Urinary angiogenic factors cluster hypertensive disorders and identify women with severe preeclampsia.
OBJECTIVE
Serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) are altered in women with clinical preeclampsia. We sought to identify whether similar alterations in urinary levels of these proteins cluster hypertensive disorders in pregnancy, and identify women with severe preeclampsia (sPE).


METHODS
Free urinary levels of sFlt-1, VEGF, and PlGF were measured by immunoassay in 68 women enrolled prospectively in the following groups: nonpregnant reproductive age (NP-CTR n = 14), healthy pregnant control (P-CTR n = 16), pregnant hypertensive and proteinuric women who did not meet criteria for severe preeclampsia (pHTN n = 21), and women with sPE (n = 17).


RESULTS
There was no difference in gestational age at the time of enrollment among groups (median [range]: sPE: 31 [24-40], pHTN: 34 [16-40], P-CTR: 28 [7-39] wks). Urinary excretion of VEGF was significantly increased in sPE women compared with NP-CTR (P = .023), but did not differ among pregnant groups. Urinary PlGF levels were significantly increased in pregnant compared with nonpregnant women, but were decreased in all hypertensive women compared with healthy P-CTR (P < .001). Urinary sFlt-1 concentrations were significantly increased in women with sPE relative to all other groups (P < .001). pHTN women had higher sFlt-1 urinary output compared with P-CTR group (P = .001). A cutoff >2.1 in the ratio log [sFlt-1/PlGF] had 88.2% sensitivity and 100% specificity in differentiating women with sPE from normotensive controls. We also described that the log[sFlt-1/PlGF] ratio identified women with sPE better than proteinuria alone (P = .03). Our regression model revealed that uric acid correlated best with log[sFlt-1/PlGF] ratio (r = 0.628; P = .005).


CONCLUSIONS
sPE is associated with increased urinary output of the antiangiogenic factor sFlt-1 and a decreased output of PlGF at the time of clinical manifestation, providing a rapid noninvasive screening of hypertensive women based on a sFlt/PlGF ratio. This ratio may be used as representation for severity of the disease, and appears to be superior to random urinary protein measurements.
Buhimschi
Catalin S
CS
Department of Obstetrics, Gynecology and Reproductive Science, Yale University, New Haven, CT 06520, USA. catalin.buhimschi@yale.edu
Norwitz
Errol R
ER
Funai
Edmund
E
Richman
Susan
S
Guller
Seth
S
Lockwood
Charles J
CJ
Buhimschi
Irina A
IA
D000328:Adult; D015415:Biomarkers / Q000652:urine*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000652:urine*; D008565:Membrane Proteins; D011225:Pre-Eclampsia / Q000652:urine*; D011247:Pregnancy / Q000652:urine; D011249:Pregnancy Complications, Cardiovascular / Q000652:urine*; D011446:Prospective Studies; D011506:Proteins / Q000032:analysis*; D011507:Proteinuria / Q000652:urine; D012720:Severity of Illness Index; D014527:Uric Acid / Q000652:urine; D042461:Vascular Endothelial Growth Factor A / Q000652:urine*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis*
D015415:Biomarkers; D008565:Membrane Proteins; C098069:PIGF protein, human; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; D014527:Uric Acid; D040281:Vascular Endothelial Growth Factor Receptor-1