Trombotik Mikroanjiyopatiler ve Böbrek
Özet
Trombotik Mikroanjiyopatiler (TMA); trombositopeni, mikroanjiyopatik hemolitik anemi (MAHA) ve akut böbrek hasarı (ABH) başta olmak üzere organ iskemisi ve disfonksiyonu ile karakterize ciddi hastalık gruplarıdır. Glomerüler dolaşımda endotel şişmesi, mezanjiyoliz ve damar tıkanıklığı gelişimi ABH'nin temel patofizyolojik mekanizmasını oluşturur. TMA'lar kalıtsal veya edinsel etkenlere göre primer ve sekonder başlıkları altında sınıflandırılır. TTP, von Willebrand faktör proteazı olan ADAMTS13 enzim düzeyinin %10'un altına düşmesi ve anti-ADAMTS13 otoantikorları ile tanımlanırken; hemolitik üremik sendromda (HÜS) ADAMTS13 düzeyleri normal seyreder. Kompleman aracılı atipik HÜS (aHÜS); alternatif kompleman yolundaki regülatör proteinlerin (CFH, CFI, CD46) mutasyonları veya faktör H otoantikorları sonucu kontrolsüz kompleman aktivasyonu ile meydana gelir. Sekonder TMA'lar arasında en sık görülen STEC-HÜS shiga toksini ile ilişkiliyken; pnömokoksik HÜS'te nöraminidaz siyalik asidi parçalar ve Coombs testi pozitif bulunur. Ayrıca gebelik, ilaçlar, nakil sonrası durumlar, malign hipertansiyon ve otoimmün hastalıklar da sekonder TMA'ya yol açabilir. Tedavide TTP tanısında ilk saatlerde plazma değişimi başlanmalı, immün aracılı vakalarda rituksimab ve steroitler eklenmelidir. Kompleman aracılı aHÜS'te C5 monoklonal antikoru olan eculizumab kullanımı belirgin iyileşme sağlayarak tedavide çığır açmıştır. Erken tanı, uygun destekleyici bakım ve spesifik tedavilerin hızlı şekilde uygulanması son dönem böbrek hastalığı ile mortalite riskini azaltmada hayati önem taşır.
Referanslar
George JN, Nester CM: Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371: 654–666.
Nester CM, Barbour T, de Cordoba SR, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship TH, Kavanagh D, Noris M, Pickering M, Sanchez-Corral P, Skerka C, Zipfel P, Smith RJ: Atypical aHUS: State of the art. Mol Immunol 2015; 67: 31–42
Scully M, Cataland S, Coppo P, de la Rubia J, Friedman KD, Kremer Hovinga J, Lammle B, Matsumoto M, Pavenski K, Sadler E, Sarode R,WuH; InternationalWorking Group for Thrombotic Thrombocytopenic Purpura: Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost 2017;15:312–322
Moschcowitz E: An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries; an undescribed disease. Am J Med 1952; 13: 567–9.
Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012; 158: 323–35.
Brocklebank V, Wood KM, Kavanagh D. Thrombotic microangiopathy and the kidney. Clin J Am Soc Nephrol 2018; 13: 300–17.
Goodship TH, Cook HT, Fakhouri F, Fervenza FC, FremeauxBacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodriguez de Cordoba S, Roumenina LT, Sethi S, Smith RJ; 14 Clinical Journal of the American Society of Nephrology Conference Participants: Atypical hemolytic uremic syndrome and C3 glomerulopathy: Conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) controversies conference. Kidney Int 2017; 91: 539–551.
El Karoui K, Hill GS, Karras A, Jacquot C, Moulonguet L, Kourilsky O, Fre´meaux-Bacchi V, Delahousse M, Duong Van Huyen JP, Loupy A, Bruneval P, Nochy D: A clinicopathologic study of thrombotic microangiopathy in IgA nephropathy. J Am Soc Nephrol 2012; 23: 137–148.
Phillips EH, Westwood JP, Brocklebank V, Wong EK, Tellez JO, Marchbank KJ, McGuckin S, Gale DP, Connolly J, Goodship TH, Kavanagh D, Scully MA. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J Thromb Haemost 2016; 14: 175–185.
Camilleri RS, Scully M, Thomas M, et al. A phenotype-genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom. J Thromb Haemost 2012; 10: 1792–801.
Thurman JM, Nester CM: All things complement. Clin J Am Soc Nephrol 2016; 11: 1856–1866.
Kavanagh D, Goodship TH, Richards A: Atypical hemolytic uremic syndrome. Semin Nephrol 2013; 33: 508–530.
Le Quintrec M, Zuber J, Moulin B, Kamar N, Jablonski M, Lionet A, Chatelet V,Mousson C,MouradG,Bridoux F,Cassuto E, Loirat C, Rondeau E, Delahousse M, Fre´meaux-Bacchi V: Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 2013; 13: 663–675.
Blanc C, Roumenina LT, AshrafY,Hyva¨rinen S, Sethi SK,Ranchin B, Niaudet P, Loirat C, Gulati A, Bagga A, Fridman WH, Saute`sFridman C, Jokiranta TS, Fre´meaux-Bacchi V, Dragon-Durey MA. Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome. J Immunol 2012; 189: 3528–3537.
Brocklebank V, Johnson S, Sheerin TP, Marks SD, Gilbert RD, Tyerman K, Kinoshita M, Awan A, Kaur A, Webb N, Hegde S, Finlay E, Fitzpatrick M, Walsh PR, Wong EKS, Booth C, Kerecuk L, Salama AD, Almond M, Inward C, Goodship TH, Sheerin NS, Marchbank KJ, Kavanagh D. Factor H: Autoantibody associated atypical haemolytic uraemic syndrome in children in the United Kingdom and Ireland Kidney Int doi:10.1016/j.kint.2017.04.028
Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G: Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010; 5: 1844–1859.
Greenbaum LA, Fila M, Ardissino G, Al-Akash SI, Evans J, Henning P, Lieberman KV, Maringhini S, Pape L, Rees L, van de Kar NC, Vande Walle J, Ogawa M, Bedrosian CL, Licht C: Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int 2016; 89: 701–711.
Fakhouri F, FilaM, Provoˆt F,DelmasY, Barbet C, Chaˆtelet V, Rafat C, Cailliez M, Hogan J, Servais A, Karras A, Makdassi R, Louillet F, Coindre JP, Rondeau E, Loirat C, Fre´meaux-Bacchi V. Pathogenic variants in complement genes and risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Clin J Am Soc Nephrol 2017; 12: 50–59.
Herlitz LC, Bomback AS, Markowitz GS, Stokes MB, Smith RN, ColvinRB,AppelGB,D’AgatiVD. Pathology after eculizumab in dense deposit disease and C3 GN. J Am Soc Nephrol 2012; 23: 1229– 1237.
Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN. Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood Adv 2017; 1: 590–600.
Bettoni G, Palla R, Valsecchi C, et al.: ADAMTS-13 activity and autoantibodies classes and subclasses as prognostic predictors in ac quired thrombotic thrombocytopenic purpura. J Thromb Haemost 2012; 10: 1556–65.
Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med 1991; 325: 393–7.
George JN: How I treat patients with thrombotic thrombocytopenic purpura. Blood 2010; 116: 4060–9
Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute ac quired thrombotic thrombocytopenic purpura. Blood 2011; 118: 1746–53.
Beck BB, van Spronsen F, Diepstra A, Berger RM, Komhoff M: Renal thrombotic microangiopathy in patients with cblC defect: Review of an under-recognized entity. Pediatr Nephrol 2017; 32: 733– 741.
Bruneau S, Ne´el M, Roumenina LT, Frimat M, Laurent L, Fre´meaux-Bacchi V, Fakhouri F: Loss of DGK induces endothelial cell activation and death independently of complement activation. Blood 2015; 125: 1038–1046.
DeschenesG, BaudouinV, LlanasB,CollardL,MajidMA,Simkova E, Nu¨rnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP: Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 2013; 45: 531–536.
Ozaltin F, Li B, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, IbsirliogluT,Korkmaz E, BilginerY, Duzova A,Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang C, Chen P, Lu D, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M: DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol 2013; 24: 377–384.
Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime´ F, DragonDurey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S,NiaudetP,DescheˆnesG,LebranchuY,ZuberJ, Loirat C. Genetics and outcome of atypical hemolytic uremic syndrome: A nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013; 8: 554–562.
Bu F, Maga T, Meyer NC, Wang K, Thomas CP, Nester CM, Smith RJ: Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2014; 25: 55–64.
Challis RC, Ring T, Xu Y, Wong EK, Flossmann O, Roberts IS, Ahmed S, Wetherall M, Salkus G, Brocklebank V, Fester J, Strain L, Wilson V, Wood KM, Marchbank KJ, Santibanez-Koref M, Goodship TH, Kavanagh D: Thrombotic microangiopathy in inverted formin 2-mediated renal disease. J Am Soc Nephrol 2017; 28: 1084–1091.
Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005 ;365: 1073–1086.
Brigotti M, Caprioli A, Tozzi AE, Tazzari PL, Ricci F, Conte R, Carnicelli D, Procaccino MA, Minelli F, Ferretti AV, Paglialonga F, Edefonti A, RizzoniG. Shiga toxins present in the gut and in the polymorphonuclear leukocytes circulating in the blood of children with hemolytic-uremic syndrome. J Clin Microbiol 2006; 44: 313–317.
Brandt JR, Fouser LS, Watkins SL, Zelikovic I, Tarr PI, NazarStewart V, Avner ED: Escherichia coli O 157:H7-associated hemolytic-uremic syndrome after ingestion of contaminated hamburgers. J Pediatr 125: 519–526, 1994
Brocklebank VKD. Complement C5 inhibiting therapy for the thrombotic microangiopathies: Accumulating evidence, but not a panacea. Clin Kidney J, 2017 Oct;10(5):600-624.
Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, Proulx F, Clermont MJ, Le Deist F. Niaudet P, Schaefer F. Eculizumab in severe Shiga-toxin associated HUS. N Engl J Med 2011 Jun 30;364(26):2561-3
Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr 2013; 25: 203–208.
Banerjee R, Hersh AL, Newland J, Beekmann SE, Polgreen PM, Bender J, Shaw J, Copelovitch L, Kaplan BS, Shah SS. Emerging Infections Network Hemolytic-Uremic Syndrome Study Group: Streptococcus pneumoniae-associated hemolytic uremic syndrome among children in North America. Pediatr Infect Dis J 2011; 30: 736–739.
Becker S, Fusco G, Fusco J, Balu R, Gangjee S, Brennan C, Feinberg J; Collaborations in HIVORUSC: HIV-associated thrombotic microangiopathy in the era of highly active antiretroviral therapy: An observational study. Clin Infect Dis 2004; 39 [Suppl 5]: S267–S275.
Nester CM, Barbour T, de Cordoba SR, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship TH, Kavanagh D, Noris M, Pickering M, Sanchez-Corral P, Skerka C, Zipfel P, Smith RJ: Atypical aHUS: State of the art. Mol Immunol 2015; 67: 31–42.
Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S,MonteferranteG, Fang CJ, Liszewski MK,Kavanagh D, Atkinson JP, Remuzzi G. International Registry of Recurrent and Familial HUS/TTP: Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006 ; 108: 1267–1279.
George JN, Nester CM, McIntosh JJ. Syndromes of thrombotic microangiopathy associated with pregnancy. Hematology (Am Soc Hematol Educ Program) 2015: 644–648.
Fakhouri F. Pregnancy-related thrombotic microangiopathies: Clues from complement biology. Transfus Apher Sci 2016; 54: 199– 202.
Scully M, Thomas M, Underwood M, Watson H, Langley K, CamilleriRS, Clark A, CreaghD,Rayment R,Mcdonald V,Roy A, Evans G, McGuckin S, Ni Ainle F, Maclean R, Lester W, Nash M, Scott R, O Brien P; collaborators of the UK TTP Registry: Thrombotic thrombocytopenic purpura and pregnancy: Presentation, management, and subsequent pregnancy outcomes. Blood 124: 211–219, 2014.
Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, Branch DW, Goodship T, Fremeaux-Bacchi V, Atkinson JP: Mutations in complement regulatory proteins predispose to preeclampsia: A genetic analysis of the PROMISSE cohort. PLoS Med 2011; 8: e1001013.
Gottschall JL, Elliot W, Lianos E, McFarland JG, Wolfmeyer K, Aster RH: Quinine-induced immune thrombocytopenia associated with hemolytic uremic syndrome: A new clinical entity. Blood 77: 306–310, 1991
Verbiest A, Pirenne J, Dierickx D: De novo thrombotic microangiopathy after non-renal solid organ transplantation. Blood Rev 2014; 28: 269–279.
Le Quintrec M, Lionet A, Kamar N, Karras A, Barbier S, Buchler M, Fakhouri F, Provost F, Fridman WH, Thervet E, Legendre C, Zuber J, Fre´meaux-Bacchi V: Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant 2008; 8: 1694–1701.
Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, Lane A, Meller J, Medvedovic M, Chen J, Davies SM: The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood 2016; 127: 989–996.
Van Laecke S, Van Biesen W. Severe hypertension with renal thrombotic microangiopathy: What happened to the usual suspect? Kidney Int 2017; 91: 1271–1274.
Timmermans SAMEG, Abdul-Hamid MA, Vanderlocht J, Damoiseaux JGMC, Reutelingsperger CP, van Paassen P; Limburg Renal Registry: Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities. Kidney Int 2017; 91: 1420–1425.
George JN. Systemic malignancies as a cause of unexpected microangiopathic hemolytic anemia and thrombocytopenia. Oncology (Williston Park) 2011; 25: 908–914.
Rodrı ´guez-Pinto´ I, Moitinho M, Santacreu I, Shoenfeld Y, Erkan D, Espinosa G, Cervera R; CAPS Registry Project Group (European Forumon Antiphospholipid Antibodies): Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of 500 patients from the international CAPS registry. Autoimmun Rev 2016; 15: 1120–1124.
