Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

Dineke Westra; Elena B. Volokhina; Renate G van der Molen; Thea J. A. M. van der Velden; Annelies Jeronimus-Klaasen; Joop Goertz; Valentina Gracchi; Eiske M. Dorresteijn; Antonia H. M. Bouts; Mandy G. Keijzer-Veen; Joanna A. E. van Wijk; Jaap A. Bakker; Anja Roos; Lambert P. van den Heuvel; Nicole C. A. J. van de Kar

doi:10.1007/s00467-016-3496-0

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

Dineke Westra^*, Elena B. Volokhina, Renate G van der Molen, Thea J. A. M. van der Velden, Annelies Jeronimus-Klaasen, Joop Goertz, Valentina Gracchi, Eiske M. Dorresteijn, Antonia H. M. Bouts, Mandy G. Keijzer-Veen, Joanna A. E. van Wijk, Jaap A. Bakker, Anja Roos, Lambert P. van den Heuvel, Nicole C. A. J. van de Kar

^*Corresponding author for this work

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Abstract

The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS.

Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, alpha FH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls.

Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients.

In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.

Original language	English
Pages (from-to)	297-309
Number of pages	13
Journal	Pediatric Nephrology
Volume	32
Issue number	2
DOIs	https://doi.org/10.1007/s00467-016-3496-0
Publication status	Published - Feb-2017

Keywords

Atypical HUS
Complement
Hemolytic uremic syndrome
STEC
Genetic aberrations
Children
ENTEROHEMORRHAGIC ESCHERICHIA-COLI
FACTOR-H AUTOANTIBODIES
THROMBOTIC MICROANGIOPATHY
SYNDROME AHUS
ACTIVATION
MUTATIONS
ECULIZUMAB
PROTEIN
C3
HUS

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Westra, D., Volokhina, E. B., van der Molen, R. G., van der Velden, T. J. A. M., Jeronimus-Klaasen, A., Goertz, J., Gracchi, V., Dorresteijn, E. M., Bouts, A. H. M., Keijzer-Veen, M. G., van Wijk, J. A. E., Bakker, J. A., Roos, A., van den Heuvel, L. P., & de Kar, N. C. A. J. V. (2017). Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome. Pediatric Nephrology, 32(2), 297-309. https://doi.org/10.1007/s00467-016-3496-0

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title = "Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome",

abstract = "The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS.Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, alpha FH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls.Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients.In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.",

keywords = "Atypical HUS, Complement, Hemolytic uremic syndrome, STEC, Genetic aberrations, Children, ENTEROHEMORRHAGIC ESCHERICHIA-COLI, FACTOR-H AUTOANTIBODIES, THROMBOTIC MICROANGIOPATHY, SYNDROME AHUS, ACTIVATION, MUTATIONS, ECULIZUMAB, PROTEIN, C3, HUS",

author = "Dineke Westra and Volokhina, {Elena B.} and {van der Molen}, {Renate G} and {van der Velden}, {Thea J. A. M.} and Annelies Jeronimus-Klaasen and Joop Goertz and Valentina Gracchi and Dorresteijn, {Eiske M.} and Bouts, {Antonia H. M.} and Keijzer-Veen, {Mandy G.} and {van Wijk}, {Joanna A. E.} and Bakker, {Jaap A.} and Anja Roos and {van den Heuvel}, {Lambert P.} and {de Kar}, {Nicole C. A. J. van}",

year = "2017",

month = feb,

doi = "10.1007/s00467-016-3496-0",

language = "English",

volume = "32",

pages = "297--309",

journal = "Pediatric Nephrology",

issn = "0931-041X",

publisher = "Springer",

number = "2",

}

Westra, D, Volokhina, EB, van der Molen, RG, van der Velden, TJAM, Jeronimus-Klaasen, A, Goertz, J, Gracchi, V, Dorresteijn, EM, Bouts, AHM, Keijzer-Veen, MG, van Wijk, JAE, Bakker, JA, Roos, A, van den Heuvel, LP & de Kar, NCAJV 2017, 'Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome', Pediatric Nephrology, vol. 32, no. 2, pp. 297-309. https://doi.org/10.1007/s00467-016-3496-0

TY - JOUR

T1 - Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

AU - Westra, Dineke

AU - Volokhina, Elena B.

AU - van der Molen, Renate G

AU - van der Velden, Thea J. A. M.

AU - Jeronimus-Klaasen, Annelies

AU - Goertz, Joop

AU - Gracchi, Valentina

AU - Dorresteijn, Eiske M.

AU - Bouts, Antonia H. M.

AU - Keijzer-Veen, Mandy G.

AU - van Wijk, Joanna A. E.

AU - Bakker, Jaap A.

AU - Roos, Anja

AU - van den Heuvel, Lambert P.

AU - de Kar, Nicole C. A. J. van

PY - 2017/2

Y1 - 2017/2

N2 - The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS.Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, alpha FH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls.Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients.In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.

AB - The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS.Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, alpha FH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls.Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients.In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.

KW - Atypical HUS

KW - Complement

KW - Hemolytic uremic syndrome

KW - STEC

KW - Genetic aberrations

KW - Children

KW - ENTEROHEMORRHAGIC ESCHERICHIA-COLI

KW - FACTOR-H AUTOANTIBODIES

KW - THROMBOTIC MICROANGIOPATHY

KW - SYNDROME AHUS

KW - ACTIVATION

KW - MUTATIONS

KW - ECULIZUMAB

KW - PROTEIN

KW - C3

KW - HUS

U2 - 10.1007/s00467-016-3496-0

DO - 10.1007/s00467-016-3496-0

M3 - Article

SN - 0931-041X

VL - 32

SP - 297

EP - 309

JO - Pediatric Nephrology

JF - Pediatric Nephrology

IS - 2

ER -

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

Abstract

Keywords

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