Endocrine DOI 10.1007/s12020-014-0511-8


Renal tubular markers in pregnant women with and without gestational diabetes mellitus: a pilot study Wen-Jin Fu • Ren-Tang Deng • Zhi-Hong Huang • Mei-Lian Chen • Du-Juan Wang • You-Ming Jiang Shu Wen • Hong-Ling Yang • Xian-zhang Huang

Received: 24 November 2014 / Accepted: 10 December 2014 Ó Springer Science+Business Media New York 2014

Introduction Gestational diabetes mellitus (GDM) is one of the most common medical complications in pregnancy and is associated with numerous adverse outcomes in both the mother and newborn. Higher risk for the development of chronic kidney disease (CKD) after delivery in women with GDM has been recently reported in some certain studies [1–3], and CKD is found to occur even for those with GDM alone in the absence of subsequent diabetes. Therefore, GDM during pregnancy may pose a direct risk for kidney lesion formation in women before delivery. At present, tubular damage is widely accepted to occur early in the course of diabetic nephropathy (DN). Certain tubular markers, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and N-acetyl-b-D-glucosaminidase (NAG) are more sensitive and specific than the widely used marker, microalbuminuria W.-J. Fu  R.-T. Deng  Z.-H. Huang  M.-L. Chen  D.-J. Wang  Y.-M. Jiang Department of Laboratory, Affiliated Houjie Hospital, Guangdong Medical College, Guangzhou 523945, China S. Wen Department of Obstetrics and Gynecology, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA H.-L. Yang (&) Clinical Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou 510623, China e-mail: [email protected] X. Huang (&) Department of Laboratory Medicine, Guangdong Province Hospital of Chinese Medicine, Guangzhou 510120, China e-mail: [email protected]

[4, 5]. However, little is known as to whether renal injury, especially tubular damage, occurs in women with GDM before delivery.

Materials and methods A total of 113 pregnant women with GDM and 20 controls with uncomplicated pregnancies were recruited in this study from September 2012 to February 2014. All pregnant women had their delivery in the Department of Gynecology and Obstetrics in the affiliated Houjie Hospital, Guangdong Medical University. Diagnosis of GDM was established according to results of 75 g oral glucose tolerance test between the 24th and 28th week of gestation [6]. Subjects with the following conditions were excluded: overt diabetes, preeclampsia, polyhydramnios, fetal anomalies, prior renal disease, liver disease, and multiple gestations. The study protocol was approved by the Ethics Research Committee at Houjie Hospital (Dongguan, China). Written informed consent was obtained from all participants. Fasting venous blood and first-voided morning urine samples were collected prior to delivery. Creatinine, glucose, and other chemistry laboratory parameters were tested using standard clinical analytical methods (Beckman Coulter, USA). HbA1c was analyzed using G8 ion exchange HPLC method (Tosoh Biosciences, San Francisco, CA, USA). Urine samples were centrifuged at 2,500 rpm for 10 min, and then aliquots were stored at -70 °C until analysis. Urinary microalbumin was measured, and urine albumin/creatinine ratio (UACR) was calculated. NGAL and KIM-1 were measured by commercial sandwich ELISA kits (Quantikine R&D Systems Inc., Abingdon, UK). Urinary NAG was detected by colorimetric



assay (O&D Biotech, China). To account for the influence of urinary dilution on biomarker concentration, all urinary markers were normalized to the urinary creatinine concentration. Differences between two groups were tested using Mann– Whitney U or Student’s test when appropriate. Correlation analyses, including Spearman’s and multiple linear stepwise regression analysis, were used to show the influences of variables on renal damage markers. All statistical analyses were performed using the SPSS statistical package, version 13.0 (SPSS Inc., Chicago, IL, USA) for Windows13. Statistical significance was defined as p \ 0.05.

UACR were elevated in the GDM group, the difference was insignificant. In the GDM group, bivariate correlation analysis indicated that urinary NGAL was positively correlated with HbA1c (r = 0.489, p \ 0.001), FBG (r = 0.289, p = 0.042), and BMI (r = 0.442, p = 0.013). Urinary KIM-1 was also positively correlated with HbA1c (r = 0.303, p \ 0.001) and FBG (r = 0.189, p = 0.042). In multiple stepwise regression analyses, age, gestational age at birth, BMI, systolic and diastolic blood pressure, UACR, FBG, HbA1C, and serum creatinine were included in the model as independent variables. BMI and HbA1c appeared to be significantly associated positively with urinary NGAL, and HbA1c is associated with urinary KIM-1 (p \ 0.05 for all).

Results The clinical characteristics and biochemical parameters of the GDM and control groups are shown in Table 1. No significant differences were found between the groups in terms of mean maternal age, gestational age at birth, BMI, systolic and diastolic blood pressures, and serum creatinine levels (p [ 0.05). Compared with the control group, the GDM group presented higher urinary NGAL, KIM-1 and fasting blood glucose (FBG; p \ 0.05). Although urinary NAG and

Table 1 The clinical and biochemical characteristics of women with GDM and controls Parameters

GDM (n = 113)

Controls (n = 20)

p value

Age (year)

31.8 ± 4.3

29.8 ± 3.1


Gestational age at birth (week)

35.8 ± 3.6

38.3 ± 1.6


BMI at birth (kg/m2)

26.7 ± 3.9

25.4 ± 3.4


Systolic BP (mmHg)

110.4 ± 14.5

105.6 ± 9.9


Diastolic BP (mmHg)

69.8 ± 8.4

70.2 ± 8.9

FPG at birth (mmol/l)

5.65 ± 1.56*

4.85 ± 0.62



HbA1c at birth (%) Serum creatinine (lmol/l)

5.92 ± 0.48* 41.7 ± 16.6

4.20 ± 0.34 48.9 ± 14.3

\0.001 0.356

UACR (mg/g)

6.4 (2.1–17.6)

5.2 (1.6–15.1)


NGAL (lg/g cr)

77.8 (27.4–128.3)*

37.6 (17.4–71.6)


KIM-1 (ng/g cr)

75.5 (38.5–200.5)*

35.5 (16.0–64.0)


NAG (U/g cr)

8.7 (5.5–14.7)

7.0 (3.9–14.4)


BP blood pressure, BMI body mass index, FBG fasting blood glucose, UACR urine albumin/creatinine ratio, NGAL neutrophil gelatinase associated lipocalin, NAG N-acetyl-b-D-glucosaminidase, KIM-1 kidney injury molecule-1 * p \ 0.05 versus controls, Data expressed as mean ± SD or median (IQR)


Discussion In the present study, we observed that the three urinary markers of tubular damage were elevated in pregnant women with GDM in comparison with those in healthy pregnant women before delivery, even though no difference was found for UACR between the two groups. These results suggest that tubular damage occurred during pregnancy in women with GDM, which was in accordance with several studies on T2DM that indicated that tubular damage occurs early in the course of DN and is not merely secondary to glomerular damage [7]. NGAL can be markedly induced in injured epithelial cells, including kidney tubular cells. Different mechanisms, including reduced clearance or increased production by injured tubular cells, or both, could account for the elevation of urinary NGAL. Plasma NGAL has been reported to be highly expressed and positively correlated with BMI in pregnant women with GDM [8]. A similar correlation with BMI was also found for urinary NGAL in the present study. In addition, we verified that urinary NGAL is also positively correlated with HbA1c in multiple regression. This correlation suggests that a high level of urinary NGAL may, at least partly, result from increased production of injured tubular cells caused by hyperglycemia. Similar to urinary NGAL, urinary KIM-1 was also highly excreted and positively correlated with HbA1c and FBG in this study. Given that relatively high molecular weight molecules preclude glomerular filtration, only increased tubular production could account for the elevation of urinary KIM-1 [9]. A high level of urinary KIM-1 and positive correlation with HbA1c and FBG indicates that high glucose in GDM may result in tubular damage. Although the present data also show elevated urinary NAG levels in the GDM group, the difference was insignificant. Discrepancies in the changes of the three markers in the GDM group imply that these biomarkers reflect


different pathophysiological mechanisms in tubulointerstitial damage. To the best of our knowledge, this study is first to explore the relationship between tubular damage and GDM in pregnancy. In agreement with other studies which suggested that GDM is a deleterious factor for renal damage after delivery, the present results provide evidence that GDM could result in tubular impairment during pregnancy. The current study involves several limitations. First, only a low number of patients were included. Second, this paper presents only one cross-sectional study. The correlation between urinary tubular markers and renal impairment or microalbuminuria after delivery should be confirmed through a longitudinal study. Acknowledgments This study was supported by the funds from the Scientific and Technological Projects of Dongguan City, Guangdong province, PR China. Conflict of interest

Nothing to declare.

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Renal tubular markers in pregnant women with and without gestational diabetes mellitus: a pilot study.

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