Study of the possible relationship between early markers of renal damage and bleeding in patients with atrial fibrillation and chronic kidney disease on apixaban therapy

Background: patients with atrial fibrillation (AF) require prescription of an anticoagulant, although this therapy is associated with an increased risk of bleeding, the risk of which is increased in the presence of chronic kidney disease (CKD). Aim: to investigate the level of podocyt damage (nephrin) markers and tubulointerstitial renal tissue damage markers (neutrophil gelatinase-associated lipocalin, NGAL; kidney injury molecule-1, KIM-1, albuminuria level) in urine in patients with AF and CKD stages 3 and 4, receiving apixaban, depending on the presence of bleeding. Methods: 142 patients with AF and CKD stages 3 and 4, receiving apixaban therapy, 58-99 years old (median age 84 84 [76; 90] years) were included in the study. Retrospective and prospective assessment of hemorrhagic complications was performed. The urine levels of nephrin, NGAL, KIM-1, and albumin were determined. Results: during prospective follow-up, patients with AF and CKD stages 3-4 with bleeding had significantly higher urinary nephrin levels compared with patients without bleeding (1.1 [0.8; 1.4] ng/mL vs. 0.9 [0.6; 1.2] ng/mL, respectively; p=0.049). In a retrospective analysis, urinary nephrin levels did not significantly differ in the patients in the presence or absence of bleeding history. Urinary levels of albumin, KIM-1, and NGAL were not significantly different between subgroups with and without bleeding. Conclusion: The results of the study indicate that there is a relationship between the level of a marker of podocyt nephrin damage in urine and the presence of bleeding in patients with AF and CKD stages 3 and 4 receiving apixaban. It can be assumed that this association can be explained by the fact that nephrinuria, which reflects the severity of podocyte damage and correlates with albuminuria, thereby, indirectly reflects an increase in the permeability of glomerular capillaries due to endothelial damage due to protein loss in urine.

фибрилляция предсердий, хроническая болезнь почек, антикоагулянты, прямые оральные антикоагулянты, апиксабан, кровотечения, нефрин, липокалин, ассоциированный с желатиназой нейтрофилов, молекула первого типа почечного повреждения, atrial fibrillation, chronic kidney disease, anticoagulants, direct oral anticoagulants, apixaban, bleeding, nephrin, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1

1. Go A.S., Hylek E.M., Phillips K.A. et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001. 285(18):2370-5. doi:10.1001/jama.285.18.2370

2. Hindricks G., Potpara T., Dagres N. et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021. 42(5):373-498. doi:10.1093/eurheartj/ehaa612

3. Ruff C.T., Giugliano R.P., Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014. 383(9921):955-62. doi:10.1016/S0140-6736(13)62343-0

4. Ocak G., Khairoun M., Khairoun O. et al. Chronic kidney disease and atrial fibrillation: A dangerous combination. PLoS One. 2022. 17(4):e0266046. doi:10.1371/journal.pone.0266046

5. Arnson Y., Hoshen M., Berliner-Sendrey A.R. et al. Risk of Stroke, Bleeding, and Death in Patients with Nonvalvular Atrial Fibrillation and Chronic Kidney Disease. Cardiology. 2020. 145(3):178-186. doi:10.1159/000504877

6. Márquez D.F., Ruiz-Hurtado G., Segura J. et al. Microalbuminuria and cardiorenal risk: old and new evidence in different populations. F1000Res. 2019. 8:F1000 Faculty Rev-1659. doi:10.12688/f1000research.17212.1

7. Vassalotti J.A., Centor R., Turner B.J. et al. Practical Approach to Detection and Management of Chronic Kidney Disease for the Primary Care Clinician. Am J Med. 2016. 129(2):153-162.e7. doi:10.1016/j.amjmed.2015.08.025

8. Ocak G., Rookmaaker M.B., Algra A. et al. Chronic kidney disease and bleeding risk in patients at high cardiovascular risk: a cohort study. J Thromb Haemost. 2018. 16(1):65-73. doi:10.1111/jth.13904

9. Molnar A.O., Bota S.E., Garg A.X. et al. The Risk of Major Hemorrhage with CKD. J Am Soc Nephrol. 2016. 27(9):2825-32. doi:10.1681/ASN.2015050535

10. Hijazi Z., Granger C.B., Hohnloser S.H. et al. Association of Different Estimates of Renal Function With Cardiovascular Mortality and Bleeding in Atrial Fibrillation. J Am Heart Assoc. 2020. 9(18):e017155. doi:10.1161/JAHA.120.017155

11. Uwaezuoke SN. The role of novel biomarkers in predicting diabetic nephropathy: a review. Int J Nephrol Renovasc Dis. 2017. 10:221-231. doi:10.2147/IJNRD.S143186

12. Chen S., Chen X.C., Lou X.H. et al. Determination of serum neutrophil gelatinase-associated lipocalin as a prognostic biomarker of acute spontaneous intracerebral hemorrhage. Clin Chim Acta. 2019. 492:72-77. doi:0.1016/j.cca.2019.02.009

13. Bolignano D., Lacquaniti A., Coppolino G. et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009. 4(2):337-44. doi:10.2215/CJN.03530708

14. Bowman M., Mundell G., Grabell J. et al. Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost. 2008. 6(12):2062-6. doi:10.1111/j.1538-7836.2008.03182.x

15. Reinecke H., Nabauer M., Gerth A. et al. Morbidity and treatment in patients with atrial fibrillation and chronic kidney disease. Kidney Int. 2015. 87(1):200-9. doi:10.1038/ki.2014.195

16. Parada Barcia J.A., Raposeiras Roubin S., Abu-Assi E. et al. Comparison of Stroke and Bleeding Risk Profile in Patients With Atrial Fibrillation and Chronic Kidney Disease. Am J Cardiol. 2023. 196:31-37. doi:10.1016/j.amjcard.2023.03.018

17. Olesen J.B., Lip G.Y., Kamper A.L. et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012. 367(7):625-35. doi:10.1056/NEJMoa1105594

18. Martin C.E., Jones N. Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond. Front Endocrinol (Lausanne). 2018. 9:302. doi:10.3389/fendo.2018.00302

19. Kandasamy Y., Smith R., Lumbers E.R. et al. Nephrin - a biomarker of early glomerular injury. Biomark Res. 2014. 2:21. doi:10.1186/2050-7771-2-21

20. Dumont V., Tolvanen T.A., Kuusela S. et al. PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease. FASEB J. 2017. 31(9):3978-3990. doi:10.1096/fj.201601265R

21. Ni W.J., Tang L.Q., Wei W. Research progress in signalling pathway in diabetic nephropathy. Diabetes Metab Res Rev. 2015. 31(3):221-33. doi:10.1002/dmrr.2568

22. Kondapi K., Kumar N.L., Moorthy S. et al. A Study of Association of Urinary Nephrin with Albuminuria in Patients with Diabetic Nephropathy. Indian J Nephrol. 2021. 31(2):142-148. doi:10.4103/ijn.IJN_305_19

23. Kostovska I., Tosheska-Trajkovska K., Topuzovska S. et al. Urinary nephrin is earlier, more sensitive and specific marker of diabetic nephropathy than microalbuminuria. J Med Biochem. 2020. 39(1):83-90. doi:10.2478/jomb-2019-0026

24. Aucella F., De Bonis P., Gatta G. et al. Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis. Nephron Clin Pract. 2005. 99(2):c31-6. doi:10.1159/000082864

25. Huh W., Kim D.J., Kim M.K. et al. Expression of nephrin in acquired human glomerular disease. Nephrol Dial Transplant. 2002. 17(3):478-84. doi:10.1093/ndt/17.3.478

26. Al-Refai A.A., Tayel S.I., Ragheb A. et al. Urinary neutrophil gelatinase associated lipocalin as a marker of tubular damage in type 2 diabetic patients with and without albuminuria. Open J Nephrol. 2014. 4(1):37-46. doi:10.4236/ojneph.2014.41006

27. Mishra J., Dent C., Tarabishi R. et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005. 365(9466):1231-8. doi:10.1016/S0140-6736(05)74811-X

28. Hirsch R., Dent C., Pfriem H. et al. NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol. 2007. 22(12):2089-95. doi:10.1007/s00467-007-0601-4

29. Ling W., Zhaohui N., Ben H., Leyi G. et al. Urinary IL-18 and NGAL as early predictive biomarkers in contrast-induced nephropathy after coronary angiography. Nephron Clin Pract. 2008. 108(3):c176-81. doi:10.1159/000117814

30. Wheeler D.S., Devarajan P., Ma Q., Harmon K. et al. Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock. Crit Care Med. 2008. 36(4):1297-303. doi:10.1097/CCM.0b013e318169245a

31. Parikh C.R., Jani A., Mishra J. et al. Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant. 2006. 6(7):1639-45. doi:10.1111/j.1600-6143.2006.01352.x

32. Mori K., Nakao K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 2007. 71(10):967-70. doi:10.1038/sj.ki.5002165

33. Bolignano D., Coppolino G., Campo S. et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is associated with severity of renal disease in proteinuric patients. Nephrol Dial Transplant. 2008. 23(1):414-6. doi:10.1093/ndt/gfm541

34. Bolignano D., Lacquaniti A., Coppolino G. et al. Neutrophil gelatinase-associated lipocalin reflects the severity of renal impairment in subjects affected by chronic kidney disease. Kidney Blood Press Res. 2008. 31(4):255-8. doi:10.1159/000143726

35. Rennert P.D. Novel roles for TIM-1 in immunity and infection. Immunol Lett. 2011. 141(1):28-35. doi:10.1016/j.imlet.2011.08.003.

36. Ichimura T., Bonventre J.V., Bailly V. et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998. 273(7):4135-42. doi:10.1074/jbc.273.7.4135

37. Ichimura T., Asseldonk E.J., Humphreys B.D. et al. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest. 2008. 118(5):1657-68. doi:10.1172/JCI34487

38. Kuehn E.W., Park K.M., Somlo S. et al. Kidney injury molecule-1 expression in murine polycystic kidney disease. Am J Physiol Renal Physiol. 2002. 283(6):F1326-F1336. doi:10.1152/ajprenal.00166.2002

39. Schröppel B., Krüger B., Walsh L. et al. Tubular expression of KIM-1 does not predict delayed function after transplantation. J Am Soc Nephrol. 2010. 21(3):536-42. doi:10.1681/ASN.2009040390

40. Waanders F., Vaidya V.S., van Goor H. et al. Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial. Am J Kidney Dis. 2009. 53(1):16-25. doi:10.1053/j.ajkd.2008.07.021

41. Gardiner L., Akintola A., Chen G. et al. Structural equation modeling highlights the potential of Kim-1 as a biomarker for chronic kidney disease. Am J Nephrol. 2012. 35(2):152-63. doi:10.1159/000335579

42. Castillo-Rodriguez E., Fernandez-Prado R., Martin-Cleary C. et al. Kidney Injury Marker 1 and Neutrophil Gelatinase-Associated Lipocalin in Chronic Kidney Disease. Nephron. 2017. 136(4):263-267. doi:10.1159/000447649

43. Waikar S.S., Sabbisetti V., Ärnlöv J. et al. Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies. Nephrol Dial Transplant. 2016. 31(9):1460-70. doi:10.1093/ndt/gfw203

44. Carter J.L., Parker C.T., Stevens P.E. et al. Biological Variation of Plasma and Urinary Markers of Acute Kidney Injury in Patients with Chronic Kidney Disease. Clin Chem. 2016. 62(6):876-83. doi:10.1373/clinchem.2015.250993

45. Bellomo R., Kellum J.A., Ronco C. Defining acute renal failure: physiological principles. Intensive Care Med. 2004. 30(1):33-37. doi:10.1007/s00134-003-2078-3

46. Hijazi Z., Oldgren J., Lindbäck J. et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet. 2016. 387(10035):2302-2311. doi:10.1016/S0140-6736(16)00741-8

47. Pantoni L. Pathophysiology of age-related cerebral white matter changes. Cerebrovasc Dis. 2002. 13(Suppl 2):7-10. doi:10.1159/000049143

48. Cho A.H., Lee S.B., Han S.J. et al. Impaired kidney function and cerebral microbleeds in patients with acute ischemic stroke. Neurology. 2009. 73(20):1645-8. doi:10.1212/WNL.0b013e3181c1defa