Epidemiology, Clinical Presentation, and Pathophysiology of Atypical and Recurrent Hemolytic Uremic Syndrome

ABSTRACT

Hemolytic uremic syndrome (HUS) includes a heterogeneous group of hemolytic disorders. Among the identified causes of HUS are infections, particularly infections with Shiga toxin-producing Escherichia coli (STEC), complement disorders, and disorders interfering with the degradation of von Willebrand factor (VWF). Other causes for atypical HUS include the cobalamin metabolism; pregnancy/hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP); drugs; and other disorders (e.g., systemic diseases appearing as HUS, such as systemic lupus erythematosus and rejection after transplantation). The group not related to STEC is often also called atypical HUS. Most of the occurrences of infectious HUS have only one episode. Recurrent episodes (recurrent HUS) have strong relationships to diseases of the complement system. In these two subgroups the prognosis is poor, with severe renal insufficiency, together with the need for renal replacement therapy. Severe arterial hypertension is common. Treatment options are limited. To better define this group of patients, the European Society for Pediatric Nephrology supported an initiative to develop a European HUS registry. In this registry, 167 patients were acquired; 73 were female (43.8%). The year of onset of the disease ranged from 1974 to 2005. The prevalence of atypical HUS/recurrent HUS can be calculated as 3.3 per million child population (< 18 years). Underlying disorders included factor H, factor I, MCP-1, pneumococci, and von Willebrand factor disturbances. In 33 patients at least one renal transplantation was performed (total, 55 kidneys); 18% were successful and 73% demonstrated recurrence or thrombosis. Treatment options were plasma substitution or plasmapheresis. Despite continued efforts, transplantation is not recommended at present for these patients. Living-related transplantation should be abandoned. New therapeutic strategies are urgently needed.

Enterohemorrhagic Escherichia coli - complement system - von Willebrand factor - transplantation - plasma treatment - recurrence - hemolytic uremic syndrome

REFERENCES

• 1 Gasser C, Gautier E, Steck A, Siebenmann R E, Oechslin R. Hemolytic-uremic syndromes: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia.  Schweiz Med Wochenschr. 1955;  85 905-909
• 2 Zimmerhackl L B. Epidemiology, pathogenesis and therapeutic modalities in hemolytic-uremic syndrome.  Kidney Blood Press Res. 1998;  21 290-292
• 3 Noris M, Remuzzi G. Hemolytic uremic syndrome.  J Am Soc Nephrol. 2005;  16 1035-1050
• 4 Loirat C, Veyradier A, Girma J-P et al.. Thrombotic thrombocytopenic purpura associated with von Willebrand factor-cleaving protease (ADAMTS13) deficiency in children.  Semin Thromb Hemost. 2006;  32 90-97
• 5 Sautter S. Klinischer Verlauf und Veränderungen im Komplementsystem bei Kindern mit rekurrierendem Hämolytisch-urämischem Syndrom [doctoral thesis]. Innsbruck, Austria; Austria Medical University Innsbruck 2004
• 6 Gerber A, Karch H, Allerberger F, Verweyen H M, Zimmerhackl L B. Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997-2000, in Germany and Austria: a prospective study.  J Infect Dis. 2002;  186 493-500
• 7 Furlan M, Robles R, Solenthaler M, Lammle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura.  Blood. 1998;  91 2839-2846
• 8 Richards A, Kemp E J, Liszewski M K et al.. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome.  Proc Natl Acad Sci USA. 2003;  100 12966-12971
• 9 Ault B H, Schmidt B Z, Fowler N L et al.. Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.  J Biol Chem. 1997;  272 25168-25175
• 10 Warwicker P, Donne R L, Goodship J A et al.. Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency.  Nephrol Dial Transplant. 1999;  14 1229-1233
• 11 Caprioli J, Castelletti F, Bucchioni S et al.. Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease.  Hum Mol Genet. 2003;  12 3385-3395
• 12 Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L. Familial hemolytic uremic syndrome associated with complement factor H deficiency.  J Pediatr. 2001;  138 412-417
• 13 Gerber A, Kirchhoff-Moradpour A H, Obieglo S et al.. Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality.  Pediatr Nephrol. 2003;  18 952-955
• 14 Esparza-Gordillo J, Goicoechea de Jorge E, Buil A et al.. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32.  Hum Mol Genet. 2005;  14 703-712
• 15 Ruggenenti P, Remuzzi G. Pathophysiology and management of thrombotic microangiopathies.  J Nephrol. 1998;  11 300-310
• 16 Licht C, Weyersberg A, Heinen S et al.. Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15.  Am J Kidney Dis. 2005;  45 415-421
• 17 O'Shaughnessy D F, Atterbury C, Bolton Maggs P et al.. British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant.  Br J Haematol. 2004;  126 11-28
• 18 Loirat C, Niaudet P. The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children.  Pediatr Nephrol. 2003;  18 1095-1101
• 19 Chiurchiu C, Ruggenenti P, Remuzzi G. Thrombotic microangiopathy in renal transplantation.  Ann Transplant. 2002;  7 28-33
• 20 Artz M A, Steenbergen E J, Hoitsma A J, Monnens L AH, Wetzels J FM. Renal transplantation in patients with hemolytic uremic syndrome: high rate of recurrence and increased incidence of acute rejection.  Transplantation. 2003;  76 821-826
• 21 Zimmerhackl L B. E. coli, antibiotics, and the hemolytic-uremic syndrome.  N Engl J Med. 2000;  342 1990-1991
• 22 Sutor A H, Thomas K B, Prüfer F H, Grohmann A, Brandis M, Zimmerhackl L B. Function of von Willebrand factor in children with diarrhea-associated hemolytic-uremic syndrome (D+ HUS).  Semin Thromb Hemost. 2001;  27 287-292
• 23 Prüfer F, Scheiring J, Sautter S et al.. Terminal complement complex (C5b-9) in children with recurrent haemolytic uremic syndrome.  Semin Thromb Hemost. 2006;  32 121-127
• 24 Quigg R J. Complement and the kidney.  J Immunol. 2003;  171 3319-3324
• 25 Remuzzi G, Ruggenenti P, Colledan M et al.. Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor h gene mutation.  Am J Transplant. 2005;  5 1146-1150
• 26 Dragon-Durey M A, Loirat C, Cloarec S et al.. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome.  J Am Soc Nephrol. 2005;  16 555-563