ANCA-associated vasculitis and atypical hemolytic uremic syndrome in a patient with DGKE mutation (Сlinical discussion)

We present a clinical case of a 34 years old female patient who simultaneously developed two rare conditions: microscopic polyangiitis and atypical hemolytic uremic syndrome (aHUS) associated with a polymorphism in diacylglycerol kinase-ε gene (DGKE), which seems to be the first case of aHUS associated with DGKE mutation in an adult patient. We suggest that the patient experienced chronic subclinical course of thrombotic microangiopathy (TMA) since adolescence, because persistent proteinuria and slowly progressive chronic kidney disease were first found when she was at the age of 13. She developed ANCA-associated vasculitis at the age of 34 with dialysis-dependent renal failure and alveolar hemorrhage that were accompanied by an acute episode of TMA. Treatment with high-dose of corticosteroids, cyclophosphamide and plasmapheresis was initiated. Alveolar hemorrhage have been resolved. However, severe hypertension, hemolytic anemia and thrombocytopenia persisted despite treatment. Plasma resistance was considered to be an indication for treatment with eculizumab, which proved to be beneficial. However, kidney function did not recover. Possible interactions between complement system, DGKE and their possible role in the pathogenesis of TMA are discussed

атипичный гемолитико-уремический синдром, тромботическая микроангиопатия, АНЦА-ассоциированный васкулит, микроскопический полиангиит, система комплемента, экулизумаб, диацлиглицеролакиназа-эпсилон, atypical hemolytic uremic syndrome, thrombotic microangiopathy, ANCA-associated vasculitis, microscopic polyangiitis, complement, eculizumab, diacylglycerol kinase-ε

1. Meri S. European Journal of Internal Medicine Complement activation in diseases presenting with thrombotic microangiopathy. Eur J Intern Med. 2013; 24(6): 496-502. doi:10.1016/j.ejim.2013.05.009

2. Chen M., Daha M.R., Kallenberg C.G.M. The complement system in systemic autoimmune disease. J Autoimmun. 2010; 34(3): J276-J286. doi:10.1016/j.jaut.2009.11.014

3. Jennette J.C. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003; 63(3): 1164-1177. doi:10.1046/ j.1523-1755.2003.00843.x.

4. Егорова Е.Т., Суханов А.В., Столяревич Е.С. и др. Гемодиализ-зависимая почечная недостаточность в дебюте нефропатий: нозологическая структура, клинико-морфологические корреляции, прогноз. Вестник трансплантологии и искусственных органов. 2007; (5): 20-26.

5. Jennette J.C., Falk R.J., Bacon P.A., et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013; 65(1): 1-11. doi:10.1002/art.37715

6. Бекетова Т.В. Микроскопический полиангиит, ассоциированный с антинейтрофильными цитоплазматическими антителами: особенности клинического течения. Терапевтический архив. 2015; 87(5): 33-46. doi: 10.17116/terarkh201587533-46

7. Villiger P.M., Guillevin L. Microscopic polyangiitis: Clinical presentation. Autoimmun Rev. 2010; 9(12): 812-819. doi:10.1016/j.autrev.2010.07.009

8. Бирюкова Л.С., Столяревич Е.С., Кальянова Е.В. и др. Опыт лечения быстропрогрессирующего гломерулонефрита при АНЦА-ассоциированном васкулите. Нефрология и диализ. 2013; 15(4): 306-307.

9. Томилина Н.А., Бирюкова Л.С., Фролова Н.Ф. и др. Клинико-морфологическая характеристика и прогноз разных гистоморфологических вариантов быстропрогрессирующего гломерулонефрита, ассоциированного с АНЦА-васкулитом. Нефрология и диализ. 2017; 19(4): 466-477. doi: 10.28996/ 1680-4422-2017-4-466-477

10. Буланов Н.М., Моисеев С.В., Новиков П.И. и др. Поражение почек при различных вариантах АНЦА-ассоциированного васкулита. Клиническая фармакология и терапия. 2016; 5: 23-29.

11. Falk R.J., Moore D.T., Hogan S.L., et al. A renal biopsy in essential for the management of ANCA-positive patients with glomerulonephritis. Sarcoidosis Vasc Diffuse Lung Dis. 1996; 13(3): 230-231.

12. Berden A.E., Ferrario F., Hagen E.C., et al. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010; 21(10): 1628-1636. doi:10.1681/ASN.2010050477

13. Kallenberg C.G.M. Pathogenesis of ANCA-associated vasculitides. Ann Rheum Dis. 2011; 70 Suppl 1: i59-63. doi:10.1136/ard.2010.138024

14. Novikov P., Smitienko I., Bulanov N., et al. Testing for antineutrophil cytoplasmic antibodies (ANCAs) in patients with systemic vasculitides and other diseases. Ann Rheum Dis. 2017; 76(8): e23. doi:10.1136/annrheumdis-2016-210890

15. Нефрология. Клинические рекомендации. Под ред. Шилова Е.М., Смирнова А.В., Козловской Н.Л. М.: ГЭОТАР-Медиа, 2016; 816 с.

16. Козловская Н.Л., Прокопенко Е.И., Эмирова Х.М. и др. Клинические рекомендации по диагностике и лечению атипичного гемолитико-уремического синдрома. Нефрология и диализ. 2015; 17(3): 242-264.

17. Lemaire M., Schaefer F., Tang W.H., et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013; 45(5): 531-536. doi:10.1038/ng.2590.Recessive

18. Bu F., Maga T., Meyer N.C., et al. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2014; 25(1): 55-64. doi:10.1681/ASN.2013050453

19. Jokiranta T.S. HUS and atypical HUS. Blood. 2017; 129(21): 2847-2856. doi:10.1182/blood-2016-11-709865

20. Shulga Y.V., Topham M.K., Epand R.M. Regulation and functions of diacylglycerol kinases. Chem Rev. 2011; 111(10): 6186-6208. doi:10.1021/cr1004106

21. Pettitt T.R., Martin A., Horton T., et al. Diacylglycerol and phosphatidate generated by phospholipases C and D, respectively, have distinct fatty acid compositions and functions. Phospholipase D-derived diacylglycerol does not activate protein kinase C in porcine aortic endothelial cells. J Biol Chem. 1997; 272(28): 17354-17359.

22. Carew M.A., Paleolog E.M., Pearson J.D. The roles of protein kinase C and intracellular Ca2+ in the secretion of von Willebrand factor from human vascular endothelial cells. Biochem J. 1992; 286 (Pt 2): 631-635.

23. Ren S., Shatadal S., Shen G.X. Protein kinase C-beta mediates lipoprotein-induced generation of PAI-1 from vascular endothelial cells. Am J Physiol Endocrinol Metab. 2000; 278(4): E656-62. doi:10.1152/ajpendo.2000.278.4.E656

24. Whatley R.E., Nelson P., Zimmerman G.A., et al. The regulation of platelet-activating factor production in endothelial cells. The role of calcium and protein kinase C. J Biol Chem. 1989; 264(11): 6325-6333.

25. Herbert J.M., Savi P., Laplace M.C., et al. Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells. Thromb Res. 1993; 71(6): 487-493.

26. Levin E.G., Marotti K.R., Santell L. Protein kinase C and the stimulation of tissue plasminogen activator release from human endothelial cells. Dependence on the elevation of messenger RNA. J Biol Chem. 1989; 264(27): 16030-16036

27. Offermanns S. Activation of Platelet Function Through G Protein-Coupled Receptors. Circ Res. 2006; 99(12): 1293-1304. doi:10.1161/01.RES.0000251742.71301.16

28. Yada Y., Ozeki T., Kanoh H., et al. Purification and characterization of cytosolic diacylglycerol kinases of human platelets. J Biol Chem. 1990; 265(31): 19237-19243.

29. Westland R., Bodria M., Carrea A., et al. Phenotypic expansion of DGKE-associated diseases. J Am Soc Nephrol. 2014; 25(7): 1408-1414. doi:10.1681/ASN.2013080886

30. Córdoba S.R. De, Tortajada A., Hidalgo M.S., et al. Genetics of Atypical Hemolytic Uremic Syndrome (aHUS). Semin Thromb Hemost. 2014; 40(4): 422-430. doi: 10.1055/s-0034-1375296

31. Ozaltin F., Li B., Rauhauser A., et al. DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN. 2017; 24(3): 377-384. doi:10.1681/ASN.2012090903

32. Muller Kobold A.C., van der Geld Y.M., Limburg P.C., et al. Pathophysiology of ANCA-associated glomerulonephritis. Nephrol Dial Transplant. 1999; 14(6): 1366-1375.

33. Savage C.O., Brooks C.J., Adu D., et al. Cell adhesion molecule expression within human glomerular and kidney organ culture. J Pathol. 1997; 181(1): 111-115. doi:10.1002/(SICI)1096-9896(199701)181:1<111:AID-PATH698>3.0.CO;2-9

34. Falk R.J., Terrell R.S., Charles L.A., et al. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990; 87(11): 4115-4119.

35. Radford D.J., Luu N.T., Hewins P., et al. Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells. Arthritis Rheum. 2001; 44(12): 2851-2861.

36. Xiao H., Schreiber A., Heeringa P., et al. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol. 2007; 170(1): 52-64. doi:10.2353/ajpath.2007.060573

37. Hao J., Meng L.-Q., Xu P.-C., et al. p38MAPK, ERK and PI3K Signaling Pathways Are Involved in C5a-Primed Neutrophils for ANCA-Mediated Activation. Arai K, ed. PLoS One. 2012; 7(5): e38317. doi:10.1371/journal.pone.0038317.

38. Hilhorst M., van Paassen P., van Rie H., et al. Complement in ANCA-associated glomerulonephritis. Nephrol Dial Transplant. 2017; 32(8): 1302-1313. doi: 10.1093/ndt/gfv288

39. Gou S.-J., Yuan J., Chen M., et al. Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int. 2013; 83(1): 129-137. doi:10.1038/ki.2012.313

40. Chen S.F., Wang H., Huang Y.M., et al. Clinicopathologic characteristics and outcomes of renal thrombotic microangiopathy in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis. Clin J Am Soc Nephrol. 2015; 10(5): 750-758. doi:10.2215/CJN.07910814

41. Schreiber A., Xiao H., Jennette J.C., et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol. 2009; 20(2): 289-298. doi:10.1681/ASN.2008050497

42. Jayne D.R.W., Bruchfeld A.N., Harper L., et al. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J Am Soc Nephrol. 2017; 28(9): 2756-2767. doi:10.1681/ASN.201611117

43. Novikov P., Kozlovskaya N., Moiseev S., et al. Therapeutic Complement Targeting in ANCA-Associated Vasculitides and Thrombotic Microangiopathy What Is It about? Biomed Hub. 2016; 1: 453106. doi:10.1159/000453106

44. Макаров Е.А., Новиков П.И., Шевцова Т.П. и др. Венозные тромбоэмболические осложнения при АНЦА-ассоциированных васкулитах. Клиническая фармакология и терапия. 2017; 26(3): 37-42.

45. Pagnoux C., Hogan S.L., Chin H., et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum. 2008; 58(9): 2908-2918. doi:10.1002/art.23800

46. Moiseev S., Novikov P., Jayne D., et al. End-stage renal disease in ANCA-associated vasculitis. Nephrol Dial Transplant. 2017; 32(20): 248-253. doi:10.1093/ndt/gfw046

47. Guillevin L., Pagnoux C., Karras A., et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014; 371(19): 1771-1780. doi:10.1056/NEJMoa1404231

48. Novikov P., Moiseev S., Bulanov N., et al. Bortezomib in refractory ANCA-associated vasculitis: a new option? Ann Rheum Dis. 2016; 75(1): e9. doi:10.1136/annrheumdis-2015-207947