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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 996-1003

Urinary podocalyxin and cyclophilin A: markers for early detection of type 2 diabetic nephropathy


1 Department of Clinical Pathology, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Menoufia University, Menoufia, Egypt

Date of Submission19-Jul-2018
Date of Acceptance18-Sep-2018
Date of Web Publication17-Oct-2019

Correspondence Address:
Doaa S Mohamed
Shebin El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_223_18

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  Abstract 

Objective
To investigate urinary podocalyxin (PCX) and cyclophilin A (CypA) as useful markers for early detection of type 2 diabetic nephropathy (DN).
Background
PCX is a transmembrane protein that localizes to the apical cell of glomerular podocytes. PCX maintains podocytes shape. PCX is shed from injured podocytes into urine as small vesicles. CypA is an 18-kD protein that is distributed in the cytoplasm and facilitates protein folding and trafficking. It acts as a cellular receptor for cyclosporine A. The expression of CypA is quite high in the kidney, where proximal tubular epithelial cells contain more CypA than other kidney tissues. CypA was detected in diabetic patients' plasma and secreted by monocytes in response to hyperglycemia, indicating that CypA could be a potential secretory marker in type 2 DN.
Patients and methods
This case–control study was conducted at the Clinical Pathology Department of Menoufia University Hospitals from September 2017 to February 2018 on 66 type 2 diabetic patients and 20 healthy participants as a control group. They all underwent full history, clinical examination, routine renal functions, urinary creatinine and albumin, urinary albumin creatinine ratio, glycated hemoglobin (%), and quantification of urinary PCX and CypA by enzyme-linked immunosorbent assay.
Results
Urinary PCX/creatinine ratio and urinary CypA/creatinine ratio were highly significant (P < 0.001) in the patient group compared with the control group.
Conclusion
Urinary PCX and CypA may be markers for early stage of DN, with more specificity of CypA.

Keywords: albuminuria, cyclophilin A, diabetic nephropathy, podocalyxin, type 2 diabetes mellitus


How to cite this article:
El-Saeed GK, Shehab El-Deen WA, Montasr BA, Omar TA, Mohamed DS. Urinary podocalyxin and cyclophilin A: markers for early detection of type 2 diabetic nephropathy. Menoufia Med J 2019;32:996-1003

How to cite this URL:
El-Saeed GK, Shehab El-Deen WA, Montasr BA, Omar TA, Mohamed DS. Urinary podocalyxin and cyclophilin A: markers for early detection of type 2 diabetic nephropathy. Menoufia Med J [serial online] 2019 [cited 2019 Dec 7];32:996-1003. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/996/268817




  Introduction Top


Diabetes mellitus (DM) is a group of metabolic disorder in which there is hyperglycemia for a long period; it develops owing to either deficiency in insulin secretion or insulin action, or both [1]. Diabetic nephropathy (DN) is a progressive kidney disease caused by long-standing hyperglycemia that causes nonenzymatic glycation reactions of proteins and peptides with production of advanced glycation end-products which are associated with inflammation and damage of renal glomeruli, resulting in progressive proteinuria, hypoalbuminemia, edema, hypertension, and lastly chronic renal failure [2]. DN is a main complication of diabetes and an important cause of end-stage renal disease (ESRD) [3]. Microalbuminuria is a predictive factor for cardiovascular actions and nephropathy in type 2 diabetes and thought to be an early marker of DN in clinical practice. However, it lacks both sensitivity and specificity to detect early stage of DN. Furthermore, some patients with DN with ESRD do not present with significant albuminuria. Moreover, some studies have noted the existence of pathological change before microalbuminuria [4]. It is essential to find an earlier and reliable marker for DN as earlier diagnosis and intervention may provide a chance to stop the permanent damage caused by DN [5]. A new biomarker for DN exists including fibroblast growth factor; tubular markers (kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein); inflammatory markers such as interleukin 6, interleukin 8, monocyte chemoattractant protein 1, and interferon gamma inducible protein; urinary 8-hydroxy-20-deoxyguanosine; urinary podocalyxin (PCX); and urinary cyclophilin A (CypA) [6]. Podocytes are highly differentiated glomerular epithelial cells that line the outside of the glomerular capillary with foot processes linked to the glomerular basement membrane with their actin cytoskeleton and act as a main barrier to protein passaging from the intravascular glomerular capillaries to the extravascular urinary space [7]. Once podocytes are injured in a disease, increased passage of proteins leads to proteinuria and PCX, which indicate damage of the podocytes at glomerular level. These urinary markers are important in early diagnosis of secondary nephropathies such as diabetic, lupus, and hypertensive nephropathy as the most common causes of ESRD [8]. PCX is a surface antigen of podocytes, and the expression of PCX on podocytes remains unchanged in various types of glomerulonephritis. Detached podocytes and their fragments (PCX) might appear in urine of diabetic patients with normoalbuminuria, and PCX-positive element might be a possible marker of early stage of nephropathy [9]. CypA, an immunophilin, is secreted from human monocytes activated by high glucose. CypA acts toward intracellular signaling, protein trafficking, and regulating activity of other proteins. CypA is also well recognized as a secreted growth factor that is induced by oxidative stress, functioning as a mediator of tissue damage associated with inflammation and oxidative stress [10]. CypA is relatively high in the kidney, where proximal tubular epithelial cells contain considerably much more of CypA rather than other kidney tissues. As CypA is directly produced by normal kidney, so its level will increase in urine with any kidney damage. Therefore, urinary CypA level would be the most suitable indicator for early diagnosis of DN as it is secreted by monocytes in response to hyperglycemia [11]. The aim of this study is to investigate urinary PCX and CypA as useful markers for early detection of glomerular dysfunction in type 2 DN.


  Patients and Methods Top


Patients

This study was approved by the Research Ethics Committee in Menoufia Faculty of Medicine, and informed written consent was taken from every participant in the study.

A total of 66 type 2 diabetic patients (average age, 58.73 ± 9.7 years) with and without DN and 20 healthy controls (average age, 57.6 ± 2.5 years) were enrolled in this study. The study was conducted at the Clinical Pathology and Internal Medicine Departments of Menoufia University Hospitals from September 2017 to February 2018.

Group I included 20 person (12 males and eight females with age range, 54–62 years) as a control group, who were age and sex matched with the patients group.

Type 2 diabetic patients were divided into three groups according to the value of the urinary albumin/creatinine ratio (ACR) as follows:

  1. Group II: normoalbuminuric diabetic group without nephropathy or albuminuria. This group included 22 patients (eight males and 14 females, with age range, 40–72 years)
  2. Group III: microalbuminuric diabetic group with early DN and microalbuminuria. This group included 22 patients (11 males and 11 females, with age range, 33–75 years)
  3. Group IV: macroalbuminuric diabetic group with overt DN and macroalbuminuria. This group included 22 patients (nine males and 13 females, with age range, 41–69 years).


All enrolled personnel were submitted to full clinical assessment including medical history and clinical examination including blood pressure measurements.

Blood samples collection

From all of the study groups, 5 ml of venous blood was collected aseptically and divided into two tubes: one on EDTA for glycated hemoglobin (HbA1c) and the other in plain tube and left to clot for 10–15 min. Serum was separated by centrifugation at 2000 round per minute for 10 min. The separated serum was used for clinical chemistry tests.

Urine specimen collection

The second voided clean-catch urine samples from all participants were collected early in the morning. Each urine sample (20 ml) was directly collected into a sterile plastic tube and immediately divided into 10 ml for immediate estimation of urine creatinine and albumin and 10 ml for centrifuged for 20 min at 1000 round per minute at 2–8°C. Collected supernatant was stored at −80°C for future PCX and CypA enzyme-linked immunosorbent assay (ELISA).

Laboratory tests

Blood urea, serum creatinine, and uric acid were measured with a Modular AU680 automatic biochemistry Analyzer (Beckman Coulter, Inc. Atlanta Vision Center Atlanta, Georgia, USA). HbA1c was estimated using Automated Glycohemoglobin Analyzer G8 (Sysmex Corporation, Wakinohama-Kaigandori, Chuo-ku, Kobe, Japan). Urinary albumin and creatinine concentrations were determined in fresh urine samples by immunoturbidimetric method (Dade Behring Holdings Inc., Marburg, Germany). Urinary ACR in mg/g was calculated.

Enzyme-linked immunosorbent assay for podocalyxin and cyclophilin A evaluation

Urine samples were prepared according to the guidelines of the PCX and CypA ELISA Kit. The PCX and CypA levels in supernatant urine were evaluated by ELISA according to the manufacturer's instructions (cloud clone crop human PCX and CypA ELISA Kit; Langham Creek, Houston, TX, USA). The urinary PCX and CypA levels were expressed as PCX and CypA/creatinine ratio in nanogram per gram creatinine.

Statistical analysis

The data collected were tabulated and analyzed by statistical package for the social sciences, version 22.0 (SPSS Inc., Chicago, IL, USA). Owing to the small sample size, nonparametric statistical analysis was used. Values were presented as mean with ranges in parenthesis. Kruskal–Wallis test was used for comparison between three or more groups having not normally distributed quantitative variables, whereas one-way analysis of variance test was used for more than two groups. Percentages of categorical variables were compared using the χ2 test. The Spearman correlation coefficient (r) was used to measure the association between two quantitative variables. Receiver operating characteristic (ROC) curve was constructed to calculate the optimized cutoff points for PCX and CypA/creatinine ratio to reach the best compromise in the prediction of DN.


  Results Top


Patient characteristics

There were no significant statistical differences between the all studied groups regarding age and sex; however, there were a significant statistical differences in duration of DM among diabetic groups. There were highly significant statistical differences between group I and group IV, group II and group IV as well as group III and group IV (P < 0.001) regarding systolic blood pressure. Regarding diastolic blood pressure, there were significant statistical differences between group I and group III and between group III and group IV (P < 0.05). Meanwhile, there were highly significant statistical differences between group I and group IV and between group II and group IV (P < 0.001) [Table 1].
Table 1: Clinical and demographic data of the studied groups

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Biochemical measurements of study participants

There were highly significant differences between the studied groups regarding serum urea and creatinine (P < 0.001). However, there were no significant statistical differences among all studied groups (P > 0.05) regarding serum uric acid. There were a highly significant differences between the studied groups regarding HbA1c% (P < 0.001). Post-hoc test showed that there were highly significant statistical differences between group I and groups II, III, and IV and between group II and group III as well as group III and group IV (P < 0.001). There were highly significant differences between the studied groups regarding microalbumin (P < 0.001) [Table 2].
Table 2: Biochemical data of the studied groups

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There were no significant statistical differences between all the studied groups (P > 0.05) regarding urinary creatinine. There were highly significant differences between the studied groups regarding urinary ACR (P < 0.001) [Table 2].

There were highly significant differences between the studied groups regarding urinary PCX/creatinine ratio and urinary CypA/creatinine ratio (P < 0.001) [Figure 1].
Figure 1: Urinary podocalyxin/creatinine ratio and urinary cyclophilin A/creatinine ratio.

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There were significant positive correlations between both urinary PCX/creatinine ratio and urinary CypA/creatinine ratio (ng/g) and duration of DM, microalbumin, urinary ACR ratio, serum urea, creatinine, and HbA1c%. However, there was no significant positive correlation with serum uric acid [Table 3].
Table 3: Correlation between both urinary podocalyxin/creatinine ratio and urinary cyclophilin A/creatinine ratio and either of diabetes mellitus duration (year) and other laboratory investigation findings of diabetic cases

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There were significant positive correlations between urinary PCX/creatinine ratio and urinary CypA/creatinine ratio (ng/g), with correlation coefficient (r) of 0.849 and P value of less than 0.001 [Table 2] and [Figure 2].
Figure 2: Correlation between urinary podocalyxin/creatinine ratio and urinary cyclophilin A/creatinine ratio.

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By using ROC curve, at a cutoff point of 13 348.4 and 31 596.4 ng/g or more of urinary PCX/creatinine ratio and urinary CypA/creatinine ratio, respectively, early glomerular dysfunction can be detect with sensitivity of 95.5 and 97.7%, respectively, specificity of 81.8 and 90.9%, respectively, positive predictive value (PPV) of 91.3 and 95.6%, respectively, and negative predictive value (NPV) of 90 and 95.2%, respectively [Table 4] and [Figure 3] and [Figure 4].
Table 4: Validity of urinary podocalyxin/creatinine ratio and urinary cyclophilin A/creatinine ratio for early detection of glomerular dysfunction in type 2 diabetic cases

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Figure 3: ROC curve of urinary podocalyxin/creatinine ratio. ROC, receiver operating characteristic.

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Figure 4: ROC curve of urinary cyclophilin A/creatinine ratio. ROC, receiver operating characteristic.

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Validity of both urinary PCX/creatinine ratio and CypA/creatinine ratio for early detection of glomerular dysfunction in type 2 diabetic cases was sensitivity of 100%, specificity of 77.3%, PPV of 89.8%, NPV of 100%, and accuracy of 92.4% [Table 5] and [Figure 5].
Table 5: Validity of both urinary podocalyxin/creatinine ratio and cyclophilin A/creatinine ratio for early detection of glomerular dysfunction in type 2 diabetic cases

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Figure 5: Validity of both markers. ROC, receiver operating characteristic.

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  Discussion Top


DN is a clinical syndrome characterized by persistent albuminuria (>300 mg/d or >200 μg/min), which is confirmed on at least two occasions 3–6 months apart; progressive deterioration in the glomerular filtration rate; and elevated arterial blood pressure [12].

Albuminuria has been accepted as the earliest marker for development of DN. However, some individuals with type 2 diabetes could have renal impairment even before the onset of albuminuria. Moreover, albuminuria has several confusing issues associated with it such as exercise, urinary tract infection, acute illness, and cardiac failure [13].

In type 2 diabetic patients, increased levels of urinary biomarkers can be detected before the onset of significant albuminuria and may be used as an early marker of renal damage in DN. This would play a significant role for the effective management and treatment approaches in diabetic care [13].

The present study describes the rising urinary PCX and CypA in diabetic patients with various degrees of albuminuria. In our study, we tried to find out the possibility of using the urinary PCX and CypA as new markers for diagnosis of DN as early as possible.

All patients and controls were subjected to full history taking and clinical examination, in addition to laboratory investigations, including kidney function tests, urinary albumin and creatinine, ACR, HbA1c%, and quantification of urinary PCX and CypA/creatinine ratio (ng/g) (PCX/creatinine ratio and CypA/creatinine ratio).

The results of the present work showed that no statistically significant difference of age and sex distribution was seen among the studied groups. These results agreed with Rahimi et al. [14] who demonstrated that no significant variations among diabeticpatients were seen regarding ageand sex;however, Wang et al. [15] report higher incidence of DN in men compared with age-matched women. The obtained results showed that the degree of albuminuria increased with prolonged duration of DM. This result was in consistent with Molitch et al. [16], who showed that there was a statistically significant increase in duration of DM with advancing stages of DN. However, Vestra et al. [17] found no difference in duration of diabetes between the stages of nephropathy. The gained data showed that systolic and diastolic blood pressures were significantly higher in diabetic patients with macroalbuminuria compared with patients with microalbuminuria and normoalbuminuria, and these results were in agreement with the results obtained from Araszkiewicz et al. [18], who reported that the susceptibility to develop overt renal failure might be influenced by higher blood pressure. However, Bruno and Merletti [19] found no significant difference of systolic and diastolic blood pressures as the nephropathy progress. According to kidney function tests, the gained results showed a significant increase of serum creatinine in microalbuminuria and macroalbuminuria diabetic group compared with the normalbuminuric diabetic group (P < 0.001), and significant increase of serum urea in diabetic patients with macroalbuminuria compared with control group, normalbuminuric patients, and microalbuminuric diabetic patients (P < 0.001). However, there was no statistically significant difference in serum uric acid among all groups. These results were in agreement with Jha et al. [20] andAhmed et al. [21] whofound significant high level of serum urea and creatinine in patients with DN compared with control group as increased serum urea and creatinine levels are strongly linked with the development of DN. Viswanathan et al. [22] found no significant change between macroalbuminuric and normoalbuminuric groups regarding serum uric acid. The results of gained study showed statistically significant increase in HbA1c% in the three diabetic groups compared with the control group (P < 0.001) and statistically significant increase in macroalbuminuric diabetic patients compared with normoalbuminuric patients and microalbuminuric patients (P < 0.001). Moreover, it found no significant difference between microalbuminuric and normoalbuminuric diabetic patients (P > 0.05). The results were in agreement with Kumar et al. [23] who showed that HbA1c% in population with nephropathy was greater as compared with the population without nephropathy. However, Jha et al. [20] found no significant difference among the three diabetic groups, reflecting they were in good glycemic control.

Regarding urinary albumin and ACR, the gained data showed that there was a statistically higher significant difference between macroalbuminuric diabetic group and microalbuminuric diabetic group compared with the control group (P < 0.001), and no statically significant difference between normoalbuminuric diabetic group and control group (P > 0.05). There was a significant increase of ACR in diabetic patients with microalbuminuria and diabetic patients with macroalbuminuria compared with the normoalbuminuric diabetic patients (P < 0.001) and between microalbuminuric group compared with macroalbuminuric group (P < 0.001). The obtained results agreed withYe et al. [9] who showed that urinary microalbumin was significantly increased in diabetic patients with microalbuminuric diabetic patients than in normoalbuminuric diabetic patients.

In this study, there were significant increases in urinary PCX/creatinine ratio and urinary CypA/creatinine ratio in diabetic patient groups compared with normal control group, and the highest level was present in macroalbuminuric diabetic patient group. There were positive significant correlation between urinary PCX/creatinine ratio as well as urinary CypA/creatinine ratio and duration of diabetes, microalbumin, ACR, serum urea, creatinine, and HbA1c%.

These results agreed with Shoji et al. [24] and Akankwasa et al. [25] who found a significant increase in the level of urinary PCX/creatinine ratio in normoalbuminuric, microalbuminuric, and macroalbuminuric diabetic groups compared with control group (P < 0.001 for all). They also found a significant increase in urinary PCX in microalbuminuric patients compared with normoalbuminuric patients (P < 0.05) and a positive correlation was shown between urinary PCX and urinary albumin, ACR, and HbA1c%.

Conti et al. [26] have found that excretion of podocyte-specific proteins and/or podocyturia precede proteinuria, increased significantly in patients with DN and, or other active glomerulonephritis, opening a promising scenario for an early diagnosis and therapeutic approach to renal damage.

Regarding urinary CypA/creatinine ratio results, our study is compatible withTsai et al. [10] and Amer et al. [11] who found significant increase in level of urinary CypA/creatinine ratio in microalbuminuric and macroalbuminuric diabetic groups compared with control group. Moreover, they found a significant increase in urinary CypA in microalbuminuric patients compared with normoalbuminuric patients (P < 0.05), and a positive correlation was showed between urinary CypA and serum urea, creatinine, urinary albumin, and ACR. However, they reported that there is no correlation between urinary CypA and HbA1c%. On the contrary, Ramachandran et al. [5] found that there was a significant positive correlation between CypA and HbA1c% P value equal to 0.019.

The ROC curve of obtained results showed that at a cutoff point 13 348.4 and 31 596.4 ng/g or more of urinary PCX/creatinine ratio and urinary CypA/creatinine ratio, respectively, early glomerular dysfunction can be detect with sensitivity of 95.5 and 97.7%, respectively, specificity 81.8 and 90.9%, respectively, PPV 91.3 and 95.6%, respectively, and NPV 90 and 95.2%, respectively.

Mohamed et al. [27] showed that the ROC curve at a cutoff point of 126.13 ng/mmol for urinary PCX/creatinine ratio gave a sensitivity of 98.2% and a specificity of 51%.

Tsai et al. [10] demonstrated that when the concentration of urinary CypA was more than 0.7250 ng/ml, we could diagnose the silent stage of DN with a sensitivity of 90.0% and specificity of 72.7%. The area under curve was up to 0.85, indicating that urinary CypA is used for the diagnosis of silent stage of DN.

Finally, it was concluded that urinary PCX and CypA could provide information of earlier glomerular impairment in patients with diabetes and can be used as earlier markers for DN than microalbuminuria, with higher sensitivity of CypA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

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



 

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