Clin Exp Nephrol (2014) 18:234–237 DOI 10.1007/s10157-013-0875-8
REVIEW ARTICLE
WCN 2013 Satellite Symposium ‘‘Kidney and Lipids’’
Causes and consequences of lipoprotein(a) abnormalities in kidney disease Florian Kronenberg
Received: 23 August 2013 / Accepted: 18 September 2013 / Published online: 16 October 2013 Ó Japanese Society of Nephrology 2013
Abstract Lipoprotein(a) is one of the strongest genetically determined risk factors for cardiovascular disease, and patients with chronic kidney disease have major disturbances in lipoprotein(a) metabolism. Concentrations are increased and are influenced by glomerular filtration rate (GFR) and the amount of proteinuria. The reason for this elevation can be increased synthesis, as is the case for patients with nephrotic syndrome or those treated by peritoneal dialysis. In hemodialysis patients, a catabolic block is the reason for this elevation. The elevated concentrations might contribute to the tremendous cardiovascular risk in this particular population. In particular, the genetically determined small apolipoprotein(a) isoforms are associated with an increased risk for cardiovascular events and total mortality. Keywords Lipoprotein(a) Apolipoprotein(a) Genetics Chronic kidney disease Cardiovascular disease Risk factor
Introduction to lipoprotein(a) concentrations and apolipoprotein(a) polymorphism Lipoprotein(a) [Lp(a)] is one of the strongest genetically determined risk factors for cardiovascular disease (CVD) [1]. Lp(a) is produced in the liver and, besides a low-densitylipoprotein (LDL) particle, contains an additional apolipoprotein, apolipoprotein(a) [apo(a)]. This apolipoprotein
F. Kronenberg (&) Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Scho¨pfstr. 41, 6020 Innsbruck, Austria e-mail: [email protected]
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shows a high homology with plasminogen. It has a tremendous size heterogeneity, which is determined by a copynumber variation. This variation is the basis for a repeated number of so called kringle IV repeats (K-IV), which results in the apo(a) K-IV repeat polymorphism with from 11 to [50 K-IV repeats. Lp(a) is synthesized in the liver. The site and mechanism of catabolism is controversial: no receptor specific for Lp(a)/apo(a) has been described, but several observations point to a role of the kidney in Lp(a) removal. Plasma concentrations of Lp(a) show a 1,000-fold interindividual range from zero to[200 mg/dl. The distribution of Lp(a) is skewed in most populations: for example, most Europeans have concentrations \10 mg/dl, and only about 25 % have concentrations [30 mg/dl. There exists a pronounced inverse correlation between apo(a) isoform size (number of K-IV repeats) and Lp(a) concentrations. This K-IV size polymorphism of apo(a) explains about 20–80 % of Lp(a) concentration variability depending on ethnicity [2]. This polymorphism and other sequence variations of the apo(a) gene explain 70–90 % of Lp(a) concentration variability. There is no other lipoprotein known with such a pronounced genetic determination. The physiological function of Lp(a) remains unexplained. However, it is very well known that Lp(a) concentrations[30 mg/dl are associated with an increased risk for coronary heart disease (CHD) [3]. As apo(a) isoforms with a low number of K-IV repeats [small apo(a) isoforms with B22 K-IV repeats] are associated with high Lp(a) concentrations, carriers of small apo(a) isoforms have a more than twofold increased risk for CHD [4–7]. The frequency of these small isoforms is about 25–30 % in the general population. Therefore, this is clearly the strongest common genetic variation known to be associated with CHD [1].
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Recent data proposed that Lp(a) binds and transports proinflammatory oxidized phospholipids [8]. Several studies demonstrated a pronounced correlation between Lp(a) plasma concentrations and the content of oxidized phospholipids on apoB-100 particles (OxPL/apoB). Experimental data revealed that the vast majority of oxidized phospholipids are bound to Lp(a) in human plasma. Epidemiological studies showed that OxPL/apoB as well as Lp(a) predicts the development of cardiovascular events, and this association was independent of traditional CVD risk factors [9–11]. The close relationship of OxPL/apoB and Lp(a) in predicting cardiovascular events strongly supports the hypothesis that the atherogenicity of Lp(a) may, at least in part, be attributable to its ability to preferentially bind proinflammatory oxidized phospholipids compared with other apoB-containing lipoproteins [12].
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Fig. 1 Lipoprotein(a) [Lp(a)] concentration at various stages of kidney disease compared with the control group. Data are provided for patients with various stages of kidney impairment but not yet requiring renal replacement therapy; patients with nephrotic syndrome; and those requiring renal replacement therapy, such as hemodialysis (HD), continuous ambulatory peritoneal dialysis (CAPD), and renal transplantation (RTX). GFR glomerular filtration rate. Data from [16–18, 22, 25]. Figure adapted and reprinted from [1] (color figure online)
Lp(a) and kidney diseases Kidney impairment has a pronounced effect on Lp(a) concentrations. Observations made in various kidney disease groups support a role of the kidney for Lp(a) metabolism. Furthermore, a role of the kidney in Lp(a) catabolism is supported by arteriovenous differences in Lp(a) concentrations between arterial and renal veins, with lower concentrations in the vein [13], as well as by apo(a) fragments in urine [14, 15]. There exists a inverse association between the glomerular filtration rate (GFR) and Lp(a) concentrations (Fig. 1). Lp(a) levels begin to increase even in the earliest stages of kidney impairment, before GFR starts to decrease [16]. Interesting but still unexplained is the observation that this increase can only be observed in patients with large apo(a) isoforms when compared with isoform-matched controls but not for those with small apo(a) isoforms. This isoform-specific increase in Lp(a) was observed in several studies in patients with nonnephrotic kidney disease and those on hemodialysis (HD) [16–20]. In contrast, in nephrotic syndrome [21, 22] and continuous ambulatory peritoneal dialysis (CAPD) patients [18], tremendous increases in plasma Lp(a) levels occur in all apo(a) isoform groups. This observation points to pivotal differences for Lp(a) elevations in these patient groups. In vivo turnover studies using stable-isotope techniques elucidated these differences in HD patients [23] and patients with nephrotic syndrome [24] (Fig. 2). Patients with nephrotic syndrome showed no changes in fractional catabolic rate of Lp(a) but an increased synthesis rate of Lp(a) when compared with controls. This is in line with the generally increased synthesis of lipoproteins in nephrotic patients. In a completely opposite
manner, production rates of Lp(a) were normal in HD patients compared with controls with similar plasma Lp(a) concentrations [23]. Most interestingly, however, the fractional catabolic rate was significantly reduced. This resulted in an Lp(a) residence time in plasma of almost 9 days in HD patients compared with only 4.4 days in controls. This decreased clearance of Lp(a) results in increased Lp(a) plasma concentrations [23]. Obviously, the reason for increased Lp(a) concentrations in HD patients derives from a catabolic block, whereas the tremendously increased Lp(a) concentrations in nephrotic syndrome are the consequence of an increased synthesis in the liver, which is triggered by the pronounced protein loss in urine. Although no turnover studies were done in CAPD patients, it can be extrapolated that the reason for the markedly increased Lp(a) concentrations in these patients might also result from an increased Lp(a) production, which might again be caused by the pronounced loss of proteins via the peritoneum into the dialysate in the peritoneal cavity [18]. Lp(a) concentrations decrease following successful kidney transplantation (Fig. 1). In line with isoform-specific elevations described above, a decrease in Lp(a) can be observed in HD patients with large apo(a) isoforms [25, 26] and in CAPD patients in all apo(a) isoform groups [27]. In summary, the research from about 20 years demonstrates that Lp(a) elevation in cases of chronic kidney disease (CKD) is an acquired abnormality, mostly influenced by the impaired GFR and the degree of proteinuria. Some studies further suggest that the often observed malnutrition and inflammation in these patients additionally increases Lp(a) levels [19, 20].
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Fig. 2 Summary of in vivo turnover studies for lipoprotein(a) [Lp(a)] in patients with nephrotic syndrome and hemodialysis patients. For patients with nephrotic syndrome, kinetic parameters are provided for Lp(a); for hemodialysis patients, data are provided for apolipoprotein(a) levels in Lp(a). Each bar represents mean ± standard error. Data for patients with nephrotic syndrome are derived from [24]; those for hemodialysis patients are derived from [23] (color figure online)
Recent observations on Lp(a) and type 2 diabetes mellitus One of the most surprising results regarding Lp(a) in years was the study by Mora et al., in which they described an association of low Lp(a) concentrations with incident and prevalent type 2 diabetes mellitus (T2DM). This data came from the Women’s Health Study that assessed *27,000 women prospectively, followed for 13 years, and were confirmed in the Copenhagen City Heart Study. Women with Lp(a) levels in the lowest quintile (\4 mg/dl) had an 18 % higher risk for T2DM than those in quintiles 2–5 combined. The risk was especially increased in women with the lowest Lp(a) levels (\1 mg/dl). This small group of 2.6 % of the studied population had a 57 % higher risk for T2DM [28]. At that time, it was not clear whether the low Lp(a) concentrations are a cause or a consequence of T2DM [29]. Only very recently has further data from the Copenhagen City Heart Study and the Copenhagen General Population Study supported the causality of this association by applying a Mendelian randomization approach. The authors demonstrate that the highest quintile of the sum of the K-IV2 repeats from the two alleles is associated with T2DM. This quintile combines large isoforms and is associated with low and medium Lp(a) concentrations and therefore supports causality [30]. As we discussed recently, it will be important to search for further responsible genetic variants explaining, in particular, the very low Lp(a) levels and extending the analysis to a more granular T2DM subphenotyping [29].
Lp(a) concentrations, apo(a) isoforms, and CVD in kidney patients Several studies have investigated whether Lp(a) concentrations and/or apo(a) isoforms are a risk factor for CVD in
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patients with kidney disease. Early studies pointed to an association between high Lp(a) levels and CVD [31], which, however, was not unequivocally confirmed. Possible explanations for these contrasting findings were the skewed distribution of Lp(a) levels, which requires particular attention during data analysis; the nonstandardized assays especially used in earlier times; and the apo(a) isoform-specific elevation of Lp(a) in HD patients, as mentioned above and previously discussed extensively [18, 32]. Studies of apo(a) phenotyping besides Lp(a) concentration measurements consistently show an association between small apo(a) isoforms and CVD events (for review, see [33]). Two large, prospective studies—from Europe and the USA—report an increased risk for CVD events and total mortality for carriers of small apo(a) isoforms [32, 34, 35]. The European study followed 440 HD patients for 5 years and found a strong association between small apo(a) isoforms and severe coronary events. Plasma Lp(a) in those with clinical events showed only a trend toward elevated levels, which did not reach statistical significance [32]. The Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study from the USA reported small apo(a) isoforms but not Lp(a) concentrations to be associated with total mortality in an inception cohort of [800 incident dialysis patients who were followed for a median of almost 3 years [34]. In the same cohort, the authors observed for both small apo(a) isoforms and Lp(a) concentrations an association with cardiovascular events, and this association was stronger for small apo(a) isoforms [35].
Conclusions The kidney seems to play a major role in Lp(a) metabolism, resulting in pronounced changes of Lp(a) levels when kidney function is impaired. Elevated Lp(a) concentrations,
Clin Exp Nephrol (2014) 18:234–237
and the small apo(a) isoforms in particular, contribute to the increased risk for CVD in patients with CKD. Conflict of interest
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18.
The author has declared no competing interest.
References 1. Kronenberg F, Utermann G. Lipoprotein(a)—resurrected by genetics. J Intern Med. 2013;273:6–30. 2. Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C. Lp(a) glycoprotein phenotypes: inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest. 1987;80:458–65. 3. Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–23. 4. Sandholzer C, Saha N, Kark JD, et al. Apo(a) isoforms predict risk for coronary heart disease: a study in six populations. Arterioscler Thromb. 1992;12:1214–26. 5. Sandholzer C, Hallman DM, Saha N, et al. Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Hum Genet. 1991;86:607–14. 6. Kraft HG, Lingenhel A, Ko¨chl S, et al. Apolipoprotein(a) Kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol. 1996;16:713–9. 7. Erqou S, Thompson A, Di AE, et al. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol. 2010;55: 2160–7. 8. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipoprotein[a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49:2230–9. 9. Kiechl S, Willeit J, Mayr M, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol. 2007;27:1788–95. 10. Tsimikas S, Kiechl S, Willeit J, et al. Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck Study. J Am Coll Cardiol. 2006;47:2219–28. 11. Tsimikas S, Mallat Z, Talmud PJ, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events. J Am Coll Cardiol. 2010;56:946–55. 12. Tsimikas S, Witztum JL. The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity. Curr Opin Lipidol. 2008;19:369–77. 13. Kronenberg F, Trenkwalder E, Lingenhel A, et al. Renovascular arteriovenous differences in Lp(a) plasma concentrations suggest removal of Lp(a) from the renal circulation. J Lipid Res. 1997;38:1755–63. 14. Mooser V, Marcovina SM, White AL, Hobbs HH. Kringle-containing fragments of apolipoprotein(a) circulate in human plasma and are excreted into the urine. J Clin Invest. 1996;98:2414–24. 15. Kostner KM, Maurer G, Huber K, et al. Urinary excretion of apo(a) fragments. Role in apo(a) catabolism. Arterioscler Thromb Vasc Biol. 1996;16:905–11. 16. Kronenberg F, Kuen E, Ritz E, et al. Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol. 2000;11:105–15. 17. Dieplinger H, Lackner C, Kronenberg F, et al. Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal
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disease are not related to the size polymorphism of apolipoprotein(a). J Clin Invest. 1993;91:397–401. Kronenberg F, Ko¨nig P, Neyer U, et al. Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis. J Am Soc Nephrol. 1995;6:110–20. Stenvinkel P, Heimbu¨rger O, Tuck CH, Berglund L. Apo(a)isoform size, nutritional status and inflammatory markers in chronic renal failure. Kidney Int. 1998;53:1336–42. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 1999;55:648–58. Wanner C, Rader D, Bartens W, et al. Elevated plasma lipoprotein(a) in patients with the nephrotic syndrome. Ann Intern Med. 1993;119:263–9. Kronenberg F, Lingenhel A, Lhotta K, et al. The apolipoprotein(a) size polymorphism is associated with nephrotic syndrome. Kidney Int. 2004;65:606–12. Frischmann ME, Kronenberg F, Trenkwalder E, et al. In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients. Kidney Int. 2007;71:1036–43. De Sain-van der Velden MGM, Reijngoud DJ, Kaysen GA, et al. Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome. J Am Soc Nephrol. 1998;9:1474–81. Kronenberg F, Ko¨nig P, Lhotta K, et al. Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation. Arterioscler Thromb. 1994;14: 1399–404. Kronenberg F, Lhotta K, Ko¨nig P, Margreiter R, Dieplinger H, Utermann G. Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation. Eur J Hum Genet. 2003;11:693–9. Kerschdorfer L, Ko¨nig P, Neyer U, et al. Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up. Atherosclerosis. 1999;144: 381–91. Mora S, Kamstrup PR, Rifai N, Nordestgaard BG, Buring JE, Ridker PM. Lipoprotein(a) and risk of type 2 diabetes. Clin Chem. 2010;56:1252–60. Lamina C, Kronenberg F. The mysterious lipoprotein(a) is still good for a surprise. Lancet Diabetes Endocrinol. 2013. doi:10. 1016/S2213-8587(13)70085-8. Kamstrup PR, Nordestgaard BG. Lipoprotein(a) levels, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol. 2013. doi:10.1016/S22138587(13)70064-0. Cressman MD, Heyka RJ, Paganini EP, O’Neil J, Skibinski CI, Hoff HF. Lipoprotein(a) is an independent risk factor for cardiovascular disease in hemodialysis patients. Circulation. 1992;86:475–82. Kronenberg F, Neyer U, Lhotta K, et al. The low molecular weight apo(a) phenotype is an independent predictor for coronary artery disease in hemodialysis patients: a prospective follow-up. J Am Soc Nephrol. 1999;10:1027–36. Kwan BCH, Kronenberg F, Beddhu S, Cheung AK. Lipoprotein metabolism and lipid management in chronic kidney disease. J Am Soc Nephrol. 2007;18:1246–61. Longenecker JC, Klag MJ, Marcovina SM, et al. Small apolipoprotein(a) size predicts mortality in end-stage renal disease: the Choice Study. Circulation. 2002;106:2812–8. Longenecker JC, Klag MJ, Marcovina SM, et al. High lipoprotein(a) levels and small apolipoprotein(a) size prospectively predict cardiovascular events in dialysis patients. J Am Soc Nephrol. 2005;16:1794–802.
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REVIEW ARTICLE
WCN 2013 Satellite Symposium ‘‘Kidney and Lipids’’
Causes and consequences of lipoprotein(a) abnormalities in kidney disease Florian Kronenberg
Received: 23 August 2013 / Accepted: 18 September 2013 / Published online: 16 October 2013 Ó Japanese Society of Nephrology 2013
Abstract Lipoprotein(a) is one of the strongest genetically determined risk factors for cardiovascular disease, and patients with chronic kidney disease have major disturbances in lipoprotein(a) metabolism. Concentrations are increased and are influenced by glomerular filtration rate (GFR) and the amount of proteinuria. The reason for this elevation can be increased synthesis, as is the case for patients with nephrotic syndrome or those treated by peritoneal dialysis. In hemodialysis patients, a catabolic block is the reason for this elevation. The elevated concentrations might contribute to the tremendous cardiovascular risk in this particular population. In particular, the genetically determined small apolipoprotein(a) isoforms are associated with an increased risk for cardiovascular events and total mortality. Keywords Lipoprotein(a) Apolipoprotein(a) Genetics Chronic kidney disease Cardiovascular disease Risk factor
Introduction to lipoprotein(a) concentrations and apolipoprotein(a) polymorphism Lipoprotein(a) [Lp(a)] is one of the strongest genetically determined risk factors for cardiovascular disease (CVD) [1]. Lp(a) is produced in the liver and, besides a low-densitylipoprotein (LDL) particle, contains an additional apolipoprotein, apolipoprotein(a) [apo(a)]. This apolipoprotein
F. Kronenberg (&) Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Scho¨pfstr. 41, 6020 Innsbruck, Austria e-mail: [email protected]
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shows a high homology with plasminogen. It has a tremendous size heterogeneity, which is determined by a copynumber variation. This variation is the basis for a repeated number of so called kringle IV repeats (K-IV), which results in the apo(a) K-IV repeat polymorphism with from 11 to [50 K-IV repeats. Lp(a) is synthesized in the liver. The site and mechanism of catabolism is controversial: no receptor specific for Lp(a)/apo(a) has been described, but several observations point to a role of the kidney in Lp(a) removal. Plasma concentrations of Lp(a) show a 1,000-fold interindividual range from zero to[200 mg/dl. The distribution of Lp(a) is skewed in most populations: for example, most Europeans have concentrations \10 mg/dl, and only about 25 % have concentrations [30 mg/dl. There exists a pronounced inverse correlation between apo(a) isoform size (number of K-IV repeats) and Lp(a) concentrations. This K-IV size polymorphism of apo(a) explains about 20–80 % of Lp(a) concentration variability depending on ethnicity [2]. This polymorphism and other sequence variations of the apo(a) gene explain 70–90 % of Lp(a) concentration variability. There is no other lipoprotein known with such a pronounced genetic determination. The physiological function of Lp(a) remains unexplained. However, it is very well known that Lp(a) concentrations[30 mg/dl are associated with an increased risk for coronary heart disease (CHD) [3]. As apo(a) isoforms with a low number of K-IV repeats [small apo(a) isoforms with B22 K-IV repeats] are associated with high Lp(a) concentrations, carriers of small apo(a) isoforms have a more than twofold increased risk for CHD [4–7]. The frequency of these small isoforms is about 25–30 % in the general population. Therefore, this is clearly the strongest common genetic variation known to be associated with CHD [1].
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Recent data proposed that Lp(a) binds and transports proinflammatory oxidized phospholipids [8]. Several studies demonstrated a pronounced correlation between Lp(a) plasma concentrations and the content of oxidized phospholipids on apoB-100 particles (OxPL/apoB). Experimental data revealed that the vast majority of oxidized phospholipids are bound to Lp(a) in human plasma. Epidemiological studies showed that OxPL/apoB as well as Lp(a) predicts the development of cardiovascular events, and this association was independent of traditional CVD risk factors [9–11]. The close relationship of OxPL/apoB and Lp(a) in predicting cardiovascular events strongly supports the hypothesis that the atherogenicity of Lp(a) may, at least in part, be attributable to its ability to preferentially bind proinflammatory oxidized phospholipids compared with other apoB-containing lipoproteins [12].
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Fig. 1 Lipoprotein(a) [Lp(a)] concentration at various stages of kidney disease compared with the control group. Data are provided for patients with various stages of kidney impairment but not yet requiring renal replacement therapy; patients with nephrotic syndrome; and those requiring renal replacement therapy, such as hemodialysis (HD), continuous ambulatory peritoneal dialysis (CAPD), and renal transplantation (RTX). GFR glomerular filtration rate. Data from [16–18, 22, 25]. Figure adapted and reprinted from [1] (color figure online)
Lp(a) and kidney diseases Kidney impairment has a pronounced effect on Lp(a) concentrations. Observations made in various kidney disease groups support a role of the kidney for Lp(a) metabolism. Furthermore, a role of the kidney in Lp(a) catabolism is supported by arteriovenous differences in Lp(a) concentrations between arterial and renal veins, with lower concentrations in the vein [13], as well as by apo(a) fragments in urine [14, 15]. There exists a inverse association between the glomerular filtration rate (GFR) and Lp(a) concentrations (Fig. 1). Lp(a) levels begin to increase even in the earliest stages of kidney impairment, before GFR starts to decrease [16]. Interesting but still unexplained is the observation that this increase can only be observed in patients with large apo(a) isoforms when compared with isoform-matched controls but not for those with small apo(a) isoforms. This isoform-specific increase in Lp(a) was observed in several studies in patients with nonnephrotic kidney disease and those on hemodialysis (HD) [16–20]. In contrast, in nephrotic syndrome [21, 22] and continuous ambulatory peritoneal dialysis (CAPD) patients [18], tremendous increases in plasma Lp(a) levels occur in all apo(a) isoform groups. This observation points to pivotal differences for Lp(a) elevations in these patient groups. In vivo turnover studies using stable-isotope techniques elucidated these differences in HD patients [23] and patients with nephrotic syndrome [24] (Fig. 2). Patients with nephrotic syndrome showed no changes in fractional catabolic rate of Lp(a) but an increased synthesis rate of Lp(a) when compared with controls. This is in line with the generally increased synthesis of lipoproteins in nephrotic patients. In a completely opposite
manner, production rates of Lp(a) were normal in HD patients compared with controls with similar plasma Lp(a) concentrations [23]. Most interestingly, however, the fractional catabolic rate was significantly reduced. This resulted in an Lp(a) residence time in plasma of almost 9 days in HD patients compared with only 4.4 days in controls. This decreased clearance of Lp(a) results in increased Lp(a) plasma concentrations [23]. Obviously, the reason for increased Lp(a) concentrations in HD patients derives from a catabolic block, whereas the tremendously increased Lp(a) concentrations in nephrotic syndrome are the consequence of an increased synthesis in the liver, which is triggered by the pronounced protein loss in urine. Although no turnover studies were done in CAPD patients, it can be extrapolated that the reason for the markedly increased Lp(a) concentrations in these patients might also result from an increased Lp(a) production, which might again be caused by the pronounced loss of proteins via the peritoneum into the dialysate in the peritoneal cavity [18]. Lp(a) concentrations decrease following successful kidney transplantation (Fig. 1). In line with isoform-specific elevations described above, a decrease in Lp(a) can be observed in HD patients with large apo(a) isoforms [25, 26] and in CAPD patients in all apo(a) isoform groups [27]. In summary, the research from about 20 years demonstrates that Lp(a) elevation in cases of chronic kidney disease (CKD) is an acquired abnormality, mostly influenced by the impaired GFR and the degree of proteinuria. Some studies further suggest that the often observed malnutrition and inflammation in these patients additionally increases Lp(a) levels [19, 20].
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Fig. 2 Summary of in vivo turnover studies for lipoprotein(a) [Lp(a)] in patients with nephrotic syndrome and hemodialysis patients. For patients with nephrotic syndrome, kinetic parameters are provided for Lp(a); for hemodialysis patients, data are provided for apolipoprotein(a) levels in Lp(a). Each bar represents mean ± standard error. Data for patients with nephrotic syndrome are derived from [24]; those for hemodialysis patients are derived from [23] (color figure online)
Recent observations on Lp(a) and type 2 diabetes mellitus One of the most surprising results regarding Lp(a) in years was the study by Mora et al., in which they described an association of low Lp(a) concentrations with incident and prevalent type 2 diabetes mellitus (T2DM). This data came from the Women’s Health Study that assessed *27,000 women prospectively, followed for 13 years, and were confirmed in the Copenhagen City Heart Study. Women with Lp(a) levels in the lowest quintile (\4 mg/dl) had an 18 % higher risk for T2DM than those in quintiles 2–5 combined. The risk was especially increased in women with the lowest Lp(a) levels (\1 mg/dl). This small group of 2.6 % of the studied population had a 57 % higher risk for T2DM [28]. At that time, it was not clear whether the low Lp(a) concentrations are a cause or a consequence of T2DM [29]. Only very recently has further data from the Copenhagen City Heart Study and the Copenhagen General Population Study supported the causality of this association by applying a Mendelian randomization approach. The authors demonstrate that the highest quintile of the sum of the K-IV2 repeats from the two alleles is associated with T2DM. This quintile combines large isoforms and is associated with low and medium Lp(a) concentrations and therefore supports causality [30]. As we discussed recently, it will be important to search for further responsible genetic variants explaining, in particular, the very low Lp(a) levels and extending the analysis to a more granular T2DM subphenotyping [29].
Lp(a) concentrations, apo(a) isoforms, and CVD in kidney patients Several studies have investigated whether Lp(a) concentrations and/or apo(a) isoforms are a risk factor for CVD in
123
patients with kidney disease. Early studies pointed to an association between high Lp(a) levels and CVD [31], which, however, was not unequivocally confirmed. Possible explanations for these contrasting findings were the skewed distribution of Lp(a) levels, which requires particular attention during data analysis; the nonstandardized assays especially used in earlier times; and the apo(a) isoform-specific elevation of Lp(a) in HD patients, as mentioned above and previously discussed extensively [18, 32]. Studies of apo(a) phenotyping besides Lp(a) concentration measurements consistently show an association between small apo(a) isoforms and CVD events (for review, see [33]). Two large, prospective studies—from Europe and the USA—report an increased risk for CVD events and total mortality for carriers of small apo(a) isoforms [32, 34, 35]. The European study followed 440 HD patients for 5 years and found a strong association between small apo(a) isoforms and severe coronary events. Plasma Lp(a) in those with clinical events showed only a trend toward elevated levels, which did not reach statistical significance [32]. The Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study from the USA reported small apo(a) isoforms but not Lp(a) concentrations to be associated with total mortality in an inception cohort of [800 incident dialysis patients who were followed for a median of almost 3 years [34]. In the same cohort, the authors observed for both small apo(a) isoforms and Lp(a) concentrations an association with cardiovascular events, and this association was stronger for small apo(a) isoforms [35].
Conclusions The kidney seems to play a major role in Lp(a) metabolism, resulting in pronounced changes of Lp(a) levels when kidney function is impaired. Elevated Lp(a) concentrations,
Clin Exp Nephrol (2014) 18:234–237
and the small apo(a) isoforms in particular, contribute to the increased risk for CVD in patients with CKD. Conflict of interest
237
18.
The author has declared no competing interest.
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