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BMC Cancer
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Chronic Kidney Disease | Research

Apolipoprotein A-IV concentrations and cancer in a large cohort of chronic kidney disease patients: results from the GCKD study

Authors: Barbara Kollerits, Simon Gruber, Inga Steinbrenner, Johannes P. Schwaiger, Hansi Weissensteiner, Sebastian Schönherr, Lukas Forer, Fruzsina Kotsis, Ulla T. Schultheiss, Heike Meiselbach, Christoph Wanner, Kai-Uwe Eckardt, Florian Kronenberg, for the GCKD Investigators

Published in: BMC Cancer | Issue 1/2024

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Abstract

Background

Chronic kidney disease (CKD) is highly connected to inflammation and oxidative stress. Both favour the development of cancer in CKD patients. Serum apolipoprotein A-IV (apoA-IV) concentrations are influenced by kidney function and are an early marker of kidney impairment. Besides others, it has antioxidant and anti-inflammatory properties. Proteomic studies and small case–control studies identified low apoA-IV as a biomarker for various forms of cancer; however, prospective studies are lacking. We therefore investigated whether serum apoA-IV is associated with cancer in the German Chronic Kidney Disease (GCKD) study.

Methods

These analyses include 5039 Caucasian patients from the prospective GCKD cohort study followed for 6.5 years. Main inclusion criteria were an eGFR of 30–60 mL/min/1.73m2 or an eGFR > 60 mL/min/1.73m2 in the presence of overt proteinuria.

Results

Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dL (median 27.6 mg/dL). 615 patients had a history of cancer before the enrolment into the study. ApoA-IV concentrations above the median were associated with a lower odds for a history of cancer (OR = 0.79, p = 0.02 when adjusted age, sex, smoking, diabetes, BMI, albuminuria, statin intake, and eGFRcreatinine). During follow-up 368 patients developed an incident cancer event and those with apoA-IV above the median had a lower risk (HR = 0.72, 95%CI 0.57–0.90, P = 0.004). Finally, 62 patients died from such an incident cancer event and each 10 mg/dL higher apoA-IV concentrations were associated with a lower risk for fatal cancer (HR = 0.62, 95%CI 0.44–0.88, P = 0.007).

Conclusions

Our data indicate an association of high apoA-IV concentrations with reduced frequencies of a history of cancer as well as incident fatal and non-fatal cancer events in a large cohort of patients with CKD.

Graphical Abstract

Appendix
Available only for authorised users
Literature
1.
Kalantar-Zadeh K, Jafar TH, Nitsch D, Neuen BL, Perkovic V. Chronic kidney disease. Lancet. 2021;398(10302):786–802.PubMedCrossRef
2.
Malyszko J, Tesarova P, Capasso G, Capasso A. The link between kidney disease and cancer: complications and treatment. Lancet. 2020;396(10246):277–87.PubMedCrossRef
3.
Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet. 2017;389(10075):1238–52.PubMedCrossRef
4.
Lees JS, Ho F, Parra-Soto S, Celis-Morales C, Welsh P, Sullivan MK, Jani BD, Sattar N, Lang NN, Pell JP, et al. Kidney function and cancer risk: an analysis using creatinine and cystatin C in a cohort study. EClinicalMedicine. 2021;38:101030.PubMedPubMedCentralCrossRef
5.
Jankowski J, Floege J, Fliser D, Bohm M, Marx N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation. 2021;143(11):1157–72.PubMedPubMedCentralCrossRef
6.
Crusz SM, Balkwill FR. Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol. 2015;12(10):584–96.PubMedCrossRef
7.
Amiri FS. Serum tumor markers in chronic kidney disease: as clinical tool in diagnosis, treatment and prognosis of cancers. Ren Fail. 2016;38(4):530–44.MathSciNetPubMedCrossRef
8.
Utermann G, Beisiegel U. Apolipoprotein A-IV: a protein occurring in human mesenteric lymph chylomicrons and free in plasma. Isolation and quantification. Eur J Biochem. 1979;99:333–43.PubMedCrossRef
9.
10.
11.
Ezeh B, Haiman M, Alber HF, Kunz B, Paulweber B, Kraft HG, Weidinger F, Pachinger O, Dieplinger H, Kronenberg F. Plasma distribution of apoA-IV in patients with coronary artery disease and healthy controls. J Lipid Res. 2003;44:1523–9.PubMedCrossRef
12.
Stein O, Stein Y, Lefevre M, Roheim PS. The role of apolipoprotein A-IV in reverse cholesterol transport studied with cultured cells and liposomes derived from another analog of phosphatidylcholine. Biochim Biophys Acta. 1986;878:7–13.PubMedCrossRef
13.
Kronenberg F. Apolipoprotein L1 and apolipoprotein A-IV and their association with kidney function. Curr Opin Lipidol. 2017;28:39–45.PubMedCrossRef
14.
Vowinkel T, Mori M, Krieglstein CF, Russell J, Saijo F, Bharwani S, Turnage RH, Davidson WS, Tso P, Granger DN, et al. Apolipoprotein A-IV inhibits experimental colitis. J Clin Invest. 2004;114:260–9.PubMedPubMedCentralCrossRef
15.
Recalde D, Ostos MA, Badell E, Garcia-Otin AL, Pidoux J, Castro G, Zakin MM, Scott-Algara D. Human apolipoprotein A-IV reduces secretion of proinflammatory cytokines and atherosclerotic effects of a chronic infection mimicked by lipopolysaccharide. Arterioscler Thromb Vasc Biol. 2004;24(4):756–61.PubMedCrossRef
16.
Xu XR, Wang Y, Adili R, Ju L, Spring CM, Jin JW, Yang H, Neves MAD, Chen P, Yang Y, et al. Apolipoprotein A-IV binds alphaIIbbeta3 integrin and inhibits thrombosis. Nat Commun. 2018;9:3608.ADSPubMedPubMedCentralCrossRef
17.
Haiman M, Salvenmoser W, Scheiber K, Lingenhel A, Rudolph C, Schmitz G, Kronenberg F, Dieplinger H. Immunohistochemical localization of apolipoprotein A-IV in human kidney tissue. Kidney Int. 2005;68:1130–6.PubMedCrossRef
18.
Stangl S, Kollerits B, Lamina C, Meisinger C, Huth C, Stoeckl A, Daehnhardt D, Boeger CA, Kraemer BK, Peters A, et al. Association between apolipoprotein A-IV concentrations and chronic kidney disease in two large population-based cohorts: results from the KORA studies. J Intern Med. 2015;278(4):410–23.PubMedCrossRef
19.
Boes E, Fliser D, Ritz E, König P, Lhotta K, Mann JFE, Müller GA, Neyer U, Riegel W, Riegler P, et al. Apolipoprotein A-IV predicts progression of chronic kidney disease: the mild to moderate kidney disease study. J Am Soc Nephrol. 2006;17:528–36.PubMedCrossRef
20.
Kronenberg F, Stühlinger M, Trenkwalder E, Geethanjali FS, Pachinger O, Von Eckardstein A, Dieplinger H. Low apolipoprotein A-IV plasma concentrations in men with coronary artery disease. J Am Coll Cardiol. 2000;36:751–7.PubMedCrossRef
21.
Li J, Song M, Qian D, Lu W, Wang J, Jiang G, Jin J, Wu X, Huang L. Decreased plasma apolipoprotein A-IV levels in patients with acute coronary syndrome. Clin Invest Med. 2013;36:E207–15.PubMedCrossRef
22.
Kollerits B, Krane V, Drechsler C, Lamina C, Maerz W, Ritz E, Wanner C, Kronenberg F. Apolipoprotein A-IV concentrations and clinical outcomes in haemodialysis patients with type 2 diabetes mellitus - a post hoc analysis of the 4D Study. J Intern Med. 2012;272(6):592–600.PubMedCrossRef
23.
Schwaiger JP, Kollerits B, Steinbrenner I, Weissensteiner H, Schonherr S, Forer L, Kotsis F, Lamina C, Schneider MP, Schultheiss UT, et al. Apolipoprotein A-IV concentrations and clinical outcomes in a large chronic kidney disease cohort: results from the GCKD study. J Intern Med. 2022;291(5):622–36.PubMedPubMedCentralCrossRef
24.
Dieplinger H, Ankerst DP, Burges A, Lenhard M, Lingenhel A, Fineder L, Buchner H, Stieber P. Afamin and apolipoprotein A-IV: novel protein markers for ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2009;18:1127–33.PubMedCrossRef
25.
Lorkova L, Pospisilova J, Lacheta J, Leahomschi S, Zivny J, Cibula D, Zivny J, Petrak J. Decreased concentrations of retinol-binding protein 4 in sera of epithelial ovarian cancer patients: a potential biomarker identified by proteomics. Oncol Rep. 2012;27(2):318–24.PubMed
26.
Timms JF, Arslan-Low E, Kabir M, Worthington J, Camuzeaux S, Sinclair J, Szaub J, Afrough B, Podust VN, Fourkala EO, et al. Discovery of serum biomarkers of ovarian cancer using complementary proteomic profiling strategies. Proteomics Clin Appl. 2014;8:982–93.PubMedPubMedCentralCrossRef
27.
Bharali D, Banerjee BD, Bharadwaj M, Husain SA, Kar P. Expression analysis of apolipoproteins AI & AIV in hepatocellular carcinoma: a protein-based hepatocellular carcinoma-associated study. Indian J Med Res. 2018;147(4):361–8.PubMedPubMedCentralCrossRef
28.
Abulaizi M, Tomonaga T, Satoh M, Sogawa K, Matsushita K, Kodera Y, Obul J, Takano S, Yoshitomi H, Miyazaki M, et al. The application of a three-step proteome analysis for identification of new biomarkers of pancreatic cancer. Int J Proteomics. 2011;2011:628787.PubMedPubMedCentralCrossRef
29.
Chang SC, Lin WL, Chang YF, Lee CT, Wu JS, Hsu PH, Chang CF. Glycoproteomic identification of novel plasma biomarkers for oral cancer. J Food Drug Anal. 2019;27(2):483–93.PubMedPubMedCentralCrossRef
30.
Farrokhi Yekta R, Arefi Oskouie A, Rezaei Tavirani M, Mohajeri-Tehrani MR, Soroush AR. Decreased apolipoprotein A4 and increased complement component 3 as potential markers for papillary thyroid carcinoma: a proteomic study. Int J Biol Markers. 2018;33(4):455–62.PubMedCrossRef
31.
Li D, Wu J, Liu Z, Qiu L, Zhang Y. Novel circulating protein biomarkers for thyroid cancer determined through data-independent acquisition mass spectrometry. PeerJ. 2020;8:e9507.PubMedPubMedCentralCrossRef
32.
Eckardt KU, Barthlein B, Baid-Agrawal S, Beck A, Busch M, Eitner F, Ekici AB, Floege J, Gefeller O, Haller H, et al. The German Chronic Kidney Disease (GCKD) study: design and methods. Nephrol Dial Transplant. 2012;27:1454–60.PubMedCrossRef
33.
Titze S, Schmid M, Kottgen A, Busch M, Floege J, Wanner C, Kronenberg F, Eckardt KU. Disease burden and risk profile in referred patients with moderate chronic kidney disease: composition of the German Chronic Kidney Disease (GCKD) cohort. Nephrol Dial Transplant. 2015;30:441–51.PubMedCrossRef
34.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, Kusek JW, Eggers P, Van LF, Greene T, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.PubMedPubMedCentralCrossRef
35.
Kronenberg F, Lobentanz E-M, König P, Utermann G, Dieplinger H. Effect of sample storage on the measurement of lipoprotein(a), apolipoproteins B and A-IV, total and high-density lipoprotein cholesterol and triglycerides. J Lipid Res. 1994;35:1318–28.PubMedCrossRef
36.
Kronenberg F, König P, Neyer U, Auinger M, Pribasnig A, Lang U, Reitinger J, Pinter G, Utermann G, Dieplinger H. 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.PubMedCrossRef
37.
Allin KH, Nordestgaard BG, Zacho J, Tybjaerg-Hansen A, Bojesen SE. C-reactive protein and the risk of cancer: a mendelian randomization study. J Natl Cancer Inst. 2010;102(3):202–6.PubMedCrossRef
38.
39.
Porta C, Bamias A, Danesh FR, Debska-Slizien A, Gallieni M, Gertz MA, Kielstein JT, Tesarova P, Wong G, Cheung M, et al. KDIGO controversies conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancer. Kidney Int. 2020;98(5):1108–19.PubMedCrossRef
40.
Lees JS, Elyan BMP, Herrmann SM, Lang NN, Jones RJ, Mark PB. The ‘other’ big complication: how chronic kidney disease impacts on cancer risks and outcomes. Nephrol Dial Transplant. 2023;38(5):1071–9.PubMedCrossRef
41.
42.
43.
44.
Ebert T, Neytchev O, Witasp A, Kublickiene K, Stenvinkel P, Shiels PG. Inflammation and oxidative stress in chronic kidney disease and dialysis patients. Antioxid Redox Signal. 2021;35(17):1426–48.PubMedCrossRef
45.
46.
Vidal-Vanaclocha F. Inflammation in the molecular pathogenesis of cancer and atherosclerosis. Reumatol Clin. 2009;5(Suppl 1):40–3.PubMedCrossRef
47.
48.
Masoudkabir F, Sarrafzadegan N, Gotay C, Ignaszewski A, Krahn AD, Davis MK, Franco C, Mani A. Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention. Atherosclerosis. 2017;263:343–51.PubMedPubMedCentralCrossRef
49.
Volovat SR, Volovat C, Miron I, Kanbay M, Goldsmith D, Lungulescu C, Badarau SC, Covic A. Oncogenic mechanisms in renal insufficiency. Clin Kidney J. 2021;14(2):507–15.PubMedCrossRef
50.
Spaulding HL, Saijo F, Turnage RH, Alexander JS, Aw TY, Kalogeris TJ. Apolipoprotein A-IV attenuates oxidant-induced apoptosis in mitotic competant, undifferentiated cells by modulating intracellular glutathione redox balance. Am J Physiol Cell Physiol. 2005;290:C95–103.PubMedCrossRef
51.
Satoh M. Endothelial dysfunction as an underlying pathophysiological condition of chronic kidney disease. Clin Exp Nephrol. 2012;16(4):518–21.PubMedCrossRef
52.
Malhab LJB, Saber-Ayad MM, Al-Hakm R, Nair VA, Paliogiannis P, Pintus G, Abdel-Rahman WM. Chronic inflammation and cancer: the role of endothelial dysfunction and vascular inflammation. Curr Pharm Des. 2021;27(18):2156–69.PubMedCrossRef
53.
Franses JW, Drosu NC, Gibson WJ, Chitalia VC, Edelman ER. Dysfunctional endothelial cells directly stimulate cancer inflammation and metastasis. Int J Cancer. 2013;133(6):1334–44.PubMedPubMedCentralCrossRef
54.
Duka A, Fotakis P, Georgiadou D, Kateifides A, Tzavlaki K, von Eckardstein L, Stratikos E, Kardassis D, Zannis VI. ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT. J Lipid Res. 2013;54(1):107–15.PubMedPubMedCentralCrossRef
55.
Ganjali S, Ricciuti B, Pirro M, Butler AE, Atkin SL, Banach M, Sahebkar A. High-density lipoprotein components and functionality in cancer: state-of-the-art. Trends Endocrinol Metab. 2019;30(1):12–24.PubMedCrossRef
56.
Cheung CYS, Parikh J, Farrell A, Lefebvre M, Summa-Sorgini C, Battistella M. Direct oral anticoagulant use in chronic kidney disease and dialysis patients with venous thromboembolism: a systematic review of thrombosis and bleeding outcomes. Ann Pharmacother. 2021;55(6):711–22.PubMedCrossRef
57.
Fernandes CJ, Morinaga LTK, Alves JL Jr, Castro MA, Calderaro D, Jardim CVP, Souza R. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev. 2019;28(151):180119.PubMedPubMedCentralCrossRef
58.
Peng H, Pan S, Yan Y, Brand RE, Petersen GM, Chari ST, Lai LA, Eng JK, Brentnall TA, Chen R. Systemic proteome alterations linked to early stage pancreatic cancer in diabetic patients. Cancers (Basel). 2020;12(6):1534.PubMedPubMedCentralCrossRef
59.
Nabeta R, Katselis GS, Chumala P, Dickinson R, Fernandez NJ, Meachem MD. Identification of potential plasma protein biomarkers for feline pancreatic carcinoma by liquid chromatography tandem mass spectrometry. Vet Comp Oncol. 2022;20(3):720–31.PubMedCrossRef
60.
Cohen RD, Castellani LW, Qiao JH, Van Lenten BJ, Lusis AJ, Reue K. Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV. J Clin Invest. 1997;99:1906–16.PubMedPubMedCentralCrossRef
61.
Duverger N, Tremp G, Caillaud JM, Emmanuel F, Castro G, Fruchart JC, Steinmetz A, Denèfle P. Protection against atherogenesis in mice mediated by human apolipoprotein A-IV. Science. 1996;273(5277):966–8.ADSPubMedCrossRef
Metadata
Title
Apolipoprotein A-IV concentrations and cancer in a large cohort of chronic kidney disease patients: results from the GCKD study
Authors
Barbara Kollerits
Simon Gruber
Inga Steinbrenner
Johannes P. Schwaiger
Hansi Weissensteiner
Sebastian Schönherr
Lukas Forer
Fruzsina Kotsis
Ulla T. Schultheiss
Heike Meiselbach
Christoph Wanner
Kai-Uwe Eckardt
Florian Kronenberg
for the GCKD Investigators
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-12053-8

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