Recurrent and de novo HUS after renal transplantation
- Christina L Klein, MD
Christina L Klein, MD
- Transplant Nephrologist
- Piedmont Transplant Institute
- Anuja Java, MD
Anuja Java, MD
- Instructor in Medicine
- Washington University School of Medicine
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Medical Director and Co-Director of the Comprehensive Transplant Center, Department of Internal Medicine, Division of Nephrology
- Johns Hopkins Medical School
Hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal impairment. There are multiple etiologies for HUS. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
HUS may result in end-stage renal disease (ESRD), requiring either dialytic therapy or transplantation. Among patients with ESRD due to 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 HUS.
This topic reviews recurrent and de novo HUS in renal transplant recipients. The causes, diagnosis, and treatment of HUS in nontransplant patients are discussed elsewhere. (See "Pathophysiology of acquired TTP and other primary thrombotic microangiopathies (TMAs)" and "Drug-induced thrombotic microangiopathy" and "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Complement-mediated hemolytic uremic syndrome".)
Most cases of HUS in the nontransplant 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, quinine, chemotherapeutic agents, and immunosuppressive drugs such as calcineurin inhibitors and mammalian [mechanistic] target of rapamycin [mTOR] inhibitors) (table 1). HUS may also be caused by genetic defects in complement proteins that regulate the alternative pathway, leading to dysregulated complement activation. This is referred to as "complement-mediated HUS" or "atypical HUS." The mutations may be familial or sporadic. (See "Complement-mediated hemolytic uremic syndrome".)
HUS that occurs in the transplant recipient may be recurrent or de novo. Nearly all patients with recurrent HUS have a complement-mediated disease that produced both the pretransplant HUS and the recurrence after transplantation . De novo HUS may be due to any of the etiologies that cause thrombotic microangiopathy in the general population or may be related to the transplantation. Causes of thrombotic microangiopathy that are common among transplant recipients include immunosuppressive drugs [2,3], ischemia reperfusion injury , viral infections, and antibody-mediated rejection [5-8]. (See 'De novo HUS' below and "Drug-induced thrombotic microangiopathy".)
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- van den Brand JA, Verhave JC, Adang EM, Wetzels JF. Cost-effectiveness of eculizumab treatment after kidney transplantation in patients with atypical haemolytic uraemic syndrome. Nephrol Dial Transplant 2017; 32:i115.
- 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.
- Wong E, Challis R, Sheerin N, et al. Patient stratification and therapy in atypical haemolytic uraemic syndrome (aHUS). Immunobiology 2016; 221:715.
- 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.
- 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.
- Watt T, Warshaw B, Katzenstein HM. Atypical hemolytic uremic syndrome responsive to steroids and intravenous immune globulin. Pediatr Blood Cancer 2009; 53:90.
- Lionet A, Provôt F, Glowacki F, et al. A case of adult atypical haemolytic uraemic syndrome related to anti-factor H autoantibodies successfully treated by plasma exchange, corticosteroids and rituximab. NDT Plus 2009; 2:458.
- Recurrent HUS
- De novo HUS
- CLINICAL PRESENTATION
- PREVENTION OF RECURRENT HUS
- Screening for mutations
- Selection of donor kidney
- Prophylactic therapy
- Patients with recurrent HUS
- Patients with de novo HUS
- SUMMARY AND RECOMMENDATIONS