Document Detail

Proteomic profiling of urine identifies specific fragments of SERPINA1 and albumin as biomarkers of preeclampsia.
MedLine Citation:
PMID:  18984079     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: The cause of preeclampsia remains unknown and the diagnosis can be uncertain. We used proteomic-based analysis of urine to improve disease classification and extend the pathophysiologic understanding of preeclampsia.
STUDY DESIGN: Urine samples from 284 women were analyzed by surface-enhanced laser desorption/ionization. In the exploratory phase, 59 samples were used to extract the proteomic fingerprint characteristic of severe preeclampsia requiring mandated delivery and to develop a diagnostic algorithm. In the challenge phase, we sought to prospectively validate the algorithm in 225 women screened for a variety of high- and low-risk conditions, including preeclampsia. Of these, 19 women were followed longitudinally throughout pregnancy. The presence of biomarkers was interpreted relative to clinical classification, need for delivery, and other urine laboratory measures (ratios of protein to creatinine and soluble fms-like tyrosine kinase-1 to placental growth factor). In the translational phase, biomarker identification by tandem mass spectrometry and validation experiments in urine, serum, and placenta were used to identify, quantify, and localize the biomarkers or related proteins.
RESULTS: We report that women with preeclampsia appear to present a unique urine proteomic fingerprint that predicts preeclampsia in need of mandated delivery with highest accuracy. This characteristic proteomic profile also has the ability to distinguish preeclampsia from other hypertensive or proteinuric disorders in pregnancy. Pregnant women followed longitudinally who developed preeclampsia displayed abnormal urinary profiles more than 10 weeks before clinical manifestation. Tandem mass spectrometry and de novo sequencing identified the biomarkers as nonrandom cleavage products of SERPINA1 and albumin. Of these, the 21 amino acid C-terminus fragment of SERPINA1 was highly associated with severe forms of preeclampsia requiring early delivery. In preeclampsia, increased and aberrant SERPINA1 immunoreactivity was found in urine, serum, and placenta, in which it localized predominantly to placental villi and placental vascular spaces adherent to the endothelium. In addition, significant perivascular deposits of misfolded SERPINA1 aggregates were exclusively identified in preeclamptic placentae.
CONCLUSION: Proteomics-based characterization of urine in preeclampsia identified a proteomic fingerprint composed of SERPINA1 and albumin fragments, which can accurately diagnose preeclampsia and shows promise to discriminate it from other hypertensive proteinuric diseases. These findings provide insight into a novel pathophysiological mechanism of preeclampsia related to SERPINA1 misfolding, which may offer new therapeutic opportunities in the future.
Irina A Buhimschi; Guomao Zhao; Edmund F Funai; Nathan Harris; Isaac E Sasson; Ira M Bernstein; George R Saade; Catalin S Buhimschi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  American journal of obstetrics and gynecology     Volume:  199     ISSN:  1097-6868     ISO Abbreviation:  Am. J. Obstet. Gynecol.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-05     Completed Date:  2008-11-24     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  0370476     Medline TA:  Am J Obstet Gynecol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  551.e1-16     Citation Subset:  AIM; IM    
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MeSH Terms
Albuminuria / urine*
Biological Markers / urine*
Observer Variation
Peptide Mapping
Pre-Eclampsia / diagnosis*,  urine
Prospective Studies
alpha 1-Antitrypsin / urine*
Grant Support
R01 HD 047321-01/HD/NICHD NIH HHS; R01 HD047321/HD/NICHD NIH HHS; R01 HD047321-01/HD/NICHD NIH HHS; R01 HD047321-02/HD/NICHD NIH HHS; R01 HD047321-03/HD/NICHD NIH HHS; R01 HD047321-04/HD/NICHD NIH HHS; R01 HD047321-05/HD/NICHD NIH HHS
Reg. No./Substance:
0/Biological Markers; 0/SERPINA1 protein, human; 0/alpha 1-Antitrypsin

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