The Value Of Kidney Injury Molecule 1 in Predicting Acute Kidney Injury
Mar 17, 2022
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The value of kidney injury molecule 1 in predicting acute kidney injury in adult patients: a systematic review and Bayesian meta-analysis
Jiwen Geng, Yuxuan Qiu, Zheng Qin and Baihai Su
Abstract
Introduction: The aim of the study was to systematically review relevant studies to evaluate the diagnostic value of urinary kidney injury molecule 1 (uKIM-1) for acute kidney injury (AKl) in adults.
Method: We searched PubMed and Embase for literature published up to November 1st, 2019, and used the Quality Assessment Tool for Diagnosis Accuracy Studies (QUADAS-2) to assess the quality. Then, we extracted useful information from each eligible study and pooled sensitivity, specificity, and area under the curve (AUC) values.
Results: A total of 14 studies with 3300 patients were included. The estimated sensitivity of urinary KIM-1 (uKIM-1)(urinary kidney injury molecule 1) in the diagnosis of AK was 0.74(95% Cr0.62-0.84), and the specificity was0.84 (95% Crl,0.76-0.90). The pooled diagnostic odds ratio (DOR) was 15.22(95% Crl, 6.74-42.20), the RD was 0.55(95% Crl0.43-0.70), and the AUC of uKIM-1(urinary kidney injury molecule 1) in diagnosing AK was 0.62(95% Crl 0.41-0.76). The results of the subgroup analysis showed the influence of different factors.
Conclusion: Urinary KIM-1(urinary kidney injury molecule 1) is a good predictor for AKI (Acute kidney injury) in adult patients with relatively high sensitivity and specificity. However, further research and clinical trials are still needed to confirm whether and how uKIM-1(urinary kidney injury molecule 1) can be commonly used in clinical diagnosis.
Keywords: Kidney injury molecule 1, KIM-1, Acute kidney injury, AKI, Meta-analysis, Systematic review
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Introduction
Acute kidney injury (AKI) is part of a series of acute kidney diseases during the renal disease processes [1]. Currently, it is determined by an abrupt increase in serum creatinine, a decrease in glomerular filtration rate, or both [2]. AKI (Acute kidney injury) is a common and serious disease among patients with acute illness in nearly all fields of medical practice [3]. It is a global issue and can be fatal if not treated well [4]. A recent epidemiologic study demonstrated that the incidence of AKI (Acute kidney injury) was 21.6% and that the AKI (Acute kidney injury)-the associated mortality rate was 23.9% in adults [5]. The early diagnosis and intervention of AKI (Acute kidney injury) can not only provide better opportunities for alternative therapeutic options but also improve patient prognosis and reduce mortality. Although an increasing number of studies have deepened our understanding of AKI (Acute kidney injury), the clinical diagnostic criteria of AKI (Acute kidney injury) remain controversial. At present, AKI is usually diagnosed by increased serum creatinine or decreased urine output, which was supported by the RIFLE (risk, injury, failure, loss, end-stage kidney disease) classification in 2004 [2], the AKIN (acute kidney injury network)classification in 2007 [6]. and the KDIGO(Kidney Disease Improving Global Guidelines)in 2012[7]. However, both serum creatinine and urine output have limitations in timely and accurately recognizing decreased renal function, resulting in poor sensitivity and specificity in diagnosing AKI (Acute kidney injury) [8]. All these findings suggest an urgent need for more effective diagnostic measurements for AKI (Acute kidney injury), and an increasing number of scholars have started related research in an attempt to change this situation.
Over the last few years, several novel AKI (Acute kidney injury) biomarkers have been discovered and characterized. Some of them are considered to have the potential to help diagnose AKI (Acute kidney injury) early, including neutrophil gelatinase-associated lipocalin (NGAL),interleukin-18(IL-18), kidney injury molecule-1 (KIM-1), and tissue inhibitor of metalloproteinases 2(TIMP-2) and so on [3,9]. Unfortunately, none of them has sufficient evidence to replace serum creatinine as a marker for measuring renal function or as a diagnostic criterion for AKI (Acute kidney injury). Among these sundry kinds of new biomarkers, many scholars have demonstrated that urinary KIM-1 (uKIM-1)(urinary kidney injury molecule 1) is a remarkably predictive marker for AKI (Acute kidney injury) detection. Moreover, KIM-1(kidney injury molecule 1) has been approved by the US Food and Drug Administration(FDA) as an AKI (Acute kidney injury) biomarker for preclinical drug development [10]. Its expression is upregulated in the early stages of AKI (Acute kidney injury), much earlier than when serum creatinine increases, providing more possibilities for treating AKI (Acute kidney injury)[3].
KIM-1(kidney injury molecule 1) is a 38.7-kDa type I transmembrane glycoprotein with an extracellular immunoglobulin-like domain topping a long mucin-like domain. As usual, it is expressed at low levels in the kidney and other organs, but it is significantly upregulated when the kidney under-goes injury, especially after ischemia-reperfusion injury [11]. In humans, proximal tubule cells are the main locations where KIM-1expression is upregulated [12]. KIM-1 plays an important role in both kidney injury and the associated recovery processes [13]. Hence, some studies have proposed uKIM-1(urinary kidney injury molecule 1) as a sensitive and specific marker of AKI (Acute kidney injury) as well as a predictor of outcome [14]. Although an increasing number of related studies have been conducted in recent years, additional clinical research and trials are required to support the clinical application of KIM-1(kidney injury molecule 1) in the early diagnosis of AKI (Acute kidney injury)[15].
To further evaluate the diagnostic value of uKIM-1(urinary kidney injury molecule 1) for AKI (Acute kidney injury), we systematically reviewed relevant studies to further clarify the predictive performance and diagnostic value of uKIM-1(urinary kidney injury molecule 1) in AKI (Acute kidney injury). Since previous research suggested that age might be a critical factor affecting the diagnostic value of uKIM-1(urinary kidney injury molecule 1), we included 14 original articles on studies conducted only on adults. We selected the Bayesian bivariate model as our main analytical method, as compared with other common methods, it has higher accuracy and is not affected by heterogeneity[16].
Methods
This meta-analysis was carried out according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements [17].
Data sources and search strategy
A comprehensive search of literature published up to November 1st,2019, was performed in the following databases: PubMed (Medline) and Embase. The search strategy was applied to identify all trials with the following keywords: kidney injury molecule 1 or KIM-1(kidney injury molecule 1) plus acute kidney injury or acute renal failure. In addition, the reference lists of all included studies and relevant reviews were scanned. The searches were performed independently by 2 researchers(J Geng and Z Qin).
Study selection
We encompassed all articles and conference papers retrieved without sample size restrictions. Studies that complied with the following criteria were finally retrieved:(1)articles and conference papers that had a prospective cohort design, a case-control design or a cross-sectional design and explored the performance of urinary KIM-1(kidney injury molecule 1) in the detection of AKI (Acute kidney injury); (2)study subjects all older than 18 years; and (3)studies that included or allowed calculation of the estimated sensitivity and specificity of urinary KIM-1(kidney injury molecule 1) in the diagnosis of AKI (Acute kidney injury). The two reviewers(J Geng and Z Qin) used the EndNote bibliographic manager to check the titles and abstracts of all citations and then retrieved and rescreened the full-text articles. The reference lists of the reviewed full-text articles were checked to ensure no additional relevant studies were missed. Any discrepancies were resolved by a third researcher(Y Qiu).
Data extraction
One reviewer (J Geng) utilized a standardized form to extract information from each eligible study. The following information was extracted:(1)research information: first author, year of publication, country of origin, study design, sample size, whether the investigators were blinded, population setting (patients after cardiopulmonary bypass surgery, patients with coronary angiography or percutaneous coronary interventions, patients with solid tumors, patients with malaria, patients in general hospital ward, patients admitted to the intensive care unit, patients admitted to the emergency department, and critically ill patients);(2) Characteristics of the study subjects: age, sex, basal estimated glomerular filtration rate, and baseline serum creatinine;(3)AKI (Acute kidney injury) information: definition of AKI (Acute kidney injury) and number of AKI (Acute kidney injury) patients;(4) KIM-1(kidney injury molecule 1) information: timing of measurements, measurement method, and the value of KIM-1; and (5)information about the outcomes, such as the optimal cutoff thresh-olds, the sensitivity and specificity, and/or the true positive, true negative, false positive, and false negative values. If a study proposed more than one cutoff threshold, we used the cutoff value with the highest product of specificity and sensitivity.
Fig. 1 Flow chart of the study identification and selection procedures
Data synthesis
Data in the 14 eligible studies were extracted and are shown in Table 3, including true positive, false negative, false positive, and true negative values; assay method and time of KIM-1(kidney injury molecule 1) measurement; and the optimal cutoff values for urinary KIM-1 with their sensitivities(95% Crl), specificities(95% Crl) and AUC-ROC(95% CrD). Our research was based on a Bayesian bivariate model, which was stable and of good consistency, as shown in Fig. 2. Four bivariate models with random effects were analyzed, and no significant difference in the DIC was found (model type=1,2,3,4:153.7636,153.7608,153.7608 and 153.7636). However, the funnel plots showed that there was significant publication bias (Fig. 2). The estimated sensitivity of urinary KIM-1 in the diagnosis of AKI (Acute kidney injury) was 0.74(95% Crl, 0.62-0.84), and the specificity was 0.84 (95%Crl,0.76-0.90), as shown in Fig.3.The pooled diagnostic odds ratio (DOR)was 15.22(95% Crl, 6.74-42.20), and the risk difference(RD) was 0.55(95% Crl, 0.43-0.70). Crosshair plots showed sensitivity, false-positive rate values, and confidence intervals for each included study. The summary receiver operating characteristic(SROC)plot suggested that the efficiency of urinary KIM-1(kidney injury molecule 1) in AKI (Acute kidney injury) diagnosis was considerable(Fig. 4), while the AUCofurinary KIM-1(kidney injury molecule 1) was 0.62 (95%Crl, 0.41-0.76).
We also performed subgroup analysis based on different standards, such as study design, population settings, the use of blinding, and assay method. The results of the subgroup analysis are shown in Table 4. Nonprospective studies were notably more sensitive and specific than prospective studies. For population settings, patients who underwent CPB showed lower specificity and emergency status, and critical patients showed lower sensitivity than others. Whether blindness was used in the research also had an impact on the results. It was also shown that detection by ELISA was significantly more sensitive than the non-ELISA method.
Table 2 Quality assessment of the included studies
Discussion
Early diagnose of AKI (Acute kidney injury) plays a major role in its treatment and prognosis. At present, AKI (Acute kidney injury) is usually diagnosed by increased serum creatinine or reduced urine output. However, current diagnostic criteria cannot meet current clinical needs. There is an urgent need to find a more effective diagnostic measurement for AKI (Acute kidney injury). Some new biomarkers are considered to have the potential to help diagnose AKI (Acute kidney injury) early, one of which is urinary KIM-1(kidney injury molecule 1).
In this diagnostic meta-analysis, we included all published studies that evaluated the diagnostic value of urinary KIM-1(urinary kidney injury molecule 1). We identified 14 eligible studies, from which we extracted relevant information. We found that urinary KIM-1 can help diagnose AKI (Acute kidney injury) with high sensitivity and specificity. Pooled analysis of the studies shows that the estimated sensitivity of urinary KIM-1(urinary kidney injury molecule 1) in the diagnosis of AKI (Acute kidney injury) was 0.74, while the specificity was 0.84. The result is similar to that of the study by Shao et al.[15] in 2014, which proposed the use of urinary KIM-1(urinary kidney injury molecule 1) in the diagnosis of AKI (Acute kidney injury) with a sensitivity of 0.74 and a specificity of 0.86. The main difference between these two studies was the age of the research objects. Our research focuses on patients above 18 years old, but the study by Shao et al. [15] included patients of all ages. In addition, the pooled DOR was 15.22(95% CrI,6.74-42.20), which suggested that uKIM-1(urinary kidney injury molecule 1) had good diagnostic effectiveness for AKI (Acute kidney injury) When the DOR is greater than 1, higher diagnostic odds ratios are indicative of better test performance [33]. The crosshair plot showed that the sensitivity and specificity of the included studies varied, with some demonstrating rather different values. The results also suggested the need to conduct a meta-analysis to summarize the study findings. The SROC plot combined the sensitivity and specificity of each study and the pooled sensitivity and specificity, which helped emphasize and visualize the difference. The area under the curve was greater than 0.5, which suggested that uKIM-1(urinary kidney injury molecule 1) had a good predictive value for AKI (Acute kidney injury).
To fully evaluate the diagnostic value of uKIM-1(urinary kidney injury molecule 1), we conducted subgroup analysis based on different standards, such as study design, population setting, the use of blinding, and assay method. The results did not show that the factors in the subgroup analysis had a significant influence on the diagnostic value of uKIM-1(urinary kidney injury molecule 1), except when using non-ELISA methods to measure uKIM-1(urinary kidney injury molecule 1). Nonprospective studies were notably more sensitive and specific than prospective studies, probably because nonprospective studies enrolled established AKI (Acute kidney injury) patients. The non-ELISA methods (chemiluminescent microparticle immunoassay or microsphere-based Luminex xMAP technology) showed much lower sensitivity than ELISA. Although ELISA is the main method of measurement, not all studies used the same kits. Te various antibodies and reagents had an impact on test performance, which also made it difficult to analyze the differences in this regard. The time to collect samples and measure uKIM-1(urinary kidney injury molecule 1) plays an important role in diagnosing AKI (Acute kidney injury) [3]. Because the included studies varied in population setting and time of measurement, it was difficult for us to perform a subgroup analysis based on time.
However, KIM-1(urinary kidney injury molecule 1)is not ready for clinical practice. Our research indicated that there is a relatively large difference in the cutoff value used for KIM-1(urinary kidney injury molecule 1). The absolute values ranged from 1.412 ng/ml to 3.1 ng/ml, while standardized cutoff values ranged from 0.42 ng/mg to 2.0 ng/mg; given the factors we mentioned before, including population setting, time of measurement, assay method, and so on, it is still difficult to determine a suggested cutoff value of KIM-1.In addition, the estimated sensitivity and specificity of urinary KIM-1(urinary kidney injury molecule 1) in the diagnosis of AKI (Acute kidney injury) were 0.74(95% Crl,0.62-0.84)and 0.84 (95% Crl,0.76-0.90), respectively. Neither is sufficiently high for clinical diagnosis. In the present study, we were only able to distinguish whether a patient with a particular KIM-1(urinary kidney injury molecule 1) value had AKI (Acute kidney injury), but we could not determine the changes in the KIM-1 value as the kidney disease progressed. If the original studies would have included additional laboratory indexes showing kidney disease progression and KIM-1 values in different stages, we would have been able to evaluate the diagnostic value of uKIM-1(urinary kidney injury molecule 1) more accurately. The KIM-1 value in different stages of kidney disease is meaningful for emergency and critical patients, as many studies suggest that KIM-1(urinary kidney injury molecule 1) can distinguish patients with diverse types of acute tubular necrosis from those without AKI (Acute kidney injury) [34]. To date, no new biomarker has been universally applied in routine use for clinical practice because each biomarker has its own advantages and disadvantages [35]. Thus, an increasing number of researchers have proposed the need for a panel of kidney-specific biomarkers that can reflect functional as well as structural damage and recovery36]. The combined panel of normalized urinary hemojuvelin and uKIM-1(urinary kidney injury molecule 1) was reported to have a sensitivity of 1.00 and specificity of 0.70 [37]. A combined panel of kidney-specific biomarkers can provide more directions for bio-marker diagnosis and is worthy of deeper exploration in future research.
Conclusion
In summary, compared with the current literature, this meta-analysis included updated clinical studies and used more accurate analysis methods to evaluate the diagnostic value of urinary KIM-1(urinary kidney injury molecule 1) in adults. Our analysis results indicate that uKIM-1(urinary kidney injury molecule 1) is a good predictor for AKI (Acute kidney injury) in adult patients with relatively high sensitivity and specificity. However, further research and clinical trials are still needed to confirm whether and how uKIM-1(urinary kidney injury molecule 1) can be widely used in clinical diagnosis. In the future, we expect KIM-1(urinary kidney injury molecule 1) or other kidney biomarkers to be comprehensively applied in AKI (Acute kidney injury), from clinical detection to treatment and even prevention.
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