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The role of ALP as predictor of cardiovascular events and vascular calcification in CKD Mathias Haarhaus, MD Stockholm, Sweden June 15, 2019 - Budapest, Hungary The role of ALP as predictor of CV events and vascular calcification in CKD

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The role of ALP as predictor of cardiovascular events and vascular calcification in CKD

Mathias Haarhaus, MD Stockholm, Sweden

June 15, 2019 - Budapest, Hungary

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The role of ALP as predictor of CV events and vascular calcification in CKD

Mathias Haarhaus

Karolinska Institutet and Diaverum Sweden

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Death 2,3
Major adverse cardiovascular events 4,5
Myocardial infarction 6
Stroke 7
Cerebral small vessel disease 8
Re-stenosis after coronary revascularization 9
Coronary slow flow phenomenon 10
Peripheral arterial disease 11
Improves CVD risk prediction models12,13

[1] Haarhaus, M, Brandenburg, V, Kalantar-Zadeh, K, et al. Nat Rev Nephrol, 2017;13:429-442. [2] Tonelli, M, Curhan, G, Pfeffer, M, et al. Circulation, 2009;120:1784-1792. [3] Abramowitz, M, Muntner, P, Coco, M, et al. Clin J Am Soc Nephrol, 2010;5:1064-1071. [4] Oh, PC, Lee, K, Kim, TH, et al. PLoS One, 2017;12:e0171914. [5] Huseynov, A, Baumann, S, Becher, T, et al. Eur J Clin Invest, 2016;46:721-729. [6] Iqbal, MP, Mehboobali, N, Azam, I, et al. Clin Chim Acta, 2013;425:192-195. [7] Ryu, WS, Lee, SH, Kim, CK, et al. Neurology, 2010;75:1995-2002. [8] Kim, J, Song, TJ, Song, D, et al. Stroke, 2013;44:3547-3549. [9] Park, JB, Kang, DY, Yang, HM, et al. Eur Heart J, 2013;34:920-931. [10] Wang, Y, Liu, MJ, Yang, HM, et al. BMC Cardiovasc Disord, 2018;18:138. [11] Chen, J, Mohler, ER, Xie, D, et al. Nephrol Dial Transplant, 2016;31:1145-1151. [12] Ndrepepa G, Xhepa E, Braun S et al. Eur J Clin Invest 2017; 47 (5): 378–387 [13] Ndrepepa G, Holdenrieder S, Xhepa E et al. Clin Biochem. 2017 Oct;50(15):828-834.

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ALP isozymes and isoforms

#Dephosphorylates different compounds #Four different ALP isozymes:

# tissue-nonspecific (TNALP) # Intestinal (IALP) # Placenta (PlALP) # germ cell ALP (PALP)

#TNAP comprises > 90% of serum ALP. #BALP and LALP isoforms of TNALP are glycoproteins and differ only due to posttranslational glycosylation.

N413 N213 N123 N286 N254

PO4

Ca Mg Zn1 Zn2

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Origin of circulating ALP

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ALP – mechanisms of increased cardiovascular risk

Vascular calcification Myocardial hypertrophy Fibrosis/fibrocalcification Oxidative stress/endothelial dysfunction Blood pressure control

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ALP essential for biomineralization

Hypophosphatasia (non-functional TNALP)

Whyte MP et al. N Engl J Med 2012;366:904-913.

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ALP in biomineralization

Haarhaus, M. et al. (2017) Nat. Rev. Nephrol. doi:10.1038/nrneph.2017.60

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Serum BALP associated with abdominal aortic calcification in hemodialysis patients

Characteristics Mild calcification (AAC ≤4) n = 46 Moderate calcification (5 ≤ AAC ≤15) n = 72 Severe calcification (AAC ≥16) n = 38 p-value Age, year 61.16 ± 10.41 62.28 ± 10.65 63.58 ± 11.07 0.53 Male, n (%) 28 (60.87) 44 (61.11) 24 (63.16) 0.91 Dialysis vintage, month 94.23 (58.53–181.00) 97.69 (72.78–152.56) 125.00 (78.00–184.00) 0.21 BMI, kg/m2 20.68 (19.22–23.53) 21.71 (19.34–24.23) 21.19 (19.48–24.03) 0.46 Kt/V 1.76 (1.52–1.91) 1.65 (1.48–1.86) 1.62 (1.39–1.92) 0.66 MABP, mmHg 89.47 ± 13.70 96.64 ± 14.54 99.12 ± 10.39 0.56 Smoke history, n (%) 19 (41.30) 26 (36.11) 17 (44.74) 0.17 CVD history, n (%) 6 (13.04) 42 (58.33) 28 (73.68) <0.01 DM history, n (%) 15 (32.61) 25 (34.72) 13 (34.21) 0.33 ALP, U/l 69.00 (56.00–90.00) 73.00 (57.75–95.75) 95.00 (60.25–123.00) 0.074 LDL, mmol/l 2.73 ± 0.80 3.18 ± 0.76 3.94 ± 0.89 <0.01 HDL, mmol/l 1.29 ± 0.32 1.18 ± 0.30 0.98 ± 0.32 <0.01 Phosphorus, mmol/l 1.66 ± 0.60 1.80 ± 0.54 1.91 ± 0.69 0.021 iPTH, pg/ml 248.20 (84.30– 495.30) 269.60 (152.90– 494.30) 347.55 (144.48–575.15) 0.34 hsCRP, mg/l 2.25 (0.81–4.31) 3.31 (0.77–4.55) 5.87 (1.86–9.28) 0.028 BALP, μg/l 17.30 (16.20–19.50) 19.80 (17.80–21.90) 21.40 (20.45–23.60) <0.01

Biomark.Med. (2018) 12(11), 1231–1239

BALP independent predictor of aortic calcification Higher serum BALP = more calcified aorta

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ALP expressing monocytes in atherosclerotic plaque

Circulating CD14+/BAP+/OCN+ cells Calcification r=0.55, p=0.006 Necrotic core r=0.53, p=0.010

Int J Cardiol. 2015 Feb 15;181:57-64.

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ALP and inflammation

PLoS ONE 11(6): e0157361

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ALP increases in myocardial fibrosis

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Elevated serum ALP in non-ischemic myocardial hypertrophy/fibrosis

Therapeutic Apheresis and Dialysis 2015; 19(6):575–581

Serum ALP predicts perfusion-metabolism missmatch in incident hemodialysis patients

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4 months of exercise training in hemodialysis patients lowers ALP and oxidative stress

Reduction from baseline (%) P TBARS 38 <0.05 ALP 27 <0.05

Nephrol Dial Transplant (2010) 25: 2695–2701

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ALP contributes to blood pressure regulation

Hypertension. 2015;66:874-880

Hypertension 2017;69:484-493

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Apabetalone inhibits ALP and improves cardiovascular risk

Haarhaus et al. Manuscript under review

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