Advertisement
Original Investigation Pathogenesis and Treatment of Kidney Disease| Volume 53, ISSUE 2, P259-272, February 01, 2009

Interventions for Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: A Systematic Review of Randomized Controlled Trials

Published:October 28, 2008DOI:https://doi.org/10.1053/j.ajkd.2008.07.038

      Background

      Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are related conditions with similar clinical features of variable severity. The objective of this systematic review is to evaluate the benefits and harms of available interventions for HUS and TTP.

      Selection Criteria for Studies

      MEDLINE (1966 to June 2006), EMBASE (1980 to June 2006), the Cochrane Central Register, conference proceedings, and reference lists were searched to find randomized controlled trials (RCTs) of any intervention for HUS or TTP in patients of all ages selected for inclusion for this systematic review.

      Interventions

      Trials that compared an intervention with placebo, an intervention with supportive therapy, or one or more different interventions for HUS or TTP.

      Outcomes

      For TTP trials, failure of remission at 2 weeks or less and at 1 month or longer, all-cause mortality rate, and relapse rate. For HUS trials, all-cause mortality, chronic reduced kidney function, and persistent proteinuria or hypertension at last follow-up.

      Results

      For TTP in adults, we found 6 RCTs of 331 patients. Two trials compared plasma infusion with plasma exchange using fresh frozen plasma and showed failure of remission at 2 weeks (2 trials, 140 patients; relative risk, 2.87; 95% confidence interval, 1.41 to 5.84), and all-cause mortality (relative risk, 1.91; 95% confidence interval, 1.09 to 3.33) occurred more frequently in the plasma infusion group. Three trials compared plasma exchange using cryosupernatant plasma with plasma exchange using fresh frozen plasma, and a meta-analysis of these trials showed no difference. Seven RCTs in 476 young children with postdiarrheal HUS have been conducted. None of the evaluated interventions (fresh frozen plasma transfusion, heparin with or without urokinase or dipyridamole, Shiga toxin–binding protein, and steroid) were superior to supportive therapy alone for any outcomes.

      Limitations

      Limitations of this review include the small number and suboptimal quality of reporting of included trials, possibility of publication bias, small number of participants with atypical HUS, and failure to report results for patients with atypical and typical HUS separately.

      Conclusions

      No additional therapy has been shown to increase efficacy over plasma exchange for TTP. No intervention has been shown to be superior to supportive therapy in patients with postdiarrheal HUS.

      Index Words

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kaplan B.S.
        Thrombotic microangiopathy: A proposal for a new terminology for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.
        J Nephrol. 1995; 8: 3-4
        • Hosler G.A.
        • Cusanamo A.M.
        • Hutchins G.M.
        Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities.
        Arch Pathol Lab Med. 2003; 127: 834-839
        • Furlan M.
        • Robles R.
        • Galbusera M.
        • et al.
        von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
        N Engl J Med. 1998; 339: 1578-1584
        • Tsai H.-M.
        • Lian E.C.Y.
        Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
        N Engl J Med. 1998; 339: 1585-1594
        • Bianchi V.
        • Robles R.
        • Alberio L.
        • et al.
        von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: A severely deficient activity is specific for thrombotic thrombocytopenic purpura.
        Blood. 2002; 100: 710-713
        • Torok T.J.
        • Holman R.C.
        • Chorba T.L.
        Increasing mortality from thrombotic thrombocytopenic purpura in the United States—Analysis of national mortality data, 1968-1991.
        Am J Hematol. 1995; 50: 84-90
        • Terrell D.R.
        • Williams L.A.
        • Vesely S.K.
        • Lammle B.
        • Hovinga J.A.
        • George J.N.
        The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: All patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency.
        J Thromb Haemost. 2005; 3: 1432-1436
        • Amorosi E.L.
        • Ultmann J.E.
        Thrombotic thrombocytopenic purpura: Report of 16 cases and review of literature.
        Medicine (Baltimore). 1966; 45: 139-159
        • Vesely S.K.
        • George J.N.
        • Lämmle B.
        • et al.
        ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: Relation to presenting features and clinical outcomes in a prospective cohort of 142 patients.
        Blood. 2003; 102: 60-68
        • Allford S.L.
        • Hunt B.J.
        • Rose P.
        • Machin S.J.
        Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology: Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias.
        Br J Haematol. 2003; 120: 556-573
        • Byrnes J.J.
        • Khurana H.
        Treatment of thrombotic thrombocytopenic purpura with plasma.
        N Engl J Med. 1977; 297: 1386-1389
        • Bukowski R.M.
        • Hewlett J.S.
        • Harris J.W.
        Exchange transfusion in the treatment of thrombotic thrombocytopenic purpura.
        Semin Hematol. 1976; 13: 219-232
        • Rock G.
        • Shumak K.H.
        • Sutton D.M.
        • Buskard N.A.
        • Nair R.C.
        Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura.
        Br J Haematol. 1996; 94: 383-386
        • Sacher R.
        • Moake J.
        Solvent detergent-treated plasma versus fresh frozen plasma in patients with TTP.
        Transfusion. 1996; 36: 63S
        • Ruggenenti P.
        • Noris M.
        • Remuzzi G.
        Thrombotic microangiopathy, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.
        Kidney Int. 2001; 60: 831-846
        • Remuzzi G.
        The hemolytic uremic syndrome.
        Kidney Int. 1995; 47: 2-19
        • Kaplan B.S.
        • Kaplan P.
        Hemolytic uremic syndrome in families.
        in: Kaplan B.S. Trompeter R. Moake J. Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura. Marcel-Netter, New York, NY1992: 213-225
        • Taylor C.M.
        Hemolytic uremic syndrome and complement factor H deficiency: Clinical aspects.
        Semin Thromb Haemost. 2001; 27: 185-190
        • Elliott E.J.
        • Robins-Browne R.M.
        • O'Loughlin E.V.
        • et al.
        Nationwide study of haemolytic uraemic syndrome: Clinical microbiological, and epidemiological features.
        Arch Dis Child. 2001; 85: 125-131
        • Rowe P.C.
        • Orrbine E.
        • Wells G.A.
        • McLaine P.N.
        Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to 1988.
        J Pediatr. 1991; 119: 218-224
        • Milford D.V.
        • Taylor C.M.
        • Gutteridge B.
        • Hall S.M.
        • Rowe B.
        • Kleanthous H.
        Haemolytic uraemic syndromes in the British Isles 1985-8: Association with verocytotoxin producing Escherichia coli.
        Arch Dis Child. 1990; 65: 716-721
        • Martin D.L.
        • MacDonald K.L.
        • White K.E.
        • Soler J.T.
        • Osterholm M.T.
        The epidemiology and clinical aspects of the hemolytic uremic syndrome in Minnesota.
        N Engl J Med. 1990; 323: 1161-1167
        • Garg A.X.
        • Suri R.S.
        • Barrowman N.
        • et al.
        Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: A systematic review, meta-analysis, and meta-regression.
        JAMA. 2003; 290: 1360-1370
        • Decludt B.
        • Bouvet P.
        • Mariani-Kurkdjian P.
        • et al.
        Haemolytic uraemic syndrome and Shiga toxin-producing Escherichia coli infection in children in France.
        Epidemiol Infect. 2000; 124: 215-220
        • Neuhaus T.
        • Calonder S.
        • Leumann E.
        Heterogeneity of atypical haemolytic uraemic syndromes.
        Arch Dis Child. 1997; 76: 518-521
        • Dickersin K.
        • Scherer R.
        • Lefebvre C.
        Identifying relevant studies for systematic reviews.
        BMJ. 1994; 309: 1286-1291
        • Hollis S.
        • Cambell F.
        What is meant by intention to treat analysis?.
        BMJ. 1999; 319: 670-674
        • Moher D.
        • Pham B.
        • Jones A.
        • et al.
        Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses?.
        Lancet. 1998; 352: 609-613
        • Schultz K.F.
        • Chalmers I.
        • Hayes R.J.
        • Altman D.G.
        Empirical evidence of bias.
        JAMA. 1995; 301: 1410-1412
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Bobbio-Pallavicini E.
        • Gugliotta L.
        • Centurioni R.
        • et al.
        Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP).
        Haematologica. 1997; 82: 429-435
        • Henon P.
        Thrombotic thrombocytopenic purpura: Clinical results of a French controlled trial.
        Transfus Sci. 1992; 13: 63-72
        • Loirat C.
        • Beaufils E.
        • Sonsino N.
        • et al.
        Treatment of haemolytic uraemic syndrome in children with urokinase.
        Arch Fr Pediatr. 1984; 41: 15-19
        • Loriat C.
        • Sonsino E.
        • Hinglais N.
        • Jais J.P.
        • Landais P.
        • Fermanian J.
        Treatment of the childhood haemolytic uraemic syndrome with plasma.
        Pediatr Nephrol. 1988; 2: 279-285
        • Perez N.
        • Spizzirri F.
        • Rahman R.
        • Suarez A.
        • Larrubia C.
        • Lasarte P.
        Steroids in hemolytic uremic syndrome.
        Pediatr Nephrol. 1998; 12: 101-104
        • Rizzoni G.
        • Claris-Appiani A.
        • Edefonti A.
        • et al.
        Plasma infusion for hemolytic-uremic syndrome in children: Results of a multicenter controlled trial.
        J Paediatr. 1988; 112: 284-290
        • Rock G.A.
        • Shumak K.H.
        • Buskard N.A.
        • et al.
        Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura.
        N Engl J Med. 1991; 325: 393-397
        • Rock G.
        • Anderson D.
        • Clark W.
        • et al.
        Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura?.
        Br J Haematol. 2005; 129: 79-86
        • Rothele E.
        • Krumme B.
        • Rump L.C.
        Design of the prospective randomised study for the treatment of patients with thrombotic microangiopathy.
        Ther Apher. 2000; 4: 327-331
        • Trachtman H.
        • Cnaan A.
        • Christen E.
        • et al.
        Effect of an oral Shiga toxin-binding agent on diarrhoea-associated haemolytic uraemic syndrome in children; A randomised controlled trial.
        JAMA. 2003; 290: 1337-1344
        • Van Damme-Lombaerts R.
        • Proesmans W.
        • Van Damme B.
        • et al.
        Heparin plus dipyridamole in childhood hemolytic-uraemic syndrome: A prospective randomized study.
        J Pediatr. 1988; 113: 913-918
        • Vitacco M.
        • Sanchez Avalos J.
        • Gianantonio C.A.
        Heparin therapy in the haemolytic uraemic syndrome.
        J Pediatr. 1973; 83: 271-275
        • Zeigler Z.R.
        • Shadduck R.K.
        • Gryn J.F.
        • et al.
        Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic prupura (TTP).
        J Clin Apher. 2001; 16: 19-22
        • Muller-Wiefel D.E.
        • Bulla M.
        • Klare B.
        • Balzar R.
        • Bambauer R.
        • Tonshoff B.
        Efficacy of therapeutic plasma exchange in haemolytic uraemic syndrome in childhood (abstracts, European Dialysis and Transplant Association-European Renal Association XXVIth Annual Congress, Göteborg, Sweden, 11-15 June 1989).
        Nephrol Dial Transplant. 1989; 4 (abstr): 446A
      1. Thomson PD, Milnor LS: A randomly selected trial of vitamin E in the haemolytic uraemic syndrome (HUS). Proceedings of Xth International Congress of Nephrology 98 (Abstracts), London, July 26-31, 1987

        • George J.N.
        Thrombotic thrombocytopenic purpura.
        N Engl J Med. 2006; 354: 1927-1935
        • Durand J.M.
        • Lefevre P.
        • Kaplanski G.
        • et al.
        Vincristine for TTP.
        Lancet. 1992; 340: 977-978
        • Udvardy M.
        • Rak K.
        Cyclophosphamide for chronic relapsing TTP.
        Lancet. 1990; 336: 1508-1509
        • Crowther M.A.
        • Heddle N.
        • Hayward C.P.
        • et al.
        Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic thrombocytopenic purpura.
        Ann Intern Med. 1996; 125: 294-296
        • Fakhouri F.
        • Vernant J.P.
        • Veyradier A.
        • et al.
        Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient TTP: A study of 11 cases.
        Blood. 2005; 105: 1932-1937
        • George J.N.
        • Woodson R.D.
        • Kiss J.E.
        • Kojouri K.
        • Vesely S.K.
        Rituximab therapy for TTP: A proposed study of the Transfusion Medicine/Hemostatsis Clinical Trials Network with a systematic review of rituximab therapy for immune mediated disorders.
        J Clin Apher. 2006; 21: 49-56
        • Maxvold N.
        • Bunchman T.E.
        Renal failure and renal replacement therapy.
        Crit Care Clin. 2003; 19: 563-575