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ORIGINAL ARTICLE
Year : 2022  |  Volume : 10  |  Issue : 2  |  Page : 47-52

Cystatin-c, beta-2-microglobulin, and other determinants of renal function in preeclampsia


Department of Chemical Pathology, University of Benin, Benin City, Edo State, Nigeria

Date of Submission30-Jun-2022
Date of Decision31-Jul-2022
Date of Acceptance08-Aug-2022
Date of Web Publication27-Oct-2022

Correspondence Address:
Dr. Ejuoghanran Oriseseyigbemi Onovughakpo-Sakpa
Department of Chemical Pathology, University of Benin, Benin City, Edo State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_5_22

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  Abstract 


Context: Preeclampsia is a serious complication of pregnancy which is avoidable with timely and effective care. Aim: The aim of this study was to monitor the renal status using biochemical indices such as serum cystatin-c, beta-2-microglobulin (B2MG), and other renal function. Setting and Design: This was a cross-sectional descriptive study. Subjects and Methods: One hundred and sixty respondents (124 preeclamptics [PE] and 36 normotensive pregnant women [NPW]) participated in this study. Fresh mid-stream urine and venous blood samples were collected for the estimation of urine albumin and creatinine, plasma creatinine and urea, serum cystatin-c, and B2MG. Statistical Analysis Used: The Statistical Package for the Social Sciences version 16 with the level of significance set at P < 0.05 was used for statistical analysis. Results: Amongst the PE, 39 (31.5%) were mild cases while 85 (68.5%) were severe. Serum cystatin-c, B2MG, plasma creatinine and urine albumin-creatinine ratio (ACR) were higher in the PE than in the NPW while plasma urea was significantly (P < 0.05) higher in NPW than in PE. Cystatin-c was significantly (P < 0.05) higher in PE than in NPW in the 3rd trimester while B2MG was significantly (P < 0.05) higher in PE than in NPW in the 2nd and 3rd trimesters. Urine ACR and serum B2MG were significantly (P < 0.05) higher in severe than in mild PE. There was a significant (P < 0.05) positive correlation between serum cystatin-c and urine ACR and between B2MG and plasma creatinine. Serum cystatin-c was increased throughout the period of gestation with higher values in the 3rd trimester while serum B2MG was higher in the 2nd trimester. Conclusion: In comparison to other biological indices of renal function, serum B2MG and serum cystatin-c could be more useful in the early detection and severity of preeclampsia.

Keywords: Beta-2-microglobulin, cystatin-c normotensive pregnant women, preeclampsia


How to cite this article:
Onovughakpo-Sakpa EO, Ayinbuomwan E. Cystatin-c, beta-2-microglobulin, and other determinants of renal function in preeclampsia. Niger J Exp Clin Biosci 2022;10:47-52

How to cite this URL:
Onovughakpo-Sakpa EO, Ayinbuomwan E. Cystatin-c, beta-2-microglobulin, and other determinants of renal function in preeclampsia. Niger J Exp Clin Biosci [serial online] 2022 [cited 2022 Dec 7];10:47-52. Available from: https://www.njecbonline.org/text.asp?2022/10/2/47/359779




  Introduction Top


Preeclampsia (PE) is a multisystem disorder of unknown etiology characterized by the development of hypertension to the extent of 140/90 mmHg or more with proteinuria after 20 weeks of pregnancy in a previously normotensive and nonproteinuric patient.[1] In clinical practice, preeclampsia is defined by its clinical manifestation and it is often discovered late in its course.[2] Signs and symptoms include the new onset of hypertension and proteinuria during the last trimester of pregnancy, usually associated with edema and hyperuricemia.[3] It occurs only in the presence of the placenta even when there is no fetus (as in hydatidiform mole) and remits dramatically postpartum.[4] Preeclampsia (PE) remains the second direct cause of maternal death as stated in the last Confidential Enquiry into Maternal and Child Health.[5]

Women with mild preeclampsia generally have no symptoms. However, women with severe preeclampsia (blood pressure [BP] ≥160/110 mmHg, proteinuria >2.5 g/24 h) may have symptoms such as renal insufficiency, hematological, and neurological disturbances. Proteinuria may rarely precede hypertension but usually accompanies or follows it.[6] Altered renal function is an important component of the pathophysiology of preeclampsia which could lead to acute renal failure, an important cause of maternal morbidity and mortality.[7] Nearly one-tenth of all maternal deaths in Africa and Asia and one-quarter in Latin America are associated with hypertensive diseases in pregnancy, a category that encompasses preeclampsia.[8] Reducing maternal mortality by 75% between 1990 and 2015 was considered part of the millennium development goals of the World Health Organization.[8]

Preeclampsia is often discovered in its course and objective screening tests to predict its onset would be valuable to identify women who require closer clinical monitoring before the onset of clinical signs and symptoms. Biological indices that have been used in the diagnosis and monitoring of PE include plasma creatinine and urea. Creatinine is an uncharged 113-Da molecule that is largely derived endogenously from creatine phosphate in muscle. The usefulness of plasma creatinine as an index for glomerular filtration rate (GFR) is limited by nonrenal factors such as muscle mass,[9] tubular secretion/reabsorption, dietary intake, and by analytical difficulties such as bilirubin, ketone bodies, and certain drugs.[10] In a normal pregnancy, GFR increases by 40%–60% during the first trimester,[11] resulting in a reduction in serum markers of renal clearance including blood urea nitrogen (BUN) and creatinine. In preeclampsia, both GFR and renal plasma flow decreased by 30%–40% compared with normal pregnancy of the same duration.[12] Prolonged renal hypoperfusion with resulting “acute tubular necrosis'' can occur in severe preeclampsia. However, in preeclamptics, BUN and creatinine often remain in the normal range as for nonpregnant women despite a significant decrease in GFR from normal levels obtained in pregnancy.[6]

Cystatin-c is a member of the cystatin superfamily of cysteine proteinase inhibitors. It is also a nonglycosylated low-molecular weight protein (13 kDa) consisting of 120 amino acids with its gene located on the short arm of chromosome 20.[13] It is secreted by all nucleated cells, freely filtered by the glomerulus, and completely reabsorbed and metabolized by the proximal tubules.[13] Thus, cystatin-c may be used as a marker not only for impaired renal function but also for the degree of glomerular endotheliosis and an increase in glomerular volume in pregnancy.[14] It is the most abundant extra-cellular cysteine protease inhibitor and the blood levels are not dependent on age, sex, diet, muscle mass, or inflammatory processes.[15] Its most important attributes in renal function are its small size and high isoelectric point (PI = 9.2) which enables it to be more freely filtered. Its serum concentration generally reflects the GFR more closely than creatinine and it is sensitive to changes in the creatinine blind area of GFR (40–70 ml/min/1.73 m2).[13] Since there is no tubular secretion of cystatin-c, it is extremely sensitive to minor changes in GFR in the earliest stages of kidney diseases. There are no known extra-renal routes of elimination, while clearance from the circulation is only by glomerular filtration.[15] Therefore, it may be of value in the monitoring of pregnancies complicated by PE[14] Beta-2-microglobulin (B2MG) is a component of the major histocompatibitity complex Class I molecules, possessing an immunoglobulin-like domain. B2MG is noncovalently associated with a heavy chain of the human leucocyte antigens.[16] B2MG is a low-molecular weight protein produced by all nucleated cells at a constant rate. It is freely filtered by the glomerulus and reabsorbed and catabolized by proximal tubular cells.[16] Some studies have found increased plasma levels in women who subsequently developed preeclampsia.[17] However, some studies found B2MG to be less adequate than cystatin-c as a GFR marker.[16] There appears to be no local study on serum cystatin-c and B2MG in preeclampsia. Therefore, in this study, we aim to determine levels of cystatin-c and B2MG in serum and relate these with albuminuria and plasma creatinine/urea in preeclamptic women.


  Subjects and Methods Top


The patients were registered preeclamptic ante-natal care (ANC) patients of the Obstetrics and Gynaecology Department of Government Specialist Hospital, Benin City, Edo State, Nigeria. The control patients were registered normotensive ANC patients of the same department and within the same age range selected through simple random sampling. Patients were considered hypertensive when BP >140/90 mmHg. Patients with diabetes mellitus and any other systemic disease were excluded from the study. The sample size was 160 (calculated from the Cochran's formulae).[18]

Before carrying out the study, ethical clearance (A732/T/1) was obtained from the Research and Ethics Committee of the Ministry of Health, Benin City, Edo State, Nigeria. Verbal and written informed consent was obtained from all participants and those who declined were exempted from the study. Structured questionnaires were administered to the study groups and used to document their bio-data, medical, and obstetric history. A physical medical examination was carried out to measure their BPs in the clinic by the researchers.

Fresh mid-stream urine samples were collected into sterile bottles in the hospital under supervision of the researchers and used for the determination of urinary albumin (protein) and creatinine. Blood samples were collected from the ante-cubital veins following a routine aseptic procedure using a 10 ml syringe and dispensed into different specimen bottles containing lithium heparin for plasma urea and creatinine estimation and plain tubes for cystatin-c and B2MG estimation.

Both samples were centrifuged at 3000 revolutions/min after allowing the sample in the plain tubes to stand for 30 min to clot in the Chemical Pathology laboratory. The plasma and serum were harvested with clean Pasteur pipette and stored at 2°C –8°C and analyzed within 48 h. Cystatin-c assay was based on latex-enhanced immunoturbidimetry.[19] B2MG test was based on the principle of a solid phase enzyme-linked immunosorbent assay.[20] Immunoturbidimetry[21] was used to analyze urine albumin while the modified Jaffe's method[22] was used in the analysis of urine/plasma creatinine and Urease-Berthelot method[23] was used for plasma urea estimation.

Data analysis was done using Statistical Package for Social Sciences (SPSS) version 16.0 (SPSS inc. Chicago IL, USA). The means and standard error of the age, serum cystatin-c, B2MG, urine-albumin-creatinine ratio (ACR), plasma urea, and creatinine were calculated while the comparison of means between two groups was done using the Student's t-test. The Pearson correlation was used to calculate the correlations between any two variables. Univariate analysis was presented as frequencies while bivariate or multivariate analysis was presented as means and standard error of mean. The level of statistical significance was set at a P < 0.05 for all tests of statistical significance. Data presentation, tables and charts were done using Microsoft Office 2007.


  Results Top


Most of the preeclamptics (44%) and normotensive pregnant women (NPW) (41.7%) were in the age brackets of 31–35 years. Among the PE, 39 (31.5%) had mild preeclampsia while 85 (68.5%) had severe preeclampsia based on a BP >160/110 mmHg [Figure l].
Figure 1: Age group distribution of subjects. PE: Preeclamptics, NPW: Normotensive pregnant women

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Mean systolic and diastolic BPs were 160.24 ± 9.34 mmHg and 108.56 ± 8.02 mmHg for the PE and 106.00 ± 11.23 mmHg and 63.38 ± 4.32 mmHg for the NPW. The systolic and diastolic BPs were found to be significantly higher in the PE (P < 0.05) than in the NPW. The serum cystatin-c level was found to be 1.99 ± 0.10 mg/L for PE and 1.42 ± 0.19 mg/L for the NPW, while serum B2MG was found to be 1.92 ± 0.15 μg/ml for PE and 0.68 ± 1.33 μg/ml for NPW. The results also showed that urine ACR was 59.61 ± 12.08 mg/g for PE and 2.95 ± 1.16 mg/g for NPW [Table 1].
Table 1: Clinical and biochemical characteristics of preeclampsia and normotensive pregnant women

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In the second trimester, there was no significant (P > 0.05) difference in the mean serum cystatin-c levels between both groups while in the third trimester it was significantly (P < 0.05) higher in the PE (2.85 ± 0.12 mg/L) than in the NPW (1.27 ± 0.37 mg/L). Cystatin-c was also found to be significantly (P < 0.05) higher in the 3rd trimester (2.85 ± 0.12 mg/L) than in the 2nd trimester (1.14 ± 0.09 mg/L) among the preeclamptics. However, mean B2MG was significantly (P < 0.05) higher in PE than in the NPW in the 2nd and 3rd trimesters (PE [1.84 ± 0.08 μg/ml and 1.75 ± 0.07 μg/ml], NPW [0.76 ± 0.16 μg/ml and 1.11 ± 0.29 μg/ml]), respectively. Urine ACR was significantly (P < 0.05) higher in the PE subjects (43.12 ± 0.40 mg/G and 66.10 ± 2.16 mg/G) when compared to the NPW (10.46 ± 0.83 mg/G and 12.21 ± 1.20 mg/G) in both trimesters. Plasma urea was not significantly different in the two groups in the 2nd and 3rd trimesters (PE [24.48 ± 0.79 mg/dl and 22.61 ± 1.21 mg/dl], NPW [25.86 ± 2.27 mg/dl and 24.45 ± 3.22 mg/dl]). The mean plasma creatinine was significantly (P < 0.05) higher in the PE than in the NPW (0.80 ± 0.03 mg/dl and 0.74 ± 0.04 mg/dl) in the 2nd trimester [Table 2].
Table 2: Renal function statuses in preeclampsia and normotensive pregnant women

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The increase in serum cystatin-c (2.20 ± 0.20 mg/L) in severe than in mild PE (1.92 ± 0.12 mg/L) was not significant (P > 0.05) while serum B2MG was significantly (P < 0.05) higher in severe PE (1.92 ± 0.06 μg/ml) than in mild PE (1.51 ± 0.06 μg/ml). Urine ACR was also significantly (P < 0.05) higher in severe PE (63.33 ± 15.02 mg/G) than in mild PE (52.90 ± 20.88 mg/G). There was a nonsignificant (P > 0.05) higher plasma creatinine in severe PE (0.93 ± 0.02 mg/dl) than in mild PE (0.85 ± 0.03 mg/dl), while there was no significant (P > 0.05) difference in plasma urea between mild (23.28 ± 1.56 mg/dl) and severe (23.66 ± 0.78 mg/dl) preeclamptics [Table 3].
Table 3: Relationship between renal function status and severity of preeclampsia

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There was a significant positive correlation between B2MG and plasma creatinine (r = 0.21, P = 0.02) while there were positive nonsignificant correlations between B2MG and serum cystatin-c (r = 0.04, P = 0.68) and plasma urea (r = 0.07, P = 0.43). The results also show a negative nonsignificant (r = −0.02, P = 0.08) correlation between B2MG and urine ACR [Table 4].
Table 4: Correlation between β2-macroglobulin and renal function status in preeclamptics

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There was a nonsignificant positive correlation between cystatin-c and plasma creatinine (r = 0.02, P = 0.86) while there was a nonsignificant negative correlation between Cystatin c and plasma urea (r = −0.06, P = 0.53). However, there was a significant positive correlation between Cystatin c and urine ACR (r = 0.33, P = 0.00) [Table 5].
Table 5: Correlation between cystatin-c and renal function status in preeclamptics

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There was a nonsignificant negative correlation between ACR and plasma urea (r = −0.03, P = 0.71) and serum B2MG (r = −0.02, P = 0.08) while there was a nonsignificant positive correlation between ACR and plasma creatinine (r = 0.03, P = 0.73). There was a significant positive correlation between ACR and cyst-c (r = 0.33, P = 0.00) [Table 6].
Table 6: Correlation between albumin creatinine ratio and renal function status in preeclamptics

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  Discussion Top


Preeclampsia is one of the most common medical complications during pregnancy. The etiology is unknown but it is characterized by vasoconstriction, metabolic changes, endothelial dysfunction, and activation of the coagulation cascade in conjunction with an inflammatory response.[24] In Nigeria PE has a prevalence rate of 5.6%.[25] It is associated with significant maternal and fetal morbidity and mortality worldwide.[26]

The findings of the present study showed that both cystatin-c and B2MG were significantly higher in patients with PE than in the NPW. This is consistent with a previous study by Yalcin et al.[27] This could be due to impaired renal function and increased placental production of cystatin-c[28] in PE. In preeclampsia, there is a partial or complete failure of the trophoblastic invasion of the spiral arteries and this may result in ischemic damage which in turn would release lysosomal cysteine proteinases and subsequent elevation of serum cystatin-c.[28]

This study also showed urine ACR to be significantly higher in PE than in the NPW. This is consistent with the findings of Burwick et al.[29] Urine albumin is a marker of glomerular dysfunction[30] and this is also observed in this study which indicated marked albuminuria in PE. Plasma creatinine is a marker of renal dysfunction and GFR. In this study, elevated levels of plasma creatinine were observed in PE when compared with NPW. This agrees with studies by Vyakaranam et al.[31]

The renal system undergoes many changes in pregnancy resulting in increased clearance of metabolites. The decreased plasma urea in PE than in NPW may be delusional due to the presence of fluid retention or edema which is one of the presenting features in PE. In this study, it was demonstrated that serum cystatin-c was higher in the 3rd trimester than in the 2nd trimester in the PE while there was no significant difference between 2nd and 3rd trimester in NPW. However, serum B2MG was higher in the 2nd trimester than in the 3rd trimester in PE. Other studies also confirmed this increase.[32] This is attributed to the possibility that there is some degree of glomerular endotheliosis in normal pregnancy; a lesion that is more prominently seen in preeclampsia.[14] It may also be due to increased production[14] and changes in glomerular charge selectivity in the third trimester.[12],[13] Strevens et al. also concluded that serum cystatin-c may be used as a marker for impaired renal function, glomerular endotheliosis and increase in glomerular volume in pregnancy.[14]

This study reported nonsignificantly higher serum cystatin-c in severe than in mild preeclampsia. This agrees with an earlier study done by Yalcin et al.[27] Increased cystatin-c levels have been reported to be caused by impaired renal function and increased placental production.[28]

There was a positive correlation and a negative correlation between ACR and serum cystatin-c and B2MG respectively in preeclampsia. Kidney injury is most commonly defined by the total excretion of urinary protein in 24 h or by the ratio of total urine protein to creatinine in a random urine collection.[33] However, the extent of proteinuria in preeclampsia does not correlate well with disease severity.[29] Their study also confirms that there is significant glomerular barrier impairment as indicated by marked albuminuria.[29]

Urine ACR was found to correlate negatively with plasma urea while there was a positive correlation with plasma creatinine in preeclampsia. Salako et al.[34] found no increase in plasma creatinine in pregnant women with hypertension in their first trimester. Magna and Sitikantha[35] in their study on preeclamptic women in India observed a nonsignificant increase in serum urea and a significant increase in plasma creatinine in preeclamptic than in NPW.

This study showed a positive correlation between serum cystatin-c and plasma creatinine. Jummaat et al.[36] in their study on hypertensive pregnancies in Malaysia discovered a potential use of cystatin-c for early detection of renal impairment. They observed a downward trend of creatinine clearance below 90 ml/min. This study also showed a positive correlation between cystatin-c and B2MG suggesting that they are associated with PE. Kristensen et al.[37] also reported similar diagnostic performance of cystatin-c and B2MG in preeclampsia.


  Conclusion Top


The findings from this study demonstrated that cystatin-c, B2MG, and urine ACR are increased in preeclampsia and this was associated with severity. Serum cystatin-c was increased throughout the gestational age with higher values in the 3rd trimester while serum B2MG was higher in 2nd trimester than in 3rd trimester suggesting that B2MG may be more useful in the early detection of preeclampsia. There was a significant positive correlation between cystatin-c and urine ACR while the correlation between ACR and urea and creatinine was not significant. Hence, serum B2MG and cystatin-c may be more useful in the determination of the severity of preeclampsia than plasma urea and creatinine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Grubb AO. Cystatin C – Properties and use as diagnostic marker. Adv Clin Chem 2000;35:63-99.  Back to cited text no. 13
    
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Strevens H, Wide-Swensson D, Grubb A, Hansen A, Horn T, Ingemarsson I, et al. Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies. BJOG 2003;110:825-30.  Back to cited text no. 14
    
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Thilaganathan B, Ralph E, Papageorghiou AT, Melchiorre K, Sheldon J. Raised maternal serum cystatin C: An early pregnancy marker for preeclampsia. Reprod Sci 2009;16:788-93.  Back to cited text no. 28
    
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Burwick RM, Easter SR, Dawood HY, Yamamoto HS, Fichorova RN, Feinberg BB. Complement activation and kidney injury molecule-1-associated proximal tubule injury in severe preeclampsia. Hypertension 2014;64:833-8.  Back to cited text no. 29
    
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Akbari A, Lepage N, Keely E, Clark HD, Jaffey J, MacKinnon M, et al. Cystatin-C and beta trace protein as markers of renal function in pregnancy. BJOG 2005;112:575-8.  Back to cited text no. 32
    
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Salako BL, Odukogbe AT, Olayemi O, Adedapo KS, Aimakhu CO, Alu FE, et al. Serum albumin, creatinine, uric acid and hypertensive disorders of pregnancy. East Afr Med J 2003;80:424-8.  Back to cited text no. 34
    
35.
Magna M, Sitikantha N. Elevated levels of serum uric acid, creatinine or urea in preeclamptic women. Int J Med Sci Pub Health 2013:2;43-7.  Back to cited text no. 35
    
36.
Jummaat F, Adnan SA, Ghaffar NA, Omar J, Noor HS, Ambak JN, et al. Sensitivity and specificity of Cystatin C in detecting early renal impairment in hypertensive pregnancies. Tropic J Pharm Res 2014;13:747-51.  Back to cited text no. 36
    
37.
Kristensen K, Lindström V, Schmidt C, Blirup-Jensen S, Grubb A, Wide-Swensson D, et al. Temporal changes of the plasma levels of cystatin C, beta-trace protein, beta2-microglobulin, urate and creatinine during pregnancy indicate continuous alterations in the renal filtration process. Scand J Clin Lab Invest 2007;67:612-8.  Back to cited text no. 37
    


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