Abstract
Objective: The objective of this study was to determine whether maternal plasma concentrations of soluble α-klotho are different between women with microbial invasion of the intra-amniotic cavity (MIAC) and those without MIAC among preterm labor and intact membranes (PTL) or preterm prelabor rupture of membranes (pPROM).
Methods: A cross-sectional study was conducted to include women in the following groups: i) PTL with MIAC (n=14); ii) PTL without MIAC (n=79); iii) pPROM with MIAC (n=30); and iv) pPROM without MIAC (n=33). MIAC was defined as a positive amniotic fluid culture for microorganisms (aerobic/anaerobic bacteria or genital mycoplasmas). Amniotic fluid samples were obtained within 48 h of maternal blood collection. Plasma concentration of soluble α-klotho was determined by ELISA.
Results: i) The median plasma concentration (pg/mL) of soluble α-klotho was significantly lower in patients with MIAC than in those without MIAC (787.0 vs. 1117.8; P<0.001). ii) Among patients with PTL, those with MIAC had a lower median plasma concentration (pg/mL) of soluble α-klotho than those without MIAC (787.0 vs. 1138.9; P=0.007). iii) Among patients with pPROM, those with MIAC had a lower median plasma concentration (pg/mL) of soluble α-klotho than those without MIAC (766.4 vs. 1001.6; P=0.045). iv) There was no significant difference in the median plasma concentration of soluble α-klotho between PPROM without MIAC and PTL without MIAC (1001.6 pg/mL vs. 1138.9 pg/mL, respectively; P=0.5). v) After adjustment for potential confounders (maternal age, tobacco use, gestational age at venipuncture), soluble α-klotho remained significantly associated with MIAC (P=0.02); and vi) Among patients without MIAC, smoking was significantly associated with a lower median plasma concentration soluble α-klotho than in non-smokers (794.2 pg/mL vs. 1382.0 pg/mL, respectively; P<0.001); however, this difference was not observed in patients with MIAC.
Conclusions: Intra-amniotic infection occurring at preterm gestations (regardless of membrane status) was associated with a decrease in maternal plasma concentrations of soluble α-klotho. Moreover, among patients without infection, the plasma concentration of α-klotho was lower in smokers.
Introduction
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide [52, 81, 154], with 40–45% following spontaneous preterm labor (PTL) and 25–30% following preterm prelabor rupture of membranes (pPROM) [172]. Preterm parturition is a syndrome with multiple etiologies [154], including uterine overdistension [122, 129, 130, 144, 179], uterine ischemia [7, 30, 56, 87, 88, 108, 181, 183], abnormal allogenic recognition [90, 92, 103, 104, 133, 200], allergic-like reaction [20, 21, 43, 44, 159, 160], cervical disease [3, 6, 15, 16, 36, 38, 53, 64–66, 79, 80, 85, 138, 139, 174, 189, 194], endocrine disorders [17, 35, 67, 70, 86, 119–121, 145, 148, 182, 188, 195, 211], intrauterine inflammation and microbial invasion of the amniotic cavity (MIAC) [4, 9, 12, 27–29, 31, 40, 41, 47, 48, 52, 54, 55, 57–61, 65, 69, 71, 89, 91, 100, 111–118, 131, 134, 140, 149–158, 161–166, 168–171, 173, 177, 193, 204, 208]. The presence of MIAC is associated with increased risk of adverse perinatal outcomes, such as early preterm birth [164, 165, 171, 177, 202, 207], neonatal sepsis [102, 167], bronchopulmonary dysplasia [48, 206], neonatal white matter brain lesions [203, 210], and cerebral palsy [13, 14, 176, 205, 209]. Although MIAC is considered to be confined to the amniotic cavity and not a systemic condition, studies with flow cytometry have shown phenotypic and metabolic changes in leukocytes [45, 46] as well as changes in maternal cytokines concentration [22, 24, 34, 41, 62, 63, 68, 125, 126, 141, 143, 198]. These observations suggest that biomarkers for MIAC may be found in the maternal circulation.
Klotho is an aging suppressor gene [96] that has gained interest because of the potential anti-inflammatory properties of its secreted protein, soluble α-klotho [105, 107]. The importance of soluble α-klotho in vitamin D metabolism has recently been investigated [135, 180]; however, its role in the maternal circulation in the presence of pregnancy complications, such as MIAC, has not been reported.
Decreased concentrations of plasma soluble α-klotho have been found in patients with cardiovascular disease [39, 123, 175], diabetes [37], and early stages of chronic kidney disease [1, 142, 178]. However, little information is available in the context of infection. Since soluble α-klotho reduces tumor necrosis factor-alpha (TNF-α)-induced expression of adhesion molecules and NF-κß activation in human umbilical vein endothelial cells [107], this protein may play a role in host defense and in the control of the inflammatory response. Indeed, recent evidence suggests that soluble α-klotho has anti-inflammatory properties [105, 107, 124, 137, 212, 213].
The aim of this study was to determine whether the plasma concentration of soluble α-klotho during pregnancy is associated with MIAC in patients presenting with PTL or pPROM.
Materials and methods
Study design
A cross-sectional study of women with singleton gestations between 20 and 34 weeks was conducted to include women in the following groups: i) PTL with MIAC; ii) PTL without MIAC; iii) pPROM with MIAC; and iv) pPROM without MIAC.
Eligible patients were approached at the Detroit Medical Center/Hutzel Women’s Hospital in Detroit, Michigan. Patients with one or more of the following conditions were excluded: i) multifetal gestation; ii) hypertensive disorder of pregnancy; iii) renal disease; iv) fetuses with chromosomal and/or congenital anomalies; and v) medically indicated preterm delivery.
Amniocentesis was performed at the clinician’s discretion to rule out MIAC. Amniotic fluid samples were analyzed for white blood cell count (WBC) glucose, and cultured for aerobic/anaerobic bacteria or genital mycoplasmas. The results of amniotic fluid testing were used in clinical management.
All patients provided informed consent prior to the collection of plasma and amniotic fluid samples. The collection and utilization of samples were approved by the Institutional Review Board of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD/NIH/DHHS).
Definition and study procedures
Gestational age was determined by the last menstrual period or earliest available ultrasound if dating by ultrasound was not consistent with the last menstrual period.
Spontaneous PTL was defined as the presence of regular uterine contractions (frequency of at least four contractions in 20 min), cervical dilation of ≥2 cm, effacement of ≥80%, or documented cervical change. PPROM was defined as spontaneous amniorrhexis before the onset of spontaneous labor, confirmed by vaginal pooling, ferning, positive nitrazine and/or amnio dye test. Maternal blood samples were collected at the time of diagnosis of PTL or pPROM.
Amniocentesis was performed within 48 h of the maternal venipuncture. MIAC was defined as a positive amniotic fluid culture for microorganisms (aerobic/anaerobic bacteria or genital mycoplasmas).
Sample collection
Maternal blood samples were obtained by venipuncture and collected in tubes containing EDTA. Amniotic fluid samples were obtained by transabdominal amniocentesis, transferred to the laboratory in a sterile capped syringe, and cultured for aerobic/anaerobic bacteria and genital mycoplasmas. The samples were centrifuged at 1300 g for 10 min at 4°C and stored at –70°C. Laboratory personnel were blinded to the clinical diagnosis.
Human plasma soluble α-klotho ELISA
Maternal plasma concentration of soluble α-klotho were determined by sensitive and specific immunoassays (Immuno-Biological Laboratories America Inc., Minneapolis, MN, USA) utilizing a sandwich-enzyme-based technique. These immunoassays had been validated for plasma determination of the analytes. The inter- and intra-assay coefficients of variation were 4.6% and 3.9%, respectively. The sensitivity of the assays was 48 pg/mL.
Statistical analysis
The Kolmogorov-Smirnov and Shapiro-Wilk tests were used to test for normality of arithmetic data distributions. The Kruskal-Wallis test was used for comparison of continuous variables among three or more groups. The χ2-test or Fisher’s exact was used to examine differences in proportions. Bivariate comparisons of continuous variables were evaluated using the Mann-Whitney U-test. General linear models were constructed to further examine the relationship between log transformed soluble α-klotho and study group, controlling for potentially confounding factors, which included gestational age at maternal venipuncture, maternal race, nulliparity, smoking status, and duration of sample storage. A two-sided P-value of <0.05 was considered statistically significant. The statistical packages used were SPSS version 19 (IBM Corp, Armonk, NY, USA) and SAS version 9.3 (Cary, NC, USA).
Results
During the study period, 156 patients met the inclusion criteria and the study groups were: i) PTL with MIAC (n=14); ii) PTL without MIAC (n=79); iii) pPROM with MIAC (n=30); and iv) pPROM without MIAC (n=33). There were 44 patients with MIAC (28.2%) and 110 (70.5%) patients delivered prior to 34 weeks of gestation. The demographic and clinical characteristics of the study population are summarized in Table 1. As expected, the median gestational age at maternal venipuncture and at delivery, the duration of sample storage, and median soluble α-klotho plasma concentrations differed between groups. There were also differences between the groups in age, nulliparity, and smoking status.
Demographic and clinical characteristics of the study population.
| Clinical characteristics | Preterm labor, without MIAC (n=79) | Preterm labor, with MIAC (n=14) | pPROM, without MIAc (n=33) | pPROM, with MIAC (n=30) | P-value |
|---|---|---|---|---|---|
| Maternal age (years) | 22.0 (19.0–26.0) | 23.5 (21.0–27.0) | 26.0 (21.0–31.0) | 24.5 (22.0–33.0) | 0.005 |
| Black race | 67 (85.9%) | 11 (84.6%) | 28 (84.6%) | 28 (93.3%) | 0.9 |
| Nulliparity | 31 (39.2%) | 7 (50%) | 9 (27.3%) | 8 (26.7%) | 0.3 |
| Smoking | 20 (25.6%) | 6 (42.9%) | 15 (45.5%) | 18 (62.1%) | 0.005 |
| Gestational age at venipuncture (weeks) | 30.6 (26.9–32.6) | 24.1 (23.3–25.0) | 30.7 (29.0–32.0) | 30.4 (27–32.4) | <0.001 |
| Gestational Age at delivery (weeks) | 33.7 (28.4–37) | 24.6 (23.4–25.9) | 31.7 (30.1–33.4) | 31.2 (27.1–32.6) | <0.001 |
| Birth weight (grams) | 1960 (1110–2740) | 679 (525–1060) | 1730 (1420–2100) | 1412 (980–1880) | <0.001 |
| Duration of sample storage (years) | 10.1 (9.7–10.8) | 10.3 (9.8–11.0) | 10.5 (10.0–11.0) | 10.0 (9.6–10.6) | 0.2 |
| α-klotho (pg/mL) | 1138.9 (791.7–1688.5) | 787 (551.9–1055.9) | 1001.6 (661.3–1820.7) | 766.4 (447.2–1177.6) | 0.001 |
Values are expressed as number (percentage) or median (interquartile range). A P-value <0.05 was considered statistically significant. Missing data are: race, n=2; smoking, n=3; birth weight, n=2.
The median soluble α-klotho plasma concentration (pg/mL) was significantly lower in patients with MIAC than in those without MIAC (772.6 vs. 1117.8; P<0.0001; Figure 1). The median soluble α-klotho plasma concentration (pg/mL) was also significantly lower in patients presenting in PTL with MIAC than in those without MIAC (787.0 vs. 1138.9; P=0.007; Figure 2). Similarly, the median soluble α-klotho plasma concentration (pg/mL) was significantly lower in pPROM patients with MIAC than in those without MIAC (766.4 vs. 1001.6; P=0.045; Figure 3). There was no significant difference in the median plasma concentration (pg/mL) of soluble α-klotho between patients with PTL (without MIAC) and those with pPROM (without MIAC) (1138.9 vs. 1001.6; P=0.5).
The median plasma soluble α-klotho concentration was significantly lower in patients with MIAC than in those without MIAC (772.6 pg/mL vs. 117.8 pg/mL; P<0.0001).
The median plasma soluble α-klotho concentration was significantly lower in patients presenting in preterm labor with MIAC than in those without MIAC (787.0 pg/mL vs. 1138.9 pg/mL; P=0.007).
The median plasma soluble α-klotho concentration was significantly lower in patients presenting in preterm prelabor rupture of membranes with MIAC than in those without MIAC (766.4 pg/mL vs. 1001.6 pg/mL; P=0.045).
Differences in the mean log soluble α-klotho concentrations between MIAC and negative MIAC groups remained significant after adjustment for maternal age, gestational age at venipuncture, and smoking status (P=0.02). This final model also revealed that maternal smoking was independently associated with the log soluble α-klotho concentration (P=0.0007). The mean log soluble α-klotho concentration was 23% lower among patients with MIAC compared to those without MIAC, and was 30.6% lower among smokers than in non-smokers, when holding other factors constant.
The relationship between smoking status and soluble α-klotho concentration appeared to differ as a function of MIAC (Figure 4). Among patients without MIAC, the median plasma concentration (pg/mL) of soluble α-klotho was significantly lower in smokers than in non-smokers (794.2 vs. 1382.0; P<0.0001). The difference in the median plasma concentration (pg/mL) of soluble α-klotho concentration between smoker and non-smokers was not observed in patients with MIAC (772.6 vs. 844.8; P=0.2). Moreover, model fit as reflected by an increase in adjusted r2 improved when including the effect-modification term of smoking status. This model revealed that in the setting of MIAC, smoking status was not associated with a difference in mean log soluble α-klotho concentration (P=0.8). In contrast, among patients without MIAC, the mean log soluble α-klotho concentration was significantly lower among smokers than non-smokers (Bonferroni P<0.001).
Among patients without MIAC, the median plasma soluble α-klotho concentration was significantly lower in smokers than in non-smokers (794.2 pg/mL vs. 1382.0 pg/mL, P<0.0001). In contrast, no significant difference in the median plasma α-klotho concentration was observed between smokers and non-smokers among patients with MIAC.
Comments
Principal findings of this study
The principal findings of this study are as follows. i) The median plasma concentration of soluble α-klotho was significantly lower in patients with MIAC than those without MIAC and this was consistent in both the PTL and pPROM groups when evaluated separately. ii) The relationship between soluble α-klotho concentration and MIAC remained significant after adjustment for potential confounders. iii) Among patients without MIAC, the plasma concentration of soluble α-klotho was significantly lower in pregnant patients who reported smoking than in those who did not.
Our results suggest that soluble α-klotho concentration is associated with MIAC. Two plausible explanations are: i) the host response to the MIAC includes a decrease in soluble α-klotho concentration; ii) a lower concentration of klotho may confer a susceptibility to infection.
Biology of klotho
Transgenic mice that have a functional loss of the klotho gene exhibit a phenotype that closely resembles patients with premature-aging syndromes, such as short lifespan, osteoporosis, age-related skin changes, ectopic calcifications, atherosclerosis and infertility [94, 96, 109, 110]. In contrast, overexpression of the klotho gene in mice extends the life span and increases resistance to oxidative stress [11, 98, 196, 201]. The human klotho gene produces two transcripts through alternative RNA splicing to form two types of klotho: a membrane-bound and a secreted protein (soluble α-klotho) [110]. Klotho is primarily expressed in the distal convoluted tubule of the kidney, parathyroid, and choroid plexus in the brain, but expression also occurs in other tissues, including the placenta [96].
Membrane-bound klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as a necessary co-receptor for FGF23 [95, 97, 128, 146]. Membrane-bound klotho also plays an integral part in the regulation of phosphate, calcium and vitamin D homeostasis in human and mice [2, 5, 8, 84, 136, 190]. Lack of expression in either klotho or FGF23 result in phosphate retention and a premature-aging syndrome in the mouse [94, 101, 128, 146, 147]. The extracellular domain of the klotho protein is cleaved on the surface by membrane-anchored protease, such as A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), ADAM17, and Beta-secretase 1 (BACE1). This leads to the release of the secreted form of klotho (soluble α-klotho) into blood, urine, and cerebrospinal fluid [18, 32, 83, 191]. Soluble α-klotho is thought to play an important role in protecting cells and tissues from oxidative stress [51, 196, 201, 214].
Soluble α-klotho regulates the activity of several ion channels and ion transporters on cell surfaces, such as calcium channel transient receptor potential cation channel, subfamily V, member 5 (TRPV5), potassium inwardly-rectifying channel, subfamily J, member 1 (potassium channel ROMK1), and type 2a Na-phosphate cotransporter (npt2a) [25, 26, 78, 77, 99, 106]. Soluble α-klotho can also suppress activation of the insulin/insulin-like growth factor-1 (IGF-1) receptor and canonical Wnt signaling induced by Wnt3 [32, 72, 75, 94, 127, 186, 199].
Klotho and vitamin D metabolism
Expression of klotho is found predominantly (although not exclusively) in the kidney, parathyroid, and choroid plexus [96]. Prior studies have focused on the roles of Klotho in chronic renal disorders [37, 74–76, 142, 178, 184, 214], disorders of calcium metabolism [2, 5, 8, 73, 82, 84, 190], hypertension [33, 123, 132, 175, 197] and aging [50, 93, 96, 109, 187, 191]. Kuro-o et al. demonstrated that klotho is also expressed in the placenta; however, its role of pregnancy complications has not been investigated [96]. Ohata et al. proposed that klotho may play an important role in mineral metabolism in the neonate. The investigators measured circulating α-klotho concentrations in the umbilical cord plasma of healthy neonates, plasma of the neonate 4 days after delivery, maternal plasma, and that of healthy non-pregnant controls [135]. The concentration of soluble α-klotho in umbilical venous blood was significantly higher than in neonatal plasma 4 days after delivery. A negative correlation was also found between FGF23 and soluble α-klotho concentrations in the umbilical cord blood samples, which was consistent with the results of previous studies in healthy children and adult volunteers [135]. Multiple regression analysis revealed that soluble α-klotho concentration was independently associated with phosphate the umbilical; thus, the authors concluded that klotho in cord blood might be a useful biomarker for calcium and phosphate metabolism in the fetus. Recently, Siahanidou et al, demonstrated that plasma concentration of soluble α-klotho was significantly lower in preterm than in full-term infants, and that it was correlated with body weight, body length, 1,25-dihydroxy-vitamin D concentration, malondialdehyde concentration, and gestational age at delivery [180]. Therefore, soluble α-klotho may play a role in vitamin D metabolism and oxidative stress in preterm neonates.
An anti-inflammatory role of klotho
Several investigators have described the protective role of soluble α-klotho from oxidative stress [11, 23, 51, 185, 196, 201, 214]. Wang et al., demonstrated that klotho suppresses Nox2 expression and significantly decreases superoxide production in rat aortic smooth muscle cells, thus attenuating apoptosis [196]. Similarly, Zuo et al., demonstrated that a disruption in klotho expression led to an increase in superoxide production, causing aging-related kidney damage [214]. Therefore, klotho plays an important protective role in the regulation of oxidative stress. The mechanism by which soluble α-klotho protects cells and tissues from oxidative stress is unknown; however, it may act through multiple ion channels and group factors, such as insulin, insulin-like growth factor (IGF-I) and the Wnt signaling pathway, which is integral in cell-to-cell communication (i.e., cell proliferation and differentiation) [32, 72, 75, 77, 94, 127, 192, 199].
Klotho has been investigated as a protective protein against harmful inflammation [50, 105, 107]. Liu et al. reported that intracellular klotho interacts with the retinoic-acid-inducible gene-I (RIG-I), resulting in the inhibition of RIG-I-induced expression of IL-5 and IL-8 in vitro studies of human umbilical vein endothelial cells (HUVECs) and mice [105]. Maekawa et al. demonstrated a similar protective effect of klotho [107]. The administration of klotho attenuated tumor necrosis factor-α (TNF-α)-induced expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), NF-κB activation and IκB phosphylation. These findings suggest that klotho may have a role in the modulation of endothelial response to the inflammatory mediators.
Our findings that plasma concentrations of α-klotho were lower in MIAC than in those without MIAC are consistent with 2 previous studies [124, 137]. Ohyama et al. reported that the administration of lipopolysaccharide to mice resulted in a significantly decreased the expression of klotho [137]. Similarly, Moreno et al. demonstrated that the administration of the proinflammatory cytokines such as TNF-like weak inducer of apoptosis (TWEAK) and TNF-α, resulted in decreased expression of klotho in the kidney in mice [124]. These results suggest that klotho is downregulated in response to microbial products or proinflammatory cytokines, resulting in accelerated aging of organs seen in chronic renal disease.
The presence of intra-amniotic inflammation/infection is known to be significantly associated with increased risks of adverse perinatal outcomes, such as early preterm birth and neonatal morbidity, in patients with PTL or pPROM [13, 14, 48, 102, 164, 167, 171, 176, 177, 202, 203, 205–207, 209, 210]. Elevated maternal plasma concentrations of inflammatory cytokines in preterm gestations complicated by PTL or pPROM are associated with an increased risk of intra-amniotic infection [22, 24, 34, 41, 62, 63, 68, 125, 126, 141, 143, 198]. The findings herein demonstrate that MIAC is associated with decreased maternal plasma concentrations of soluble α-klotho.
Decreased plasma concentration of α-klotho in smokers
This is the first report to find a relationship between exposure to tobacco and decreased plasma concentration of soluble α-klotho. No studies have been published on the effect of smoking on soluble α-klotho concentrations in non-pregnant subjects. Smoking is known to be associated with aging and this has been attributed to chronic inflammation and oxidative stress, which tend to be more severe in women [19]. Indeed, the term “inflammaging” has been coiled to stress the relationship between chronic inflammation and aging [42, 49]. Moreover, smoking is associated with reduction in telomere length, a putative molecular marker of aging [10]. Klotho has anti-aging properties and protects against oxidative stress. The findings that plasma concentration of α-klotho is lower in smokers suggest that the aging effect of smoking may be mediated by a decrease in the anti-aging factor klotho. A relative deficiency in α-klotho will make subjects more susceptible to oxidative stress. Further studies are required to test this hypothesis.
Strengths and limitations
This is the first study to evaluate changes of soluble α-klotho in the context of infection. Replication of this finding is desirable for both pregnant and non-pregnant subjects. Limitations are those inherent to an observational cross-sectional study in which a temporal relationship cannot be established.
Conclusion
Patients who present with preterm labor or preterm prelabor rupture of membranes with MIAC have a lower median plasma concentration of soluble α-klotho than those without MIAC at the time of presentation. These results suggest that klotho plays a protective role during pregnancy. However, further studies are required to evaluate whether patients who subsequently developed MIAC began the pregnancy with lower concentrations of soluble α-klotho, making them susceptible to infection, or vice versa. Prospective studies appear warranted to evaluate soluble α-klotho as a non-invasive biomarker for the prediction of infection and inflammation in pregnancies with adverse outcomes.
This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C.
- a
Presented at the 33rd annual meeting of the Society for Maternal-Fetal Medicine, February 11–16, 2013, San Francisco, CA, USA
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The authors stated that there are no conflicts of interest regarding the publication of this article.
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