Recurrent and de novo TTP-HUS after renal transplantation
- Christina L Klein, MD
Christina L Klein, MD
- Transplant Nephrologist
- Piedmont Transplant Institute
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Washington University School of Medicine
Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal impairment. There are multiple different etiologies for TTP-HUS. (See "Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults".)
TTP-HUS may result in end-stage renal disease (ESRD), requiring either dialytic therapy or transplantation. Among patients with ESRD due to TTP-HUS who undergo transplantation, the risk of recurrence depends upon the underlying etiology. Less commonly, patients who undergo renal transplantation for other causes of ESRD may also develop TTP-HUS; this is termed de novo TTP-HUS.
This topic reviews recurrent and de novo TTP-HUS in renal transplant recipients. The causes, diagnosis, and treatment of TTP-HUS in the non-transplant patient are discussed elsewhere. (See "Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults" and "Diagnosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults" and "Treatment and prognosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndromes in adults".)
Most cases of TTP-HUS in the non-transplant population, particularly among children, are secondary to infection with Shiga toxin-producing Escherichia coli serotypes and Streptococcus pneumoniae. Other causes include human immunodeficiency virus (HIV), pregnancy, cancer, and medications (eg, antiplatelet agents ticlopidine and clopidogrel, chemotherapeutic agents, and immunosuppressive drugs used in organ transplantation such as calcineurin inhibitors and mechanistic target of rapamycin [mTOR] inhibitors) (table 1). Rarely, HUS is caused by genetic defects in complement proteins that regulate the alternative pathway, leading to dysregulated complement activation. These mutations may be familial or sporadic. (See "Complement-mediated hemolytic uremic syndrome".)
TTP-HUS that occurs in the transplant recipient may be recurrent or de novo. De novo TTP-HUS may have any of the underlying etiologies, like TTP-HUS in the general population, or be related to the transplantation. Causes of TTP-HUS that are common among transplant recipients include immunosuppressive drugs [1,2], ischemia reperfusion injury , and viral infections [4-7]. (See 'Epidemiology' below.)
- Zarifian A, Meleg-Smith S, O'donovan R, et al. Cyclosporine-associated thrombotic microangiopathy in renal allografts. Kidney Int 1999; 55:2457.
- Ruggenenti P. Post-transplant hemolytic-uremic syndrome. Kidney Int 2002; 62:1093.
- Kwon O, Hong SM, Sutton TA, Temm CJ. Preservation of peritubular capillary endothelial integrity and increasing pericytes may be critical to recovery from postischemic acute kidney injury. Am J Physiol Renal Physiol 2008; 295:F351.
- Murer L, Zacchello G, Bianchi D, et al. Thrombotic microangiopathy associated with parvovirus B 19 infection after renal transplantation. J Am Soc Nephrol 2000; 11:1132.
- Waiser J, Budde K, Rudolph B, et al. De novo hemolytic uremic syndrome postrenal transplant after cytomegalovirus infection. Am J Kidney Dis 1999; 34:556.
- Olie KH, Goodship TH, Verlaak R, et al. Posttransplantation cytomegalovirus-induced recurrence of atypical hemolytic uremic syndrome associated with a factor H mutation: successful treatment with intensive plasma exchanges and ganciclovir. Am J Kidney Dis 2005; 45:e12.
- Ardalan MR, Shoja MM, Tubbs RS, et al. Postrenal transplant hemophagocytic lymphohistiocytosis and thrombotic microangiopathy associated with parvovirus b19 infection. Am J Transplant 2008; 8:1340.
- Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361:1676.
- Zuber J, Le Quintrec M, Sberro-Soussan R, et al. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol 2011; 7:23.
- Le Quintrec M, Lionet A, Kamar N, et al. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant 2008; 8:1694.
- Agarwal A, Mauer SM, Matas AJ, Nath KA. Recurrent hemolytic uremic syndrome in an adult renal allograft recipient: current concepts and management. J Am Soc Nephrol 1995; 6:1160.
- Hebert D, Sibley RK, Mauer SM. Recurrence of hemolytic uremic syndrome in renal transplant recipients. Kidney Int Suppl 1986; 19:S51.
- Artz MA, Steenbergen EJ, Hoitsma AJ, et al. Renal transplantation in patients with hemolytic uremic syndrome: high rate of recurrence and increased incidence of acute rejections. Transplantation 2003; 76:821.
- Oyen O, Strøm EH, Midtvedt K, et al. Calcineurin inhibitor-free immunosuppression in renal allograft recipients with thrombotic microangiopathy/hemolytic uremic syndrome. Am J Transplant 2006; 6:412.
- Miller RB, Burke BA, Schmidt WJ, et al. Recurrence of haemolytic-uraemic syndrome in renal transplants: a single-centre report. Nephrol Dial Transplant 1997; 12:1425.
- Quan A, Sullivan EK, Alexander SR. Recurrence of hemolytic uremic syndrome after renal transplantation in children: a report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation 2001; 72:742.
- Bresin E, Daina E, Noris M, et al. Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. Clin J Am Soc Nephrol 2006; 1:88.
- Ducloux D, Rebibou JM, Semhoun-Ducloux S, et al. Recurrence of hemolytic-uremic syndrome in renal transplant recipients: a meta-analysis. Transplantation 1998; 65:1405.
- Lahlou A, Lang P, Charpentier B, et al. Hemolytic uremic syndrome. Recurrence after renal transplantation. Groupe Coopératif de l'Ile-de-France (GCIF). Medicine (Baltimore) 2000; 79:90.
- Donne RL, Abbs I, Barany P, et al. Recurrence of hemolytic uremic syndrome after live related renal transplantation associated with subsequent de novo disease in the donor. Am J Kidney Dis 2002; 40:E22.
- Loirat C, Fremeaux-Bacchi V. Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 2008; 12:619.
- Nester C, Stewart Z, Myers D, et al. Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2011; 6:1488.
- Zimmerhackl LB, Hofer J, Cortina G, et al. Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N Engl J Med 2010; 362:1746.
- Zuber J, Le Quintrec M, Krid S, et al. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant 2012; 12:3337.
- Saland JM, Ruggenenti P, Remuzzi G, Consensus Study Group. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 2009; 20:940.
- Jalanko H, Peltonen S, Koskinen A, et al. Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H. Am J Transplant 2008; 8:216.
- Saland JM, Emre SH, Shneider BL, et al. Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant 2006; 6:1948.
- Larrea CF, Cofan F, Oppenheimer F, et al. Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation 2010; 89:903.
- Nürnberger J, Philipp T, Witzke O, et al. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 2009; 360:542.
- Châtelet V, Lobbedez T, Frémeaux-Bacchi V, et al. Eculizumab: safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome: case report. Transplant Proc 2010; 42:4353.
- Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368:2169.
- Davin JC, Gracchi V, Bouts A, et al. Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation. Am J Kidney Dis 2010; 55:708.
- Springate J, Fildes R, Anthone S, et al. Recurrent hemolytic syndrome after renal transplantation. Transplant Proc 1988; 20:559.
- Stevenson JA, Dumke A, Glassock RJ, et al. Thrombotic microangiopathy: recurrence following renal transplant and response to plasma infusion. Am J Nephrol 1982; 2:227.
- Kaplan BS, Papadimitriou M, Brezin JH, et al. Renal transplantation in adults with autosomal recessive inheritance of hemolytic uremic syndrome. Am J Kidney Dis 1997; 30:760.
- Remuzzi G, Ruggenenti P, Codazzi D, et al. Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet 2002; 359:1671.
- Miller BW, Hmiel SP, Schnitzler MA, Brennan DC. Cyclosporine as cause of thrombotic microangiopathy after renal transplantation. Am J Kidney Dis 1997; 29:813.
- Schwimmer J, Nadasdy TA, Spitalnik PF, et al. De novo thrombotic microangiopathy in renal transplant recipients: a comparison of hemolytic uremic syndrome with localized renal thrombotic microangiopathy. Am J Kidney Dis 2003; 41:471.
- Karthikeyan V, Parasuraman R, Shah V, et al. Outcome of plasma exchange therapy in thrombotic microangiopathy after renal transplantation. Am J Transplant 2003; 3:1289.
- Holman MJ, Gonwa TA, Cooper B, et al. FK506-associated thrombotic thrombocytopenic purpura. Transplantation 1993; 55:205.
- Trimarchi HM, Truong LD, Brennan S, et al. FK506-associated thrombotic microangiopathy: report of two cases and review of the literature. Transplantation 1999; 67:539.
- Pham PT, Peng A, Wilkinson AH, et al. Cyclosporine and tacrolimus-associated thrombotic microangiopathy. Am J Kidney Dis 2000; 36:844.
- Kiykim AA, Ozer C, Yildiz A, et al. Development of transplant renal artery thrombosis and signs of haemolytic-uraemic syndrome following the change from cyclosporin to tacrolimus in a renal transplant patient. Nephrol Dial Transplant 2004; 19:2653.
- Sartelet H, Toupance O, Lorenzato M, et al. Sirolimus-induced thrombotic microangiopathy is associated with decreased expression of vascular endothelial growth factor in kidneys. Am J Transplant 2005; 5:2441.
- Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008; 358:1129.
- Feinberg JE, Hurwitz S, Cooper D, et al. A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group. J Infect Dis 1998; 177:48.
- Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (Baltimore) 1997; 76:369.
- Frem GJ, Rennke HG, Sayegh MH. Late renal allograft failure secondary to thrombotic microangiopathy-human immunodeficiency virus nephropathy. J Am Soc Nephrol 1994; 4:1643.
- Hochstetler LA, Flanigan MJ, Lager DJ. Transplant-associated thrombotic microangiopathy: the role of IgG administration as initial therapy. Am J Kidney Dis 1994; 23:444.
- Pham PT, Danovitch GM, Wilkinson AH, et al. Inhibitors of ADAMTS13: a potential factor in the cause of thrombotic microangiopathy in a renal allograft recipient. Transplantation 2002; 74:1077.
- Canaud G, Bienaimé F, Noël LH, et al. Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies. Am J Transplant 2010; 10:2051.
- Satoskar AA, Pelletier R, Adams P, et al. De novo thrombotic microangiopathy in renal allograft biopsies-role of antibody-mediated rejection. Am J Transplant 2010; 10:1804.
- Bren A, Pajek J, Grego K, et al. Follow-up of kidney graft recipients with cyclosporine-associated hemolytic-uremic syndrome and thrombotic microangiopathy. Transplant Proc 2005; 37:1889.
- Ashman N, Chapagain A, Dobbie H, et al. Belatacept as maintenance immunosuppression for postrenal transplant de novo drug-induced thrombotic microangiopathy. Am J Transplant 2009; 9:424.
- Midtvedt K, Bitter J, Dørje C, et al. Belatacept as immunosuppression in patient with recurrence of hemolytic uremic syndrome after renal transplantation. Transplantation 2009; 87:1901.