- Email: [email protected]
Dialysis removes apolipoprotein C-I, improving very low-density lipoprotein clearance
co m m e nt a r y
http://www.kidney-international.org © 2007 International Society of Nephrology
see original article on page 871
Dialysis removes apolipoprotein C-I, improving very low-density lipoprotein clearance GA Kaysen1–3 Chronic kidney disease (CKD) is associated with dyslipidemia, characterized by increased levels of triglyceride-rich lipoproteins (TRLPs), including very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL), with no change or a reduction in low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) levels. Serum triglycerides and IDL are risk factors for vascular disease in dialysis patients, whereas LDL is not. The principal cause of the increase in TRLPs is decreased removal, not increased synthesis. The clearance defect arises from a reduction in specific lipoprotein receptors, decreases in the activity of lipases, and increased levels of low-molecular weight apolipoproteins that inhibit the interaction between TRLPs and both the receptors and the lipases that catabolize them. VLDL from dialysis patients is structurally abnormal and is not metabolized at a normal rate by lipoprotein lipase (LPL). Kidney International (2007) 72, 779–781. doi:10.1038/sj.ki.5002478
Dautin et al. establish that apolipoprotein C-I (apoC-I), a potent inhibitor of lipoprotein lipase (LPL) and of the engagement of triglyceride-rich lipoproteins (TRLPs) with the lipoproteinlike receptor, is removed specifically from very low-density lipoprotein (VLDL) by dialysis, normalizing the affinity between VLDL and LPL. Because apoC-I is also an inhibitor of cholesterol ester transfer protein, an enzyme that may accelerate degradation of high-density lipoprotein (HDL), its removal could potentially further depress HDL levels. Fortunately, this was not observed. Thus, dialysis could potentially correct aspects of 1Division of Nephrology, Department of Medicine
and 2Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA; and 3Department of Veterans Affairs Northern California Health Care System, Mather, California, USA Correspondence: GA Kaysen, Division of Nephrology, Genome and Biomedical Sciences Facility, 451 East Health Sciences Drive, University of California, Davis, California 95616, USA. E-mail: [email protected] Kidney International (2007) 72
chronic kidney disease (CKD)-associated dyslipidemia. The risk of death from cardiovascular disease among patients with CKD is increased between three- and tenfold compared with that among the general population.1 This increased risk occurs even prior to initiation of dialysis.2 Although total cholesterol levels3 and low-density lipoprotein (LDL) cholesterol levels4 are not predictive of mortality, disorders in other lipoprotein components, notably increased triglyceride levels,5 VLDL, and intermediate-density lipoprotein (IDL), are associated with aortic stiffness, an indicator of vascular injury.6 Decreased HDL cholesterol level is also associated with cardiovascular disease in CKD patients.7,8 Thus two lipoprotein-related risk factors, low HDL and high levels of non-LDL, nonHDL lipoproteins, remain risk factors for vascular disease among dialysis patients. The lipid disorders of CKD are represented more by a dyslipidemia than by hyperlipidemia. In many regards, disordered lipid metabolism of kidney failure
resembles that of the metabolic syndrome. Despite the increased prevalence of the metabolic syndrome among patients with CKD, there are significant differences in the mechanisms responsible for establishing the levels of specific lipoprotein subclasses.9 Whereas, in the metabolic syndrome, dyslipidemia and hyperlipidemia arise mostly from increased lipoprotein synthesis, specifically that of triglyceride-rich VLDL1, the dyslipidemia of CKD, specifically of the apolipoprotein B (apoB)-containing lipoproteins, is characterized by reduced clearance.10 This may contribute to their increased atherogenicity, as long-lived lipoproteins are more subject to oxidation.11 VLDL is synthesized by the liver and chylomicrons by the intestines. They carry with them, among others, apoE and apoC-I through III (Figure 1). ApoE engages with a variety of receptors (VLDL receptor and the lipoprotein-like receptor (LRP), as well as enzymes, including LPL necessary for lipolysis.12 The levels of several lipoprotein receptors are reduced in CKD, 13 as is LPL, 12 combining to reduce the clearance of VLDL and IDL. However, decreased clearance of these lipoproteins is due not only to a reduction in LPL and receptor levels, but also to intrinsic defects in the capacity of lipoproteins harvested from CKD patients to act as appropriate substrates for lipolytic enzymes,14 providing yet a third mechanism prolonging the half-life of these lipoproteins. Dautin and co-workers15 (this issue) now address potentially correctable mechanisms responsible for this defect in lipoprotein structure. ApoC-I and C-III are both increased in CKD, and both apolipoproteins inhibit the interaction between these lipoproteins and their receptors.16 ApoE is a ligand effecting binding of TRLPs to the LRP, to the VLDL receptor, and to LPL. ApoC-I disrupts the interaction between apoE and lipoprotein receptors17 and is also a powerful inhibitor of LPL,18 reducing the activity of the already reduced levels of this enzyme. Thus dialysis patients face three hurdles in the path of clearance of TRLPs: reduced receptor numbers, inhibition of LPL, and competitive interference with binding of the lipoproteins to their sites of catabolism. 779
co mmentar y
Figure 1 | Very low-density lipoprotein (VLDL) is secreted by the liver and chylomicrons (CM) by the intestine, containing apolipoprotein E (apoE) and apoC-I, C-II, and C-III. Triglycerides are lipolized on the vascular endothelium by lipoprotein lipase (LPL) that is bound there to heparan sulfate proteoglycans (HSPG). CM remnants engage the lipoprotein-like receptor (LRP) through an apoE bridge and are taken up by the liver. VLDL remnants follow the same path or are converted into low-density lipoprotein (LDL) through interaction with high-density lipoprotein (HDL) by the enzyme cholesterol ester transfer protein (CETP) and are taken up by the LDL receptor. HDL is composed of apoA-I and apoA-II secreted by liver and gut and acquires cholesterol interacting with lipid-laden macrophages through the ATP-binding cassette A1 (ABCA1). The nascent β-migrating HDL is matured by action of lecithin cholesterol acyltransferase (LCAT) in a stepwise manner to the large HDL2 isoform that either is taken up by the liver, interacting with the HDL receptor (SR-B1), or transfers its core to the VLDL remnant, creating LDL and more rapidly metabolized small HDL3. In chronic kidney disease (CKD), expression of the LRP is reduced, LPL levels are reduced on the vascular endothelium, and apoC-I and C-III inhibit LPL activity as well as interaction between apoE and both the LRP and LPL. HDL maturation is impaired because of decreased levels of LCAT. Enzymes and pathways that are adversely affected in CKD are indicated in red. IDL, intermediate-density lipoprotein.
HDL levels are primarily established by the rate of HDL catabolism. This in turn is linked to HDL density or size. Renal failure is characterized by small HDL size and, in contrast to metabolism of the TRLPs, an increased catabolic rate.9 HDL maturation is impaired by low lecithin cholesterol acyltransferase (LCAT) activity in dialysis patients,19 yielding small dense rapidly catabolized β-migrating HDL. The final step in HDL maturation is an exchange of its cholesterol ester-rich core for triglycerides carried by VLDL remnants by cholesterol ester transfer protein (CETP) producing LDL and small dense α-migrating HDL3. Like β-migrating HDL, HDL3 is also catabolized at an increased rate, causing low HDL levels (Figure 1). ApoC-I inhibits CETP.20 Thus decreasing apoC-I levels could potentially result in an accelera780
tion of this reaction, such as occurs in the metabolic syndrome,9 causing a further decline in HDL in dialysis patients beyond that associated with reduced LCAT activity alone as a consequence of the removal of an endogenous CETP inhibitor. Thus removal of apoC-I could have an adverse effect. The low atomic mass of these apolipoproteins (apoC-I 6630.6 daltons and apoC-III 8765.7 daltons21) makes them potential targets for removal by dialysis. Dautin and co-workers15 have carefully established that dialysis selectively removes apoC-I from the VLDL pool, improving its capacity as a substrate for LPL, while not affecting the HDL apoC-I pool. This was possible because of the relationship of the duration of dialysis treatments to the relatively rapid half-life of VLDL (hours) as compared with that of HDL (days). This
suggests that dialysis is removing a labile apoC-I pool and that lipoprotein structure is changed by replacement of abnormally structured lipoproteins with newly formed normally structured isoforms during dialysis. CETP activity was also not increased, suggesting that it is the apoC-I delivered to this enzyme by HDL and not by the VLDL substrate that inhibits CETP activity. Fortunately, HDL metabolism was unaltered. After dialysis, VLDL was a better substrate for LPL than was VLDL obtained before dialysis, suggesting that VLDL obtained after dialysis was newly formed and that the uremia-associated alteration in the structure of VLDL that makes it a poor substrate for LPL is mediated by a substance that can be removed during dialysis, most likely apoC-I. The effect of dialysis on either the removal of or the level of IDL, the highly atherogenic remnants of both VLDL and chylomicron metabolism, was not explored; however, because the halflife of IDL is shorter than that of VLDL, any contribution of decreased apoC-I to the removal of IDL should also have been affected by dialysis. ApoC-I inhibits binding of β-migrating VLDL to the LRP22 and impairs the clearance of both VLDL and CM remnant particles. Additionally, hepatic LRP gene regulation is downregulated in CKD.13 Increased apoC-I levels in conjunction with decreased receptor numbers then provide a double defect conspiring to increase the levels of these atherogenic lipoproteins. Thus dialysis patients have a dual defect in that the enzymes necessary for catabolism of TRLPs are reduced while at the same time inhibitors of these enzymes and receptors found on the lipoprotein targets are increased. Dialysis appears to play a role in reducing at least one of these defects. Effective treatment strategies for reducing cardiovascular risk among dialysis patients have been elusive. The use of statins to reduce LDL cholesterol was of small and statistically insignificant benefit.23 ApoC-I levels returned to baseline by 24 hours; however, prolonged or daily dialysis might have the potential to normalize metabolism of the TRLPs and thus reduce cardiovascular risk. REFERENCES 1.
United States Renal Data System. 17th Annual Report. National Institutes of Health, National Kidney International (2007) 72
co m m e nt a r y
2.
3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13. 14.
15.
16.
17.
18.
Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA. Division of Kidney, Urologic, and Hematologic Diseases Annual, Data Report 2005, pp128–129. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1305. Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15: 458–482. Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 2002; 61: 1887–1893. Stompor T, Pasowicz M, Sullowicz W et al. An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis. Am J Kidney Dis 2003; 41: 203–211. Shoji T, Nishizawa Y, Kawagishi T et al. Intermediatedensity lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol 1998; 9: 1277–1284. Koch M, Kutkuhn B, Grabensee B, Ritz E. Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Transplant 1997; 12: 2603–2611. Okubo K, Ikewaki K, Sakai S et al. Abnormal HDL apolipoprotein A-I and A-II kinetics in hemodialysis patients: a stable isotope study. J Am Soc Nephrol 2004; 15: 1008–1015. Kaysen GA. Disorders in high-density metabolism with insulin resistance and chronic kidney disease. J Ren Nutr 2007; 17: 4–8. Ikewaki K, Schaefer JR, Frischmann ME et al. Delayed in vivo catabolism of intermediatedensity lipoprotein and low-density lipoprotein in hemodialysis patients as potential cause of premature atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: 2615–2622. Walzem RL, Watkins S, Frankel EN et al. Older plasma lipoproteins are more susceptible to oxidation: a linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease. Proc Natl Acad Sci USA 1995; 92: 7460–7464. Chan MK, Persaud J, Varghese Z, Moorhead JF. Pathogenic roles of post-heparin lipases in lipid abnormalities in hemodialysis patients. Kidney Int 1984; 25: 812–818. Kim C, Vaziri ND. Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure. Kidney Int 2005; 67: 1028–1032. Lee DM, Knight-Gibson C, Samuelsson O et al. Lipoprotein particle abnormalities and the impaired lipolysis in renal insufficiency. Kidney Int 2002; 61: 209–218. Dautin G, Soltani Z, Ducloux D et al. Hemodialysis reduces plasma apolipoprotein C-I concentration making VLDL a better substrate for lipoprotein lipase. Kidney Int 2007; 72: 871–878. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of beta-migrating very low density lipoproteins. J Lipid Res 1994; 35: 134–142. van der Hoogt CC, Berbee JF, Espirito et al. Apolipoprotein CI causes hypertriglyceridemia independent of the very-low-density lipoprotein receptor and apolipoprotein CIII in mice. Biochim Biophys Acta 2006; 1761: 213–220. Berbee JF, van der Hoogt CC, Sundararaman D et
Kidney International (2007) 72
al. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL. J Lipid Res 2005; 46: 297–306. 19. Mekki K, Bouchenak M, Remaoun M, Belleville JL. Effect of long-term hemodialysis on plasma lecithin: cholesterol acyltransferase activity and the amounts and compositions of HDL2 and HDL3 in hemodialysis-treated patients with chronic renal failure. A 9-year longitudinal study. Med Sci Monit 2004; 10: CR439–CR446. 20. Dumont L, Gautier T, de Barros JP et al. Molecular mechanism of the blockade of plasma cholesteryl ester transfer protein by its physiological inhibitor apolipoprotein CI. J Biol Chem 2005; 280: 38108–38116.
21. Bondarenko PV, Cockrill SL, Watkins LK et al. Mass spectral study of polymorphism of the apolipoproteins of very low density lipoprotein. J Lipid Res 1999; 40: 543–555. 22. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of beta-migrating very low density lipoproteins. J Lipid Res 1994; 35: 134–142. 23. Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238–248 [published erratum appears in N Engl J Med 2005; 353: 1640].
see original article on page 814
Hypertension in connexin40-null mice: a renin disorder DC Spray1 Studies described in this issue indicate that the gap junction protein connexin40 (Cx40) appears to play an unexpected role in blood pressure regulation. In mice lacking this gap junction protein, renin secretion is high and not regulated by arteriolar pressure. Kidney International (2007) 72, 781–782. doi:10.1038/sj.ki.5002515
Gap junction channels uniquely fulfill the vital role of providing a pathway for intercellular diffusion of ions and small molecules between coupled cell populations within a tissue. In chordates, these channels are formed by connexin proteins, a family of about 20 members in mammals, where expression of isoforms is cell type and tissue specific, with some overlap. The biophysical properties of channels formed by individual connexins vary, as do those of proteins that bind to the connexins; this presumably confers differences tuned to match the function that these channels serve in various tissues, such as second messenger exchange in the liver and perhaps astrocytes in the brain, electrical signal propagation in excitable systems such as the heart, brain, and 1Dominick P. Purpura Department of Neuroscience,
Albert Einstein College of Medicine, Bronx, New York, USA Correspondence: DC Spray, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, New York 10461, USA. E-mail: [email protected]
pancreatic islet, and metabolite exchange in the lens. Because of the tissue-specific distribution of connexins and the well-known exchange of ions and signaling molecules through them, connexin-null mice might have been expected to have well-predicted and perhaps quite restricted phenotypes. For example, the ventricles of mice lacking connexin43 (Cx43) might be expected to beat arrhythmically because of loss of the most abundant gap junction protein, the liver of Cx32-null mice might be dysfunctional because of lack of signaling between periportal and perivenous hepatocytes, and Cx50 knockouts might be expected to display cataracts. In fact, although these changes are seen to one extent or another as part of the overall mouse phenotype, the major changes in the animals are different, revealing hitherto unsuspected (and to some degree still not well understood) roles of the individual connexins in the animal. Cx43-null mice die at birth as a result of congenital malformation in the right ventricle, blocking outflow to the lung; Cx32-null mice display reduced peripheral myelination (now known to be the genetic 781
http://www.kidney-international.org © 2007 International Society of Nephrology
see original article on page 871
Dialysis removes apolipoprotein C-I, improving very low-density lipoprotein clearance GA Kaysen1–3 Chronic kidney disease (CKD) is associated with dyslipidemia, characterized by increased levels of triglyceride-rich lipoproteins (TRLPs), including very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL), with no change or a reduction in low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) levels. Serum triglycerides and IDL are risk factors for vascular disease in dialysis patients, whereas LDL is not. The principal cause of the increase in TRLPs is decreased removal, not increased synthesis. The clearance defect arises from a reduction in specific lipoprotein receptors, decreases in the activity of lipases, and increased levels of low-molecular weight apolipoproteins that inhibit the interaction between TRLPs and both the receptors and the lipases that catabolize them. VLDL from dialysis patients is structurally abnormal and is not metabolized at a normal rate by lipoprotein lipase (LPL). Kidney International (2007) 72, 779–781. doi:10.1038/sj.ki.5002478
Dautin et al. establish that apolipoprotein C-I (apoC-I), a potent inhibitor of lipoprotein lipase (LPL) and of the engagement of triglyceride-rich lipoproteins (TRLPs) with the lipoproteinlike receptor, is removed specifically from very low-density lipoprotein (VLDL) by dialysis, normalizing the affinity between VLDL and LPL. Because apoC-I is also an inhibitor of cholesterol ester transfer protein, an enzyme that may accelerate degradation of high-density lipoprotein (HDL), its removal could potentially further depress HDL levels. Fortunately, this was not observed. Thus, dialysis could potentially correct aspects of 1Division of Nephrology, Department of Medicine
and 2Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA; and 3Department of Veterans Affairs Northern California Health Care System, Mather, California, USA Correspondence: GA Kaysen, Division of Nephrology, Genome and Biomedical Sciences Facility, 451 East Health Sciences Drive, University of California, Davis, California 95616, USA. E-mail: [email protected] Kidney International (2007) 72
chronic kidney disease (CKD)-associated dyslipidemia. The risk of death from cardiovascular disease among patients with CKD is increased between three- and tenfold compared with that among the general population.1 This increased risk occurs even prior to initiation of dialysis.2 Although total cholesterol levels3 and low-density lipoprotein (LDL) cholesterol levels4 are not predictive of mortality, disorders in other lipoprotein components, notably increased triglyceride levels,5 VLDL, and intermediate-density lipoprotein (IDL), are associated with aortic stiffness, an indicator of vascular injury.6 Decreased HDL cholesterol level is also associated with cardiovascular disease in CKD patients.7,8 Thus two lipoprotein-related risk factors, low HDL and high levels of non-LDL, nonHDL lipoproteins, remain risk factors for vascular disease among dialysis patients. The lipid disorders of CKD are represented more by a dyslipidemia than by hyperlipidemia. In many regards, disordered lipid metabolism of kidney failure
resembles that of the metabolic syndrome. Despite the increased prevalence of the metabolic syndrome among patients with CKD, there are significant differences in the mechanisms responsible for establishing the levels of specific lipoprotein subclasses.9 Whereas, in the metabolic syndrome, dyslipidemia and hyperlipidemia arise mostly from increased lipoprotein synthesis, specifically that of triglyceride-rich VLDL1, the dyslipidemia of CKD, specifically of the apolipoprotein B (apoB)-containing lipoproteins, is characterized by reduced clearance.10 This may contribute to their increased atherogenicity, as long-lived lipoproteins are more subject to oxidation.11 VLDL is synthesized by the liver and chylomicrons by the intestines. They carry with them, among others, apoE and apoC-I through III (Figure 1). ApoE engages with a variety of receptors (VLDL receptor and the lipoprotein-like receptor (LRP), as well as enzymes, including LPL necessary for lipolysis.12 The levels of several lipoprotein receptors are reduced in CKD, 13 as is LPL, 12 combining to reduce the clearance of VLDL and IDL. However, decreased clearance of these lipoproteins is due not only to a reduction in LPL and receptor levels, but also to intrinsic defects in the capacity of lipoproteins harvested from CKD patients to act as appropriate substrates for lipolytic enzymes,14 providing yet a third mechanism prolonging the half-life of these lipoproteins. Dautin and co-workers15 (this issue) now address potentially correctable mechanisms responsible for this defect in lipoprotein structure. ApoC-I and C-III are both increased in CKD, and both apolipoproteins inhibit the interaction between these lipoproteins and their receptors.16 ApoE is a ligand effecting binding of TRLPs to the LRP, to the VLDL receptor, and to LPL. ApoC-I disrupts the interaction between apoE and lipoprotein receptors17 and is also a powerful inhibitor of LPL,18 reducing the activity of the already reduced levels of this enzyme. Thus dialysis patients face three hurdles in the path of clearance of TRLPs: reduced receptor numbers, inhibition of LPL, and competitive interference with binding of the lipoproteins to their sites of catabolism. 779
co mmentar y
Figure 1 | Very low-density lipoprotein (VLDL) is secreted by the liver and chylomicrons (CM) by the intestine, containing apolipoprotein E (apoE) and apoC-I, C-II, and C-III. Triglycerides are lipolized on the vascular endothelium by lipoprotein lipase (LPL) that is bound there to heparan sulfate proteoglycans (HSPG). CM remnants engage the lipoprotein-like receptor (LRP) through an apoE bridge and are taken up by the liver. VLDL remnants follow the same path or are converted into low-density lipoprotein (LDL) through interaction with high-density lipoprotein (HDL) by the enzyme cholesterol ester transfer protein (CETP) and are taken up by the LDL receptor. HDL is composed of apoA-I and apoA-II secreted by liver and gut and acquires cholesterol interacting with lipid-laden macrophages through the ATP-binding cassette A1 (ABCA1). The nascent β-migrating HDL is matured by action of lecithin cholesterol acyltransferase (LCAT) in a stepwise manner to the large HDL2 isoform that either is taken up by the liver, interacting with the HDL receptor (SR-B1), or transfers its core to the VLDL remnant, creating LDL and more rapidly metabolized small HDL3. In chronic kidney disease (CKD), expression of the LRP is reduced, LPL levels are reduced on the vascular endothelium, and apoC-I and C-III inhibit LPL activity as well as interaction between apoE and both the LRP and LPL. HDL maturation is impaired because of decreased levels of LCAT. Enzymes and pathways that are adversely affected in CKD are indicated in red. IDL, intermediate-density lipoprotein.
HDL levels are primarily established by the rate of HDL catabolism. This in turn is linked to HDL density or size. Renal failure is characterized by small HDL size and, in contrast to metabolism of the TRLPs, an increased catabolic rate.9 HDL maturation is impaired by low lecithin cholesterol acyltransferase (LCAT) activity in dialysis patients,19 yielding small dense rapidly catabolized β-migrating HDL. The final step in HDL maturation is an exchange of its cholesterol ester-rich core for triglycerides carried by VLDL remnants by cholesterol ester transfer protein (CETP) producing LDL and small dense α-migrating HDL3. Like β-migrating HDL, HDL3 is also catabolized at an increased rate, causing low HDL levels (Figure 1). ApoC-I inhibits CETP.20 Thus decreasing apoC-I levels could potentially result in an accelera780
tion of this reaction, such as occurs in the metabolic syndrome,9 causing a further decline in HDL in dialysis patients beyond that associated with reduced LCAT activity alone as a consequence of the removal of an endogenous CETP inhibitor. Thus removal of apoC-I could have an adverse effect. The low atomic mass of these apolipoproteins (apoC-I 6630.6 daltons and apoC-III 8765.7 daltons21) makes them potential targets for removal by dialysis. Dautin and co-workers15 have carefully established that dialysis selectively removes apoC-I from the VLDL pool, improving its capacity as a substrate for LPL, while not affecting the HDL apoC-I pool. This was possible because of the relationship of the duration of dialysis treatments to the relatively rapid half-life of VLDL (hours) as compared with that of HDL (days). This
suggests that dialysis is removing a labile apoC-I pool and that lipoprotein structure is changed by replacement of abnormally structured lipoproteins with newly formed normally structured isoforms during dialysis. CETP activity was also not increased, suggesting that it is the apoC-I delivered to this enzyme by HDL and not by the VLDL substrate that inhibits CETP activity. Fortunately, HDL metabolism was unaltered. After dialysis, VLDL was a better substrate for LPL than was VLDL obtained before dialysis, suggesting that VLDL obtained after dialysis was newly formed and that the uremia-associated alteration in the structure of VLDL that makes it a poor substrate for LPL is mediated by a substance that can be removed during dialysis, most likely apoC-I. The effect of dialysis on either the removal of or the level of IDL, the highly atherogenic remnants of both VLDL and chylomicron metabolism, was not explored; however, because the halflife of IDL is shorter than that of VLDL, any contribution of decreased apoC-I to the removal of IDL should also have been affected by dialysis. ApoC-I inhibits binding of β-migrating VLDL to the LRP22 and impairs the clearance of both VLDL and CM remnant particles. Additionally, hepatic LRP gene regulation is downregulated in CKD.13 Increased apoC-I levels in conjunction with decreased receptor numbers then provide a double defect conspiring to increase the levels of these atherogenic lipoproteins. Thus dialysis patients have a dual defect in that the enzymes necessary for catabolism of TRLPs are reduced while at the same time inhibitors of these enzymes and receptors found on the lipoprotein targets are increased. Dialysis appears to play a role in reducing at least one of these defects. Effective treatment strategies for reducing cardiovascular risk among dialysis patients have been elusive. The use of statins to reduce LDL cholesterol was of small and statistically insignificant benefit.23 ApoC-I levels returned to baseline by 24 hours; however, prolonged or daily dialysis might have the potential to normalize metabolism of the TRLPs and thus reduce cardiovascular risk. REFERENCES 1.
United States Renal Data System. 17th Annual Report. National Institutes of Health, National Kidney International (2007) 72
co m m e nt a r y
2.
3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13. 14.
15.
16.
17.
18.
Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA. Division of Kidney, Urologic, and Hematologic Diseases Annual, Data Report 2005, pp128–129. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1305. Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15: 458–482. Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 2002; 61: 1887–1893. Stompor T, Pasowicz M, Sullowicz W et al. An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis. Am J Kidney Dis 2003; 41: 203–211. Shoji T, Nishizawa Y, Kawagishi T et al. Intermediatedensity lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol 1998; 9: 1277–1284. Koch M, Kutkuhn B, Grabensee B, Ritz E. Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Transplant 1997; 12: 2603–2611. Okubo K, Ikewaki K, Sakai S et al. Abnormal HDL apolipoprotein A-I and A-II kinetics in hemodialysis patients: a stable isotope study. J Am Soc Nephrol 2004; 15: 1008–1015. Kaysen GA. Disorders in high-density metabolism with insulin resistance and chronic kidney disease. J Ren Nutr 2007; 17: 4–8. Ikewaki K, Schaefer JR, Frischmann ME et al. Delayed in vivo catabolism of intermediatedensity lipoprotein and low-density lipoprotein in hemodialysis patients as potential cause of premature atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: 2615–2622. Walzem RL, Watkins S, Frankel EN et al. Older plasma lipoproteins are more susceptible to oxidation: a linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease. Proc Natl Acad Sci USA 1995; 92: 7460–7464. Chan MK, Persaud J, Varghese Z, Moorhead JF. Pathogenic roles of post-heparin lipases in lipid abnormalities in hemodialysis patients. Kidney Int 1984; 25: 812–818. Kim C, Vaziri ND. Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure. Kidney Int 2005; 67: 1028–1032. Lee DM, Knight-Gibson C, Samuelsson O et al. Lipoprotein particle abnormalities and the impaired lipolysis in renal insufficiency. Kidney Int 2002; 61: 209–218. Dautin G, Soltani Z, Ducloux D et al. Hemodialysis reduces plasma apolipoprotein C-I concentration making VLDL a better substrate for lipoprotein lipase. Kidney Int 2007; 72: 871–878. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of beta-migrating very low density lipoproteins. J Lipid Res 1994; 35: 134–142. van der Hoogt CC, Berbee JF, Espirito et al. Apolipoprotein CI causes hypertriglyceridemia independent of the very-low-density lipoprotein receptor and apolipoprotein CIII in mice. Biochim Biophys Acta 2006; 1761: 213–220. Berbee JF, van der Hoogt CC, Sundararaman D et
Kidney International (2007) 72
al. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL. J Lipid Res 2005; 46: 297–306. 19. Mekki K, Bouchenak M, Remaoun M, Belleville JL. Effect of long-term hemodialysis on plasma lecithin: cholesterol acyltransferase activity and the amounts and compositions of HDL2 and HDL3 in hemodialysis-treated patients with chronic renal failure. A 9-year longitudinal study. Med Sci Monit 2004; 10: CR439–CR446. 20. Dumont L, Gautier T, de Barros JP et al. Molecular mechanism of the blockade of plasma cholesteryl ester transfer protein by its physiological inhibitor apolipoprotein CI. J Biol Chem 2005; 280: 38108–38116.
21. Bondarenko PV, Cockrill SL, Watkins LK et al. Mass spectral study of polymorphism of the apolipoproteins of very low density lipoprotein. J Lipid Res 1999; 40: 543–555. 22. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of beta-migrating very low density lipoproteins. J Lipid Res 1994; 35: 134–142. 23. Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238–248 [published erratum appears in N Engl J Med 2005; 353: 1640].
see original article on page 814
Hypertension in connexin40-null mice: a renin disorder DC Spray1 Studies described in this issue indicate that the gap junction protein connexin40 (Cx40) appears to play an unexpected role in blood pressure regulation. In mice lacking this gap junction protein, renin secretion is high and not regulated by arteriolar pressure. Kidney International (2007) 72, 781–782. doi:10.1038/sj.ki.5002515
Gap junction channels uniquely fulfill the vital role of providing a pathway for intercellular diffusion of ions and small molecules between coupled cell populations within a tissue. In chordates, these channels are formed by connexin proteins, a family of about 20 members in mammals, where expression of isoforms is cell type and tissue specific, with some overlap. The biophysical properties of channels formed by individual connexins vary, as do those of proteins that bind to the connexins; this presumably confers differences tuned to match the function that these channels serve in various tissues, such as second messenger exchange in the liver and perhaps astrocytes in the brain, electrical signal propagation in excitable systems such as the heart, brain, and 1Dominick P. Purpura Department of Neuroscience,
Albert Einstein College of Medicine, Bronx, New York, USA Correspondence: DC Spray, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, New York 10461, USA. E-mail: [email protected]
pancreatic islet, and metabolite exchange in the lens. Because of the tissue-specific distribution of connexins and the well-known exchange of ions and signaling molecules through them, connexin-null mice might have been expected to have well-predicted and perhaps quite restricted phenotypes. For example, the ventricles of mice lacking connexin43 (Cx43) might be expected to beat arrhythmically because of loss of the most abundant gap junction protein, the liver of Cx32-null mice might be dysfunctional because of lack of signaling between periportal and perivenous hepatocytes, and Cx50 knockouts might be expected to display cataracts. In fact, although these changes are seen to one extent or another as part of the overall mouse phenotype, the major changes in the animals are different, revealing hitherto unsuspected (and to some degree still not well understood) roles of the individual connexins in the animal. Cx43-null mice die at birth as a result of congenital malformation in the right ventricle, blocking outflow to the lung; Cx32-null mice display reduced peripheral myelination (now known to be the genetic 781