Urinary proteins as novel early diagnostic tools in preeclampsia

preeclampsia, characterized by new onset maternal hypertension occurring after the week 20 of gestation, is a major cause of maternal morbidity and mortality, prenatal death, intrauterine growth restriction, and contributes to ∼15% of all preterm deliveries (3, 7). Preeclampsia is quite common and occurs in ∼3–7% for nulliparous and 1–3% for multiparous pregnancies (5). In addition to the hypertension, preeclampsia is also characterized by proteinuria, widespread maternal endothelial dysfunction, and imbalance of angiogenic factors, including increased soluble fms-like tyrosine kinase (s-Flt1), the soluble vascular endothelial growth factor (VEGF) receptor, soluble endoglin, and reductions in VEGF and placental growth factor (PlGF) (3, 4). Hypertension associated with preeclampsia typically remits after delivery, implicating the placenta as a central culprit in the disease. The mechanisms responsible for preeclampsia are not clear, although lack of adequate placentation leading to placental ischemia with subsequent release of vasoconstrictors and cytokines has been proposed (3, 4, 7). The risk of developing preeclampsia is increased in women with obesity and with prior preeclamptic pregnancies, but at this time there is no a way to predict, before onset of the symptoms including hypertension, the women who will develop preeclampsia during pregnancy. In a recent issue of the American Journal of Physiology-Renal Physiology, Wang and colleagues (8) provide evidence for increased urinary levels of three proteins originating in glomerular podocytes that are present in women with preeclampsia that are not present or are significantly lower in normal pregnant women or women with existing hypertension before the pregnancy. The proteins measured were nephrin, podocalyxin, and βig-h3, a transforming growth factor β-induced protein (TGF-βI), and the urinary protein levels were higher for preeclamptic women regardless of whether absolute values were measured or whether they were factored for urinary creatinine. In contrast, serum vascular endothelial growth factor (VEGF), known to be affected in preeclampsia (3, 4), was not consistently different in women with preeclampsia compared with normal pregnant women. These data support a previous report by Wang and colleagues (10) that renal biopsy samples from women with preeclampsia showed that nephrin and glomerular epithelial protein 1 (GLEPP1) were significantly reduced in glomeruli compared with glomeruli from women with normal pregnancies or patients with chronic hypertension, leading to the theory of glomerular protein shedding in preeclampsia. The data in the current report also support previous studies done by Garovic and colleagues (2), in which they showed that urine of women with preeclampsia had a significantly higher number of podocytes in their urine (measured by the presence of podocin, along with podocalyxin, nephrin, and synaptopodin) compared with women with normal pregnancy, pregnancy with preexisting hypertension, or in women with preexisting proteinuria independent of hypertension, thus showing that podocyturia during pregnancy is not merely a marker for hypertensive renal injury or proteinuria per se (2). Podocyturia in animal models has been shown previously to occur with active renal injury (experimental puromycin aminonucleoside, 5/6 renal ablation with hypertension), but not in chronic glomerular disease (such as with aging) (9). In a comparison between the present study and those of Garovic and colleagues (2), the women in the cohorts were of similar ages, but in the study by Wang and colleagues (8), the women were at a slightly earlier gestational age, 31 ± 5 wk, compared with the study by Garovic and colleagues (2) in which the women were at 34.3 ± 3.8 wk. Aita and colleagues (1) also reported that podocyturia was present in women with preeclampsia at 35-wk gestation and 4 days postdelivery (delivery at 35 wk), but was absent by 30 days postdelivery. How soon during gestation podocyturia is present in women destined to develop preeclampsia is not clear from studies done up to this time, however. Garovic and colleagues (2) found a better correlation for preeclampsia in women who had both podocyturia and increases in circulating levels of s-Flt1, the soluble fms-like tyrosine kinase, that is the soluble receptor for VEGF. Increased plasma sFlt-1 at midgestation was found to be indicative of development of preeclampsia later in pregnancy (6). In the present study, Wang and colleagues (8) found no significant correlation between urine VEGF levels between normal and preeclamptic pregnancies. Taken together, these studies provide the potential for novel markers for early detection of preeclampsia. Studies need to be performed in a large cohort of women to determine how soon podocytes or podocyte-shed proteins appear in the urine of women destined to develop preeclampsia, and to determine whether this noninvasive determination can be used to make an early diagnosis for development of preeclampsia. If these studies are positive, diagnosis could be done by measuring podocyturia, perhaps along with measurement of plasma angiogenic factors, such as sFlt-1, to further hone the accuracy of the prediction of preeclampsia. More and more studies are finding that pregnancy may be a litmus test for future cardiovascular disease and that adverse fetal life and development, as occurs with an ischemic placenta in preeclampsia, may program an increased risk for cardiovascular disease later in life. Thus the development of an early diagnostic tool for preeclampsia adds excitement for the potential to provide better early treatment for both mother and fetus.