels, there is an increase in both unesterified cholesterol and cholesteryl esters in VLDL and IDL but not in LDL. However, the concentrations of HDL-cholesterol are significantly decreased, affecting equally HDL2- and HDL3-cholesterol levels both in the early renal insufficiency and in advanced renal failure) -~°'~3'25'32'33 *Address for correspondence: Department of Nephrology, University of 06teborg, Sahlgrenska sjukhuset, S-41345, G6teborg, Sweden. 275
276
P. O. ATrMA~ and P. ALxuvowc TABLE 1. Lipid and Apolipoprotein Mass of Lipoprotein Density Classes in Patients with Renal Insufficiency* Lipid mass Patients
VLDL
IDL
LDL
CRF I (n = 12)
32.6t (19.2)
31.6 (19.6)
CRF II (n = 12)
92.0 (86.4)
Controls~ (n = 13)
28.7 (19.4)
Apolipoprotein mass HDL VLDL (mg/100 dl)
IDL
LDL
HDL
108.6 (33.3)
46.9 (27.8)
5.7 (4.3)
10.8 (5.9)
75.3 (20.5)
125.3 (20.3)
51.1 (29.8)
145.4 (42.5)
53.5 (19.9)
18.5 (17.3)
20.4 (14.5)
89.0 (27.8)
95.1 (37.2)
25.3 (25.9)
124.6 (40.2)
62.4 (24.9)
4.8 (2.9)
5.3 (3.5)
75.4 (22.9)
168.7 (49.6)
*Patients with renal insufficiency (CRF) arc separated into two groups according to renal function (glomerular filtration rate, GFR). CRF I -- GFR > 15 ml/min; CRF II -- GFR ~< 15 ml/min. Lipid mass is the sum of triglyceride and cholesterol concentrations in each density class. Apolipoprotein mass is the sum of ApoB, ApoC-II, ApoC-III and ApoE concentrations in VLDL and IDL, and of ApoA-I, ApoA-II, ApoB, ApoC-II, ApoC-III and ApoE concentrations in LDL and HDL. tMean (S.D.). :~Controls arc healthy, asymptomatic and normolipidemic subjects.
The dyslipoproteinemia is reflected primarily in an altered apolipoprotein profile of plasma and lipoprotein fractions? .s-~°,25 It is characterized by reduced concentrations of apolipoproteins A-I and A-II, normal or slightly increased levels of ApoB and ApoC-I, increased levels of ApoC-II and normal or even reduced levels of ApoE. The most characteristic abnormality is a significant increase in plasma levels of ApoC-III. s.9,25 Although the ApoC-III levels are usually well correlated with the TG levels, increased concentrations of ApoC-III are also frequently found in normotriglyceridemic patients. A reduced ApoA-I/ApoC-III ratio appears to be the hallmark of renal disease characterizing both the early renal insufficiency and patients with advanced renal failure, irrespective of whether the TG concentrations are increased or not. s,9,25 When present, the increased concentrations of ApoB are found in VLDL and IDL, whereas the levels of ApoB in LDL are normal. 1°There is a shift in the distribution of ApoC and ApoE from HDL to TG-rich lipoproteins in VLDL, IDL and LDL.I° This redistribution is reflected in the characteristically reduced ratio of ApoC-III in heparin supernate to ApoC-III in heparin precipitate (ApoC-III-ratio) found in both hypertriglyceridemic and normotriglyceridemic uremic patients. 9 In addition, apolipoproteins of intestinal origin such as ApoA-IV and ApoB-48 have been identified in VLDL and LDL or uremic patients. 6,32 The redistribution of lipids and apolipoproteins is more prominent in advanced renal failure but can also be detected in the early renal insufficiency (Table 1). m°'25In advanced renal failure, the lipid and apolipoprotein mass is increased more than 3-fold in VLDL, 2- to 3-fold in IDL but is often normal in LDL. In HDL, the lipid and apolipoprotein mass is reduced by 40-45% of its normal concentration. In the early renal insufficiency, there is a 2-fold increase in the apolipoprotein mass in IDL and a 25-30% decrease in the lipid mass of HDL. As a result of a proportionally greater increase in ApoC-III concentrations, the ratio of ApoC-III to ApoE is significantly increased in lipoproteins of lower density classes both in the advanced renal failure and in the early renal insufficiency?° Despite decreased levels of ApoA-I and ApoA-II, their ratio is normal or slightly reduced.! ° Patients on hemodialysis have a distribution of lipids and apolipoproteins similar to that of patients with advanced renal insufficiency in the predialytic stage, s,~°,~3,33 III. L I P O P R O T E I N C O M P O S I T I O N
The results of lipid and apolipoprotein determinations in patients with renal insufficiency show that the dyslipoproteinemia is more frequently reflected in the altered distribution and concentration of apolipoproteins than lipids. The distribution of apolipoproteins and
Lipoprotein abnormafities in renal insufficiency
277
lipids indicates an increase in the ApoB-containing lipoproteins of lower density classes on one hand and a decrease in the ApoA-containing lipoproteins in HDL on the other. Preliminary results on the fractionation of apolipoprotein-defined lipoprotein families by sequential immunoprecipitation3 have shown that, in patients with advanced renal insufficiency both before and during hemodialysis, increased concentrations of ApoBcontaining lipoproteins are due to elevated levels of triglyceride-rich lipoprotein B:C (LP-B:C) and lipoprotein B:C:E (LP-B:C:E). There is no change in the concentration of cholesteryl ester-rich lipoprotein B (LP-B), a major lipoprotein family in the LDL density region characterized by ApoB as the sole protein constituent. Patients before dialysis have a 5-fold increase in the concentration of LP-B :C particles and a less pronounced increase in the concentration of LP-B: C: E particles. However, in hemodialysis patients, there is a nearly 3-fold increase in the concentration of LP-B: C: E with little change in that of LP-B:C. The reason for this difference between patients before and during dialysis is not known. The increased concentrations of LP-B: C: E particles may also be due to increased levels of LP-A-II: B: C: D: E (LP-A-II: B complex) particles coprecipitated with anti-ApoE serum during the sequential immunoprecipitation of ApoB-containing lipoproteins. 2,3 The ApoB-containing lipoprotein particles seem to be distributed throughout the entire lower density spectrum with an increase of LP-B: C and LP-B: C: E in VLDL, IDL and LDL, and an increase of LP-B in VLDL and IDL. These findings show that the dyslipoproteinemia of renal failure is characterized by increased accumulation of intact and partially delipidized TG-rich ApoB-containing lipoproteins including LP-B:C, LP-B: C: E and LP-A-II: B complex. IV. L I P I D M E T A B O L I S M A N D ITS R E L A T I O N TO R E N A L F U N C T I O N
The accumulation of intact or partially delipidized TG-rich lipoprotcin families of intestinal and hepatic origin with abnormal lipid and apolipoprotein composition suggests that reduced catabolism and clearance of these lipoproteins may be one of the main underlying defects of lipoprotein transport in renal insufficiency?'7'~8This interpretation is supported by findings that patients with renal failure have reduced clearance of exogenous lipid emulsions and radiolabeled TG 11'2°'~4'4~-43as well as increased postabsorptiv¢ plasma concentrations of retinyl esters transported by intestinal lipoproteins." Individual variations in TG production may further modulate the triglyceridemic response to the reduced catabolism. 1~-2°,42The observed alterations in the HDL composition may be due, at least partially, to this catabolic defect. The impaired catabolism may be attributed to a number of underlying factors that are still only partially identified. A significant factor seems to be the impaired activity of tissue and plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). A low activity of LPL repeatedly detected in renal f a i l u r e 12,17'21'26'2sc a n also be identified during the earlier stages of renal insufficiencye8 resulting in decreased conversion of VLDL to IDL and LDL. It may be due, in addition to reduced enzyme concentrations, to the presence of still unidentified inhibitors of LPL in uremic plasma e~ or reduced insulin-mediated activation caused by insulin resistance or relative insulin deficiency,m,4°It has been suggested that secondary hyperparathyroidism may be a significant factor contributing to the reduced insulin-mediated stimulation of LPL in patients with renal failure.~ The reduced activity of HTGL may result in further delay of lipoprotein transport because of impaired catabolism and/or uptake of remnant lipoproteins. 5'3~'36Although the precise mechanisms of reduced lipolytic activities have not been identified, treatment of chronic renal failure with drugs that promote lipolysis, such as fibrates, may significantly improve the LPL and HTGL activities and results in reduced concentrations of TG and VLDL and increased concentrations of HDL. ~6~ It has been suggested that the reduced activity of lecithin:cholesterol acyltransferase may be, at least partially, responsible for a decreased transfer of apolipoproteins C and E between HDL and VLDL and IDL as well as reduced catabolism of TG-rich lipoproteins. 29 The compositional abnormalities of TG-rich lipoproteins may render them less suitable as substrates for lipolysis and receptor mediated
278
P.O. ATT~IANand P. ALAUPOVlC
uptake. Studies from our laboratory have shown that uremic VLDL contain a TG-rich lipoprotein family, the LP-A-II: B complex, which displays a low reactivity towards human milk LPL. 2"3 The reduced uptake of uremic LDL by fibroblasts may be related, at least in part, to the altered composition of LDL particles, u The increased APOC-III/APOE ratio in TG-rich lipoproteins could impair their recognition by lipoprotein receptors and prolong their residence time in the circulation. The altered composition of VLDL and LDL has also been incriminated as an important factor inhibiting the transfer of cholesteryl esters from HDL to these lipoprotein density classes in hemodialysis patients. 22 In contrast to the progress made in characterizing compositional abnormalities of lipoproteins that accumulate in renal insufficiency, much less is known about the pathophysiological relationships between the progressive impairment of renal function and the abnormalities of lipid transport. The findings of characteristic, albeit subtle, changes in patients with only moderate reduction of renal function suggest that factors other than uremic toxicity may be of significant importance. Whether these changes are directly related to the metabolic functions o f renal parenchyma or secondary events, such as alterations of insulin effects, remains to be established. It has been suggested that certain apolipoproteins may be synthesized or metabolized by the kidney15,23and that, even in the terminal renal failure in dialysis, the kidney parenchyma could contribute to the metabolism of TG-rich lipoproteins as shown by Robert e t al. 3s in bilaterally nephrectomized patients. V. CLINICAL SIGNIFICANCE OF RENAL DYSLIPOPROTEINEMIA The clinical significance of renal dyslipoproteinemia has not been fully clarified. Vascular disease is a frequent complication of chronic renal failure, and the possible atherogenic potential of uremic dyslipoproteinemia has not emerged as a significant risk factor for vascular disease in dialysis patients when compared to hypertension.37'39In view of recent findings that TG-rich ApoB-containing lipoproteins may be associated with a more rapid development of atherosclerosis in nonrenal patients 14 and the well known atherogenic properties of remnant lipoproteins, as exemplified in type III hyperlipoproteinemia, it is possible that, in certain patients, the uremic dyslipoproteinemia may contribute to the development of atberosclerotic vascular disease during the progression of renal insufficiency and be manifested by increased cardiovascular morbidity during dialysis. Although, generally, there is no increase in the concentration of atherogenic LDL fraction, the uremic dyslipoproteinemia is characterized by a significant elevation of the remnant IDL fraction and a marked reduction of the anti-atherogenic APOA-I and ApoA-II-containing HDL fraction. Furthermore it has recently been reported that increased concentrations of lipoprotein(a) are frequently found in patients with renal failure, which could constitute an additional risk factor for atherosclerosis in these patients. 35 It has also been suggested recently that the characteristic development of glemerulosclerosis leading to destruction of glomerular function and progressive renal failure is an atberomatoid process resembling that of atherosclerosis in other segments of the vascular system. 27 In experimental renal disease, the development of this deleterious lesion is significantly promoted by hyperlipidemia and retarded by lipid lowering measures.27Thus, the dyslipoproteinemia caused by the renal disease could possibly contribute to the progression of the glomerular and tubular lesions and further deterioration of renal function. 3° VI. CONCLUSION Renal insufficiency is accompanied by characteristic abnormalities of lipoprotein composition primarily related to the altered metabolism of triglyceride-rich lipoproteins and reflected in abnormal apolipoprotein rather than lipid profiles in the plasma. The pathophysiological background is complex and the clinical significance of the dyslipoproteinernia remains to be clarified.
Lipoprotein abnormalities in renal insufficiency
279
Acknowledgements--Some of the studies reviewed in this paper have been supported by the Swedish Medical Research Council (Project B 88/90-19X08312) and the resources of the Oklahoma Medical Research Foundation. We thank Mrs Ann Stenman and Mrs Margo French for the secretarial and editorial assistance.
(Received 2 8 M a y 1991) REFERENCES
1. AKMAL,M., ~ , S. E., SOLIMAN,A. R. and MASm~Y,S. G. Kidney Int. 37, 854-858 (1990). 2. ALAUI~VlC,P., KNIGHT-GIBSON,C., WANG,C.-S., DOWNS,D., KOKEN,E., BREWER,H. B., JR and GREGG,R. E. J. Lipid Res. 32, 9-19 (1991). 3. ALAUt~VIC, P., TAVELLA,M., BARD, J. M., WANG, C. S., ATTMAN,P..-O., KOREN, E., CORDER, C., KN[GHT-GmSON,C. and DOWNS,D. Adv. Exp. Med. Biol. 243, 289-297 (1988). 4. API~L, G. Kidney Int. 39, 169-193 (1991). 5. APPLEBAUM-BOWDEN,D., CK)LDBERG,A. P., HAZZA~, W. R., StmsJg~, D. J., BRUNZELL,J. D., HUTTU~N, J. K., NIKIGL~,E. A. and EHNHOLM,C. MetQ~ol~m ~J~ 917--924 (1979). 6. ATGER,V., BEYNE,P., FROMmnmZ,K., ROULLET,J. B. and DR01W~,T. Ann. Biol. Clin. 47, 497-501 (1989). 7. ATTMAN,P.-O. and ALAUVOVIC,P. Kidney Int. 39 (Suppl. 31) (1991). 8. ATTMAN,P.-O. and ALAUPOVIC,P. Nephron 57, 401-410 (1991). 9. ArrMAN,P.-O., ALAUPOWC,P. and GUSTmSON,A. Kidney Int. 32, 368-375 (1987). 10. ATTMAN,P.-O., ALAUPOVXC,P., K~oHT-GmSON,C. and TAWLLA,M. Am. J. Kidney Dis. 14, 432 (Abstr.) (1989). I1. Aal'MAN,P.-O. and GUSTAFSON,A. Fur. J. Ciin. Invest. 9, 285-291 (1979). 12. ATT~N, P.-O., GUSTM~ON,A., ALAUPOWC,P. and WANG,C.-S. Am. J. Nephroi. 4, 92-98 (1984). 13. BAGDADE,J. K., CASARETTO,A. and ALmmS, J. J. J. Lab. Clin. Med. 87, 37-48 (1976). 14. BLANKENHORN,D. H., ALAUPOWC,P., WICKHAM,E., CI-nN,H. A. and Azlm, S. T. Circulation 81, 470--476 (1990). 15. BLUE,M.-L., WILLIAMS,D. L. ZUCKER,S., KHAN,S. A. and BLUM,C. B. Proc. Natl. Acad. Sci. U.S.A. 80, 283-287 (1983). 16. CHAN,M. K. Metabolism 38, 939-945 (1989). 17. CH~, M. K., PERSAUO,J., VARGI-n~,Z. and Moogtm~, J. F. Kidney Int. 25, 812-818 (1984). 18. CHAN,M. K., VARGHF,~S,Z. and MOOmtEAD,J. F. Kidney Int. 19, 625-637 (1981). 19. C-MAN,M. K., VARGHESE,Z., PERSALro,J., BAILLOD,R. A. and MOOm4EAD,J. F. Clin. Nephrol. 17, 183-190 (1982). 20. CHAN,P. C. K., PERSAUD,J., VARGHE~,Z., KINGSTONE,D., BAILLOD,R. A. and Moom~s~, J. F. Cl/n. Nephrol. 31, 88-95 (1989). 21. CRAW~'OitO,G. A., MAHONY,J. F. and STEWART,J. H. Clin. Sci. 60, 73-80 (1981). 22. DIEPLINGER,H., SCHOENFELD,P. V. and FIELDING,C. J. J. Clin. Invest. 77, 1071-1083 (1986). 23. GLASS,C. K., PITTMAN,R. C., KELLER,G. A. and STEINBERG,D. J. Biol. Chem. 2,q8, 7161-7167 (1983). 24. G-ON~N,G., GOLDSERG,A. P., HARTER,H. R. and SCHOm~LD,G. Metabolism 34, 10-14 (1985). 25. GROTZMACHER,P., M~Z, W., PESCHKE,B., GROSS,W. and SCHO~I~, W. Nephrnn .~0, 103-111 (1988). 26. HUTTUNEN,J. K., PASTERNACK,A., VgNTTINEN,T., EHNHOLM,C. and NIKKIL~,E. Acta Med. Scand. 204, 211-218 (1978). 27. KEAr,m, W. F., KASlSKE,B. L. and O'DOm~'F.L,M. P. Am. J. Nephroi. 8, 261-271 (1988). 28. McCosH, E. J., SOLANGI,K., RIVERS,J. M. and GOODMAN,A. Am. J. Clin. Nutr. 28, 1036-1043 (1975). 29. McLEOD,R., Rimw, C. E. and FROHLICH,J. Kidney Int. 2.~, 683--688 (1984). 30. MOORtm~, J. F., EL-NAHAS,M., CHAN,M. K. and VARGHIGSE,Z. Lancet If, 1309-1312 (1982). 31. MORDASINI,R., FREY,F., FLURY,W., KLOSI~G. and GRI~'EN,H. N. Engi. J. Med. 297, 1362-1366 (1977). 32. NESTEL,P. J., FUME,N. H. and TAN, M. H. N. Engl. Y. Med. 307, 329-333 (1982). 33. NORBECK,H. E. and CARLSON,L. A. Acta Med. Scand. 209, 489-503 (1981). 34. NORBECK,H. E. and ROss~R, S. Acta Med. Scand. 211, 69-74 (1982). 35. PARSY,D., DRACON,M., CACHERA,C., PAm~, J.-H., VAmtOUTm,G., TAQtmT,A. and FRUCHART,J.-F. Nephrol. Dial. Transplant 3, 51-56 (1988). 36. PASTERNACK,A., V,~rl'TINEN,T., SOLAKIVI,T., KUU$1,T. and KORTE,T. Clm. Nephrol. 27, 163-168 (1987). 37. RITZ,E., AUOUSXaN,J., BOMM~,J., GNmSO,A. and HAmmeOSCH,W. Kidney Int. Suppl. 17, $84-$87 (1985). 38. ROeERT,D., JEANMONOD,R., FAV~, H., FRUCH~T,J.-F., S ~ G C m R , E. and Rinse, W. Metabolism 38, 514-521 (1989). 39. ROSTAND,S. G., KIRK,K. A. and RUTSKY,E. A. Kidney Int. 22, 304-308 (1982). 40. ROULLET,J. B., LACOUR,B., YVERT,J. P. and DRO~g2, T. Am. J. Physiol. 7,$0, E373-E376 (1986). 41. RUSSEL,G. J., DAVmS,T. G. and WALLS,J. Ciin. Nephroi. 13, 282-286 (1980). 42. SANFELIPPO,M. L., SV4ENSON,R. S. and REAWN,G. M. Kidney Int. 11, 54--61 (1977). 43. SAWIE,E., GmSON,J. C., CRAWFORD,G. A., S~ONS,L. A. and M~dtONV,J. F. Kidney Int. 18, 771-782 (1980). 44. WILSON,D. E., CHAN,I.-F., CHEUNG,A. K., DUTZ,W. and Bucm, K. N. Atherosclerosis 37, 189-197 (1985).
