Acute pyelonephritis during pregnancy changes the balance of  angiogenic and anti-angiogenic factors in maternal plasma.
OBJECTIVE
Angiogenic factors have been implicated in the pathophysiology of sepsis. In experimental models of sepsis (endotoxemia and/or cecal ligation puncture), there is increased expression of vascular endothelial growth factors (VEGF) and the administration of exogenous soluble VEGF receptor (sVEGFR)-1, an antagonist to VEGF, reduces morbidity and mortality. Moreover, a dramatic elevation in sVEGFR-1 has been demonstrated in human sepsis. Although a balance between angiogenic and anti-angiogenic factors is essential for feto-placental development, the changes of angiogenic factors during pregnancy in the context of infection have never been explored. Angiogenic factors also play crucial roles in the pathophysiology of preeclampsia (PE). This study was conducted to determine if maternal plasma concentrations of placental growth factor (PlGF), sVEGFR-2, and soluble endoglin (sEng) change in pregnancies complicated by acute pyelonephritis (AP) compared with normal pregnancy and PE.


METHODS
A case-control study was conducted in patients with AP, normal pregnant (NP) women, and patients with PE (n=36 for each group) matched for gestational age. AP was diagnosed in the presence of fever (temperature >or=38 degrees C), clinical signs of infection, and a positive urine culture for microorganisms. Plasma concentrations of PlGF, sVEGFR-2, and sEng were determined by ELISA. The results of plasma sVEGFR-1 concentrations have previously been reported, but were included in this study to provide a complete picture of the angiogenic/anti-angiogenic profiles. Serum concentrations of interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-gamma, granulocyte macrophage colony stimulating factor, and tumor necrosis factor (TNF) were also determined using high sensitivity multiplexed immunoassays in patients with AP and NP.


RESULTS
AP was associated with a lower median plasma concentration of PlGF and sVEGFR-2 than NP (both p<0.001). There were no significant differences in the median plasma concentrations of sEng and sVEGFR-1 between AP and NP (p=0.7 and 0.5, respectively). In contrast, there was a 5-fold decrease of the median plasma concentration of PlGF, and an 8-10-fold increase of the median plasma concentrations of sVEGFR-1 and sEng in PE compared with those in AP (all p<0.001). No significant difference in the median plasma concentration of sVEGFR-2 was observed between patients with PE and AP (p=0.5). Pregnant women with AP had median plasma concentrations of IL-6, IL-7, IL-8, IL-10, IFN-gamma, and TNF-alpha significantly higher than those in NP women (all p<0.001, except IL-7 p=0.004).


CONCLUSIONS
AP is associated with changes in the profile of angiogenic and anti-angiogenic factors. Although some of these changes resemble those in PE (decreased PlGF and sVEGFR-2), the magnitude of the changes of PlGF is much higher in PE. We conclude that despite high plasma inflammatory cytokine concentrations, acute systemic inflammation in pregnancy has a different angiogenic/anti-angiogenic profile than that of PE.
Chaiworapongsa
Tinnakorn
T
Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, Michigan, USA.
Romero
Roberto
R
Gotsch
Francesca
F
Kusanovic
Juan Pedro
JP
Mittal
Pooja
P
Kim
Sun Kwon
SK
Erez
Offer
O
Vaisbuch
Edi
E
Mazaki-Tovi
Shali
S
Kim
Chong Jai
CJ
Dong
Zhong
Z
Yeo
Lami
L
Hassan
Sonia S
SS
D000208:Acute Disease; D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000097:blood*; D020533:Angiogenesis Inhibitors / Q000097:blood*; D015703:Antigens, CD / Q000097:blood; D016022:Case-Control Studies; D000071063:Endoglin; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000097:blood; D007378:Interleukins / Q000097:blood; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood*; D011256:Pregnancy Outcome; D011257:Pregnancy Proteins / Q000097:blood; D011704:Pyelonephritis / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D011956:Receptors, Cell Surface / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D007378:Interleukins; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D000072483:Placenta Growth Factor; D007371:Interferon-gamma; D040301:Vascular Endothelial Growth Factor Receptor-2