Skip to main content

Advertisement

SpringerLink
Log in

PCSK9 in chronic kidney disease

  • Nephrology – Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Purpose

Chronic kidney disease (CKD) is accompanied by a number of secondary metabolic dysregulations, such as lipid abnormalities, presenting with unique characteristics. Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have been introduced as the new era in the management of dyslipidemia with promising results in groups with refractory lipid abnormalities. Increasing number of studies investigate the possible association of PCSK9 levels with kidney function, especially with nephrotic range proteinuria, as well as its role as a prognostic cardiovascular risk marker in CKD. In this review, we discuss the existing evidence for PCSK9 levels in patient groups with nephrotic syndrome, non-dialysis CKD, end-stage renal disease and kidney transplantation.

Methods

Online research was conducted in MEDLINE database to identify articles investigating PCSK9 in all different aspects of CKD. References from relevant studies were screened for supplementary articles.

Results

Four cross-sectional studies, one secondary analysis, one publication from two independent cohort studies and one multicentre prospective cohort study assessed PCSK9 plasma levels in different subgroups of CKD patients. PCSK9 levels increase in nephrotic syndrome and have a positive correlation with proteinuria. In CKD patients, no correlation was found between PCSK9 levels and estimated GFR. Peritoneal dialysis patients have higher PCSK9 levels compared with hemodialysis and renal transplant patients as well as general population.

Conclusion

Accumulative evidence focuses on the possible association of PCSK9 levels with kidney function. No data are available for the administration of PCSK9 inhibitors in CKD patients. Further research will optimize knowledge on the role of PCSK9 levels and PCSK9 inhibitors in CKD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Centers for Disease Control and Prevention (CDC) (2008) Chronic Kidney Disease Surveillance System—United States. Chronic Kidney Disease (CKD) Surveillance Project. https://nccd.cdc.gov/ckd/detail.aspx?Qnum=Q8. Accessed 19 March 2016

  2. United States Renal Data System (2014) USRDS annual data report: epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. Survey NE, Protection P, Act AC. Chapter 3 : Morbidity and Mortality. https://www.usrds.org/2014/view/v1_03.aspx Accesed 15 April 2015

  3. Herzog CA, Asinger RW, Berger AK, Charytan DM, Díez J, Hart RG et al (2011) Cardiovascular disease in chronic kidney disease. A clinical update from kidney disease: improving global outcomes (KDIGO). Kidney Int 80(6):572–586. doi:10.1038/ki.2011.223

    Article  PubMed  Google Scholar 

  4. Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lameire N (2005) Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant 20(6):1048–1056. doi:10.1093/ndt/gfh813

    Article  CAS  PubMed  Google Scholar 

  5. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351(13):1296–1305. doi:10.1056/NEJMoa041031

    Article  CAS  PubMed  Google Scholar 

  6. Magnus P, Beaglehole R (2010) The real contribution of the major risk factors to the coronary epidemics. Arch Intern Med 161(22):2657 (American Medical Association)

    Article  Google Scholar 

  7. Sarnak MJ, Coronado BE, Greene T, Wang SR, Kusek JW, Beck GJ et al (2002) Cardiovascular disease risk factors in chronic renal insufficiency. Clin Nephrol 57(5):327–335

    Article  CAS  PubMed  Google Scholar 

  8. Weiner DE, Tighiouart H, Elsayed EF, Griffith JL, Salem DN, Levey AS et al (2007) The Framingham predictive instrument in chronic kidney disease. J Am Coll Cardiol 50(3):217–224. doi:10.1016/j.jacc.2007.03.037

    Article  PubMed  Google Scholar 

  9. Park S-H, Stenvinkel P, Lindholm B (2012) Cardiovascular biomarkers in chronic kidney disease. J Ren Nutr 22(1):120–127. doi:10.1053/j.jrn.2011.10.021

    Article  CAS  PubMed  Google Scholar 

  10. Tsimihodimos V, Dounousi E, Siamopoulos KC (2008) Dyslipidemia in chronic kidney disease: an approach to pathogenesis and treatment. Am J Nephrol 28(6):958–973. doi:10.1159/000144024

    Article  CAS  PubMed  Google Scholar 

  11. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C et al (2011) The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377(9784):2181–2192. doi:10.1016/S0140-6736(11)60739-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J et al (2009) Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 360(14):1395–1407. doi:10.1056/NEJMoa0810177

    Article  PubMed  Google Scholar 

  13. Krane V, Schmidt K-R, Gutjahr-Lengsfeld LJ, Mann JFE, März W, Swoboda F et al (2016) Long-term effects following 4 years of randomized treatment with atorvastatin in patients with type 2 diabetes mellitus on hemodialysis. Kidney Int 637:1–8. doi:10.1016/j.kint.2015.12.033

    Google Scholar 

  14. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S et al (2003) The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 100(3):928–933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Farnier M (2014) PCSK9: from discovery to therapeutic applications. Arch Cardiovasc Dis 107(1):58–66. doi:10.1016/j.acvd.2013.10.007

    Article  PubMed  Google Scholar 

  16. Denegri A, Petrova-Slater I, Pasotti E, Rossi MG, Pedrazzini GB, Moccetti T et al (2016) PCSK9 inhibitors: an overview on a new promising lipid-lowering therapy. J Cardiovasc Med (Hagerstown) 17(4):237–244. doi:10.2459/JCM.0000000000000360

    Article  CAS  Google Scholar 

  17. Giugliano RP, Sabatine MS (2015) Are PCSK9 inhibitors the next breakthrough in the cardiovascular field? J Am Coll Cardiol 65(24):2638–2651. doi:10.1016/j.jacc.2015.05.001

    Article  CAS  PubMed  Google Scholar 

  18. Shimada YJ, Cannon CP (2015) PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future. Eur Heart J 36(36):2415–2424. doi:10.1093/eurheartj/ehv174

    Article  PubMed  Google Scholar 

  19. Lipari MT, Li W, Moran P, Kong-Beltran M, Sai T, Lai J et al (2012) Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels. J Biol Chem 287(52):43482–43491. doi:10.1074/jbc.M112.380618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tavori H, Rashid S, Fazio S (2015) On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects. Atherosclerosis 238(2):264–270. doi:10.1016/j.atherosclerosis.2014.12.017

    Article  CAS  PubMed  Google Scholar 

  21. Han B, Eacho PI, Knierman MD, Troutt JS, Konrad RJ, Yu X et al (2014) Isolation and characterization of the circulating truncated form of PCSK9. J Lipid Res 55(7):1505–1514. doi:10.1194/jlr.M049346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang D-W, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD et al (2007) Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 282(25):18602–18612. doi:10.1074/jbc.M702027200

    Article  CAS  PubMed  Google Scholar 

  23. Fisher TS, Lo Surdo P, Pandit S, Mattu M, Santoro JC, Wisniewski D et al (2007) Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation. J Biol Chem 282(28):20502–20512. doi:10.1074/jbc.M701634200t

    Article  CAS  PubMed  Google Scholar 

  24. Roubtsova A, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A, Lazure C et al (2011) Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler Thromb Vasc Biol 31(4):785–791. doi:10.1161/ATVBAHA.110.220988

    Article  CAS  PubMed  Google Scholar 

  25. Seidah NG, Awan Z, Chrétien M, Mbikay M (2014) PCSK9: a key modulator of cardiovascular health. Circ Res 114(6):1022–1036. doi:10.1161/CIRCRESAHA.114.301621

    Article  CAS  PubMed  Google Scholar 

  26. Abifadel M, Varret M, Rabès J-P, Allard D, Ouguerram K, Devillers M et al (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34(2):154–156. doi:10.1038/ng1161

    Article  CAS  PubMed  Google Scholar 

  27. Abifadel M, Guerin M, Benjannet S, Rabès JP, Le Goff W, Julia Z et al (2012) Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Atherosclerosis 223(2):394–400. doi:10.1016/j.atherosclerosis.2012.04.006.6

    Article  CAS  PubMed  Google Scholar 

  28. Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC et al (2006) A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 78(3):410–422. doi:10.1086/500615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37(2):161–165. doi:10.1038/ng1509

    Article  CAS  PubMed  Google Scholar 

  30. Le May C, Kourimate S, Langhi C, Chétiveaux M, Jarry A, Comera C et al (2009) Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol 29(5):684–690. doi:10.1161/ATVBAHA.108.181586

    Article  PubMed  Google Scholar 

  31. Tremblay AJ, Lamarche B, Lemelin V, Hoos L, Benjannet S, Seidah NG et al (2010) Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men. J Lipid Res 52(3):558–565. doi:10.1194/jlr.M011080

    Article  PubMed  Google Scholar 

  32. Mayne J, Dewpura T, Raymond A, Cousins M, Chaplin A, Lahey KA et al (2008) Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis 7(1):22. doi:10.1186/1476-511X-7-22

    Article  PubMed  PubMed Central  Google Scholar 

  33. Davignon J, Dubuc G (2009) Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc 120:163–173

    PubMed  PubMed Central  Google Scholar 

  34. Leander K, Mälarstig A, van’t Hooft FM, Hyde C, Hellénius M-L, Troutt JS et al (2016) Circulating PCSK9 predicts future risk of cardiovascular events independently of established risk factors. Circulation 133(13):1230–1239. doi:10.1161/CIRCULATIONAHA.115.018531

    Article  CAS  PubMed  Google Scholar 

  35. Ridker PM, Rifai N, Bradwin G, Rose L (2015) Plasma proprotein convertase subtilisin/kexin type 9 levels and the risk of first cardiovascular events. Eur Heart J 37(6):554–560. doi:10.1093/eurheartj/ehv568

    Article  PubMed  PubMed Central  Google Scholar 

  36. Werner C, Hoffmann MM, Winkler K, Böhm M, Laufs U (2014) Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment. Vasc Pharmacol 62(2):94–102. doi:10.1016/j.vph.2014.03.004

    Article  CAS  Google Scholar 

  37. Press Announcements—FDA approves Praluent to treat certain patients with high cholesterol (2015) U.S. Food and Drug Administration http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Accessed 11 Oct 2015

  38. Press Announcements—FDA approves Repatha to treat certain patients with high cholesterol (2015) U.S. Food and Drug Administration http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm. Accessed 11 Oct 2015

  39. European Medicines Agency—Repatha http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003766/human_med_001890.jsp&mid=WC0b01ac058001d124. Accessed 5 June 2016

  40. European Medicines Agency—Praluent http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003882/humanmed001915.jsp&mid=WC0b01ac058001d124. Accessed 5 June 2016

  41. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R et al (2014) Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY Outcomes trial. Am Heart J 168(5):682–689. doi:10.1016/j.ahj.2014.07.028

    Article  CAS  PubMed  Google Scholar 

  42. Sabatine MS, Giugliano RP, Keech A, Honarpour N, Wang H, Liu T et al (2015) Rationale and design of the further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER) trial. Am Heart J 173:94–101. doi:10.1016/j.ahj.2015.11.015.69

    Article  PubMed  Google Scholar 

  43. Study of the Safety and Efficacy of REGN727/SAR236553 in Patients With HeFH Hypercholesterolemia ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01266876. Accessed 5 June 2016

  44. Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) in Patients With Primary Hypercholesterolemia on Stable Atorvastatin Therapy ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01288443. Accessed 5 June 2016

  45. Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) When Co-administered With High Dose of Atorvastatin in Patients With Primary Hypercholesterolemia ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01288469. Accessed 5 June 2016

  46. LAPLACE-TIMI 57: Low-density lipoprotein cholesterol (LDL-C) Assessment with PCSK9 monoclonaL antibody inhibition combined with statin thErapy. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01380730. Accessed 5 Jun 2016

  47. Monoclonal antibody against PCSK9 to reduce elevated low-density lipoprotein cholesterol (ldl-c) in adults currently not receiving drug therapy for easing lipid levels. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01375777. Accessed 5 June 2016

  48. Reduction of low-density lipoprotein cholesterol (LDL-C) with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder study. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01375751. Accessed 5 June 2016

  49. Goal achievement after utilizing an anti-pcsk9 antibody in statin intolerant subjects. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01375764. Accessed 5 June 2016

  50. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ et al (2015) Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol 9(6):758–769. doi:10.1016/j.jacl.2015.08.006

    Article  PubMed  Google Scholar 

  51. Robinson JG, Colhoun HM, Bays HE, Jones PH, Du Y, Hanotin C et al (2014) Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies. Clin Cardiol 37(10):597–604. doi:10.1002/clc.22327

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U et al (2015) Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J 169(6):906–915. doi:10.1016/j.ahj.2015.03.004

    Article  CAS  PubMed  Google Scholar 

  53. Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R et al (2015) Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J 36(19):1186–1194. doi:10.1093/eurheartj/ehv028

    Article  PubMed  PubMed Central  Google Scholar 

  54. Study to evaluate the efficacy and safety of an every four weeks treatment regimen of alirocumab (REGN727/SAR236553) in patients with primary hypercholesterolemia (ODYSSEY CHOICE 1). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01926782. Accessed 5 June 2016

  55. Kastelein JJP, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R et al (2015) ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 36(43):2996–3003. doi:10.1093/eurheartj/ehv370

    PubMed  PubMed Central  Google Scholar 

  56. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J et al (2014) Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 63(23):2531–2540. doi:10.1016/j.jacc.2014.03.018

    Article  CAS  PubMed  Google Scholar 

  57. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF et al (2014) Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 63(23):2541–2548. doi:10.1016/j.jacc.2014.03.019

    Article  CAS  PubMed  Google Scholar 

  58. Robinson JG, Rogers WJ, Nedergaard BS, Fialkow J, Neutel JM, Ramstad D et al (2014) Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy. Clin Cardiol 37(4):195–203. doi:10.1002/clc.22252

    Article  PubMed  Google Scholar 

  59. GLobal assessment of plaque regression with a PCSK9 antibody as measured by intravascular ultrasound. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01813422. Accessed 5 June 2016

  60. Trial evaluating PCSK9 antibody in subjects with LDL receptor abnormalities.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01588496. Accessed 5 June 2016

  61. Trial assessing long term use of PCSK9 inhibition in subjects with genetic LDL disorders. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01624142. Accessed 5 June 2016

  62. Study of low-density lipoprotein cholesterol (LDL-C) reduction using evolocumab (AMG 145) in Japanese patients with advanced cardiovascular risk. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01953328. Accessed 5 June 2016

  63. A 52 week study to assess the use of bococizumab (PF-04950615; RN316) in subjects with heterozygous familial hypercholesterolemia. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01968980. Accessed 5 June 2016

  64. Randomized clinical trial of bococizumab (PF-04950615; RN316) in subjects with hyperlipidemia or mixed dyslipidemia at risk of cardiovascular events. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01968954. Accessed 5 June 2016

  65. Kwan BCH, Kronenberg F, Beddhu S, Cheung AK (2007) Lipoprotein metabolism and lipid management in chronic kidney disease. J Am Soc Nephrol 18(4):1246–1261. doi:10.1681/ASN.2006091006

    Article  CAS  PubMed  Google Scholar 

  66. Vaziri ND, Moradi H (2006) Mechanisms of dyslipidemia of chronic renal failure. Hemodial Int 10(1):1–7. doi:10.1111/j.1542-4758.2006.01168.x

    Article  PubMed  Google Scholar 

  67. Vlagopoulos PT, Sarnak MJ (2005) Traditional and nontraditional cardiovascular risk factors in chronic kidney disease. Med Clin North Am 89(3):587–611. doi:10.1016/j.mcna.2004.11.003

    Article  PubMed  Google Scholar 

  68. Vaziri ND (2016) Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences. Kidney Int 90(1):41–52. doi:10.1016/j.kint.2016.02.026

    Article  CAS  PubMed  Google Scholar 

  69. Vaziri ND (2016) HDL abnormalities in nephrotic syndrome and chronic kidney disease. Nat Rev Nephrol 12(1):37–47. doi:10.1038/nrneph.2015.180

    Article  CAS  PubMed  Google Scholar 

  70. Kronenberg F, Utermann G (2013) Lipoprotein(a): resurrected by genetics. J Intern Med 273(1):6–30. doi:10.1111/j.1365-2796.2012.02592.x

    Article  CAS  PubMed  Google Scholar 

  71. Saeedi R, Frohlich J (2016) Lipoprotein (a), an independent cardiovascular risk marker. Clin Diabetes Endocrinol 2(1):7. doi:10.1186/s40842-016-0024

    Article  Google Scholar 

  72. Filippas-Ntekouan S, Elisaf MS (2016) Pathophysiological mechanisms of dyslipidemia in patients with nephrotic syndrome: a fresh look. Hell J Atheroscler 7(3):102–110

    Google Scholar 

  73. Haas ME, Levenson AE, Sun X, Liao W-H, Rutkowski JM, de Ferranti SD et al (2016) The role of proprotein convertase Subtilisin/Kexin type 9 in nephrotic syndrome-associated hypercholesterolemia. Circulation 134(1):61–72. doi:10.1161/CIRCULATIONAHA.115.020912

    Article  CAS  PubMed  Google Scholar 

  74. Luc G, Bard J-M, Arveiler D, Ferrieres J, Evans A, Amouyel P et al (2002) Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study. Atherosclerosis 163(2):377–384

    Article  CAS  PubMed  Google Scholar 

  75. Ashfaq F, Goel PK, Sethi R, Khan MI, Ali W, Idris MZ (2013) Lipoprotein (a) levels in relation to severity of coronary artery disease in North Indian patients. Heart Views 14(1):12–16. doi:10.4103/1995-705X.107114

    Article  PubMed  PubMed Central  Google Scholar 

  76. Kronenberg F, Lhotta K, König P, Margreiter R, Dieplinger H, Utermann G (2003) Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation. Eur J Hum Genet 11(9):693–699. doi:10.1038/sj.ejhg.5201016

    Article  CAS  PubMed  Google Scholar 

  77. Kronenberg F (2014) Causes and consequences of lipoprotein(a) abnormalities in kidney disease. Clin Exp Nephrol 18(2):234–237. doi:10.1007/s10157-013-0875-8

    Article  CAS  PubMed  Google Scholar 

  78. Kronenberg F, Trenkwalder E, Lingenhel a, Friedrich G, Lhotta K, Schober M et al (1997) Renovascular arteriovenous differences in Lp[a] plasma concentrations suggest removal of Lp[a] from the renal circulation. J Lipid Res 38(9):1755–1763

    CAS  PubMed  Google Scholar 

  79. Lin J, Khetarpal SA, Terembula K, Reilly MP, Wilson FP (2015) Relation of atherogenic lipoproteins with estimated glomerular filtration rate decline: a longitudinal study. BMC Nephrol 16:130. doi:10.1186/s12882-015-0122-5

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kidney Disease Outcomes Qualitive Initiative (K/DOQI) Group (2003) K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 41(4 Suppl 3):I–IV (S1–91)

    Google Scholar 

  81. Tonelli M, Wanner C (2014) Lipid management in chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2013 clinical practice guideline. Ann Intern Med 160(3):182–189. doi:10.7326/M13-245358

    Article  PubMed  Google Scholar 

  82. Treatment Trialists C (2016) Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol 8587(16):1–11. doi:10.1016/S2213-8587

    Google Scholar 

  83. Wong MG, Perkovic V (2016) Knowing what we do not know: statin therapy in advanced chronic kidney disease. Lancet Diabetes Endocrinol 8587(16):9–10. doi:10.1016/S2213-8587(16)30192-9

    Google Scholar 

  84. Holdaas H, Fellstrom B, Jardine AG, Holme I, Nyberg G, Fauchald P et al (2003) Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 361(9374):2024–2031. doi:10.1016/S0140-6736(03)13638-0

    Article  CAS  PubMed  Google Scholar 

  85. Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Perkovic V, Hegbrant J et al (2014) HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane database Syst Rev 31(5):CD007784. doi:10.1002/14651858.CD007784.pub2

    Google Scholar 

  86. Kwakernaak AJ, Lambert G, Slagman MCJ, Waanders F, Laverman GD, Petrides F et al (2013) Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment. Atherosclerosis 226(2):459–465. doi:10.1016/j.atherosclerosis.2012.11.009

    Article  CAS  PubMed  Google Scholar 

  87. Jin K, Park BS, Kim YW, Vaziri ND (2014) Plasma PCSK9 in nephrotic syndrome and in peritoneal dialysis: a cross-sectional study. Am J Kidney Dis 63(4):584–589. doi:10.1053/j.ajkd.2013.10.042

    Article  CAS  PubMed  Google Scholar 

  88. Konarzewski M, Szolkiewicz M, Sucajtys-Szulc E, Blaszak J, Lizakowski S, Swierczynski J et al (2014) Elevated circulating PCSK-9 concentration in renal failure patients is corrected by renal replacement therapy. Am J Nephrol 40(2):157–163. doi:10.1159/000365935

    Article  CAS  PubMed  Google Scholar 

  89. Abujrad H, Mayne J, Ruzicka M, Cousins M, Raymond a, Cheesman J et al (2014) Chronic kidney disease on hemodialysis is associated with decreased serum PCSK9 levels. Atherosclerosis 233(1):123–129. doi:10.1016/j.atherosclerosis.2013.12.030

    Article  CAS  PubMed  Google Scholar 

  90. Rogacev KS, Heine GH, Silbernagel G, Kleber ME, Seiler S, Emrich I et al (2016) PCSK9 plasma concentrations are independent of GFR and do not predict cardiovascular events in patients with decreased GFR. PLoS ONE 11(1):e0146920. doi:10.1371/journal.pone.0146920

    Article  PubMed  PubMed Central  Google Scholar 

  91. Elewa U, Fernández-Fernández B, Mahillo-Fernández I, Martin-Cleary C, Sanz AB, Sanchez-Niño MD, Ortiz A (2016) PCSK9 in diabetic kidney disease. Eur J Clin Invest 46(9):779–786. doi:10.1111/eci.12661

    Article  CAS  PubMed  Google Scholar 

  92. Grefhorst A, McNutt MC, Lagace TA, Horton JD (2008) Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J Lipid Res 49(6):1303–1311. doi:10.1194/jlr.M800027-JLR200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Schmidt RJ, Beyer TP, Bensch WR, Qian Y-W, Lin A, Kowala M et al (2008) Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo. Biochem Biophys Res Commun 370(4):634–640. doi:10.1016/j.bbrc.2008.04.004

    Article  CAS  PubMed  Google Scholar 

  94. National Kidney Foundation. A clinical update on dialyzer membranes state-of-the-art considerations for optimal care in hemodialysis. natl kidney found. https://www.kidney.org/sites/default/files/02-10-6050_FBD_Clinical_bulletin.pdf. Accessed 13 Oct 2015

  95. Karkar A (2013) In: Hiromichi Suzuki (ed) Advances in Hemodialysis Techniques. InTech. doi:10.5772/52444

  96. Tsimihodimos V, Mitrogianni Z, Elisaf M (2011) Dyslipidemia associated with chronic kidney disease. Open Cardiovasc Med J 5(Vldl):41–48. doi:10.2174/1874192401105010041

    Article  PubMed  PubMed Central  Google Scholar 

  97. Johansson AC, Samuelsson O, Attman PO, Haraldsson B, Moberly J, Knight-Gibson C, Alaupovic P (2000) Dyslipidemia in peritoneal dialysis—relation to dialytic variables. Perit Dial Int 20(3):306–314

    CAS  PubMed  Google Scholar 

  98. Kronenberg F, Lingenhel A, Neyer U, Lhotta K, König P, Auinger M et al (2003) Prevalence of dyslipidemic risk factors in hemodialysis and CAPD patients. Kidney Int Suppl 63(84):S113–S116. doi:10.1046/j.1523-1755.63.s84.23.x

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nephrology, Medical School, University of Ioannina, 45 110, Ioannina, Greece

    P. Pavlakou & E. Dounousi

  2. Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece

    E. Liberopoulos & M. Elisaf

Authors
  1. P. Pavlakou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Liberopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Dounousi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Elisaf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Dounousi.

Ethics declarations

Conflict of interest

Authors have no conflict of interest relevant to this article to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pavlakou, P., Liberopoulos, E., Dounousi, E. et al. PCSK9 in chronic kidney disease. Int Urol Nephrol 49, 1015–1024 (2017). https://doi.org/10.1007/s11255-017-1505-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-017-1505-2

Keywords

Search

Navigation