|Year : 2019 | Volume
| Issue : 4 | Page : 101-108
Urinary neutrophil gelatinase-associated lipocalin as a clinical biomarker in patients with diabetic nephropathy in Beni-Suef Governorate, Egypt
Heba H El Demellawy1, Mohammed A El Feki1, Hesham H Eissa2, Mohamed S Tawfik3, Dina F Elessawi3
1 Internal Medicine Department, Faculty of Medicine, Beni Suef University, Egypt
2 Clinical Pathology Department, Faculty of Medicine, Beni Suef University, Egypt
3 Internal Medicine Unit, Health Radiation Research Department, National Centre for Radiation Research and Technology, Egyptian Atomic Energy Authority, Egypt
|Date of Submission||03-Apr-2019|
|Date of Decision||30-Jul-2019|
|Date of Acceptance||30-Sep-2019|
|Date of Web Publication||25-Nov-2019|
PhD Mohamed S Tawfik
3 Ahmed El Zommor Street, Nasr City, Cairo, 12411
Source of Support: None, Conflict of Interest: None
Aim To demonstrate the importance of the marker of tubulointerstitial damage, urinary neutrophil gelatinase-associated lipocalin (uNGAL), in the follow-up of the progression of chronic kidney disease in patients with type 2 diabetes mellitus.
Patients and methods A total of 60 patients with type 2 diabetes mellitus with various degrees of renal impairment were subdivided into three categories based on urine albumin/creatinine ratio (UACR): 20 patients with normoalbuminuria (<30 mg albumin/g Cr), 20 with microalbuminuria (30–300 mg albumin/g Cr), and 20 with macroalbuminuria (>300 mg albumin/g Cr). Few exclusion criteria were considered such as infections, neoplasia, and any inflammation that could interfere with uNGAL measurement. Twenty healthy individuals were taken as a control group. Serum creatinine, UACR, urine protein, and estimated glomerular filtration rate (eGFR) are measured to determine their correlation with uNGAL, which was measured using a suitable human NGAL ELISA kit. The Modification of Diet in Renal Disease formula was used to calculate the eGFR in patients.
Results The differences between the means of uNGAL in the different patients’ groups were found to be highly statistically significant (P<0.05). There was a significant negative relationship (inverse correlation) between uNGAL levels and eGFR in the three patient groups (P<0.05) and also a converse correlation was noted between uNGAL and UACR in the various patient groups involved in the study (P<0.05).
Conclusion NGAL may be useful as a clinical marker to predict and assess the progression of diabetic nephropathy in patients with type 2 diabetes mellitus with nephropathy.
Keywords: albuminuria, diabetic nephropathy, neutrophil gelatinase-associated lipocalin
|How to cite this article:|
El Demellawy HH, El Feki MA, Eissa HH, Tawfik MS, Elessawi DF. Urinary neutrophil gelatinase-associated lipocalin as a clinical biomarker in patients with diabetic nephropathy in Beni-Suef Governorate, Egypt. J Egypt Soc Nephrol Transplant 2019;19:101-8
|How to cite this URL:|
El Demellawy HH, El Feki MA, Eissa HH, Tawfik MS, Elessawi DF. Urinary neutrophil gelatinase-associated lipocalin as a clinical biomarker in patients with diabetic nephropathy in Beni-Suef Governorate, Egypt. J Egypt Soc Nephrol Transplant [serial online] 2019 [cited 2019 Dec 13];19:101-8. Available from: http://www.jesnt.eg.net/text.asp?2019/19/4/101/271564
| Introduction|| |
Diabetes has been recognized as a worldwide health problem, affecting people at variable ages with increasing incidence and prevalence, leading to various complications .
A longer duration of diabetes and earlier age at diagnosis, with poor glycemic control, are part of the risk factors that lead to the development of diabetic kidney disease (DKD). Other risk factors include positive family history, smoking, and hypertension.
Diabetic nephropathy is a major concern for the development of microvascular and macrovascular complications of diabetes and for diabetes-related overall mortality.
Besides that, with inadequate treatment and late diagnosis, diabetic nephropathy has become the most common diagnosis at initiation of renal replacement therapy .
The key pathophysiologic event in diabetic nephropathy is likely to involve an interaction of metabolic and haemodynamic pathways that lead to the development of basement membrane damage . In addition, active inflammation caused by the passage of macromolecules through the basement membrane will result in secondary damage to the membrane. In relation to the glomerular lesion, there will be persistent diabetic proteinuria. The sustained passage of this molecule within the tubular lumen may activate the intratubular complement cascade and eventually contribute to tubular injury . This last condition can lead first to tubular inflammation and then to tubulointerstitial fibrosis, which ultimately signals the appearance of an irreversible renal impairment .
There have been many efforts to reduce the burden of DKD focus on early screening for microalbuminuria to identify patients with an elevated risk of progressive renal disease ,,. However, microalbuminuria has limitations as a test for renal impairment.
First, 25–55% of type 2 diabetic patients with chronic renal insufficiency who are described as having a sustained reduction in measured or estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m are in fact normoalbuminuric ,,.
Second, in longitudinal studies, 45–55% of patients with type 2 diabetes who develop chronic kidney disease (CKD) diagnosed by laboratory investigations and ultrasonography are normoalbuminuric ,,, demonstrating that the presence of microalbuminuria is not a strong and constant predictor of progression of renal disease as was initially postulated ,,.
The limitations of microalbuminuria as a marker of early renal impairment have raised concerns regarding the use of albumin excretion as a surrogate renal end point in therapeutic trials ,. The discovery of sensitive and specific biomarkers for renal impairment would improve management and strengthen efforts to develop reno-protective drugs.
Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family that is expressed at low levels in several human tissues and is rapidly released from renal tubular cells in response to various insults to the kidney ,. Serum and urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels are arguably the most promising emerging biomarkers for early detection of acute kidney injury ,,,.
Several recent studies have also defined the role of NGAL in CKD and showed that serum and uNGAL levels are good markers of kidney disease and severity in CKD . In addition, though all forms of CKD are also associated with tubulointerstitial injury, regardless of whether the primary pathology is glomerular or otherwise, it is now widely accepted that in some CKD-associated diseases, such as diabetic nephropathy, the rate of deterioration in renal function and the overall outcome are more accurately associated with the degree of renal tubulointerstitial damage than with the severity of glomerular lesions. These factors suggest that NGAL may have a unique predictive value in diabetic nephropathy.
| Aim|| |
The aim was to demonstrate that the marker of tubulointerstitial damage, uNGAL, could be used as a novel and appropriate marker for following up the progression of CKD in patients with type 2 diabetes mellitus.
| Patients and methods|| |
The current work was carried out as a cross-sectional study conducted at Bani-Seuf University Hospital on patients visiting the Diabetes and Internal Medicine Outpatient Clinic from 2017 to 2018. A total of 80 participants, both male and female, were divided into two groups. The first included 60 patients with type 2 diabetic mellitus with various degrees of renal impairment who were further subdivided into three subcategories based on urine albumin/creatinine ratio (UACR): 20 patients with normoalbuminuria (<30 mg albumin/g Cr), 20 with microalbuminuria (30–300 mg albumin/g Cr), and 20 with macroalbuminuria (>300 mg albumin/g Cr). Moreover, 20 healthy individuals were included in the study as a control group with no history of hypertension, diabetes mellitus, inflammation, neoplasia, or any cardiovascular or renal disease.
To minimize the confounding factors, few exclusion criteria were taken into consideration. These included patients having infections, neoplasia, or any inflammation that could interfere with uNGAL measurement.
The following data was collected: demographic characteristics, disease duration, urine albumin (mg/24 h), urine protein (mg/24 h), UACR (mg albumin/g Cr), fasting blood sugar (mg/dl), glycosylated hemoglobin (HbA1C), serum creatinine (mg/dl), eGFR (ml/min/1.73 m2), and uNGAL (ng/ml).
The Modification of Diet in Renal Disease formula was used to calculate the eGFR in patients.
NGAL was measured in urine using commercially available ELISA kits according to the manufacturer’s instructions.
Normally distributed data were expressed as mean±SD whereas abnormally distributed values were presented as the median and interquartile range. Correlations between uNGAL and eGFR as well as other variables were evaluated by Pearson’s test. Comparisons between the different groups were evaluated by analysis of variance test.
| Results|| |
The study included 60 patients having type 2 diabetes mellitus with various degrees of renal impairment and 20 matched controls. The male : female ratio was in 14 : 6 in both the control group and diabetic patients with normoalbumiuria. However, the male : female ratio was 12 : 8 in diabetic patients with microalbuminuria, whereas in diabetic patients with macroalbuminuria, it was 13 : 7.
The mean age for the control group was 47.2±9.71 years, whereas for diabetic patients with normoalbuminuric patients, it was 61.1±10.71 years. As for diabetic patients with microalbuminuria, the mean age was 57.45±8.5 years, whereas for diabetic patients with macroalbuminuria, it was 58±11.1 years.
The mean duration of diabetes in diabetic patients with normoalbuminuria was 7.44±7.86 years, whereas in diabetic patients with microalbuminuria, it was 9.45±7.95 years. As for diabetic patients with macroalbuminuria, the mean duration of diabetes was 15.1±6.94 years.
The laboratory investigations and disease-related characteristics of the patients and control are presented in [Table 1].
|Table 1 Laboratory investigations and disease-related characteristics of the patients and controls|
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The median interquartile range of uNGAL was found to be 10.27 ng/ml (0.72–25 ng/ml) in the control group, whereas in diabetic patients with normoalbuminuria, it was 16.92 ng/ml (0.12–21.46 ng/ml). In diabetic patients with microalbuminuria, the median interquartile range of uNGAL was 9.24 ng/ml (12.42–21.46 ng/ml), whereas in diabetic patients with macroalbuminuria, it was 9.32 ng/ml (19.5–37.20 ng/ml). This is illustrated in [Figure 1].
|Figure 1 Comparison between urinary NGAL in control and diabetic groups. NGAL, neutrophil gelatinase-associated lipocalin.|
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The difference between the means of uNGAL in different patient groups was found to be statistically significant. The P value was 0.0001, which is less than the significance level α of 0.05.
The confidence intervals for the difference between means of both groups did not contain a zero, which indicated that the differences were statistically significant. A statistically significant difference was found between groups 1 and 3, groups 1 and 4, groups 2 and 3, groups 2 and 4, and groups 3 and 4. No statistically significant difference was found between groups 1 and 2.
There was a significant moderate negative relationship (inverse correlation) between uNGAL level and eGFR, with r=−0.429 and P value less than 0.05, as shown in [Table 2] and [Figure 2]a.
|Table 2 Pearson’s correlation between urinary neutrophil gelatinase-associated lipocalin and disease-related variables of the patients and controls|
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|Figure 2 (a) Correlation between urinary NGAL and eGFR. (b) Correlation between urinary NGAL and HbA1C. (c) Correlation between urinary NGAL and serum creatinine. eGFR, estimated glomerular filtration rate; HbA1C, glycosylated hemoglobin; NGAL, neutrophil gelatinase-associated lipocalin.|
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Moreover, there was a moderate positive relationship (converse correlation) between uNGAL level and diabetes duration, with r=0.352 and P value less than 0.05. In addition, a moderate positive relationship (converse correlation) was noticed between uNGAL level and urine albumin, with r=0.445 and P value less than 0.05. A moderate positive relationship (converse correlation) was found between uNGAL level and urine protein, with r=0.480 and P value less than 0.05. A converse correlation was noted between uNGAL level and UACR, with r=0.527 and P value less than 0.05.
There was a very weak positive relationship (converse correlation) between uNGAL level and fasting blood sugar, with r=0.292 and P value more than 0.05. Regarding the correlation between uNGAL level and HbA1C, a very weak positive relationship (converse correlation) was noted, with r=0.280 and P value more than 0.05, as shown in [Table 2] and [Figure 2]b.
There was a moderate positive relationship (converse correlation) between uNGAL level and serum creatinine, with r=0.464 and P value less than 0.05, as seen in [Table 2] and [Figure 2]c.
Regarding eGFR, the mean value in control group was 109.31±17.59, whereas in the normoalbuminuria group, it was 88.45±25.77. In the microalbuminuria group, the mean value of eGFR was 80.58±31.37, whereas it was 49.69±26.28 in the macroalbuminuria group, as shown in [Figure 3].
|Figure 3 Comparison between eGFR in control and diabetic groups. eGFR, estimated glomerular filtration rate.|
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There was a moderate negative relationship (inverse correlation) between eGFR and urine albumin, with r=−0.434 and P value less than 0.05. Moreover, there was a moderate negative relationship (inverse correlation) between eGFR and urine protein, with r=−0.510 and P value less than 0.05.
There was a significant strong negative relationship (inverse correlation) between eGFR and serum creatinine, with r=−0.73 and P value less than 0.05. Regarding the correlation between eGFR and UACR, a moderate negative relationship (inverse correlation) was found, with r=−0.504 and P value less than 0.05.
There was a very weak negative relationship (inverse correlation) between eGFR and fasting blood sugar, with r=−0.247 and P value of 0.027 (P<0.05). There was a very weak negative relationship (inverse correlation) between GFR and HbA1C, with r=−0.111 and P value of 0.328 (P>0.05).
| Discussion|| |
NGAL is a small 25-kDa protein recently discovered by nephrologists. It is a small 25-kDa protein, consisting of a polypeptide chain of 178 amino acids and belongs to the ‘lipocalin’ superfamily. It is expressed by neutrophils and various epithelial cells. This protein is released in blood and urine following ischemic and nephrotoxic injury from the tubular cells. Variable degrees of NGAL gene expression are demonstrated in human tissues like uterus, prostate, salivary glands, lung, trachea, stomach, colon, and kidney .
Present studies have reported that NGAL is a marker that has outperformed other recent renal markers. They have demonstrated that NGAL may represent a novel early urinary biomarker particularly for the detection of acute renal injury ,,,.
This is because NGAL is able to manifest in the urine after 3 h of tubular injury. In comparison, serum creatinine will only be elevated after 24 h of reperfusion .
Recent studies have also suggested that NGAL may somehow also be involved in the pathophysiology of chronic renal diseases, such as autosomal polycystic kidney and glomerulonephritis, as the biological levels of this protein have been seen to correlate well with the severity of renal impairment, probably expressing the degree of active damage in the chronic failure conditions .
Many clinical studies have demonstrated the utility of NGAL as a specific, sensitive, and early predictor of acute kidney injury ,,,,. In CKD, there are also many reports suggesting that NGAL is also a novel, independent marker of renal disease progression, which provides a good reflection of the severity of renal disease. A variety of clinical settings have been examined, including cardiac surgery, contrast administration, septic shock, ICUs, the emergency department, and even renal transplantation ,,,,,,,.
The present study aimed at evaluating uNGAL levels in a small cohort of patients affected by type 2 diabetes mellitus, categorized into three groups depending on their different clinical degree of kidney damage (normoalbuminuria, microalbuminuria, and macroalbuminuria).
The present study tried to demonstrate that uNGAL can be used as an early marker for the detection of nephropathy in these patients, particularly in those with incipient nephropathy.
However, a few studies have demonstrated that NGAL might also be elevated in some other conditions, not necessarily pertaining only to renal injury ,,. Therefore, the present study excluded those likely to interfere with the results. These factors included patients with infection, neoplasia, and inflammation.
The current study involved 60 patients with type 2 diabetes and 20 healthy controls. A significant negative relationship (inverse correlation) between uNGAL level and eGFR was found. In addition, a significant difference in uNGAL levels was observed between the control group on one hand and microalbuminuria or macroalbuminuria groups on the other. However, no significant differences were found between the control and normoalbuminuria groups regarding uNGAL levels.
The current study results obtained showed that all diabetic patients presented elevated uNGAL values compared with an age-matched and sex-matched control group. Furthermore, a characteristic trend was observed among the three groups of patients as uNGAL values increased in parallel with the severity of renal involvement, reaching higher levels in patients with manifest diabetic nephropathy.
These first results are in perfect agreement with recent studies that reported similar tendencies for other biomarkers of tubulointerstitial damage, such as cathepsin B, N-acetyl-β-D-glucosaminidase, and MCP-1, whose levels were found to be strictly proportionate to the degree of urinary albumin excretion ,,.
Interestingly, in this study, uNGAL was also elevated in some normoalbuminuria diabetic patients. Additionally, results obtained showed a few patients with normal UACR demonstrating elevated uNGAL. From this point of view, it could be concluded that uNGAL may be used as an early biomarker for diabetic nephropathy, particularly in incipient nephropathy. This is very important because early identification of CKD and timely detection are global priorities that can help prevent further complications and reduce the cost of treatment. Generally speaking, it is worth noting that in the advanced stages of CKD, creatinine does not correlate well with eGFR .
The current work has thus shown that uNGAL values were increased even before the appearance of pathological albuminuria, the earliest measurable sign of renal diabetic involvement. This interesting finding supports the growing hypothesis of a ‘tubular phase’ of diabetic disease that precedes the manifestation of classic glomerular lesions. For example, a tubular hypertrophy and a reduced organic ion transport activity were demonstrated to be already apparent before the onset of albuminuria, probably as the renal tubule is persistently exposed to a variety of metabolic and hemodynamic factors associated with diabetic disease .
Therefore, the increase in uNGAL values may express the degree of subclinical tubular impairment, thus representing an earlier measurable index of renal suffering compared with classic glomerular signs. Generally, it could not be ruled out that extra renal tissues, instead of the kidney tubule, may be the most important factors responsible for increased uNGAL levels reported in diabetic patients.
However, further data reported from the present study seem to support the idea that a stressed kidney represents the main source of increased uNGAL values. The absence of statistical differences that are noticeable between patients with normoalbuminuria and microalbuminuria regarding uNGAL, the latter being significantly higher in those patient groups with microalbuminuria or macroalbuminuria compared with healthy controls, suggests that the kidney by itself may contribute significantly to an increase in uNGAL levels. This opinion is strengthened by the report that patients belonging to the diabetic nephropathy group all showed a compromised renal function (decrease in eGFR) and presented the highest uNGAL values in comparison with other groups.
In the current study, it was found that there was a moderate positive relationship (converse correlation) between uNGAL level and diabetes duration, whereas there was a moderately negative relationship (inverse correlation) between eGFR and diabetes duration. Consequently, an increase in the duration of diabetes was found to be accompanied by an increase in uNGAL levels and a decrease in eGFR and the progression of diabetic nephropathy.
The correlation between uNGAL and the amount of urinary excretion of protein was analyzed, including albumin and UACR. Previous reports have shown a direct correlation between proteinuria and uNGAL levels ,. Consistent with these reports, a significant moderate positive relationship (converse correlation) was found between both uNGAL level and urine albumin, as well as urine protein and UACR. These results suggest that uNGAL could be useful as a marker of renal function in patients with diabetic CKD.The correlation between the eGFR and the amount of urinary protein excretion as well as the correlation between urinary albumin and UACR were both evaluated in the current study. A significant moderate negative relationship (inverse correlation) was found between eGFR and urine albumin. The eGFR was significantly lower in patients with CKD than in healthy controls, and the extent of difference was higher than that observed for uNGAL. Therefore, the present study did not demonstrate that the rate of deterioration in renal function in diabetic patients with CKD was more accurately associated with the degree of renal tubulointerstitial damage than with the severity of glomerular lesions. Although there are many studies suggesting that creatinine levels and eGFR, which is calculated based on these levels, show low accuracy for measuring of renal function, eGFR is still thought to be a reliable marker for estimating renal function in the present study ,.
The correlation between uNGAL and serum creatinine was investigated. A moderate positive relationship (converse correlation) was observed between uNGAL level and serum creatinine. In addition, there was a significant strong negative relationship (converse correlation) between eGFR and serum creatinine. Consequently, an increase in serum creatinine was associated with a decrease in eGFR and a parallel increase in uNGAL levels.
The correlation between NGAL and age, sex, fasting blood sugar, and glycated hemoglobin was also evaluated. Interestingly, no relationship was found between uNGAL levels and age, sex, and diabetic indices (such as fasting blood sugar and glycated hemoglobin).
The correlation between eGFR and age, sex, fasting blood sugar, and glycated hemoglobin was also studied. A moderate negative relationship (inverse correlation) was found between eGFR and age in the current study. No relationship was observed between eGFR levels and sex or diabetic indices, such as fasting blood sugar and glycated hemoglobin.
The difference between the control group and diabetic groups regarding the excretion of urine albumin, urine protein, and UACR was evaluated. A statistically significant difference was found between the different groups studied regarding these parameters. The present study also distinctively demonstrated that diabetic patients showed increased levels of uNGAL that well reflected the severity of renal damage caused by diabetic disease.
These findings are of importance for at least two reasons. First, as previously reported for other CKD-associated conditions, it could be presumed that uNGAL may play an important role in the pathophysiology of renal adaptation to diabetes. This is probably achieved through a compensatory or defensive mechanism aiming at mitigating persistent tubular suffering caused earlier by metabolic and hemodynamic factors and later by severe proteinuria. Furthermore, the current findings suggest some important diagnostic implications, which therefore have to be validated in the future in larger populations. Consequently, NGAL measurement might become a useful, practical, and noninvasive tool for the evaluation of renal involvement in the course of diabetes.
| Conclusion|| |
It is possible to conclude that uNGAL may be a reliable marker for the assessment of renal function in diabetic patients with CKD. The current study demonstrated that uNGAL outperformed other renal markers such as eGFR that are currently used to diagnose and evaluate DKD. It was found to be able to predict renal impairment at an early stage of diabetic CKD. Further multicentre studies are required and anticipated to establish uNGAL as a reliable early diagnostic and prognostic marker of chronic renal injury.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]