Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 7  |  Issue : 3  |  Page : 321-325  

Kidney injury molecule-1: A urinary biomarker for contrast-induced acute kidney injury


1 Department of Biochemistry, Micropath Med.Center, Gurgaon, Haryana, India
2 Department of Biotechnology, Bharathiyar University, Coimbatore, Tamil Nadu, India
3 Department of Radiation Oncology, Salmaniya Medical Complex, Bahrain

Date of Web Publication18-Mar-2014

Correspondence Address:
M Vijayasimha
Department of Biochemistry, Micropath Med.Center, Gurgaon, Haryana, India.

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.128974

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  Abstract 

Background: Urinary kidney injury molecule 1 (KIM-1) is an early biomarker for renal damage. A few studies have been published analyzing the potential use of urinary KIM-1 as a biomarker for acute kidney injury (AKI). However, no study has been done related to AKI associated with contrast administration. Aim: To search for new markers to identify AKI associated with contrast administration earlier than serum creatinine. Materials and Methods: We studied 100 consecutive patients with normal serum creatinine undergoing angiographic procedure. We assessed urine KIM-1, at 4, 8, and 24 hours after the angiographic procedure. Serum creatinine was measured at basal, 24, and 48 hours after the procedure. Results: There was a significant rise in urinary KIM-1 levels at 24 hours after the angiographic procedure. The presence of contrast induced nephropathy associated with AKI was 12%. Conclusion: The present study highlighted the importance of urinary KIM-1 in detecting AKI associated with contrast administration earlier than Serum creatinine.

Keywords: Contrast-induced nephropathy, Cystatin C, glomerular filtration rate (GFR), kidney injury molecule-1 (KIM-1), neutrophil-gelatinase-associated lipocalin


How to cite this article:
Vijayasimha M, Padma V V, Mujumdar SD, Satyanarayana P, Yadav A. Kidney injury molecule-1: A urinary biomarker for contrast-induced acute kidney injury. Med J DY Patil Univ 2014;7:321-5

How to cite this URL:
Vijayasimha M, Padma V V, Mujumdar SD, Satyanarayana P, Yadav A. Kidney injury molecule-1: A urinary biomarker for contrast-induced acute kidney injury. Med J DY Patil Univ [serial online] 2014 [cited 2021 Jan 19];7:321-5. Available from: https://www.mjdrdypu.org/text.asp?2014/7/3/321/128974


  Introduction Top


The requirement for radiological investigations using contrast media has increased. Contrast-induced nephropathy is emerging as a significant source of hospital morbidity and mortality with the ever increasing use of iodinated contrast media in diagnostic imaging and interventional procedures such as angiography. The rate of incidence of contrast-induced nephropathy as a complication of radiographic diagnostic and interventional studies varies markedly, depending on the definition used and on other variables such as the type of radiology procedure performed, the dose and type of contrast agent administered, the differing patient populations in regard to number and type of risk factors, and the length of patient follow-up renal function deterioration according to most authors is referred to an increase of serum creatinine concentration of >0.5 mg/dl or 25% above baseline, within 48 hours after contrast medium administration. Contrast-induced nephropathy is most commonly defined as Acute Kidney Injury (AKI) occurring within 48 hours of exposure to intravascular radiographic contrast material that is not attributable to other causes. [1] Contrast-induced acute kidney injury (CIAKI) has subsequently become the third most common reason for the development of in-hospital AKI accounting for 12% of cases. [2] This iatrogenic complication has been a subject of concern in recent years because of its adverse effects on prognosis and addition to healthcare costs. The exact underlying mechanisms of nephrotoxicity have yet to be fully elucidated but are likely to involve the interplay of several pathogenic factors. Several studies revealed that contrast medium can cause kidney damage and even cell death. Moreover, contrast medium can reduce blood flow through kidney areas that are risk for hypoxic damage and tubular fluid flow is similarly affected. Traditional biomarkers of renal injury, including serum creatinine and blood urea, have lacked the sensitivity and/or specificity to adequately detect nephrotoxicity prior to significant loss of renal function. The absence of sensitive and specific biomarkers for the early detection of AKI has impaired progress in the diagnosis and treatment of patients with AKI. Therefore, there is a need to identify a more specific AKI biomarker that is produced at the site of injury and that can be measured easily in blood or urine and should be reasonably stable in body fluid to substantially improve the diagnosis.

Kidney Injury molecule-1 (KIM-1) as a type I membrane glycoprotein, which contain a 6-cystein immunoglobulin-like domain in its extracellular portion, and a Thr/Ser-Pro rich domain characteristic of mucin-like O-glycosylated proteins. [3] KIM-1 presence in the urine is highly specific for kidney injury. No other organs have been shown to express KIM-1 to a degree that would influence kidney excretion. KIM-1 expression is induced in a variety of renal diseases, whereas in healthy kidney tissue KIM-1 is virtually undetectable. [3],[4] In the case of kidney damage, KIM-1 is expressed on the apical membrane followed by cleavage of the ectodomain (90 kDa) which is released in the urine in human beings. [5],[6]

KIM-1 is upregulated in the proximal tubule during dedifferentiation of the kidney epithelium, an early manifestation in response to damage. [7] There are no studies to date that have examined KIM-1 for detection of AKI associated with contrast administration. There is an urgent need for improved and non-invasive renal biomarkers to permit early detection of AKI associated with contrast-induced nephropathy. KIM-1, a transmembrane tubular protein, is undetectable in normal kidneys, but it is markedly induced in renal injury including AKI and chronic kidney disease (CKD). [7],[8],[9] Many studies indicate that KIM-1 is a sensitive and specific marker of kidney injury as well as a predictor of prognosis. [10],[11] The above characteristics make KIM-1 an ideal marker for AKI. The objective of the present study was to examine the ability of KIM-1 in detecting contrast-induced AKI. We assessed urinary KIM-1 values in relation to serum creatinine in these patients.


  Materials and Methods Top


The study was performed in one hundred consecutive patients undergoing angiographic procedure. The study was approved by the Ethics Committee of Micropath Medical Center, Gurgaon, Haryana. Written informed consent was obtained from each patient before enrolment. All consecutive adult patients undergoing coronary angiographic procedure from January, 2012 to April, 2013 were included. Clinical characteristics of all patients from whom urine was evaluated for KIM-1 are reported in [Table 1]. Patients with diabetic mellitus comprised 38 of 21 males and 17 females. Patients with non-diabetic mellitus comprised 62 of 41 males and 21 females. Among diabetic patients, 14 were treated with insulin and the rest with oral hypoglycemic drugs.

All subjects were discharged home from the angiography area after 8 hours of their procedure with advice to give specimen at scheduled time and encouraged to drink about 1.5 l of water at least for the first 24 hours. The coronary angiography was performed by a consultant doctor in a standard manner using femoral artery. We excluded patients with pre-existing CKD, serum creatinine greater than 1.5 mg/dl in males and 1.3 mg/dl in females. None of the subjects investigated had received nephrotoxic drugs at least 2 weeks before and during the study period. Before the procedure, all of the participating patients had given their urine and blood specimens for investigations such as cholesterol, High Density Lipoprotein, (HDL), Triglycerides, Hemoglobin, HbA1C, and Fasting Blood Sugar (FBS). Blood pressure (BP) was also studied on admission. Each patient was given low-osmolar contrast (iodizanol or iopromide) medium. Specific protocols and medications for contrast-induced nephropathy prevention were not used in this study, but patients were persistently encouraged to drink plenty of fluids and oral fluid intake was maximally encouraged.
Table 1: Basal clinical characteristics of patients undergoing angiography

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Blood samples were collected for serum creatinine and other screening evaluation before (at basal level). Thereafter, urine samples were collected at 4, 8, 12, and 24 hours after the angiographic procedure. Urinary samples were kept for 30 minutes at room temperature, then supernatant was stored at -80°C. Serum creatinine was assessed before (at basal level), and 24 and 48 hours after the procedure using Jaffe method. KIM-1 was evaluated using a commercially available enzyme-linked immunosorbent assay (USCN Life Science Inc, Wuhan 430056, P.R. China). KIM-1 test was performed according to manufactures instruction. For the choice of optimal cut-off, receiver operating characteristic (ROC) curve were constructed and the Youden index was calculated. [12] The Youden index is defined as follows: (sensitivity+specificity)-1. The best cut-off is the highest Youden index. The commercial statistical software package SPSS17.0 (SPSS, Inc, Chicago, IL, USA) was utilized. Results are evaluated with 95% confidence intervals. The significance level was <0.05.


  Results Top


Clinical and biochemical characteristics of patients with normal serum creatinine values undergoing angiographic procedure are presented in [Table 1]. We found a significant rise in urinary KIM-1 at 24 hours after the angiographic procedure. When AKI was defined as an increase in serum creatinine by >25% of the baseline level 48 hours after contrast exposure, the prevalence of AKI was 12%. The patients with AKI did not significantly differ with regard to age, blood pressure, serum creatinine, and serum lipid levels before angiography when compared to patients without AKI. The serum creatinine levels 48 hours after the angiography were significantly higher in the patients with AKI than in those without AKI (1.39 ± 0.27 vs 1.12 ± 0.17 mg/dl, P < 0.001).

[Figure 1] shows curve (ROC) against serum creatinine 48 hours vs 24 hours urinary KIM-1 and CIAKI, defined as a serum creatinine increase by 0.5 mg/dl at 24 hours. Using a cutoff value of 4.5 ng/ml, sensitivity, specificity, and area under the ROC curve for prediction of AKI was very good for urinary KIM-1 at 24 hours (89%, 81%, and 0.95, respectively).
Figure 1: Receiver operative characteristics (ROC) showing curve against serum creatinine 48 hrs vs 24h urinary KIM-1 and Contrast induced Acute Kidney Injury, defi ned as a serum creatinine increase by 0.5 mg/dl at 24 hours

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The eGFR by MDRD formula 48 hours after the angiography was significantly lower in the patients with AKI than in those without AKI (63.45 ± 18.64 vs 82.95 ± 24.35 ml/min, P < 0.05). The AKI was diagnosed in 12 patients at 24 hours following angiographic procedure. No significant differences were noted between patients with and without AKI in respect of age, sex, DM, and Non-DM. [Table 2]. Urinary KIM-1 values were higher at 24 hours after the angiographic procedure. There was a mild increase in serum creatinine at 24 hours and milder at 48 hours after the angiographic procedure, but there was no significant increase in eGFR during 48 hours of the procedure.
Table 2: Time course changes in serum creatinine and urinary KIM-1, eGFR, and blood pressure (BP) in patients undergoing angiography

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We used AKI definition as rise in serum creatinine by 0.5 mg/dl over baseline, 48 hours after angiographic procedure. Patients after angiographic procedure are typically discharged within 48 hours sometimes even earlier; therefore, we could miss patients with AKI developing 48 hours after angiography. 24 hours after angiography, compared with the non-CIN group, urinary KIM-1 (ng/ml) levels of AKI group increased significantly 5.32 (4.64, 5.74) vs 4.24 (3.91, 4.61), P < 0.05, the urinary KIM-1(ng/ml) levels were significantly increased 5.32 ((4.64, 5.74) vs 3.31 (2.73, 4.28), P < 0.05, from levels of 4 to 24 hours after contrast administration in the AKI group.

Using the Youden index, the best cutoff value for urinary KIM-1 at 24 hours to predict Acute Kidney Injury was: 4.5 ng/ml, with diagnostic sensitivity 89% and specificity 81%


  Discussion Top


The traditional laboratory approach for detection of renal disease does not allow for early detection of acute renal injury. Damage to renal tubules can be insufficient to result in a change in a parameter of kidney function such as blood urea and serum creatinine. In addition, in cases of more extensive tubular injury, there is a lag in time between the injury and an increase in serum creatinine. RIFLE and AKIN Criteria: In 2002, the Acute Dialysis Quality Initiatives (ADQI) group proposed a standard definition and classification system for the syndrome of acute renal failure through a broad consensus of experts across disciplines and international boundaries. The classification systems coined the acronym RIFLE that has three levels: Risk, injury, and failure; and two outcomes: Persistent acute renal failure (termed loss) and End stage Kidney disease. A unique feature of the RIFLE classification is that it provides retrospectively for three grades of severity of renal dysfunction on the basis of a maximum change in serum creatinine, reflecting changes in GFR or duration, and severity of decline in urine output from the baseline. Based on the findings that small alterations of serum creatinine result in adverse outcomes, the Acute Kidney Injury International collaborative Network (AKIN) recently changed the definition of risk group to include patients with an increase in serum creatinine of 0.3 mg/dl. [13] The proposed diagnostic and staging criteria for AKI are designed to facilitate acquisition of knowledge and to validate the emerging concepts. Serum creatinine is the most widely used parameter for everyday assessment of glomerular filtration rate (GFR), but it has poor sensitivity and specificity in ARF because serum creatinine lags behind both renal injury and renal recovery. [13] Therefore, sensitive biomarkers of renal tubular injury are needed to detect early kidney injury.

About a decade ago, KIM-1 was discovered in the search for molecule involved in the pathogenesis of AKI. Ichimura et al. were the first to describe KIM-1 as a type I membrane glycoprotein, which contain a 6-cystein immunoglobulin-like domain in its extracellular portion, and a Thr/Ser-Pro rich domain characteristic of mucin-like O-glycosylated proteins. [3] The presence of KIM-1 in the urine is highly specific for kidney injury. No other organs have been shown to express KIM-1 to a degree that would influence kidney excretion. In the study of nephrotoxicity, urinary KIM-1 levels increased severely earlier than the increase of blood urea nitrogen and plasma creatinine. [7] KIM-1 is also a tissue and urinary biomarker for nephrotoxicant-induced kidney injury. Tissue and urinary expressions were measured with different nephrotoxic doses of cisplatin, folic acids, cadmium, gentamycin, mercury, and chromium. [14],[15],[16] In fact, the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) have included KIM-1 in the small list of kidney injury biomarkers that they will now consider in the evaluation of kidney damage as part of their respective drug review processes of new drugs. FDA, European medicines agency to consider additional test results when assessing new drug safety collaborative effort by FDA and EMEA expected to yield additional safety data. [17] Therefore, new promising markers were investigated to find the ways to diagnose AKI at the earliest possible time. Serum creatinine levels began to rise within 24 hours in 80% of the patients, reaching maximum at 48 to 72 hours after contrast administration, returning to baseline after 2 weeks. [13]

In our present study, the prevalence of AKI due to contrast administration was 12%. The reported incidence of AKI due to contrast-induced nephropathy varies widely, ranging from 0 to >50%. [18] This variability results from whether presence or absence of risk factors (primarily renal sufficiency), the definition of CIN, amount and type of contrast agent administered, the exact radiologic procedure, and whether other causes of AKI unrelated to contrast media were excluded. There have been over 16 definitions used for the diagnosis of acute renal failure in previously published studies, with most of them based on serum creatinine values. Recently, the Acute Kidney injury Network has supported the use of the term "acute kidney injury" to reflect the broad spectrum of acute kidney disease, including conditions that do not progress to failure. [19] ROC showed curve against serum creatinine 48 hours vs 24 hours urinary KIM-1 and CIAKI, defined as a serum creatinine increase by 0.5 mg/dl at 24 hours. Using a cutoff value of 4.5 ng/ml, sensitivity, specificity, and area under the ROC curve for prediction of AKI was very good for urinary KIM-1 at 24 hours (89%, 81%, and 0.95, respectively).

In a study conducted by WK Han et al. revealed that the Urinary KIM-1 increased at 6 to 12 hours after cardio-pulmonary bypass surgery (CPB) and remained significantly elevated up to 48 hours after CPB. In their study, urinary KIM-1 had an AUC-ROC of 0.57 at 2 hours, 0.83 at 12 hours, and 0.78 at 24 hours. [20] Nejat M et al. found in a study that the KIM-1 is elevated in pre-renal azotemia to a lesser extent than in more severe AKI (lasting more than 48 hours). [21] Therefore, the heterogeneity of AKI suggests that more than one marker may be necessary to obtain sufficient sensitivity and specificity for AKI screening. Analysis of multiple biomarkers such as NGAL, Cystatin C with KIM-1 may optimize early detection of AKI associated with contrast administration at the earliest.


  Conclusion Top


KIM-1 is an epithelial cell adhesion molecule that is induced in damaged tubular epithelial cells undergoing dedifferentiation and proliferation and the role of KIM-1 as a biomarker has a robust future. The present study revealed that the urine KIM-1 at 24 hours after angiographic procedure can detect AKI associated with contrast administration earlier than serum creatinine. The limitation of this study is that we could not include L-FABP which is a new marker for AKI. And, we could have missed patients who developed AKI after 48 hours of the procedure. In summary, this is the first study to test the efficiency of new bio-markers in this setup revealing advantages of urinary KIM-1. The population studied is not representative of the global group of patients with AKI associated with contrast administration.

Our findings may have important implications for the clinical management of patients undergoing angiographic procedure. Further studies in patients undergoing radio-contrast administration are required to assess the usefulness of KIM-1 as a biomarker for early diagnosis.

 
  References Top

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15.Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: A tissue and urinary biomarker for nephrotoxicant-induced renal. Am J Physiol Renal Physiol 2004;286:F552-63.  Back to cited text no. 15
    
16.Zhou Y, Vaidya VS, Brown RP, Zhang J, Rosenzweig BA, Thompson KL, et al. CompAKIson of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury and chromium. Toxicol Sci 2008;101:159-70.  Back to cited text no. 16
    
17.FDA News. FDA, European medicine agency to consider additional test results when assessing new drug safety collaborative effort by FDA and EMEA expected to yield additional safety data. FDA News 2008;12 June.  Back to cited text no. 17
    
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21.Nejat M, Pickering JW, Devarajan P, Bonventre JV, Edelstein CL, Walker RJ, et al. Some biomarkers of acute kidney injury are increased in pre-renal acute injury. Kidney Int 2012;81:1254-62.  Back to cited text no. 21
    


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