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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: 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.

METHODS: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) 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.

RESULTS: 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.

CONCLUSIONS: 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 languageEnglish
Pages (from-to)297-309
Number of pages13
JournalPediatric Nephrology
Volume32
Issue number2
DOIs
Publication statusPublished - Feb 2017

Cite this

Westra, D., Volokhina, E. B., van der Molen, R. G., van der Velden, T. J. A. M., Jeronimus-Klaasen, A., Goertz, J., ... van de Kar, N. C. A. J. (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
Westra, Dineke ; Volokhina, Elena B ; van der Molen, Renate G ; van der Velden, Thea J A M ; Jeronimus-Klaasen, Annelies ; Goertz, Joop ; Gracchi, Valentina ; Dorresteijn, Eiske M ; Bouts, Antonia H M ; Keijzer-Veen, Mandy G ; van Wijk, Joanna A E ; Bakker, Jaap A ; Roos, Anja ; van den Heuvel, Lambert P ; van de Kar, Nicole C A J. / Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome. In: Pediatric Nephrology. 2017 ; Vol. 32, No. 2. pp. 297-309.
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abstract = "BACKGROUND: 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.METHODS: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) 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.RESULTS: 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.CONCLUSIONS: 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.",
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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 {van de Kar}, {Nicole C A J}",
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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 & van de Kar, NCAJ 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

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome. / Westra, Dineke; Volokhina, Elena B; van der Molen, Renate G; van der Velden, Thea J A M; Jeronimus-Klaasen, Annelies; Goertz, Joop; Gracchi, Valentina; Dorresteijn, Eiske M; Bouts, Antonia H M; Keijzer-Veen, Mandy G; van Wijk, Joanna A E; Bakker, Jaap A; Roos, Anja; van den Heuvel, Lambert P; van de Kar, Nicole C A J.

In: Pediatric Nephrology, Vol. 32, No. 2, 02.2017, p. 297-309.

Research output: Contribution to journalArticleAcademicpeer-review

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 - van de Kar, Nicole C A J

PY - 2017/2

Y1 - 2017/2

N2 - BACKGROUND: 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.METHODS: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) 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.RESULTS: 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.CONCLUSIONS: 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 - BACKGROUND: 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.METHODS: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) 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.RESULTS: 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.CONCLUSIONS: 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.

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DO - 10.1007/s00467-016-3496-0

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JO - Pediatric Nephrology

JF - Pediatric Nephrology

SN - 0931-041X

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Westra D, Volokhina EB, van der Molen RG, van der Velden TJAM, Jeronimus-Klaasen A, Goertz J et al. Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome. Pediatric Nephrology. 2017 Feb;32(2):297-309. https://doi.org/10.1007/s00467-016-3496-0