cardiovascular events and vascular calcification in CKD Mathias - PowerPoint PPT Presentation

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 Mathias Haarhaus Karolinska Institutet and Diaverum Sweden

• Death 2,3 [1] Haarhaus, M, Brandenburg, V, Kalantar-Zadeh, K, et al. Nat Rev Nephrol, 2017;13:429-442. • Major adverse cardiovascular events 4,5 [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 • Myocardial infarction 6 Nephrol, 2010;5:1064-1071. [4] Oh, PC, Lee, K, Kim, TH, et al. PLoS One, 2017;12:e0171914. • Stroke 7 [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, • Cerebral small vessel disease 8 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. • Re-stenosis after coronary revascularization 9 [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. • Coronary slow flow phenomenon 10 [11] Chen, J, Mohler, ER, Xie, D, et al. Nephrol Dial Transplant, 2016;31:1145-1151. • Peripheral arterial disease 11 [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 • Improves CVD risk prediction models 12,13 Oct;50(15):828-834.

ALP isozymes and isoforms #Dephosphorylates different compounds #Four different ALP isozymes: N413 # tissue-nonspecific (TNALP) N213 # Intestinal (IALP) 3- PO 4 # Placenta (PlALP) N286 N123 # germ cell ALP (PALP) Ca Mg Zn1 N254 Zn2 #TNAP comprises > 90% of serum ALP. #BALP and LALP isoforms of TNALP are glycoproteins and differ only due to posttranslational glycosylation.

Origin of circulating ALP designed by Macrovector and Brgfx - Freepik.com

ALP – mechanisms of increased cardiovascular risk Vascular calcification Myocardial hypertrophy Fibrosis/fibrocalcification Oxidative stress/endothelial dysfunction Blood pressure control

ALP essential for biomineralization Hypophosphatasia (non-functional TNALP) Whyte MP et al. N Engl J Med 2012;366:904-913.

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

Serum BALP associated with abdominal aortic calcification in hemodialysis patients Higher serum BALP = more calcified aorta Characteristics p-value Mild calcification Moderate Severe calcification (AAC ≤ 4) n = 46 calcification (5 ≤ AAC (AAC ≥ 16) n = 38 ≤ 15) n = 72 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 0.21 (78.00 – 184.00) BMI, kg / m 2 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 < 0.01 CVD history, n (%) 6 (13.04) 42 (58.33) 28 (73.68) DM history, n (%) 15 (32.61) 25 (34.72) 13 (34.21) 0.33 BALP independent predictor of aortic calcification ALP, U / l 69.00 (56.00 – 90.00) 73.00 (57.75 – 95.75) 95.00 0.074 (60.25 – 123.00) < 0.01 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 Phosphorus, mmol / l 1.66 ± 0.60 1.80 ± 0.54 1.91 ± 0.69 0.021 iPTH, pg / ml 248.20 (84.30 – 269.60 (152.90 – 347.55 0.34 495.30) 494.30) (144.48 – 575.15) hsCRP, mg / l 2.25 (0.81 – 4.31) 3.31 (0.77 – 4.55) 5.87 (1.86 – 9.28) 0.028 < 0.01 BALP, μ g / l 17.30 (16.20 – 19.50) 19.80 (17.80 – 21.90) 21.40 (20.45 – 23.60) Biomark.Med. (2018) 12(11), 1231 – 1239

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.

ALP and inflammation PLoS ONE 11(6): e0157361

ALP increases in myocardial fibrosis

Elevated serum ALP in non-ischemic myocardial hypertrophy/fibrosis Serum ALP predicts perfusion-metabolism missmatch in incident hemodialysis patients Therapeutic Apheresis and Dialysis 2015; 19(6):575 – 581

4 months of exercise training in hemodialysis patients lowers ALP and oxidative stress Reduction from P baseline (%) TBARS 38 <0.05 ALP 27 <0.05 Nephrol Dial Transplant (2010) 25: 2695 – 2701

ALP contributes to blood pressure regulation Hypertension 2017;69:484-493 Hypertension. 2015;66:874-880

Apabetalone inhibits ALP and improves cardiovascular risk Haarhaus et al. Manuscript under review

Conclusions – ALP, a novel target for cardiovascular risk reduction In a variety of clinical conditions increased ALP determines cardiovascular risk ALP- related mechanisms of increased cardiovascular risk include vascular calcification, fibrosis, cardiac hypertrophy, oxidative stress, and inflammation Pharmacological inhibition of ALP improves cardiovascular risk profile and outcome Haarhaus, M. et al. (2017) Nat. Rev. Nephrol. doi:10.1038/nrneph.2017.60