Discussion
Since PE is a very serious complication during pregnancy, researchers have been searching for various biological markers to enable early detection. To date, clinical signs such as high blood pressure and cerebral symptoms are considered to be the most important symptoms of PE; many studies have reported the predictive value of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF)16-19. However, few guidelines have selected the sFlt-1/PlGF ratio as a diagnostic tool for PE, and a major disadvantage of the sFlt-1/PlGF ratio is that it is measured in maternal blood, which means the test is available only in medical centers. Here, we identified the possibility of detecting a marker for PE in maternal urine. This has significant implications for the early detection of PE because urine tests are easier to perform and typically less costly than other tests using samples–such as serum.
Several studies have suggested podocyturia as a novel marker for the diagnosis of PE since significant excretion of podocytes in urine was found among women diagnosed with PE; these studies also demonstrated that acute but transient podocyturia in PE tends to be closely related to continued heavy proteinuria20,21. Nevertheless, diagnosing podocyturia has only been done in laboratory settings involving the incubation and staining of urinary cells with podocyte-related proteins such as podocin and nephrin12,22-25. To solve this time-consuming problem, many studies were conducted to discover the urinary podocyte-specific proteins associated with PE, and several of them showed that the urinary concentration of nephrin was significantly higher in patients with PE than in those with normal pregnancies13,14,26.
Main findings: In this study, we analyzed the diagnostic value of nephrin for PE. In addition to measuring the urine concentration of nephrin, we developed a point-of-care kit using nephrin-specific aptamers. The signals expressed by the kit were related to the presence and severity of PE. In the PE group: signals 1, 2, and 3 were found in 45%, 25%, and 12% of participants, respectively. In the control group: 84% was found to have signal 0, and the difference between the PE group and the control group was significant because signal 0 was found in only 18% of the PE group (P <0.001). The sensitivity and specificity of positive signals (1, 2, and 3) to predict PE were 82% and 84%, respectively. This study suggests the possibility of nephrin as a noninvasive and useful test to diagnose PE. Although the predictive values still need to be further studied and refined, the urine test kit using nephrin can be used to predict the development of PE in the general population.
Interpretation: The critical interval (of increasing or decreasing various biomarkers studied previously for the detection of PE) is relatively large. For example, the time interval in which soluble endoglin (sEng) increases is known to be from 5 weeks to 3 months after the onset of PE. For the sFlt-1/PlGF ratio, the positive predictive value reaches its highest point at 4 weeks of PE development. Compared to those markers, the level of nephrin in urine abruptly increases within 9 days of the onset of a clinical manifestation of PE27,28. This short interval of nephrin detection in urine related to the development of PE could be useful to predict the disease process early in pregnancy and to apply effective interventions to manage the disease29-32.
For the last few decades, nephrin as a structural component of the podocyte slit diaphragm has been studied; however, the potential roles in extra-renal tissues and in acquired kidney diseases are not yet well known. Several groups studied the function of nephrin in various kidney diseases either by analyzing the production of nephrin mRNA and/or protein or by sequencing the nephrin gene for mutations in the samples of affected patients10,33-36. In a previous study, Jim et al. investigated whether the detection of nephrin in urine could be used as an early biomarker of diabetic nephropathy10. Another study investigated the association between nephrinuria and various traits causing renal dysfunctions in type 2 diabetes37.
Strengths and limitations: A limitation of the present study is the relatively small sample size; however, the data collected prospectively were sufficient in showing one of the possibilities of nephrin: as a valuable predictive tool for PE, and to suggest the use of nephrin for an easy point-of-care test. Since urine is non-invasive and an easily obtainable sample, which can be acquired readily and repeatedly, using urinary markers to detect PE warrants the affirmative market feasibility in medical practice. Research on urine markers is especially promising because proteinuria and kidney malfunction are the main features of PE. Since the samples were collected at the time of diagnosis for PE, the association between nephrin and the development of PE might not represent the predictive value of nephrin.