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.