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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 3  |  Page : 760-765

Liver-type fatty acid-binding protein as an early biomarker of nephropathy in type-2 diabetes


1 Department of Internal Medicine, Faculty of Medicine - Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine - Menoufia University, Menoufia, Egypt
3 Department, Internal Medicine, Military academy, Cairo, Egypt

Date of Submission16-Dec-2018
Date of Decision05-Jan-2019
Date of Acceptance08-Jan-2019
Date of Web Publication30-Sep-2020

Correspondence Address:
Sameh A Serag
Menouf, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_392_18

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  Abstract 


Objective
The aim of this study was to evaluate serum liver-type fatty acid-binding protein (L-FABP) level as an early biomarker of diabetic nephropathy (DN) in type-2 diabetic patients.
Background
Tubular hypoxia upregulates the expression of the L-FABP gene in the kidney and increases the urinary excretion of L-FABP from the proximal tubules. Thus, in early stage DN, it is possible that chronic hypoxia could have induced an increase in urinary excretion of L-FABP.
Patients and methods
This was a case–control study that included ninety patients with type-2 diabetes mellitus selected from Military Hospital and Menoufia University Hospital who were divided into three groups: the first group comprised diabetic patients with microalbuminuria, second group comprised diabetic patients with macroalbuminuria, and the third group comprised nondiabetic patients with chronic kidney disease. A fourth group of healthy participants served as the control group.
Results
We found a significant increase of urinary L-FABP level in microalbuminuric diabetic patients and a significant positive correlation between urinary L-FABP level and the duration of diabetes. By using receiver operating characteristics curve analysis, calcium level at a cutoff point (≤8.3) discriminated patients with microalbuminuria from patients with macroalbuminuria, with excellent accuracy, sensitivity of 95% and specificity of 96%.
Conclusion
We conclude that the L-FABP level could be a suitable biomarker for early detection with good value to detect DN in patients with type-2 diabetes.

Keywords: albuminuria, liver-type fatty acid-binding protein, nephropathy, type-2 diabetes


How to cite this article:
Rabie AA, Ragheb AT, Mohammed WF, Serag SA. Liver-type fatty acid-binding protein as an early biomarker of nephropathy in type-2 diabetes. Menoufia Med J 2020;33:760-5

How to cite this URL:
Rabie AA, Ragheb AT, Mohammed WF, Serag SA. Liver-type fatty acid-binding protein as an early biomarker of nephropathy in type-2 diabetes. Menoufia Med J [serial online] 2020 [cited 2020 Oct 28];33:760-5. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/760/296682




  Introduction Top


Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). Diabetic nephropathy (DN) is the leading cause of end-stage renal failure and increases the risk of cardiovascular disease. Therefore, early diagnostic markers for predicting and monitoring the progression of DN are needed to enable the timely administration of the most appropriate protective treatments. CKD [1]. The kidney injury is often irreversible when DN enter albuminuria. Albuminuria is an early clinical marker for DN, which is associated with disease progression to end-stage renal disease. Liver-type fatty acid-binding protein (L-FABP) is emerging as an excellent biomarker in urine and plasma in early prediction of kidney injury and CKD [2]. L-FABP is expressed in renal proximal tubular cells and is assumed to be shed into urine in response to hypoxia caused by decreased peritubular capillary blood flow [3]. L-FABP may be a useful clinical biomarker for monitoring chronic glomerular disease and reflects the clinical diagnosis of CKD. L-FABP is widely known to be associated with the severity of DN and with respect to the relationship between urinary L-FABP and DN, increased urinary progression of DN in the future. Furthermore, there have been numerous reports of intervention studies in which urinary L-FABP possesses response to renoprotective treatment. However, the clinical application of L-FABP as a predictor to the progression of DN is still uncertain [4]. The aim of this study was to evaluate the clinical value of urinary L-FABP as a urinary biomarker in the early stage of nephropathy in patients with type-2 DM.


  Patients and Methods Top


This was a case–control study that was conducted on patients with type-2 DM, to evaluate the clinical value of urinary L-FABP as a urinary biomarker in the early stage of nephropathy in patients with type-2 DM. The study was approved by the ethics committee in Menoufia University and Military Hospital.

Ninety patients recruited from Military Hospital and Menoufia University Hospital were classified into three groups, and each group comprised 30 patients including 18 male individuals and 12 female individuals; their ages ranged from 40 to 60 years.

Controls: 30 age-matched and sex-matched healthy volunteers without any known chronic diseases comprised the control group.

Methods

All patients underwent detailed history evaluation, including age, sex, duration of diabetes, full clinical examinations, measuring of arterial blood pressure, weight, height, BMI and laboratory parameters such as serum albumin, complete blood picture, urea, creatinine, fasting blood glucose, postprandial blood glucose (PP-BS), hemoglobin A1C, estimation of glomerular filtration rate, aspartate aminotransferase, and alanine transaminase, estimation of albumin creatinine ratio, serum calcium, serum phosphorus, and parathyroid hormone, and estimation of L-FABP by enzyme-linked immunosorbent assay.

Statistical analysis

Data entry, processing and statistical analysis were carried out using MedCalc ver. 15.8. (MedCalc, Ostend, Belgium). Tests of significance (χ2, Kruskal–Wallis test, multiple regression analysis, Spearman's correlation, and receiver operating characteristics curve analysis) were used.


  Results Top


A highly significant increase in fasting blood sugar, PP-BS, and glycosylated hemoglobin (HbA1C) in microalbuminuric and macroalbuminuric DM groups was observed (P < 0.01, respectively) [Table 1], [Table 2], [Table 3].
Table 1: Comparison among four groups as regards age and sex

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Table 2: Comparison among four groups as regards basic laboratory data

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Table 3: Comparison among four groups as regards blood sugar laboratory data

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Highly significant increase in creatinine and urea was seen in the CKD group (P < 0.01, respectively).

Highly significant decrease in estimated glomerular filtration rate in macroalbuminuric DM and CKD groups was seen (P < 0.01, respectively).

Highly significant increase in albumin creatinine ratio (ACR) and urinary albumin in macroalbuminuric DM and CKD groups (P < 0.01, respectively) was observed.

There was a highly significant increase in L-FABP in macroalbuminuric DM and CKD groups (P < 0.01, respectively) [Table 4].
Table 4: Comparison among four groups as regards renal laboratory data

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Multiple regression analysis shows that the increase in PP-BP, HbA1C, and creatinine had an independent effect on increasing L-FABP, with significant statistical difference (P < 0.05, respectively) [Table 5].
Table 5: Multiple regression model for the factors affecting liver-type fatty acid-binding protein

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Spearman's correlation analysis shows that disease duration, diastolic blood pressure, mean arterial pressure, phosphorus, parathyroid hormone, HbA1C, creatinine, urea, ACR, and urinary albumin had a highly significant positive correlation with L-FABP, with a highly significant statistical difference (P < 0.01, respectively) [Figure 1] and [Figure 2].
Figure 1: Receiver operating characteristics curves of renal laboratory data.

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Figure 2: Receiver operating characteristics curve of urinary liver-type fatty acid-binding protein.

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Spearman's correlation analysis shows that high-density lipoprotein, calcium, and estimated glomerular filtration rate had a highly significant negative correlation with L-FABP, with highly significant statistical difference (P < 0.01, respectively) [Table 6].
Table 6: Spearman's correlation analysis for baseline clinical/laboratory factors associated with liver-type fatty acid-binding protein

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  Discussion Top


DN is one of the important microvascular complications of DM. It is responsible for 25% of cases of uremia [1].

Nine FABPs have been identified of which liver-type (L-FABP) is mainly present in mammalian hepatocytes and enterocytes. It constitutes 2–5% of cytosolic protein content and very rapidly leaks out of damaged cells, leading to an early rise in plasma level [2].

The aim of this study was to evaluate the clinical value of L-FABP as a biomarker in early stage of nephropathy in type-2 MD patients. The 120 participants were classified according albuminuric state into four independent groups: control, microalbuminuric, macroalbuminuric, and non-DM CKD groups.

We found that there was no significant difference in the mean age and sex distribution among the studied groups.

We found that the duration of diabetes in diabetic patients with macroalbuminuria [16 (15–17) years] was statistically significantly longer than in microalbuminuric diabetic patients [four (3–5) years]. The duration of diabetes in diabetic patients with microalbuminuria was statistically significantly longer than in normoalbuminuric diabetic patients.

Kondaveeti et al. [3] noticed that there was a direct correlation between the duration of diabetes and the development of microalbuminuria, because of a prolonged exposure to hyperglycemia as well as deposition of advanced glycated end products [3].

However, Dalla et al. [4] found that there is no difference in duration of diabetes among stages of nephropathy [4].

The results of the present work showed that fasting blood glucose was significantly higher in patients with advanced stage of DN (macroalbuminuric diabetic patients). There was a significant increase in the levels of fasting blood glucose in diabetic patients with microalbuminuria.

The results of fasting blood glucose among the studied groups were in agreement with Yano et al.[5].

The marker of glycemic control, HbA1c, was significantly higher in patients with DN (microalbuminuric and macroalbuminuric diabetic patients) compared with the control and CKD groups. HbA1c was significantly higher in macroalbuminuric diabetic patients compared with microalbuminuric diabetic patients.

In diabetic patients, glucose reacts with amino groups on proteins to form covalently bonded glycated products. An example of such a product is the glycated hemoglobin used to monitor the long-term control of glucose in diabetic patients [6].

The results confirm that uncontrolled state of diabetes reflected by elevated fasting blood sugar and HbA1c with long duration of diabetes facilitate the progression of DN.

Shoji et al. [7] demonstrated that, in type-2 diabetes, patients have a state of chronic hyperglycemia, and glucose-dependent processes are likely to be involved in the pathogenesis of diabetic complications, including nephropathy. Glucose-induced tissue injury may be mediated by generation of advanced glycated proteins, which have been implicated in nephropathy [8].

The present study showed a statistically significant increase in the mean of total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and triglyceride levels in diabetic patients with macroalbuminuria. There was a significant increase in the serum level of triglyceride, total cholesterol, and LDL-C in diabetic patients with microalbuminuria. The mean of high-density lipoprotein-cholesterol level was significantly decreased in patient groups.

These results were in agreement with Xiang et al. [9] who noticed that lipid profile was significantly higher in the microalbuminuric diabetic group, and markedly increased in the macroalbuminuric group [9].

Shoji et al. [7] reported that increased albuminuria correlates with increased levels of cholesterol and LDL-C. This may explain why increased proteinuria in diabetic patients is associated with an increase in cardiovascular deaths even in the absence of renal failure [7].

The results of the present study showed that there is a significant increase in the serum level of creatinine in diabetic patients with microalbuminuria and diabetic patients with macroalbuminuria. These results were in agreement with Hellmich et al. [10] and Paczek et al. [11].

The progression from microalbuminuria to macroalbuminuria (overt nephropathy) is associated with several risk factors including elevation of urinary albumin excretion, poor glycemic control, genetic factors, long duration of diabetes, and abnormalities in lipid spectrum and hemostatic parameters [12].

Microalbuminuria is an early clinical marker for DN, which is associated with disease progression to end-stage renal disease and cardiovascular events [13].

The kidney injury is often irreversible when the DN enters the macroalbuminuria or CKD stages [14].

The present study represented that there was an increase in the level of urinary L-FABP (μg/g creatinine) in the macroalbuminuric diabetic patients' group. There was increase in the level of urinary L-FABP (μg/g creatinine) in the microalbuminuric diabetic patients' group.

Nakamura et al. [15] noted that L-FABP has been established as a promising biomarker in CKD. It is noticed that L-FABP may be a suitable biomarker of the progression of CKD and tubular ischemia [15].

Yamamoto et al. [16] reported that the urinary levels of L-FABP increased in proteinuric and/or tubular ischemic human kidney diseases.

Najafian et al. [17] demonstrated that urinary tubular damage markers, such as KIM-1, NGAL and L-FABP, may have the potential to be clinical markers for identifying the development or progression of DN.

Urinary L-FABP was a highly sensitive marker of a renal microcirculation disorder induced by anemia, which is a factor in the progression of DN. Although the mechanism by which anemia increased urinary L-FABP excretion was not revealed, it was speculated that tubular hypoxia induced by anemia upregulates the gene expression of L-FABP and promotes the urinary excretion of L-FABP. In future, when new treatments for kidney disease that improve tubular hypoxia are developed, urinary L-FABP will be a useful target for therapeutic regimens [18].

The results of the present study showed that by using receiver operating characteristics curve analysis, urinary L-FABP level at a cutoff point (>13.6) discriminated patients with microalbuminuria from patients with macroalbuminuria, with excellent accuracy, sensitivity of 98% and specificity of 100% (P < 0.01). Hence, it is suggested that urinary L-FABP is a prognostic and a predictive marker for overt DN.

Araki et al. [19] noted that urinary L-FABP may be a predictive marker for renal and cardiovascular prognosis in type-2 diabetic patients without advanced nephropathy.

Nakamura et al. [15] and Suzuki et al. [20] reported that, in type-2 diabetes, urinary L-FABP concentrations increased with the progression of DN and reflected DN severity.

There was a positive correlation between urinary L-FABP and markers of DN such as ACR, and there is a positive correlation between urinary L-FABP and other factors incriminated in the pathogenesis of DN, mainly duration of diabetes, marker of glycemic control (fasting blood sugar and HbA1c).


  Conclusion Top


Finally, we conclude that L-FABP could be a suitable biomarker for early detection with good value to detect DN in patients with type-2 diabetes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Nielsen SE, Schjoedt KJ, Astrup AS, Tarnow L, Lajer M, Hansen PR, et al. Neutrophil gelatinase-associated lipocalcin (NGAL) and kidney injury molecule (KIM1) in patients with diabetes nephropathy: a cross-sectional study and the effects of lisinopril. Diabet Med 2010; 27:1144–1150.  Back to cited text no. 14
    
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Nakamura T 1, Inoue T, Sugaya T, Kawagoe Y, Suzuki T, Ueda Y, et al. Beneficial effects of olmesartan and temocapril on urinary liver-type fatty acid-binding protein levels in normotensive patients with immunoglobin A nephropathy. Am J Hypertens 2007; 20:1195–1201.  Back to cited text no. 15
    
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    Figures

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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