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.
KEYWORDS
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
Lothar Bernd ZimmerhacklM.D. Ph.D.
Professor, Universitätsklinik für Kinder und Jugendheilkunde, Medizinische Universität
Innsbruck, Anichstr
35, A-6020 Innsbruck, Austria
Email: lothar-bernd.zimmerhackl@uklibk.ac.at